AU2006201266A1 - 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: Vertek Pharmaceuticals Incorporated CULLEN CO Patent Trade Mark Attorneys, 239 George Street Brisbane Qld 4000 Australia Pyrazole Compounds Useful as Protein Kinase Inhibitors The following statement is a full description of this invention, including the best method of performing it, known to us: O -la- C FIELD OF THE INVENTION

(N

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.

15 associated- with tadget diseases. One 'important class of enzymes that has been the subject of extensive study is .the protein kinases.

C0 Protein kinases mediate intracellular signal transduction. They.do this by effecting a phosphoryl

(N

c1 i ,FIELD OF THE INVENTION The present invention is in the field of tram edicinal chemistry and relates to ompounds that are acceprotein kinaseis inhibitors, composignaling pathway. There 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.

.15 associated-with target diseases. One important class of enzymes that has been the subject of extensive study is .the protein kinases,.

Protein kinases mediate intracellular signal transduction. They. do this -by effecting a phosphoryl •transfer from-a nucleoside triphosphate toa protein acceptor that is involved in a signaling pathway. There are a. number of kineses and pathways through which

NO

o extracellular and other stimuli cause a variety of (C cellular responses to occur inside the cell. Examples of t such stimuli include environmental and chemical stress signals osmotic shock, heat shock, ultraviolet C- 5 radiation, bacterial endotoxin, H 2 0 2 cytokines (e.g.

interleukin-l (IL-1) and tumor necrosis factor a (TNF- ND and growth factors granulocyte macrophagecolony-stimulating factor (GM-CSF), and fibroblast growth 0 factor An extracellular stimulus may effect'one .D 10 or more cellular responses related to cell growth, S. migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle.

Many diseases'are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, 'inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and'.

asthma, Alzheimer's disease or hormone-related diseases.

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

Aurora-2 is a.serine/threonine protein kinase that'has been.implicated in human cancer, such as colon, breast and other solid tumors. This kinase is believed to be.involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-2 may play a role in'controlling the accurate segregation of chromosomes during;mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, the aurora- 2 protein has been.'found to be overexpressed. See Bischoff et EMBO 1998, 17, 3052-3065; Schumacher C et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et Sal., J. Biol. Chem., 1997, 272, 13766-13771.

Glycogen.synthase kinase-3 (GSK-3) is a C- 5 serine/threonine protein kinase comprised of a and P isoforms that are each encoded by distinct genes [Coghlan D et al., Chemistry Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)].

GSK-3 has been implicated in various diseases including 0D 10 diabetes, Alzheimer's disease, CNS disorders such as o 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.

O phbsphorylation and deactivation of glycogen synthase.

Ci The inhibition of GSK-3 leads to increased glycogen Ssynthesis and glucose uptake [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. 303, 21-26 q 5 .(1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J. 299, 123-128 (1994)].

DO However, in a diabetic patient where the insulin response Cq is impaired, glycogen synthesis and glucose uptake fail Sto increase despite the presence of relatively high blood \O 10 levels of insulin. This leads to abnormally high blood 0 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 ishown 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.

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

-2 Neuropathol. Exp, 56', 70-78 (1997)].

C- As a result of the biological importance of GSK-3, there is current interest in therapeutically Ce effective GSK-3 inhbitors. Small molecules that inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)].

For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating the same diseases. However, 'he various protein kinases often act through different biological pathways. For example, certain quinazoline derivatives have been reported recently as inhibitors of p38 kinase (WO 00/12497 to Scios). The compounds are reported to be useful for treating conditions characterized by enhanced p38-a activity and/or enhanced TGF-' 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 0 kinases Aurora-2 and GSK-3 are especially attractive Cr targets for the discovery of new therapeutics due to.

Stheir important roles in cancer and diabetes, Srespectively.

DESCRIPTION OF THE INVENTION \O It has now been.found that compounds of this Cq invention and pharmaceutical compositions thereof are o effective as protein kinase inhibitors, particularly as \O 10 inhibitors of Aurora-2. These compounds have the general Sformula

I:

R 2

R

2 R 2

N

H

Sx RY ZI Q-RI

I

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 at least one of Z I and Z2 2 is nitrogen; Rx and R Y are independently selected from T-R 3 or L-Z-R 3 or Rx and RY are taken together with their.intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from.oxygen, sulfur, or nitrogen, 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 IND -7o nitrogen of said ring formed by Rx and RY is independently substituted by R 4 Q is selected from

-C(R

6 2 1,2cyclopropanediyl,.l, 2 -cyclobutanediyl, or 1,3cyclobutanediyl; R' -is T-(Ring

D);

NO

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

NO

heterocyclyl ring having 1-4 ring hetetoatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by ox6,-T-R5, or V-Z-Rs, and each substitutable ring nitrogen of Ring .D is independently substituted by -R T is a valence bond or a Ci-4 alkylidene chain, wherein when Q is -C(R 6 2 a methylene unit of said C-4 alkylidene chain is optionally replaced by

-N(R

4 -CONH-, -NHCO-, -SO 2 -S0 2 NH-, -NSO 2 -CO2-, -OC(0)NH-, or -NHCO 2 Z is a C1-4 alkylidene chain; L is SO-, -SO2-,

-SO

2

N(R

6 -CO2-, -N(R 6

-N(R

6 -N (R 6 CON (R 6 -N (R 6 SO2 -N N

-C(O)N(R

6 -OC(0)N(R 6 2

-C(R

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

-C(R

6 )2SO 2 I- -CR6)2SO2N(R6)-, -C(R)2N(R6)s -C(R6) 2N(R)

J-C(R

6 2 -C(R')=NNi(R 6 -C(R2N(RN(R)-,C(RN(R)NR6)

C(R

6 )2N(R')S0 2 or

-C(R

6 2

N(R

6

CON(R)

R and R' are independently selected from -T-W-R or R2 and R21 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having o-3 ring. heteroatoms I-8oeetdfo irgn oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by ct R 2 and R 2 is independently substituted by halo, o:xo;), -NO, 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 R3 is selected from -halo,

-CO

2

R,

__-COCOR,

-COCN

2 COR, -NO 2 -CN, S(O)R, -S(O) 2 R, -SR, o-N(R 4 2 -CON(R') 2

'-SO

2 N (R'7) 2 -N(R 7

COR,

-N(R?)C0 2

(C

1 6 aliphatic),.-N(R 4 )N(R 4 2 -C=NN(Rt) 2 o-C=N-0RI

-N"(R

7

)CON'(R')

2 -N(R7) 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 C 1 6 is aliphatic, E,5-ao aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atbms;, *each R 4 is independently selected from -R 7

-COR',

-CO

2 (optionally substituted C 16 aliphatic) -OON(R 7 2 or _S27 each R.

5 is independently selected 'from halo, -OR, -C(oO)R, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, N N(R.

4 2

-CON(R

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

COR,

-N(R 4 (optionally. substituted C 1 L- aliphatic) -N(R 4

)N(R

4 2 -C=NN(R 4) 2 -C=N-OR, N(R 4 CON(R 4 2 -N (R4)S 2 N (R 4 2 -N"(Rt)SO 2 R, or -C=)(42 V is _SO2_, -N(R5)S0 2

-SO

2 N (R 6

(R

6

-CO

2 -N (R 6 -N (R 6 C(0)O0-,

-N(R

6

)CON(R

6

-N(RS)SO

2

-N(R

6

N(R

6 -C (0)k(R 6 C N(R 6 C. -(R 6 2 -C(R 6 2

S-,

-C (PI)C 0 -C(R'5 2

SO

2

-C(R

6 2 So 2

N(R

6

-C(RS)

2 N(Rs)-

-C(R

6 2 N(Rfi)c(o)-, -C(R 6 2 N(nf)c(O)o-, -C(Rh)=NN(R 6

I

-C(RS)

2

N(R

6

-C(R

6 2

N(R

6

)SO

2

N(R

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

-C(R

6 2 SO-, -C(R) 2 S0 2 -C(R6) 2

SO

2

N(R

6

-C(R

6 2

N(R

6 -C0 2 s -C(R 6

-C(R

6

-C(R

6 2

N(R

6

)CO-,

-C(R

6 2 -C(R 6

)=NN(R

6

-C(R

6 NO -c(R 6 2

N(R)N(R

6

-C(R)

2 N(R) S 2

-C(R)

2

N(R

6

CON(R

6 or -CON(R)-; 0 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 may be taken togetherwith the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R 6 is independently selected from hydrogen or a C 1 4 aliphatic group, or two R 6 on the same carbon atom are taken together to form a 3-6 membered carbcyclic ring; each R' is independehtly selected from hydrogen or an optionally substituted C 1 aliphatic group, or-two R' on the same nitrogen are taken together with the nitrogen to form.a 5-8 membered heterocyclyl or heteroaryl ring; and Ra is selected from R, halo, -OR, C0 2 R, -COCOR,

-NO

2 -CN, -S0 2 R, -SR, -N(R 4 2

-CON(R)

2 S-S0 2

N(R)

2 -N(R)CO-N( R N(R' CO2 (optionally substituted

C

1 6 aliphatic), -N (R4)N(R 4 2

-C=NN(R

4 2

-N(R

4 CON 2

-N.(R

4

SO

2

N(R

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

-OC(=)N(R

4 2 As used herein, the following definiti6ns 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

I

VO

o .each substitutable' position of the group, and each c substitution is independent of the other.

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

-C

12 hydrocarbons CA- 5 which are completely saturated or which contain one or more units of unsaturation but which are not aromatic.

NO For example, suitable aliphatic groups include c substituted or unsubstituted linear, branched or cyclic S. alkyl, alkenyl, alkynyl groups and hybrids thereof such OD 10 as (cycloalkyl)alkyl, (cycloalkenyl)alkyl .or S. (cycloalkyl)alkenyl.. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", used alone or as part of a larger moiety includesboth 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 3

-C

2 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" mean's F, Cl, Br, or I.

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

-Also the term "nitrogen" includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the 'I \o 1 1 0D nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR t (as in N-substituted Spyrrolidinyl).

The terms "carbocycle", "carbocyclyl", C 5 -"carbocyclo", or "carbocyclic" as used herein means an aliphatic ring system having three to fourteen members.

IO The terms "carbocycle", "carbocyclyl", "carbocyclo",. or "carbocyclic" whether saturated or partially unsaturated, 0 also refers to rings that are optionally substituted.

0D 10 The terms "carbocycle", "carbocyclyl", "carbocyclo", or o "carbocyclic" also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as in a decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to aromatic ring groups having five to fourteen members, such as phenyl, benzyl, phenethyl, 1-naphthyl, 2-naphthyl, l-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.

The term "heterocycle", "heterocyclyl", or "heterocyclic" as used herein includes non-aromatic ring -12- Va 0

IN

ci ci

IND

IND

systems having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replacd by a heteroatom such as N, 0, or 5: Examples of heterocyclic rings include 3-IH- 5 benzimidazol-2-one, (1-substituted) -2-oxo-benzimidazol-3yl, 2-tetrahydrofuranyl, -tetrahyarofuranyl, 2tetrahydropyranyl, 3-tetrahydropyranyl, 4tetrahydropyranyl, 1, 31]-dioxalanyl, [1,31 -dithiolanyl, [1,31-dioxanyl, 'etrahydrothiophenyl, 3tetrahydrothiophenyl, 2 -morpholinyl,. 3-morpholinyl, 4morpholinyl, 2-thiomorpholinyl, 3-thiom6rphblinyl, 4thiomorpholinyl, 1-pyrrolidinp, 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, phenahthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. The term "heterocycle", "heterocyclyl",- or Yheterocyclic" 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", Irefers to heteroaromatic ring groups having five to fourteen members-.. Exaniples.of heteroaryl rings include.2-furanyl, 3-furanyl, 3-furazanyl,

N-

I. i

L:

i' -13- Q)imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3- ;4isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, oxadiazolyl, 2-oxazoly, 4-oxazolyl, 5-oxazolyl, 1pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 2pyrazolyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyli 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2- N thiazolyl, 4-thiazolyl, 5-thiazolyl,- 5-tetrazolyl, 2triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl,.carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, o 10 quinolinyl, benzotriazolyl, benzothiazolyl, cbenzooxazolyl, 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, tetrahydroisoguinolinyl, and pyrido13,4-d]pyrimidinyl.

The term "heteroaryl" also refers to rings that areoptionally 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 heterbarylalkoxy and the like) group may contain one or more-substituents. Examples of suitable substituents on the.unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group include a halogen, -R 0 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy)., phenyl substituted Ph, substituted -O(Ph), substituted -CH 2

-CH

2

CH

2 substituted

-CH

2 CH2(Ph), -NO 2 -CN, -N(R 9 2 -NROC(O)R -NROC(0)N.(R) 2 -14o-NRO 0

O

2

R

0

-NR

0

NR

0 C(O)RO,' -NlR 0 NRC N(R 0 2

-NR

0

NP.

0 C0,R 0 00 -C C (O)R -C (O)CH 2 c o) R 0 -00 2

R

0

-C(O)R

0 -c(O)N(R 0 2 -0C(Q)N(R) 2

-S(O)

2

R

0 -S0 2

NOR

0 2 -s(o)R 0

-NR

0 2

N(R

0 2

-NR

0 S0 2 RO, -C(r=S)N(R 0 2

-C(=NH)-N(R

0 2

-(CH

2 )yNHC(0)R 0 S UCH)yNHC(Q)CH(vR)(R); wherein each R 0 is independently selcte frmhdoen, z substituted or unsubstituted INO aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl substituted Ph, -0 (Ph), substituted

CH

2 or substituted -C1 2 y is 0-6; and V is a linker group. Examples of CAsubstituents on the ciliphatic group or.-the phenyl ring of R' include amino, alkylamino, dialkylamind, aminocarbonyl, halge, alkyl, alkylaruinocarbonyl, dialkylamninocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, 'or haloalkyl.

An aliphatic gr'oup or a non-aromatic heterocyclic ring may contain 'one or more substituents..

Examples of suitable substituents 'on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring include those listed above for the unsaturated carbon of an aryl or- heteroar 1 group and the-following: =NNI{R*- =NN(R 2 =NNHC =NNC 2 (alkyl)

-NNRSO

2 (alkyl) or =tNR*, where each iC is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples' of substituients on the Aliphatic group include amino, alkylamino, dialkylamino, aminodarbonyl, halogen, alkyl,., alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminbearbonylox>, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, orhaloalkyl.

Suitable substituents on the.nitrogen of a non- (N aromatic heterocyclic ring. include -N(R 2 -C(0)R

.CO

2 -C C()R -c(0o)CHC(0)R,

-SO

2

-SO

2

N(R*)

2 -C 2 -C(=14H) -N (R 2, and -NR'SO 2 R; wherein each R* C( 5 is independently selected from hydrogen, an aliphatic group, a substituted aliphatic group, phenyl (Ph), ^substituted Ph, substituted

CH

2 (Ph), 'substituted

CH

2 or an unsubstituted heteroaryl or o heterocyclic ring.! Examples of substituents on the I N 10 aliphatic group or the phenyl ring include amino, S. alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyll, 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 -CH 2 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, pieferably in the.range of.14 to 96 with a.length of up to about six atoms. Examples of linkers include a saturated or unsaturated C1-6 alkylidene chain which is optionally substituted, and wherein one or two saturated carbons of .the chain are optionally replaced by -CONH-,; -CONHNH-, -CO2-, -NHCO2-, -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -SO2-, ,-SO 2 NH-, or -NHSO 2 The term;"alkylidene chain" refers to an optionally substituted, straight or branched carbon chain that may.be fully saturated or-have one or more units of -16-

VO

S unsaturation. The optional substituents are as described C-i above for an aliphatic group.

c- 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 IND the chemical structure is not substantially altered when

VO

C-i kept at a temperature of 40 oC or less, in the absence of o moisture or other chemically reactive conditions, .for at D 10 least a week.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms f 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 13 C- 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 D -17o or prevent an Aurora-2-mediated condition and a pharmaceutically dcceptable carrier, adjuvant, or Svehicle, may be formulated for administration to a patient.

cI 5 Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated S disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a S- treatment a therapeutically effective amount of a V. 10 compound of formula I.or a pharmaceutical composition Sthereof.

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 *-18-

NO

O administering to a patient in need of such a treatment a CA therapeutically effective amount of a- compound of formula c I or a pharmaceutical composition thereof.

SThe terms "GSK-3-mediated disease" or "GSK-3- 5 mediated condition", as used herein, mean any disease or.

other deleterious condition or state in which GSK-3 is D known to play a role. Such diseases or conditions C( include, without limitation, diabetes, Alzheimer's o disease, Huntington's Disease, Parkinson's Disease, AIDS- IND 10 associated dementia, amyotrophic lateral sclerosis (AML), Smultiple 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 hal-ting 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.

-19- O 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 comprisesadministering to a patient in need of such a treatment a

C

NI 5 therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof.

\0 The terms "CDK-2-mediated disease" or "CDK-2mediated condition", as used herein, mean any disease or C other deleterious condition in which CDK-2 is known to play a role. The terms "CDK-2-mediated disease" or "CDK- S" 2-mediated condition" also mean.those diseases or Sconditions 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 O therapeutically effective amount of a compound of formula N I or a pharmaceutical composition'thereof.

c The terms "ERK-mediated disease" or "ERKmediated condition", ias used herein mean any disease or C- 5 other deleterious condition in-which ERK is known to play a role. The terms "ERK-2-mediated disease" or "ERK-2- S.D mediated condition" also mean those diseases or.

IO

S. conditions that are alleviated by treatment with a ERK-2 o inhibitor. Such conditions include, without limitation, IND 10 cancer, stroke, diabetes, hepatomegaly, cardiovascular o *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 f 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 i MD -21o al., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol.

S16, 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, Science 260, 1658; Frey and Mulder, 1997, Cancer Res. 57, ID 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, Cl 589].

Anotheraspect of the invention relates to 0q 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].

-22o Another.aspect of the invention relates to CA inhibiting AKT activity in, a biological sample or a t patient, which method comprises administering to the patient a.compound of formula I or a composition ci 5 comprising said compound.

Another aspect of this invention relates to a I method of treating or preventing a Src-mediated disease CA with a Src inhibitor, which method comprises Sadministering to a patient in need of such a treatment a VNO 10 therapeutically effective amount of a compound of formula S..I or a pharmaceutical composition thereof.

The terms "Src-mediated disease" or "Src- i mediated condition", as used herein mean any disease or other deleterious condition in which Src is known to play a role. The terms "Src-mediated disease" or "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, 693 .(1991); Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli, Drugs of the Future 2000, 25(7), 717, (2000); Talamonti, J. Clin. Invest., 91, 53 (1993) ;Lutz, Biochem. Biophys.

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

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

Another aspect of this invention relates to a

VO

\D method of treating or. preventing an Lck-mediated diseases with an Lck inhibitor, which method comprises 0< administering to a patient in need of such a treatment a cO o 10 therapeutically effective'amount of a compound of formula 0 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 -24-

VO

o which does not destroy the pharmacological activity thereof.

tThe term "patient" includes human and veterinary subjects.

5 The term-"biological sample", as used herein, includes, without limitation, cell cultures or extracts IND thereof; preparations of an enzyme suitable for in vitr6

INO

C( assay; biopsied material obtained from a mammal or o extracts thereof;irand blood, saliva, urine, feces, semen, \D 10 tears, or other body fluids or extracts thereof.

o An amount effective to inhibit protein kinase, for example, Aurora-2 and GSK-3, is an amount that causes measurable inhibition of the kinase activity when compared to the activity of the enzyme in the absence of an inhibitor. Any method may be used to determine inhibition, such as, for example, the Biological Testing Examples described below.

Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions are generally known in the art. They include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin,.

buffer substances'such as phosphates,. glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

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

0 Preferably, the compositions are administered orally, IN 10 intraperitoneally or intravenously.

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

These suspensions maylbe 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

'I

Sbland 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 -26- 8 dosage forms including emulsions and suspensions. Other c( commonly used surfactants, such as Tweens, Spans and t other emulsifying agents or bioavailability enhancers which are commonly.used in the manufacture of Cq 5 pharmaceutically acceptable solid, liquid, or-other dosage forms may also be used for the purposes of ND formulation.

IO

C-i The pharmaceutical compositions of this O invention may be orally administered in any orally D 10 acceptable dosage 'form including, but not limited to, o 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 L. -27tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation Ci 5 (see above) or in-a suitable enema formulation.

Topically-transdermal patches may also be used.

\D For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topicalo 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, sbrbitan 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 ND -28- 0 techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in'saline, t employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, C( 5 fluorocarbons, -and/or other conventional .solubilizing or dispersing agents.

\D In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of Sthe compounds of this invention may also be employed in IND 10 compositions to treat or prevent the above-identified Sdiseases 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

I

\oD -29o pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include t acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, ri 5 camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, Sfumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, Shydrobromide, hydroiodide, 2 -hydroxyethanesulfonate, .D 10 lactate, maleate, malonate, methanesulfonate, 2- Snaphthalenesulfonate,l nicotinate, nitrate, oxalate, S' 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 the inhibitor can be administered to a patient receiving these-compositions.

t It should also be understood that a specific dosage and treatment regimen for any particular patient C 5 will depend-upon a variety-of-factors, including the activity of the specific compound employed, the age, body D weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and Sthe judgment of the treating physician and the severity

C.

D 10 of the particular disease.being treated.' The amount of o the inhibitor will also depend upon the particular compound in the composition.

Depending upon the particular protein kinasemediated conditiof to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that-condition, may be administered Stogether with thejinhibitors of this invention. For example, in the treatment of cancer other chemotherapeutic agents or other anti-proliferative agents may be comiined 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 ;1 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 IND -31o agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, Scyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole,. and anti-

NO

IND Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, 0 nitrates, calcium .channel blockers, and statins; agents cO o 10 for treating liver disease such as corticosteroids, Scholestyramine, 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.

-32-

R

2 R2 0R

R

2 N R

NH

FHN HN N RX zA RX

R

Y

'Z

1 Q-R R y

Q-R

1 i ii

IN

IN

Rx and R Y may be taken together to form a fused Cq 5 ring, providing a bicyclic ring .system containing Ring A.

NO

SPreferred Rx/Ry rings include a or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said RX/R 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 8 and Z 2 is nitrogen or

C(H).

R

2 NH

HN

S Z Z2 N rZ 2

Z

SZ1 Q-RI I-A I-B .I-C HN/ HN>? HN/

S

2 NR4"-N Z 2 rz 2 SR4Z R Z z1j I-D I-E

I-F

HN" .i N i 4 z2 R: NC" "I -33- R 4 HN>.31 N z 2 H N'3I HNt I-H I-I

IND

IND

cIN HNt N Nz 2

I-L

I -3L

I-K

HNtZ

N

Nj

I-M

HN2

S

I-p I-N I -a

HN>?

S HNt' HN>3

I-U.

I-S I-T -34- HN' HN HN

NHN

N 7 Z2 Z2

Z

tk Z 2

C

N N z R R I-V w I-X HN HN HN> 2 N Z NNts 0 Preferred bicyclic Ring.A systems include I-A, CI-Y I-Z I-AA f

HN

2 1-B Preferred bicyclic Ring-A systems include I-A, and I-U, more preferably I-A, I-B, I-D, I-E, I-J, I-P, and I-V, and most preferably I-A, I-B, I-D, I-E and I-J.

In the monocyclic-Ring A system, preferred RX groups,-when present, include hydrogen, alkyl- or dialkylamino, acetamido, or.a 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 is -C(R6)2-, -CO- or -N(R 4 and k3 is -N(R 2 or -OR. Preferred RY groups include5-6 membered heteroaryl or heterocyclyl rings, such as 2-pyridyl, 4-pyridyl, pyrroidinyl, piperidinyl, morpholinyl, or piperazinyl; C-_6 aliphatic, such as methyl, ethyl, cyclopropyl,.isopropyl, or 4 0 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 IDphenyl.

.In the bicyclic Ring A system, the ring formed when RX and RY are taken together may be substituted or unsubstituted. Suitable substituents include halo, S-0 (CH) 2 4

-N(R)

2 -0 (CH 2 2.

4 -OR, -N(R 4

(CH

2 2- 4 2,

(CH

2 2 4 -C R, -C0 2 R, -COCOR, -NO 2

-CN,

-SO

2 R, -SR, N (R) 2

-CON(R

4 2 1

-SO

2

N(R

4 2 COR, -N(R 4 C02 (optionally substituted Cj_ 6 aliphatic), 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(R2 4)SO 2 R, or

-OC(=O)N(R)

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 C -CN, -o(CH 2 )2- 4

-N(R

4 2

-OCH

2 24

-R,

-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 C1- 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 optionally substituted. These are -exemplified in the following formula I compounds having a pyrazole-containing bicyclic ring system: -36- HN N N% N'%N NH 3N H> NH Van *Preferred substituents' on the R 2

/R

2 fused ring oinclude one or more of the following: -halo, -N(R 4 2 -C2-.

3 alkyl, -C 1 2 3 haloalkyl, -NO 2

-O(C

1 3 alkyl), -C0 2

(C

1 3 oaikyl), -CN, -S0 2 Ca 3 alkyl) -sozNx 2 r -OC'(O)NH 2 Ci -NH 2

SO

2

(C

1 3 alkyl.), -NHC(O) (C 1 3 alkyl), -C(O)N1 2 and -CO (C- 3 alkyl),' wh'erein the (Ca-3alkyl) is' most preferably methyl.

When the-pyrazole ring system-is monocyclic, preferred R 2 groups include hydrogen, C3.-4 aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mnono- or dialkylaminocarbonyl, aminoalky. alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl,, ethyl,' isopr~pyl, propyl,' t-butyl,'cyclopentyl, phenyl, C0 2

H,

CO

2

CE

3

CH

2 OH, CH 2

OCH

3 2, .CH 2

CH

2

CH

2 OH, 0H 2 C11 2

CH

2 0CH 3

CH

2 0CH 2

IOC

2 Ph, C11 2

CH

2 0H 2 N11 2

CH

2

CR_

2

CH

2 NHCOOC (CR 3 3 CONTECH (CR 3 2

CONRCH

2

CH=CH

2 CONHCHnCH 2 0CH 3

CONHCH

2 Ph, -CONH (cyclohexyl) 'CON (Et) 2 CON (CE 3

CH

2 Ph, CONH(n-C 3

H

7 CON (Et) CH 2

CH

2

CH

3

CONHCH

2

CH(CH

3 2 CON (n-C 3

H

7 2 COC3r .methoxymethylpyrrolidin-1-yl) CONH(3-tolyl) 'CONH(4tolyl), CONECH 2 CO(Morpholin-1-yl)j, 'CO(4-methylpiperazinl-yl CONHCH 2 cH 2 OH, CONE 2 anid CO(piperidin-1-yl). 'A preferred R 2 group is''hydrogen.

-37- SAn embodiment that is particularlyuseful for treating Aurora-2-mediated diseases relates to compounds Sof formula IIa: 2 2o

R

R2•

S.HNN

0 -H N H SRy N'S-R 1 SIIa or a pharmaceutically acceptable derivative or prodrug thereof, wherein; 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 and each substitutable ring nitrogen of said ring formed by Rx and R Y is independently substituted by R

R

I 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 -R4; T is a valence bond or a C 1 4 alkylidene chain; I-38- Z is a C14 alkylidene chain; L is -S02-, -N(R 6 )S0 2

-SO

2

-N(R

6 -CO2-,

-N(R

6 C 0-,

-N(R')CON(R

6

-N(R

6

)SO

2

-N(R)N(R

6 Cl 5 -C()N(R 6

-C(R

6 2

-C(R

6 2

S-,

-C(R

6 2 SO-, 2

SO

2 2 S0 2

-C(R

6 2 N IND-C(R)2N -C(Rr)2N.(R6)C(0)O -C(R6)=NN(R

-C(R

6

N(R)N(R

6

-C(R

6

)N(R

6

)SO

2 N(R) or

S-C(R

6 2

N(R

6 CON (R 6 NO 10 'R and R' are independently selected from -T-W-R 6 or o

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, whrein 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 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, -COCH2COR, -NO 2 -CN, -S(0) 2 R, -SR, 2

-CON(R')

2 S0 2 N(R)

-N(R')COR,

-N(R')CO

2

(C

1 2 6 aliphatic),

-N(R

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

-N(R)SO

2

N(R')

2

-N(R)S

2 kR, or -OC(=0)N(P )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 4 is independently selected frdm -COR', -CO2 (optionally substituted C16 aliphatic), -CON(R') 2 or -SO 2

R

039 each R 5 is independently selected from halo, -OR, R, -CO 2 R, '-COCOR,

-NO

2 -CN,

-SO

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

-CON(R

4 2 -S 4 2 p-N (p 4

COR,

-N(R C02C(optionaaly substituted C1,-(6aliphatic) (p45

-N(R')N(R

4 2 -C=N-OR, -N(R 4 )CO 4R) 2 -N(R')s0 2

N,(R

4 2

-N(R

4

)SO

2 R, or -O(ON(42 V0V is

-SO

2 -N (R 6 S0 2 -S0 2 N (R6)ci-N

-CO

2

-N(R

6

-N(R

6 o-N

(R

6 )CON -N (R 6

SO

2 N(R)y, -N (Rs)NK(R),

-C(O)N(R

6

-OC(O)N(R

6 2

-C(R

6 2

S-,

o -C 2 S0-, -C (Rtf)2SO2- -b (R 6 2 S0 2 N -c CR 6 2 N CR 6 C (R 2 R 6 C.

-C(R

6 2N( R 6 C 0 C( I l(R

C(R

6

C(.R

6 2 N(Rc'yN(R6)-,

-C(RS)'

2 N(RG5)S0,N(R6)- or -C (R6) 2 N (R6) CON W, is, -C (RtI) 2

-C(.R

6 2 S 2 so-, -C(Rt,2So 2 -C(R6) 2 S0 2 N (R6) 2 -C025-i

-CCR

6 -C(Rt) 2 N(R6) CO_, -C(R6) 2 N (R 6 C(0)O0-, C(RG) 2 NR0) 7-CC(R6) 2 N(R0) S0 2 N (R')S (R6)CO( or. -CON each R' 'is independently selected from hydrogen or an optionally substitute c 1 phatic group, or two R6 groups on the same nitrogen atom are taken together I with the'nitrogen atom to form a 5-6 membet~ed leterocyclyl or heteroaryi ring; and each R 7 is independently selected from hydrogen or an optionally substituted C,1_ aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to formla 5-8 metbered heterocyclyl or heteroaryl ring..

Preferred rings' formed by RX and RY include a or 7-metbered unsaturated or partially **unsaturated ring having 0-2 heteroatoms, wherein'said RX/RY ring is optionally substituted. This provides a (N bicyclic ring system containing a pyrimidine ring.

Examples of preferred pyrimidine ring systems of formula ha aare shown below.

R2 R2, I NH H/L N~

NON>-

HN N CA S-R'

N

V.0a-A ha-B a-C HN' I HNI HNOZL7 R 4N k 'N'f hfa-J ha-S fla-F HN MW> HN hIa-J h Ia-K Ia-LC HNt MW>1L HN>L rN N

"NN

N '4 Ila-P Ia-R IlIa-V IND -41-

HN

N

F1 4 IIa-W Va Va c- More preferred pyrimidine ring systems of.

o formula IIa include IIa-A, IIa-B, IIa-D, IIa-E, IIa-J, ID IIa-P, and Ila-V, most preferably Ita-A, IIa-B, IIa-D, Ia-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 4

-N(R

4 2 -o (CH 2 2 4 -OR, -N.(R 4

-(CH

2 2 4 -N (R 4 2 -N (C 2 4

-R,

-CO

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

-N(R)

21

-CON(R

4 2

-SO

2

N(R

4 2

-N(R

4

)COR,

-N (R 4

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(R

4 S62N(R 4 -N(R )SO 2 R, or -OC(=O)N(R 2 wherein R and

R

4 are as defined above. Preferred RX/RY ring substituents include -halo, -OR, -COR, -C0 2

R,

-CON(R

4 2

-O(CN

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

-NO

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

The R 2 and R 2 groups of.formula Ia 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 IIa compounds having a pyrazole-containing bicyclic ring system: -42- HN NI1 N N N N HNAN

/N

_q RI I N NH NH NH NH RY

S-RI

IDYR and Preferred'substituents on the R 2

/R

2 fused ring of formula IIa inclide one or more of the following: S -halo, -N(R4) 2 -Cp.4.alkyl, -C.1 4 haloalkyl, NO 2

-O(C

1 4 Cakl ,2(4alkyl), -CO -alky -CN, -S0 2

(C

1 4 alkyl), -S0 2

NH

2

-OC(O)NH

2 -NH2SO 2

(C

1 4 alkyl), -NHC (C1- 4 alkyl),

-C(O)NH

2 and -CO(C3.

4 alkyl), wherein the (C> 4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the 4 alkyl) group is methyl or ethyl.

When the pyrazole ring system of formula IIa 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, methoxypropyl, and benzyloxypropyl. A preferred R 2 group is hydrogen.

When Ring D of formula Ila is monocyclic, preferred RingD 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, benzolb]thiophenyl, indazolyl, benzothiazolyl, IND -43o cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIa, preferred T-Rs 5 or V-Z-Rs substituents include -halo, -CN, -NO 2

-N(R

4 2 optionally substituted aliphatic group, -OR, -C(O)R, -C0 2 R, -CONH (R 4 COR,

CO

2 R, -SO 2 N(R 2, -N (R 4 SOR, -N (R 6

COCH

2 N 2, -N COCH 2

CH

2 N CR) 2, and

-N(R')COCHZCH

2

CH

2

N(R

4 2 wherein R is selected from 0y hydrogen, C1s aliphatic, phenyl, a 5-6 membered ci heteroaryl ring, or a 5-6 membered heterocyclic ring.

C .More preferred R- substituents include -Cl, -Br, -CN,

-CF

3 -COOH, -CONHMe, -CONHEt, -Ni 2 -NHAc, -NHS0 2 Me,

-NHSO

2 Et, -NHS0 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH2NHC3,

-NHCOCH

2

N(CO

2 t-Bu) Cs, -NHCOCH2N (C 3 2

-NHCOCH

2

CH

2 N (CH 3 2

-NHCOCH

2

CH

2

CH

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

-NHCOCH

2 (morpholin-4yl) -NHCOCH 2

CH

2 (morpholin-4-yl) -NHCOC 2

CH

2 CH2 (morpholin- 4 -NHCO2(t-butyl),

-NH(C

1 4 aliphatic) such as -NHMe,

-N(C

1 4 aliphatic) 2 such as -NMe 2 OH, -O(C 1 4 aliphatic)' such as -OMe, C 1 4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C1-4 aliphatic).

Preferred formula Ita compounds have one or more, and more preferably all, of the features selected from the group consisting of: 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, T-R 3 or and each substitutable ring nitrogen of -44said ring formed by Rx and R Y is independently' substituted by R 4

R

1 is (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 R2 and R' are taken together to form an optionally substituted benzo ring; and

R

3 is selected from -halo, -OR, or 'i 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 heieroaryl 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, Ci~ aliphatic, or 5-6 membered heterocyclyl, phenyl, 'or.5-6 membered heteroaryl, and L 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: f I o RX and RY. are taken together. to form a benzo, pyrido, piperidino, or cyclohexo ring; R" is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl cI 5 ring; R is hydrogen or C1-4 aliphatic and R2 is NO I NDhydrogen;

R

3 is selected from -OR, or -N(R 4 2 wherein 0 R is selected from hydrogen, C3. aliphatic, 5-6

CA

membered heterocyclyl, phenyl, or 5-6 membered 0 heteroaryl, and L is or and Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 2 optionally substituted C16 aliphatic group, -OR, -CO 2 R, -CONH(R), -N(R 4

)COR,.

-N(R

4 )C0 2 R, -SO 2

N(R

4 2 -N(R4)SO 2

R,

-N (R6) COCH 2 N 2 -N (R 6

COCH

2

CH

2 N(Rd) 2, or

-N(R

6

COC

2

CH

2

CH

2 4)(R 2 wherein R is selected from hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

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

Table 1.

Me Me Me HN Ht HNP H HN H NS N S CIS

C

CI

IIa-1 IIa-2 IIa-3 -4S- Me Me HNt HAP Et I Ia-4 IMa-S Me

HN$

cl IIa-7 Me HN ~4NH C4e hla-lb Me HNitg 1

NH

ia-a Me

HNJXH

LOH

hla-li.

Me IIa-14 Me HN r IlIa-17 Me gH HNf-l CF 3 Ila-E Me

HN

Me HN4

J~H

OJ7S

F.

F

Ila-12 Me HNitNH OMe Me HN JN Ila-18 Me lIa-13 Me HN4

NH

II a -16, -47-

IND

IND

cIN Me

HN&

HN4

HNH

Ila-22

HN

4 tP I Ia-25 Me HN

NH

2

HN

4 hla-23

HN

4 Ila-26

HN

Ila-21

HN

lIa-24 IIa-27 N

F

Ila-28

H

4 H N4 Ila-29

HN

cl

HN

4 rl''C CI

H

4 IIa-31 h~a31 Ila-32 Ila-33 -48-

H.

Ila-34 HN4 Q( NJ .C 2M 6 Ila-35 Ila-36 Me Me

HN'

4 P. Hi HN$ HN 4 q j 0 jjNMS oiz*cu NHAc f Ila-37 Ila-38 Ila-39 Me N ,,,NHAc OMe Me H N g N

HC

NHN

C

0 IIa-41 Me

HN

4

PH

C7It" _cxco2Me" TIa-42 Me rrNNr9NHAo Ila-43 Me **Me C) -eOc& Y :[Ia-44 Va 0 0 ci ci -49- Me c $Hx IIa-46 Me

HA

N S-aBr Ila-47 Me HN PH H N j';%jN soiPr Ila-48 Me Me Me HNejtN HN<P HNP i~r tS~tYNHAEt autN IIa-49 11a-50 Ila-Si Me HN

PN

q j, S~ HAc

OH.

Ila-52 me Me.

NIL 9,JdlNHBoc IIa-58 .Me Me HN dV HNXI~kt H 02N-o n-Nc I Ia -53 Ila-54 Me Hc

N

H

Iha-SE Me H2N N Ila-59 Me NS~NHyiBu Ia-57 me HN< PH* hla-SO -so-

HN

4

H

Mee

HN

IIa.-64.

Me sle Me IIa-6 7 Me HNJfH 0~tzNH2 I1-a-62 HN NHAc Ita-63 Me

%_N

0 (NSMe OMe Ia-ES Me .1N Me.r lta-68 Me,

,C

OH

Ha-ED Me .Me

HN

4 P 0 H

HN

4 yN QN Me QNi~ NHAc e OMe Ita-i).

Ila-72 Me Me HN HNFN NAHO "N NHAc NiMe Me NHAc

N

N% S Ila-73 h~~a-73 IIa-74 ai IIa-75 D *-51- 0 Me Me HNP H PHN H H

HN

Q< Q N NO VII tc'e Sta NHAc

F

I D IIa-76 IIa-77 IIa-78 0 HN

SHNN

IIa-79 In another embodiment, this invention provides a composition comprising a compound of formula hIa 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 Streatment a therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition S- 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 Va

IN

Ct

IN

cIN cIN

CA

-52therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering 5 blood levels of.glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition thereof. .This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in 'halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of P-catenin, which is useful for treating schizophrenia.

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

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

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

Another aspect of this invention relates to a method of treating or'preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a 1'i 1, ID -53o therapeutically effective amount of a compound of formula SIIa or a pharmaceutical composition thereof.

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

IND Another method relates to inhibiting Aurora-2, F- GSK-3, CDK2, or Srcactivity in a biological sample, Ci which method comprises contacting the biological sample o 10 with the Aurora-2, GSK-3, CDK2, or Src inhibitor of 0. 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 tIb:

R

2 R 2

NH

HN- N R" N

R

Y

N* O-R 1 Iib or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

R

x 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 IN D -54from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by t Rx and. R is independently substituted by oxo, T-R 3 or L-Z-R and each substitutable ring nitrogen of said Ci 5 ring formed by Rx and R Y is independently substituted by R 4 R is T-(Ring D); Ring D is a 5-7 membered monocyclic ring or 8-10 membered o bicyclic ring selected from aryl, heteroaryl, .D 10 heterocyclyl or. carbocyclyl, said heteroaryl or o 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-2-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; Z is a Ci- 4 alkylidene chain; L is -SO2-, -N(RSO-, -SO 2

N(R

6

-N(R

6

-N(R

6 -N (R CON(R 6

-N(R

6

).SO

2

N(R

6

-N(R

6

N(R

6

-C(O)N(R

6 -OC(0) N(R 6 C(R 2 0r, -C(R 6 2

S-,

-C(R

2 SO-, -C(R 2S0 2

-C(R

6 2

SO

2 N -C (R 6 2 N

(R

6 N(R C(O) -C(R 6 2 NR) =NN (R 6

-C(R)

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

N(R

6

)SO

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

R

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

I

\O SN, -NO, -R7, or -V-R6, and each substitutable'ring.

nitrogen of said ring formed by R2 and R 2 is independently ubstituted by R 4 R' is selected from -halo, -OR, -CO 2

R,

-COCOR, COCH2CO~, -NO2,- -CN, _S(O)2R, -SR, -CON(R)7

-SON(R

7 )S2, ON(RJ) 2 -N(RtC

O

R,

Ii -N (a Ctic, aiphatic) )Netrr -C=NN(R4) -C=N-OR, -NR (a -Nh y2N(Rclr -N(R -0R, or

IND

each R is independently selected from hydrogen or an optionally substituted group selected from COR) aliphatic, CG-:iolaryl, a heteroaryl ring having 5-10 ring aoms, or'a heterocyclyl ring having 5-10 ring atoms; each R4 is. indepe~dently selected from -R7, -COR7 -C02 (optionallyl substituted aliphatic) -CON W) 2, or -S0 2

R

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

-CO

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

-N(R

4 2

-CON(R

4 2

-SO

2

N(R

4 2 -OCU=O)R, -N(R4tCOR,

-N(R

4

CO

2 (optionally substituted C 1 6 aliphatic),

-N(R

4 )N(p4 2 1 -C=NN(R4)2, -C=N-OR,

-N(R

4

)CON(R

4 2

-N(R

4 )S0 2

N(R

4 2 -N(R4)so 2 R, *or -Od(=O)N(R 4 )2; V is -sot-, -N(a 6

-SO

2

N(R

6 7NR6) -C02-, -N(R6)C(0)0-,

-N(R

6 )CONP(R)- -N(RtS0 2

N(R

6

-N(R

6

)N(R

6

-OC(O)N(R

6

-C(R

6 2 2

S-,

-C(R

6 2 S0-, -C(R 6 2 S0 2

-C(R

6 2 S0 2

N(R

6 -C(Rt) 2 w(R 6

-C(R

6

R

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

C(R

6

)=NN(R

6

-C(R

6

-C(R

6 2 NRtNR), -C(R 6 2

N(

R

)'SO

2

N(R

6 or -C CON R') W is -C(R) 2

-C(R

6 2

-C(R

2 SO-, -C(R 6 2 S0 2 C (Rt) 2

SO

2 -C(R6) 2 -CC 2 -56o

-C(R

6 )OC(0)N(R

G

-C(R)

2

N(R

6

CO-,

-C(R 2N(R 6

-C(R

6

=NN(R

6 2 N(Rt

N

(R

6

-C(R

6 2

N(R

6

)SO

2

N(R

6

-C(R

6 2

N(R

6

)CON(R

6 or -CON(R 6 C( 5 each R 6 is independently selected from hydrogen or an optionally substituted CI-4 aliphatic group, or two R 6 IN groups on the same nitrogen atom are taken together CA with the nitrogen atom to form a 5-6 membered 0 heterocyclyl or heteroaryl ring; and IN 10 each R 7 is independently selected from hydrogen or an 0 optionally substituted Ci-' aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred rings formed by Rx and RY include a or.7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said Rx/R Y 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..

R

2 2' UN

H

N

HN>

R NH IIb-A IB IIb-A IIb-B IIb-C

"N

IIb-F .IIb-D IIb-E -57- HNN HN'? HN' Z N

(N

NJ.N

IIb-JT IIb-K IIb-L HWt HWN o~r (11 xx oR '4 Ilb-P IIb-R IIb-V

HN>%

R

4 I lb -W more preferr ed pyrimidine ring systems of *formula :Ib include Ilb-A, Ilb-B, IIW-fl, I1b-E I:b-J, 11WP, and Ilb-V, most preferably IIb-A, *IIb-B,'IIb-n, 5 IIb-E, and Ilb-7.

The-ring formed when RX and RY are taken *together may be substituted or tinsubstituted. *Suitable *substituents include IiR, halo, -O(CH 2 4 -N(R 4 2 (CI2) 2 4 -OR, -N(R -C 2 2 -N (R4) 2 N 01(C 2 2 4

R

10 -C R, -C0 2 -COCOR, -NO 2 -CN, S -5021?, -51?,

-N(R

4 2 -CON(R 4 2

-SO

2

N(R

4 2

-N(R

4

)COR,

-N (R CO 2 (optionally substituted aliphatic), -N(R )N(Rt 2 -C=NN(Rfl 2 -C=N-OR -()CON(R 4 2 -N SO 2 N (Rt 2 -N (R 4 )'S0 2 or 4 2 R? and R 4 are, -58as defined above. Preferred R 2 /R ring substituents (N include -halo, -OR, -COR, -C02R, -CON(R 4 2

-CN,

S-0

(CH

2 2 -4-N(R 4 2

-O(CH

2 2

-NO

2

-N(R

4 2

-NR'COR,

-NR

4

SO

2 R, -SO 2 N(R4) 2 wherein R is hydrogen or an optionally C 5 substituted Ci- aliphatic group.

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

o Preferred fused rings include benzo, pyrido, pyrimido, ND 10 and a partially unsaturated 6-membered carbocyclo ring.

o These are exemplified in the following formula IIb compounds having a pyrazole-containing bicyclic ring system: 2 NHN N N

N

HNH

RX NNH NH NH

NH

RY NOR and Preferred substituents on the R 2

/R

2 fused ring of formula IIb include one or more of the following: -halo,

-N(R

4 2 -Cj-4 alkyl, -C1-4 haloalkyl,

-NO

2 -0(C_-4 alkyl) -C02 (C 1 4 alkyl) -CN, -S0 2

(C

1 -4 alkyl) -SO2NH 2 -OC NH 2

-NH

2

SO

2 (CI.4 alkyl), -NHC (C1-4 alkyl), -C ()NH 2 .and -Co (CI.4 alkyl) wherein the 4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (CI- 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 C1.r aliphatic group. Examples of such opreferred

R

2 groups, include H, methyl, 'ethyl,' propyl,, cyclopropyl, i-propyl, cyclopentyl, h1roypop1 methoxypropyl, and'-ben zyl oxypropyi. A preferred R2' group is hydrogen.' ci When Ring D of formula lib is rnonocyclic, preferred Ring D groups include phenyl, pyridyl', Va pyridazinyl, pyrimidinyl, and .pyrazinyl.

When Ring D of. formula ZIIb is bicyclic, cipreferred bicyclic Ring D groups include naphthyl,

IND

tetrahydronaphthyl,4 indanyl, benzimidazolyi, guinolinyl, 0indolyl, isoindolyl, inidolinyl, benzoijblfuryl, benzofblthiophenyl,, indaz olyl, benzothiazolyl, cinnolinyl, phthalazinyl, giinazolinyl, guinoxazolinyl, 1, 8-naphthyridinyl and isoguinolinyl.

On Ring D 'of formula I1h, preferred T-R 5 or V-Z-

R

5 substituents- include -halo, -ON, -NO 2 -NCR 4 2 optionally. substituted 01.6G aliphatic group-, -OR, R'; ONH R 4

NC

4 COR, -N (Ri) 0 2

,-SQ

2 N CR 4 2 -N CR) 0R, -N CR 6

)COH

2 N( CR) 2

N(CR

6 docu 2 cl 2 N(R 2 and

-N(R)COC_

2 CH CH 2 N(R4) 2 wherein P, is selected from hydrogen, C-r aliphatic, phenyl, a 5-6 membered heterdaryl ring, or a 5-6, membered heterocyclic ring.

More preferred Rs substituents' include -01, -ON, -CF3, -GOGH, -OONHMe; CONHEt, -NH 2 -NEAc, -NHISO 2 Me,

-NHSO

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

-NHCOOH

2 NHCH3, -NHCOCIN C002 t Bu)C13, -NHCOCH 2 N (OH 3 2

-NIICOCH

2

OH

2 N (CO 3 2 -NHCOCH2CfI 2

CH

2 N (CO 3 2 -NHO cyclopropyl),: -NHCO Cisobutyl)., -NW4OOH 2 Cmorpholin-4 yl), -NHCOH2H 2 (morpholin-4-yl) -NHCOOH 2

CH

2

OH

2 Crorphol in- 4-yl), -NHC0 2 t-but r1), -NH(C0 1 4 aliphatic) 'such as -NHM4

-N(C

1 4 aliphatic') 2 'such as -NMe 2 0H' aliphatic) such as -OMe, CI4at aliphatic such a.s methyl, ethyl, Scyclopropyl, isopropyl, or t-butyl, and -C0 2

(C

1 -4 aliphatic) Preferred formula lib compounds have one or more, and more preferably all, of the features selected C 5, from the group consisting of: Rx and R Y are taken together with their I\ intervening atoms to form a fused, unsaturated or.partially unsaturated, 5-6 membered ring 0(e having 0-2 heteroatoms selected from oxygen, IND 10 sulfur, or nitrogen, wherein each substitutable ring carbbn of said fused ring formed by RX and

R

y is independently substituted by oxo, T-R3, 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

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

R

x and RYi 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 IND -61- S' 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; S(c) R 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

VO

°D

R

3 is selected from -halo, -OR, or -N(R4)2, wherein R is selected from hydrogen,

C.-

6 aliphatic, or 5-6 membered heterocyclyl, phenyl,

VO

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:

R

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

R

1 is T-Ring 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

3 is selected from.-R, -OR, or -N(R 4 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.

6 aliphatic group, -OR,

'-CO

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

-N(R

4

)CO

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

)SO

2

R,

-N (R COCH2N (R 4

-N(R

6

COCH

2

CH

2

N(R

4 2 or

COCH

2 CH2CH 2 N(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 lib are shown below in Table 2.

Table 2.

VO

O

Oi rcl

HN-

IIb-i Me HN

H

IIb-2 H H HN HN 4

N

OKcN O

NM

IIb-4 IIb-5 Me Me H.N H HN IN NLO 0OMe 0'ONO IIb-7 IIb-8 Me

HN#H

HNtt IIb-3 Me

HN#

H

N' OMe IIb-6 Me HN N O CO 2 Me IIb-9.

1 In another embodiment, this invention provides a composition comprising a compound of formula lib and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treatinglor 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 Scompound of formula lib or a pharmaceutical composition Sthereof.

Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, 0 which method comprises administering to the patient a IND compound of formula lib or a composition comprising said S compound.

CA Another aspect of this invention relates to a O 10 .method of treating or preventing a GSK-3-mediated disease Cq 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 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 IIb or a composition comprising said compound.

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

I

I*D -64- 0 comprises contacting the biological sample with the Aurora-2 or GSK-31 inhibitor of formula lib, or a Spharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.

C 5 Each of the-aforementioned methods directed to the inhibition of' Aurora-2 or GSK-3, or the treatment of ID a disease alleviated thereby, is preferably carried out C with a preferred compound of formula lib, as described above.

IND 10 Another! embodiment of this invention relates to compounds of formula lIc: ft

R

2 R2' N R

NH

HNYN

N Y

RX.

RY N N-A

H

IIc or a pharmaceutically acceptable derivative or prodrug thereof, wherein; 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 RY is independently substituted by oxo, T-R 3 or

L-Z-R

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

R

I

is T-(Ring Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heterdaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each INDsubstitutable ring carbon of Ring D is independently substituted by oxo, T-Rs, or V-Z-Rs, and each substitutable ring nitrogen of Ring D is independently CR substituted by -R 4 O 10 T is a valence bond or" a C7.

4 alkylidene chain; Ci Z is. a C 1 4 alkylidene chain; L is

-SO

2

-N(R)SO

2

-SON(R

6 -C0 2

-N(R

6 -N CON (R6) -N (R SO2N -N (R6) N -C(0)N(R -C(R6)20-,

-C(R

6 2 SO-, -C(R 6 2

SO

2

-C(R)

2

SO

2

C(R

6 )2N(R6)-,

-C(R

6 )2N(R 5

-C(R

6 2

N(R

6

-C(R

6

-C(R

6 2

N(R

6

-C(R

6 2

N(R

6

)SO

2

N(R

6 or -C (R 6 2 N CON

R

2 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 6arbon of said fused ring formed by

R

2 and R2' is independently substituted by halo, oxo, -CN, -NO 2 or -V-R 6 and each-substitutable ring nitrogen of said.ring .formed by R 2 and R 2 is independently substituted by R 4

R

3 is selected from -halo, -CO 2

R,

-COCOR, -COCH 2 COR, -NO 2 -tCN, -S(0) 2 R, -SR, -N(Rt).

2

-CON(R

7 2

-SO

2

N(R

7 2

N(R

7

COR,

-N (R C1 6 aliphatic) -N (R N -C=NN (R4) 2, 7 -7 6

-N(R

7 )CON 2 -N SO 2 N 2 -N (R 4 S0 2 or 00H0=)N(R 7 2 each R is independently selected from hydrogen or an optionally suibstituted group selected from C16, a liphatic, Os-3o aryl, heteroaryl ring having 5-10 ring atoms, or a he -terocyclyl ring having 5-10 ring atoms,: cieach

R

4 i independently selected from C R", c ,-C0 2 (optionally substituted Cl-caliphatic) -CQN(R 7 2 or' -S0 2

R

7 each Rs i's independently selected from halo, OR,.

-00 2 R, COCOR, -1102, -CN,

-SQ

2 R, -SR, 4N(t 2 -01( 4 -SO2N(R 4 -N (R 4

COR,

-N(Rt4 CO 2 (optionally substituted C16r aliphatic),

-N(R

4 S02N N()SOR, o V i.s 1 -SO2-, -N(R 6 -50,11(R 6 *-NCR 6 _C02-, -N(R 6 -N(R 6 )C(o0)o-,

-N(R

6

)CON(R

6 -N(RtISO 2

-N(R

6

-C(O)N(R

6

-OC(O)N(R

6 -C(R)7s-, -C(R6)2S-c )2SON(R 6

-C(R

6 6 -C (R 6 2N1 (R 6 C C 6 2N (R 6 C (R 6 =NN (R 6 -C(R 6

-C(R

6 )2N(R 6 )so 2 or 2 W is

-C(R

6 2 -C(RtF,so-, -C(Rr')2SO, -C(R'),so2w(R 6

-C(R

6

),N(R

6 -CO2'-, -C(R 6 -C(Rt)oc(o)N(R 6 -c(R ,)N(R 6 )cO-, -C0(R 6 2N -C0(R 6 c(E1--

(R

6 ),2N(R 6 N(R 6 N sPy(R -C(RS)2N(RE)C0N(R6)-, or -0011(R 6 each R 6 is independently selected from hydrogen or an optionally substituted C2-4 a~liphatic group, or two R 6 groups on the same niti:ogen atom are taken together IND -67- 0 with the nitrogen atom .to form a 5-6 membered Sheterocyclyl or heteroaryl ring; and t each R 7 is independently selected from hydrogen or an Soptionally substituted Cij- aliphatic group, or two R' on the. same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or \D heteroaryl ringl Preferred rings formed by Rx and RY include a C or 7-membered unsaturated or partially

ID

unsaturated ring having 0-2 heteroatoms, wherein said 01 RX/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring.

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

R

2

R

2

HNH

HN N HN'< HN3 fJ N

S^

N'N-R

IIc-A IIc-B IIc-C HN HNt

HN>Z

4 N rAS RN N i N II-D hIc-E IIc-F -6- HN' HN' HN-]

NNN

.N 5J

:NK

IIc-J IIe-K IIc-L

NO

N,

o S% 0 lIe-P IIc-R IIe-V HN>31 NN IIc-W More preferred pyrimidine'ring systems of formula lie include Ili-A, IIc-B, Ic-D, Ile-E, IIc-J, I~c-P, and Ihe-V most- preferably IIc-A, lIc-B, ic-D, Ic-E,,and IIc-J.

The ring formed when RX and Ry of formula le are taken together may be substituted or unsubstituted.

Suitable substituents include halo, -O(CH2) 24 -N(R4) 2

-O(CR

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

-N.(R

4 2

-N(R

4 (CH)-4-R,

-CO

2 R, -COCOR,. -NO 2

-SQ

2

-SR,

-N(R4) 2

-CON(R

4 2 -so 2

N(R

4 2

-N(R

4

)COR,

-N(R 4 CO (optionally substituted CI- 6 aliphatic), -N(Rt)N(Rt) 2

-C=NN(R)

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 or -OC(=O)N(R4)2, R and R 4 are as defined above. Preferred RX/RY ring substituents \D -69o include -halo, -OR, -COR, -C02R, -CON(R 4 2

-CN,

-0 (CH 2 2 -4-N(R 4 2 -0CH 2 4

-NO

2

-N(R

4 2

-NR'COR,

-NR

4

SO

2 R, -SOaN(R 4 wherein R is hydrogen or an optionally S_ substituted CI-6 aliphatic group.

c 5 The R 2 and R 2 groups of formula IIc may be taken together to form a fused ring, thus providing a

VO

IND bicyclic ring system containing a pyrazole ring.

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

These are exemplified in the following formula IIc (0 compounds having a pyrazole-containing bicyclic ring system: l

NH

HN N N N NR NH N H NH

R

Y N N-R 1

Z

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 Ci-4alkyl, haloalkyl,

NO

2 -O(CI4 alkyl), -C02(CI-4 alkyl) -CN, -SO2 (CI-4 alkyl), -S0 2

NH

2

-OC(O)NH

2

-NH

2

SO

2 (CI4 alkyl), -NHC (C1-4 alkyl), -C(0)NH2, and -CO (C4 alkyl), wherein the (C1-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C-4 alkyl) group, is methyl.

When the pyrazole ring system of formula lIc is monocyclic, preferred. R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Cj, aliphatic group. Examples of such preferred R 2 groups 'include H, methyl, ethyl, propyl,cyclopropyl, i-prdpyi, cyclopentyl, hydroxypropyl, CImethoxypropyl, and benzyloxypropyl. A pref erred R 2 group Ct is hydrogen.

When Ring D of formula hoc is monocyclic, preferred Ring D groips. include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.' When Ring D of formula lic is bicyciic, CA preferred bicyclic Ring D groups include naphthyl, Otetrahydronaphthyl, indanyl, benzimidazolyl, quinol inyl, IND 10 indolyl, isoindolyl, indolinyl, benzo[blfuryl, obenzo[b]ehiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, guinoxazolinyl, .1,8-naphthyridinyl arid isoquinolinyl.

On Ring D of formula 11c, preferred T-R 5 or

V-Z-R

5 substituents i Include -halo,

-NO

2

-N(R

4 2 optionally substituted

C

1 _6 aliphatic group, -OR,

CO

2 R, -CONII(R 4 -N(Rt)COR,

'-N(R

4

CO

2 R, -SO 2 N4.(R 4 2 -N (R 4

SO

2 R, -N COCH 2 .N (R4) 2, -N (R6) COCH 2

CH

2 N (R 4 2, and

-N(R

6

)COCH

2

CH

2

CH

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, -CN,

-CF

3 -COOR, -CONEMe, -CONHEt, -NH 21 -NRAc, -NHSO 2 Me,

-NILSO

2 Et, -NHS 2 (n-prpyl) -NHS 2 (isopropy'l),:- -NIICOEt,

-NRCOCH

2

NI{CH

3

-NHCOCH

2 N (CQ 2 t -BU) CR: 3

-NHCOCH

2 N (CR 3 2

-N'HCOCH

2

CH

2 N (CH3 2

-NIICOCH

2

CH

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

CH

2 (morphiolin-4-yl),

-NHCOCN

2 C4 2

CR

2 (morpholin- -NHC0 2 (t-butylj -NH'(C 1 4 aliphatic) ;,such as -MiMe,

-N(C

1

L

4 aliphatic) 2 .suc'h as OH, aliphatic) such as -OMe, C0>4 alliphatic such as methyl, ethyl, *cyclopropyl,'isopropyl1, or t-butyl, and -C02 (CI4.

aliphatic).

O* -71- S Preferred formula IIc compounds have one or more, and more preferably all, of the features selected Sfrom 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 C( ring carbon of said fused ring formed by RX and

R

y is independently substituted by oxo,-T-R 3 or C L-Z-R 3 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 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 IIc 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 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; -72-

NO

R

2 is'-R and R 2 is hydrogen, wherein R is ci selected from hydrogen, CI- 6 aliphatic, phenyl, a t 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and I 5

R

3 is-selected from -halo, -OR, or -N(R4)2, wherein R is selected from.hydrogen, Ci-G .0 aliphatic, or'5-6 membered heterocyclyl, phenyl,.

C _or 5-6 membered heteroaryl, and L is O or IN 10 Even more preferred compounds of formula IIc o 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

I 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' is hydrogen;

R

3 is selected from.-R, -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

-N(R

4 2 optionally substituted. C-6 aliphatic group, -OR, -CO 2 R, -CONH(R4), -N.(R 4

)COR,

-N(R

4

CO

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

SO

2

R,

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

COCH

2

CH

2 N (R4) 2 or.

-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.

ND -73- SPreferred compounds of formula IIc include compounds of formula lIc': 2' R 2

HN

O RXCx R NN-R 1 C H ID IIc' ho' Sor a pharmaceutically acceptable derivative or prodrug thereof, wherein;

R

x and R y are taken together with their intervening atoms to form a fused benzo ring, wherein each substitutable ring carbon of said fused ring formed by Rx and 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 15 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; Z is a C 1 .4 alkylidene chain; L is -S02-, -N(R 6

-SO

2

N(R

6

-N(R

6 -N CON(R 6 N SO, -(R 6 -N (R)N(R 6 S -C(0)N(R 6 -C(R6)20-,

-C(R

6 )2S-, -74- 06 o -C(R 2 SO-, -C(R2-,C(R) 2

-C(R

6 )2SO 2

N(R

6

-C(R)

2

N(R

6 CC (R 6 2 N C -C 2

N(R

6 -C =NN(R 6

-C(R)

2 N(R -CR 6 2

(R

6 )SO0N(R)-, or -C(R 2N (R')CON((R6) CO 5 R2 and R2' are independently selected from -T-W-R5, or.

R

2 and R 2 are taken together with their intervening Va IDatoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms 0 selected from nitrogen,, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and is independently substituted by halo, oxo, 76 -CN, -NO 2 -R or -V-R 6 and each substitutable ring nitrogen of -said ring formed by R 2 and R 2 is independently substituted.by

R

4

R

3 is selected from haio, -OR, -C0 2

R,

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

-CON(R

7 2

SO

2 N(R 7 2 -N(R7)COR,

CO

2 (C1-6 aliphatic), -N(R 4

)N(R

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

)SO

2

N(R

7 2

-N(R

4

)SO

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

1 o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independdntly selected from -COR 7 -C02(optionally substituted Cz-s aliphatic), -CON(R),, or -S0 2

R

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

-CO

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

-CON(R

4 2

-SO

2

N(R

4 2, -OC -N(R 4

COR,

CO2 (optionally substituted CI-6 aliphatic), I .N o N (R 4 2

-C=NN(R

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

)SON(R

4 2 -N(R )SO 2 R, or -OC(=O)N(R4)2; V is

-SO

2

-N(R

6 S0 2

-SO

2

N(R)-

-CO -1 -N(R6)CO-, -N CON(R') -N(R SO2N -C(0)N(R -C(R6'20-, -C(R6)2S-, IN 2 SO-, -C(R 6 2

SO

2

-C(R)

2 S0 2

N(R

6

-C(R)

2

-C(R)

2

N(R

6

-C(R)

2

N(R

6

-C(R')=NN(R

6

-C(R

6 2

N(R

6

)N(R

6

SO

2

N(R

6 or O 10 -C(R) 2 N(R')CON(R) W is -C(R) 2

-C(R)

2

-C(R)

2 SO-, -C(R 6 2

SO

2

-C(R

6 2 so 2

N(R

6

-C(R

6 2

N(R

6

-CO

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

-C(R)

2 0 C(R 6

-C(R

6 C (R 6 2

N.(R

6 2 N (R 6 S02N (R 6

-C(RS)

2

N(R

6 CON(R6)-, or -CON(R 6 each R 6 is independently selected from hydrogen or an optionally substituted C.- 4 aliphatic group, or.two R groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen.or an optionally substituted C-6 aliphatic group, or two k' 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.and RY of formula 1Ic' are taken together may-be substituted or unsubstituted.

Suitable substituents' include halo, -O(CH 2 )2- 4 2

-(CH

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

(CH

2 2- 4 -N (R 4 2

-N(R

4 -(CH2)2-4-R,

-CO

2 R, -COCOR, -NO 2 -CN, -S0 2 R, -SR,

-N(R)

2 -CON (R 4 2 -S02N (R) 2 -N (R 4

)COR,

-N(R

4 )CO0 2 (optionally substituted C,_ 6 aliphatic), -76-

NO

-N(R

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

)SO

2 R, or N (R 4 wherein R and R4 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 2, -O(CRH 2 )2- 4

-NO

2 -N(R 2 -NR'COR, -NR 4

SO

2 R, -SO2N(R 4 2 wherein R is INDhydrogen or an optionally substituted C.-6 aliphatic group.

The R 2 and R 2 groups of formula IIc' may be taken together to form a fused ring, thus piroviding a IN 10 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: N

,NH

HN 'N N N N

RXN

R NH NH NH NH N -A N N N1 NN-R''I-Nt

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

-C

1 -4 alkyl, -C 1 4 haloalkyl,

-NO

2 -o(C 1 4 alkyl), -CO 2 (CI4 alkyl) -CN, -S0 2

(C

1 4 alkyl), -SO 2

NH,,

-OC(O)NH2, -NH2SO 2

(C

14 alkyl) -NHC() (C 4 alkyl), -C(0)NH, and -CO(C 1 4 alkyl), wherein the (C 1 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 TIc' is monocyclic, preferred R 2 groups include hydrogen or a -77substitutedor unsubstituted'group selected from aryl, hetroryl, or a C aliphatic group. Examples of. such preferred R 2 groups include H, 'methyl, ethyl, propyl, cyclopropyl, i-prbpyl, cyclopentyl, hydroxypropyl, 'methozypropyl, and-benzyloxypropyl.. A preferred R 2 group IND is hydrogen..

When Ring D of formula ho'I is 'monocyclic, preferred Ring D groups in clude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula t1c' is bicyclic, (Npreferred bicyclic, Ring D groups include naphthyl, *tetrahydronaphthyl, indanyl, benzimidazol-.l quinolinyl, *indolyl,. isoindolyl, indolinyl, benzo[blfuryl, benzo[bllthiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyi, quinazolinyl, quinoxazoiinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula 11c preferred T-R 5 or

V-Z-R

5 .substituents include -halo, -ON, -NO 21 -N(Rt) 2 optionally substituted Oz..6 aliphatic group, -C(0O)R,

-CO

2 R, -CONH(R 4 -N(R)CR -N(R 4 )0R S 2 4 2 -N(R 4)SO 2 R, -N (R 6 COcI 2 N (R4) 2 -N (R 6 cocl 2 ca 2 N (Rt) 2 and -N(R 6

COCH

2

CH

2

OH

2

N(R

4 2 wherein R is selected from hydrogen, C2_ aliphatic, phenyl, a hd'teroaryl ring, or7 a 5-6 membered heterocyclic ring.

More preferred R 5 9 sub'stituents include -01, -Br, -ON,

-OF

3 0001, -OONH~e, -CONHEt, -NH 2 -NHAc, -NI-SO 2 Me,

-NBSO

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

-NHSO

2 (isopropyl), -N1HCOEtr- -NHCOC%2NHCH,

-NHCOCH

2 N (CO2t- Bu)C013, -NHCOOH 2 N (CH1Th, -NHC0001 2 011 2 N (CHO3)3, 1-NHOH 2

OH

2

CH

2 N (013)'2, -NHCO (cyclo'pr6pyl), -NHO isobutyl), -NHCOOH 2 CmorPholiri-4- AI), -NHCOCH 2

OH

2 (morpholin-4-yl), -NHC011 2 1 2 01 2 (MOrpholin- 4-yl), N110 2 (t-butyl),-<-NU(c 1 4 aliphatic) such as -NHMe, -N(0 1 4 aliphatic) 2 such -as -N14e 2 OH, -O(O:L4 aliphatic) N) -78o such as -OMe, C 1 i 4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2 (C-4 aliphatic).

Preferred formula IIc' compounds have one or 5 more, and more preferably all, of the features selected from the group consisting of:

VO

D

R

1 is T-(Ring wherein T is a valence bond or a methylene unit; C Ring D is a.5-7 membered monocyclic ring or an ID 1 0 8-10 membered bicyclic ring selected from an 0 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 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-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 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 I -79o .Even more preferred compounds of formula I1c' have one or more, and more preferably all, of the Sfeatures selectedlfrom the group consisting of: R1 is T-Ring D, wherein T is a valence bond and CI 5 Ring D-is-a 5-6 membered aryl or heteroaryl ring; \D

R

2 is hydrogen or C1- 4 aliphatid and R 2 is hydrogen; C- R 3 is selected from -OR, or -N(R 4 2 wherein ND 1 0 R is selected from hydrogen, Ci- 6 aliphatic, 5-6, Smembered' 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(R4) 2 optionally substituted CI- 1 aliphatic group, -OR, -CO 2 R, -CONH(R 4

-N(R

4

)COR,

-N(R

4

)CO

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

R,

-N(R COCH 2 N -N (R 6

COCH

2 CHN (R 4 2, or

-N(R

6

)COCH

2 CHaCH 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.

Other preferred compounds of formula IIc include compounds of formula IIc": 2 R2 R

NH

HRN-R'

R N.I N-R

H

IIc" o or a pharmaceutically acceptable derivative or prodrug thereof, wherein; Rx and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5 5-7 membered .ring having 0-3 ring heteroatoms selected CA from oxygen, sulfur, or nitrogen, wherein each ^O substitutable ring carbon of said fused ring formed by

R

x and R y is optionally substituted by oxo, T-R 3 or L- 0

Z-R

3 and each substitutable ring nitrogen of said ring C0 10 formed by Rx and R Y is optionally substituted by R 4 NO d Sprovided that said fused ring formed by R x and R Y is C other than benzo;

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 heterocyciyl 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; Z is. a C 1 4 alkylidene chain; L is -SO2-,

-SO

2 -CO2-, -N(Ra CO-, -N (R CON(R 6 -N(R SO 2 N (R 6 -N (R 6 )N -C(O)N(R

-OC(O)N(R

6 -C(R 2

-C(R

6 2

S-,

(R)

2

C(R

6 2 S02-, -C(R 6 2

SO

2

N(R

6

-C-(R

6 2

N(R

6

-C(R)

2 2 =NN(R 6

-C(R

6

-C(R)

2 N(R')N (R 2

N(R'

6

.SO

2 or

-C(R

6 2 N (R 6 CON -81-

R

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

SR

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 C 5 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, S-CN, -NO 2

-R

7 or -V-R 6 and each substitutable ring nitrogen of said ring formed by R 2 and R 2 is IN D10 independently substituted by R'; SR3 is selected from.-R, -halo, -OR, -CO 2

R,

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

-N(R

4 2 -CON(Ri) 2

-SO

2 N(R 2

-N(R

7

COR,

-N(R

7 C02 (C.

6 aliphatic), -N (R 4 N (R) 2

-C=NN(R

4 2 -CN-OR, -N(R)CON (R) 2

-N(R')SO

2

N(R')

2

-N(R

4 )S0 2 R, or 2; each R is independently selected from hydrogen or an optionally subseituted group selected from C,6 aliphatic, C6-a aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from -R 7

-COR

7 -CO2 (optionally substituted C1-6 aliphatic), -CON(R 7 2 7 or -SO 2 R each R 5 is independently selected from halo,.-0R, -C0 2 R, r-COCOR,. -NO 2 -CN, -S0 2 R, -SR,

-N(R

4 2

-CON(R

4 2

-SO

2

N(R')

2

-N(R

4

)COR,

C0 2 (optionally substituted aliphatic), -N(R)N(R4) 2 -C=NN(R4) 2 -C=N-OR, -N(Rf).CON(R') 2

-N(R

4

)SO

2

N(R

4 2

IN(R

4 S0 2 R, or -OC(=0)N(R4) 2 V is -SO2, -N(R 6

)SO

2

-SO

2

N(R

6 -CO0 2 -N CON (R 6

N(R

6

)SO

2

N(R

6

-N(R

6

)N(R

6 -82-

-C(R)

2

-C(R

6 2

S-,

C'

-C(R)

2 S0-, -C(R 6 2 S0 2

-C(R

6 2 SO2N(R 6

-C(R

6 2

N(R

6

-C(R)

2

N(R

6 -C 6

-C(R

6 )=NN(a 6

-C(R

6

-C(RE)

2 N(R)N(

N(RN(R

6

)SO

2

N(R

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

-C(R

6 2

-C(R)

2 SO-, -C(R6) 2 S02-,

-C(R

6 2

SO

2

N(R

6

-C(R)

2 -C02-, c -C(R 6 OC N -C(R 6 2

N(R

6

CO-,

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

)=NN(R

6

-C(R

6 2

N(R

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

-C(R

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

4 aliphatic group, or two R' groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered.

heterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an optionally substituted C36 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 RY of formula IIc" include a or 7-membered unsaturated or partially unsaturated ring having 1-2 heteroatoms, or a partially unsaturated carbocyclo ring,- wherein said R 1

/R

M

ring is optionally substituted. This.provides a bicyclic ring system containing a-pyrimidine ring. Examples of preferred pyrimidine ting systems of formula IIc"-are shown below.

-83- I17 IIc"-E I Ic" -C Va Va ci 0 ci Va 0 0 ci f IIC3-D

HN

IIcH-3*

HN

1III-K IIc"-F IIc~-L TI~c-P H0>

COD"-R

HN3'?

NI

N

N

ie *Ilco-W.

More Preferred pyrimidine ring systems offormula 11c" include IIc"-B, IIc-r, IIc-E, IIc-J, IIc-P, and IIc-V, most preferably Ic-B', iec-fl, IIc7E, and Ic-

J.

The ring formed when RX and RY of formula l1i" are taken together may be substituted or unsubstituted.

SuitabliA substituents include halo, -O(CH 2 2 4 -N(Rt4 2

O(CH

2 2 4 -OR,

HC

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

-R

IND -B4-

-CO

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

-SR,

*-N(Rt) 2

-CON(R

4 2

-SO

2

N(R')

2 -N(Rt)COR, -N WR) C0 2 (optionally 'substitute I6aihtc -N(RtN(Rl 2

C=NN(R

4 2 -C=N-OR, -N(R 4 )CON(R 2 -N (R 4 S0 2 N (R 4

-N(R

4

)SO

2 R,.or -OC(=O)N(Rt) 2 wherein R and R R 4 are as defined. above. Preferred RX/RY ring IND substituents include,-halo, -OR, -COR, -C0 2

R.,

-CON (R 4 2 -CN, -O(CH2t)2 4 -N(R 4) 2 ,-O(CUi 2 2 4

-NO

2 *0-N(R 4) 2 -NR4COR, -NR 4

SO

2 R, -SO 2 N'(R 4 2 wher~in'R is hydrogen IND* 10 or an optionally substituted C 1 6 aliphatic group.

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

Pref erred fused rings include benzo, pyrido, pyrimido, and-a partialiy unsaturated .6-mentered carbocyclo ring.

These are exemplifiled in the followin formula lic" compounds having a pyrazole-containing bicyclic ring system: 9NH HN N N N N -7N RYtNR1~KNH NH NH N H and Pr~eferred subst'ituents on the R 2 /R 2 fused ring, of formula IIt include one or more of the followzing: -halo, -N(R 4 4 alkyl', -C 1 4 haloalkyl,'-NO 2 -0O(C3..

4 *alkyl), *-CO2' (c 1

L-

4 alkyl),' -Cli, -So 2 (C1-4 alkyl) -SO 2

NH

2 OC (0)NH 2

-NH

2

SO

2

(CI-

1 Falkyi), -NHC (C 1 4 alkyl),F -C N 2 and -CO 4 balkyl) wherein the (CI-.

4 alkyl) is' a straight, branched, or cyclic alkyl group. Preferably, the (C1.4 alkyl) group is methyl.

When the pyrazole ring system of formula IIc" is monocyclic, preferred R 2 groups include hydrogen or a substituted or unsubstituted-group selected from aryl, heteroaryl, or a CO4 aliphatic group. Examples of such IDpreferred

R

2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2 group o 10 is hydrogen.

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

When Ring D of formula IIc" is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, indazolyl,- benzothiazolyl, cinnolinyl, phthdlaziryl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinblinyl.

On Ring D of formula IIe", preferred T-R 5 or V-Z-Rs substituents include -halo, -CN, -NO 2

-N(R

4 2 optionally substituted aliphatic group, -OR, -C(0)R, S -CO 2 R, -CONH(R 4

-N(R

4 )COR, -N(R)C0 2 R, -SO 2

N(R

4 2 -N (R 4 SOz 2 R -N (R 6

COCH

2 N (R 4 2 -N (R 6

COCH

2

CH

2 N (R 4 2t and

-N(R

6

)COCH

2

CH

2

CH

2

N(R)

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,

-CF

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

-NHSO

2 Et, -NHS02 (n-propyl), -NHS0 2 (isopropyl) -NHCOEt,

-NHCOCH

2 NHCH3 -NHCOCH 2 N (C02t-Bu) CH 3

-NHCOCH

2 N (CH 3 2,

-NHCOCH

2

CH

2 N (CH 3 2 -NHCOCH2CH 2

CH

2 N(CH3) 2 \o -86- 0 -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH 2 (morpholin-4yl), -NHCOCH 2

CH

2 (morpholin-4-yl),

-NHCOCH

2

CH

2 CH2(morpholin- C 4 -NHC02(t-butyl), -NH(C-.4 aliphatic) such as -NHMe, -N(Ci.

4 aliphatic) 2 such'as -NMea, OH, -O(CI-4 aliphatic) C( 5 such.as -OMe, CI-4-aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02 (C-4 ND aliphatic) Preferred formula IIc" compounds have one or Smore, and more preferably all, of the features selected ND 10 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.1-2 heteroatoms selected.from oxygen, sulfur, or.nitrogen, or a partially unsaturated 6-membered carbocyclo ring, wherein each substitutable ring carbon of said fused ring formed by Rx and 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, 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 1 are taken together to form an optionally substituted benzo 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: k(D -87- Rx and R Y are taken together to form a benzo, Spyrido, cyclopento, cyclohexo, cyclohepto, Sthieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by-RX and R Y is independently O substituted by oxo, T-R 3 or L-Z-R 3 and each O. substitutable ring nitrogen of said ring formed by R x and'R y is. independently substituted by R 4 CQ R 1 is T-(Ring wherein T is-a valence bond and Ring D is a 5-6 membered monocyclic ring or an S. 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(R4)2, wherein R is selected from hydrogen, Cie 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 IIc" have one or.more, and more preferably all, of the S. 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 R y is independently substituted by oxo, T-R, :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 -88- R1 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; R3 is selected from -OR, or -N(R 4 2 wherein IND R is selected from hydrogen, C3_ 6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered 0 heteroaryl, and t is or and Ring D is substituted by up to three o substituents selected from -halo, -cN, -NO 2

-N(R

4 2 optionally substituted C.

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

-N(R

4

)CO

2 R, -SO 2 N(R 2

-N(R

4

)SO

2

R,

-N(R

6

COCH

2

N(R

4 2 COCCHzN (R 4 2 or

-N(R

6

)COC

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.

Representative compounds .of formula IIc are showni below in Table 3.

Table 3.

Me Me

OH

IIc-I IIc-2 IIc-3 -89- Me.

H

Me

HN<

Me

HN

H

IND

IND

cIN IIC-4 me NN 0) IIc-7 Me HN H IIc-.O 1-S- IIc-6 Me Me HNt .H H I~c-8 IIc-9 Me HNJ t

H

Me

NN

H

IIc-12 Me HN NV

H

me

HN

4

V

NHt IIC-J.3 IIc-14 Me

HN

N O2QH

H

1 -i16 Me HNt

H

0&NQ.NOH

H,

IIc-17.

HN

4 J NH N N

H

HN 5 H CeMe

H

lIC-19 HNjdq

H

Ilc-20

HN

4

NN

H

Ilc-21

HN

H H IIc-22 N'NN N N W Me H H Ilc-23 IIc-24

H

H

HNJ P

H

HN

4

H

IIc-26

HN

4 cN&

H

HNr 4

H

NN

H

IIc-27

HN

C INQ

OCOQH

H

Ilc-28 1 IIC-29 -91-

HN

4 '4N jCN

H

IIC-31

H

Ilc-32

HN

4 t Me

H

Ilc-33 IIc-34 Ilc-35

HN

Q&N JNCCO

H

Ilc-36

HN

4

!X

ZI$1)'aNZO'OMe

H

Ilc-39

H

tIlc-37 IIc-38

HN

H, t

HN~

$NQ

H

HN

4 H Me IIC-41 Ic4 IIC-42 -92- HN'd{ C~laN-aNoMe

H

QIN ZiNl OMe

H

Me

H

IIc-43 IIc-44 Ilc-46 Ilc-47 Me

H

IIc-50 Me HNeq ',NHAc NAN ~Me

H

IIc-48 Me HN"erMe H Cl Ilc-si Mr N N

H

Ilc-49 NN 2.

H

IIc-52 Me

HN

H

IIC-53 Me

HN<

HN

I Ic- 54

IND

IN

IN

cIN -93- Me HN4 Hi

H

Ile-55 Me Fl N Me N N-S Me

HN<

NLNjaDMe.

H

IIC-56 Me HN4N

H

IIe-59 I .Me HN rNH CY$ rN gHAc

H

Me HNi z>N

H

IIC-GO

Me

HN

lIc-63 Me Me H H le-6l IIe-6Z- Me -Me Me HN~Ii HN tP -§tN JY2OM6 EiANf2COO HtyjNflH2 Me Me H H H lle -64 li- s le-ES Me Me Et HN HN< H Cli HN'iHaH B H H IIC-67 Ilc-68 lIC-69 -94-

H

HN2 0&N QCFS IIc-71

H

IIc-72

H

IIC-73 H. CF 3 IIC-76 Me

HN

c$Ne

H

Ilc-79 H9& Me IIc-74 HN2 H CI.

Me H ~H (DNtN4Po H~

H.

Ilc-77 IIc-78 Me- Me H~eHN iV BrtONAN BntO&NQ H H H IIc-80 lb- 81 Me Me Me HN HN H HN H Bn. N I Bn.N N N- Bn.I H HNHJ N

H'N-

H H H H

VO

VO

Oi 0 0 0i IIc-82 Me.

HN N H Ni

N

H

IIc-83 IIc-86 IIc-84

N

HN-H

IIc-87 HN N NON H I- CN HN HN.N N N

CN

H

H

IIc-88 IIc-89 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 lic,.lc', or IIc", or a pharmaceutical composition thereof.

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

Another'aspect of this invention relates to a Ci 5 method of treating-or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises \D administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIe, Ic', or IIc", or a pharmaceutical composition NO 10 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 therapeutically effective amount of a compound of formula IIe, IIc', or IIc", or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of P-catenin,.which is useful for treating schizophrenia.

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

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

C Another aspect of the invention relates to Sinhibiting Src activity in a patient, which method comprises administering to the-patient a compound of 0 'formula IIc, IIc', or IIc", or a composition comprising IND 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 cq administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIc, IIc', .or IIc", or a pharmaceutical composition thereof.

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

Another aspect of this invention relates to a method of treating or preventing an AKT-mediated diseases with an AKT inhibitor, which method comprises administering to a patient in need of such a treatment a Stherapeutically effective amount of a compound of-formula IIc, Ic', 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 1Ic", or a composition comprising said compound.

Another method relates-to inhibiting Aurora-2,.

GSK-3 Src, ERK-2, or AKT activity in a biological S. -98- S. 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 IIc', or a pharmaceutical composition thereof,. in an amount effective to inhibit Aurora-2, GSK-3, Src, ERK-2, or AKT.

Each of the aforementioned methods directed to

\O

\D 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 cO

ID

formula IIc, IIc', or IIc", as described above.

C Another embodiment that is particularly useful for treating Aurora-2.-mediated diseases relates to compounds of formula lid: R2' R R N y N'0 N H lid or a pharmaceutically acceptable derivative or prodrug thereof, wherein; Q' is selected from -C(R 6 1,2-cyclopropanediyl, 1,2cyclobutanediyl, or 1,3-cyclobutanediyl;

R

x and R Y are taken together with their intervening.atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring haying 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 -99ring formed by RX and R. is independently substituted by R 4 R' is T-(Ring

D);

Ring D is a 5-7 membered monocyclic ring or.8-10 membered Sbicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo;T-Rs, or V-Z-Rs, and each substitutable ring nitrogen of Ring D is independently substituted by -R4; T is a valence bond or a C1.4 alkylidene chain, wherein when Q'is -C(R 6')2-'ia methylene group of said C 1 -4 alkylidene chain is optionally replaced by -CONH-, -NHCO-, -S02-, -SO 2 NH-, -NHS02-,

-CO

2 -OC(0)NH-, or'-NHCO,-; Z is a C 1 4 alkylidene chain; L is -S02-, -N(R 6 )S0 2

-SO

2 -N(R

-CO

2 -N(Rt)CO-, -N(R6)C(0)0-, -N (R 6 CON (R 6 _N SO 2 N (R6) -N (R 6 N (R 6 -C(o)N(R 6

-OC(O)N(R

6 -C(R6)20-, -C(R6)2S-,

-C(R)

2 S0-, -C(R 6 2 so 2 -C R 6 2

S

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

-C(R

6 2 N(R) C LC(R 6 2 N(R) C C (R 6

=NN(R

6

-C(R

6 2 -C(R 6 2

N(R

6 or -C (RP) 2 N cON R and R 2 are independently selected from -T-W-R 6 or

R

2 and R 2 are taken together with their intervening atoms to form .a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and RI is independently substituted by halo, oxo,.

i.! -100- -ON, -NO 2 -R7, or -V-RS 6 and each substitutable ring nitrogen of said ring formed by R 2 'and R 2 i S independently substituted by RU R3 is selected from -halo, -OR,

-CO

2

R,

*S -COCOR, COCH 2 COR, NO 2 -ON, 2

-SR,

-N -doN(R') 2

-SO

2

N(R')

2 -N(R7) COR, -N(R)C02(C3i 6 aliphatic), -N(R)N(R 2

-C=NN(R)

2 1 -CzN-OR, -N (R')CON(R'7) 2 -N (R SO 2 N (R7) 2 -N (R 4

SO

2 R, or each R is independently selected from hydrogen or an 0 optionally substituted group selected from 01.6 aliphatic, C62 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring h~aving 5-10 ring' atoms;each R 4 is independently selected from -RW, -OR' -00, (optionally substituted C3- al ipha t ic), CON (R7)2 or -SO 2 R 7 each R' is independently seledted from halo, -OR, -00001?, -NO 2 -ON, -SO2R, -SR, -N(R 4 -CON(R 4

-SO

2 N(R4) 2 -N (R 4

)OCOR,

-N(R 4ICO 2 (optionally substituted C- 6 aliphatic), -N(R 4)N(R 4 2, -O=NN(R -C=N-OR, -N (R4)CON -N(R 4 SON(R 4 -N (R')SOR, or O(=)NR4)2 V is

-SO

2 -SO 2

N(R

6

-N(R

6 -N(Rs)co-, -N(R 6 )C0O)O-, -N(R)CjON(R 6

-N(R

6 )SO2N(R)-,

-N(R

6

).N(R

6 -O(O)N(R 6 OO(O) N(R 6 -c(Pz 6 -C(RW)2S-, C -(R 6 2SO-, -O 2 S0 2 -C (R 6 2 S ON (R 6 C (R 6 2N1 (R 6

-C(R

6 )2N(RY)c(O) -0(R 6

AN(R

6 )C 0(0) 0- -C (R 6 =NN(Rh)-, -O(RG),2N(R 6 -C(R6)2N(R 6

)SO

2 or -C (R 6 2N (R 6 CON (R 6 W is -C(R 6)20-, -C(.RU5 2 -C (R6) -c(Rt) 2 so2-,

-C(R

6 )2So02N

-O(R

6 )2N (R 6 -C0- -002-, S. 1 0 1 0

-C(R

6

-C(R

6 C (R 6 2N(R 6

CO-,

-C(R)

2

N(R

C

-C(R)=NN R 6

-C(R

6 S-c(R 6 2 N (R 6

-C(R)

2 N SO 2

N(R

6

-C(R

6 2N R

CON

R 6 or -CON(R 6 .each R r is independently selected from hydrogen or an optionally substituted C 1 -4 aliphatic group, or two R 6 IND groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered Ci heterocyclyl or heteroaryl ring; 0 10 each R 6 is independently selected from hydrogen or a C 1 4 Ci aliphatic group, or two R6' on the same carbon atom are taken together to form a 3-6 membered carbocyclic ring; and each R' is independently selected from hydrogen or an optionally substituted C1- 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 Rx and RY 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.

SExamples of preferred pyrimidine ring. systems of formula IId are-shown below.

R

ReNH HN HN' IId-A IId-B lid-C -102- HN7

NJN,

Ild-fl H3? ld-F.

'ld-E H??31

NN

IId-J lId-K IId-L

H?

rxt;N! Ild-Il .HNk

N

Ild-.V

HN'

NN

IId-W More preferred- pyrimidine ring-systems o't formula 3ld'includeIld-A, ld-B, Ild-fl, .Ild-E, I1d-J, lid-?, and .ld-V, most preferably Ild-A,Ild-B, lId-fl, IId-E, and Ild-J.' ring formed when R' and RY of formula. ld are taken together may be Substituted or unsubstituted.

Suitable substituents -iniclude h~al:o, -0O(CH 2 2 4 -N (Rt4) 2 -o (OH 2 2 4 -N (R 4

(H

2 z-4N (Rh 2, -N (Rh 4- (02) 2 4 -R4l o

-CO

2 R, COCOR, -NO 2 -CN, S(O)R,-S 2

,SR

-N(R)

2

-CON(R

4 2

S

2

N(R

4 2 -O o R -CR 4 )CR, -S C2 (optionally substituted

C

1 6 aliphatic), -N (R 4 N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N (R 4 CON (R4 2 -N(RtSO 2

N(R

4 2

-N(R

4 )so 2 or -O(owR) 2 R-and R 4 are as defined above. Preferred RX/RY ring substituents Va include -halo, -OR, -COR, -CO 2 R, -CON (R 4 -O(Ca 2 2 4 -OC 2 2 N 2 4 2

-NR

4 00R,

-NR

4

SO

2

R,-_SO

2 N(R) werein R is hydrogen or an optionally

IND

substituted

C

1 6 aliphatic group.

The R 2 and R 2 gi-oups .of formul a id may be taken together to formn a fused ring, thus providing a bicyclic ring system containing a- pyrazole ring; Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated S-memtered-carbocyclo ring.

These are exemplified [in the following formula zIa *compounds having a pyrazole -containing bicyclic, ring.

*System:

~NH

N NX HN N jtI, N$

H

NNH NH NH

N

Ry(' and- Pre ferred'substituents on the R 2

/R

2 fused ring of formula IId include one or more of the following: alkyl), -C0 2

(C

1 4 alkyl), -CN, -S0 2

(C.

1 4 alkyl)

-SO

2

NH

2

-O(ONH

1 NHS0(C 4 alkyl), -NHC (Cl4 alkyl), NH, and CO (Ca- 4 akyl) wherein' the (C 1 4 alkyl) is'a IN -104straight, branched, or cyclic alkyl group. Preferably, the (C 1 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 C'-6 aliphatic group. Examples of such Va ID preferred R. groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, -methoxypropyl, and benzyloxypropyl. A.preferred R 2 group o 10 is hydrogen.

C When Ring D of formula IId is monocyclic, preferred Ring D gioups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

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

On Ring D of formula lid, preferred T-R 5 S.or V-Z-

R

5 substituents include.-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 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')

2 and

(R

6

CCH

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.

More preferred R 5 substituents include -Cl, -Br, -CN,

-CF

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

-NHSO

2 Et, NHS2(n-propyl),

-NHSO

2 (isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3

-NHCOCH

2

N(CO

2 t-Bu)CH 3

-NHCOCH

2 N(CH3)2,

-NHCOCH

2 CH2N (CH3) 2, -NHCOCH 2

CH

2

CH

2 N (CH 3 2 DO -105o -NHCO(cyclopropyl), -NHCO(isobutyl),

-NHCOCH

2 (morpholin-4yl), -NHCOCH 2

CH

2 (morpholin-4-yl),

-NHCOCH

2

CH

2

CH

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

-N(C

1 4 aliphatic) 2 such as -NMe 2 OH, -O(Ci-4 aliphatic) such as -OMe, Ci.- aliphatic such as methyl, -ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(Ci-4 VO aliphatic).

Preferred Q' groups of formula lid include C -C(R6') 2 or 1, 2 -cyclopropanediyl, wherein each R 6 is 1 0 independently selected from hydrogen or methyl. A more S. 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 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 R4;

R

I 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 -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 sD -106- 0 i. 432.

D R is selected from -halo, -OR, or -N(R4) 2 More preferred compounds of formula IIc have one or more, and more preferably all, of the features selected.from the group consisting of: C 5 RX and RY are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto,

VO

\O thieno, piperidino, or imidazo ring; R' is T-(Ring wherein T is a valence bond or C a methylene unit and wherein said methylene unit cO o 10 is optionally replaced by and Ring D is a Cq 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-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- 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or -N(R 4 and Q' is -C(R6') 2 or 1,2-cyclopropanediyl, wherein each R 6 is independently selected from hydrogen or methyl.

Even more preferred compounds of formula IIe 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; i ND -107- S R2 is hydrogen or C..

4 aliphatic and R 2 is hydrogen, R3 is selected from -OR, or -N(R4) 2 wherein R is-selected from hydrogen,

C

1 6 aliphatic, 5-6 membered 'het-erocyclyl, phenyl, or 5-6. membered heteroaryl, and L is or -NH-; IND(e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 dptionally substituted

C

1 6 aliphatic o 10 group, -OR,

-CO

2 R, -CONH(R 4

-N(R

4

)COR,

S-N

(R)CO

2 R, -S0 2

N(R

4 2

-N(R

4

SO

2

R,

COCH

2 N (R4 2

COCH

2

CH

2 N (R 2 Or -N(RCOCH2CCH2N )2 wherein R is selected .from hydrogen, C.- 6 aliphatic, phenyl, a 5-6 membered hieteroaryl ring, or a 5-6 membered heterocyclic ring; and Q' is -CH2-.

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

Table 4.

HN HN H

HN

N O t O N 0 N NId- IId-1 IId-2 Ild-3

IND

IN

IN

cIN

CA

me Ild-4 Ild-S Me

HN

lId-B Id-S Me N Me ld-S 11Id-7 Me

HN

cl lId-bo Me

HN<V

Nk 116-13 Me HN Jt

NH

No N-Cl Me

HN

116-12 Me HNeJpNH lId-is IN -109- SH d H

H

HN H HN

H

IId-16 IId-17 IId-18 Me 0 H cs HN M lid-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 I d 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 administeringto the.patient a .compound of formula lid 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 \o -110o therapeutically effective amount of a compound of formula lid or a pharmaceutical composition thereof.

SOne aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering c( 5 blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a

\O

ND therapeutically effective amount of a compound of formula SlIId or a pharmaceutical composition thereof. This method 0 is especially useful for diabetic patients. Another ND 10 method relates to inhibiting the production of o 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 pharmaceuticalcomposition 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 Ilia: -111- CA R2

NH

HN'it Rx> Ry N S-R' \D IIIa o or a pharmaceutically acceptable derivative or prodrug thereof, wherein: RX and Ry are independently selected from T-R 3 or L-Z-R 3 SR 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 C1- 4 alkylidene chain; Z is a C1..I4 alkylidene chain; L is -SO2-, -N(R 6 )S0 2

-SO

2

-N(R

6 -CO2-, -N(R 6

-N(R

6 -N CON -N(R 6

SO

2

-N(R

6 -C(R6)20-, 2-

-C(R)

2 SO-, -C (R 6 2 S0 2 -C(R')20 2

-C(R

6 2

N(R

6

-C(R

6 2 -C(R 6 2

N(R

6

-C(R

6

-C(R

6

-C(R)

2 N(R6)N(R6)-, -C(Rt)2N(R)SO 2 or 2 N(R) CON (R 6 R 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 -112partially 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, 5 -CN, -N0 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 is selected from -halo, -OR,

-CO

2

R,

-COCOR,

-COCH

2 COR, -NO2, -CN, -S(0)2R,

-SR,

('4

-N(R

4 2 -CON (R 7 2

-SO

2 2 -N(R 7

)COR,

o

-N(R

7 )C0 2

(C-

6 aliphatic),

-N(R')N(R

4 2

-C=NN(R

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

N(R')

2

-N(R')SO

2 R, Or -OC(=0)N(R 7 )2; each R is independently selected from hydrogen or an optionally-substituted group selected from C.C, aliphatic, C61o 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 -COk', -CO2 (optionally substituted C>-6 aliphatic),

-CON(R

7 2, or -SO2R 2 each Rs 5 is independently selected from halo, -OR, -C02R, -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')CO2(optionaily substituted C-,s aliphatic),

-N(R

4

)N(R

4

-C=NN(R

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

N(R')

2

-N(R

4

S

2 R, or -OC(=0)N(R4)2; V is -S02-, -N(R')S0 2

-SO

2

-N(R

6 -CO2-, -N(R 6

-N(R

6 -N(R6) CON -N4.(R 6) SO2NP- 6 R6)-, -C -C ()N(R 6 6 2

S-,

-C(R)

2 -CRS2- -C(R)SON(R-,

(R)

2

N(R

6 -C (R6) 2N C (0 -C(R 2N (R6) C -C =NN (R6) \O -113-

-C(R)

2

N(R

6 )N(R62, -C(RS) 2 N(R')S0 2 or C 2 N(RE) CON(R) W is -C(R 6

C(R

6 2 2 SO-, 2 S2-,

-C(R

6 2 S0 2

N(R

6

-C(R

6

-CO

2

-C(R

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

CO-,

-0-C(R 6 2

N(R

6 )C -C(R 6

-C(R

6

-C(R)

2

N(RR)N(R

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

R

6

-C(R

6 2

N(R

6 )CON(R) or -CON(R 6 each R 6 is independently selected from hydrogen or an o 10 optionally substituted CI- 4 aliphatic group, or two R 6 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' is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred RX groups of formula I1Ia include hydrogen, alkyl- or dialkylamino, acetamido, or a C1-4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.

Preferred RY groups of formula IIIa include T-R or L-Z-R wherein T is a valence bond or a.methylene, L is or -N(R -CO- andR' is -R, 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 IND -114- O dimethylaminopropyloxy, acetamido, optionally substituted c .phenyl such as phenyl or halo-substituted phenyl.

t The R 2 and R 2 groups of formula IIIa may be taken together to form a fused ring, thus providing a C.i 5 bicyclic ring system containing a pyrazole ring.

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

These are exemplified in the following formula IIIa 0 compounds having a pyrazole-containing bicyclic ring ND 10 system: ~N NH J N N N Z N N

NIN

HN N N $NH NH NH NH -N N ZN N Ry N/

^S-R

1 and Preferred substituents on the R/R 2 fused ring of formula .IlIa include one or more of the following: -halo, -N(R 4 2

-C

1 -4 alkyl, -C 1 -4 haloalkyl,

-NO

2 -0(C 1 4 alkyl), -C0 2

(C

1 -4 alkyl), -CN, -SO2 (Cz-4 alkyl) -SO 2

NH

2 -OC NH 2

-NH

2 S0 2

(C-

4 alkyl), -NHC (C1- 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.

When the pyrazole ring system of formula *IIIa 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, 0methoxypropyl, and benzylokypropya. A preferred R 2 group i s hydrogen..

when Ring ID of formula 111a is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrirnidinyl, and pyrazinyl.

When Ring D of. formula ilia is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronapithyl, i ndanyl, benzirnidazolyl, guinolinyi, -indolyl, isoindolyl, indolinyl, benzo[blfuryrl, benzo[blthiophenyl, indazolyl, benzothiazolyl, c-i cinnolinyl, phthalazinhyl, quinazolinyl, guinoxazolinyl, 1, 8-naphthyridinyl And isoquinolinyl.- On Ring D of fo -rmula IlIa, preferred

T-R

5 or V- Z -R, 5 .subs tituents include -halo, -CN, -NO 2 -N(Rt4 2 optionally substituted

C

1 aliphatic group, -OR, -C(O)R,

-CO

2 R, -CONH(R 4 -N(Rt4)CcR,

-N(R

4 )C0,R,

-SO

2 N(R 4 2 -N(Rt4)SO 2 R, -N(R 6

)COCH

2 N(R,4) 2 -W(R5)COCH2CM 2 N (R4) 2 and -N (R 6 )COCu 2 cw 2 cH 2 NcR) wherein R is selected from hydrogen,

C

1 6 aliphaiic, pheriyl, a 5-6 membered heteroary, ringr, or a,:5-6 membered heterocyclic ring.

More preferred Rs substituents include -Br,

-CN,

-CF

3 '-COGH, -CONEMe, -CONHEL, -NHAc, -NHSO 2 Me, -NHSO Et, -NHSO 2 (n-propyl)

-NXSO

2 (isopropyl), -NHCOEt,

-NHCOCH

2

N{CH

3

NHCOCH

2 N (CO 2 t-Bu) H 3

-NHCQCH

2 N (Cu 3 2

-NI{COCH

2

CH

2 N (OH 3 2

-NIICOCH

2

CH

2 &k 2 N (CHS) 2 -NHCO(CYClopZ'opy1),.-UHCO(isobUty1),

-NHCOCH

2 (rnorpholin-4yl), -NHCOCH 2 Ci 2 (morpholin-4-yl), -tIHCOCHCH 2

CH

2 (morpholin-

-NHCO

2 (t-butyl),

-NH(C

1 4 aliphatic) such as -NEMe, -N 4 aliphatic) 2 such as -Nme 2 OH, -0O(Ca.4 aliphatic) such as -OMe, C 1 4 aliphatic such 'as methyl, ethyl, cyclopropyl,'isopropyl', or t-butyl, and -C02(C%4 aliphatic).

0 -116- O Preferred formula IIIa compounds have one or more, and more preferably all, of the features selected E from the group consisting of: Rx is hydrogen, alkyl- or dialkylamino, Ci 5 acetamido, or-a C1- 4 aliphatic group; R is T-R 3 or L-Z-R 3 wherein T is a valence bond NO or a methylene and R 3 is -N(R 4 2 or -OR;

R

1 is T-(Ring wherein T is a valence bond or eC a methylene'unit; Ring D is a 5-7 membered monocyclic or an 8-10 0 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 IIa 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,

C

1 -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, Ca-6 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 IIIa have one or more, and more preferably all, of the features selected from the group consisting of: -117- Rx is hydrogen methyl, ethyl, propyl, 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;

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(R4)2, optionally substituted Ci-6 aliphatic group, -OR, -CO 2 R, -CONH(R 4

-N(R

4 COR, -N(R 4 S0 2 R, -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; and

R.

2 is hydrogen or a substituted or unsubstituted

C

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

Representative compounds of formula ilia are shown below.in Table

HN

4 HN N N NScoMe N IIIa-1 IIIa-2 IIIa-3 -118- HN XH MeN IIla-4

HN

IlIa-5 IiIa-6 Me

HNP'

.Me IIIa-9 IIla-7 Ila-B Me I HHt

ANA

Me H N Apt N _N yNHAc Illa-11 IIIa-12 Me HNIZN H N

NS

Illa-13 Me HN

J*JH

Pr M&Ne IIla-14 Me HN

JZNH

N NH )rEt CIN 0 -119-.

.M .e gNH, HN--N H N N Et lIIa-18 Illa-16

IND

IND

cIN IIla-17 Me

HNI

ii-is IIla-2 0 IIla-21 Me Me

HN.

2N jayNHAO. Al N (NHAC IIla-22 lIla-23 Me *HN(IPx

ON

IIa-24 Me

HNH

HNX

cl.

IIIa-27 .IIla-26' Ce'N, Me

HN

0~eX.

II~a-28 .IIaa-3 .11la-2s .11la-30 -120- Me HN~tV H IIIa-32 HNt H NfldNrE t IIIa-33 MeN

IND

IND

cIN IIla-32.

Me 4gP

H

0a IIIa-34 Illa-35 IIla-36 Me MeD *Me MeD

CN-

Me'N, oj IIla-37 Me-

HAP

AN

rl-NI 4-S OMe I lIIIa-38 IIIa-39 Me H N J ,tJ

H'

N"

IIla-42 IIla-41

IND

IN

IN

Ni -121- Me IIla-43 IIla-44 Me H N JIpH H (N I' wMe IIla-46 Me Me H N iVp H HNf-rt H <~rrN Et <NfrN Et o0 0 IIIa-47 IIIa-48 Me HNi 0 I IIa-49 Me HNt 2 PH H I K Me.Nm lilaSQ IIla-Si Me 4H k~~04sAMNHAc IIIa-52 Me Me Me HN'ri H HN f-t H hP

M

e/NZN(E t MeG IcN?, Me Me Me Me lIIIa-53 IIIa-54 Me *Me MeM H HN<lP.

Me'Q Me HN* H CN4S'07 N Me Me %eH IIIa-SS IIa-SEI6aS Illa-57 IN -122- 0 SHN H HN H M NISv NHAc O N NEt S NI N N O Me N IIIa-58 IIIa-59 HN H

HNNH

HN HN H N Ni^NMe2 MN S^ N H~ N N N Et a N 0 VAN NHAc' H MeO AN N N t(>Si& 0 Me Me J O 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 Ilia 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 Ilia or a composition comprising said compound.

-123- C 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 therapeutically effective amount of a compound of formula D I I I a or.a pharmaceutical composition thereof.

CD 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, o 10 which method comprises administering to the patient a -iq therapeutically effective amount of a compound of formula lila 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 liIa 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 IlIa or a pharmaceutical composition thereof.

Another aspect of the invention'relates to inhibiting Src activity in a patient, which method Va

IN

Ct

IN

cIN cIN

CA

-124comprises administering to the patient a compound of formula liIa or a composition comprising said compound.

Another method relates to inhibiting Aurora-2, GSK-3, or Src activity in a biological sample, which 5 method comprises contacting the biological sample with the Aurora-2, GSK-3, or Src inhibitor of formula IIIa, or a pharmaceutical .composition thereof, in an amount effective to inhibit Aurora-2, GSK-3, or Src.

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

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

R

2

NH

HN" N

R

R'

'RYNO-R'

IIlb or a pharmaceutically acceptable derivative or prodrug thereof, wherein: R 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 selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently

T

-125substituted by oxo, T-R5, 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.

4 -alkylidene chain; Z is a C-4 alkylidene chain; INDL is -SO2-, -N(R 6 )S0 2 -S0 2

N(R

6

ID-N(R

6

-CO

2

-N(R

6

-N(R

6

-N(R

6

-N(R')SO

2

N(R

6

-N(R

6

)N(R

6

-OC(O)N(R

6

-C(R

6 2

-C(R

6 2

S-,

-C(R

6 2SO-, 2S02-, -C(R 6 )2S02N(R 6

-C

6 2

(R

6 0 -C(R 6 2 N C (R N C -C =NN(R) -C(Rt) 2

N(R')N(R

6

-C(R

6 2

N(R

6 S02N(R 6 or -C (R 6 2 N CON R and R 2 are independently selected from -T-W-R 6 or

R

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

R

2 and R 2 is independently substituted by halo, oxo, -CN, -NO 2 or and each substitutable ring nitrogen of said ring formed by R" and R 2 is independently substituted by RU;

SR

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

R,

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

-N(R

4 2

-CON(R

7 2

-SO

2

N(R

7 2 -N (R')COR, -N (R 7 )CO2(C..

6 aliphatic), -N(R 4

N(R)

2 -C=NN(R4) 2 -C=N-OR, -N(RCON(R 7 2

-N(R

7 S0 2

N(R

7 2 -N(R4)SO 2 R, or -OC(=0)N(R 7 )2; each R is.independently selected from hydrogen or an optionally substituted group selected from CI-6 aliphatic, Cs- 6 o 10 aryl, a heteroaryl ring having 5-10 or.ing atoms., or a heterocycly. ring having 5-10 ring atoms; ct each R 4 is independently selected from -R 7

__-CO

2 (optionally 'substi tuted C 1 _6 aliphatic) -CON (R7) 2 or S 2 R7; each R 5 is independently selected from halo, -OR,

-CO

2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, C]-N(R 4 2 -CON(R 4

-SO

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

COR,

0-N(R 4 C0 2 (optionally s.ubstituted 01_6 aliphatic), IN 10 -N(R 4 )N(R 4 2

-C=NN(R

4 2

-N(R

4

)CON(R')

2 o-N (R 4

SO

2 N(R4) 2 -N (R 4

SO

2 R, or )2 is S- S 2 6 S0 2

-SO

2

N(R-

-N(R 6 -C0 2 -N (R 6 CON (R 6 N (R'S)S0 2 N (R 6 -N CR 6 N (R0)is -C (o)N(R 6

-OC,(OYN(R

6 -C(Rt) 2 -C (R 6 2

S-,

-C(R

6 2 S0-, -C(Rt) 2

SO)

2

-CCR

6 2 S0 2

-C(R

6 2

N(R

6

-C(R

6 5) 2

-C(R

6 2 N(Rt)c(O -C(Rt6)=NN -c (R 6 -C (Pt6) 2

N(R

6 )N(R6) -c(R6) 2 N (R 6 3) S0 2 N (R 6 -,or -C (R 6 ),2N(R 6 )CON W is -C'(R 6 2

-C(R

6

-C(R

6 2 S0,-,

C()

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

-C(R

6 -C(R')OC(o)w(R 6 -C(Rt 2 ,N(Rt)CO-, -C (R 6 2

N(R

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

-C(R

6 -C (R 6 2

N(R

6 N(R, CR 6 2

N(R

6

SO

2

N(R%-

-C(Rt) 2

N(R

6 or -CON(R)each R 6 is independently selected from hydrogen or an optionally substituted C 1 4 aliphatic group, or two groups on the same nitrogen atom are taken together with the nitrogen atomto form a 5-6 membered 3O -hetero'cyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an optionally substituted C3_.s aliphatic group, or two R 7 on the same nitrogen are taken together with the O -127nitrogen to form a 5-8 membered heterocyclyl or Sheteroaryl ring.

C Preferred Rx, groups of formula IIIb include Shydrogen, alkyl- or dialkylamino, acetamido, or a C 1 -4 aliphatic group-such as-methyl,, ethyl; cyclopropyl, or IND isopropyl.

CD Preferred R Y groups of formula IIIb include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is or -N(R -C(R 6 2 0 and R 3 is -R,

-N(R

4 2 or -OR. Examples of preferred R y groups include CN 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, alkyi- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.

SThe 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.

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

NH

HN N Rx N NH NH NH NH RY N O-R.

AO and I -128- Preferred substituents on the R 2

/R

2 fused ring C of formula IIIb include one or more of the following: -halo, -N(R4)2, -C1.4 alkyl, -Cl-4 haloalkyl, -NO 2 tO(C.4 alkyl), -CO2(C.-4 alkyl), -CN, -S0 2

(C.

4 alkyl),--S0 2

NH

2 -OC NH 2

-NH

2

SO

2

(C

1 4 alkyl), -NHC(O) (C1-4 alkyl), Va I-C NH 2 and -CO(C.

4 alkyl) wherein the (C1-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, 0g the (C14 alkyl) group is methyl.

ci oN 10 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 C1-, 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 bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl,.indolinyl, benzo[b]furyl, benzb[blthiophenyl, 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

4 2 optionally substituted CI-6 aliphatic group, -OR, -C(O)R,

-CO

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

)CO

2 R, -SO 2

N(R

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

COCH

2 N (R) 2

-N(R

6

)COCH

2

CH

2 N 2 and -N (R 6

COCH

2

CH

2

CH

2 N (R4) 2 wherein R is selected from \D -129o hydrogen, C2- 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

More preferred

R

5 substituents include -C1, -Br,

-CN,

-CF

3 -COOH, -CONHMe, -CONIEt,

-NH

2 -NHAc, -NHSO 2 Me,

-NHSO

2 Et, -NHSO2(n-propyl)

-NHSO

2 (isopropyl), NHCOEt, -NHCOCH2NHCH 3

-NHCOCH

2

N(CO

2 t -Bu) CE 3

-NHCOCH

2 N (CH 3 2

-NHCOCH

2

CH

2 N (CH3) 2, -NHCOC H 2 CH2CH 2

N(CH

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

-NHCOCH

2 (morpholin-4yl), -NHCOCH 2

C.

2 (morpholin-4-yl),

-NHCOCH

2

CH

2

CH

2 (morpholin- I 10 4-yl), -MNHCO 2 (t-butyl),

-NH(C

1 4 aliphatic) such as -NRMe,

S-N(C

1 -4 aliphatic) 2 such as -NMe 2 .OH, -O(C 1 -4 aliphatic) such as -OMe, C1.4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(CI- 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 C1.Y'aliphatic group; RY is T-R 3 or L-Z-R 3, wherein T is a valence bond or a methylene and R3 is -N(R 4 2 or -OR; R1 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 IIIb 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 Rp is selected from

-OR,

-130- -or -N(R 4 wherein R is selected from hydrogen,

C

1 -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, C 1 i- 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: Rx is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido; RY is selected from 2-pyridyl, 4-pyridyl, pyrroli'dinyl, piperidinyl, morpholinyl, piperazinyl, 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(R4): 2 optionally substituted Ci.aliphatic group, -OR, -C02R, -CONH(R 4 -N (R 4 COR, N(R4)SO 2 R, -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; and r f

VC

ci -131-

R

2 is hydrogen or a substituted or unsubstituted CI-6 aliphatic, and L is or -NH-.

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

Table 6.

m

H

N

N CIb-Me IIIb-2

HNI

IIIb-3 IIIb-1 HN

H

m III IIIb-4

HN

Me

N

II1b-5 IIHNb- IIIb-6 N Q Me.N2 IIIb-8 IIIb-7 IIIb-9 -132- IIlb -10 Me

HN

4 N NLQa IIlb-ji.

Me iPr HNi IIlb-14 me

HN

4 IHAc N Oj IIlb-12 Me HN gr4 N NjNHWEt IlIb-is IlIb-13 Me HN<PXH H IIIb-16 IIlb-171 Illb-18 Me Me HN<V H

HN<PNN

IN %~r~iz 0 Me NKNHAc IlIb-19 II lb -20 IIIb-21 Me Sf"t Me AcHN4 NH~c 2 IIlb-23 Me

H

Nr?%aNS-0 2 N N A O Q iP r IIlb-24.

IIlb-2: I -133- SMe Me Me H H H HN N H NMe 2 HNPN

HN'P

NO CNNN O iN O2 MeOQIE

C

i cI \D IIIb-25 IIIb-26 IIIb-27

VO

Me Me Me H N HN H HNN 'N rN Nr"" 0 Me'N O N Me' N O, Cl .IIIb-28 IIIb-29 In another embodiment, this invention provides a composition comprising a compound of formula IIIb and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a Scompound 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 acompound 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 1 -134- Sadministering 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

C.

l 5 method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, IND which method comprises administering to the patient a therapeutically effective amount of a compound of formula 0 IIIb or a pharmaceutical composition thereof. This *D 10 method is especially useful for diabetic patients.

SAnother 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 ip-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.

O -135- Another embodiment of this invention relates to compounds of formula IIIc: N R 2 R2' .0R 1s RNH HN' -N R' N N-R'

H

¢1 5 LC) IIne CI or a pharmaceuticall, acceptable derivative or prodrug thereof, wherein:

R

x and R Y are independently selected from T-R' or L-Z-R'; R is. T-(Ring

D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl,-said heteroaryl or heterocyclyl.ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ringcarbon of Ring D is independently substituted by oxo, T-Rs, or V-Z-R s and each substitutable ring nitrogen of Ring D is independently substituted by -R4; T is a valence bond or a C 1 4 alkylidene chain; Z is a. C1-4 alkylidene chain; L is -S0 2

-N(R

6 )S0 2 -S0 2

-N(R

6 -CO2-,

-N(R

6

-N(R

6

-N(R

CON(R

S

-N(RE')SO

2

N(R'

-N(R

6

)N(R

6

-OC(O)N(R

6

-C(R

6 2

-C(R

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

-C(R

6 2

S

0 2

N(R

-C(R6)2N(R 6 -C (R 2N (R 6 C -C (iR 2N (R C -C (R 6 =NN -136o -C(R 6 -C(R6) 2

N(R)N(R

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

N(R

6 or

C

N -C 2 N(R) CON 6

R

2 and R 2 are independently selected from or

R

2 and R' are taken together with their intervening C- 5 atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms IND selected from nitrogen, oxygen, or sulfur, wherein each C( substitutable ring carbon of said fused ring formed by o

R

2 and R 2 is independently substituted by halo, oxo, Va 10 -CN, -NO 2 -R7, or -V-R 6 and each substitutable ring 0 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) 2 R, -SR,

-N(R

4 2

-CON(R

2

-SO

2 -N(R 7

)COR,

-N(R

7

)C

0 2 (CI aliphatic), -N(R 4

)N(R

4 2

-C=NN(R

4 2 -C=N-OR, CON(R 7

-N(R

7

SO

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

)SO

2 R, or -OC 2; each R is independently selected from hydrogen or an optionally substituted group selected from C.-6 aliphatic, CG-lo aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -COR 7 -CO2 (optionally substituted Ci-6 aliphatic), -CON(R 7 2 or -SO2R; each R 5 is independently selected from halo, -OR, -C0 2 R, -COCOR, -N02, -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 C0 2 (optionally substituted Ci-6 aliphatic),

-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 (R4)2; -13 7- V is -SO- -N(R')S0 2

-SO

2 -C02-, I.-N(R 6 CO-, -N(R 6 C(0) 0-, -N (R 6 )CON

-N(R

6 S0 2 N -N (R 6

N(R

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

-C(R

6 2 -C(Rt) 2

S-,

S C (R 6 2 So-, -'C(Rt)jso 2

-C-(R

6 5)2So 2 -C(*R 6 IND C (R 6 2 N(a0) C0(0) -0(R 6 2

N(R

6

=NN(R

6 Cl -C(R 6 )2N (Rk 6

)N(R

6

'-C(R

6 2 N (R 6

SO

2

N(R

6 or C WR) 2 N (R 6 )CON(RW) IND WN is -C(R 6 2

-C(R

6 2 s- -C(R 6 2

-C(R

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

C(RW)

2 02-,

-C(R

6 2 -C )CAR 6

-(R

6 N-0)C-,

-C(R

6 2

N(R

6 )w(R 6

-C(R

6 2 N (R 6

SO

2 -C(Ra) 2

N(R

6 )CON (R 6 or -CON(R 6 each R' is inuependently selected from hydrogen or an optionally substituted C:,4 aliphatic 'group, or two R' groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 muembered heterocyclyl or heteroaryl ring; and 77 optionially substituted Ca 6 aliphatic group, or two R 7 ont the same nitrogen re taken together with the nitrogen to form a 5-8.membered heterocyclyl or: heteroaryl ring..

Preferred RX groups. of formula IlIc include -hydrogen, alkyl or. dialkylamino, acetamido, or 'a C1-4 aliphatic group such as. methyl, ethyl, cyclopropyl, or isopropyl.

Preferred Ry groups of formula l11y include"T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is or 2 -Co- and R 3 is -Rf, -NiR or -OR. Examples of preferred Rygroups include.

2-pyridyl, 4'-pyridy1, pyrrolidinyi, piperidinyl, \o -138- 0 o morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as Smethoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as ID dimethylaminopropyloxy, acetamido, optionally substituted IND phenyl such as.phenyl or halo-substituted phenyl.

The R 2 and R 2 groups of formula IIIc may be 0 taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.

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

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

NH

HNr- N N,,N NN H H NH

$NH

R-N N_ -N SN N-R 1

N

SH ,and Preferred substituents on the R 2

/R

2 fused ring of formula IIIc includeone or more of the following: -halo, -N(R 4 2

-CI-

4 alkyl, 4 haloalkyl,

-NO

2

-O(C.

4 alkyl) -C0 2 (CI-4 alkyl) -CN, -S0 2

(C

1 -4 alkyl) -SO2NH 2 -OC (O)NH 2

-NH

2 S0 2 (CI-4 alkyl), -NHC(O) (Cz- 4 alkyl), -C(O)NH2, and -CO(CI-4 alkyl), wherein the (CI-4 alkyl) is .a straight, branched, or cyclic alkyl group. Preferably, the (CI-4 alkyl) group is methyl.

When the pyrazole ring system of formula IIIc is moriocyclic, preferred R 2 groups include hydrogen or a IND -139substituted 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 benzyloxypropy. A preferred

R

2 group 1-10is hydrogen.

Va C When Ring D of formula IIc is inonocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrinidinyl, and pyrazinyl.

When Ring D of formula IIc is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo(b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, guinazolinyl, guinoxazolinyl, 1,8-naphthyridinyl and isoguinolinyl.

On Ring D of formula IlIc, preferred T-R 5 or

V-Z-R

5 substituents include -halo, -CN, -NO 2

-N(R

4 2 optionally substituted C3; 6 aliphatic group, -OR, C(O)R,

-CO

2 R, -CONH(Rt,

-N(R

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

N(R)

2 -N (Rt) S0 2 R, -N(R 6

COCH

2 N (R4) 2 -N(R6) COCH 2

CH

2 N (R4) 2 and'

-N(R

6

)COCH

2 CHa 2 c 2

(R)

2 wherein R is selected from hydrogen, C 1 6 aliphatic, phenyl. a 5-6 membered heter'aryl ring, or a 5-6 m'mbered heterocyclic ring.

More preferred R 5 substituents include -Cl, -Br, -CN,

-CF

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

-NHSO

2 Et, -NHSO 2 (n-propyl)

-NHSO

2 (isopropyl), -NHCOEt,

*NHCOCH

2

NHCH

3

-NHCOCH

2 N (CO 2 t-Bu) CH3, -NI{COCH 2 N (CH3) 2

-NICOCH

2

CH

2 N (CH3)2, -NHCQCk 2CH2 CH 2

N(CM

3 2 -NHCOcycloprpyl), -NHCO(isobutyl),

-NRCOCH

2 (morpholin-4yl), -NHCOCH2C 2 (morpholin-4-yl),

-NHCOCH

2

CH

2

CE

2 (orpholin- 4-yl), -NHcO(t-butyl),.

-NIC

1 4 aliphatic) such as -NHMe,

N(C

1 4 aliphatic) 2 such as -NMe 2 OH, -(C,1 4 aliphatic) -140o such as -OMe, C-.4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C 1 -4 Saliphatic).

Preferred formula IIIc compounds have one or more, and more preferably all, of the features selected \D from the group consisting of:

\O

eCq R x is hydrogen, alkyl- or dialkylamino, o acetamido, or a CI- 1 aliphatic group; \O R Y is T-R 3 or L-Z-R 3 wherein T is a valence bond S 10 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

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 ItIc 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 CI-.

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 iR 2 is hydrogen, wherein R is selected from hydrogen, Ci.

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclici ring; and L is or -N(R 4 -141- S. Even more preferred compounds of formula -IIc c have one or more, and more preferably all, of the Sfeatures selected from the group consisting of: Rx is hydrogen methyl, ethyl, propyl, *cyclopropyl, isopropyl, methylamino or ND acetimido;

R

y is selected from 2-pyridyl, 4-pyridyl, Spyrrolidinyl, :piperidinyl, morpholinyl, cO 0 piperazinyl, methyl, ethyl, cyclopropyl, S 10 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

C

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

)SO

2 R, -N(R 6

COCH

2

CH

2

N(R)

2 or -N (R COCH2CH 2 CHN (R 4 2; and

R

2 is hydrogen or a substituted or unsubstituted C:.1 aliphatic, and L is or -NH-.

Representative compounds of formula IIIc are shown below in Table 7.

Va 0 0 ci ci -142- Table 7.

I1Th-i IIIc-2 lIla-3 HNf

N

11-r N Na- Me

HN

NN

IIlc-4 Me HN* tH MeQ N MeO N N-),-4CI MeOI

*H

OMe 111c-7 Me

JH

AtNH Et NLNAN

H-

Me0 HNfg,NH ~SONH 2 k MeO N LI N NrA H Me N Na~ MeO. H OMe Il-S- TIla-S Ph Me IH HH

HH

IIIC-lo lilab ~IlIC-lillaf IlIc-12 -143-

IND

IND

cIN tBu -NAI 3<H N NNC

H

NO

2 IIIc-13 Ph

*HN

4 Pe-~

H

IIIc-IG Me Mey N js~C Me NLN42~

H

IIIc-19 IIIC-14 IIIc-17

H)?H

HN 2f N N NN~

H

Me HNJ~t Me<L-NZ

H

IIXIc-l Me

HN*P

MeG, 4u Na

H

IIIC-21 Me

HN

'N

Me N

H

IIIc-24 Me Me

N

H

I11C-20 Me Me MeOJ N9MeOJk'Z H -H IIlc-22 IIIC-23

I

D0 -144- HH HN

N

SMe N Me N S H

H

IND IIIc-25 IIIc-26

IO

In another embodiment, this invention provides 0D a composition comprising a compound of formula IIIc and a ID Spharmaceutically acceptable carrier.

SAnother 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 Va

IN

Ct

IN

cIN cIN

CA

-145- IIIc or a pharmaceutical composition thereof. This method is especially useful for diabetic patients.

Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the -progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of 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 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 t -146- Va 0 carried out with a preferred compound of formula IIIc, as described above.

Another embodiment of this invention relates to compounds of formula IIId: IIId 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;

R

x 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 selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-RS, or V-Z-R 5 and each substitutable ring nitrogen'of Ring D is independently substituted by -R4; 20 T is a valence bond or a C 1 -4 alkylidene chain, wherein when Q' is a methylene group of said CI-4 alkylidene chain is optionally replaced by

-N(R

4 -CONH-, -NHCO-, -SO 2 -S0 2 NH-, -NHSO 2

-CO

2 -OC(O)NH-, or -NHCO 2 Z is a CI- 4 alkylidene chain; i v. -147- L is

-N(R

6

)SO

2

-SO

2

N(R

6

S-N(R

6

-CO

2

'-N(R

6

-N(R

6 -N (R6) CON -N SO2N -N (R6) N S-C(0)N(R) -OC(0)N(R5)

-C(R

6 2

-C(R

5 2

S-,

-C(R

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

-C(R

6 2

N(R

6 C(R) 2N -C (R6.)2N(RC(0)0 c

-C(R

6 2

N(R

6

-C(R

6 2

N(P

6

)SO

2 or

-C(R

6 2

N(R

6 IND R 2 and R 2 are independently .selected from -T-W-R 6 or S 10 R 2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having '0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R and R 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 4 R is sel6cted from -halo, -OR,

-CO

2

R,

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

-SR,

-N(R

4 2

-CON(R)

2

-SO

2

N(R

7 2

-N(R')COR.,

-N(R

7 )C0 2

(C

1 6 aliphatic), -N(R 4

-C=NN(R

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

)CON(R

7 2 -N(R7 SO 2 N 2

SO

2 R, or OC(=O)N(R7) 2 each R is independently selected from hydrogen or an optionally substituted group selected from C 1 aliphatic, C- 10 aryl, a heteroaryl ring having 5-10 -ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R4 is independently selected from -COR 7

-CO

2 (optionally substituted C- 1 aliphatic), -CON(R 7 2 or -SO 2

R

7 -14 8oIND oeach R -is independently selected from halo, -OR, -C RI -C0 2 R, -COCOR, -NO 2 -CN, -S -SO 2 R, SR, ct ~-NCR 4 2 -CON(R 4 2

SO

2 N(R 4 2 -0C -N(R 4

COR,

R

4 C0 2 (optionally substituted C3.- 6 aliphatic) -N(Rt N(Rt4 2

:C=NN(R

4 -,N(Rt4)CON

(R)

2

-NC(R')SO

2 NC(R 4 2

-NC(R

4 s0 2 R, .Or -OC (R 4 2 V is -S7, 7S0-, N(R6)S0 2 S0 2 -C0 2 -N(R 6 -NAR5)so 2 -NCR')N(Rh)-, o 10 -C (O)N (R 6) -C(R6) 2 CCRt 2

S-,

-cCR6) 2 N(R) C -C(R6) 2 NCR5)

=NNCR')-

-C CR 6) -cCR 6 N)N(R (R5R) SO 2

N(CR

6 or" -C (CR6) 2 N(R")CON (R6) W is -CCR') 2 0O-, -C(R 2 -C(R6) 2 so-, 2 S0 2 2 So 2

N(R

6 2 -C0 2 -1

-C'(R

6 0C(o) NCR 6 -C (R 6 2 NC(R') Co-, CCRt 2 N(R')CCO)O-, -C(Rt=N-o-, 2 NCRt)NCR)-, -C(R6) 2

N(R')SC

2

N(R)-

-C(R6) 2 NCR6)CONRt)-, or.-O(r- *each'RG' 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 togetherwith the nitrogen atom to form a 5-6 membered heter'ocyclyl or heteroaryl ring; each R" is independently selected from hydrogen or a Cp_ 4 aliphatic group, or two R6 on the same carbon".atom are *taken together to form a 3-6 membered. carbocyclic ring; and each R7 is independently selected from hydrogen or an optionally substituted C3.

6 aliphatic group, or two R7 on the same nitrogen are'taken together with the, D. -149c nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred Rx groups of formula IIId include Shydrogen, alkyl- or dialkylamino, acetamido, or a Ci-4 aliphatic group such-as:methyl, ethyl, cyclopropyl, or ND isopropyl.

IO

CA Preferred R Y groups of formula IIId include T-R 3 Sor

L-Z-R

3 wherein T is a valence bond or .a methylene, L is or -N(R 4 -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 suchas 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 IIId compounds having a pyrazole-containing bicyclic ring system:

NN\

RX NH NH

NNH

N CH 2 R and -150- Preferred substituents on the R'/R 2 fused ring of formula 111d include one or more of the following: -halo, -N(R 4 2 t. -C 1 4 alkyl, 4 haloalkyl, -NO 2 -O(C.4 alkyl), -c0 2

(C

1 4 alkyl) CN,- -SO (C 1 4 alkyl) -SO2NH 2

-OC(O)NH

2

-NH

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

NO

-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, D the (C 1 4 alkyl) group is methyl.

o 10 When the pyrazole ring system of formula Ild is monocyclic, preferred. R groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C-6 aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, cyclopbopyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen.

When Ring D of formula IIId is monocyclic, preferredRing D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidiny, and pyrazinyl.

When Ring D of formula 1ILd is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indinyl, benzimidazolyl, quiholinyl, indolyl, isoitndolyi, indolinyl, benzo[b]furyl, benzo[blthiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIId, preferred T-R or

V-Z-R

5 substituents include -halo, -CN, -NO 2 -N(R 2 optionally substituted C 1 .s aliphatic .group, -OR, -C(O)R,

-CO

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

)CO

2 R, -SO 2

N(R)

2

-N(R

4

SO

2 R, -N (R 6

COCH

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

COCH

2

CH

2 N (R 4 2 and

-N(R

6

COCH

2

CH

2

CH

2

N(R)

2 wherein R is selected from \L -151- 0 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 -C1, -Br, -CN, -COOH, -CONHMe, -CONHEt, -NH 2 -NHAc, -NHSO 2 Me,

-NHSO

2 Etj -NHSO2(n-propyl),

-NHSO

2 (isopropyl), -NHCOEt,

IND-NHCOCH

2

NHCH

3

-NHCOCH

2

N(CO

2 t-Bu) CH 3

-NHCOCH

2 N(CH3) 2 Ci

-NHCOCH

2

CH

2 N (CH 3 2, -NHCOCH 2

CH

2

CH

2 N (CH3) 2 r o -NHCO(cyclopropyl), -NHCO(isobutyl),

-NHCOCH

2 (morpholin-4- 1 yl), -NHCOCH 2

CH

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

CH

2

CH

2 (morpholin- 4-yl), -NHC2 (t-butyl) -NH (C 1 4 aliphatic) such as -NHMe,

-N(C

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

I

4 aliphatic) such as -OMe, C1: 4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl,-and -C0 2

(C

1 4 aliphatic).

Preferred Q' groups of formula IIId include -C(R S)2- or 1,2-cyclopropanediyl, wherein each R 6 is independently selected from hydrogen or methyl. A more preferred Q' .group is -CH2-.

Preferred formula IIId compounds have one or more, and more preferably all, of the features selected from the group consisting.of: RX is hydrogen, alkyl- or dialkylamino,.

acetamido, or a C.I- 4 aliphatic group; RY is T-R3 or L-Z-R3, wherein T is a valence bond or a methylene. and R3 is -N(R4) 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 (d).Ring D is a 5-7Tmembered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and

R

2 is -R or -T-W-R 6 and R' is hydrogen,.or R 2 and R2 are taken together to form an optionally substituted benzo ring.

-152- More preferred compounds of formula IIId have one or more, and more preferably all, of the features Sselected 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; MD or -N(R 4 2 wherein R is selected from hydrogen,

C

1 .G aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; R' is T-(Ring wherein T is a valence bond; 1 1 0 Ring D is a 5-6 membered monocyclic or an 8-10 cI 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: Rx is hydrogen methyl, ethyl, propyl, 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;

VO

VO

VO

cIN

CAD

-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,

-NO

2

-N(R

4 2 optionally substituted-C-1_ aliphatic group, -OR, -C02R, -CONH(R 4

-N(R

4 )COR, -N(R 4 S02R, -N(R 6 COCH2CH 2 N (R 4 2 or -N (R 6

COCH

2

CH

2

CH

2 N (R 4 2

R

2 is hydrogen or a substituted or unsubstituted 1C-6 aliphatic; and L is or and Q' is -CH 2 Representative compounds of formula IIId are shown below in Table 8., Table 8.

Ph

HN

,fN CI Me N'O IIId-I 0, HN NH MeX NtO 0

HNJI

Me N IIId-2 HN H Ph

H

HN N IIId-3 Ph HN N

N

Me4 N' 'Me IIId-4 IIId-5 IIId-6 -154- 0

HNJI

M

Ild-7 Me, HN g(H Me HN JftNH Me Me IIId-13 Ph

HPH

Et N IlId-Il

HNW

Me N k *a IIId-9 Me

HN<

Et400 o-a IIld-12 Ph

HN<NH

Met flL IlId-14 IIId-is Me

HNAH

Meo "4t-L Me N CI Me N Y: .cI IIId-is IIId-17 "di IlId-18 ID -155- C Me S MeMe Me HN NH 'HNP HNZ HN A H H H MeN CI HA

HN

e J El' N Et Me 0 IIId-19 .IIId-20 IIId-21 IIId-22 IIId-23 IIId-24 o Me Me Me 0 HNN.n HNtN

HN<P

Me N'N NEt EtN IIId-22 IIId-23 IIId-24 In another embodiment, this invention provides a composition comprising a compound of formula IIId and a Ir pharmaceutically acceptable carrier.

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

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

Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor,' which method comprises administering to a patient in need of such a treatment a ND -156- C therapeutically effective amount of a compound of formula IIId 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, 0D which method comprises administering to the patient a ND therapeutically effective amount of a compound of formula SIId or a pharmaceutical composition thereof. This 0 method is especially useful for diabetic patients.

o 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 hIId 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 Aurbra-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: D -157p2

SNH

HN N R.z 2 SRY Z .S-R' SIVa ci

IN

o 5 or.a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

1 is nitrogen or C-R 6 and Z 2 is nitrogen or CH, wherein one of Z 1 or 2 2 is nitrogen; RX and R Y are independently selected from T-R 3 or L-Z-R 3 or R 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'RY is independently substituted by oxo, T-R3, or L-Z-R 3 and each substitutable.ring nitrogen of said ring formed by Rx and R 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 IO -158o T is a valence bond or a C 1 .i 4 alkylidene chain; Z is a C.- 4 alkylidene chain; L is SO-, -802-, -N(R 6 )S0 2

-SO

2

N(R

6

-C

2 -N(R 6

-N(R

6 -N(R);SO0 2

-QC(O)N(R

6 -C(Rt) 2

S-,

IND 2 SO-, -C(R 6 2 S0 2

-C(R

6 2

SO

2

-C(R

6

),N(R

6

-C(R

6 2 2 N(R) C C(R 6

)=NN(R

6

-C(R

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

-CCR

6 2 N(RN')S0 2 or S 10 -C (R 6 2 N (R 6

R

2 and R 2 are independently selected from -T-W-R or R2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms 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 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 -S(0) 2 R, -SR,

-N(R)

2

-CON(R)

2 -S02N(R 7 2

-N(R')COR,

-N(R

7

CO

2

(C

1 -6 aliphatic), -N(R 4

)N(R

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

CON(R

7 2

-N-(R

7

SO

2 N (R)2 -N(R SO 2 R, or -OC(=0)N(R each R is independently selected from hydrogen or an optionally substituted group selected from C1_6 aliphatic, oaryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; A *~JLj*JAJ..t1ALU o 47 each R is independently selected from -R 7, -COR'7, -C002 (opt ionally substituted C aliphatic), -CNR7 2 or -S02R.' *each Rs is independently selected from halo,. -OR, R, _C 0 2 i -COCOR, -NO 2 -CN, -S SO 2 R, -SR, IND ~-N(R 4 2

-CON(R.

4 2 S0 2 N (R 4 2 -NCR 4

COR,.

ci-N(R 4 C02 (optionally substituted C1- aliphatic), o 2 -CNNC(Rt -C=N-OR, -N(RtCONC(R 2 IND

-N(R

4

SO

2 N (Ri) 2

-N(R

4

)SO

2 R, or -OC(=O)N(R 4 2 o 10 V is -SO2-, -N(R 6 )S0 2 -SO2N(Rt-)

-N(R

6

-N(R

6

)SO

2 -N(R 6 )N(R 6 -C(o)NCR 6 -C C)N(R 6 -C (R 6 y- 2 s-,

CC(R

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

-C(R

6 2

SO

2

NCR

6

C(R')

2

N(R

6

-CCR

6 2

N(R

6

-C(R

6 2

NCR

6

-C(R

6 -C (R5) -C CR 6 2

N(R

6

N(

6 -cCR 6 2 N (R 6

SO

2 N (R6) or -C (R 6 2 N (R 6 CON (RG) W is -C(R6)2O-, -CCR')2S-, -C(R6)2sO-,

-C(R

6 2 S0 2 -C (Re) 2 S0 2 N -c (R 6 2 N CR 6 -C0 2 -C oc -CC(R 6

-C(R

6 2 NC2)co-, -cCR 6 2 N CR 6 -cCR 6 NN (RE)

-!C(R

6 2

N(R

6 )N(PY) -C(Rt6) 2 N (R0) s 2 'y)

-C(RE)

2 N(RE)CON(R6)-, or *each R6 is independently selected f rom hydrogen or an optionally substituted C..4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form membered heterocyclyl or heteroaryl ring; each R7 is inde pendently selected from hydrogen or an optionally substituted C31_ aliphatic group, or two R.7 on the same'nitrogen are .taken together with the nitrogen to form a 5-8 menmbered heterocyclyl or *heteroaryl ring; and -160-

O

o R' is selected from halo, -C0 2 R, -COCOR,

-NO

2 -CN, -S0 2 R, -SR, -N(R 4 2

-CON(R

4 2

-SO

2

N(

4 2

-N(R

4 )COR, -N(R 4 )C0 2 (optionally substituted C 1 -6 aliphatic), -N(R)N(R) 2 -C=NN(R4) 2 ci/ -C=N-OR, -N(R 4

)CON-(R

4

N(RI)SO

2 N(R 2 -N.(R)S0 2 R, or -OC(=O)N(R 2 IDPreferred rings formed by RX and RY of formula IVa include a or 7-membered unsaturated or NO partially unsaturated ring having.0-2 heteroatoms, 0 o 10 wherein said.RX/R 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 R2't

HNH

HN HNO HN37? Qt2 2. Ott IVa-A IVa-B IVa-C HN131 HN,31 HN,31

RN.RN

R N zi KhJt-K IVa-D IVa-E IVa-F HN HN% HN Z2 N 2 ;N Z

Z

Ia-J IVa-K 1a-L IVa-J IVa-K IVa-L NO -161- HN H HN HN S 2 0%tz N Z14Y ZIY N Z14 IVa-P IVa-R IVa-V oHN3 N2

NZ

R4 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 is nitrogen and Z 2 is CH.

Preferred.Rx"groups of formula IVa 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 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 -CO- and R'3 is -R,

-N(R

4 2 or -OR. Examples of preferred RY groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl,.piperidinyl, morpholinyl, .piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl,. alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as O -162-

O

o dimethylaminopropyloxy,, acetamido, optionally substituted phenyl such as. phenyl or halo-substituted phenyl.

The ring formed when the Rx and Ry groups of Sformula IVa are taken together may be substituted or unsubstituted. Suitable substituents -include halo, IO -0 (CH 2 2 .4-N (R 4 -0(CH2 24-R, -OR, -N (R 4

(CH

2 2-4 -N (R 2, \O 2 2 4

-CO

2 R, -COCOR, -NO 2

-CN,

ci: o -SO 2 R, -SR, -N(R 4 2 -CON(R) 2

-SO

2

N(R

4 2 Ci i \O -N(R4)COR, -N(R CO 2 (optionally substituted C 1 0 S 10 aliphatic), -N(R)N(R 4 2

-C=NN(R

4 2

-C=N-OR,

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

-N(R

4

)SO

2 R, or

-OC(=O)N(R

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

-CO

2 R, -CON(R) 2 -CN, -0 (CH 2 )2-4-N(R 4 2

-O(CH

2 2 4

,-NO

-N(R4) 2

-NR

4 COR, -NR 4 S02R, -SO 2

N(R

4 2 wherein R is hydrogen or an .optionally substituted C 1 6 aliphatic group.

The R 2 and 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: 9 NH N N HN N NN Rx ZNH NH N H NH RY Z S-R' ,and IND -163- Preferred substituents on the R 2

/R

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

-C

1 4 alkyl, haloalkyl,

-NO

2

-O(C

1 4 alkyl), -C0 2 (C-4 alkyl), -CM, -S0 2 (C1.4 alkyl), -SO 2

NH

2

-OC(O)NH

2

-N

2 S0 2

(C:

1 4 alkyl), -NHC(O) (C1-4 alkyl), I.N -C(O)NH 2 and -CO(C 1 -4 alkyl), wherein the 4 alkyl) is a C straight, branched, or cyclic alkyl group. Preferably, the (C 1 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 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 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, isbindolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl,. quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of 'formula.IVa, preferred T-Rs or V-Z- Rs substituents include -halo, -NO 2 -N(R4) 2 optionally substituted C 1 aliphatic group, -OR, -C(O)R,

-CO

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

COCH

2

CH

2 N 2 and

-N(R

6

COCHCH

2

CH

2 N (R 4 2 wherein R is selected from hydrogen, C._ 6 aliphatic, phenyl,.a 5-6 membered IND -164o heteroaryl ring, or a 5-6 membered heterocyclic ring.

More preferred R 5 substituents include -C1, -Br, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH 2 -NHA,, -NHS02Me,

-NHSO

2 Et, -NHS2 (n-propyl), -NHSO 2 (isopropyl) -NHCOEt,

-NHCOCH

2

NHCH

3

-NHCOCH

2

N(CO

2 t -Bu) CE 3 -NHCOCHzN (CH 3 2

-NHCOCH

2

CH

2 N (C 3 2

-NHCOCH

2

CH

2

CH

2 N (CH 3 2 -NHCO (cyclopropyl), -NECO (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 (CI-.

4 aliphatic) such as -NHiMe, S 10 -N(C 1 4 aliphatic) 2 such as -NMe 2 OH, -O(C 1 4 aliphatic) such as -OMe, C1-.

4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02 4 aliphatic).

Preferred R 8 groups of formula IVa, when present, include R, OR, and N(R)2. Examples of preferred

R

8 include methyl, ethyl, NH 2

NH

2

CH

2

CH

2 NH, 3

C

2

C

2

N,

N (CH3) 2CH 2

CH

2 O, (piperidin-1-yl)CH 2 CH20, and NH 2

CH

2

CH

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 C1-4 aliphatic group and Ry is 3 3 T-R or 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 RY are taken together with their intervening atomsto 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-

R

3 and each substitutable ring nitrogen of said OD -165o ring 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 k\ membered bicyclic aryl or heteroaryl ring; and

VO.

C

R

2 .is.-R or -T-W-R 6 and R 2 is hydrogen, or R 2 and O R 2 are taken together to form an optionally ID substituted benzo ring.

o 10 More preferred compounds of formula IVa 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 2 wherein R is selected from hydrogen,

C

1 -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, 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 bxo, 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 R4;

R

I 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 -166o (d).R 3 is selected from -halo, -OR, or wherein R is selected from hydrogen, C.I- Saliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or -N(R 4 Even more preferred compounds of formula IVa.

Ohave 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 CI and RY is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or R x 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, -C02R, -CON (R 4 2 -CN, -0O(CH 2 2-4-N(R 2 -0 (CH 2 2 4-R, -NO 2

-N(R)

2

-NR

4 COR, -NR 4

SO

2 R, or -SO 2 N(R) 2 wherein R is hydrogen or an optionally substituted Ci-6 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(R

4 2 optionally substituted Ci,- aliphatic, -OR,

-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

)COCH

2

N(R

4 2,

COCH

2

CHN(R

4 or COCCH 2

CHC

2 N(R4 2 \D -167- 0(c) R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a OI-6 aliphatic group, and R 2 is hydrogen; and R' is selected from or -N(R 4 2 wherein R is selected from hydrogen,

C

1 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered, I heterbaryl, and.L is or and Ring D is substituted by up-to three V. substituents selected from -halo, -CN, -NO 2 S 10 optionally substituted Cj- 6 aliphatic c group, -OR, -C -CO 2 R, -CONH(R' 4

-N(R

4

)COR,

-N(R COR, -S0 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 2 or

-N(R

6

COCH

2

CH

2

CH

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

Representative compounds of formula Iva are shown below in Table 9.

.Table 9.

-Me

H

H H HN HNi H HN NAc O

N

IVa-1 IVa-2 IVa-3 -168- Me HN <aN IVa-4 IVa-4 H NN 4 IVa-5

IH

HN'

S iOMe IVa-6 Me 6 H HN NN H N -7 IVa-7 fH HN3H

SN

IVa-8 IHN H N "N'Ac IVa-11 IVa-9 Me HN

H

HN IVa-12 IVa-12 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 heed of such a treatment a therapeutically effective amount of a compound of formula IVa or a pharmaceutical composition .0 thereof.

ii a 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 -169compound of formula IVa 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 ID administering to a patient in need of such a treatment a C- therapeutically effective amount of a compound of formula O IVa or a pharmaceutical composition thereof.

IND One aspect of this invention relates to a o 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 P-caterin, 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 -170- 0O 0a disease alleviated thereby, is preferably carried out with a preferred compound of formula IVa, as described Sabove.

Another embodiment of this invention relates to C i compounds of formula-IVb:

\O

IND R2 o

NH

IND HN N' S. zRX c

RY

IVb 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; Rx and R F 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,,i.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 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 ID -171from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon df 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; T is a.valence bond or a C 1 4 alkylidene chain;

IND

c Z is a C 1 4 alkylidene chain; o L is -SOz-, -N(R 6 )so 2

-SO

2

N(R

6

-CO

2 -N(R6)C(0)0-,

-N(R

6 )CON

-N(R)SO

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

-C(R

6

-C(R

6 )2S-, 2 SO-, -C(R')2s02-, -C(R)2SO 2 N(R) -C(R 6 )2N(R 6

-C(R

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

)=NN(R

6

-C(R)

2

N(R

6

)N(R

6 2

N(R

6

SO

2 or R and R 2 are independently selected from -T-W-R or R2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring.formed by SR2 and R 2 is independently substituted by halo, oxo, -CN, -NO 2 -R 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)

2 R, -SR,

-N(R

4 2 -CON(R) 2 -SOjN(R') 2 -N(R 7

)COR,

-N(R')C0 2

(C

1 6 aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R

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

CON(R')

2

-N(R')SO

2

N(R')

2

SO

2 R, or -OC(=0)N(R 7 2 each R is independently selected from hydrogen or an optionally substituted group selected from C 16 -172aliphatic, C6_,o aryl, a heteroaryl ring having ring'atoms, or a heterbcyclyl ring having s-io ring atoms; each R4 is independently selected from -COR 7 -CO2 (optionaily.. substituted C3-6 aliphatic), -CON (R) 2 or -SO 2 R7; 'each R5 is independently selected from halo, -OR,

-CO

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

-SO

2 R, -SR,

-N(R

4 2

-CON(R

4 2

-SO

2

N(R

4 2 -N(R4)COR, -N(R4) C02(optionally substituted

C

16 aliphatic), -N(Rt)N(R) 2

-C=N(R

4 2 -C=N-OR,

-N(R

4

CON(R

4 2

-N(R

4

)SO

2

N(R

4 2 -N(R)S0 2 R, or -OC(=O)N(R 4 2 V is -5,I -N(RS0 2 -1 -SO 2

-N(R

6 )s0 2

N(R

6

-OC(O)N(R

6

-C(R)

2 2

S-,

-C(R

6 2 s0-, -C(R6) 2 So 2

-C(R)

2

SO

2

-CR

6 2 2 -C(R6) 2 N(R)C(0)0o-, )6; -C(Rt)' 2 -C(R) 2

N(R

6 S02N(R6)-, or C (R6) 2 W -is -C(R 6 2 -C(Rt 2 2 SO-, C(R6) 2 so 2 _C.(Ro NR6) N (R6) 2!N C02

-C(R

6

-C(R

6 -C(R6) 2

N(R')CO-'

-C (R6) 2 -C (6)=NN(K 6 -0(R 6 -C(Rt) 2

N(R

6 -C(R6) 2 N(R6)So 2 4G C(R) 2N (R6) CON (R 6 each R6 is independently "elected from hydrogen or an optionally substitutedic..

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

C

16 aliphatic groupor two R 7 1. IND -173- 0 o on the same nitrogen ate taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and R is selected from halo, -OR,

-CO

2 R, -COCOR,

-NO

2 -CN, '-SO2R, -SR, -N(R) 2 -CON (R 4 2

-SO

2 2, R, -N(R 4 COR, 2 O, (optionally substituted C.1 aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R

4 2 -C=N-OR,

-N(R

4 -N SO 2 N (R) 2

-N(R')SO

2 R, or IN -OC(=O)N(R 4 2 o 10 Preferred rings formed by RX and RY of formula IVb include a or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said RXRY ring is optionally substituted. This provides a bicyclic ring ystem containing a pyrimidine ring. Preferred pyrimidihe ring systems of formila IVb are shown below.

R'

::NH HN HN3' z 2 ;t2 01 ZXO-I-R I rVb-A IVb-B IVb-C HN> HN> HN>2 R42 N 2 RCl2v ce 'N (XzZZ IVb-Df IVb-E IVb-F -174-

IO

0 ,2

HN

IVb-J 2? xS IVb -P IVb-K IVb-L

HN

IVb-R

HNA'

N N Z' 14

R

IVb-V

HN

z22 N I JI n 4 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

1 is nitrogen and Z 2 is CH.

Preferred RX.groups of formula IVb include hydrogen, alkyl- or dialkylamnino, acetamido, or a C 1 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 2 0- -CO- and R 3 is -R, -N(R or -OR. Examples of preferred RY groups include IO -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 INDor.dimethylamino, alkylt or dialkylaminoalkoxy such as C- dimethylaminopropyloxy, acetamido, optionally substituted o phenyl such as phenyl or halo-substituted phenyl' ND The ring formed when the RX and RY groups of o 10 formula IVba are taken together may be substituted or' unsubstituted. Suitable substituents include halo', -O (CH 2 2 -4 -N(R4.) 2 -O (CH 2 2

-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,

-SO2R, -SR, -N(R 4 2 -CON(R 2

-SO

2

N(R

4 2

-N(R

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

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

-C=NN(R

4 2

-C=N-OR,

-N CON 2

-N(R

4

SO

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

-CO

2 R, -CON(R')2, -CN, -O (CH2)2- 4 -N(R 4

-O(CH

2 )2_ 4

-NO

2 2

-NR

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

The R 2 and R 2 groups of formula IVb may be taken together to form a fused ring, thus providing a 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: -176-

NO

0

NNH

NH

HNr #N I I N 'N Z NH NH NH

NH

R Z O-R N ju 'N N' ,and \.9 Va c Preferred substituents on the R 2

/R

2 fused ring o of formula IVb include :one or more of the following: IND-halo,.

-N(R)

2

-C

1 4 alkyl, haloalkyl,

-NO

2

-O(C.

4 o alkyl), -C2 (C4 alkyl), -CN, -SO 2 (C-4 alkyl -S0 2

NH

2 -OC(0) NH 2 -NH2SO2 (C2- 4 alkyl), -NHC(O) (C.4 alkyl), -C NH 2 and -CO (CI4 alkyl), wherein the (C.4 alkyl) is astraight, branched, or cyclic alkyl group. Preferably, the (01-4 alkyl) group is methyl.

When the pyrazole ring.system of formula IVb is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 16 aliphatic group. Examples of such preferred R2 groups include hydrogen, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropy.

A

preferred R 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, benzolbJfuryl, benzo[b]thiopenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8 -naphthyridinyl and isoquinolinyl.

ID -177o On Ring D .of formula IVb, preferred T-Rsor V-Z-Rs substituents include -halo, -CN, -NO 2

-N(R

4 2 Soptionally substituted C 6 aliphatic group, -OR, -C(O)R,

-CO

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

)CO

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

-N(R

4

SO

2

-N(R

6 COCHN (R) 2

-N(R

6

COCH

2

CH

2 N(R4) and IND -N(R 6

COCH

2

CH

2

CH

2 N (R 4 2 wherein R is selected from C hydrogen, C.1-6 aliphatic, 'phenyl, a 5-6 membered 0 heteroaryl ring, or a 5-6 membered heterocyclic ring.

IND More preferred R 5 substituents include -Cl, -Br, -CN, o 10 -CF 3 -COOH, -CONHMe, -CONHEt, -NH 2 -NHAc, -NHSO 2 Me, Ci i i -NHS02Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NECOEt,

-NHCOCH

2

NHCH

3

-NHCOCH

2

N(CO

2 t-B) CH 3

-NHCOCH

2 N (CH 3 2

-NHCOCH

2

CH

2 N (CH 3 2, -NHCOCH 2

CH

2

CH

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

CH

2 CH2 (morpholin- 4-yl), -NHCO 2 (t-butyl), -NH(C.A4 aliphatic) such as -NHMe,

-N(C

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

(C

1 -4 aliphatic) Preferred R 8 groups of formula IVb, when present, include R, OR, And N(R 4 2 Examples of preferred Re include methyl, ethyl,; NH 2

NH

2

CH

2

C

2 NH, N (C 3 2

CH

2

CH

2

NH,

N(CH

3 2

CH

2

CH

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

CH

2 0, and NHCH 2

CH

2 0: Preferred formula IVb compounds have one or more, and more preferably all, of the features selected from the group consisting of: RXis hydrogen, alkyl- or dialkylamino, acetamido, or a 1

C

1 4 aliphatic group and R" is T-R or 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 RY are taken together with. their intervening atoms to form a fused, unsaturated or partially -178- D unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or Snitrogen, 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 ,R and R Y is independently substituted by R 4

R

1 is T- (Ring wherein T is a valence bond or S 10 a methylene unit; C Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyciic aryl or heteroaryl ring; and

R

2 is -R or -T-W-R 6 and R 2 is hydrogen, or'R 2 and

R

21 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 3 is selected from -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; or Rx 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 -179-

R

I 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

R

3 is selected from -halo, -OR, or -N(R 4 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 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

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, -CO 2

R,

-CON(R')

2 -CN, -O(CH 2 2 4

-N(R

4 2 -0(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 Cis aliphatic group;

O-IBO-

C R 1 is T-(Ring wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring Soptionally substituted with one or two groups selected from r -halo, -CN, -NO 2

-N(R

4 2 optionally substituted CI-6 aliphatic, -OR, O

-CO

2

-CONH(R

4

-N(R

4 COR, -N(R 4

)CO

2

R,

.D

-SO

2 N (R 4 2

-N(R

4

)SO

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

COCH

2

CH

2 N (R 4 2 or -N COCH2CH 2

CH

2 N (R 4 2; S R 2 is hydrogen or a substituted or unsubstituted 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, C1-6 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, -NO 2

-N(R

4 2 optionally substituted Ci-s aliphatic group, -OR, -CO 2 -CONH(R -N'(R 4

)COR,

-N(R

4

CO

2 R, -S0 2

N(R

4

-N(R

4

SO

2

R,

-N(R

6

COCH

2 N R 4 2

COCH

2

CH

2

N(R

4 2 or -N(R' COCH 2

CH

2

CH

2 N (R 4 2 wherein R is selected from hydrogen, 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

IND

IND

cIN Me HN<V'P H' N A IVb-1 Me

HNP

M~-4 HNr3H

NN

I Vb-2

HN

4

H.

Ivb-s IVb-3 IVb-E Me N~ OaNAc IVb-7 Me

HN<-PH

IVb-1Q HN JXH Tmb-s HN~ H H~ NAH IVb -11 i/b-sg IVb-12 **-182- 8 Me H H H HN HN HN S CN l ON CN m CN N 0 .N 0 jOrC IVb-13 IVb-14 C Me C H 0 HN IDO CN IVb-16 In another embbdiment, 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. IND -183- S.One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering Sblood 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 ND IVb or a.pharmaceutical'composition thereof. This method D is especially useful for diabetic patients. Another Smethod relates.to inhibiting the production of IND hyperphosphorylated Tau' protein, which is useful in 10 halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of P-catenin, which is useful for treating schizophrenia.r 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 sampie with the Aurora-2 or GSK-3 inhibitor of formula IVb, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.

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

Another embodiment of this invention relates to compounds of formula IVc: .D -184- SD

R

2 R2, J3NH HN N

SRK

_Ry Z! N-R IND

H

NO IVc or a pharmaceutically acceptable derivative or prodrug 0 'thereof, wherein: C

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, or Rx and R are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused 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 8-10membered 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 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; Va 0 ct ci Va Va cIN

IN

cIN -185- Z is a C1-4 alkylidene chain; L is

-SO

2 -N(R')S0 2

-SO

2

N(R

6 -CO02-, -N(R 6

-N(R

6

)SO

2

N(R

6

-N(R

6 .5 -C(O)N(R 6 -OC(o)N(R 6

-C(R

6

-C(R)

2

S-,

-C(RS)

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

SO

2

N(R

6

-C(R

6 2

N(R

6

-C(R

6 2

N(R

6

-C(R

6 2 -C(R)=NN(R 6 -C(R6) 2 N(R6)N(R6) C (R) 2 N(R) SO 2 N or -C (R 6 2 N (R6) CON (R 6

R

2 and R" are independently selected from -T-W-R 6 or R2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered,'unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen; oxygen, or sulfur, wherein each substititable ring carbon of said fused ring formed by R' and R" 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 R2 is independently substituted by R 4

R

3 is selected from -halo, -OR,

-CO

2

R,

-COCOR, -COCH2COR,

-NO

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

-N(R

4 2

-CON(R')

2

-SO

2

N(R)

2 -N(R 7

)COR,

-N(R 7 CO2 aliphatic), -N(R')N(R 4 2 -C=NN (R) 2 -C=N-OR, -N(R 7

)CON(R')

2

-N(R

7 S0 2 N (R7) 2

-N(R

4

)SO

2 R, or N (R 7 2; each R is independently selected from-hydrogen or an optionally substituted group selected from aliphatic, C5.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 -R7, -COR7, -CO2 (optionally substituted C.,5 aliphatic), -CON(R) 2 or -SO 2

R

7 IND -1867o each p is.-independently selected from halo, -OR, -Ck=O)R, -00 2 R, -COCOR, -CN, -SO 2 R, -'SR, -NCR 4 2 -CON(R 4 2

-SO

2

N(R

4 2 -NCR 4

COR,

-N (R 4 c0 2 (optionally substituted C 1 6 aliphatic), S -NCR 4

)N(R)

2

-C=NN(R*)

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

CON(

4 2 -N (Rt4)SO 2 NC(Rt4 2 -NCR 4

SQ

2 R, or -OC%=O)N(R 4 2 NOAt is SO-, -SO02-, -N(R')S0 2

SO

2 NRt-) -N(R -NCR)CO-, -NCR 6C(O)O-, -NC(R)CON(R) -NC(R6)so 2 N -NC(R)N o 10 -C N -OC N(p) (R 6) 2 -CCRt) 2

S-

-C CR') 20-, CR) 2S02-;' -C 2 S0 2 N R 6 -cCR') 2 N CR 6

C(R')

2

-CCR')

2 N(R6)Cc)o-, R5) -OC' N N(R6) C R 6 2

SO

2 or 2 CON (R6) is. W is -CC(Rh,O-, -C(R6) 2 -C (Rt6 2 80-1 -CCR56) 2 S0 2

-CCR)

2

SO

2 C (R )ZN (R6) CO C -(R)OC -C (R 6 )oc(0) N -C(R 6 2 NiR500C-, -CCRt) 2 NCR')CCO)O-, -CR6)

=N-O-,I

-CC(Rt) 2 NC(R5) NC(Rt-, -CC(R") 2 N (R6) S0 2

NC(R')-

2 N(Rt)CON(R')-, each R' is independently seled'ted from hydrogen or an optionally substituted -CI4 aliphatic group, or two'R 6 groups on the same'nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R' is independently' selected' from hydrogen or an *optionally substituted Cl-r aliphatic group, or toa 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, -CO 2 R, -COCOR,

-NO

2 -ON, -SCO)R, -SO 2 R, -SR, -NCR 4 2

-CONCR

4 2

-SO

2 NCRt4) 2 -OC -NC(Rt4COR, '-NC(R 4 C02CoPtionall1y.

-187substituted Ci-6 aliphatic) -N(R4)N(R 4 2

-C=NN(R

4 )2, -C=N-OR,

-N(R

4

)CON(R

4 2

SO

2

N(R

4 2

-N(R

4 SO 2 R, or

-OC(=O)N(R

4 2 Preferred rings formed by R x and R y of formula IVc 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 ringI system containing a pyridine ring.. Preferred pyridine ring systems of formula IVc are 10 shown below.

VO

VO

ID

ND

ci Ci rcl

H

IVc-A SHN3Z IVc-B IVc-C IVc-F R 4

N

R"*N.

IVc-D IVc-E IVc-J IVc-K IVc-L -188-

O

HN> HN> HN S %Z2 0 Z2S

N$

C-yZS' IVc-P IVc-R IVc-V Va

IN

HN'

Va z 2 N

Z

IVC-W

More preferre'd pyridine ring systems of formula IVc include IVc-A, IVc-B, IV-D, IVc-E, IVc-J, IVc-P, and IVc-V, most preferably IVc-A, IVc-B, IVc-D, IVc-E, and IVc-J. Even more preferred pyridine ring systems of formula IVc are those described above, wherein Z' is nitrogen and Z 2 is CH Preferred R groups of formula IVc include hydrogen, alkyl- or diAlkylamino, acetamido, or a c.

4 aliphatic group such a6 methyl, ethyl, cyclopropyl, or isopropyl.

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

(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, piperazinl, 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 v.0 -189o dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.

SThe ring formed when the RX and RY groups of formula Ive are taken together may- be substituted or unsubstituted. Suitable substituents include halo, IND-0

(CH

2 2-4-N(R 4 2

-O(CH

2 2 4 -OR, -N(R 4

(CH

2 2 4 -N (R 2 -N(R -(CH2) 2 -CO 2 R, -COCOR, -NO 2

-CN,

O

-SO

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

-CON(R

4 2

-SO

2

N(R)

2

-N(R

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

C

1 o .10 aliphatic) -N(R )N(R) 2

-C=N(R

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

SO

2

N(R

4 2

-N(R

4

)SO

2 R, or

-OC(=O)N(R

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

-CO

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

-O(CH

2 2 4

-NO

2

-N(R

4 2 -NR4COR, -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 R 2 groups of formula IVc may be taken together 'to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.

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

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

NH

HN N N N-zk\ N-"kN Rx NH NH NH NH Ry ZXN-R 1 eNN INi H ,and -190-

\O

0 Preferred substituents on the R/R' fused ring of formula IVc include one or more of the following: -halo, alkyl., -C,--4haloalkyl, -No2, -0(CI.4 alkyl), -CO 2 (C.4 alkyl) -CN, -SO 2 (C14 alkyl) -SONH 2 -OC(0)NH 2 -NH2SO 2

(C.

4 alkyl), -iHC(0) (CI-4 alkyl),

-C(O)NH

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

c When the pyrazole ring system of formula IVc is

NO

S .monocyclic, .preferred R 2 groups include hydtogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1-6 aliphatic group. Examples of such preferred R groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cydclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R 2 group is hydrogen.

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

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

On Ring D of formula IVc,'preferred.T-R 5 or V-Z-Rs substituents include -halo, -CN, -NO 2

-N(R)

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

-CO

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

-N(R

6

COCH

2

CH

2

CH

2 N (R 4 2 wherein. R is selected from.

hydrogen, C1_ aliphatic, phenyl, a 5-6 membered -191- Sheteroaryl ring, or a 5-6 membered heterocyclic ring.

SMore preferred R 5 substituents include -Cl, -Br, -cN, -CF3, -COOH, -CONHMe, -CONHEt, -NH 2 -NHAc, -NHSO 2 Me,

-NHSO

2 Et, -NHSOz(n-propyl), -NHS02(isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3

-NHCOCH

2

N(C

2 t-Bu) CH 3

-NHCOCH

2

N(CH

3 2

-NHCOCH

2

CH

2 N CH) 2

-NHCOCH

2

CH

2

CH

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

-NHCOCH

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

CH

2 (morpholin-4-y)

-NHCOCH

2

CH

2

CH

2 (morpholin- ID 4-yl), -NHCO 2 (t-butyl), -NH(C 1 4 aliphatic) such as -NHMe, S 10 -N(C 1 4 aliphatic)2. such as -NMe 2 OH, -O(Ci4 allphatic) such as -OMe, C1- 4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C 1 4 aliphatic) Preferred Re groups of formula IVc, when present, include R, OR, and N.(R4) 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(CH

3 2

CH

2

CH

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

CH

2 0, and NH 2

CH

2

CH

2 0.

Preferred formula IVc 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 and RY is

T-R

3 or L-Z-R 3 wherein T is a valence bond or a methylene and R3 is 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'-

R

3 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 0 d(d) R 2 is -R or -T-W-R 6 and R 2 is hydrogen, or R 2 and

R

2 are taken together to form an optionally \c substituted benzo ring.

o 10 More preferred compounds of formula IVc have

C

N 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, 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, thleno, 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

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, C

I

-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, ora. 5-6 membered heterocyclic.ring;and Va 0

IN

ci ci

IND

IND

-193- R? is selected from -halo, -OR, or wherein R is selected from hydrogen,

C,_

6 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 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, acetamido, optionally substituted phenyl, or methoxymethyl; or R 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, -CO 2

R,

-CON(R

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

-O(CH

2 2 4

-NO

2

-N(R

1 2

-NR

4 'COR, -NR 4

SO

2 R, or -SO 2

N(R

4 wherein R is hydrogen or an optionally substituted

C,-

6 aiiphatic group;

R

1 is T-(Ring wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroary1 ring optionally substituted with one or two groups selected from -halo, -CN, -NO 2

-N(R

4 2 optionally substituted C.-6 aliphatic,

-OR,

-CO

2 R, -CONH(R 4

-N(R

4 )COR, -N(R 4

CO

2

R,

-SO2N 2 SO2R -N(R 6 COCN 2, -N (R 6

COCH

2 Cw2N 2 or -N (R 6

COCH

2

CH

2

CH

2 N (R 4 2; \D -194-

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci-6 C 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 k\ membered heterocyclyl,. phenyl, or 5-6 membered heteroaryl, and L is or and o Ring D is substituted by up to three c0 substituents selected from -halo, -CN, -NO 2

SI

1 0 N(R 4 2 optionally substituted C 1 aliphatic group, -OR, -C02R, -CONH(R 4

-N(R

4

)COR,

-N(R

4

CO

2 R, -SO 2

N(R

4

-N(R

4

)SO

2

R,

-N COCH 2 N -N 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.e aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-.6 membered.

heterocyclic ring.

Representative compounds of formula IVc are shown below in Table li.

Table 11.

Me N N N N' SO2M H H H IVc-1 IVc-2 IVc-3 v. -195ci .Me TD IVc-4 IVc-5 IVc-6 SMe HN N HN HN 0

HH

H HH

H

IVc-7 IVc-8 IVc-9 Me HN2 N N '4Q HN N H IVc-1 IVc-12 In another embodiment, this invention provides a composition comprising a compound of formula Ie 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, Mner seto hsivninrltst me Ho of i h b t n Aur ra- aciHt in a -pa i n -196- Swhich method comprises administering to the patient a compound of formula IVc or a composition comprising said t 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.

ND 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.

S 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 a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IVc or a composition comprising said compound.

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

I

-197- Each of the aforementioned methods directed to the inhibition of AuroraL2 or GSK-3, or the treatment of Sa disease alleviated thereby, is preferably carried out Swith a preferred compound of .formula IVc, as described above.

Another embodiment of this invention relates to Scompounds of formula'IVd:

R

2 HN

-N

Rx Z2 R Z Q'-R 1 rvd or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Z ,is nitrogen or C-R 8 and'Z 2 is nitrogen or CH, wherein one of Z 1 or Z 2 is nitrogen; is selected from 2 1,2-cyclopropanediyl, 1,2cyclobutanediyl, or 1,'3-cyclobutanediyl; Rx 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 Rx and R Y is independently substituted by oxo, T-R or L-Z-R and each substitutable ring nitrogen of said ring :formed by Rx and R Y is independently substituted by R4; R is T- (Ring -198o 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, e'ygen or sulfur, wherein each INDsubstitutable ring carbon of Ring D is independently INO substituted by oxo, T-R5, 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 CL.

4 alkylidene chain, wherein w jhen Q' is -C(R 6 a methylene group of said C3.

4 alkylidene chain is optionally replaced by -N(R -CONH -NHCO-, -SO2-, -SO2NH-', -NHSO2-, -CO2-, -OC(D)NH-, or -NHCO 2 Z is a CI.

4 alkylidene chain; L is S0 2 -S0 2

N(R-,

-N(R

6

-CO

2 C

-N(R

6

CON(R

6 -N SO 2 N -N (R 6 )N (R 6 -C(0)N(R6) -OC(0) N(R 6

-C(R

6 2

-C(R

6 2

S-,

-C(R

6 )ZS0-, 2

SO

2

-C(R

6 2

S

2

N(R

6 2

N(R

6

-C(R

6 2

N(R

6

-C(R)=NN(R'

6 2

N(R

6

-C(R)

2 N(R')S0 2 or zN (R6) CON (R6) d

R

2 and R' are independently selected from -T-W-R 6 ,or

R

2 and R are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring 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 R2' is independently substituted by halo, oxo, -CN, -NO 2 -R or 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,

-CO

2

R,

-COCOR, -COCH4 2 00R, -NO 2 -ON, -S(O)R,-S)RSR -N (R 7 C0 2

(C

1 6 aliphatic). -N (R 4 N(R 4 2 -C=NN (Rt 2 -C=N-OR, -N(R'cNR), -N S0 2 -N (R 4

)SO

2 R, or c-e ach R'is independently selected from hydrogen or an o optionally- substituted group selecte'd from C1-6 aliphatic, C,5..Lo aryl, a heteroaryl ring -having 5-10 o0 ring 'atoms,, or a heterocyclyl ring having 5-10 ring atoms; ~each R 4 i s independently selecte.ed from -COR 7

-CO

2 (optionally subs tituted C1..6 aliphatic),I -CON (Rl) 2 Or -S0 2 R 7 each R 5 is independently selected from halo, '-OR, R, CO 2 -COCOR, -NO 2 -ON, S(0)2, -90 2 R, -SR., -U(R 4 b, -CON(R 4 2 1 -S0 2

N(R

4 2 -N(R4) CORI

-N(P

4 )CO2(optionally substituted CaG- aliphatic), -N (Rt)N (Rz) -C=NN(R 4 2 -C=N-OR,

-N(R

4

)ONR)

2 -N(R 4 S0 N(R 4 2 -N(R 4 So 2 R, or 2 V is -S02-, -N (R 6 S0 2

_SO

2

N(R)-

-CO-i -C0 2

-N.(R

6

-N(R

6 -N(R 6 CON (R 6 6 S0 2 N (R6) -N (Rt)N(R 6 -OC 2 6 2

S-,I

-C(R 6 2 S0-,

-C(R

6 %so 2 N2rz' -(R 6 )bNI C (R 6 -,6

-C(R

6

-C(RE)

2

N(R

6

-C(R

6 2

N(RS)SO

2 or C(R6) 2 N (R 6 CON (R 6 W is. -C (R 6 2 -dC.(R 6 2 -C(RW) 2so, -C (R 2 S0 2 -C 2 So 2 N _C (R 6 2 N (R 6 -C02-, -C (R 6 2 N(Ri) -C (R 6 -C (R 6 -200-

S-C(R'

2

N(R

6

)N(R

6

-C(R

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

N(R

6

)CON(R

6 or -CON(R 6 each R 6 is independently selected from hydrogen or an optionally substituted CI.4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken-together O with the nitrogen atom .to form a 5-6 membered IN heterocyclyl or heteroaryl ring; each R 6 is independently selected from hydrogen or a CI-4 Va aliphatic group, or two R 6 on the same carbon atom are

O

S 10 taken together to form a 3-6 membered carbocyclic ring; each R 7 is independently selected from hydrogen or an optionally substituted C.-l aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen' to form a 5-8 membered heterocyclyl or heteroary -ring; and

R

8 is selected from halo, -OR, -C02R, -COCOR,

-NO

2 -CN, -SO2R, -SR, -N(R 4 2

-CON(R

4 2 -S0 2

N(

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

-C=NN(R

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

)CON(R

4 2

-N(R

4

SO

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

Preferred rings formed by R x and R Y 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.

1.

-2 01-.

N

IVd-D HN3L *IVd-J

V

IVd-B rId- C IVd-E' lid-F IVd-L IVd-K lid-P

HN>?

N Z.~ '41

R

IVd-W IVd- R 4 rId-V i -202-

O

o More preferred 'pyridine ring systems of formula IVd.include IVd-A, IVd-B, IVd-D, IVd-E, IVd-J, IVd-P, and IVd-V, most preferably IVd-A, IVd-B, IVd-D, IVd-E, and IVd-J. Even more preferred pyridine ring systems of formula IVd include those described above, wherein Z 1 is IND nitrogen and Z 2 is CH.

Preferred RX groups of formiila'Ivd include hydrogen, alkyl- or dialkylamino, acetamido, or a C 1 -4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.

Preferred RY gtoups of formula IVd 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(k6) 2 -CO- and R 3 is -R, 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, alkox alkyl such as methoxymethyl or methoxyethyl,. alkyl- or dialkylamin& such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or 'halo-substituted phenyl.

The ring formed when the RX and RY groups of formula IVd are taken together may be substituted or unsubstituted. Suitable substituents include halo, -0 (CH 2 2 4 -N 2

-O(CH

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

(CH

2 2 4 -N(R4) 2

-N(R

4 (C1 2 2 4

-CO

2 R, COCOR,--NO 2

-CN,

-SO

2 R, -SR, -N(R 2 -CON(R 2 -S0 2

N(R

4 2

-N(R

4 )COR, -N(R',)CO 2 (optionally substituted C 1 aliphatic), -N(R )N(R 4 2 -C=NN(R4)2, -C=N-OR, -N (R 4 CON(R) 2

-N(R

4 )SOzNN (R) 2

SO

2 R, or -OC(=o)N(R) 2 R and R 4 are as defined above. Preferred RX/RY ring substituents include -halo, R, -OR, -COR, VO ID 0

IND

cI

VO

VO

ci ci -203-

-CO

2 R, -CON(R 4 2 -CN, -0 (CH 2 )2-4-N(R 4 2 -0 (CH 2 2 -4-R -NO 2 -N (R 4 2

-NR

4 COR, -NR 4

SO

2 R, -SO 2

N(R

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

The R 2 and R 2 The R 2 and Rgroups of formula IVd may be.

taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.

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

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

N

NH NH and Preferred substituents on the R 2

/R

2 fused ring of formula IVd include ohe or more of the following: -halo, -N(R 4 2 -Ci-4 alkyi, -Ci_ 4 haloalkyl,

-NO

2

-O(CI_

4 alkyl)., -C0 2 (CI alkyl), -SO2(CI- 4 alkyl), -SO2NH 2 -OC(0) NH 2

-NH

2 SO2 (CI.4 alkyl) -NHC (Cz-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 tmethyl.

When the pyrazole ring system of formula IVd is monocyclic, preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1- 6 aliphatic group. Examples of such preferred

R

2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl,. hydroxypropyl, -2 04-

NO

omethoxypropyl,'and benzyloxypropya. A preferred RP 21 group Is hydrogen.

When Ring D of formula IVd i s monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyi, and pytazinyl.

When Ring D of formula IVd is bicyclic,

IND

IND preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, 'indolinyl, benzo[blfuryl,.

o 1 benzo [b]jthiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, -quinazoliny'l, quinoxazolinyl, l,8-naphthy-ridinyl and isoguinolinyl.

oh Ring D of forrula-lvd, preferred T-R5 or

V-Z-R

5 'Substituerxts include -halo, -CN, -NO 2 -N(Rt4) 2 optionally substituted C 1 6 aliphatic group, -OR, -C(O)R,

-CO

2 R, -CONH(R 4 -N (R 4 COR, -kP(Rt4)c 2 R,-so 2

N(R

4 2 -N (R 4

SO

2 R, -N (R 6

COCH

2 N (R 4 2t -N (R 6 )-CoCH 2

CH

2 N (Rt) 2 and *N COCH 2

CH

2

CH

2 N (R 4) 2 wherein R is selected from hydrogen, 'C 16 aliphatic, phenyl, a .5-6 membered heteroaryl, ring, or -a 5-6 rnembered heterocyclic ring.

More pref erred R 5 substituents 'include -Cl, -Br, -CN, -CF3, -COON, -CONEMe, -CONHEt, NH 2 -NHAc, NHSQ 2 Me,

*-NHSO

2 Et, -NHS 2 (n-propyl), -NHS 2 (isopropyl), -NNCOEt,

-NHCOCH

2 NTHCH3, -NHCOCH 2

N-(CO

2 t-Bu) CII, -NNCOCH 2 N (Cm3) 2

-NHCOCH

2

CH

2 N 2

-NHCOCH

2

CH

2

CH

2 N (CH3-) 2 -~NCO cyiopopy),-NHICO(isobutyl), -NRCOC4 2 (morpholin-4yl),-NHQCHCH 2 (morpholin-4-Lyl)

-NHCOCH

2

CH

2

CH

2 (mophln 4 4-yl), -NHCO 2 (t-butyl) rNH (C 1 4 aliphatic) such as -NHMe, -N (C 1 4 aliphatic) 2 such as -N~e 2 OH, -o (c 1 4 aliphatic) such as -OMe, C 1 4 aliphatic such as methyl,'ethyl, cyclopropyl, isoprdpyl, o6rt-butyl, and -C0 2

C

1 4 aliphatic).

ID -205o Preferred R 8 groups of formula IVd, when present, include R, OR, andN'(R) 2 Examples of preferred

R

B include methyl, ethyl, NH 2 i NH 2

CH

2

CH

2 NH, N(CH 3 2 CH2CHNH,

N(CH

3 )2CH 2 CH20, (piperidin-l-yl)

CH

2 CH20, and NH 2

CH

2 .Preferred groups -of formula IVd include D -C(R6) 2 or 1,2-cyclopropanediyl, wherein each R 6 is

NO

C independently selected from hydrogen or methyl. A more o preferred Q' group is -CH2-.

IND Preferred formula IVd compounds have one or o 10 more,.and more-preferably, all, of the features selected from the group consisting of: Rx is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1 -4 aliphatic group and R Y 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

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 Rx and:RY is independently substituted by oxo, T-R 3 or L-Z-

R

3 and each substitutable ring nitrogen of said ring formed by Rx and R Y is independently substituted by R4;

R

1 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

2 is -R or -T-W-R and R 2 is hydrogen, or R 2 and R' are taken together to form an optionally substituted beizbo ring..- D -206- D More preferred compounds of formula IVd have one or more, and more preferably all, of the features Sselected from the group consisting of:

R

Y is T-R 3 or L-Z-R' 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- aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or Rx and R

Y

\0 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 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

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;

R

3 is selected from -halo, -OR, or -N(R 4 2 -wherein R is selected from hydrogen,

C

16 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.

V

\U -207o Even more preferred compounds of formula.IVd have one or more, and more preferably all, of the features selected from the group consisting of: Rx is hydrogen methyl, ethyl, propyl, cyclopropyl, -isoropyl, methylamino -or acetamido IND and RYis selected from 2-pyridyl 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, S piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, o 10 alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl;-or RX and RY are taken together with their intrvening atoms to form a benzo, pyrido, piperidino, or .cyclohexo ring, wherein said ring is. optionally substituted with -halo, -OR, -COR, -C02R, -CON(R) 2 -CN, -O(CH 2 )2- 4 2

-O(CH

2 -NO 2

N(R

4 2 -NRCOR, -NR 4

SO

2 R, or -SO 2

N(R

4 2 wherein- R is hydrogen or an optionally substituted Q..g aliphatic group;

R

1 is T-(Ring wherein T is a valence bond'and Ring D.is a.5-6 miembered aryl or heteroaryl ring optionally substituted with one or two groups selected from -halo, -CN, -NO 2 -N.(R4)2, optionally substituted C16s aliphatic,

-OR,

C(O)R,

-CO

2 R, -CONH(R N COR, -N(R 4 C0 2

R,

-SO

2 -N(R')S0 2 R, -N(R')COCH 2

N(R')

2 -N COCH 2

CH

2 N R 4 2 Or -N(R 6

)COCH

2

CH

2

CIN(R')

2

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or-a Ci-s aliphatic group, 'and R 2 'is hydrogen; and

R

3 is selected from -OR, or -N(R wherein R is selected from hydrogen,' Cr-6. aliphatic, .5-6 -208membered 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(R4).

2 optionally substituted C,_6 aliphatic S group, -OR, -CO 2 R, -CONH(R), -N(R')COR, O.

N(R

4

)CO

2 R, -SO 2

-N(R

4

)SO

2

R,

-N COCH 2 N (R 4 2 1 -N (R 6

COCH

2

CH

2 N 2 or -N (R 6 COCHzCH 2

C

2 (R 2 wherein R is selected from hydrogen, C 16 aliphatic, phenyl, a 5-6 c .membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and Q' is -CH 2 Representative .compounds of formula Ivd are shown below in Table 12.

Table 12.

Hv- H iI~- H

HN

4 HN 0 C) INN 0-O IVd-1 IVd-2 IVd-3 Me Me Me CNH H HN H HN H HNJ' i S CI O O C IVd-4 *IVd-5 IVd-6 OD -209o Me Me H

H

IVd-7 IVd-8

VO

VO

eg In-another embodiment, this invention provides a composition comprising a compound of formula IVd and a \O pharmaceutically acceptable carrier.

SAnother 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 comprisesadministering to a patient in need of such a treatment a therapeutically effective amount of-a compound of formula IVd or a pharmaceuticai 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 -210o 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 irelates to inhibiting the ID phosphorylation of P-catenin, which is useful for IC treating schizophrenia.

Another aspect 'of this invention relates to a D method of inhibiting GSK-3 activity in a patient, which o 10 method comprises administering to the patient a compound of formula IVd or a composition comprising said compound.

Another method irelates 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 compositi6n 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.

ID -211- O Scheme I SR2

R

2 CI H NH

N

SR

Y C1 H2' R

Y

C+ Y H C• R Q.R IN 1 -N -R 1 1 2 3

II

IND Reagents: EtOH, Et3N', room temperature; R'-QH (Q o S, NH or O) or R 1 -CH2-M/catalyst (M is Al or Mg or-Sn, Ci catalyst =Pd° or Ni°) Scheme I above shows a general route for the preparation of the present compounds. The dichlorinated starting material 1 may be prepared using methods similar to. the those reported in J. Indian. Chem. Soc., 61, .690- 693 (1984) or in J. Med.-Chem., 37, 3828-3833 (1994).

The reaction of 1 with aminopyrazole (or aminoindazole) 2 in a manner as described in Bioorg. Med. Chem. Lett, 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) (0-Link) or Bioorg. Med. Chem. Lett, 8, 20, 2891-2896, (1998).(C- Link).

.O -212- 0 Scheme II ci

R

2

R

OH CI

R

2

HN

Rx N R N 2 b R x

N

Y RN' Q-R

R

Y

NQ-R

1 H RN R' N 0Q 4 .5 2 II ci c Reagents: POC1 3 Pr 3 110C; 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 6his 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, 703-706 (2000) (S-Link), or J. Med. Chem., 41, 21, 4021-4035 (1998) (C- Link).

-213- Scheme III

OH

Rx

N

RY N S-Me 6 CI a R N M R N S -Me R2,

R

2 H N

H

2

N

b

R

2 R fH

HN-N

R N 'S-Me 8

R

2

R

2 r HN

N

RX SMe R N '-Me 0t) d 2 R 2

IHN

R

Y N" Q-R'

II

Reagents: (a).POC1 3 EtOH, Et 3 N, room temperature; (c) Oxone; R-QH (Q S, NH or O) or R'-CH 2 -M/catalyst

(M

is Al or Mg or Sn, catalyst. Pd or Ni Scheme III above shows another-alternative route for preparing the present compounds. The starting material 6 may be .chlorinated to provide intermediate 7.

Displacement of the 4-chloro group in 7 with aminopyrazole (or aminoindazole) 2 gives intermediate 8 which, upon oxidation of the methylsulfanyl group, provides the methylsulfonL 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).

S -214o Scheme IV ci

S

OH Rx C1 R2 H N H R N a N H b-

R

HO NS-Me CI N S-Me HNN Cl N S.Me vO 1 11 2 12 IO R2 R2 R2 R2

R

S tH tN teete HN-N d HN e

HN"N

RrN RXN NRXtN Ry NY S -Me RYN Me R 'N Q-R 13 14 II Reagents: POCl 3 EtOH, Et 3 N, room temperature; (c) RY-H (R S, NH or oxone; R'-QH S, NH or 0) or R-CH 2 -M/catalyst (M is Al or Mg or Sn, catalyst Pd° or Ni°) Scheme IV above shows a general route for the preparation of 'the present compounds wherein R y 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 2585906 (ICI, 1949). The methylsulfanyl group of 13 may then be oxidized to provide the methylsulfone 14. Displacement of the methylsulfonyl group of 14 gives the desired product II -215- Scheme V

VO

VO

ID

ND

ND

rcl CIl 1CI 17 R. R 2 H2N

N

2 2

NH

2 a a -h 1 b

R

2 HN RY N Q-R'

IV

2' R 2 R2 R t H R 2' RX. N R b

HN

Ry Cl R Y Q-R1 18

IV

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 19 a 19 R R b SRK N C1 ,Al Me"

'NH

2 2 0 R6' R 6

R

1

NH

2

NH

21 IND -216- D Scheme VI above shows a general route for preparing the aryl guanidine intermediate used to prepare t compounds where Q is -C(R 6 2 The mono- or bisalkylation of 19 at step to prepare compound 20 can be achieved by using methods substantially similar to .O those described by Jeffery, J. et al, J. Chem Soc, I Perkin Trans 1, 1996 (21) 2583-2589; Gnecco, et al, S Org Prep Proced Int, 1996, 28 478-480; Fedorynski, SM. and Jonczyk, Org Prep Proced Int, 1995, 27 355-359; Suzuki, S, et al, Can J Chem, 1994, 71 357- S" 361; and Prasad, et, al, .J Org Chem, 1991, (25),.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

O

HNH2 C a NHb.

,ftNH2

NH

22 23 24 0

CI

26 Scheme VII above shows a.general method that may be used to prepare compounds of formula II wherein Q ID -217is 1,2-cyclopropanediyl. Compound 26 may then be used to prepare the desired amino-pyrazole compounds using the methods described above at Scheme I step Method A. To a solution of 2,4dichloroquinazoline (12.69g, 63mmol) and 3-amino-smethylpyrazole (6.189, 63mmol) in ethanol (220mL) is added triethylamine (8.13mL, 63mmol) and the reaction mixture is stirred-for 3 hours at room temperature. The S pale yellow precipitate is then collected by filtration, 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 (1mL/3mL).

KCO

3 (83 mg, 0.6 mmol-) is added and the suspension is stirredl for 2h at room temperature.

The solid that forms is collected and dried under vacuum to give the product chlorophenylamino)-quinazolin- 4-yl'- (5-methyl-2H-pyrazol-3-yl) -amine.

Method B. SodiuSm hydride (45 mg, 1.12 mmol) in THF (2 mL) is treated with 3-methoxyphenol (0.94g, 7.6 mmol) and the reaction mixture is stirred until effervescence ceases. The THF is removed in vacuo and the above-prepared. 2 -chloroquinazolin-4-yl) 2 H-pyrazol-3-yl).-amine (150 mg, 0.51 mmol)) is added.

The reaction mixture is stirred at l00C for 20 h,.then poured into aqueous K2CO3 and stirred for 2h at room temperature. The solid.that forms is collected and recrystallized from ethanol 'to'give the product ION -218o methoxyphenoxy) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3yl)-amine.

Method C. To a solution of 4-hydroxy-2phenoxymethylquinazol'ine (2 g, 7.93 mmol) in phosphorus oxychloride. (10mL) is added,-tripropylamine (3.02 mL, 15.8 ID mmol) and the reaction mixture is heated for 30 minutes at 110 0 C. The excess phosphorus oxychloride is evaporated in vacuo, the-residue is poured on ice cold I aqueous NaHCO 3 and extracted with ethyl acetate. The S 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 NiC1 2 (dppp) (12 mg, 2.I.10-s mol), followed by IM benizylmagnesium chloride in THF (2.15 mL, 2.15 mmol).

The 'solution is heateddat 5000 .for 20-hours and the reaction mixture is then quenched with aqueous NHI 4 C1 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-21H-pyrazol-3-yl)-amine.

IND -219- Method E. A solution of (2-chloroquinazolin-4yl)-(5-methyl-2H-pyrazol-3-yl).-amine (200 mg, 0.77 mmol) and 4-acetamidothiophenol (644 mg, 3.85 mmol) is refluxed in tert-butanol (3 mL) over a 20 hour period.

Diethylether (10 mtL) is added to the mixture and a solid NO forms that is collected by filtration. This solid is

IND

Ci suspended in EtOH/B20 lmL/3mL), then K2C03 (110 mg, 0.8 o mmol) is added and the suspension is stirred for 2h at V. room temperature. A solid forms and is collected and o 10 dried under vacuum to give the' product (4acetamidophenylsulfanyl) -quinazolin-4-yl] (5-Tmethyl-2Hpyrazol-3-yl)-amine.

Method F. -To a solution of 2,4-dichloro- 5,6,7,8-tetrahydroquinazoline (500 mg, 2.46 mmol) and 3amino-5-cyclopropylpyrazole (303 mg, 2.46 mmol) in DMF is added triethylamine (0.357 mL, 2.56 mmol) followed by sodium iodide (368 mg, 2.46 mmol) and the reaction mixture is.heated at 90 OC for 20 h. The -reaction mixture is partitioned between ethyl acetate and aqueous saturated NaHC 3 The organic layer is washed with brine and evaporated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/AcOEt gradient) to give (2-chloro-5,6,7,8-tetrahydroquinazolin- 4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

The above-prepared (2-chloro-5,6,7,8tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3yl)-amine is reacted with 2-naphthalene mercaptan as described in Method L to.yield the desired cyclopropyl-2H-pyrazol-3-yl).-[2-(naphthalen-2ylsulfanyl) 8-tetrahydroquinazolin-4-yl] -amine.

Method G. A solution of (5-cyclopropyl-2Hpyrazol-3-yl) [2-(3-methoxycarbonylphenylsulfanyl)quinazolin-4-yl]-amine .(110 mg, 0.26 mmol) in a mixture -220of THF/water (1/1,.10 mL) is treated with IM LiOH (0.75 mL, 0.75 mmol). The mixture is stirred for 20 hours at room temperature and then neutralized with iM HC1 (0.75 mL, 0.75 mmol). A solid forms and is collected by -filtration to afford the desired MD D 2H-pyrazol-3-yl) -amine.

Method H. A.solution of Sacetamidophenylsulfanyl) -7-methoxy-quinazolin-4-yl] methiyl-2H-pyrazol-3-yl)-amine (23 mg, 5.54.10-5 mol) in dichioroethane (3.mL) is- treated with 1M BBr 3 in dichloromethane (222 JLL, 2.21.10-4 mol). The-mixture os heated at 80 OC for 4 hours before 1M BBr 3 in DCM (222 pL, 2.21.104 mol) is added. The reaction mixture is heated at 80 OC for a further3 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 colledted by filtration and suspended in a-mixture water/EtOH 8 mtL). The mixture is neutralized with NaHCO 3 and stirred for 2.hours at room temperature. The solid is then collected by filtration, rinsed with water and diethyl ether to give the desired [2-(4-acetamidophenylsulfanyl)- 7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)amine.

Method I. To 'a solution of acetamidophenylsulfanyl)- 7 -hydroxy-quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-amine (32 mg, 7.87.10.mol) in DMF (1 mL) is added potassium carbonate (65 mg, 4.72.10-4 mol) and the reaction mixture is heated to 80 OC. N-(3- Va 0 0O ci ci -221chloropropyl)morpholine (39 mg, 2.36.10"- 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 des'ired 2 -(4-acetamidophenylsulfanyl)-7- (3-morpholin-4-yl-propoxy) -quinazolin-4-yl] (5-methyl-2 Hpyrazol-3-yl) -amine.

Method J. To a solution of [2-(4-acetamidophenylsulfanyl) 7 -nitroquinazolin-4-yl] (5-methyl-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 [2-(4-acetamido-phenylsulfanyl) -7hydroxyaminoquinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl) amine.

Method K. .[2-(4-Acetamido-phenylsulfanyl)-7nitroquinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl) -amine (182 mg, 4.18.10' 4 mol) is dissolved in a mixture EtOH/water/AcOH (25/10/1, 36 mL).and the reaction is heated at 90 OC. Iron powder (93 mg) is added and the mixture is stirred at 90 °C for 4 hours, cooled to room temperature and filtered through a pad of celite. The pad is washed with methanol and the combined filtrate is concentrated in vacuo. The residue is purified by flash chromatography (Si0 2 DCM/MeOH gradient) to give the desired 4 -acetamido-phenylsulfanyl)-7aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

-222-

ID

D Method L. To a solution of 2,4-dichloro-6phenyl-pyrimidine (300 mg,. 1.33 mmol). and 3-amino-S- Smethylpyrazole (129 mg, 1.33 mmol) in DMF (7 mL) is added triethylamine (195 IL, 1.40 mmol) followed by sodium iodide (200 mg, 1.33 mmol) and the reaction mixture is ND stirred for 15 hours at 90 OC. The- resulting solution is Cq partitioned between ethyl acetate and water and the o organic phase washed with brine, dried over MgS0 4 then IND concentrated in vacuo. The residue is triturated in i methanol and the resulting white solid collected by filtration to afford (2-chloro-6-phenyl-pyrimidin-4-yl)- 2H-pyrazol-3-yl)-amine (236 mg, 62%).

The above prepared (2-chloro-6-phenylpyrimidin-4-yl)-(5-methyl-2H-pyrazoi-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 (SiO2, 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 4,6- Sdihydroxymercaptopyrimidine (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..

'1IUVU-lrlllLIV IND -223- 0 The above-prepared 4,6-dihydroxy-2-(4-methoxybenzylsulfanyl)-pyrimidine (2.5 g, 9.46 mmol) is E suspended in POC1 3 (20 mL), and tripropylamine (3.60 mL, S 18.9 mmol) is added dropwise to the mixture. T he S reaction is then heated at 110 oC for 4 hours. The brown I 1solution is cooled-to room temperature and the solvent is ci evaporated. The residue is poured on ice cold NaHCO 3 and o the product is then extracted with ethyl acetate. The IDorganic phase is dried over MgSO 4 concentrated in vacuo S 10 and the residue is purified by flash chromatography (SiO 2 hexane/AcOEt gradient) to give 4,6-dichloro-2-(4-methoxy-.

benzylsulfanyl)-pyrimidine.

To a solution of above-prepared 4,6-dichloro-2- (4-methoxy-benzy1sulfanyl)-pyrimidine (915 mg, 3.04 mmol) and 3-amino-5-methylpyrazole (310 mg, 3.19 mmol)'-in BuOH mL) is added diisopr'opylethylamine (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 (Si0 2 hexane/AcOEt gardient) to give [6-chloro-2-(4-methoxy-benzy1sulfanyl)-pyrimidin-4yl) (5-methyl-2H-pyrazol'-3-yl) -amine.

The above-prepared [6-chloro-2-(4-methoxybenzylsulfanyl)-pyrimidin-4-yl)-(-methyl-2H-pyrazol-3yl)-amine (500 mg, 1.38 inmol) 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 (Sib 2 dichloromethane/MeOH gradient) to give the desired product [2-(4-methoxybenzylsulfanyl)- 6-(4-methylpiperazin-1-yl)-pyrimidin-4yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

Method N. .A solution of (4-acetamido-.

phenyl-sulfanyl) -6-.(4-methoxyphenyl) -pyrimidin-4-yl]- IND -224- 0 methyl-2H-pyrazol-3-yl)-amine (100 mg, -2.24.10-.mol) in.

dichloroethane (5 mL) is treated with IM BBr 3 in DCM (896 8.96.10- mol). The mixture is then heated at80 C for 4 hours before 1M BBr 2 in DCM (896. gL, 8.96.10-4. mol) is added. The reaction mixteure is then heated at 80 OC I NOfor a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench any residual 0; BBr 3 The solvent is eiaporated in vacuo and this evaporation step is repeated 3 times. 1MHC1(8-mL) is added.to the solid residue and the suspension is stirred at room temperature for. 15 hours. The solid is collected by filtration and suspended'in a mixture of water/EtOH- 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-2S-pyrazol-3yl)-amine.

To a solution of the above-prepared 12-(4acetamido-phenyl sulfanyl) 6 (4-hydroxyphenyl) -pytimidin- 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (70 mg, 1.62.10-4 mel) in DMF (3 mL) is added potassium carbonate (134 mg, 9.71.10-4 mel). The reaction mixture is heated to80 0

C

before 1-dimethylamino-3-chloropropane hydrochloride (77 mg, 4.86.10-4 mel) is added. The mixture is stirred at 0 C for 4 hours, cooled to room temperature and the solvent is evaporated. The residue is purified by flash chromatography to afford the desired product. acetamido-phenyl-sulfanyl)-6- 14-(3-dimethylaminopropoxy)-phenyl -pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3yl)-amine.

Method O. To .a solution of [6-methoxycarbonyl- 2- (4-propionylamino-phenyl-sulftanyl) -pyrimidin-4-yl] NO -225- 0 methyl-2H-pyrazol-3-yl)-amine (2g, 4.85 mmol) in THF (100 mL) is added lithium borohydride (0.32.g, 14.5 mmol) The reaction mixture is stirred at 50C for 1.5 hours.

The reaction is then quenched with dilute HC1 and extracted with ethyl acetate. The organic layer is INDsuccessively.washed with aqueous saturated NaHCO 3 and (N brine, dried over MgSO 4 and evaporated. The solid residue Sis triturated in ethyl acetate and the resulting white solid is collected by filtration to give the desired 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-2methylsulfanyl-pyrimidine (S5 g, 25.6 mmol) and methylpyrazole 2.sl g, 26.9 inmol) 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, hexane/AcOEt gradient) to give [6-chloro-2-methylsulfanyl-pyrimidin-4-yl) (5-methyl-2Hpyrazol-3-yl)-amine.

The above-prepared [6-chloto-2-methylsulfanylpyrimidin-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. 12-methylsulfanyl-6-(morpholin-4-yl)pyrimidin-4-ylJ-(5-methyl-2H-pyrazol-3-yl)-amine.

To a suspension of the- above-prepared [2methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(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 D -226- C mL). The reaction mixture is stirred at room temperature for 15 hours and most of the solvent is evaporated. The Sresidue is partitioned between DCM and aqueous saturated NaHC03. The organic layer is washed with brine, dried, filtered and evaporated. The residue is triturated in QD MeOH and the resulting white-solid is collected by

\O

filtration to give [2-methylsulfonyl-6-(morpholin-4-yl)- C pyrimidin-4-yl] (5-methyl-2H-pyrazol-3-yl).-amine.

D "The above-prepared [2-methylsulfonyl-6o 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 NaHCO 3 The organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo.. The residue is purified by flash chromatography to give the desired product [2-(4-acetamidophenylsulfanyl)-6-(morpholin-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.

~-IU~Yrl~'lL~V S-227- 0 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) 0D over 4.0 min, hold at 100% acetonitrile for 1.4 min and return to initial conditions. Total run time o min. Flow rate: 0.8 mL/min.

o 10 HPLC-Method B: Column: C18, 5 urn, 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 S(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 2.0x5Omm, S5, 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 ND -228- S0.8 min and return to initial conditions. Total run time 7.0 min.

Flow rate: 1.0 mL/min.

HPLC-Method E: Column: 50x20.Omm Hypersil C18 BDS;5 gm Gradient: elution 100% water TFA), to 5% water TFA), 95% acetonitrile (containing 0.1% TFA) N over 2.1 min, returning to initial conditions after .10 2.3 min.

Flow rate: 1 mL/min.

Example 1 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylsulfanylquinazolin-4-yl)-amine (Ila-1): Prepared in a manner similar to the above described Method E to afford a pale yellow sdlid, mp >300 0 C H NMR (DMSO) B 2.07(3H, 5.54(1H, 7.38(1H, tm), 7.56-7.45(4H, 7.65(2H, in), 7.73 (1K, 8.55(1H, 10.43(1H, 12.05(1H, br IR (solid) 3259, 3170, 3109, 1618, 1594, 1565, 1525, 1476; MS 334.0 Example 2 4 -Chlorophenylsulfanyl) -quinazolin-4-yl] (5-methyl-2H-pyrazo-3-yl)-amine Prepared in a manner similar to the above described Method*E to afford a pale yellow solid, mp 259-2600C; 1 H NMR (DMSO) 8 2.12 (3H, 5.40 (1K, 7.60 (1H, 7.64 (2K, 7.76 (3H, 7.92 (1H, 8.70 (1H, d) 11.50 (1H, br IR (solid) 1627, 1606, 1557, 1484, 1473, 1433, 1400, 1339, 1286, 1219; MS 368.0 Example 3 2 2 ,4-Dichlorophenyisulfanyl)-quinazolin-4yl]-(5-methyl-2-pyrazol-3-yl)-amine (IIa-3): Prepared in o -229- 0 C a manner similar to the above described Method E to- C afford a pale yellow solid, mp 258-259OC; 'H NMR (DMSO) 6 2.12 (3H, 5.40 (1H, 7.54 (11, 7.63 (1H,m), Cl 7.68 (1H, 7.86 (IH, 7.92 (1H, 7.96 (1H, 8.66 (1H, d) 11.20 (11, br IR (solid) 1623, 1610, ND 1551, 1488, 1435, 1410, 1339, 1284, 1217; MS 402.0

NO

Cl Example 4 4 -Methoxypheny1sulfanyl) -quinazolin-4-yl]- S(5-methyl-2a-pyrazol-3-yl)-amine (IIa-4): Prepared in a q 10 manner similar to the above described Method E to afford a pale yellow solid, mp 264-268 0 C; 'H NMR (DMSO) 6 2.04 (3H, 3.85 (3H, 5.43 (1H, 7.12 (2H, 7.53 (1u, 7.61 (3H, 7.84 (3H, 8.63 (IH, 11.09 (1H, br 12.30 br IR (solid) 1622, 1598, 1552, 1492, 1404, 1340, 1292, 1249, 1219,.1171, 1161; MS 364.1 (M+H) Example 5 2 methyl-2H-pyrazol-3-yl)-amine (IIa-5): Prepared in a.

manner similar to the above described Method E to afford a pale yellow..solid, mp 205-2080C; 1H NMR (DMSO) 6 2.05 (3H, 5.19 (1H, 7.38 (1H, t),.7.52-7.64 (3H, m), 7.68 (2H, 7.90 (1H, 8.68 (1H, IR (solid) 3262, 2967, 1632, 1605, 1558, 1492, 1434, 1403,_ 1344, 1294, 1224, 1162; MS 362.1 Example 6 {2-[2,4-Bis(trifluoromethyl)phenylsulfanyl]quinazolin-4-yl)-.(5-methyl-2 H-pyrazol-3.-yl)-amine (IIa-6): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp >300 0 C; 1H NMR (DMSO) 6 1.98 5.37 (1H, 7.50 (1l, 7.59 (2H, 7.84 (1H, 8.32 (1H, 8.40 -230- (2H, 8.66 (1H, 10.73 (1H, br-s);.IR (solid) .1628, 1603, 1577, 1548, 1512,.1493, 1448, 1417, 1354, 1275, 1196, 1124; MS 470.1 (M+H)4 Example 7 2 -Chlorophenylsufany)-quinazolin-4-ylp- IND(5-methyl-2H-pyrazol-3.yl)-amine (IIa-7): Prepared in a IDmanner similar to the above described Method E to afford o a pale yellow solid, mp 262-2630C; 1H NMR (DMSO) 8 2.05 \D (3H, s),5.35 (1H, 7.52 (2H, 7.65 (2H, 7.74 o 10 (1H, 7.83 (1H, 7.88 (1Hi, 8.62 10.97 (1H, br IR (solid) 1621,.1603, 1569, 1544, 1491.

1448, 1400, 1376, 1336, i288, 1208; MS 368.0 (M+H) Example 8 [2-(2,3-Dichlorophenylsulfanyl)-quinazolin-4yl]- (5-methyl-2H-pyrazol-3-yl)-amine (IIa-8): Prepared in a manner similar to t e above described Method E to afford a pale yellow solid, mp >300 0 C; 1H NMR (DMi4SO) S 2.05 (3H, 5.34 (1H, 7.50 (2H, 7.60 (IH, d), 7.75 (1i, 7.88 (2H, 8.62 (11, 10.72 (1H, br IR (solid) 1632, 1609, 1561, 1532, 1492, 1432, 1400, 1380, 1345, 1298, 1228, 1162, 1125; MS 402.0 4 Example 9 .2-(3-Chlorophenylsulfanyl) -quinazolin-4-yl3 (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; 1'H NMR (DMSO) 8 2.05 (3H, 5.42 (11, s)A 7.55 (2H, 7.66 (3H, 7.81 (1H, 7.85 (1H, 8.62 (1H, d),.11.10 (1H, br IR (solid) 1628, 1611, 1551, 1487, 1432, 1410, 1341, 1292, 1217, 1165; MS 368.0 (M+H) 4 -1 -~C IN -231- Ci Example 10 [2-(1-Methylimidazol-2-ylsulfanyl)-quinazolin- 4-yl]-(5-methyl-23-pyrazol-3-yl)-amine (Ila-lO): Prepared in a manner similar to the above described Method E to c afford an off white solid, mp 255-2560C; H NMR (DMSO) B 2.19 (3H, 3.59 (1H, s),"5.51 7.18 (1H, s), y 7.45 (1H, t),.7.57 (IH, 7.59 (IH, 7.77 (1H, t), 8.57 (IH, 10.57 (1H, 12.13 (1H, br IR (solid) 0 1628, 1565, 1550, 1532, 1492, 1430, 1376, 1333, 1292, ci o 1278, 1211; MS 338.2 0 Example 11 E2-(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 273-275 0 C; :H NMR (DMSO) 6 2.06 (3H, 5.41 (IH, 6.99 (1H, 7.07. (18, 7.50 (1H, 7.57-7.62 (2H, 7.73 (1i, 7.94 (1H, t), 8.71 (1H, 10.29 (1H, br 11.66 (18, br IR- (solid) 1623, 1597, 1552; 1485, 1442, 1404, 1354, 1341, 1289, 1221, 1165; MS 350.1 (M+H) 4 Example 12 [2-(2,4-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 olid,. mp 256-2580C; 1H NMR (DMSO) 2.10 (3H, 5.41 (18, 7.33 (1H, 7.51-7.58 (2H, 7.65 (1H, 7.82-7.91 (2H, 8.63 11.06 (1H, br IR (solid) 1626, 1608, 1556, 1482, 1409, 1341, 1288, 1270, 1219, 1162, 1140; MS 370.1 Example 13 [2-(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 229-2320C;-H NMR (DMSO) IN -232o 2.05 (3H, 3.70 (3H, 3.85 5.39 (1H, s), 6.95 (11, 7.30 (2H, 7.60 7.77 (11, 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, 1137- MS 394.1 Va Example 14 [2-(3-Methylphenylsulfanyl)-guinazolin-4-yllo (5-methyl-2H-pyrazol-3-yl)-amine (IIa-14): Prepared in a ND manner similar to the above described Method E to afford o o 10 a pale yellow solid, mp 249-2500C; 1 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 (1H, 8.68(1H, d), 11.66 (1H, br IR (solid) 1617, 1587, 1558, 1496, 14414, 1387, 1341, 1283, 1221, 1162, 1140; MS 348.1 .Example 15 [2-(2-Methoxyphenylsulfanyl)-quinazolin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (Ia-15): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp,237-239 0 C; 1H NMR (DMS0) 8 2.07 (3H, 3.71 5.35 (1H, 7.12 (1H, 7.23 (11, 7.55 (i1, 7.60-7.67 (3H, 7.87 (11, t), 8.66 (1H, 11.20'(1H, br IR (solid) 1632, 1606, 1561, 1480, 1430, 1405, 1344, 1292, 1276, 1251,.1224; MS 364.1 Example 16 12-(2-Naphthalenylsulfanyl)-quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl)-amine (IEa-16): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 267-270 0 C; 1H NMR (DMSO) 6 2.05 (3H, 5.09 (11, 7.57 (1H, 762-7.75 (4H, m), 7.90 (in, 8.07 (3H, It), 8.40 (1H, 8.66 d), -233- Cl 11.28 (1H, br IR (solid) 1624, 1606, 1550, 1487, 1435, 1407, 1341, 1285, '1216, 1158; MS 384-.1 (M+H)4 Cl Example 17 [2-(2,6-Dichlorophenylsulfanyl) -quinazolin-4-, yl]- (5-methyl-2H-pyrazol--3-yl) -amine (IIa-17): Prepared INin a manner similar to the above described Method E to afford a pale brown solid, mp >300WC; 1H NMR (DMSO) 8 2.11 0 (3H, 5.49 (1H, 7.49 (1H, 7.59-7.67 (2H, m), o 7.76 (2H, 7.81 (1H, 8.60 (11, 10.60 (1H, s); Cl 10 IR (solid) 1618, 1599, 1565, 1533, 1486, 1424,-1401, 1361, 1344, 1285, 1246, 1216, 1188, 1172; MS 402.0 (M+H) 4 Example 18 2 -(3,4-Dichlorophenylsulfanyl)-quinazolin-4ylJ (5-methyl-2H-pyrazol-3-yl)-amine (IIa-18): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 268-272-C;-1H NMR (DMSO) 6 2.11 (3H, 5.47 (1H, s),;7.56 (IH, 7.68-7.72 (2H, 7.83 (21, 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 (M+H) 4 Example 19 [2-(Benzimidazol-2-ylsulfanyl)-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 solid6, mp 192-196 0 C; H NMR (DMSO) 6 1.60 (3H, 5.48 (1H, 7.44 (2H, 7.53 (11, t), 7.69 (2H, 7.76 (2H, 7.85 8.64 (IH, d), 10.79 (1H, IR (solid) 1618, 1606, 1569, 1537, 1487, 1411, 1395, 1369, 1343, 1288, 1273, 1170; MS-374.1 Example 20 [2-(2-Aminophenylsulfanyl)-quinazolin-4-yl- (5-methyl-2H-pyrazol-3-yl)-amine (IIa-20): Prepared in a IO -234o manner similar to the above described Method E to afford a bright yellow solid, mtp 257-259oC; H NMR '(DMSO) 8 2.11- 2.30 (3H, 2xbr 6.10 br 7.10-7.80 (7H, m), 8.60 (1H,.br 9.80 (iH, br 10.80 (1W, br IR S (solid) 1623, 1592, 1567,>1538, -1496, 1483, '1410, 1351 Example 21 (5-Cyclopropyl-2H-pyrazol-3-yl)-(2o phenylsulfanyl-quinazolin-4-yl)-amine (IIa-21): Prepared ID in a manner similar to the above described Method E to S 10 afford a yellow solid, mp, 233-2360C; H NMR (DMSO) 6 0.89 (2H, 0.98 (2H, 1.67 (1H, 5.48 (11, 7.54 7.73 (7H, 7.89 (1i, 8.68 (1N, 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) methoxycarbonylphepylsulfanyl) -quinazolin-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;

1H NMR (DMSO) 8 0.52 (2H, 0.86 (2H, 1.67 (1H, m), 3.86 (3H, 5.60 (12, 7.45 (1H, 7.56 (11, d), 7.66 7.76 (1H, 7.93 8.10 (1H, d), 8.18 (1H, 8.57 (1H, 10.48 (11, 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 Example 23.(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-43methylphenylsulfanyl -quinazolin-4-ylJ-amine (IIa-23): Prepared in a manner similar to the above described Method E to afford a white solid, nmp 241-243 0 C; NMR (DMSO) 0.55-0.63 (2H, 1.87-1.97 (1H, 1.67-1.79 IND -235- (1H, 2.35 (3H, 5.72 (1H, 7.30-7.60 (6H, m), 7.68-7.78 8.50-8.60 (1H, 10.38 (1H, 12.02 (1H, IR (solid) 1617, 1594, 1568, 1529, 1480, 1401, 1344, 1287, 1176,-758, 665,656; MS (M+H) Example 24 {S-Cyclopropyl-2H-pyrazol-3-yl)-2-(3- INDmethoxyphenylsulfanyl)-quinazolin-4-yl] -amine (IIa-24): o Prepared in a manner similar to the above described ND Method E to afford a white solid, mp 232-234oC; 1 NMR o 10 (DMSO) 8 0.55-0.62 (2H, 0.88-0.97 (2H, 1.70-1.80 m(1, 3.79 (3H, 5.79 (1H, 7.08 (11, 7.22- 7.29 (2H, 7.40-7.50. (2H, 7.60 (1iH 7.79 (1H, 8.57 (1H, 10.40 (1H, 12.04 (1I, IR (solid) 3100, 1618, 1592, 1567, 1527, 1477, 1402, 1345, 1284, 1246, 1231, 1171, 1041, 1,001, 969, 826, 761, 692, 667; MS Example 25 (5-Cyclopropyl-2H-pyrazol-3-yl) dimethoxyphenylsulfanyl). -quinazolin-4-yll -amine Prepared in a manner similar to the above described Method E to afford a white solid, mp 250-252 0 C; 'H NMR (DMSO) 5 0.54-0.60 (2H, 0.83-0.91 (2H, 1.68-1.77 (1H, 3.79 (3H, :3.85 (3H, 5.79 (1K, 7.10 (1H, 7.20-7.26 7.45 (1H, 7.57 (1H, d), 7.77 (1H, 8.55 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 Example 26 3 -Carboxyphenylsulfanyl)-quinazolin-4-yl] (S-cyclopropyl-2H-pyrazol-3-yl)-amine (IIa-26): Prepared from IIa-22 according t6 Method G to afford a yellow -236- Ssolid, mp >300 0 C; 1H NMR (DMSO) 0.53 (2H, 0.86 (2H, 1.65 (12, 5.37 (12, 7.55 (1H, 7.68 (12, 7.81 (12, 7.88 (1H, 7.95 (1H, 8.15 (1H, 8.15 (1H, .8.71 (1H, 11.32 (1H, br IR S (solid) 1702, 1626,' 1609, 1559,-1490, 1412, 1355, 1293, I N 1222, 1170; MS 404.7(M+H)+

(N

Example 27 (S5-Cyclopropyl-2z-pyrazol-3-yl) -[12-(naphtalen-.

2-ylsulfanyl)-quinazolin-4-yl]-amine (IIa-27): Prepared S 10 in a manner similar to the above described Method E to afford an off-white solid, mp 285-2880C; 'H NMR (DMSO) S 0.25 (2H, br 0.52 (2H, br 0.87 (1H, 5.54 (1H, br 7.42 7.77 (4H, 8.00 (3H, 8.30 (12, br 8.56 (12, br 10.42 and 11.88 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-2a-pyrazol-3-yl)-[2-(2,4difluorophenylsulfanyl) -quinazolin-4-yl] -amine (IIa-28): SPrepared in a manner similar-to the above described Method E to afford an off-white solid, mp 250-253 0 C; 'H NMR (DMSO) 6 0.61 (2H, 0.91 (2H, 1.74 (IH, m), 5.67 (12, 7.24-7.28 (1H, 7.44-7.48 (3H, 7.53- 7.81 (2H, brm), 8.55 (1H, 10.47 and 12.10 (12H,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) 4 Example 29 (5-Cyclopropyl-2-pyrazol-3-yl)-[2- (naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydroquinazolin-4ylJ-amine (IIa-29): Prepared in a manner similar to the -237above described Method F to afford a white solid, mp 244CC; 1H NMR (DMSO) 8 0.13 0.45 0.79 (IH, C 1.73 (4H, 2.42 (2H, 2.58-(2H, 5.28 (1H, 7.58 (21, 7.61 (2H, 7.97 (3H, 8.23 (IH, Cl 5 8.56 (1H, 11.63 (1H, IR (solid) 1594, 1561, 1514, 1477, 1423, 1333, 1279, 1251, 990, 808, 744, 657, Va IN 651; MS 414.7(M+H)* Example 30 (5-Cyclopropyl-2H-pyrazol-3-yl)- dichlorophenylsulfanyl)-quinazolin-4-yl]-amine o Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 250-2520C;

'H

NMR (DMSO) 8 0.60 (2H, 0.93 (2H, 1.70 (111, m), 5.54 (1H, 7.47 (2H, 7.57 (1H, 7.76 (11, t), 7.86 (2H, 8.57 (1H, 10.48 (1H, 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)+ Example 31 [2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl] (5-cyclopropyl-2H-pyrazol-3-yl)-amine (IIa-31 Prepared in a manner similar .to the above described.Method E to afford an off-white solid, mp 235-2380C; 'H NMR (DMSO) S 0.58 (2H, 0.92 (2H, 1.75 (1H, 5.71 s), 7.44 (1H, 7.50 7.63 (411, 7.73 (1H, 7.75 (11, 8.57 (12, 10.46 (111, 12.08 (1H, 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-(2-Chlorophenylsulfanyl)-quinazolin-4-yl]- (S-cyclopropyl-2-pyIrazol-3-yl)-amine (IIa-32): Prepared -238-

VO

O in a manner similar to the above described Method E to c afford an off-white solid, mp 255-257 0 C; 1H NMR (DMSO) 6 t 0.59 (2H, 0.91 (2H, 1.71 (1H, 5.62 (IH, s), 7.45 (2H, 7.5.7 (1H, 7.69 (1H, 7.75 (1H, t), (C 5 7.85 (1H, 8.56 (1H, 10.43 (1H, 12.-03 (1H, s); IR (solid) 1619, 1596, 1564, 1529, 1480,. 1446, 1398, ND 1370, 1343, 1289, 1246, 1218, 1165, 1148, 1089, 1054, (Cl 1030, 997; MS 394.7(M+H) 10 Example 33 (5-Cyclopiopyl-2H-pyrazol-3-yl)- o dimethylphenylsulfanyl)-quinazolin-4-yl] -amine (IIa-33): Prepared in a manner similar to the above'described Method E to afford an off-white solid, mp 255-256 0 C; 'H NMR (DMSO) 5 0.56 (2H, 0.90 (2H, 1.67 (1H, m), 2.26 and 2.29 (6H, 2 x 5.75 (1H, br 7.26 (1H, m), 7.35-7.55 (4H, 7.74 (1H, 8.54 (1H, br 10.44 and 12.06 (2H, 2 x br s) IR (solid). 1617, 1596, 1569, 1526, 1479, 1459, 1404, 1366, 1343, 1287, 1243. 1218-, 1167, 1145, 1017, 996, 966; MS 388.3(M+H)* Example 34 [2-(Benzimidazol-2-ylsulfanyl)-quinazolin-4yl] -(5-cyclroroppl-2-pyrazol-3-yl)-aine (IIa-34): Prepared in a manner!isimilar to the above described Method E to afford an off-white solid, mp 201-203 0 C; 'H NMR (DMSO) 8 0.44 (2H, 0.71 (2H, 1.17 5.72 (IH, 7.23 (2H, 7.51-7.81 (5H, 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+H)' Example .35. (5-Cyclopropyl-2H-pyrazol-3-yl) (4methoxycarbonylphenylsulfanyl) -quinazolin-4-yl] -amine IoD -239- Prepared in a manner similar to the above described Method.E to afford an off-white solid, mp 245t 246 0 C 1 H NMR (DMSO) 8 0.47 (2H, br 0.80 (2H, br s), 1.62 (1H, 3.85 (3H, 5.69 (1H, br 7.46 (1H, C 5 7.58 (1H, 7.76-7.81 (3H, 8.02-8.05 (2H, m), 8.57 (1H, 10.48 and 12.11 (2H, 2 x br s) IR (solid)

VO

0 .1721, 1712, 1616, 1596, 1572, 1564, 1523, 1481, 1435, .1404, 1360, 1346, 1277,, 181, 1114, 1106, 996, 971; MS 0 418.2(M+H) D o Example 36 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 239-2410C;

H

NMR (DMSO) 6 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) (naphthalen-1-ylsulfanyl) -quinazolin-4-yl] -amine (IIa- 37): Prepared in a manner similar to the above'described Method E to afford an off-white solid, mp 271-273oC; 1H 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 (1H, 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) -240- Va N Example 38 4 -Acetamidophenylsulfanyl)-quinazolin-4- Syl] (5-methyl-2H-pyrazl1-3-yl)-amine (IIa-38): Prepared in a manner similar tothe above described Method E to C( 5 afford an white solid, mp 268-271OC; 1H NMR (DMSO) 8 2.02 (3H, 2.09 (3H, 5.56 (1H, 7.40 (1H, 7.55 ID(3H, 7.75 (3H, d),L8.55 (IH, 10.21 (1HI, 10.40 (1H, 12.03 (1H, s)t IR (solid) 1662, 1620, 1599, 1572, 1531, 1438, 1397, 1370, 1358, 1341, 1323, 1312, IN 10 1278, 1265, 1245, 1216, 1161, 1006, 966;.MS 391.2(M+H)+ Example 39 4 -Methanesulfonylamino-phenylsulfanyl)quinazolin-4-yll (5S-methyl-2H-pyrazol-3-yl)-amine (IIa- 39): Prepared in a manner similar to the above described Method E to afford an 6ff-white solid, mp 219-222 0 C; 1H NMR (DMSO) 5 2.15 (3H, 2.61 (3H, 5.84 (1i, s), 6.91 (2H, 7.22 (2H, 7.36 (11, 7.52 (1I, d), 7.69 (1H, 8.53 (1i, 10.31 (1H, 11.96 (1H, s); IR (solid) 1621, 1602, 1584, 1567, 1528, 1486, 1351, 1287, 1253, 1207, 1179 1102, 1091, 983; MS 427.0(M+H)' Example 40 [2-(4-Acetamidophenylsulfanyl)-7-methoxyquinazolin-4-yl]-(5-methyl-20-pyrazol-3-yl)-amine (IIa- Prepared in a manner similar to the above described Method E to afford a white solid, mp 291-293 0 C; 'H NMR (DMSO) 5 2.01 (3K, 2.09 (3H, 3.87 (3H, 5.55 (1H, 6.96 (1H, 6.99 (1H, 7.55 (2H, 7.73 (2H, 8.45 (1I, 10.21 10.23 (1H, s), 11.99 (IH, IR (solid) MS 421.2(M+H) t Example 41 [2-(4-Acetamidophenylsulfanyl)-8-(3-morpholin- 4 -yl-propoxy)-quinazolin-4-yl]-(5-methyl-25-pyrazol-3- IND -241o yl)-amine (IIa-41): Prepared in a manner similar to the q above described Method E to afford a white solid, mp 262t 264 0 C; H NMR (DMSO).5 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 (1H, 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, S2954, 2918, 2845, 1663, 1609, 1586, 1527, 1468, 1391, Cl 1332, 1268, 1254, 1159, 1136, 1114, 1054, 995, 823 MS

VO

o 10 534.4(M+H) Example 42 [2-(4-Methoxycarbonylphenylsulfanyl)quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa- 42): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 257-260°C; 1H NMR '(DMSO) 6 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]- 2 H-pyrazol-3-yl)-amine (IIa-43): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 263-265-C; H NMR'(DMSO) 6 1.98- 5.50 (1H, 7.46 (1H, 7.60 (1H, 7.78 (3H, 8.02 (2H, 8.58 (1H, 10.58 (1H, 12.50 (1H, br IR (solid) 1623, 1605, 1574, 1560, 1533, 1490, 1401, 1349, 1318, 1285, 1249, 1216, 1174, 1131, 1088, 1018; MS 378.2(M+H)

I

-242o Example 44 4 -Acetamidophenylsulfanyl)-8-methoxy- Cl quinazolin-4-ylJ-( S-methyl-28-pyrazol-3-yl)-amine (IIa- 44): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 247-249aC; 1H NMR (DMSO) 1.99 2.10 (3H, 3.93 (3H, 5.40 (11, 7.31 (1H, 7.38 (1H, 7.57 (2H, 7.76 (2H, 8.11(1, 10.28 (1H, 10.61(1, s), 12.11 (1H, br IR (solid) 3234, 3052, 2938, 1673, 1618, 1591, 1536, 1481, 1459, 1390, 1372, 1345, 1317, 1267, 1249, 1158, 1058, 985, 830; MS 421.2(M+H)* Example 45 4 -Acetamidopheny1sulfanyl)-7-(3-morpholin- 4-yl-propoxy) -quinazolin-4-yll (5-methyl-2H-pyrazol-3yl)-amine (Ia-45): Prepared from IIa-74 according to Method I to afford an off-white solid, mp 153 0 C 'H NMR (DMSO) S 2.02 (311, 2.09 (3H, 2.29 (2H, quint.), 3.16 (2H, 3.36 3.57 (4H, 4.11 (2H, 5.58 (11, 7.22-7.29 (2H, 7.55 (2H, d), 7.76 (2H, 8.07 (1H, 10.26 (1H, br 10.35 (IH, 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-Br 6 mophenylsulfanyl)-quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl)-amine (Ila-46): Prepared in a manner similar to the above described Method E tb afford an off-white solid, mp >30 1c; 'H NMR (DMSO) 8 2.15 (3H, 5.63 (11, br 7.44 (1H, 7.55-7.62 (3H, 7.69-7.77 (3H, 8.56 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(M+H) 4 IND -243- D Example 47 3 -Bromophenylsulfanyl) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa-47): Prepared in a Smanner similar to the above described Method E to afford an off-white solid, mp 280-281 0 C; 'H NMR (DMSO) 5 2.12 (3H, 5.54 (1H, br s) 7.46 (1H, 7.55-7.68 (3H, 7.75-7.88 (3H, 18.81 (1H, 10.49 and 12.11 ND (2H, 2 x br IR (solid) 1617, 1600, 1567, 1530, 1483, S1399, 1362, 1342, 1282,, 1200, 1168, 1054, 1034, 1005, 0 C Example 48 [2-(4-Isopropanesulfonylamino-phenylsulfanyl) quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa- 48): Prepared in a manner similar to the above described Method E to afford a white solid, mp 294-297oC; aH NMR (DMSO) 8 1.26 (6H, 2.13 (3H, 5.75 (1H, 7.34 (2H, 7.41 (1H, 7.54 (1H, 7.59 (2H, 7.73 (1H, 8.53 (1H, 10.16 10.42 (1H, s), 12.07 (1H, 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 (4-Isobutyrylamino-phenylsulfanyl) quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa- 49): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 285-287 0 C; H NMR (DMSO) 6 1.12-1.13 (6H, 1.99 (3H, 2.64 (1H, 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, 1617, 1590, 1566, 1516, 1481, 13.95, 1358; 1341, 1286,. 1247, 1214, 1155, 1052, 1032, 1006, 969; MS 4 1 9.3(M+H) N -244- 0 0 Example 50 (5-Methyl-2H-pyrazol-3-yl)-[2-(4propionylamino-phenylsulfanyl)-quinazolin-4-yl]-amine Prepared in a manner similar to the above C( 5 described Method E to.afford an off-white solid, mp 281- 282°C; 'H NMR (DMSO) 1.11-1.13 (3H, 1.98 (3H, s),

\O

0D 2.33 (2H, 5.51 (1H, br 7.41 (1H, 7.55-7.57 (3H, 7.71-7.78 (3H, 8.54 (1H, 10.11, 10.41 C and 12.04 (3H, 3 x br IR (solid). 1654, 1621, 1599, cO o 10 1571, 1527, 1476, 1398, 1358, 1341, 1286, 1244, 1216, 1155, 1006, 969; MS 405.3(M+H) Example 51 [2-(4-cyclopropanecarbonylaminophenylsulfanyl)-quinazolin-4-yll-(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, mp 300-303°C; 1H NMR (DMSO) 8 0.82-0.84 (4H, 1.83 (1H, 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 (2H, 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-phenylsulfanyl)-8hydroxyquinazolin-4-yll (5-methyl-2H-pyrazol-3-yl) -amine (IIa-52): tan solid, .mp 258-259oC; H NMR (DMSO) 6 1.99 (3H, 2.09 (3H, 5.45 (1H, 7.10 (1H, 7.22 (1H, 7.57 (2H, 7.75 (2H, 7.95 (1H, 9.35 (1H, 10.22 (1H, 10.26 (1H, 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) C -245- Example 53 4 -Acetamido-phenylsulfanyl)-7-.

nitroquinazolin-4-yll (5-methyl-2a-pyrazol-3-yl) -amine (IIa-53): Prepared in a manner similar to the above described Method-E to'afford'a yellow solid; 'K NMR (DMSO) 5-2.02 (3H, 2.09 (3H, 5.54 (1K, 7.58 (2H, d), Va IND 7.75 (2H, 8.08 (1HI 8.22 (1H, 8.80 (15, 10.24 (1H, 10.85 (1H, 12.15 (1H, IR (solid); 010 o Example 54 (5-Methyl-2a-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) S 0.95 (3H, 1.71 (21, 2.13 (3H,s), 3.18 (2H, 5.70 (1H, 7.31 (2H, 7.41 (1H, t), 7.52 (1H, 7.58 (11; 7.73 (1H, 8.55 d), 10.16 (1H, 10.42 (iH, 12.07 (1H, IR (solid) 1615, 1594, 1563, 1530' 1481, 1389, 1362, 1346, 1325, 1291,-1245,. 1147, 969; MS 455.2(M+H)+ Example '55 4 -Ethylsulfonylamino-phenysulfanyl)quinazolin-4-yl] (5-methyl-2a-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) S 1.28 (3H, 2.19 (3H1,s), 3.25 (2H, 5.76 (1E, 7.36 (2H, 7.48 7.53 (1H, 7.65 (15, 7.80 (1H, 8.61 (IH, 10.23 (1H, 10.49 (1H, 12.13 (11, IR (solid) 1615, 1597, 1564, 1532, 1506, 1485, 1455, .1388, 1361, 1347, 1323, 1294, 2218, 1150, '1033, 1016, 998, 968, 918; MS 441.2(M+H)+ -246- Example 56 L2-(4-Acetamido-phenylsulfanyl)-7hydroxyaminoquinazolin-4-yl (5-methyl-2H-pyrazol-3-yl) amine (IIa-56): Prepared from IIa-53 according to Method J to afford a yellow solid; 'H NMR (DMSO) 6 1.97 (3H, s), 2.11 (3H, 5.19 (iH, 6.88-6.91 (2H, 7.65 (2H, 7.85 (2H, 8.44 (1H, 9.27 (1H, br 10.49 Va IND(1H, 11.38 (1H, 14.58 br IR (solid); MS 422.2(M+H)' Example 57 2 -(4-Isobutanecarbonylamino-phenylsulfanyl)- 0 quinazolin-4-yll-(5-methyl-2H-pyrazol-3-yl)-amine (Ila- 57): Prepared in a manner similar to the above described Method E to afford a white solid, mp 281-2820C; '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 (1H, 7.54-7.57 (3H, 7.72-7.78 (3H, 8.54 (1H, 10.14, 10.41 and 12.03 (3H, 3 x bi 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)* Example 58 [2-(4-tert-Butoxycarbonylamninophenylsulfanyl)-quinazolin-4-yll-(5-methyl-2H-pyrazol-3yl)-amine (Ia-58): Prepared in a manner similar to the above described Method E to afford a white solid, mp 243- 2461C; 1H NMR (DMSO) 8 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 449.2(M+H)* IND -247o Example 59 E 2 4 -Acetamido-phenylsulfnyl) -7aminoquinazolin-4-yllj-(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; 1 WNMR (DMSO) S 1.99 (3H, 2.09 (1Hs), 5.53 (1H, 5.97 (2H, s), 6.47 (1i, 6.68 (iH, 7.52 (2H, 7.7 (2H, d), ID* 8.15 (1H, 9.83 (iH, br 10.19 (1H, 10.87 (1H, c br IR (solid); MS 406.2(M+H)" o 0 Eaple 60. IN 10 Example 60 (5-Methyl- 2-pyrazol-3-yl) (2-morpholin-

S

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 6C; 'H NMR (DMSO) S 2.03 (3H, 2.57 (4H, 3.23 3.69 (4H, 5.58 (1W, 7.40 (IH, 7.55- 7.62 (3H, 7.75 (1H, 7.80 (2H, d 8.54 (1H, d), 10.02 (1H, 10.41 (18, 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 (5-Cycloprpyl-2.-pyrazol-3-yl)-[2-(4methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yllamine (IIa-61): Prepared in a manner similar to the above described Method E to afford a white solid, mp 235-2380C; 1 H NMR (DMSO) 8 0.61 (2H, 0.92 (2H, 1.82 (1H, br 2.98 5.90 (iN, 7.23 (2H, 7.41 (1H, 7.54 (3H, 7.72 (1H, t),'8.55 (1I, 10.16 (1H, br 10.38 (18, 11.99 (1W, IR (solid) 1621, 1605, 1573, 1532, 1494, 1455, 1375, 1342, 1316, 1290, 1232, 1143, 1113, 985, 972; MS 453.3(M+H)'

C~

ID-248- Example 62 4 -Amino-phenylsulfanyl) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa-62): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp >3000C; 1H NMR (DMSO) 8 2.16 (3H, 5.58 (11, 6.78 7.36 (2H, 7.64 (2H, 7.94 (1H, 8.74 (1H, d, 11.82 (1i, br IR Va IN (solid)1615, 1591, 1561, 1532, 1495, 1480, 1387, 1363, 1344, 1288, 1244, 1148,,966; MS 349.2(M+H) t IN 10 Example 63 2 4 -Acetamido-pheny1sulfanyl)-quinazolin-4yll-(2H-pyrazol-3-yl)-a ine (IIa-63): Prepared in a manner similar to the above described Method E to afford a white solid, 1H NMR (DMSO) 8 2.11 (3H, 5.93 (1H, s), 7.31-7.68 (8H, 8.54 (1w, 10.17 (1H, 10.54 (1H, 12.38 IR (solid); MS 377.4(M+H)t Example 6 4 (5-Methyl-2H-pyrazol-3-yl)-{(2-[4-(4-morpholin- 4-yl-butyrylamino) -phenylsulfanyl]-quinazolin-4-yl}-amine (IIa-64): Prepared in a manner similar to the above described Method E to afford a white solid, mp,240-243OC; 1 H NMR (DMSO) .8 1.77 (2H, 2.00 (3H, 2.31-2.38 (8H, 3.57 (4H, 5.54 (1H, 7.39-7.76 8.53 (1H, br 10.15 (1H, 10.41 (1H, 12.00 (1H, br IR (solid); MS 504.3(M+H) Example 65 (5-Methyl-21-pyrazol-3-yl)-(2-[4-(2-morpholin- 4-yl-ethylcarbamoyl)-phenylsulfanyl -quinazolin-4-yl}amine (IIa-65): Prepared in a manner similar to the above described Method E to afford a white solid, mp 246-24o8 0

C;

'H NM? (DMSO) 1.97 (3H, 2.43 (4H, br 3.30-(2H, 3.42 (2H, 3.58, (4H, br 5.52 (1H, 7.43 (11, 7.55 (11, 7.76 (3H, 7.97 (2H, 8.56

I

IND -249o (2H, 10.45 (1H, 12.05 (1H, br IR (solid) 1637, 1618, 1596, 1568, 1530, 1484, 1396, 1362, 1343, 1286, 1247, 1216, 1159, 1116, 1006, 967; MS 490.3(M+H)' Example 66- [8-Methoxy-2-(4-methylsulfonylaminophenylsulfanyl) -quinazolin-4-ylJ (5-methyl-2H-pyrazol-3- INDyl)-amine (IIa-66): Prepared in a manner similar to the above described Method -E to afford an off-white solid, mp ci275-277 OC; 1H NMR (DMSO) 6 2.10 (3H, 3.07 (3H, s), 3.89 (3H, 5.58 (1H, 7.24 (1H, 7.26-7.36 (3H, c 7.60 (2H, 8.07 (1H, 10.13 (11, 11.26 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 -Dimethylamino-ethylcarbamoyl)phenylsulfanyll -quinazolin-4-yl-(S5-methyl-2H-pyrazol-3yl) -amine (Ila-67): Prepared in a manner similar to the above described MethodE to afford a white solid, mp'192- 193 0 C; 1H NMR (DMSO) 8 1.99 (3H, 2.20 2.42 (2H, 3.40 (2H, 5.56 (11, 7.43 (IH, 7.57 (1H, 7.77 (3H, 7.92 (2H, 8.56 (2H, 10.44 (1H, 12.04 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 B to afford a white solid, mp 241- 243 0 C; 1H NMR (DMSO) 2.00 (3H, 2.33 (6H, 3.14 (2H, 5.60 (1H, 7.40 (11, 7.58 (3H, m 7.77 -250- (111, t 7.76 (211, 8.58 (111, 10.04 (111, s), 10.42 (1H1, s) 11.99 (111, IR. (solid) 1707, 1617, 1601, 1571, 1509, 1485, 1420, 1397, 1365, 1304, 1290, 1243, 1215, 1161, 97 0, 847, 213, 7265, '716, 683, 656; MS 434 3(M+1)" INO Example 69 [8-Hydroxy (4-methyjlsulfonylamino- C']phenylsulfanyl) -quin azolin-4-ylJ (5-methyl-2fi-pyrazol-a- 0 yl) -amine (Ila-69): "pale green soli'd, mp 29l-293-C; 'H1 NMR No 10 (DMSO0) 8 2:_-10 (31H, 3.09 (3H1 s) 5. 57 (1H1, s) 7. 11 0 (111, 7.24 (1H1, 7.31 (2H1, d) 7.62 (2H1, d) 7.96 (11-1, d) 9. 32 (in, s)1, 10.16 (1Hi, s) 11. 28 (111, s), 12.-02 (111, s) IR (solid) 3256, 1596, 1531, 1460, 1392, 1317, 1334, 1296, 1267, 1146, 993, 968, 931, 824; MS is 443.2(M+1)+ Example 70 -Dime thyl amino -propyl carbamoyl) phenylsulfanyl] -quina~zolin-4-y1) (5-methyl-2H-pyrazol-3- *yl) -amine (IIa-7 0) Prepared in a. manner sim ilar to the above described Method E to afford apink solid, mp 210- 21300; 1H1 NI4R (DMSO) 8 1.48 (211, in), 2.0. (311, 2.24 (6H1,s) 2.38 (211, br ),2.93 (2H1, s) 5.57 (ill, 7.48 (Ill, 7.62 (111, 7.80 (311, mn), 8.02 (2H1, 8..61 (111, d) 8.74 (1H1, s) 10. 50 (iH, s) 12.15 (1H1, br s) IR (solid) 1682, 1618, 1595, 1567, 1528, 1484, 1400, 1361, 1344, 1285, 1247, 1219, 1172, 1084, 1006,, 969; MS Example 71 -Dime tbyl amino -propionylamino)phenylsulfanyl] -quinazolin-4-yl}- (5-methyl-2H-pyrazol-3yl) -anine (Ila-71): Prepared in a manner 'similar to the above described Method E to afford an off-white solid, mp 28000 (dec.) "1H NMR (DM50) 82.09 (311, s) 2.60 (6H1, s) IND 251- S2.93.(2H, 3.10 (22, 5.64 (1H, 7.47 (In, t), 7.59-7.70 (3H, 7.80-7.87 (3H, 8.61 (12, 10.47 (12, 10.48 (1H, 12.15 (IH, IR (solid) 1670, 1619, 1598, 1586, 1571, 1534, 1515, 1481, 1397, 1364, C 5 1 3 4 8 ,-1286, 1178, 1162, 764; MS 448.4(M+H) 4

NO

INDExample 72 4 -Acetamido-phenylsulfanyl) -8-methoxyquinazolin-4-yl (5-cyclopropyl-2-pyrazol-3yl) -amine 0 (IIa-72): Prepared in a manner similar to the above Cl described Method E to afford an off-white solid, mp 265- 2l 2680C; H NMR (DMSO) 5 0.49-0.56 (2H, 0.79-0.83 (2H, 1.55-1.70 (12, 2.06 (3H, 3.89 (3H, 5.61 (1H, 7.25 (1H, 7.33 (12, 7.56 (2H, 7.74 (2H, 8.07 (IH, 10.17 (15, 10.26 (1H, s), 11.94 (1H, br IR (solid) 3250, 1671, 1617, 1595, 1536, 1480, 1460, 1396, 1373, 1335, 1254, 1160, 1131, 1071, 1011, 984, 869,1815; MS 447.4(M+H) 4 Example 73 4 -Acetamidophenylsulfanyl)-8-(3dimethylamino-propoxy) -quinazolin-4-yl (S5-methyl-2pyrazol-3-yl)-amine (IIa-73): Prepared in a manner similar to the above described Method E to afford an offwhite solid,. mp 170-1i2C; 1H NMR (DMSO)' 8 1.91 (2H, quint.), 2.03 (31, 2.09 (3H, 2.17 (6H, 2.40 (2H, 4.10 (2H, 5.59 (1H, 7.23 (1H, 7.30- (12, 7.57 (2H, 7.73 (2H, 8.06 (12, 10.20 (1H, s),.10.24 (12, 12.02 (12, br 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 4 -Acetanidophenylsulfanyl) -7 -hydroxyquinazolin-4-yl] (5-me hy1-2H-pyrazol-3-yl)-amine -252- 0 (IIa-74): Prepared from IIa-40 according to Method 1 to afford an off-white solid, mp 246-248C; 'H NMR (DMSO) 8 2.00 (3H, 2.08 (3H, 5.52 (11, 6.78 (1w, s), 6.87 (1H, 7.54 (2H, 7.72 (2H, 8.37 (1w, d), C- 5 10.06 10.17 (1H, 10.37 s),-11.95 (1H, br IR (solid) 1661, 1633, 1594, 1572, 1539, 1492, 1420, ID1389, 1359, 1298, 1223, 1176, 1148, 1087, 1026, 1010, 965; MS 407.4(M+H) t IN 10 Example 75 2 4 -Acetamidophenylsulfanyl)-7-(3- S. dimethylamino-propoxy) -quinazolin-4-yll (5-methyl-2Hpyrazol-3-yl)-amine (IIa-75): Prepared in a manner.

similar to the above described Method I to afford an offwhite solid, mp 249-250OC; 1 H 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 6.98 (1H, 7.55 (2H, 7.73 (2H, 8.43 (1H, 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+4H) Example 76 (2-(4-[2-(tert-Butoxycarbonyl-methyl-amino)- 2 1 -pyrazol-3-yl)-amine (Ia-76): Prepared in a manner similar to the above described Method E to afford a white solid, mp 228-229 0 C 1 H NMR (DMSO) 8 1.37 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 (11, 7.55-7.63 7.75-7.80 (3H, 8.60 10.28 10.30 (1H, 2xs), 10.45 (1H, 12.08 (1H, IR (solid) 1698, 1683, 1653, 1617, 1594, 1559, IND -253o 1538, 1532, 1507, 1488, 1457, 1418, 1397, 1364, 1346, 1307, .1287, 1246, 1151, 842, 827, 759; MS 520.4 (M+H) t Ct Example 77 (2-E4-(2-Methylamino-acetylamino)- C S phenylsulfanyl) -quinazolin-4-y1)- (5-methyl-2H-pyrazol-3yl)-amine (IIa-77): Prepared in a manner similar to the Va IO above described Methdd E to afford a white -solid, mp 242- 244 0 C; 1H NMR (DMSO) &2.01 (3H, 2.34 (3H, 3.32 01 (2K, 5.58 (1H, 7.45 (1H, 7.50-7.60 m), ci 7.75 (12, 7.80 (2H, 8.55 (12, 10.10 (1H, br 0 10.42 (1K, 12.02 (12, 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 Example 78 1 2 4 -Acetamidophenylsulfanyl)-8-fluoroquinazolin-4-yll (5-methyl-2-pyrazol-3-yl) -amine (IIa- 78): Prepared -in a manner similar to the above described Method E to afford a white solid, mip 257-259d; 1H NMR (DMSO) 52.01 (3H, 2.09 (3H, 5.49 (1H, 7.42 (1H, 7.57-7.68 (3H, 7.75 (2H, d)Y 8.40 (IH, d), 10.28 (12, s) 10.75 (1H, s) 9 F NMR (DMSO) 6-127.3 IR (solid) 1690, 1670, 1637, 1609, 1588, 1543, 1519, 1493, 1456! 1434, 1395, 1366, 1332, 1315, 1289, 1254, 1242, 1032, 838, 829, 808, 7144; MS 409.4(M+H)+ Example 79 (1H-Indazol-3-yl)-(2-phenylsulfanylquinazolin-4-yl) -anine (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 12), 7.37 2H), 7.39 1H), 7.52 (dd, 1H), 7.54 1H), 7.55 -254- 1H), 7.56 IH), 7.83 1H), 8.53 1H), 10.71 1H), 12.85 1H); MS 370.1 Example 80 2 -Hydroxyethyl)phenylemino]-quinazolin-4cl 5 yl}-(S5-methyl-2H-pyrazol-3-yl)-amine (IIc-1):..Prepared in a manner similar to the above described Method A to IDafford a brown solid, mp 217 0 C; H NMR (DMSO) 8 1.99 (3H, 3.69 (2H, 4.05 (2H, 5.00 (1H, br 5.53 0 (1H, br 7.09 (1H, 7.25-7.40 (4H, 7.40-7.48 (2H, 7.54 (11, 8.34 (1H, 10.07 (iN, 11.67 o br IR (solid).3395, 3155, 3052, 2934, 1623, 1598, 1577, .1475, 1434, 1393; MS 361.2 (M+H) t Example 81 [2-(Methylphenylamino)-quinazolin-4-yl-(5methyl-2HE-pyrazol-3-yl)-amine (IIc-2): Prepared in a manner similar to the above described Method A to afford a white solid, mp 154-156 0 C; 1 H NMR (DMSO) 6 2.03(3H, s), 3.51(3H, 5.70(1, 7.13(1H, .7.36-7.25(3H, m), 7.48-7.37 (3H, 7.58 8.38 (1H, 9.98(1H, 11.91 (1H IR.-(solid) 1621, 1598, 1578, 1540, 1494, 1473, 1398, 1374; MS 331.0 (M+H) 4 Example 82 (5-methyl-2a-pyrazol-3-yl)-{2-tN-methyl-N- (pyridin-3-ylmethyl)amino]-quinazolin-4-yl}-amine (IIc-3): Prepared in a manner similar to the above described Method A to afford a yellow solid, mp 177 0 C; H NMR(DMSO) 6 0.45 (2H, 0.84 (2H, 1.80 (1i, s), 3.16 (3H, 4.93 (2H, 6.18 (1H, br 7.10 (IH, 7.34 (2H, 7.55 (1H, 7.64 8.36 (1H, 8.45 (1H, 8.52 (1H, 10.03 (1H, 12.17 (1iH, IR (solid) 3104, 2995, 2936, 1618,.-1591, 1559, 1541, 1518, 1477, 1409, 1386, 1350, 1300, 1018, 991, 873, 827;' MS 372.3 Example 83 (S-Methyl-2-pyrazol.3..yl) (2-phenylaminoquinazolin-4-yl) -amine (I1c-4): Prepared in a manner similar to the above described Method A to afford a white S' solid; 1 LH NMR j(DMSO @6'0CC) 5 2.27 (3H, 6.47-(1K, br s), 6.92(1w, in), 7.31(3H, in), 7.53(1K, mn), 7.70 (1H, mn), 7.91.

(2K, mn), 8.37 (2K, d)f' 9.16 (1K, br 10.05 (1K, br s), C']12.15 (1K, br IR (solid) 1623,, 1601, 1573, 1541, 0 1478; MS 317.0 NO 0Example. 84 (2-Benzylam no6quinazolin.4.y1) -(5-methyl-2Hpyrazol-3-yl)-amine (IIc-5): Prepared-in a manner similar to the above described Method A to afford a white solid, mp 225.22700; 'H NNR (DM50) 5 2.20 (3H, s) 4.62 (2H, d) 7.18 (1K, 7.43-7.60(8H, in), 8.22 (1H, 9.99 (1H, br s),-12.05 (1H1, br IR (solid) 1630, 1609, 1578; 1538, 1511; MS 331.0 (t4KH)+ Example 85S 2 -Cyclohexylamino-ninazoln..4.jl) '2H-pyrazol-3-yl) -amine 1(IIc-G) Prepared in a manner similar to the above described Method A to afford an of fwhite solid, mp 2800C (dec.) 'H NMR (DMS0) 5 1.11- 1.44(5K, in), 1.56 (1K, in), 1.71(2H, mn), 1.92 (2H,-in), 2.26 (3H, 3.75 (1H, 6.63, (1w, br s) 7.04 (1K, s), 7.28 (1K, 7151I(1w, mn), 8.26(1K, 9.97(1K, br s), 12. 08(1H, br s) 12.75 (1E, br s) ;IR (solid) 2927,' 2853, 1619, 1596, 1569, 1522,'1482; MS 323.0 Example 86 [2 2 3 -Dihrdrobenzor11,4]aioxin- 6 .ylaminov..

quinazolin-4-ylJ .(S-methyl-2H-pyrazol.3y1) -amine (Ilc-7): Prepared in a inanner similar to the above described Method A to afford an off-green solid, top -256- >250 0 C; 'H NM? (DMSO) 5 2.23 (3H, 4.15 (4H, 6.32 br 6.76 (1H, 7.16 (1H, 7.22 (1K, dd), 7.39 (1H, 7.57 (18, 7.66 (1H, 8.34 (18, d), 9.07 (1H, br 10.20 (1H, br 12.15 (1i, br IR (solid) 3445, 3045, 2968, 2927, 2868, 1618, .1595, 1577, 1559, 1509, 1441, 1377, 1073; MS 375.1 Va Va Example 87 2 0g methyl-2E-pyrazol-3-yl)-amine (IIc-8): Prepared in a ci N 10 manner similar to the above described Method A to afford C- a white solid, mp 211 0 C; H NMR (DMSO) .6 0.85-1.30 1.50-1.85 (6H, 2.22 (3H, 3.19 (2H, 6.50- 7.00 (1H, br 7.06 (IH, br 7.29 (1H, br 7.51 (1H, 8.26 (1H, br 9.97.(1H, br 12.04 (1K, br 12.75 (iH, br IR (solid) 3333, 2927, 2850, 2831, 1627, 1609, 1577, 1540, 1508, 1449, 1422, 1340, 988; MS 337.4 Example 88 -[2-(1H-Indazol-6-ylamino)-quinazoiin-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 .>250C; 'H NMR (DMSO) 6 2.24 (3H, 5.93 and 6.89 (IH, 2xbr 7.05-8.15 (611, 8.25- 8.90 (2H, 9.25 and 9.97 (1H, 2xbr 10.11 and 10.57 (18, 2xbr 12.15 and 12.80 (2H, 2xbr IR (solid) 3456, 3315, 2923, 1613, 1600, 1577, 1549, 1467; MS 357.1 Example 89 (5-Methyi-2;pyrazol-3-yl)- 12-(pyridin-3ylmethylamino)-quinazol n-4-yll -amine (Ic-10): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 218 0 'H NMR (DMSO) 8 2.20

VO

VO

ID

ND

0

ND

CA

ri -257- (3H, 4.59 (2H, 6.30 (1H, br 7.10 (1H, s), 7.33 (2H, 7.54 (1H, 7.78 (1H, 8.31 (1H, s), 8.43. (1H, 8.61 (1H, 10.0 (1H, br 12.15 (1H, br IR (solid) 3308, 2945, 2919, 2858, 1623, 1593, 1577, 1552, 1501,-1475,. 1449, 1383; MS 332.1- Example 90 3 -Chlorophenylamino)-quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-amine (IIc-1l): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp >250 0 C, H NMR (DMSO) 6 2.29 (3H, 5.30-6.98 (1H, 6.96 (1H, 7.28 (2H, 7.51 (1H, 7.67 (1H, 7.77 (IH, 8.23 (1H, 8.46 (1H, 9.35 and 10.00 (1H, 2xbr 10.14 and 10.64 (1H, 2xbr 12.20 and i2.82 (IH, 2xbr IR (solid) 3447, 3078, 2945, 2914, 2863, 1618, 1600, 1572, 1549, 1472, 1440, 1403, 1372; MS 351.1 (M+H) 4 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 'H NMR (DMSO) 8 2.27 (3H, 5.20-6.80 (1H, 7.26 (1H, 7.33 (2H, 7.51 (1H, 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 Example 92 [2-(4-Fluorobenzylamino) -quinazolin-4-yl methyl-2H-pyrazol-3-yl)-amine (IIc-i3): Prepared in a manner similar to the above described Method A to afford a white solid, mp 216 0 C; 'H NMR (DMSO) 8 2.20 (3H, s),

I

\o -258o 4.56 (2H, 6.30 (1H, br 7.05-7.20 (3H, 7.31 (IH, 7.42 (2H, 7.54 (1H, 8.32 (1H, 10.01 and 10.34 (1H, 2xbr 12.09 and 12.75 2xbr IR (solid) 3333, 2854, 1632, 1609, 1577, 1536, 1508, 1367; MS 349.3 (M+H)

VO

\D Example 93 (2-Hydroxyethyl)phenylamino -quinazolin- 4-yl}-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-14): Prepared Sin a manner similar to the above described Method A to \c o 10 afford a white solid, mnp 222 0 C; H NMR (DMSO) 6 2.09 (3H, 2.80 2H 3.61 (2H, 4.87 (1H, br 5.85 (1H, br 7.30-7.53 i(5H, 7.63 (1H, 7.86 (1H, 8.68 (1H, 10.11 (1H, br 11.55 (1H, br s), 12.49 (1H, br 13.50 (1H, br IR (solid) 3193, 3171, 3111, 3084, 1636, 1577, 1559, 1509, 1486, 1413, 1340, 1058; MS 361.3 (M+H) Example 94 2 4 -Cyanomethylphenylamino) -quinazolin-4yl- (5-methyl-2H-pyrazol-3-yl)-amine (IIc-15): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp >2500.C; H NMR (DMSO) 2.23 (3H, 4.09 (2H, 6.28 (1H, br 7.41 (2H, d), 7.48 (1H, 7.57-7.63 (3H, 7.87 (1H, 10.70 (1H, 11.56 (1H, 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) Example 95 [2-(3-Hydroxymethylylphenylamino)-quinaolin-4yl- (5-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 >25 0 oC; IH NMR (DMSO) 2.20 (3H, 4.53 (2H, 5.22 (1H, br 6.31 (1H, br 7.24 (1H, 7.33-7.53 (4H, 7.61 (1H, 7.86 (1H, \D -259- 8.67 (N1H, 10.61 (1H, br 11.52 (1i, br s), 12.59 (IH, br 13.10 (LH, br IR (solid) 3401, 3209, 3108, 3071, 2975, 2916, 1632, 1609, 1595, 1554, 1485, 1421, 1371, 1348, 1046, 1005, 813; MS 347.3 DExample 96 3 -Hydroxyphenyamino) INDmethyl-2H-pyrazol-3-yl)-amine (IIc-17): Prepared in a c manner similar to the above described Method A to afford cia white solid, mp >250OC; 1 H NMRl (DMSO) 5 2.22 (31, s), 6.42 (1H, br 6.72 (1H, 6.97 (2H, 7.21 (1iH, Ci 7.47 (1H, 7.60 (N1H, 7.85 (1H, 8.67 (Ia, 9.76 10.53 (N1H, 11.53 12.58 (1i, br 12.99 (1H, br IR (solid) 3354, 3027, 2893, 2817, 1654, 1588, 1541, 1490, 1436, 1418, 1332, 1154, 1004; MS 333..2 Example 97 (5-Cyclopropyl-2-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 0 C; 1H NMR (DMSO) 8 0.74 (2H, 0.92 (2H, 1.91 5.83 and 6.54 (1H, 2xbr 6.94 (iN, 7.30 (3H, 7.50 (1I, 7.65 (1Hi, 7.91 (2H, 8.27 (1iN, 9.13 and 9.77 (1H, 2xbr 10.07 and 10.52 (1iN, 2xbr 12.19 and 12.82 (1H, 2xbr IR (solid) 3443, 1622, 1595, 1577, 1554, 1486, 1449, 1413, 1376, 1340, 1235, 1171, 988, 806; MS 343.2 Example 98 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3methylphenylamino) -quinazolin-4-yl]-amine (Ic-19): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 117C; 1H NMR (DMSO) 5 0.72 (2H, 0.92 (2H, 1.90 (111, 2.32 -260-

NO

(3H, 6.20 (1N, br 6.80 (1H, .7.20 t), 7.27 (11, br 7.51 (1H, br 7.55-7.85 (3H, 8.43 (1H, br 9.50 (1H, br 10.44 (1H, 12.55 (1H, br IR (solid) 3303, 1618, 1581, 1554, 1536, 1495, 1472, 7K 5 1436, 1413, 1372, 1336, 1240, 990; MS 357.4 INDExample 99 (5-Cyclopropyl-2Ha-pyrazol-3-yl)- methoxypyridin-3-ylamino) -quinazolin-4-yl] -amine Prepared in] a manner similar to the above ID 10 -described Method A to afford a pink solid, mp 120 0 C; H NMR (DMSO) 8 0.72 (2H, 0.91 (2H, 1.89 (1H, m) 3.85 (3H1, 6.20 (11, br 6.82 (1H, 7.25 (1H, 7.48 (11, 7.66 (1H, 8.13 (1H, br 8.42 (1H, br 8.61 (1H,.br 9.50 (1H, br 10.48(1H, br 12.55 (1H, br IR (solid) 3457, 3439, 1622, 1604, 1577, 1554, 1481, 1422, 1386, 1363, 1272, 1235, 1035, 985, 821; MS 374.2 Example 100 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(indan-5ylamino)-quinazolin-4-yll-amine (IIc-21): Prepared in a manner similar to the.above described Method A to afford a pale brown solid, mt 199-204 0 1H NMR (DMSO) 6 0.69 (2H, br 0.91.(2H, br 1.90 (1H, 2.02 (2H, m), 2.68 (1H, 2.83 (3H, 6.46 (1H, br 7.18 (1H, 7.26 (1H, br 7.50 (1H, 7.67 (1H, 7.75 (1H, br 8.45 (1H, br 9.70 (11, br 10.60 (l1, br 12.30 and 12.80 (1H, 2xbr IR (solid) 1621, 1601, 1572, 1552, 1495, 1474, 1439, 1425, 1408, 1382, 1363, 1319, .1267; MS 3,83.3 Example 101 (5-Cycloptopyl-2H-pyrazol-3-yl) (1H-indol- 6-ylamino)-quinazolin-'4-yll-amine (IIc-22): Prepared in a manner similar to the 'above described Method A to afford

I

Ls) -261- Sa dark brown solid, mp >3000C; 1H NMR (DMSO) 8 0.69 (2H, br 0.89 (2H, br 1.88 (1H, 5.77 and 6.74 (1H, S2xbr 6.35 (1H, 7.22 (3H, br 7.45 (2H, d), 7.65 (IH, 8.35 (2H, br 8.86, 9.70 and 10.01 (1H, 3xbr 10.49, 12.12-and 12:84 (IH, 3xbr 10.94 (s, 1H); IR (solid) 1623,. 603, 1571, 1549, 1495, 1477, 1460, IND 1419, 1383, 1336, 12641 1250, 1238; MS 382.4 (M+H) C] Example 102 4 -Acetamido-3-methylphenylamino)

IND

S

1 0 quinazolin-4-yl (5-cyclopropyl-2H-pyrazol-3-yl) -amine C (IIc-23): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp >188°c 1H NMR (DMSO) 6 0.72 (2H, br 0.94 (2H, br 1.92 (1H, 2.\03 (3H, 2.19 (3H, 5.80 and 6.69 (1H, 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, 10.531, 12.16 and 12.81 (1H, 3xbr IR (solid) 1637, 1624, 1578, 1542, 1502, 1474, 1428, 1403, 1343, 1320, 1307, 1250; MS 414.4 (M+H) Example 103 4 -Chloro-3-nethylphenylamino)-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 244-2460C; 1H NMR (DMSO) 8 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 (IH, br 9.17, 9.81 and 10.06 (1H, 3xbr 10.58, 12.19 and 1278 (1H, 3xbr IR (solid) 1615, 1578, 1549, 1475, 1419, 1397, 1365,- 1331, 1296, 1261, 1238, 1187, 1139; MS 391.4 (M+H) -262- Example 104 (5-Cyclopropyl-2H-pyrazol-3-y)- 12- (4- Cl ethylphenylamino)-quinazolin-4-yl] -amine Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 250-251C; 1H Cl 5 NMR (DMSO) 8 0..72 (2H, br 0.91 (2H, br 1.19 (3H, 1.91 (1H, 2.58 (2H, 5.81 and 6.64 (1H, 2xbr N 7.15 (2H, 7.22 (1H, 7.47 (11, 7.64 (1H, 7.78 8.36 br.s), 9.03, 9.66 and 10.05 (1H, 3xbr 10.49, 12.20 and 12.80 (1H, 3xbr IR IND 10 (solid) 1603, 1574, 1546, 1509, 1497, 1474, 1439, 1417, o 1386; MS 371.5 Example 105 (5-Cyclopropyl-2f-pyrazol-3-yl)-12-(4propylphenylanino)-quinazolin-4-yl] -amine (IIc-26): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 255-256-C; 1H NMR (DMSO) S 0.72 (2HI; br 0.91 (5H, 1.60 (2H, m), 1.90 (1H, 2.58 (2H, 5.81 and 6.63 (1H, 2xbr a), 7.12 (2H, 7.21 (11, 7.47 (1H, 7.63 (11, a), 7.77 (2H, 8.36 (1H1, br 9.01, 9.70 and 10.11 (1H, 3x br s, 10.51, 12.17 and 12.80 (1H, 3xbr.s); IR (solid) 1595, 1571, 1545, 1499, 1477, 1442, 1413, 1388; MS 385.6

(M+H)

Example 106 (5-Cyclopropyl-2H-pyrazol-3-yl)-{2-[4-(2hydroxyethyl) phenylaminoJ -quinazolin-4-yl}-amine (IIc-27): Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 255- 256 0 C; 1H NMR (DMSO) 5 0.73 (2H, br 0.91 (5H, 1.90 (1H, 2.69 (2H, 3.60 (2H, 4.62 (IH, 5.81 and 6.65 (1H, 2xbr 7.15 (2H, 7.22 (1H, 7.46 7.63 (1H, 7.77 (211, 8.36 (1H, br s), IND -263o 9.05, 9.69 and 10.02 (1N, 3xbr 10.52, 12.17 and 12.79 (11, 3xbr IR (solid) 1632, 1569, 1546, 1483, 1452, 1434, 1402, 1371, 1267, 1231; MS 387.4 Example 107 (5-C yclopropyl-2H-pyrazol-3-yl)-(2- INDphenetylamino-quinazolin-4-yl)-amine (IIc-28): Prepared in a manner similar to the above described Method A to afford a white solid, mp >250CC; 'H NMR (DMSO) 8 0.66 (2H, c- 0.84 (2H, 1.83'(1H, 2.90 (2H, 3.56.(2H, 6.29 (11, br 7.01 (1H, 7.12-7.38 (6H, m), Ci 7.48 (IN, 8.42 (1H, 10.91 (1H, br 13.11 (1H, br IR (solid) 2922, 1650, 1627, 1577, 1550, 1500, 1482, 1395, 1368, 1004, 832; MS 371.3 (M+H) t Example 108 (2-Cyclohexylethylamino)-quinazolin-4-yll- (5-cyclopropyl-2H-pyrazol-3-yl).-amine (IIc-29): Prepared in a manner similar to the above described Method A to afford a white solid, mp.>250 0 C; 1H NMR (DMSO) 6 0.70 (2H, 0.80-1.00 (4H, 1;05-1.30 (4H, 1.30-1.50 (3H, 1.55-1.80 (5H, 1.87 (11, 5.40-6.70 (21, br 7.04 (1H, 7.25 7.49 (1H, 8.25 (1H, 10.06 br s),11.93 br IR (solid) 3448, 2920, 2852, 1618, 1600, 1568, 1550, 1486, 1418, 1395, 1367, 1258, 1008, 985; MS 377.4 Example 109 [2-(4-Carboxymethoxyphenylamino)-quinazolin- 4-yl]-(5-cyclopropyl-2.-pyrazol-3-yl)-amine Prepared in a manner similar to the above described Method A to afford a yellow solid, mp >250OC; 1H NMR (DMSO) 0.72 (2H, 0.91 (2H, 1.90 (11, 4.62 (2H, 6.24 6.88 (2H, 7.21 (1H, 7.45 (1H, 7.62 (iN, 7.78 (2H, 8.35 9.31 (1H, 10.25 (11, 11.70 (1H, br IR (solid) IN -264o 1663, 1595, 1563, 1509, 1422, 1331, 1240, 1176, 1053, 999; MS 417.3 Ct Example 110 4 -Cyanomethylphenylamino)-quinazolin-4c S yl}-(5-cyclopropy1-.2H-pyrazol-3-yl).-amine- (IIc-31): Prepared in a manner similar to the above described Va *O Method A to afford a white solid, mp 2220C; 1H NMR (DMSO ci6 0.74 (2H, 0.93 (211, 1.92 (1H, 3.97 (2H, s), 0 5.82 and 6.65 (1H, 2xbr 7.29 (3H, 7.50 (1H, m), ci o 10 7.66 (1H, 7.92 (2H, 8.39 (1H, 9.21 and 9.85 0 (1H, 2xbr 9.90 and 10.56 (1H, 2xs), 12.19 and 12.80 (1H, 2xbr IR (solid) 1641, 1622, 1595, 1581, 1554, 1513, 1486, 1463, 1408, 1372, 985, 821; MS 382.3 Example 11 [2-(Benzothiazol-6-y1amino) -quinazolin-4-yl]- (5-cyclopropyl-2H-pyrazol-3-y1)-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; 1H NMR (DMSO) 6 0.73 (2H, 0.92 (2H, 1.92 5.83 and 6.63 (1M, 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 (1H, 9.58 and 10.10 (1H, 2xbr 10.57, 12.21 and i2.85 3xbr IR (solid) 1624, 1592, 1575, 1512, 1472, 1411, 1377, 1333, 1244; MS 400.3

(M+H)

4 Example 112 (S-Cyclopropyl-2H-pyrazol-3-y1)-f2-(3,4dimethylphenylamino)-quinazolin-4-yl]-amine (IIc-33): Prepared in a manner similar to the above described Method A to afford a white solid, mp 245-246 0 C; -H NMR (DMSO) 5 0.72 (2H, br 0.90 (2H, br 1.90 (11, m), 2.18 (3H, 2.23 (3H, 5.77 and 6.63 (1H, 2xbr s), OD -265- S7.09 (1H, 7.23 (1H, br 7.47 (1H, br 7.59 (IH, br 7.64 (1H, br 8.36 (IH, br 9.02, 9.55 and S10.07 (1H, 3xbr 10.49, 12.31 and 12.80 (1H, 3xbr s); IR (solid) 1620, 1600, 1574, 1552, 1497, 1474, 1436, Cq.

1416, 1 3 8 5 1262; MS 371.5 (M+H) 4 \o 0D Example 113 (5-Cyclopropyl-2H-pyrazol-3-yl) 2-(2phenoxyethylamino) -quinazolin-4-yl]-amine (IIc-34) Ci Prepared in a manner similar to the above described o 10 Method A to afford a wiite.solid, mp 203°C; 'H NMR (DMSO) C 8 0.70 (2H, 0.88 (2H, 1.87 (1H, 3.73 (2H, d), 4.16 (2H, 5.75 and 6.70 (1H, 2xbr 6.93 (1H, t), 6.90-7.20 (3H, 7.20-7.45 (3H, 7.55 (1H, 7.76 (1H, br 8.32 (IH, 9.95 and 10.35 (1H, 2xs), 12.13 and 12.75 (IH, 2xbr IR (solid) 3434, 1622, 1600, 1572, 1554, 1499, 1476, 1422, 1399, 1385, 1303, 1267, 1226, 1212, 1052, 829; MS 387.4 (M+H) Example 114 (5-Cycloprop'l-2H-pyrazol-3-yl) (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 212 0 C; 3H NMR (DMSO) 6 0.67 (2H, 0.90 (2H, 1.86. (1H, 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 (1H, 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 (M+H) Example 115 2 4 -Carboxymethylphenylamino)-quinazolin-4yll-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (IIc-36): Prepared in a manner similar to the above described Method A to afford a brown solid, mp >2100.C 1H NMR -266- (DMSO) 6 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 (11, 7.49 (1H, 7.64 (1H, 7.84 (2H, 8.37 (1H, 10.27 and 12.25 (1H1, 2xbr IR (solid) 1648, Cl 5 1591, 1555, 1512, 1489, 1428, 1411;, 1374; MS 401.4

\O

INDExample 116 (5-Cyclopropy1-2a-pyrazol-3-y1--)-[2-(11indazol-5-ylamino)-quinazolin-4-yl]-amine (Ila-37): 0 Prepared in a manner similar to the above described o 10 Method A to afford a purple solid, mp 268-271 0 C; 'H NMR 0 .(DMSO) 6 0.69 (21H, br's), 0.90 (2H, 1.88 (1H. m), 5.86 and 6.58 (1l, 2xs),-7.22 (1H, 7.61 (1H, 7.71 (21. 8.01 (1H, 8.37 (2H, 8.58, 9.05 and 9.58 (1H, 3xbr 10.01, 10.68-and 12.38 3xbr 12.90 (1H, IR (solid) 1626, 1605, 1576, 1546, 1512, 1495, 1476, 1447, 1431, 1416, 1393, 1261, 1224; MS 383.3 Example 117 5 -Cyclopropyl-2H-pyrazol-3--yl)-1[2-(pyridin- 3-ylmethlaino)-quinazolin-4-yl]-amine (IIc-38): Prepared in a manner similar to the above described Method A to afford a yellow solid, mp 1930C; 1H NMR (DMSO) 6 0.69 (2H, 0.89 (2H, 1.86 (1H, 4.60 (2H1, s), 5.76, 6.22 and 6.66 (11, 3xbr 7.10 7.33 (2H, 7.54 (1H, 7.78 (1H, 8.31 (1H, 8.44 (1H, 8.61 (1H, 10.00 and 10.32 (11, 2xs), 12.15 and 12.63 (11, 2xbr IR (solid) 2927, 2850, 1623, 1600,.1577, 1536, 1477, 1418, 1332, 1254, 814; MS 358.3 Example 118 (5-Cyclopropy1-2H-pyrazol-3-yl)-[2-(3- methoxycarbonylphenylamino)-quinazolin-4-yl]-amine (IIc-39): Prepared in a manner similar to the above ND -267- C 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, Sm), 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), 9.36, 9.84 and 10.00 (iH, 3xbr 10.63, 12.17 and 12.79 (1H, 3xbr IR (solid) 1716, 1615, 1591, 1579, 1557, I 1473, 1432, 1416, 1379, 1334, 1298, 1276, 1226, 1191, 1142, 1110, 1020, 985; MS 401.3 (M+H) o .10 Example 119 [2-(3-Carboxyphenylamino)-quinazolin-4-yl]- Ci (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 298-302-C; 'H NMR (DMSO) 6 0.73 (2H, br 0.91 (2H, 1.90 (1H, 7.26 (IH, 7.35 (1H, 7.50 j(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)-[2-(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 186-188 0 C; 1H NMR (DMSO) 6 0.73 (2H, br 0.91 (2H, br 1.22 (3H, 1.90 (IH, 2.62 (2H, 5.81 and 6.70 (lH,.2 x br 6.78 7.20 (2H, 7.48 (1H, 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) ND -268- O Example 121 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3dimethylphenylamino) -quinazolin-4-yl] -amine (IIc-42) Prepared in a manner similar to-the above described Method A to afford an off-white solid, mp 241-242°C; H NMR (DMSO) 8 0.58 (2H, br .86 (2H, 1.-77 (1H, br 2.11 (3H, br 2.28 (3H, 5.77 and 6.14 (1H, 2 x ND br 7.01 (1H, 7.11 (1H, 7.22. (1H, br 7.29 (1H, 7.5.6 (1H, s),'8.36 (1H, br 8.49, 8.98 and Cl 9.98 (1H, 3 x br 10.48, 12.04 and 12.68 (1H, 3 x br

VO

o 10 IR (solid) 1622, 1603, 1573, 1552, 1495, 1471, 1440, Cl 1428, 1412, 1384, 1268; MS 371.4 Example 122 (5-Cyclopropyl-2H-pyrazol-3-yl)- dimethoxyphenylamino) -quinazolin-4-yl]-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) 6 0.69 (2H, 0.86 (2H, 1.89 (1H, 3.61 (3H, s), 3.67 (3H, 5.76 (1H, br 6.12 (1H, 6.31 (1H,.

6.66 (1H, 6.94: (1H, 7.27 (1H, 7.50 (1H, 7.68 (1H, 8.45 and 9.36 (1H, br s, rotamers), 9.42 and 10.54 (1H, rotamers), 12.29 and 12.82 (1H, br s, rotamers); IR (solid) 3331, 3000, 2959, 2931, 2836, 1627, 1604, 1577, 1536, 1509, 1463, 1441, 1418, 1336, 1259, 1232, 1200, 1027; MS 403.8 Example 123 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3methoxyphenylamino) -quinazolin-4-yl] -amine (IIc-44) Prepared in a manner similar to the above described Method A to afford a grey solid, mp 207-211°C; 1H NMR (DMSO) 5 0.73 (2H, br 0.91 (2H, br 1.91 (1H, m), 3.77 (3H, 5.81 and 6.71 (1H, 2 x br.s), 6.53 (1H, d), 7.19 7.85 (7H, 8.34 (1H, .9.08, 9.79 and 10.06 I N -269o (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, 992; MS 373.7 ci k Example 124 (5-Methyl-2H-pyrazol-3-yl)- (2-phenylamino- ID 5,6,7,8-tetrahydroquinazolinin-4-yl)-amine Prepared in a manner similar to the above described Ci Method C.

o Ci Example 125 (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 153 0 C; 'H NMR (DMSO) .6 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 (IH, 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 1890C; 1H NMR (DMSO) 6 0.71 (2H, 0.91 (2H, 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 (solid) 1622, 1595, 1572, 1545, 1499, 1481, 1417, 1390, 1367, 1048, 997, 829; MS 385.4 -270- Example 127 [2-(4-acetamido-3-methylphenylamino) quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl) -amine (IIc-48): Prepared in a manner similar to the above c 5 described Method A to-afford-a-pale brown solid, mp 251°C; 1H NMR (DMSO) 6 2.04 (3H, 2.19 (3H, 2.56

\O

\D (3H, 5.92 and 6.80 (1H, br s, rotamers), 7.22 (2H, 7.48 (1H, 7.64 (1H, 7.73 (2H, 8.40 (1H, C 9.05 and 9.74 (1H, br s, rotamers), 9.20 (1H, s), cO I 10 10.05 and 10.54 (1H, 'br s, rotamers), 12.15 and 12.82 0 (1H, br s, rotamers)j 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-2H-pyrazol-3-yl)- [2-(indan-2ylamino)-quinazolin-4-yl]-amine (IIc-49): Prepared in a manner similar to the above described Method A to afford a brown solid, mp 233-234C; 'H NMR (DMSO) 680.65 (2H, s), 0.84 1.83 (1H, 2.91 (2H, 3.33 (2H, s), 4.72 (1H, 6.07 (1H, br 7.00-7.60 (8H, 8.29 (1H, 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 (M+H) Example 129 [2-(3-Methylphenylamino)-quinazolin-4-yl methyl-2H-pyrazol-3-yl)-amine (IIc-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) 6 2.25 (3H, 2.30 (3H, 5.95 (1H, br 6.76 (1H, d), 7.10-7.35 (2H, 7.48 (1H, 7.55-7.85 (3H, 8.40 (1H, 9.05 and 9.74 (1H, br s, rotamers), 10.07 and 10.55 (1H, br s, rotamers), 12.14 and 12.81 (1H, br s, NO -271rotamers); IR (solid) 3443, 2914, 2859, 1622, 1586, 1549, 1536, 1481, 1445, 1408; 1372, 1330, 1267, 1239, 1184, 1166, 1139, 993, 838, 806; MS 331.3 (M+H) 4 Example 130 2 4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (I1c-51): Prepared in a manner similar tothe above described Method A to afford a grey solid, mp 246-247oC; 1H NMR (DMSO) 5 2.19 (3H, 2.31 (3H, 6.37 (1H, br 6.94 (1H, d), o 10 7.23 (1H, 7.37 (1H, 7.43 (11, 7.64 t), ci 7.97 (1H, 8.19 (1H, 8.42 (1K, br 10.17 (1iH, 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 Example 131 (5-Cyclopropyl-2H-pyrazol-3-yl)-(2-[4- (morphoiin-1-yl)phenylminol -quinazolin-4-yl)-amine (IIc-52): Prepared in a manner similar to the above described Method A to afford a grey solid, mp 275-2760C; 'H NMR (DMSO) 8 0.71, (2H, 0.90 (211, 1.89 (1H, s), 3.05 (4H, 3.75 (4H, 5.78.and 6.61 (1H,.br s, rotamers), 6.93 (2H, 7.20 (1l, 7.43 (1H, s), 7.50-7.90 (3H, 8.39 (1H, 8.95 and 9.58 (11, br s, rotamers), 10.07 and 10.47 (111, br a, rotamers), 12.16 and 12.81 (11, br s, rbtamers); 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 Example 132 [2-(Benzothiazol-6-ylamino)-quinazolin-4-yl]- (5-methyl-2H-pyrazol-3y1)j-amine (IIc-53): Prepared in a manner similar to the-above described Method A to afford an off-white solid, mp 236-239W; 1 NMR (DMSO) 2.25 IND -272o (3H, 6.35 (1H, br 7.22 7.53 (1H, d), 7.62 (1H, 7.76 (1H, 7.98 (1H, 8.39 (1H, d), 9.05 9.17 (1H, 9.59 (1H, br 10.30 (1H, br's), 12.35 (IH, br IR (solid) 1622, 1605, 1567, C 5 1546, 1505, 1473i,-1441, -141-7, 1385, 1341, 1297, 1273, 1253, 1192, 1130; MS 374.1

VO

c\ Example 133 (3,4-Dimethylphenylamino) -quinazolin-4- Cq yl]- (5-methyl-2Hrpyrazol-3-yl)-amine (IIc-54): Prepared o 10 in a manner similar to the above described Method A to 0 afford an off-white solid, mp 249-251°C; 'H NMR (DMSO) 6 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 (1H, 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 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°C; 1H NMR (DMSO) 5 1.21 (3H, 2.25 (3H, br 2.61 (2H, 5.92'and 6.80 (1H, 2 x br 6.78 (1H, 7.21 (2H, br 7.48 (iH, 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 [2-(3-Methoxyphenylamino)-quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl)-amine (IIc-56): Prepared in a NO -273o manner similar to the above described Method A to afford an off-white solid, mp 212-215oC; 1H NMR (DMSO) 5 2.25 S(3H, br 3.77 (3H, 5.92 and 6.84 (1H, 2 x br s), 6.55 (1H, 7.13 7.41-7.50 (2H, 7.65 (1H, 7.77 (1H, 8.41 (1H, br 9.10, 9.79 and 10.10 ND (1H, 3 x br 10.55, 12.13 and 12.82 (1H, 3 x br IR I (solid) 1610, 1576, 1532, 1494, 1468, 1425, 1337, .1277,.

1256, 1201, 1159; MS 347.4 (M+H)

IN

o 10 Example 136 [2-(4-Acetamido-3-cyanophenylamino)- Ci quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl) -amine (IIc-57): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 294- 296 0 C; 'H NMR (DMSO) 6 2.08 (3H, 2.28 (3H, 6.67 (1H, br 7.27 (1H, 7.43 (1H, 7.53 (1H, s), 7.68 (1H, 8.04 (1H, 8.45 (2H, 9.41, 10.35 and 12.18 (2H, 3 x br 10.00 (IH, 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) 4 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, 222-223 0 C; 1H NMR (DMSO) 8 2.22 (3H, 3.75 (3H, 6.82' 1 (1H, br 7.05-7.11 (1H, m), 7.15-7.25 (1H, 7.30-7.36 (IH, 7.40-7.50 m) 7.49-7.55 (2H, 7.55-7.70 (1H, 7.70-7.82 (1H, m), 7.90-8.02 8.30-8.50 (1H, IR (solid) 1625, 1604, 1574, 1556, 1496, 1473, 1444, 1403, 1384, 1258, 1234, 1182, 1018, 824, 806, 755, 698; MS 423.4 (M+H) IO -274- O Example 138 4 -Acetamidophenylamino) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIc-59): Prepared in a Smanner similar to the above described Method A to afford an off-white solid, mp 253-256oC; 1H NMR (DMSO) 5 2.02 (3H, 2.25 (3H, br -5.92 and 6.77 (1H, 2 x br s), 7.21 (1H, 7.49 (3H, 7.63 (1H, 7.83 (2H, d),

VO

8.38 (1H, br 9.03 and 10.05 (1H, 2 x br 9.81 (1H, 12..13 and 12.80 (1H, 2 x br IR (solid) 1669, Ci 1635, 1617, 1574, 1535, 1512, 1486, 1422, 1394, 1366,

VO

o 10 1316, 1268, 1231, 1184, 1119, 1101; MS 374.1 (M+H) 0 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; 'H NMR (DMSO) 6 1.48 (9H, 2.24 (3H, 6.23 (1H, 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 IR (solid) 1698, 1620, 1555, 1520, 1475, 1443, 1405, 1371, 1310, 1241, 1167, 1055, 996; MS 432.1 (M+H) Example 140 4 -Cyanophenylamino) -quinazolin-4-yl] methyl-25-pyrazol-3-yl)-amine (IIc-61): Prepared in a manner similar to the above described Method A to afford an off-white solid,.mp 293-298 0 C; 1H NMR (DMSO) 8 2.25 (3H, 6.50 (1H, br 7.27 (1H, 7.51 (1H, s), 7.64 (1H, 7.71 .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) IND -275o Example 141 (5-Methyl 7 2H-pyrazol-3-yl)1 [2-(6-oso-6,10bdihydro-4aH-benzo chromen-2-ylamino) -quinazolin-4-yl]- C amine (IIc-62): Prepated in a manner similar to the above described Method A to. afford a pale yellow solid, mp 293- 298WC; 1H NMR (DMSO) 1.72 (3H, br 6.23 (1I, br s), 7.50 (1i, 7.66 7.75 7.87(1, t), I ND7.77 (11, 8.26 (1H, 8.33 (1H, 8.58-8.72 (2H, 10.55 (IH, 11.55 (1H, 12.40 (11, IR 0 (solid) 1707, 1629, 1607, 1579, 1540, 1497, 1488, 1471, O 10 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-ylamnino) -quinazolin-4-yll- methyl-2H-pyrazol-3-yl)-amine (IIc-63): Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 206-207 0 C; 1H NEMR (DMSO) 6 2.20 6.80 (11, brs), 7.24-7.27 (2H, 7.36-7.40 (2H, 7.48-7.52 (31, 7.67-7.69 (3H, 7.94 (11, 8.26 8.42 (1H, 9.30 (11, br 10.16 (11, br 12.13 (1H, br IR (solid) 1593, 1578, 1544, 1498, 1479, 1414, 1384, 1251, 1209, 1003; MS 393.2 Example 143 4 -MethoxycarbonyLmethy-3methylphenylamino) -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)i 2.23 (3H, 2.26 (3H, 3.63 (3H, 3.64 (2H, 5.99 (0.SH,.br 6.80 (0.5 H, br 7.10 (1H, 7:25 (1H, 7.50 (1H, 7.61-7.80 (3H, 8.44 (1H, 9.10 (0.5H, br 9.78 (0.5H, br 10.11 (0.5H, br's), 10.56, (0.5H, br 12.18 IN -276o br 12.90 (0.5H, br IR (solid) 1732, 1710, 1622, 1581, 1554, 1538, 1508, 1490, 1446, 1411, 1371, 1336, Ct 1306, 1257, 1244, 1204' 1146, 1016, 998, 797, 754, 692; MS 403.4 (M+H) 4 Example 144 [2-(4-Carboxymethyl-3-methylphenylamino)quinazolin-4-yll-(5-methyl-2HB-pyrazol-3-yl)-amine A solution of [2-(4-methoxycarbonylmethyl-3- 0 methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol- 3-yl)-amine (IIc-64, 200 mg, 0.5 mmol) in a mixture of methanol/water 8'mL) was treated with.1M NaoH (2 mL, 2 mmol). The mixture was heated at 70 0 C 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, 95%) as a pale yellow solid, mp 245 0 C H NMR (DMSO) 2.27 (6H, 2xs), 3.55 (2H, 6.49 (1H, 7.13 (1H, 7.26 (1H, 7.50 (1H, 7.62-7.78 (3H, 8.42 (11, 9.34 10.26 (1H, 12.36 (1H, IR (solid) 1660, 1590, 1562, 1504, 1427, 1385, 810' 776, .751, 693; MS 389.4 Example 145 [2-(4-Aminophenylamino)-quinazolin-4-yl-(5methyl-2H-pyrazol-3-yl)-amine (IIc-66): A solution of [2- (4-tert-Butoxycarbonylamino-phenylamino)-quinazolin-4yl]-(5-methyl-2H-pyrazol-3-yl)-amine (Ilc-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 K 2 C0 3 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 164-167 0 C; 1H NMR (DMSO) 8 2.24 (3H1, 6.33 (1H, br 7.12 (2H, d), 7.48 (3H, 7.58 (1H, 7.86 8.64 (11, d), ND -277o 10.86 (1H, br 11.46 (1H, IR (solid) 1681, 1512, 1496, 1433, 1415, 1187, 1129; MS 332.4 (M+H) Example 146 4 -Bromophenylamino)-quinazolin-4-yl] methyl- 2 H-pyrazol-3-yl)-amine-(IIc- 6 7 Prepared in a manner similar to the above described Method A to afford

NO

ND an off-white solid, mp 290-293-C; 1 H NMR (DMSO) 6 2.27 (3H, 6.71 (1H, br 7.22 (1H, 7.46-7.50 (3H, c 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, C( 1548, 1486, 1436, 1409, 1372, 1238, 1186, 1136, 1071, 997; MS 395.1/397.1

(M+H)

Example 147 2 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 0 C; 1 H NMR (DMSO) 6 1.11 (6H, 2.15 (3H, 2.62 (1H, 6.25 (1H, br 7.41 7.46 (1H, 7.63 (1H, d), 7.71 (2H, 7.84 (1H, 8.64 (1i 10.00 (IH, 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 3 -amino-5-ethylpyrazole (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 ID-278o off-white solid, mp 248-2520C; 'H NMR (DMSO). 8 1.30 (m, 6H), 2.7? 4H), 6.12 (br.s, 1H), 6.54 and 6.90 (br. s, Ct11), 7.58 11), 7.74 1H), 7.90 1H), 8.78 (d, 1H); IR (solid) 1639, 1602, 1591, 1555, 1418; MS 349.2 Va INDExample 149 (1H-Indazol-3-yl) (2-phenylamino-quinazolin- 4-yl)-amine (IIc-70): Prepared in a manner similar to the 0 above described Method A to afford a white solid; 'H NMR Cl o 10 (DMSO) 5 6.90 7.11 11), 7.19 2H), 7.44 0 1H), 7.57 1H), 7.62 1H), 7.67 2H), 7.71 1H),.7.93 1H), 8.59 11), 11.55 (br. s, 11), 13.15 IH); MS 353.2 Example 150 (1H-Indazol-3-yl)-[2-(3trifluoromethylphenylamino)-quinazolin-4-yl] -amine (IIc-71): Prepared.in a manner similar to the above described Method A to afford a pale yellow solid. 'H NYR (DMSO) 8 7.00 1H), 7.02 1H), 7.22 11), 7.37 (td, 1H), 7.56 3H), 7.61 1H), 7.66 2H), 7.92 11), 8.60 1H), 10.61 (br. s, 11), 11.42 (br. s, 11), 13.12 1H); MS 421.2 Example 151 (1H-Indazol-3-yl)-[2-(4trifluoromethylphenylamino)-quinazolin-4-yl]-amine (IIc-72): Prepared in a manner similar to the above described Method A to afford a pale yellow solid. 'H NMR (DMSO) 8 7.08 111), 7.16 2H), 7.44 3H), 7.58 1H), 7.6 2Hj,.7.69 11), 7.95 IH), 8.62 1H), 10.82 (br. s, 1H), 11.50 (br. s, 1H), 12.20 (s, 11); MS 421.2 IND -279o~ Example 152 [2-(Adamantan-2-ylamino)-quinazolin-4-yl]- (1H-indazol-3-yl)-amine (IIc-73): Prepared in a manner similar to the above described Method A to afford a white solid. 1H NMR (DMSO) 8 0.83 (br. s, 1H), 0.85 (br. s, 1H), 1.44 4H), 1.55 3H); 2.63 1.73 1H), IND1.82 1H),-1.84 1H), 3.56 1H), 7.10 1H), IO 7.41 1H), 7.51 1H), 7.54 1H), 7.57 1H), 7.69 1H), 7.90 1H), 8.45 IH), 8.58 1K), 11.60 1H), 13.10 1H); MS 411.3 o c Example 153 (1B-Indazol-3-yl)- 2-methyl-phenyl-aninoquinazolin-4-yl)-amine (IIc-74): Prepared in a manner similar to the above described Method A to afford a white solid; 1 H NMR (DMSO) 5 3.27 1H), 6.88 1H), 6.93 2K), 7.04 1K), 7.14 2H), 7.22 12), 7.36 2H), 7.48 1K), 7.54 1H), 7.62 1K), 8.37 1H), 10.11 1H), 12.71 1H); MS 367.2 Example 154 [2-(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. 1H NMR (DMSO) 5 6.81 1H), 6.87 (td, 1H), 7.07 1H), 7.34 (dd, 12), 7.35 IH), 7.40 1H), 7.53 1K), 7.56 1H), 7.63 2H), 7.72 1K), 8.07 1H), 8.46 1H), 10.37 1H), 12.89 1H); MS 387.1 Example 155 (1H-Indazol-3-yl)- 12-(2trifluoromethylphenylamino)-quinazolin-4-yl]-amine. (IlIc- 76): Prepared in a manner similar to the above described Method A to afford a white solid; 1H NMR (DMSO) S 7.01 (t, 1H), 7.20 1H), 7.32 1H), 7.36 1H), 7.43 (d, IN -280o 1H), 7.49 12), 7.55 7.61 1H), 7.64 (d, 1H), 7.69 1H), 7.95 2H), 8.62 1H), 10.15 (m, 1H), 11.62 1H), 13,.03 1H); MS 421.2 CA S Example 156 4 -Cyanomethylphenylamino)-quinazolin-4yl]-(1H-indazol-3-yl)-amine (IIc-77): Prepared in a

VO

manner similar to the above described Method A to afford a white solid; 1H NMR (DMSO) 6 13.16 1H), 11.49 (br.

0 s, 1H), 10.38 (br. s, 12), 8.58 1H), 7.92 1H), o 10 7.67 2H), 7.61' (d 1H), 7.56 1H), 7.44 1H), 0 7.22 2H), 7.08 12), 6.86 2H), 3.87 2H); MS 392.2 Example 157 [2.-(4-Chlorophenylamino)-5,6,7,8tetrahydroquinazolini: n-4-yl] (5-methyl-2H-pyrazol-3-yl)amine (IIc-78): Prepared in a manner similar to the above described Method C; MS 355.5 (M+H)I Example 158 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino- 6,7,8,9-tetrahydro-5H-cycloheptapyrimidin- 4 -yl) -amine (IIc-79): Prepared .i a manner similar to the above described Method C; MS 335.3 Example 159 [2-(Benzimidazol-2-ylamino)-7-benzyl-5,6,7,8tetrahydro-pyrido [3 1 4-d]pyrimidin-4-yll (5-methyl-2Hpyrazol-3-yl)-amine (IIc-80): Prepared in a manner similar to the abovd described Method C; MS 452.0 (M+H) Example 160 7 -Benzyl-2-phenylamino-5,6,7,8-tetrahydropyrido[3, 4 -d]pyrimidin- 4 -yl) (5-methyl-2H-pyrazol-3-yl) amine (lic-81): Prepared in. a manner similar to the above described Method MS 412.1 (M+H) 4 INO -281- 0 Example 161 [6-Benzyl-2-(4-chlorophenylamino) -5,6,7,8tetrahydro-pyrido 4 1 3-dlpyrinidin-4-yl] (-methyl-2apyrazol-3-yl)-amine (Ilc-82): Prepared in a manner similar to the above described Method C; MS 446.3 (M+HV+ IND Example 162 (Benzi'.midazo1-2-ylamino) -6-benzyl-5,6,7, 8- IND tetrahydro -pyrido [4, 1 3-d] pyrimidin 4-yl] (5 -methyl -2Hpyrazol-3-yl)-amine (IIc-83): Prepared insa manner similar to the above described Method C; MS 452.2 (M+H) 4

IND

01 ci Example 163 6 -Benizyl-2-phenylamino.., 6,7,8-tetrahydropyrido (4,3-dlpyrimidin-4-y1) -(5-methyl-2H-pyrazol-3-yl) amine (IIc-84); Prepared in a-manner similar to the above described Method C; MS 411.9 Example 164 (5-Methyl-2H-pyrazol-3-yl} (2-phenylamino- 6,7, 8- tetrahydro-pyrido 4-d] pyrimidin-4-y.) -amine Prepared in a manner similar to the above 'described Method C;,MS 322.3 (M+KY+ Example 165 4 -Cyanubme thy lphenylamino) -qninazolin-4- Yl)'-(lH-PYrazolQ[3..4-b]Pyridin-3-y1) -amine (Ilc-B).

Prepared in a manner s imilar to the above described.

-Method A to af ford 'Ln off -white solid; 'H NNR (DMSO.)S 13.65- 1H) 12.82 (br. s, 1K) 11.69 (br. S, 1K), 8.55 (dd, 2H), 8.12 1K), 7.8B (in, 1K), 7.66 (mn, 1H), 7.50 (mn, 1H), 7.30 (in, 2K), 7.09 (mn, 1H), 6.94 (in, 2H), 3.89 MS 393.1 (M+H) 4 Example 166 4 -Cyanobenzylamino) -quinazolin-4-yl] -(iNpyrazolo[3,4-blpyridin-3-y1) -amine (Ilc-67): Prepared in a mainer similar to the above described Method A to afford an off-white solid; 'KI NMR (DMSQ)- 8 13.68 11-), IND -282o 12.82 (br. s, 1K), 11.70 (br. s, 1H), 8.55 3H), 8.00 1H), 7.92 1H), 7.59 4H), 6.96 2H), 6.86 1H), 4.23 2H); MS 393.1 Example 167 2 -(4-Cyanomethylphenylamino)-quinazolin-4yll-(4-fluoro-1H-indazol-3-yl)-amine (IIc-88): Prepared Va ID in a manner similar to the above described Method A to afford a white solid; 'H NMR (DMSO) 8 13.49 1H),.11.61 Cl (br. s, 1K), 10.64 Cbr. s, 1H), 8.56 1H), 7.95 (t, o 10 1H), 7.67 1H), 7.58 1K), 7.46 1H), 7.43 (dd, Ci 1H), 7.14 2H), 6.85 (dd, 3H), 3.88 2H); MS 410.1 Example 168 [2-(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; 1H NMR (DMSO) 5 13.14 1H), 11.31 (br. s, 1K), 10.5i (br. s, 1H), 8.59 iH), 7.91 1H), 7.65 (d, 3H), 7.56 1H), 7.50. 2H), 7.45 (dd, 1K), 7.26 (d, 2H), 7.08 1H); MS 378.2 Example 169 [2-(4-Cyanobenzylamino)-quinazolin-4-yl] (1Hindazol-3-yl)-amine (IIc-S90): Prepared in a manner similar to the above described Method.A to afford a white solid; 1H NMR (DMSO) 6 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 1K), 6.84 (br.

d, 2H), 4.19 2H); MS 392.2 Example 170 (5-Cyclopropyl-25-pyrazol-3-y)-[2- (naphthalen-2-ylosy)-quinazolin-4-yl -amine (Ib-1) Prepared in a manner similar to the above described ND -283o Method.B to afford a white solid, mp 327-328 0 C; 'H NMR (DMSO) 5 -0.05-0.07 (2H, 0.50-0.68 (2H, 1.28-1.40 (1H, 5.68 7.40-7.50 (2H, 7.50-7.64 (3H, 7.70-7.80 (2H, 7.82-8.08 (3H, 8.64 (1H,d), 10.58 (1H, 12.07 IR (solid) 1621,1595, 1575, 1554, 1508, 1480, 1410, 1385, 1320, 1254, 1240, IN 1212, 1166, 830, 819, 758; MS 394.4 Example 171 (5-Methyl-'2E-pyrazol-3-yl)-[2-(naphthalen-2o 10 yloxy)-quinazolin-4-y]-amine (IIb-2): Prepared in a Ci manner similar to thel'above described Method B to afford a pale brown solid, ,mp >300 0 C; 1H NMR (DMSO) S 1.62 (3H, 5.65 (1H, 7.96 (2H, br 7.55 (3H, 7.76 (2H, 7.92 (1H, 8.00 (2H, 8.58 (1H, 10.56 (1H, 11.99 (1H, IR (solid) 1625, 1601, 1571, .1556, 1479, 1377, 1315, 1250, 1236, 1210, 1159;.MS 368.7(M+K)* Example 172 (5-MethylZ2H-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; 1H NMR (DMSO) 6 2.10 (3H, 5.92 (1H, 7.23 (2H, 7.29 (1H, 7-38 (1H, 7.46- 7.53 (3H, 7.85 (1H, 8.58 (1H, 10.55 (1r, a), 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 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(5,6,7,8tetrahydronaphthalen-2-yloxy)-quinazolin-4-yll-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 ND -284- 0 (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 7.58 (1H, 7.76 (1H, 8.58 (1H, 10.54 (IH, 12.20 (1H, IR (solid) 1731, 1641, 1614, 1570, 1506, 14-95, 1464, 1424, 1362, 1340, 1240, 880, 831, 812, 776, 758; MS 398.4 (M+H)

\O

ci Example 174 (5-Cyclopropyl-2H-pyrazol-3 yl)- (3- C methylphenoxy) -quinazolin-4-yl] -amine (IIb-5) Prepared o 10 in a manner similar to the above described Method B to Ci afford an off-white solid, mp 283-2840C; 1H NMR .(DMSO) 6 0.49-0.53 (2H, 0.89-0.96 (2H, 1.72-1.81 (1H, m), 2.40 (3H, 5.82 (1H, 7.03 (1H, 7.08 (1H, s), 7.15 (1H, 7.35-7.46 (2H, 7.58 (1H, 7.78 (1H, 8.62 (IH, 10.58 (1H, 12.25 (1H, IR (solid) 1622, 1604, 1576, 1557, 1483, 1419, 1381, 1319, 1253, 1189, 1158, 997, 842, 789, 763; MS 358.4 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 277-2780C; 1H NMR (DMSO) 6 2.15 (3H, s), 3.78 (3H, 6.00 (1H, 6.77-6.90 (3H, 7.30-7.41 (2H, 7.52 (1H, 7.70 (1H, 8.59 (1H, 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 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- IN -285o (3H, 3.70 (3H, 3.78 (3H, 5.98 (1H, 6.73- 6.77 (1H, 6.90 (1H, 7.00 (1H, 7.35-7.45 (1H, 7.58 (1H, 7.70-7.78 (1H, 8.63 (1H, 10.55 U_ (1H, 12.19 (IH, IR (solid) 1626, 1603, 1576,

CI

5 1557, 1509, 1481,-1436-, 1409, 1382, 1372, 1318, 1249, 1227, 1195, 1180, 1158, 1120, 1029, 965, 835, 803,

VO

\D 767,753; MS 378.4 (M+H)

ND

Ci Example 177 (Benzo [1,3]dioxol-5-yloxy) -quinazolin-4yll- (5-methyl-2H-pyrazol-3-yl)-amine (IIb-8): Prepared in 0 -a manner similar to the above described Method B to afford an off-white solid, mp 296-299 0 C 1H NMR (DMSO) 8 2.13 (3H, 6.05 (1H, 6.09 (2H, 6.69 (1H, 6.90 (1H, 6.98 (1H, 7.39 (1H, 7.53 7.70 8.58 (1H, 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, 752; MS 362.4 (M+H) Example 178 [2-(3-Methoxycarbonylphenoxy)-quinazolin-4yl]-(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 269-270°C; 1H NMR 2.05 (3H, 3.90 (3H, 5.88 (1H, 7.00-7.90 (7H, 8..50-8.65 (IH, 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) t Example 179 (5-Cyclopropyl-2H-pyrazol-3-yl) phenoxymethyl-quinazolin-4-yl)-amine (IId-1): Prepared in a manner similar to the above described Method C to afford a pale yellow solid, mp 265-267 0 C; 'H NMR (DMSO) 8 ND -286o 0.67 (2H, 0.93 (2H, 1.87 (1H, 5.19 (2H, s), 6.55 (11, br 6.90-7.02 (3H, 7.26-7.30 (2H, m), 7.54 (18, 7.74-7.83 (2H, 8.61 (1H, 10.45 (1H, br 12.18 (11, br MS 358.4 Example 180 (2-Benzyloxymethyl-quinazolin-4-yl)-(5- ID cyclopropyl-2H-pyrazol-3-yl)-amine (IId-2): Prepared in a manner similar to the above described Method C to afford Cl a white solid, mp 211-2130C; 1H NMR (DMSO) 8 0.65 (2H, m), 0.90 (2H, 1.86 (1H, 4.63 (2H, 4.68 (1H, s), C 6.71 (11, 7.28-7.54 (6H, 7.76-7.81 (2H, 8.61 (1H, 10.41 (11, 12.19 MS 372.3 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 219-221 0 C; 'H NMR (DMSO) 8 0.66 (2H, 0.95 (2H, m), 1.87 (11, 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 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; 'H NMR (DMSO) 8 2.31 (3H, 2.71 (3H, 6.73 (1H, 7.75 (2H, 8.04 (1a, 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 -287to the above described Method C to afford a white solid; 1H NMR (DMSO) 81.58 1.68 (2H, 1.85 (2H, m), 2.20 (3H, 2.90 (2H, 3.00 (2H, 5.26 (2H, s), 6.15 (1H, s) 7.15 (2H, 7.40 (2H, 10.25 (1H, br); MS 384.3 (MiH)*.

INDExample 184 t 2 -(4-Chlorophenoxymethyl)-5,6,7,8tetrahydro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)amine (IId-6): Prepared in a manner similar to the above described Method C'to afford a white solid; 'H NMR (DMSO) Cl 61.80 (4H, 2.15 (3H, 2.55 (2H, mn obscured), 2.75 (2H, 5.25 (2H, 6.12 (1H, 7.08 (2H, 7.35 (2H, 9.80 (IH, bt); MS 370.2 Example 185 (5-Cyclopropyl-2-pyrazol-3-yl)-[2- (naphtalen-2-ylsulfanyl)-6-phenylpyrimidin-4-yll-amine (IIIa-1) Prepared in a manner similar to the above described Method L to afford a white solid, rmp 233-234oC; H NMR (DMSO) 6 0.21 (2H, br 0.56 (2H, br 1.17 (1H, br 5.35 (1H, br 7.02 (1H, br 7.49 (3H, 7.59 (2K, 7.73 (1K, 7.88 (2H, 8.02 (3H, 8.30 (1H, m) 10.01 (1H, 11.75 (1H, br IR (solid); MS 436.7(M+K) Example 186 (5-Cyclopropyl-2-pyrazol-3-yl)-[2-(3methoxycarbonyl-phenyylsulfany1)-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; H'NMR (DMSO) 0.52 (2H, 0.87 (2H, 1.69 (1H, 3.87 (3H, 5.47 (1H, 7.03 (1H, br s), 7.49 (3H, 7.67 (1H, 7.87 (2H, 7.94 (1H, m), ND -288- 8.09 (1H, 8.23 (1H, m),l10o.07 (1H, 11.94 (1i, s); IR (solid); MS 444.7(M+E)+ Example 187 (5-Cyclopropyl-2H-pyrazol-3-yl)-12- (naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine (IIIa-3): Prepared in a manner similar to the above described IND Method L to afford a white solid, mp 248-250 0 C; 1 H N4R (DMSO) S 0.21 (2H, br 0.55 (2H, br 0.94 (1H, br 5.31 (IH, br 6.55 (1H, br 7.57-7.66 (3H, m),

NO

7.99-8.03 (4H, 8.25 (1H, 9.94 11.75 (1H, Cl br IR (solid); MS 360.7(M+H)+ Example 188 (5-Cyclopropyl-2a-pyrazol-3-yl)-[5,6dimethyl-2-(naphthalei-2-ylsulfanyl)-pyrimidin-4-ylamine (IIIa-4): Prepared in a manner similar to the above described Method L td afford a white solid, mp >270 0 C; 1H NMR (DMSO) 5 0.14 (2H, 0.45 (2H, 0.78 (1H, s), 2.05 (3H, 2.27 (3H, 5.26 (1H, 7.60 (3H, d), 7.99 (3H, 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) t Example 189 (5-Cyclopropyl-2H-pyrazol-3-yl) [5-methyl-2- (naphthalen-2-ylsulfanyl)-pyrimidin-4-yll-amine Prepared in a manner similar to the above described Method L to afford a 4 white solid, mp 1970C; H NMR (DMSO) 8 0.21 (2H, 0.51(2H, 0.78 (11, 2.08 (3H, s), 5.40 (1H, 7.57 (2H, 7.62 (11, 7.92 (1H, s), 7.97 (3H, 8.22 (11H, 8.88 (1H, 11.70 (1H, a); IR (solid) 1738, 1583, 1563, 1488, 1460, 1364, 1234,1216, 808, 656; MS 374.2(M+H)' S-289- Example 190 (5-Cyclopropyl-2.-pyrazol-3-yl) -6-methyl-2- (naphthalen-2-ylsulfanyl)-pyrimidin-4-yl -amine (IIIa-6): Prepared in a manner similar to the above described Method L to afford a white solid, mp 232 0 C; 1H NMR (DMSO) 6 0.15 (2H, 0.51'(2H, 0.92 (1H, 2.20 (3H, s), IND5.22 (1H, 7.60 (2H, 7.67 (11, 7.98 (3H, s), IND8.24 (1H, 9.79 (1i, 11.60 (1H, IR (solid) 1586, 1508.7, 1485, 1282, 1180, 815, 788, 744, 674, 666; MS 374.2(M+H)+ C Example 191 (5-Cyclopropyl-2-pyrazol-3-yl)-[6- (morpholin-4-yl)-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4ylJ-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 mL) was .added triethylamine (456 JL, 3.27 mmol) and the reaction mixture was stirred for 15 hours at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (SiO2, Hexane/AcOEt gradient) to afford (5-cyclopropy1-2H-pyrazol-3-yl)-(2,6dichloropyrimidin-4-yl)-amine (705 mg, To-a solution of (5-cyclopropyl-2H-pyrazol-3yl)-(2,6-dichloropyrimidin-4-yl)-amine (211 mg, 0.781 mmcl) and 2-naphthalenethiol (125 mg, 0.781 mmol) in tert-butano (5 mL) was added triethylamine (174 jaL, 1.25 mmol) and the resulting mixture was heated at reflux for hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate.and aqueous NaHC03. The organic layer was washed with brine, dried over MgS 4 and concentrated in vacuo. The residue was purified by flash chromatography (Si0 2 Hexane/AcoEt gradient) to afford [6-chloro-2-(naphthalen-2- IND -290o ylsulfanyl) -pyrimidin-4-yll (5-cyclopropyl-2H-pyrazol-3yl)-amine.

The above formed [6-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 1200C for Va INDhours. The solvent was evaporated and the residue was purified by flash chromatography to afford IlIa-7 (50 mg, Ci 63%) as a white solid, mp 118-120-C; 1H NMR (DMSO) 8 0.34o 10 0.91 (4H, 4xm), 1.28 and 1.78 (1H, 2xm), 3.32 (2H, m), Ci 3.60 (6H, 5.38-6.16 (2H, brm), 7.55-7.66,(3H, m), 7.95-8.02 8.19 and 8.23 (18, 2xs), 9.28 and 9.31 (1H, 2xbr 11.71 and 11.84 (1H, 2xbr IR (solid); MS 445.2(M+H) Example 192 (5-Cyclopropyl-2a-pyrazol-3-yl)-[6-(1methylpiperazin-4-yl)-2-(naphthalen-2-ylsulfanyl)pyrimidin-4-yll-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 0 C; 1 NMR (DMSO) 5 0.35-0.9i (4H, 4xm), 1.31 and 1.78 .(18, 2xm), 2.17 and 2.19 (3H, 2xs), 2.29 (4H, 3.35 (2H, 3.61 (2H, 5.38-6.20 (2H, br 7.55-7.66 (3H, 7.95-8.02 (3H, m) 8.17 and 8.23 (1H, 2xs), 9.26 and 9.32 (1H, 2xbr 1171 and 11.85 (1H, 2xbr IR (solid); MS 458.3(M+H)+ Example 193 [6-(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- 1520C; 'H NMR (DMSO) 5 2.10 (6H, 2.26 (3H, 5.09 and 6.31 (1H, 2x br 7.03 (38, 7.22 (1H, 7.59 IND-291- H(2, 7.69 (12, 7.99 (3H, 8.28 (1H, 9.93 (1H, 11.67 (1H, br IR (solid) 2970, 1739, 1436, 1365, 1229, 1217, 1205; MS 438.3(M+H) t Example 194 [6-(2-Methylphenyl)-2- (naphthalen-2ylsulfanyl)-pyrimidin-4-yl- (5-methyl-2H-pyrazol-3-yl)-

NO

INDamine (IIIa-10): Prepared in a manner similar to the above described Method L to afford a white solid, mp 211- Ci 214 0 C; 'H NMR (DMSO) 6 1.41 (3H, 2.30 (3H, 5.26 Va o 10 and 6.55 (1H, 2x br 7.34 (5H, 7.62 (2H, 7.70 0 (1H, 7.99 (3H, 8.30 (1H, 9.97 (1H, 11.73 br IR (solid) 2356, 1615, 1582, 1483, 1265, 851, 822, 761; MS 424.0(M+H)+ Example 195 [2-(4-Acetamido-phenylsulfanyl) -6-phenyl-

I

pyrimidin-4-yl]-( 5-#ethyl-2H-pyrazol-3-yl)-amine (IIIa- 11): Prepared in a manner similar to the above described Method L to afford a white solid, mp 153-155-C; 'H NMR (DMSO) 8 2.01 (3H, 2.08 (3H, 5.43 (1H, 6.96 (1H, br 7.49-7.88 (9H, 10.00 (1H, br 10.23 (1H, 11.86 MS 417.2(M+H)+ Example 196 (5-Methyl-2H-pyrazol-3-yl)-[2-(naphthalen-2ylsulfanyl)-6-phenyl-pyrimidin-4-yl] -amine (IIIa-12) Prepared in a manner similar to the above described Method L to afford a white solid,. mp 237-239 0 C; 'H NMR (DMSO) 6 1.39 (3H, br 5.12 (1H, br 6.98 (1H, br 7.50 (3H, 7.62-7.63 (2H, 7.72 (1H, 7.90 (2H, 8.03-8.05 (3H, 8.31 (12, 10.00 s), 11.73 (1n, br-s); IR (solid) MS 410.2(M+H)* Example 197 E2-(4-Isobutyrylylamino-phenylsulfanyl)-6phenylpyrimidin-4-y] (5-methyl-2H-pyrazol-3-yl)-anine \O -292o (IIIa-13): Prepared in a manner similar to the above described Method L to afford an off-white solid, mp 201- 202°C; 'H NMR (DMSO) 8 1.05-1.13 (6H, 1.97 (3H, s), 2.65 (1H, 5.37 (1H, br 6.93 (1H, br 7.50-7.58 (5H, m) 7.78-7.90 (4H, 9.99, 10.12 and 11.84 (3H, 3 x br s);.IR (solid) 1676, 1614, 1586, 1573, 1514, 1483,

VO

DO 1395, 1299, 1262, 1242, 1214, 1168, 1089, 988; MS 445.3 0 S10 Example 198 [6-(4-Methylpiperazin-l-yl)-2-methylsulfanyl-

<D

0 pyrimidin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIIa- 14): Prepared in a manner similar to the above described Method M to afford an off-white solid; 1H NMR (DMSO) 6 2.18 (3H, 2.20 (3H, 2.36 (4H, 2.41 (3H, s), 3.46 (4H, 5.91 (1H, 6.41 (1H, br 9.20 (1H, 11.87 (1H, IR (solid); MS 320.3(M+H)* Example 199 (5-Methyl-2H-pyrazol-3-yl) -[6-phenyl-2-(4propionylamino-phenylsulfanyl) -pyrimidin- 4 -yl] amine (IIIa-15): Prepared..in a manner similar to the above described Method L to afford a pale pink solid, mp 204- 206 0 C; "H NMR (DMSO) 8 1.09-1.13 (3H, 2.00 (3H, s), 2.33-2.37 (2H, 5.40 (IH, br 6.95 (1H, 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 [2-(4-Cyclopropanecarbonylaminophenylsulfanyl) -6-phenylpyrimidin-4-yl] (5-methyl- 2Hpyrazol-3-yl)-amine (IIIa-16): Prepared in a manner similar to the above described Method L to afford an off- -293white solid, mp 253-255 0 C; 1H NMR (DMSO) B 0.82-0.83 (4H, 1.83 (1H, 2.00 (3H, 5.41 (1H, br 6.88 br 7.42-7.50 (3H, 7.56-7.58 (2H, 7.76- 7.78 (2H, 7.89-(2H, 9.99, 10.47 and 11.85 (3H, 3 x br IR (solid)"1672, 1621, 1591, 1581, 1573, 1537, IND 1495, 1448, 1405, 1390, 1312, 1254, 1246, 1202, 1192, IND 1179, 1119.2, 1005, 959; MS 443.2(M+H)* Example 201 (5-Methyl-2H-pyrazol-3-yl)-{6-phenyl-2- [4- (propane-1-sulfonylmino)-phenylsulfanyl] -pyrimidin-4yl}-amine (IIIa-17): Prepared in a manner similar to the above described MetAod L to afford an off-white solid, mp 232-235 0 C; IH NMR (DMSO) 8 0.94 (3H, 1.71 (2H, m), 2.12 3.13 (2H, 5.59 (1H, 7.31 (2H, d), 7.49 (3H, 7.59 (2H, 7.85 (2H, 10.00 (11iH, br 10.16 (11, 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-phenylsulfanyl)-6phenyl-pyrimidin-4-yll-(5-methyl-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- -254cC; 1H NMR (DMSO)l 8 1.21 (3H, 2.12 3.15 (2H, 5.59 (1H, 7.32 (2H, 7.49.(3H, 7.57 (2H, 7.85 (2H, 9.99 (1H, br si, 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) 4 Example 203 2 4 -Acetamidophenyl-sulfanyl)-6-(2methylphenyl) -pyrimidin-4-yl] (5-methyl-2H-pyrazol-3-yl) IND -294o amine (IIIa-19):.Prepared in a manner similar to the above described Method L to. afford a white solid, mp 212- E 214°C; 'H NMR (DMSO) 6 2.01 (3H, 2.08 (3H, 2.24 (3H, 5.43 (1H, 6.56 (1H, br 7.49-7.88 (g9; 10.00 (1H, br 10.23 11.86 (1H, br IR (solidl701, 1634, 1588, 1555, 1496, 1390, 1307, 1208, ND 1169, 823, 803; MS 431.4(M+H) Cq Example 204 2 4 -Isobutanecarbonylamino-phenylsulfanyl) -6-phenyl-pyrimidin-4-yl] (5-methyl-2H-pyrazol- C 3-yl)-amine (IIIa-20): Prepared in a manner similar to the above described Method L to afford an off-white solid, mp. 241-243 0 C; 1H NMR (DMSO) 6 0.95-0.96 (6H, m), 2.00 (31H, 2.11 (IH, 2.23-2.25 (2H, 5.43 (1H, br 6.95 (1H, br 7.50-7.58 (5H, 7.77-7.89 (4H, m),-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-2H-pyrazol-3-yl) -amine (IIIa-21): Prepared in a manner similar to the above described Method L to afford a pale pink solid, mp 276- 277C; 'H NMR (DMSO) 6 1.98 (3H, 2.08 (6H, 5.41 (1H, 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) Example 206 [2-(4-Acetamido-phenyl-sulfanyl)-6-(4methoxyphenyl) -pyrimidin-4-yl] (5-methyl-2H-pyrazol-3yl)-amine (IIIa-22): Prepared in a manner similar to the N -295o above described Method L to afford an off white solid, mp 241-245WC; H NMR (DMSO) 8 1.99 2.06 (3H, 3.82 (3H, 5.44 7.03 (2H, 7.53 (2H, 7.71 (2H, 7.83 (2H, 10.12 (1H1, 10.23 (1H, s), 11.84 (1I, IR (solid) 1627, 1606, 1571, 1511, 1313, 1257, 1181, 830; MS1447.2

(M+H)

Va Example 207 etamidophenyl)- 2-(4-acetamidophenyl-sulfanyl)-pyrimidin-4-yll-(5-methyl-2H-pyrazol-3yl)-amine (IIIa-23)- Prepared in a manner similar to the Ci above described Method L to afford a brown solid, mp 227- 230 0 C; 1H NMR (DMSO) 5 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 (3H, 8.19 (1i 10.09-10.18 (2H, br 10.23 (1H, 12.20 (1H, br IR (solid) 1635, 1573, 1533, 1488, 1372, 1318, 1297, 827, 798; MS 474.3 Example 208 4 -Isopropanesulfonylamino-phenylsulfanyl)-6-phenyl-pyrimidin-4-yll-(5-methyl-2H-pyrazol- 3-yl)-amine (IIla-24): Prepared in a manner similar to the above described 'Method L to afford a white solid, mp 255-257 0 C; H NMR (DMSO) 8 1.28 (6H, 2.14 3.32 (1H, 5.60 (1H, 7.36 (2H, 7.49 (3H, 7.60 (2H, 7.85 (2H, 10.00 (1H, br 10.11 (1H, s), 11.92 (1H, br IR (solid) 1625, 1587, 1574, 1545, 1525, 1495, 1313, 1295, 1257, 1234, 1136, 3000, 934; MS 481.2 (M+H) 4 Example 209 2 -Dimethylamino-acetylamino)phenyisulfanyl] -6-phenyl-pyrimidin-4-yl)-(5-methyl-2Hpyrazol-3-yl)-amine (IIIa-25): Prepared in a manner 1 IND-296- 0I o similar to the above described Method L to afford an offwhite solid, mp 213-215 0 C; 'H NMR (DMSO) 82.00 (3H, s), 2.31 (6H, 3.15 (2H, 5.45 (1H, 6.83 (1H, br 7.46-7.51 (3H, 7.59 (2H, 7.80-7.92 (SH, m), 9.98 (1H, 10.05 IR (solid) 1701, 1617, 1587, 1571, 1509, 1480, 1456, 1304, 1284, 1254, 1238, 1213, ND 1181, 1156, 987, 833, 782, 754, 695; MS 460.3 (M+H) ci .Example 210 [2-(3-Chloro-benzylsulfanyl)-6-morpholin-4- Va yl-pyrimidin-4-yl] (5 methyl-2H-pyrazol-3-y1) -amine 0 (IIIa-26): Prepared in a manner similar to the above described Method M to.afford a white solid, mp 224-225 0

C;

1 NMR (DMSO) 6 2.17 (3H, 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) -pyrimidin4-yl] (5-methyl-2H-pyrazol-3-yl)amine (IIxa-27): Prepared in a manner similar to the above described Method M to afford a white solid, mp 101- 1020C;.XH 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, bra); IR (solid) 1598, 1555 1527, 1336, 1293, 1117, 1079, 974, 783;'MS 405.4 Example 212 [2-Benzysulfanyl-6-(4-methylpiperazin-1-yl) pyrinidin-4-yl] (5-methyl-25-pyrazol-3-yl) -amine

II

(IIIa-28): Prepared in a manner similar to the above described Method M to!lafford.a yellow gumn; 1H NMR (CDC1 3 iL ND -297- O 2.23 (3H, 2.28 (3H, 2.31-2.64 (4H, 3.30- 3.65 (4H, 4.38 (2H, 5.83 (1H, 6.23 (1H, br s 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

VO

ND Example 213 [2-Benzylsulfanyl-6-morpholin-4-yl-pyrimidin- 4-yl (5-methyl-2H-pyrazol-3-yl)-amine (IIIa-29): C Prepared in a manner similar to the above described o 10 Method M to afford an off-white foam; 'H NMR (CDC13) 6 Cl 2.31 (3H, 3.39-3.80 (8H, 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 Example 214 [2-(3-Chloro-benzylsulfanyl)-6-(4methylpiperazin-1-yl) -pyrimidin-4-yl] (5-methyl-2Hpyrazol-3-yl)-amine (IIIa-30): Prepared in a manner similar to the above described Method M to afford a white foam; IH NMR (CDCI 3 8 2.31 (3H, 2.35 (3H, 2.40- 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, IR (solid) 1553, 1514, 1484, 1446, 1277, 1228, 999, 799; MS 430.4 (M+H) 4 Example 215 4 -methoxy-benzylsulfanyl)-6-(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; H NMR (CDC1 3 6 2.28 (3H, 2.33 (3H, 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), \O -298o 7.34-7.36 (2H, IR (solid) 1659, 1554, 1508, 1485, cN 1449, 1366, 1318, 1302, '1277, 1230, 1166, 1146, 1030, S999, 973, 948; MS 443.4 (M+H) C 5 Example 216 [2-(4-Acetamido-phenyl-sulfanyl)-6-tertbutyl-pyrimidin-4-yll -(5-methyl-2H-pyrazol-3-yl) -amine ND (IIIa-32): Prepared in a manner similar to the above described Method L to:afford a white solid, mp 227-2280C; Hq H NMR (DMSO) 5 1.10 (3H, br 1.20 (9H, 2.00 (3H, o 10 2.35 (2H, 5.35 (1H, br 6.55 (1H, br 7.55 0- (2H, 7.75 (2H, 10.1 (1H, br.s), 1.15 (1H, s), 12.1 (1H, br IR (solid); MS (M+H) Example 217 (5-Cyclopropyl-2H-pyrazol-3-yl)- [6-phenyl-2- (4-propionylamino-phenyl-sulfanyl).-pyrimidin-4-yl] -amine (IIIa-33): Prepared in a manner similar to the above described Method L to afford an off-white solid, mp 208- 209 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, 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 (M+H) Example 218 [2-(3-Chloro-benzylsulfanyl)-6- (piperidin-1yl) -pyrimidin-4-yl] (5-methyl-2H-pyrazol-3-yl) -amine (IIIa-34): Prepared in a manner similar to the above described Method M to afford .a white solid, mp 234-235°C; IH NMR (DMSO) 5 1.40-1.64 (6H, 2.13 (3H, 3.42-3.51 (4H, 4.27 (2H, 5.85 (11, br 6.46 (1H, brs), 7.23-7.41 (3H, 7.48 (1H, 9.18 (1H, 11.83 (1H, oS s; IR (solid) 15.98, 1546,' 1483, 1398, 1317, 1227, 974, '798, 779; MS 415.4 Example 219 (S-MethYl-2H-pyraz..3yl..{2.r 4 (morpholinesulfonyl) -benzylsul-fanyl] 6-morpholin-4-yl.

IND Pyrimidin-4-yl}-ominle (IIla-35): Prepa red in a manner IND Similar to the above described Method M to afford a White solid; 'H NMR (D)M50) 8 2.-24 (3H, 2.90-3.02. (4H, mn), Cl 3.29-3.36 (4H, in), 3.48-3.57 (4H, in), 3.67-3.7S (414, m), O 10. 4.43 (2H, 5.82-6.10 (2W, in), 7.50-7.70 (SN, mn); IR (solid) 1550, 1483, 1441, 1346, 1308, 1255, 1160, 1112, 941, 726; MS 532.5 Exampl .e 220 2 -Methoxcy-ethylamino) (4- 1s (morpholinesulfonyl) -benzylsulfanyii -pyrimidin-4-yl.. methyl-2-pyrazol.3y1) -amine (IIla-36): Prepared in a manner similar to the above described Method M to afford a white solid, inp 193-1.95WC; 'H NNR (DMsQ) 5 2.15 (3H, s), 2 .79-2.89 (4H, mn), 3.34 (311, s) 3.40-3.51 (4H, mn), 3.59- 3.-6 7 (4 H, 4. 41 (2H1, 5. 7 6-5. 72 (1H, 6. 20 (1H, brs), .7.10 (12, brs), 7.61-7.74 (4H, mn), 9.03 (1W, brs), 11.81 (Iii, brs); IR'(solid) 1593, 1555, 1484, 1350, 1298, 1255, 1160, 1107, 936; MS'520.s Example 221 (4-methylpiperazin1..yl).2.[4- (morpholinesulfonyl) -benzylsulfanyl] -pyrimiidin-4-yl)- inethy1-2H-pyrazolpa-y)..a 1 in (IIla-37): Prepared in a manner similar to the above described Method M to afford a white solid, mp 206-207c; 3-H 1'ThR (DM50) 8 2.09 (3H1, s) 2.20 (32, 2.26-2.40 (4H,im), 2.78-2.88 (4H1, mn), 3..38- 3.49 (4H1, Wn, 3.56-3.67 (4H1, mn), 4.41 (2H, 5.82 (1K, brs) 6.42 (1H, brs), 7.60-7.74 (4H, mn), 9.26'(1H1, s), IN -300o 11.89 (1H, brs); IR (solid) 1583, 1558, 1479, 1346, 1231, 1160, 1112, 998, 969, 926; MS 545.5 (M+H)V Example 222 [6-Methoxymethyl-2-(4-propionylamino-phenylsulfanyl) -pyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl) amine (IIIa-38): Prepared in a manner similar to the

IO

IN above described Method L to afford a white solid; 1H NMR Ci (DMSO) 8 1.03-1.14 (3H, 2.00 (3H, 2.29-2.40 (2H, Sm), OMe under DMSO, 4.22 (22H, 5.26 (1H, brs), 6.45 Va o 10 brs), 7.44-7.56 (2H, 7.68-7.80 (21, 9.86 0g (1H, brs), 10.11 (1Kj 11.79 (11, brs); IR (solid) 1670, 1593, 1517, 1479, 1393, 1360, 1269, 1174, 1107; MS 399.4 Example 223 [2-(4-Methoxycarbonyl-phenyl-sulfanyl)-6methoxymethyl-pyrimidin-4-yl] (5-methyl-2I-pyrazol-3-yl) amine (IIIa-39): Prepared in a manner similar to the above described Method L to afford a white solid, mp 204- 205WC; 1H NMR (DMSO) 8 1.89 (3H, brs), 3.85 (3H, OMe under DMSO, 4.23 (2H, 5.22 (1H, brs), 6.51 (1H, brs), 7.70-7.81 (2H, 7.96-8.06 (2H, 9.99 (1H, brs), 11.85 (1H, brs); IRi(solid) 1721, 1621, 1583, 1519, 1484, 1289, 1271, 1178, 1119, 1109, 997, 841; MS 386.3 (M+HK) Example 224 [2-(3,5-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; 'H NMR (DMSO) 8 2.15 (3H, 3.40-3.49 (4H, 3.60-3.74 4.25 (2H, s) 5.88 (1H, brs), 6.31-6.61 (5H, 9.32 11.86 IR (solid) 1581, 1556, 1470, 1439, 1315, 1232, 1205, 1159, 1144; MS 443.4 (M+H)V \O -301- Example 225 2 3 ,5 tDimethoxy-benzylsulfanyl)-6pyrrolidin-4-yl-pyrimidin-4-yl (5-methyl-2H-pyrazol-3yl)-amine (IIIa-41) Prepared in a manner similar to the above described Method M to afford a white solid; 1H NMR (DMSO) 8 1.80-1.97 (4H, 2.15 (311, 3.43-3.45 (4H, IND 3.69 (6H, 4.26 (2H, 5.85 (12, brs), 6.18 (1H, brs), 6.35 (1H, brs), 6.60 (2H, 9.12 (1H, 11.88 (11, IR (solidl598, 1560, 1474, 1470, 1346, 1303, 1207, 1136, 1050; MS 427.4 Example 226 (5-Methyl-2H-pyrazol-3-yl)-[6-morpholin-4-yl- 2- (naphthalene- 2 -ylmethylsulfanyl) -pyrimidin- 4 -yl] -amine (IIIa-42): Prepared in a manner similar to the above described Method M Co afford an off-white solid; 'H NMR (DMSO) 6 2.15 (3H, 3.37-3.50 (4H, 3.59-3.70 (4H, 4.48 (21, 5.88 brs), 6.40 brs), 7.40- .7.60 (3H, 7.78-7.95 (4H, 9.30 (1H, 11.89 (1H, brs); IR (solid) 1607, 1555, 1484, 1441, 1398, 1365, 1308, 1231, 1179, 1112; MS 433.4 Example 227 4 -Acetamido-phenyl-sulfanyl)-6-[4-(3dimethylamino-propo r)-phenyl] -pyrimidin-4-yl}- 2H-pyrazol-3-yl)-amine (IIIa-43): Prepared in a manner similar to the above described Method N to afford a white solid, mp 219-222*C; 1H NMR (CDC1 3 6.1.97-2.07 (21, m), 2.14 (3H, 2.18 (3H, 2.30 (6H, 2.52 (2H, t), 4.09 (2H, 5.56 (1H, 6.80 (11, br 6.99 (2H, 7.60 (12H, 7.68-7.78 (3H, 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

(M+H)

4 IND -302- Example 228 4 -Acetamidophenylslfanyl) -6-(morpholin- 4-yl)-pyrimidin-4-yl]- (5-methyl-2H-pyrazol-3-yl)-amine (IIIa-44): Prepared in a manner similar.to the above described Method P toafford a white solid;-MS 426.4 Va Va 2 Example 229 [6-Hydroxymethyl-2-(4-propionylamino-phenyl- 0 sulfanyl)-pyrimidin-4-yl-(5-methyl-2H-pyrazol-3-yl)amine (IIla-45): Prepared from IIIa-48 according to 0 Method O to afford a white solid; 1 H NMR (DMSO) 5 1.08- 1.18 (3H, 1.96 (3H, brs), 2.29-2.40 (2H, 4.20- 4.40 (3H, 5.20-5.46 (2H, 6.56 7.50 (2H, 7.79 (2H, 9.90 (11, brs), 10.13 11.78 (1H, brs); MS 385.4 (M+H) 4 Example 230 [2-(4-Acetamido-phenyl-sulfanyl)-pyrimidin-4yl]- (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 249-250OC; H NMR (DMSO)6 1.99 (3H, 2.08 (3H, 5.38 (1H, br 6.45 (1H, br 7.50 (2H, 7.71 (2H, 7.98 9.89 (1H, br 10.19 (1H, 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-(1-Butoxycarbonyl)-2-(4-propionylaminophenyl-sulfanyl)-pyrimidin-4-ylJ-(5-methyl-2H-pyrazol-3yl)-amine (IIIa-47): Prepared in a manner similar to the above described Method L to afford a.yellow solid, 1H NMR (DMSO) 5 0.90-0.98 (3H, 1.03-1.12 (3H, 1.31-1.45 (2H, 1.60-1.71 (2H, 1.94 (3H, brs), 2.29-2.40 NO -303- 0 (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, brs), 10.32 (11, brs), 11.89 brs); IR (solid) 1736, .1679, 1622, 1584, 1517, 1489, 1284, 1174; MS 455.4 Example 232 E6-Methoxycarbony1-2-(4-propionylamino- ND phenyl-sulfanyl) -pyrimidin-4-yll (5-mnethyl-2H-pyrazol-3yl)-amine (IIIa-48): Prepared in a manner similar to the above described Method L to afford a yellow solid; 'H NMR (DMSO) S 1.10 (3H, 1.94 brs), 2.35 (2H, 3.84 (3H, 5.22 (11, brs), 7.05 (iR, 7.52 (2H, 7.79 (2H, 10.18 (1H, brs), 10.38 bra), 11.89 (11, bra).; IR (solid) 1741, 1679, 1617, 1589, 1512, 1484, 1374, 1284, 1250; MS 413.4 Example 233 (5-Methyl'2-pyrazol-3-yl) (6-phenyl-2phenylamino-pyrimidin- 4 -yl) -amine (IIIc-1): white solid; MS 343.4 Example 234 (5-Cyclopropyl-2H-pyrazol-3-yl)-(6-phenyl-2phenylamino-pyrimidin-4-yl)-amine (IIIc-2): white solid, mp 267-269 0 C; 'H NMR (DMSO) S 0.63 (2H, 0.96 (2H, m), 1.87 6.07 (1H, 6.84 (1H, br 7.20 (11, m), 7.33-8.05 (9H, 10.52 (11, br 11.08 (iH, br-s), 12.53 (1H, br IR I(solid); MS 369.7 Example 235 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3methyphenylamino) -6-phenyl-pyrimidin-4-yl -amine (IIIcwhite solid, mp 267-270C; H NMR (DMSO) 8 0.63 (2H, 0.94 (2H, 1.87 (1Hm), 2.36 6.12 (1H, 6.81 (1H, br 7.03 (1H, 7.29-7.94 (8H, m), 10.43 (1H, br 11.12 (1H, br 12.47 (1H, br IR (solid); MS.383.7 IND -3 04- Examle 236 (4-cyanomethylphenylamino) -6-phenylpyrimidin-4-yl (5-cyclopropyl-2H-pyrazol-3-yl) -amine (II1c-4). pale yellow solid, mp 294-297WC; H NMR (DM50)5 0.64 (2H, 0.9-7 1.89 (1H, mn), 4.,06 (2H, s), 6.07 (i1N, 6.87 (111, br 7.40 (2H, in), 7.63-7.90 IND (SN, 7.95 (2K; in), 10.51 (iN, br 11.02 (1H, br 12.57 (1H, br IR (solid); MS 408.8 (NMiH) t o 10 Example 237 (5-Cyclopropyl-2a-pyrazol-3-yl) 6-phenyl-2ci (pyridin-3-ylmethylamino) -pyrimidin-4-yl] -amine off-white solid, rnp 191-193 0 C; 1N NMR (DMSO) 60.659 (211, 0. 89 (2 H, m)l, 1. 83 (1K, m) 4. 59 (2KH, 6. 04 (1K, br 6.76 (1H, br s) 7.32-7.56 (5H, mn), 7.77 (1K, m), 7.88-7.97 (2H, 8.43,(in, 8.61 (iN, 9.47 (1N, br* sI, 11.93 (IN, br IR (solid); MS 384.8 (M+KP" Example 238 (3-Chiorophenyl) aaino-6- (3-nitrophenyl) pyrimidin-4-ylJ-(S-methyl-2H-pyrazol-3-yl) -amine (I1ic- 6) off-white solid; 'H NMR (CD 3 OD) 6 5. 95 (1H, s) 6. (1H1, 6.90 (iN, 7.18 (iN, 7.32 (1H, 7.58 (iN, 7.82 (iN, 8.18 (iN, 8.25 (iN, 8.65 (1H, s) MS 422.1 Excample 239 [2-(3-Chiorophenyl)amino-6-(3,4,5trimethoxyphenyl) -pyrimidin-4-yl (5-methyl-2H-pyrazol-3yi)-amine (IlIc-7): white solid; MS 467.7 (M+N) t Example 240 Methyl-2H-pyrazol-3-y1)- (4sulfamoylphenylamino) 5-trimethoxyphelyl) pyrimidin-4-yl)-amine (IlIcr8); white solid; MS 512.6 -3 C] Example 241 4 -Chloropheny1) amino-s...methy1..pyrimiainwhite solid; MS 367.1:' 4 Example 242 (Ben 'imidazo-2-yamino.) 6-ethyl- INDpyrimidin-4-yl (S-methyl-2Hpyrazo.3.yl) -mine (IlI Icion MS 335.5 C]Examle 243 4 -Ch-lorophen yl) amino- 6-methyl-pyrimin.

o 10 4-ylJ -(5-phenri-2H-pyrrazo.3.y1) -amnine (I11c-11): MS C] 377.5 (M+HV* Examle 244 4 -Chlorophenyl)amino6-ethy..pyriaiin.4 yl] -(5-methyl-2H-pyazo.3.y)..mij (IIIc-12): MS 329.4 F~xap e 2 45A (S-tert-Butyl-2pyazo.3.yl) (3chiorophenyl) an~ino 6- 3 -nitrophenyl) -pyrimidin- 4-yl] amine (IIlc-13): off-white s olid; 1H NMR (CD 3 OD) 8 1.32 (9H, 6.18 (1K, 7.04 (1K, 7.14 (1K, 7.33 (1K, 7.58 (1K, 7-82 (1R, 7.91 (i14, 8.35 (1K, 8.40 (1H, 8.90 (1K, MS 464.2 (M+iH) 4 -Example 246 [2 (3 -Chiorophenyl) amino-E6- (3 -nitrophenyl) pyrimidin-4-ylJ (5-Phenyl-2H-pyrazol-3-yl) -mine (IIlc-1L4): 8 off-white solid; 'H NMF. (CD 3 OD) 8 6.66 (1H, s) 7.12 (1K, d) 7.3 0-7.45 m, 7.50 (1K, '7.E2 (2H, 7.78 (lB, t) 7.88 (111, s) 8.35 8.42 (1K, 8.85 (1K, s) MS 48B4.1I PFx 2± (Furan-2-yl) -2E-pyrazoi-3-ylJ 6pey-2phenyl amino -pyrimi dil -4 -y1) -amine (Ilic-15): MS 395.4 IND -306- Exampl1e 248 (Benzimidazol-2-ylamino) -6-methylpyrimidin-4-yl (5-phenyl-2H-pyrazol-3-yl) -amine (IlIc- 16): MS 383.2 (M+H)V Example 249 (Eenzimidazol-2-ylamino) -6-methyl-

IND

pyrimidin-4-yl]- [5-(Furan-2-yl) -2H-pyrazol-3-yl-anine Cl (IIlc-17): MS 373.4 (N-4I)+ oN .10 Example 250 C4-Chlorophenylamin6) -6-methyl-pyrimidin- 0 4-yl]-(S-methyl-2H-pyrazol1-3-yl)-anine (IIlc.-18): MS 315-4 (M+H) 4 Example 251' [2 (4 -Chlorophenyl) amino-S 1 6 -dimethylpyrimidin-4-ylJ -(5-methyl-2H-pyrazol-3-yl) -amine (Ilic- 19): MS 329.4 (NMiH) 4 Example 252 6-Dimethyl-2-phenylamino-pyrimidin-4-yl) (5-methyl-2H-pyrazol-3-yl)-amine (IIIc-20) MS 295.5 (M-iH) 4 Example 253 (4-Chiorophenyl) amino-6-methoxymethylpyrimidin-.4-yl CS-methyl-2H-pyrazol-3-yl) -am~ine (Ilic- 21): MS 345.1 (M+H)V Example 254 [2-(E3enzimidazol- 2-ylamino) -6-methoxymethylpyrimidin-4-yl (5-methyl-2H -pyrazol-3-yl) -amine (Ilic- MS 351.2 (M+H) 4 Example 255 (6-Methoxymethyl-2-phenylalnino-pyrimidin-4yl)-(5-methyl-2H-pyrazol-3-yl)-amine (IIlc-23) MS 311.2 (m+Hi) IND -307- 0 Example 256 (E-Methyl-2..pnenylaino-pyrimidin.4.yl)-.(5.

methy1-2II-pyrazoJ-3y)-amjne (IIlc-24): MS 281.1 4 Example 257 2 .Chlrophenoxymethy1) -6-methylpyrimidin-4-yl] 5 -phenyl-2a-pyrazol-..yl) -amine (Ild- IND MS 392.1 Example 258 2 -Chlorophenoxrnethy1) -6-methylpyrimidin-4-ylJ (furan-2 -yl) -2H-pyrazol-3 -ylJ -amine *(IhId-2): MS 382.1 CM+E) 4 ExU~e 259 (E-rethyl-2-phenoxymethy..pyrimidin.4-.yl) phenyl-2H-pyrazo-3..y1)..nine (IId-3): MS 358.2 Example 260 (S-(Furan-2-y1)2pyrazo3yl(s..methy.2.

PhenoxYmethY1-pyrimidin-4-yl) -amine (lId-4): MS 348.2

(M+H)

4 Example 261 [S-(Furan-2-yl) -2H-pyrazol-3-yl (6-ulethyl-2- PhtflsulfanYlmethy1,-pyrimidin-4-y1) -amine (lIId-5): MS 364.1 (M+HY" Example 262 [6-Methyi-2- (4-methyl-phenylsultanylmethyl) pyrimidin-4-ylJ- (5-phenyl-2H-pyrazol-3-yl) -amine (Id- MS 388.1 Example 263 (Furan-2-yl) -2H-pyrazol-3-yJ [6-Methyl-2- 4 -methyl-phenylsulfanylmethyl) -pyrimidin-4-ylJ -amine MS 378.1 (M+H4)* Example264 (4-Fluoro-phenoxymethyl) -6-methyl- ~~Pyrimidin-4-ylJ- (5-phenyl-2-pyrazol-3.y.) -amine (IIla- MS 376.2 IND -308- Exarpple 265 E2- (4-Fl uoro-phenoxymethyl) -6-methylpyrimidin-4-yl (furan-2-yl) -2H-pyrazol-3-ylJ -amine (Id-SI MS 366.2 (Mi-H)' Example 266 (6-Ethyl-2-phenylsiflfanylmethyl-pyrimidin-4- IND yl) -(5-methyl-2H-pyrazol-3-yl) -amine (IlId-0) MS 326.2 Example 267 (6-Ethyi-2-phienoxynethyl-pyrimidin-4-yl)-(Scimethyl-2H-pyrazol-3-yl)- amine (hIld-li) MS 310.2 Examp~le 268 [6-Ethyl.-2- (4-f luorophenoxymethyl) -pyrimidin- 4-y] (5-methyl-2H-pyrazol-3-yl) -amine (hId-12): MS 328.2 Example 269 EG-Ethyl-2- (1 -methyl-1I-phenayl -ethyl) pyrimidin-4-ylJ (-methyl-2H-pyrazol-3-yl) -amine (h11d- 1k3): MS 322.2- Example 270 (4-Chlororophenoxynethyl) 6-methylpyrimidin-4-yl (5-phenyl-2H-pyrazol-3-yl) -am~ine (111d.- 141: MS 392.2 (M+H)t Example 271 (2-(4-Chbororophenoxynethyl) -6-methylpyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl} -amine (1116.- MS 330.2 *Example 272 (4-Chiororophenoxymethyl) -6-methoxymethylpyrimidin-4-ylJ- (5-methyl-2H-pyrazol-3-yl) -amine 41116.- 16): white solid; 1 H.NNR (DMSO) 5 2.20 (3H, 3.43 (3H!, s),49 (2H1, 5.20 (21, 6.0.5 (in, br), 7.05 (2E, 7.33 (2H1, 10.55 (111, br); MS 360.,2 -309- Exaniple 273 4 -Chlororophenos-ynethyl) -6-methylpyrimidin-4-ylJ (furan-2-yl) -2H-pyrazol-3-yl] -amine (IIld-17). MS 382.2 IND Example 274 (S-Methy1 '-2H-pyrazo1-3-yl) INDphenylsulfanylmethyl-s,E,7, 8-tetrahydro-quinazolin4.yl) amine (Ild-7): MS 352.5 (M-iH)' o 10 Example 275 4 -Methylphenylsulfanyl-methyl) 8,9ci tetrahydro-5H-cycloheptapyrindin.4ylJ (5-methyl-2rpyrazol-3-yl)-amine (Ild-8):Ms 380.2 tetrahydro-5-cyc3oheptapyrimiin4.yl) (5-methyl-2Hpyrazol-3-yl)-anine (IId-9): -MS 362.3 (M+1D 4 Example 277 2 6 -Dichlorobenzyl)-5,,7,-tetrahyro.

qu inazclin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (lid- MS 388.1l ExamQle 278 E 7 -Eenzy1-2-(2,s-dichorobenzyv...,,7,..

tetrahdropyrido [3,4dpyrimiin4.yl] pyrazol-3-yl)-amine (lid-1l): MS 479.5 (M+H) 4 Example 279 [6-Eenzyl-2- (4-chlorophenoxymethyl)-5,s,7,atetrahydro-pyrido 4 1 37dlpyrimidin-4-yl (5-methyl-2Hfpyrazol-3-yl)-amine (Ild-l2): MS 461.2 (M+E) 4 Examle 280 2 4 -Chlorophenoxrmethyl).-s,6,7,8tetrahydro-pyrido 4 3 -dlpyrimidin-4-yl (5-methyl-2Hpyrazol-3-yl)-arine (lid-13): MS 371.3 (M+Hi)+ -310- Example 281 5-Dichlorobenzyl) -S-methyl-pyrimidin-4ctyl]- (5-methyl-2H-pyrizol-3-yl) -amine (IIId-18): MS 348.1 IND pyr::::2;tyl-(tZ '::yl2;22;?aol3-y:Z±i (111d- Cl19): whtesli; 1-*NMR (DM50) 0 8.50 (111, 7.70 (lI-, 0 7.3-7.1 (311, m),-5.25 (1H1, 4.10 (111, 2.30 IND 10 (31-H, s) 2. 10 (311, s) 1. 80 (311, s) MS 3 62. 1 Example 283 (LH-Indazol-3-yl) (2-phenyl-cyclopropyl) quinazolin-4-yl]-ani'ne (lid-is):- 1 HflMR (DMSO) 13.2(111, s), 12.0(1-H, 8.76(1W mn), 8.10(111, mn), 7.85(2H, in), 7.75(111, mn), 7.61(111, in) 7.41(114, in), 7.30(2H1, m), 7.20(2H1, in), 7.12(21,, in), 2.35(2H1, in), 1.60(111, M), 1.35(111, mn); MS: 378.1 NHi; HPLC Rt=3.21 min.

Example 284 (7-Fluoro-1H-indazol-3-yl) (2-phenaylcyclopropyl) -quinazolin-4-ylJ-amine (116-17): 'HEMP. 13.8(111, 12.05(1-H, 8:75(111, in), 8.10(111, m), 7.85(2H1, mn), 7.E0(1H, in), 7.35(3H1, m) 7.25-7.10(4H1, m), 2.35(2H1, mn), 1.60(11, in,13(Ht;MS: in/z, 396.1 MH+; 11PLC Rt,=3.26 min.

Examle 2 8S (5-Fluoro-1Ii-indazol-3-yl) E2- (2-phenylcyclopropyl) -quinazolin-4-yl) -amine (116-18): 'HNMR 13.3(111, 12.0(1k1, 8.75(111, mn), 8.10(111, m), 7.85(2H1, mn), 7.65(21, in), 7.35(3H1, mn) 7.20(111, m), 7.10(21, in) 2.40 (211, mn), 1.65(111, in), 1.35(111, in); MS:.

in/z, 396.1 MH+; HPLC Rt=3.26 min.

ID -311- O Example 286 (5-Methyl-1H-pyrazol-3-yl)- 2 -phenylcyclopropyl)-quinazolin-4-yl]-amine (IId-19): 1 HNMR (DMSO) S12.8 (1H, 11.90(1H, 8.80(1H, 8.10(1H, m), 7.85(2H, 7.30-7.20(5H, 6.55 (1H, s) 2.80 (1H, m), Cl 5 2.55(1H, 2.35 (3H,s) 2.00(2H, MS: m/z, 342.1 MH+; HPLC Rt=3.13 min.

VO

VO

BIOLOGICAL TESTING e The activity of the compounds as protein kinase o 10 inhibitors may be assayed in vitro, in viva or in a cell 0 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-30 (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 NaCI, 300 pM NADH, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the.assay were 20 pM ATP (Sigma Chemicals, St Louis, MO) and 300 pM peptide \O -312o (HSSPHQS(PO3H 2 )EDEEE, American Peptide, Sunnyvale, CA).

ci Reactions were carried out at 30 °C and 20 nM GSK-3p.

SFinal concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 zM 5 NADH, 30 pg/ml pyruvate kinase and 10 pg/ml lactate dehydrogenase.

VO

0D An assay stock buffer solution was prepared containing all of the reagents listed above with the exception of ATP and the test compound of interest. The cI assay stock buffer solution (175 pl) was incubated in a 96 well plate with 5 1l of the test compound of interest at final concentrations spanning 0.002 M 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 il of ATP (final concentration 20 M).

Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 min at 30 C. The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 M for GSK-3: IIa-2, IIa-3, IIa-8, IIa-9, IIa-11, IIa-12, IIa-17, IIa-18, IIa-21 to IIa-24, IIa-26, IIa-28, IIa-30 through IIa-32, IIa-39, IIa-43, IIa-46, IIa-47, IIa-61, IIc-3, IIc-6, IIc-8, 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-i, IIIa-2, IIIa-3, IIIa- 6, IIla-17, IIIa-18, Ilia-24, IIa-27, IIIc-2 through IIIc-9, IIIc-11, IIIc-12, IIIc-15, IIIc-18, IIIc- -3 13o 19, IIIc-21, IIlc-24, IIIb-1 through IIIb,-E, IIIb-8 through Ilb-lO, IlIb-1'3, IIIb-14, IIId-20, 1116-21,. lId- Ct 14, and id-iS.

__The follow ing compounds were shown to have Kj values between 0.1 and 1:0 .M for GSK-3: ha-i, II&-4, Iha-S 1 Iad-7, Ila-14', IIa-l'5, IIa-20, IIa-29, Ila-34 through IIa-36, IIa-'38, Ila-41, IIa-42, IIa-48, Ila-54, IIa-SS, IIa-62, Ila-.63, Ila-E6, Iha-ES, IIa-78, IIc-1, ci IIc-2, tIc-4, IIc-S, IIc-7, IIc-S, IIc-13, I1c-14, hIcoN 10 16, IIc-17, IIc-iS, IIc-23, IIc-26, I1c-28, IIc-29, I 033, IIc-34, IIc-40, Ilc-41, I1c-43 through IIc-4S, Ilc-47 through Ic-52, IIc-$4 through IIc-57, lic-ES, IIc-63 through I1c-66, IIc-72, 11c-75, I1c-76, IIc-79, I1c-6, lIb-7, IIb-9, 116-2, 116-5, 116-6,. il~a-i, IIIa-4, Ila- 5, IIa-7, ila-B, Illa-10, Illa-il, Illa-iS, IIla-22, IIIa-23, IIIa-26, IIIa-29, IlIa-30, Il~a-3i, IIa-33, IIla-34, IIIa-37, IIIa-42, IlIc-l, IIIc-B, IIIc-20, IlIc- 23, IlIb-7, Tu~b-li, IIb-12, IlIb-is, IlIbI-is, 116-16, 116-17, and Ild-ia.

The following compounds were shown to have Ki values between 11'0 and 7.0 p.M for GSK-3: Ila-lO, ha-is, Ila-2S, Ila-40, I Ia-45, Ila-49, Ila-SO through Ila-52, IIa-64, hla-ES, Ila-67,''Ila-EB, Ila-71, IIa-72, Ila-74-, IIa-76, Iia-77, IIa-81, Ilc-58, Ic-EQ, 1 1Ic-62, Ilc-EB through 11c-71, IIcL74, l16-3, 116-4, lia-iS, hhla-16,' IIIa-21, IIla-2B, IIIa-35, Ila-3E, lila-3B, IIIa-41, IIIa-43, hIIa-45, ITIa-49, IIIc-lO, 111&-1E, Ihc-i7, and IIIc-22.

.BIOLOGICAL TESTING EXAMPLE 2 Ki- DETERMINATION. FOR THE INHI131TION OF AJRORA-2 Compounds were screened in the following manner for their ability to. inhibit Aurora-2 using a. standard IN -314- 0 o coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249).

E To an assay stock buffer solution containing 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 kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and

\O

ID 800 uM peptide (LRRASLG, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present Ci invention to a final concentration of 30 pM. The

\O

resulting mixture was incubated at 30 'C for 10 min. The Ci reaction was initiated by the addition of 10 pL of Aurora-2 stock solution to give a final concentration of nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over a 5 minute read time at 30 OC using a BioRad Ultramark plate reader (Hercules, CA) The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 p M 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-1 through IIIa-8, IIIa-10 through IIIa-13, IIIa-15 through IIIa-32, IIIa-36 through Ilia- 41, IIIa-44 through IIIa-49, IIIc-1 through IIIc-5, IIIc- 12, and The following compounds.were shown to have Ki values between 0.1 and 1.0 pM for Aurora-2: IIa-20, IIa- 65, IIa-67, IIa-70, IIa-80, IIc-14, .Ic-66, IId-5, IId-6, IIIa-14, IIIa-33 through IIIa-35, IIIc-9, IIIc-11,. IIb- 1, IIIb-2, IIIb-7, IIIb-10 through IIIb-13, IIIb-16, and -315- 0 .The following compounds were shown to have Ki values between 1.0 and 10.0 pM for Aurora-2: IIa-10, IIc- 71, IIc-75, IIc-76, iId-4, IIIa-42, IIIa-43, IIIb-3-6, IIIb-8, IIIb-9, and IIIb-14.

ci BIOLOGICAL TESTING EXAMPLE 3 Va CDK-2 INHIBITION ASSAY Compounds were screened in the following manner C -for their ability to inhibit CDK-2 using a standard

VO

o coupled enzyme assay (Fox et al (1998) Protein Sci 7, Ci 10 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgC1 2 1 mM DTT, 25 mM NaC1, 2.5 mM 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 iL 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 iM for CDK-2: IIa-14, IIa-36, IIc-27, IIc-32, IIc-53, and IIIc-4.

ND -316o The following compounds were shown to have Ki values between 1.0 and 20.0 pM for CDK-2: IIa-38, SIIa-44, IIa-52, andIIa-54.

BIOLOGICAL TESTING EXAMPLE 4 ERK INHIBITION ASSAY k\ Compounds; were assayed for the inhibition of C< ERK2 by a spectrophotometric coupled-enzyme assay (Fox et C al (1998) Protein Sci 7, 2249). In this assay, a fixed cO o 10 concentration of activated ERK2 (10 nM) was incubated 0 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 upM NADH, 150 pg/mL pyruv-ate kinase, 50 pg/mL lactate dehydrogenase, and 200 uM erktide peptide. The reaction was initiated by. the addition of 65 pM ATP. The.rate of decrease of absorbahce at 340 nM was monitored. The ICso was evaluated from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 1 p-M for ERK-2: IIc-15, IIc-27, IIc-32, IIc-53, and IIIc-4., The following compounds were shown to have Ki values between 1.0 and 20.0 pM for ERK-2: IIc-18, 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 MgC12, 25 mM l ,C -317- SNaCl 1 mM DTT and 1.5% DMSO. Final substrate .concentrations in the assay were 170 uM ATP (Sigma SChemicals) and 200 jM 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, IND 300 pM NADH, 30 pg/ML pyruvate kinase and 10 pg/ml lactate dehydrogenase.

g An assay stock buffer solution was prepared o 10 containing all of the reagents listed above, with the (C 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 ul 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 pl 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 IC 50 values.

The following compounds were shown to have Ki values between 1.0 and 20.0 pM 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.

\0 -318- 0 O Src Inhibition Assay A: Radioactivity-based Assay The compounds were assayed as inhibitors of t full length recombinant human Src kinase (from Upstate Biotechnology, cat. no. 14-117) expressed and purified from baculo-viral cells. Src kinase activity-was monitored by following the incorporation of "P from ATP

NO

IND into the tyrosine of a random poly Glu-Tyr polymer e- substrate of composition, Glu:Tyr 4:1 (Sigma, cat. no.

C P-0275). The following were the final concentrations of cO the assay components: 0.05 M HEPES, pH 7.6, 10 mM MgC1 2 2 0 mM DTT, 0.25 mg/ml BSA, 10 pM ATP (1-2 pCi "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 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 "P-ATP. After 20 min of reaction, the reactions were quenched with 150 pl of trichloroacetic acid (TCA) containing 20 mM Na 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

PO

4 and.then 4 times with methanol. 200l ofscintillation 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 kineticsimodel to get the Ki for the compound.

O -319- Src Inhibition Assay B: Spectrophotometric Assay SThe ADP produced from ATP by the human recombinant Src kinase-catalyzed phosphorylation of poly Glu-Tyr substrate-was quanitified using a coupled enzyme NO assay (Fox et al (1998) Protein Sci 7, 2249). In this assay one molecule of NADH is oxidised to NAD for every molecule of ADP produced in the kinase reaction. The adisappearance of NADH can be conveniently followed at 340 o 10 nm.

C( 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 M NADH, 30 pg/ml pyruvate kinase and 10 ug/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 pM 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, Ic-1, -1 IIc-19, IIc-21 through IIc-24, IIc-31 through IIc-35, IIc-37 IN -320o through IIc-39, IIc-41 through IIc-44, IIc-51, Ild-i, IId-2, IIIa-1, IIIa-6 through IIIa-8, IIIa-26 through and IIIc-1 through IIIc-S.

The following compounds were shown to have a Ki value of between 100#M and 11M for. SRC: IIa-i; IIa-2, IIa-7, IIa-9, IIa-12, IIa-14, IIa-22, IIa-25, IIa-26, Va ND IIa-29, IIa-34 through IIa-42, IIa-46, IIa-47, IIa-49 through IIa-52, IIa-56, IIa-57, IIa-59, IIa-l61, IIa-62, i IIa-66, IIa-67, IIa-s69, IIa-72, IIa-73, Ila-75, IIb-6, o 10 Ib-8, IIc-4 through IIc-7, IIc-9, IIc-11, IIc-12, IIc- 04 14, IIc-G16, 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-6.5, 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 1M and 6M for SRC: IIa-13, IIa-44, IIa-45, IIaI48, IIa-54, IIa-55, IIa-63, IIa-68, IIa-70, IIa-71, IIa-74, Ia-77, IIa-78, Ia-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 Ia-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 bi way of example.

Claims (5)

1. A compound of formula IIa: IND R 2 R L- N H H N CN Ry .R N S-R' IIa or a pharmaceutically acceptable derivative or prodrug thereof, wherein; 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 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 IN -322- o substitutable ring nitrogen of Ring D is independently substituted by -R T is a valence bond or a C1-4 alkylidene chain; Z is a CI-4 alkylidene chain; L is -SO2-, -SOzN(R 6 -N -CO2-, -N CO-, -N (R 6 C 0-, Va -N(R6SON(R)-, -N(R6)N(R6-, -C(0)N(R 6 C(R6)20-, -C(R6)2S-, -C.(R6)2SO-, 2 SO 2 -C(R 6 2 S0 2 N R) -C (R 6 2 N(R) -C(R6),N 2 N(R5)C -C(R6) 2 -C(R6)=NN(RE)-, o -C(R 6 -C(R) 2 N(R')SO 2 N(R 6 or -C 2 N (R)CON(R) R2 and R2 are independently selected from -T-W-R6, or R2 and 2R are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R2 is independently substituted by halo, oxo, -CN, -NO2, -R7, or -V-R6,.and each substitutable ring nitrogen of said.ring formed by R2 and R2 is independently substituted by R4; R3 is selected from -haio, -OR, -C02R, -COCOR, -COCH2COR,.-NO2, -CN, -S(0)2R, -SR, -N(Rt)2, -CON(R 2 -SO2N(R 7 -N(R 7 )COR, -N(R 7 )CO2 (C- 6 aliphatic), -C=NN(R 4 )2, -C=N-OR, -N(R 7 )CON(R2,, -N(R SON(R 7 2 -N(R4)SO2R, or -OC(=0)N(R )2; each R is independently selected from hydrogen or an optionally substituted group selected from CI-6 aliphatic, Cs-o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; IO -323- each R 4 is independently selected from -R 7, -COR 7 -CO 2 (optionally substituted C 1 6 aliphatic), -CON 2 or -S0 2 R 7 each R5 is independently selected from halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO2R, -SR, -N(R 4 2 -CON(R 4 -SO 2 N (R 4 2, -N(R 4 )COR, NO IND -N (R4 02 (optionally substituted Cj_(5 aliphatic), -N(R )N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R )CON(R'), -N(R 4 )SO 2 N(R) 2 -N(R 4 )SO 2 R, or -OC(=)N(R)2 \O V is -SO2-, -N(R 6 )S 2 -SO 2 -N(R 6 -C0 2 -N(R')SO 2 -N(R 6 -C(R 6 )2 0 2 SO-, -C(R) 2 2 SO 2 -C(R 6 2 N(R 6 -C(R5)2N(R6)C{O)-, -C(R6)2N](R6)C{O)O-, -C(R 6 -C(R 6 2 N(R 6 )N(R 6 -C(Rt) 2 N(R')S 2 N(R) or C (R 6 2 N CON (R 6 W is -C(R 6 2 -C(R 6 2 -C(R 6 2 SO-, 2 SO 2 -C (R 6 2 S 2 N(R 6 2 N(R 6 -CO 2 -C(R 6 -C(R 6 OC N -C(R) 2 N(R 6 CO-, -C(R5)2N(R6)C(0) O_ -C(R -C(R 6 2 -C(R 6 2 N(R 6 )SO 2 N(R 6 -C(R 2 N CON(R) or -CON(R 6 each R 6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken.together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an optionally substituted 6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form 'a 5-8 membered heterocyclyl or heteroaryl ring. D -324- 2. The compound according to claim 1, wherein said compound as one or more features selected from the group consisting of: C< Rx and R Y are taken together with their intervening atoms to form a fused, unsaturated V. or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, O sulfur, or nitrogen, wherein each substitutable IND ring carbon of said fused ring formed by R x and O 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 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 3. The compound according to claim 2, wherein: 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 x and R Y is independently substituted by oxo, T-R 3 or L-Z-R 3 and each substitutable ring nitrogen of ND -325- O said ring formed by R x and R Y is independently substituted by R 4 S(b) R- 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 M\ aryl or heteroaryl ring; R 2 is -R or. -T-W-R 6 and R 2 is hydrogen; or R 2 and 0 2,' Ci R are taken together to form an optionally Ssubstituted benzo ring; and 0 R 3 is selected from -halo, -OR, or -N(R4). c2 4. The compound according to claim 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; 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 R 3 is selected from -halo, -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, and L.is or -N(R 4 The compound according to claim 4, wherein: IN -326- o S(a) R 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 I\N aryl or heteroaryl ring; R 2 is -R and R 2 is hydrogen, wherein R is 0 selected from hydrogen, CI- 1 aliphatic, phenyl, a IN 5-6 membered heteroaryl ring, or a 5-6 membered o heterocyclic ring; and R 3 is selected from -halo, -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, and L is or -N(R 4 6. The compoundaccording to claim 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 CI- 4 aliphatic and R 2 is hydrogen; R 3 is selected from -OR, or -N(R4) 2 wherein R is selected from hydrogen, C1- 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 IND -327- D -N(R 2 optionally substituted C 1 aliphatic .group, -OR, -CO 2 R, -CONH (R 4 -N(R COR, -N.(R)CO 2 R, S0 2 N(R 4 2 -N(R 4 SOR, -N (R 6 COCH2N (R 4 -N(R COCHCH2N (R 4 2, or -N (R6) COCH2CH2CH2N(R4)2, wherein R is selected from hydrogen, C 6 -e aliphatic, phenyl, a 5-6 \O membered heteroaryl ring, or a 5-6 membered *heterocyclic ring. VO 7. The compound according to claim 6, wherein: a Rx and 'R are taken together to form a benzo, pyridb, 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; 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- 6 aliphatic group, -OR, -CO 2 R, -CONH(R 4 -N(R)COR, -N(R 4 )CO 2 R, -SO 2 N(R 4 -N(R 4 2 SOR, -N COCH 2 N (R 4 2 -N COCH 2 CH 2 N(R 4 2 or -N (R)COCH 2 CH 2 CH 2 N(R4)2, wherein R is selected from hydrogen, C 1 -e aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring: IND -328- o 8. A compound selected from the group consisting of: Ct (5-Methyl-2H-pyrazol-3-yl) -(2-phenylsulfanyl- gquinazolin-4 -yl) -amine; (4-Oblorophenylsulfanyl) -guin azolin-4-ylJ (-methyl- 2H-pyrazol-3 -yl) -amine; IND ID[2- (2,4-Dichlorophenylsulfanyl) -guinazolin4-l-(- ci methyl-2H-pyrazol-3-yl) -amine; 0 (4-Methoxyphen'ylsulfanyl) -quinazolin-4-yl] oN methyl-2H-pyrazol- -y1) -amine; 0 1[2- (2-Ethyiphenylisulfanyl) -guinazolin-4-yl]- 2H-pyrazol-3-yl) -amine; [2,4-Eis(trifluoromethyl)phenylsulfanyll -quinazolin- 4-yl}- (5-methyl-2H-pyrazol-3-yl) -amine;

12- (2-Chlo~rophenylsulfanyl) -guinazolin-4-yl 2H-pyrazol-3-yl) -amine; 12- 3-Dichiorophenylsulfanyl) -quinazolin-4-yll Tnethyl-2H-pyrazol-3r.yl) -amine; (3-Chlorophenylsulfanyl) -guinazolin-4-ylJ 2H-pyrazol- 3-yl) -amine; (l-Methylimidcizol-2-ylsulf anyl) -quinazolin-4-yll methyl-211-pyrazol-3-yl) -amine; 12- (2-Hydroxyphenylsulfanyl) -cpinazolin-4-ylJ methyl-2H-pyrazol-3-yl) -amine; (2,4-Difluorophenylsulfanyl) -guinazolin-4-yl] methyl-2R-pyrazol-3-yl) -amine; (3.,4-Dimethoxyphenylsulfanyl) -guinazolin-4-yl] methy1-2H-pyrazol-3-yl) -amine; (3-Methyiphenylsulfanyl) -quinazolin-4-yl 2H-pyrazol-3-yl) -amine; 12- (2-Methoxyph~nylsulfanyl) -quinazolin-4-ylJ methyl-2H-pytazol-3-yl) -amine; -329- o (2-Naphthalenylsulfanyl) -quinazolin-4-yl] 2H-pyrazol-3-yl) -amine; (2,6-Dichlorophenylsulfanyl) -guinazolin-4-yl] methylL-2H-pyrazol-3-yl) -amine; 3 1 4'-Dichlorophenylsufany.) -guinazolin-4-yl] methyl-2H-pyrazol-3-yl) -amine; IND (Benzimidazol-2-ylsulfanyl) -quinazolin4-y.] *methyl-2H-pyrazol-3-yl)yamine; 0 (2-Aminophenylsulfanyl) -uinazoln-.4-y] No 2H-pyrazol-3-yl) -amine; *(S-CyClopropyl-2H-pyrazol-3-yl) -(2-phenylsulfany.- quiniazolin-4-yl) -amine; (5-Cyclopropyl-2H-pyrazol-3y1)_ -[2-Ca3- me thoxycarbonylphenylsulf anyl) guinazol in-4 4-yl amine; (S-CyclopropylS2H-pyrazol-3-yl) (3- methylphenylsulfanyl) -quinazolin-4-ylJ -amine; (5-Cyclopropyl-2n'-pyrazol-3-yl)- (3- methoxyphenylsultanyi} -quinazolin-4-yl) -amine; (5-Cyclopropyl-2H-pyrazoa-3-yl) (a,4- dimethoxyphenylsulranyl) -guinazolin-4-ylJ -amine; (3-Carboxyphenylsulfanyl) -guinazolin-4-yl) cyclopropyl-2M-pyrazoa-3.yl) -amine; (S-Cyclopropyl-2n-pyrazol-3.yI) (naphtalen-2- ylsulfanyl) -quinazolin-4-yl) -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (2,4- dif luorophenyl sulr anyi) -quinazolin- 4-ylI amine; (5-Cyclopropyl-2.u-pyrazol-3-yl) (naphthajlen-2- ylsulfanyl) 8- tetrahydroguinazolin-4-ylJ -amine; (S-Cyclopropyl-21--pyrazol-3-yl) (2,3- dichlorophenylsulf anyl) -quinazolin-4-ylI -amine; (3-Chlorophenylsulfanyl) -gninazolin-4-yl) cyclor-ropyl-2H-pyrazol-3-y1) -amine; IND -330- o (2-Chiorophenylsulfanyl) -guinazolin-4-yl cyclopropyl -2H-pyrazol amine; ct ~(5-Cyclopropyl-2H-pyrazol-3-yl) (3,4- dimetbylphenylsulfanyl) -quinazolin-4-yl] -amine; (N (Benzimidazol-2-ylsulfanyl) -quinazolin-4-ylJ cyclopropyl-2H-pyrazcl-3-yl) -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (4- methoxycarbon:Vlphenylsultanyl) -quinazolin-4-yl] -amine; 2 2- (4 -Acetamido-phenylsulf anyl )-quinazolin-4-yl) o cyclopropyl-2H-pyrazol-3-yl) -amine; (N C5-Cyclopropyl-2Hl-pyrazol-3-yl) (naphthalen-1- ylsulfanyl) -quinazolin-4-yl) -amine; (4-Acetamidophenylsu.fanyl) -quina.zolin-4-yl] methyl-2H-pyrazol-3-yl) -amine; (4 -Methane sultfonyl amino -phenyl sul fanyl) -quinazolin- 4 -yl]I (5 -methyl 2H-pyrazol -3 -yl) amine; (4-Acetamidophenylsulf anyl) -7-methoxy-guinazolin-4- yl) (5-metlhyl-2Y1-pyrazol-3-yl) -amine; (4-Acetatnidophenylsulf anyl) 8- (3-morpholin-4 -yl- propoxy) -quinazolin-4-yl] (5-rethyl-2.H-pyrazol-3-y.) amine; (4-Methoxycarbonylphenylsulfanyl) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl) -amine; (4-Carhoxyphe-nylsulfanyl)'-guinazolin-4-ylJ methyl-211-pyrazol-3-yl) -amine; 2- (4-Acetamidophenylsulfanyl) -8-methoxy-quinazolin-4- ylJ (5-methyl-2H-pyrazol-3-yl) -amine; (4-Acetamidophenylsulfanyl.) (3-morpholin-4-yl- propoxy) -quinazolin-4-yl] (5-methyl-2RH-pyrazol-3-yl) amine; (4-Bromophenylsulfanyl) -quinazolin-4-yl] 2H-pyrazol-3-yl) -amine; IND -331- 0 {B-Bromophenylsuxfanya) -guanazolin- 42yl] -(S-methyl- 2H-pyrazol-3-yl) -amine; ct 4 -IsoProPanesilnfonyl amino phenylsultanyl) uanazolin-4-yl (5-rmethy-2Hpyrazo-3-yl)amine; c-I 7(4-:Isobutyrylamino-phenyasulfanyl) -quinazolin-4-yl] (S-methyl-2R-pyrazoj-3-y1) -amine; IND (S-Methyl-2.H-pyrazolp3.yl) (4 -propi onyl amino- Ci phenylsulfanya) -quinazolin-4-ylJ -amine; o (4-cyclopropanecarbonylamino-phenylsuafanyl) IND quinazolin-4-yl) (S-methyl-2H-pyrazol-3pyl) -amine; (4-Acetamido-phenylsulfanya) -8-hydroxyqluinazolin.4- yl (5-methyl-2H-pyr azolp3. 1 -amine; (4-Acetamido-phenylsulfany1) 7 -nitroquinazolin-4- ylJ (5mty-2-y. ao3yl-amine; (S-Methy1-2H-pyrazolp3.l) (propane-i- sulfonylamino) -phenyisulf yjq'nzln4yIl}-amine; (4-EthylsulfonPlamino-phenylsuifanyi) -quinazoiin-4- yl (5-methyl-2H-pyt-azol-3.y1)-amine; 4 -Acetamido-phenyls-ulfanyl) -7- hydroxyaminoquinazoflin4-y]-(5-methyi-2s'-pyrazop>yl) amine; (4 -Isobutanecarbonyiamino-phenylsulf any1) quinazolin-4-yi) (S-methyi-2H-pyrazoi-3.y1) -amine; (4-tr-uo -peysufnl- *guinazolin-4-y.]- (S-nmethyt-2H-pyrazo>3.y1) -amine; 4 -Acetamido-phenyasuifanyi) 7 -aminogjuinazoiinl4- yl) (S-methy1-2H-pyr; zol-3.yl) -amine; CS-Methyl-2H-pyrazos-3. 7 y{- 2 [4-(2-mo~rpholin-4-yp. acetylamino) -phenylsuitanyij -guinazolin-4-yl}-amine; (S-Cycloprpyl-2H-pyrazolp3.y) methYlsulfonylamino-phenylsulfanyl) -quinazolin-4-yl amine; :1 IND -332- o (4-Amino-phenylsulfanyl) -quinazolin-4-yl] 2H-pyrazol-3-yl) -amine; (4-Acetamido-phenylsulfanyl) -quinazolin-4-yll -(2H- pyrazol-3-yl) -amine;, (5-Ivethyl-2H-pyrazol-3-yl)-{2- (4-mcrpholin-4-yl- butyrylamino) -phenylsulfanyl] -quinazolin-4-yl}-amine; V.0 (5-Methyl-2H-pyrazol-3-yl) (2-morpholin-4-yl- ethylcarbamoyl) -phenylsulfanyl] -quinazclin-4-yl}-amine; 0 [8-Methoxy-2- (4-methylsulfonylaminc-phenylsulfanyl) oN quinazolin-4-yl] (-methyl-2H-pyrazol-3-yrl) -amine; 0 (2-Dimethyl~amino-ethylcarbamoy-) -phenylsulfanyl] quinazolin-4-yl}- (5-methyl-2H-pyrazol-3-yl) -amine; 1 2- (2-Timethylamino)-acetylamino) -phenylsulfaniyl] guinazolin-4-yl} (-methyl-2R-pyrazol-3-yl) -amine; [S-Hydroxy-2- (4-methylsulfonylamino-phenylsulfanyl) quinazolin-4-yl] C5methyl-2H-pyrazol-3-yl) -amine; [4 (3 -Dimethylamino-propylcarb Lmoyl) phenylsulfanyl] -guinazolin-4-yl}- (S-methyl-2H-pyrazol-3- yl) -amine; (3-Oimethyiamino-propionylamino) -phenylsulfanyll quinazolin-4-yl (5-methyl-2.H-pyrazol-3-yl) -amine; 12- (4-Acetamido-phenylsulfanyl) -8-methoxy-quinazolin-4- yll (5-cyclcpropyl-2H-pyrazol-3-yl) -amine; (4-Acetainidophenylsulfanyl) -8-(3-d'imethylamino- propox-y) -quinazolin-4-yl] (-methyl'-2H-pyrazol-3-yl) amine;

112- (4-Acetamidophenylsulfanyl) -7-hydroxy-quiflazolin-4- yl (5-methyl-2H-p ,razcl-3-yl) -amine; (4-Acetamidophenylsulfanyl) (3-dimethylamino- propoxy) -guinazolin-:4-yl] (-methyl-2H-pyrazol-3-yl) amine; O y -333- CD (2-{4-[2-(tert-Butoxycarbonyl-methyl-amino)- S2H-pyrazol-3-yl)-amine; S(' 2 2 -Methylamino-acetylamino) -phenylsulfanyl] quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine; [2-(4-Acetamidophenylsulfanyl)-8-fluoro-quinazolin-4- VO \D yl] -(5-methyl-2H-pyrazol-3-yl)-amine; and (1IH-Indazol-3-yl) (2-phenylsulfanyl-quinazolin-4-yl)- S amine. VO 0 9. A composition comprising a compound according to- any one of claims 1-8, and a pharmaceutically acceptable carrier. The composition according to claim 9, further comprising an additional therapeutic agent. 11. The composition according to claim 9, wherein said composition is formulated for administration to a human. 12. A method of inhibiting Aurora-2, GSK-3, CDK-2, or Src activity in a.biological sample comprising the step of contacting said biological sample with a compound according to any one of claims 1-8. 13. A method of inhibiting Aurora-2 activity in a patient comprising the step of administering to said patient a composition according to claim 9. 14. A method of inhibiting Aurora-2 activity in a patient comprising the step.of administering to said patient a composition according to claim IND -334- A method of treating an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically Ci effective amount of a composition according to-claim 9. D 16. The method according to claim 15, whereinsaid disease is selected from colon, breast, stomach, or o ovarian cancer. ci IND o 17. The method according to claim 16, wherein said method further comprises administering an additional therapeutic agent. 18. The method according to claim 17, wherein said additional therapeutic agent is a chemotherapeutic agent. 19. A method of inhibiting GSK-3 in a patient comprising the step of administering to said patient a composition according to claim 9. A method of inhibiting GSK-3 activity in a patient comprising the step of administering to said patient a composition according to claim 21. 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 composition according to claim 9. 22. The method according to claim 20, wherein said GSK-3-mediated disease is selected from diabetes, Alzheimer's disease, Huntington's Disease, Parkinson's D -335- O Disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis schizophrenia, Scardiomycete hypertrophy, reperfusion/ischemia, or baldness. 23. The method according to claim 21, wherein said IsO GSK-3-mediated disease is diabetes. ci eC 24. A method of enhancing glycogen synthesis or VO o lowering blood levels of glucose in-a patient in need thereof, which method comprises administering to said patient a therapeutically effective amount of a composition according to claim 9. 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 composition according to claim 9. 26. A method of inhibiting the phosphorylation of 0-catenin, which method comprises administering to a patient in need thereof a therapeutically effective amount of a composition according to-claim 9. 27. A method of inhibiting CDK-2 activity in a patient comprising the step of administering to said patient a composition according to claim 9. 28. A method of method of treating CDK-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a composition according to claim 9. -336- 29. A method of inhibiting Src activity in a patient comprising the step of administering to said patient a composition according to.claim 9. A method of treating a Src-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutidally effective amount of a composition according to claim 9. DATED this 21 st day of March 2006 Vertex Pharmaceuticals Incorporated By their Patent Attorneys CULLEN CO.