AU2006201396B2 - Pyrazole Compounds Useful As Protein Kinase Inhibitors - Google Patents

Description

VO

0 0 0 0, Name of Applicant:

AUSTRALIA

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

ND

en ci

C

\O

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

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

Protein kinases mediate intracellular signal transduction. They do this by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There acceptor that is involved in a signaling pathway. There -la- IND are a number of kinases and pathways through which O extracellular and other stimuli cause a variety of cellular responses to'occur inside the cell. Examples of Ssuch stimuli include environmental and chemical stress signals osmotic shock, heat shock, ultraviolet o radiation, bacterial endotoxin, 1H202), cytokines (e.g.

interleukin-l (IL-1) and tumor necrosis factor a (TNF- C" and growth factors granulocyte macrophagecolony-stimulating factor (GM-CSF), and fibroblast growth C 10 factor (FGP). An extracellular stimulus may effect one o or more cellular responses related to cell growth, Cq 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. 'Ii human colon cancer tissue, the aurora- -2- QD 2 protein has been found to be overexpressed. See oBischoff et al., EMBO 1998, 17, 3052-3065; Schumacher k et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et c al., J. Biol. Cbem., 1997, 272, 13766-13771.

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

C 10 GSK-3 has been implicated in various diseases including.

o diabetes, Alzheimer's disease, CNS disorders such as C 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 -3- IND phosphorylation and deactivation of glycogen synthase.

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

However, in a diabetic patient where the insulin response IND is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood o 10 levels of insulin. This leads to'abnormally high blood N e levels of.glucose with acute and long term effects that Smay 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 are therefore potentially useful for treating diabetic patients suffering from an impaired response to insulin.

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

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

IN Another substrate of GSK-3 is 3 -catenin which o is degradated after phosphorylation'by GSK-3. Reduced levels of p-catenin have been reported in schizophrenic <patients and have also been associated with other diseases related to increase in neuronal cell death [Zhong et al., Nature, 395, 698-702 (1998) Takashima et ND al., PAS, 90, 7789-93 (1993); Pei et al., J.

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

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

For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating the same diseases. However, the various protein kinases often act through different biological pathways: For example, certain quinazoline derivatives have been reportedrecently 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 insulinsignaling pathway that regulates glycogen synthesis or glucose uptake.

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

There is a continued need to find new therapeutic agents to treat human diseases. The protein kinases aurora-2 and GSK-3 are especially attractive

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0 0 c O1 .targets for the discovery of new therapeutics due to their important role in cancer, diabetes, Alzheimer's disease and other diseases.

DESCRIPTION OF THE INVENTION It has now been found that compounds of this invention and pharmaceutical compositions thereof are effective as protein kinase inhibitors, particularly as inhibitors of aurora-2 and.GSK-3. These compounds have the general formula I: 0' or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

1 to Z 4 are as described below; Ring A is selected from.the group consisting of: NdN d a b

N"LN

RY K Fl 9

NRN

RX N

N-

I

-6- Ie f g9 h G is Ring C or Ring D; i N -G is Ring C or Ring D; C Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, Spyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, 0 wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R 8 Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, Iheteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted'at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; R is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 membered beteroaryl ring, 5-6 membered heterocyclyl ring, or Ci-6 aliphatic group, said phenyl, heteroaryl, -7and heterocyclyl rings each optionally substituted by up to three groups independentlyselected from halo, oxo, or -R 8 said Ci- 6 aliphatic group optionally O- -substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their o intervening atoms form said ring fused to Ring C;.

R

X and RY are independently selected from or R x and ION R Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 Smembered ring having 0-3 ring heteroatoms selected from IO oxygen, sulfur, or nitrogen, wherein any substitutable Scarbon on said fused ring formed by R x and R Y is substituted by oxo or T-R 3 and any substitutable.

nitrogen on said ring formed by R x and R Y is substituted by.R 4 T is a valence bond or a C-.

4 alkylidene chain;

R

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

R

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

-R

7 or

-V-R

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

R

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

R,

-COCOR, -COCH 2 COR, -NO 2 -CN, -S(0)2R, -SR, -N (R 4 2 -CON (R 2

-SO

2 N (R 2

-N(R'COR,

-N (R 7 C02 (optionally substituted Cz-s aliphatic),

-N(R

4 2

-C=NN(R

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

)CON(R

7 2

-N(R

7 )S0 2

N(R)

2

-N(R')SO

2 R, or -OC(=O)N(R 7 )2; each R is independently selected from hydrogen or an optionally substituted group selected from C 1 IND aliphatic, C 6 1 0 aryl, a heteroaryl ring having 5-10 o ring atoms, or a heterocyclyl, ring having 5-10 ring atoms; each R' is independently selected from -COR 7 -C0 2

(C

1 aliphatic), -CON(R 7 2 Or -S0 2

R

7 or two R 4 on the same 0 -nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl-ring; each R 5 is independently selected from halo, -OR,

-CO

2 R, -COCOR, -NO 2 -S0 2 R, -SR, 0 -N(R 4 2

-CON(R

4 2

-SO

2

N(R')

2 -N(Rt)COR, o -N (R 4 )0(pinflly substituted C 1 6 s aliphatic), 0-FI(RtN1(Rt) 2 -C=N9N(R 4 2 -C=N-OR, -N(R 4 )CON(Rt) 2 -N (R 4

SO

2 N(Rl 2

-N(R

4 )s0 2 R, or -OC(=O)N(R4) 2 or.R 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is

-SO

2 -N(R6)S0 2

SO

2

*-N(R

6 C0 2

-N(R

6

-N(R

6 is -WN(R0)CON (R 6 -N (R6) SO 2 N -N (Ri) N(R)-

-C(RC)

2 -:C(R6) 2

S-,

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

-C(R

6 2 S0 2 N(R5) 2

N(R

6

-C(R)

2

N(R

6 2 N(nP 6 -c(R6) =NN(u')z,

-C(R

6 2 -C,(R'h2N(R)SO 2 or 2 CON W is 2

-C(R

6 2 2 so;-, -C(R)bsoNC(R 6

-C(R

6 2 N(R6) -co 2

-C(R

6

),N{R

6

)CO-,

-C(R

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

N(R

6 )N(Rr) -C(Rr) 2 N(R6)So 2 N(R6) 2

N(R

6 CON (R 6 or CON each R' is independently selected from hydrogen or an optionally substituted C3_ aliphatic group, or two R 6 grotips on the same nitrogen atom are taken together ND with the nitrogen atom to form a 5-6 membered o heterocyclyl or heteroaryl ring; C1 each R 7 is independently selected from hydrogen or an 0^ optionally substituted C..6 aliphatic group, or two R 7 on the same nitrogen are taken together with the o nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; I each R 8 is independently selected from an optionally Ssubstituted C.-4 aliphatic group, -OR 6

-SR

6

-COR

6 -S0 2

R

6 2

-N(R)N(R

6

-NO

2

-CON(R)

2 or IO -CO2R'; and o R 9 is selected from halo, -OR, -CO 2 R, -COCOR, -N02, -CN, -SO2R, -SR, -N(R 4 2

-CON(R

4 2

-SO

2

N(R)

2

-N(R

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

)N(R

4 2

-C=NN(R)

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

)CON(R)

2

-N(R

4 )S0 2

N(R

4 2

-N(R

4

)SO

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

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

The term "aliphatic" as used herein means straight-chain, branched or cyclic CLC12 hydrocarbons which are completely saturated or which contain one or more units of unsaturation but which are not aromatic.

For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or 00 straight and branched chains containing two to twelve O carbon atoms. The term "cycloalkyl" used alone or as part of a larger moiety shall include cyclic C 3

-C

1 2 r hydrocarbons which are completely saturated but which are C 5 not aromatic.

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

\s 10 The term "heteroatom" means nitrogen, oxygen, or Ssulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.

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

The terms "carbocycle", "carbocyclyl", "carbocyclo", or "carbocyclic" as used herein means an aliphatic ring system having three to fourteen members. The terms "carbocycle", "carbocyclyl", "carbocyclo", or carbocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted. The terms "carbocycle", "carbocyclyl", "carbocyclo", or "carbocyclic" also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as in a decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to aromatic ring groups having DO "carbocyclic" also include aliphatic.rings that are fused to one or more aromatic or nonaromatic rings, such as in Sa decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.

I

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to aromatic ring groups having NO I *h five to fourteen members, such as phenyl, benzyl, phenethyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2- C- 10 anthracyl. The term "aryl" also refers to rings that are Soptionally substituted. The term "aryl" may be used C interchangeably with the term "aryl ring". "Aryl" also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2anthracyl. Also included within thb scope of the term "aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring., The term "heterocycle", "heterocyclyl", or.

"heterocyclic" as used herein includes non-aromatic ring systems having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S. Examples of heterocyclic rings include 3-1Hbenzimidazol-2-one, (1-substituted) -2-oxo-benzimidazol-3yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2tetrahydropyranyl, 3-tetrahydropyranyl, 4tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl, [1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4- -12morpholinyl, 2 -thiomorpholinyl, 3-thiomorpholinyl, 4thiomoxpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1piperidinyl, 2 -piperidinyl, 3 -piperidinyl, 4 -piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1phtbalimidinyl, 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-aromati 'c heteroatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the.

radical or point of attacbment is on the non-aromatic 15 heteroatom-containing ring. The term "heterocycle", "heterocyclyl", or "lheterocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted.

The term "heteroaryl"f, used alone or as part of 20 a larger moiety as in "heteroaralkyl" *or "heteroarylalkoxy", refers to he teroaromatic ring groups having five to fourteen members. Examples of heteroaryl rind's include 2-furanyl, 3-f uranyJ' IN-imidazolyl, 2imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2triazolyl, 5-triazolyl, 2-thienyl, 3- thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyi., benzimidazolyl, isoquinolinyl, indolyl, -13- INDisoindolyl, acridinyl, or benzoisoxazoly. Also included within the scope of the term "heteroaryl", as it is used herein, is a group in which a heteroatomic ring is fused C to one or more aromatic or nonaromatic rings where the radical or point of attachment is on the heteroaromatic o ring. Examples include tetrahydroquinolinyl, tetrahydroisoguinolinyl, and pyrido 3 pyrimidinyl.

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

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Examples of suitable substituents on the unsaturated carbot atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group include a halogen, -ORO, -SRo, 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl substituted Ph, substituted -O(Ph), -CH2(Ph), substituted -ICH2(Ph), -CH2CH2(Ph), substituted

-CH

2

CH

2

-NO

2 -CN, -N(R) 2

-NR

0

-NROC(O)N(R)

2

-NROCO

2 RO, -NRNR 0 C(O) Ro, -NRNRC(O)N (Ro) 2

-NRONROCO

2

R,

-C(O)C(O)Ro, C(O)CH2C(o)RO, -C0 2 R, C(O)Ro, -C(0)N(R) 2

-OC(O)N(R)

2 -S(0) 2 RO, -SO 2

N(RO)

2

-NROSO

2 N(Ro) 2

-NR*SO

2 2

-C(=NE)-N(ROY

2

-(CH

2

)YNHC(O)R,

-(CH

2 yNHC CH (RO) wherein R is hydrogen, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl substituted Ph, substituted -O(Ph), CH;(Ph), ot substituted -CH2(Ph); y is 0-6; and V is a linker group. Examples of substituents on the aliphatic -14- IND group or the phenyl ring of Rt 0 include amino, alkylamino, o dialkylanino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkyrlaminocarbonyl, alkylaminocarb onyloxy, dialkylaminoc arbonyloxy, alkoxy, nitro,,cyano, carboxy, alkoxycarbonyl, aJlcylcarbonyl, 0 hydroxy, haloalkory, or haloalkyl.

An aliphatic group or a non-aromatic heterocyclic ring may contain one orL more.L substitnents.

Examples of suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic

IND

ring in'clude those listed above for :the uns a ted ci carbon-of. an aryl, or heteroaryl. group-and the following: =IQNHPP, =NN(R*) 2 =NNHC(O)R%, =NNHC 2 (alkyl), =N14}S0 2 (alkyl), or =NR, where each R* is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of substituents on the aliphatic group include amino, alkylamino,.dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkzylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

Suitable substituents on the nitrogen of a nonaromatic-heterocyclic -ring include RX-N 2

R+,

-CO2II+, XC, -0(0)CH20(0) at, -SO 2

,R

t

-SO

2

(R)

2

-C(=S)N(R

t 2 and -NR t

SO

2 wherein R t is hydrogen, an aliphatic group, a substituted aliphatic group, phenyl substituted Ph, substituted

CH

2 ]Isubstituted 0H 2 (Ph), or an unaubstituted heteroaryl or heterocyclic ring.

Exmples of substituents on the aliphatic group or the phenyl ring include aminoi alkylamino, dialkylanino, axninocarbonyl, halogen, alkyl, alkylmanocarbonyl, IND dialkylaminocarbonyl, alkylaminocarbonyloxy, o dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, C( alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or C haloalkyl.

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

Linkers are typically comprised of an atom such as oxygen I or sulfur, a unit such as -CHa-, -C(0)NH-, Sor a-chain of atoms, such as an alkylidene chain. The molecular mass of a linker is typically in the range of ND about 14 to 200, preferably in the range of 14 to 96 with o a length of up to about six atoms. Examples of linkers include a saturated or unsaturated Ci-. alkylidene chain which is optionally substituted, and wherein one or two saturated carbons, of the chain are optionally replaced by -CONH-,.-CONHNH-, -C02-, -NHC0 2 -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -S02-, -SO2NH-, or -NHS02-.

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

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

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms -16- -r q0 of the structure; the R and S configurations for o each asymmetric center. Therefore, single stereochemical Sisomers 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 Va enriched atoms. For example, compounds having the enI present structures except for the replacement of a ri 10 hydrogen by a deuterium or tritium, or the replacement of 0- a carbon by a nC- or 4 "C-enriched carbon are within the 0 C- 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 GSK-3, in a biological sample or in a patient. In another embodiment, compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of the protein kinase inhibitor effective to treat or prevent a GSK-3-mediated condition and a pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient.

The term "GSK-3-mediated condition" or "disease", as used herein, means any disease or other deleterious condition or state in which GSK-3 is known to play a role. Such diseases or conditions include, without limitation, diabetes, Alzheimer's disease, Huntington's Disease, Parkinson's Disease, AIDSassociated dementia, amyotrophic lateral sclerosis (AML), -17multiple sclerosis schizophrenia, cardiomycete o hypertrophy, reperfusion/ischemia,. and baldness.

C

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 which method comprises administering to the patient a therapeutically effective amount ofl a compound of formula SI or a pharmaceutical composition thereof. This method i_ is especially useful for diabetic patients. Another method relates to inhibiting the production of o° hyperphosphorylated Tau protein, which is useful in Shalting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of j-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 Aurora-2 activity in a patient, which method comprises administering to the patient a f compound of formula I or a composition comprising said compound.

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

The term "Aurora-2-mediated condition" or "disease", as used herein, means any disease or other -18- IN0 deleterious condition in which Aurora is known to play a o role. The term "Aurora-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with an! Aurora-2 inhibitor.

S

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

Another aspect of the invention relates to inhibiting Aurora-2_activity in a biological sample, c 10 which method comprises contacting the biological sample o with the Aurora-2 inhibitor of formula I, or a Scomposition thereof.

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

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

and Lane, Current Medicinal Chemistry, 7, 1213-1245 (2000); Mani, Wang, Wu, Francis, R. and Pestell,. Exp. Opin. Invest. Drugs, 9, 1849 (2000); Fry, D.W. and Garrett, CurrentI Opinion in -19- Oncologic, Endocrine Metabolic Investigational Drugs, 0 2, 40-59 (2000).

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

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

The term "ERK-mediated condition", as used herein means any disease state or other deleterious condition in which ERK is known to play a role. The term "ERK-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a ERK-2 inhibitor. Such conditions include, without limitation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone-related diseases. The term "cancer" includes, but is not limited to the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, ND papillary carcinoma, seminoma, melanoma, sarcoma, bladder o carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colonrectum, large intestine, rectum, brain and central nervous system, and leukemia. ERK-2 protein kinase and Ch its implication in various diseases has been described [Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et 0 10 al., 1990, Nature 343, 651; Crews et al., 1992, Science 0 258, 478;' Bjorbaek et al., 1995, J. Biol. Chem. 270, 0g 18848;.Rouse et al.; 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al.

1996; Chen et al., 1993 Proc. Natl. Acad. Sci. USA 10952; Oliver et al., 1995, Proc. Soc. Exp. Biol. Med.

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

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

Another aspect of this invention relates to a method of treating or preventing an ART-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 term "AKT-mediated condition", as used herein, means any disease state or other deleterious condition in which AKT is known to play a role. The term -21- NOJ "AKT-mediated condition" or "disease" also means those o 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 o association of AKT, also known.as protein kinase B, with various diseases has been described [aKhwaja, Nature, pp. 33-34, 1990; Zang, Q. et al, Oncogene, 19 2000; _Kazuhiko, et al,_The Journal of Neuroscience, 0 10 2000].

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

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

The term "Src-mediated condition", as used herein means any disease state or other deleterious condition in which Src is known to play a role. The term "Src-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment 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, -22- IND Drugs of the Future 2000, 25(7), 717,. (2000); Talamonti, o 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); ^O Staley, Cell Growth Diff., 8, 269 (1997)].

Another aspect of the invention relates to gC 10 inhibiting Src activity in a biological sample or a patient, which method comprises administering to the CA patient a compound of formula I or a composition comprising said compound.

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

The term "patient" includes human and veterinary subjects.

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

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

Any method may be used to determine inhibition, such as, -23- \D for example, the Biological Testing Examples described below.

Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum o stearate, lecithin, serum proteins, Isuch as human serum albumin, buffer substances such as phosphates, glycine,

VO

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

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

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

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

These suspensions may be formulated according to techniques known in the art.using suitable dispersing or wetting -agents and suspending agents.. The sterile injectable preparation may also be a' sterile injectable -24solution or suspension in a non-toxic parenterallyo acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's 5 solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed IND as a solvent or suspending medium. iFor this purpose, any bland fixed oil may be employed including synthetic monoor di-glycerides. Fatty acids, such as oleic acid and ^C 10 its glyceride derivatives are useful in the preparation Sof injectables, as are natural pharmaceutically- Ci acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a .long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, .or other dosage forms may also be used for the purposes of formulation.

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

For oral administration in a capsulei form, useful diluents include lactose and dried cornstarch. When \O aqueous suspensions are required for oral use, the active 0 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

VO

h prepared by mixing the agent with a suitable nonirritating excipient which is solidat room temperature C 10 but liquid at rectal temperature and therefore will melt o in the rectum to release the drug. Such materials 0 include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including .diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

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

Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or -26- ID -cream containing the active components suspended or Sdissolved in one or more pharmaceutically acceptable ci Scarriers. Suitable carriers include, but are not limited <to, mineral oil, sorbitan monostearate, polysorbate Scetyl 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, C 10 as solutions in isotonic, pH adjusted sterile saline, Va Seither with or without a preservative such as ci benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

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

A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically -acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or -27- IND indirectly, a compound of this invention or an 0 inhibitorily active metabolite or residue thereof.

C Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a o patient by allowing an orally administered compound to be more readily absorbed into the blood) or

VO

I which enhance delivery of the parent compound to a biological compartment the brain or lymphatic system) relative to the parent species.

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

Pharmaceutically acceptable salts of the compounds of this invention include, those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, ihydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in -28- INO obtaining the compounds of the invention and their o pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal sodium and potassium), alkaline earth metal magnesium), ammonium and N+(C.

4 alkyl) 4 0D salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds Va 'disclosed herein. Water or oil-soluble or dispersible o products may be obtained by such quaternization.

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

Preferably, the compositions should be formulated so that a dosage of between 0.01 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.

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

Depending upon the particular protein kinasemediated condition to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the, inhibitors of this invention. For example, in the treatment of diabetes other anti-diabetic -29- IND agents may be combined with the GSK-3 inhibitors of this invention to treat diabetes. These agents include, CI without limitation, insulin or insulin analogues, in P- injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides,, insulin sensitizers,.

O and sulfonyl ureas.

Other examples of agents the inhibitors of this invention may also-be combined with include, without limitation, chemotherapeutic agents or other anti- 0 10 proliferative agents such as adriamycin, dexamethasone, o vincristine, cyclophosphamide, fluorouracil, topotecan, o taxol, interferons, and platinum derivatives; antiinflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti- Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

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

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

Compounds of this invention may exist in S 5 alternative tautomeric forms, as in tautomers 1 and 2 shown below. Unless otherwise indicated, the representation of either tautomer is meant to include the Sother.

R

2 R2 S2

NH

CM HN N HN N Z3 Z 2

Z

3

Z

2 I A A

Z

1 G G 1 2

R

1 and R y (at positions Z 3 and respectively) may be taken together to form a fused ring, providing a bicyclic ring system containing Ring A. Preferred Rx/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R 1

/R

Y ring is optionally substituted.

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

H A N H HN Z HN3 I-A I-B

I-C

-31- Va 0 0 ci 0 I-D I-H I-F Me I z~rsj I-G I-H I-I I-a. I-K I-L H N-1

H??

I-K

I-N

I-P 3-Q I-R -32- Va 0 0, ci

HN

I-S

HN?

S. Z 2

I-V

I-T

I-U

I-W

I-X

I-Y

I-Z

I-AA

I-BB

I-CC I-DD Preferred bicyclic Ring A systems include I-A, I-B, I-C, I-D, I-E, I-F, I-H, I-I, I-J, I-K, I-L, and I-M, more preferably I-A, I-B, I-C, I-F, and I-H, and most preferably I-A, I-B, and I-H.

In the monocyclic Ring A system, preferred RX groups, when present, include hydrogen, alkyl- or dialkylamino, acetamido, or a C-.

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

Preferred R Y groups, when present, include T-R 3 wherein T is a valence bond or a methylene, and R 3 is -N(R 4 2 -33- IO or -OR. Examples of preferred R y include 2-pyridyl, 4o pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, CN isopropyl, t-butyl,. alkyl- or dialkylamino, acetamido, 0 optionally substituted phenyl such as phenyl or halosubstituted phenyl, and methoxymethyl.

o In the bicyclic Ring A system, the ring formed when Rx and RY are taken together may be substituted or

VO

unsubstituted. Suitable substituents include halo, -OR, -CO 2 R,_-COCOR, -NO 2 -CN, -S0 2

R,

-SR, -N(R) 2

-CON(R

4 2 -S0 2

N(R

4 2

-N(R

4

)COR,

Io -N(R 4 C2 (optionally substituted C.G aliphatic), o -N(R 4

)N(R

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

-N(R

4

SO

2 N(R 2, -N(R 4

)SO

2 R, or -OC(=6)N(R 4 2 wherein R and

R

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

R,

-CON(R')

2 -CN, or -N(R 4 2 wherein R is hydrogen or an optionally substituted C.-6 aliphatic, group.

R

3 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 carbocycio ring, wherein said fused ring is optionally substituted. These are exemplified in the following formula I compounds having a pyrazole-containing bicyclic ring system:

INH

HN-3 3 2 N NH N KZ NH NH JNH PH'N o i, and -34- -~r IND ~Preferred substituents."on, the R/t2 fused ring o include one or more of the following: -halo, -N(R 4 2

-C

1 3 alkcyl, -C 1 3 haloalkyl,

-NO

2

-O(C

1 3 alkyl), -C0 3

(C

1 3 alkyl), -Ot, -S0 2

(C

1 3 alkyl), -SO 2

NH

2

-OC(O)NH

2

-NSO

2

(C

3 alkyl), -NHC(o) (C 1 alkyl),, -C(O)NH 2 and -CO(C 1 0 3 alkyl), wherein the (C 1 3 alkyl) is most preferably IND methyl.

When the pyrazole ring system is monocyclic, preferred R 2 groups include hydrogen, CI-.4 aliphatic, C110 allcoxycarbonyl,. (un)substitutea phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkyJlaninoalkyl, phenylaminocarbonyl,.and

(N-

heterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO 2 1

CO

2 QCi 3 CH20H, CH 2 0CH 3

GH

2 O 2 dU 2 OH, CH 2

CH

2

GH

2

OCH

3 0CH,2CHOC{Ph,

CH

2

OH

2 CH2NH 2 CH2CH2CH 2 NHcOC (a 3 3 CONHCR (Cw 3 2 qONHCH 2 CiH=CH2, CONHO{ZcH 2

OCH

3

CONHOH

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

CON(CH

3 )01 2 ph, CONH(n-C 3 11,), CON (Et) 012012053, 'CONHC2CH (Gil 3 2 CON(n-C 3 54 7 2 00(3methoxymethylpyrrolidin-i-yi), COH(3-tolyl), CONH(4-.

tolyl) CONHCH 3 CO (morpholin-l-yl) ICO (4-metbhylpiperazin- 1-yl); CONHCH 2 CH2OH, CONH2, and CO(piperid in-l-yl). A preferred R 2 group is hydrogen.

An embodiment that is particularly useful for treating GSK3-mediated diseases relates to compounds of ftormula II: D R 2 S.R2 1 SHN

N

RX

II

or a pharmaceutically acceptable derivative or prodrug thereof, wherein; Cq Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, o pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, q 5 wherein said Ring C has one or two ortho substituents.

independently selected from -R 1 any substitutable nonortho carbon position on Ring C'is independently substituted by.-R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R 8 R is selected from -halo, -CN, -NO 2

T-V-R

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

R

Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 -36- IND membered ring having 0-3 ring heteroatoms selected from o oxygen, sulfur, or nitrogen, wherein any substitutable N carbon on said fused ring formed by RX and R Y is substituted by oxo or T-R 3 and any substitutable .4 nitrogen on said ring formed by Rx and R Y is o substituted by R 4 T is a valence bond or a C1-4 alkylidene chain; O R 2 and R' are independently selected from -T-W-R 6 or

R

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

-R

7 or

-V-R

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

R

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

R,

-COCOR, -COCH 2 COR, -NO 2 -CN, -S(O)2R, -SR, -N(R4)2, -CON(R')2, -S02 -N(R 7

)COR,

-N C0 2 (optionally substituted Ci-S aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R

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

CON(R

7 )2, -N (R S0 2

N(R

7 2

-N(R

4

)SO

2 R, or -OC(=0)N(R 7 2 each R is independently selected from hydrogen or an optionally substituted group selected from C 1 aliphatic, C 6 s-o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -R 7

-COR',

-CO, (optionally substituted Ci-. aliphatic), -CON(R 2 or -S02R 7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; -37each R 5 is independently selected from halo, -OR, O -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR,

-N{R)

2

-CON(R')

2

-SO

2

N(R

4 2 N(Rt)COR, C02 (optionally substituted C1-6 aliphatic), -N (R )N (R 4 2

-C=NN(R

4 2 -C=N-OR, -N(R )CON(Rt) 2 o -N(Rt)SO 2 N(R) 2 -N(Rt)SD 2 R, or -OC(=O)N(R) 2 or R 5 and an adjacent substituent taken together with their Va intervening atoms form said ring fused to Ring C; V is -S02-, -SO 2

-N(R

6 -CO2-, -N(R 6 o -N(R 6

-N(R

6

SO

2 N o 2

S-,

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

-C(R

6 2

N(R

6

-C(R

6 2

C(R')

2

-C(R

6

-C(R)

2 -C 2 N(R) SO 2

N(R

6 or

-C(R)

2

N(R

6

)CON(R

6 W is 2 2 SO-, -C(R 6 2 S0 2 2 S0 2 2 CO, -C02-, -C(R -c(R 6 2 N(aR')CO-, 2 N(R6)C(0)O-, -C(R 6

-C(R

6 C 2 N (R 6

-C(R

6 2 S0 2 N C 2 N CON(R) or -CON(R) each R' is independently selected from hydrogen, an optionally substituted C1.4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R' is independently selected from hydrogen or an optionally substituted C3-s aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and -38each R 8 is independently selected from an optionally substituted

C..

4 aliphatic group,

OR

6 -SR6, -COR 6

-SO

2

R

6 2 2 -CN, -N0 2

-CON(R

6 2 or -CO2R When the RX and RY groups of formula II are taken together to form a fused ring; preferred R/RY rings include a or 8-membered unsaturated or CO partially unsaturated ring having 02 heteroatoms, wherein said RX/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula II are the mono- and bicyclic systems shown below.

R2 Rz HN. HN 6 H -2 HN C IHN>7 II-A II-B

II-C

HN? HN> HN

RNR

II-D II-

II-F

HN HN HN' HeN S MeN t II-G I-H

I-I

-39- O HN HN HN' HN HN HN ~xtN Not~ II M II-N II-L HNeN S. N j5.7)

I-P

10 More preferred pyrimidine ring systems of o NN formula II include II-A, II-B, II-C, II-F, and II-H, most preferably I I-A, II-, and II-H.N -0

N>

More preferred pyrimidine rin~g systems of formula 11' include 11-A, Il-B, Il-C, 11-F, and 11-H, most preferably 11-A, l1-S, and Il-H.

In the monocyclic pyrimidine ring system of r formula II, preferred RX groups include hydrogen, alkylor dialkylamino, acetamido, or a.C 1 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred RY groups include T-R 3 wherein T is a valence bond or a methylene, and-R 3 is -N(R) 2 or -OR. When

R

3 is -R or -OR, a preferred R is an optionally substituted group selected from Cj.

6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred RY include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl ND such as phenyl or halo-substituted phenyl, anid

O

Smethoxymethyl.

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

-CO

2

R,

\O -COCOR, -NO 2 -CN, -S02R, -N(R 4 2

-CON(R

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

-N(R)N(R

4 2

-C=NN(R

4 2 c- 10 -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO 2

N(R

4 2 -N(R)SO2R, or

S-OC(=O)N(R)

2 wherein R and R 4 are as defined above.

C- Preferred RX/R y ring substituents include -halo, -OR, -COR, -C0 2 R, -CON(R') 2 -CN, or -N(R 4 2 wherein R is an optionally substituted Ca-s aliphatic group.

The R 2 and R 2 groups of formula II may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula II compounds having a pyrazole-containing bicyclic ring system:

YNH

HN N N N R N NH

N

H NH NH RY N CNN -NN t N S, and Preferred substituents on the R 2

/R

2 fused ring of formula II include one or more of the following: -halo, -N(R 2, -CI-4 alkyl, -CI-4 haloalkyl, -NO2, -0 (C.4 alkyl), -CO2 (Ci- alkyl), -CN, -S02 (C-4 alkyl), -SO 2

NH

2 -41- -OC (O)NH 2

-NH

2 S02(Ci-4.alkyl), -NHC(0) alkyl), O -C(0)NH 2 and -CO(C 1 .4 alkyl), wherein the (CI.

4 alkyl) is a Cl straight, branched, or cyclic alkyl group. Preferably, e the 4 alkyl) group is methyl.

When the pyrazole ring system of formula II is o monocyclic, preferred R 2 groups include hydrogen, a substituted or unsubstituted group selected from aryl, O heteroaryl, or a CI- 6 aliphatic group. Examples of such Spreferred R 2 groups include methyl, t-butyl, -CH20CH3, cyclopropyl, furanyl, thienyl, and phenyl. A preferred IND R' group is hydrogen.

O More preferred ring systems of formula II are the following, which may be substituted as described above, wherein R 2 and R 2 are taken together with the pyrazole ring to form an indazole ring; and Rx and R y are each methyl, or RX and R Y are taken together with the pyrimidine ring to form a quinazoline or tetrahydroquinazoline ring: NH NH NH HN HN t HN N H3C N H3C N II-Aa II-Ba II-Ha Particularly preferred are those compounds of formula II-Aa, II-Ba, or II-Ha wherein ring C is a phenyl ring and R 1 is halo, methyl, or trifluoromethyl.

Preferred formula II Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is -42- \D contained in a bicyclic ring system. 'Preferred fused D rings include a benzo or pyrido ring. Such rings k preferably are fused at ortho and meta positions of Ring C. Examples of preferred bicyclic Ring C systems include 5 naphthyl, quinolinyl and isoquinolinyl.

An important feature of the formula II compounds is the R' ortho substituent on Ring C. An ortho C position on Ring C or Ring D is defined relative to the c.

Sposition where Ring A is attached. Preferred R 1 groups SCn 10 include -halo, an optionally substituted C 1 .s aliphatic Sgroup, phenyl, -COR 6

-OR

6 -CN, -S0 2

R

6

-SO

2

NH

2

-N(R

6 2 0g -C0 2

R

6

-CONH

2

-NHCOR

6

-OC(O)NH

2 or -NHSO 2

R

6 When RX is an optionally substituted aliphatic group, the most preferred optional substituents are halogen. Examples of preferred R 1 groups include -CF3, -Cl, -CN, -COCH 3 -OCH3, -OH, -CH 2

CH

3 -OCH2CH 3 -CH3, -CF 2 CHa, cyclohexyl, tbutyl, isopropyl, cyclopropyl, -CCH, -C=C-CH 3 -S02CH 3

-SO

2 NH2, -N(CH 3 2 -C0 2

CH

3

-CONH

2

-NHCOCH

3 -OC(0)NHa,

-NHSO

2

CH

3 and -OCF 3 On Ring C of formula II, preferred R substituents, when present, include -halo, -CN, -NO 2

-N(R

4 optionally substituted Ci-s aliphatic group, -OR,

-CO

2 R, -CONH(R 4

-N(R

4 )COR, -SO 2

N(R

4 2 and

-N(R')SO

2 R. More preferred R 5 substituents include -Cl, -CN, -CFa, -NH 2 -NH(CI-4 aliphatic), -N(C1.

4 aliphatic) 2 aliphatic), C,.4 aliphatic, and -C02 (C-4 aliphatic). Examples of such preferred R substituents include -Cl, -CN, -CF 3

-NH

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

Preferred formula II compounds have one or more, and more preferably all, of the features selected from the group consisting of: -43- ID Ring C is a phenyl or pyridinyl ring; O optionally substituted by -R 5 wherein when Ring C and two C adjacent substituents thereon form a bicyclic ring Ssystem, the bicyclic ring system is selected from a naphthyl, quinolinyl.or isoquinolinyl ring; o R x is hydrogen or Ci.

4 aliphatic and R Y is

T-R

3 or R x and R Y are taken together with their

VO

IN intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; IN R 1 is -halo, an optionally substituted Ci-s aliphatic group, phenyl, -COR 6 -CN, -SO 2

-SO

2

NH

2

-N(R

6 2

-CO

2

R

6 -CONH2, -NHCOR 6

-OC(O)NH

2 or -NHSO 2

R

6 and

R

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

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

R

x is hydrogen or.methyl and R Y is -R, N(R4)2, or -OR, or R X and R y are taken together with their intervening atoms to form a 5-7 membered. unsaturated or partially unsaturated carbocyclo ring optionally substituted with halo, -OR, -CO 2 R, -COCOR,

-NO

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

-CON(R')

2 -44- ID -S0 2

N(R

4 2, COR, C02 (optionally O substituted Ci., aliphatic), -N(R N(R 4 2

-C=NN(R

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

N(R)

2

-N(R)SO

2 R, or -oc N(R 2;

R

1 is -halo, a Ci- haloaliphatic group, a aliphatic group, phenyl, or -CN; k

R

2 is hydrogen and R 2 is hydrogen or a C substituted or unsubstituted group selected from aryl, or a C 1 -6 aliphatic group, or R 2 and R 2 are taken together Cl 10 with their intervening atoms to form a substituted or

VO

Sunsubstituted benzo, pyrido,. pyrimido or partially Cq unsaturated 6-membered carbocyclo ring; and each R 5 is independently selected from -halo, -CN, -NO 2

-N(R

4 2 optionally substituted Cialiphatic'group, -OR,

-CO

2 R, -COBH(R 4

-N(R

4

)COR,

-SO2N(R 4 or -N(R 4 )S.2R.

Even more preferred compounds of formula II have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl ring optionally substituted by -R 5

R

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

Y

are taken together with their intervening atoms to form an optionally substituted benzo ring or partially unsaturated 6-membered carbocyclo ring;

R

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

R

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

-CI-

4 alkyl, -CI-4 haloalkyl, -N02,' -0 (CI- alkyl), -602 (1-4 alkyl), -CN, -S02 (C 1 4 alkyl), -SO 2

NH

2

-OC(O)NH

2

-NH

2

SO

2

(C

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

4 alkyl), -C(O)NH 2 or -CO(C.

4 alkyl), wherein the (C 1 4 alkyl) is a straight, branched, or cyclic alkyl o group; and each R 5 is independently selected from -C1, Va -CN, -CF 3 -NH2, -NH(C1- 4 aliphatic), -N(CI-4 aiiphatic) 2 4 _aliphatic), C.4 aliphatic, and -C0 2

(C.

4 aliphatic).

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

Table 1.

F

CH

3 FI 4H Hj H H HNHNQ tN HC N CI N C N CF HC N4N 6

N

1-1 11-2 11-3 2:QF F FF F HH H 1-4 II-5 II-6 -46- Va 0 0 ci 0 11-7 F

C

HN

.11-1 111-8 11-11

F

'e't N C N CF 3 11-12

F

H?>

11-15

F

.HZ

0-,,rj N CF 3 11-1:3 .11-14 II1-1 11-1:7 11-19 11-20 11-21 -47- Va 0 0 ci 0 11-22 11-23 11-24 11-25 11-26 11-27

H

H.,C

11-28 H3CtN Cl

HC

11-29 11-30 11-31

HN

11-32

CH

3

OCH

3 -48-

CH

3 HN tP 11-33

CH

3

HN

HN

CH'

HN

HN

;0- 11-34

CH

3 QjNNOCHs 11-37

CH

3 cN .CH3 N

H

11-40 11-43 HNJ1p 0N CFS 11-46 11-35

CH

3

NCH

3 11-38

CR

3 64H II-4L 11-36

CH-I

HN&4 N CCH

N'

11-39

CH

3

HNAI

C ON CH2CH3 11-42

CH

3

HN

4

*H

QtN OCH 2

CHS

N

11-45 11-48

CH

3 HNtt

NOH

11-44

I-N

Q(N CF 3 11-47 -49- ;0-

CH

3

Q(NCFS

11-49 0

HN

11-52

HN

,N CFS H2 Z% N CF 3 'I-so-

JH

HNN

QfN CF3 11-51 HN t*Hr WYN CF 3

YAN.

11-53 HNXS6

NCF

3

H

CF

3 11-59

OH

HNr

N'

11-54

N

11-57

C)

11-5 11-58

F

H

HN

C N CF3 CliW'b 'I-G0 -so- Va 0 0 ci 0 N F F3Cy Q~NCF3 11-64 H2N

N

N( CFs

N

11-70 11-62

HN

KJN CF 3 HN7p

NCF

3 a

N

Is 11 :p

HN

11-66

NN

11-72 11-71 -51- Va 0 c 0O 11-73 11-74 N Cl 11-76

F

3

C

N CI 11-77

H

N C 11-75

HN

11-78

CF

3

F~

-dZ

HN

Nr CF3 NI CF 11-84

C

Br A-l

HN

N CF3 11-79 Br

HZ

N CF3 11-82 Cl

NCF

3

F

4%N CF 3 11-83 f, -52- Va 0 0 ci 0

HN

11-85

F

HN'

N~f~NCF3

NN

OC11-940

F

NCFS

&F

11-86 HN r

NCF

3

RN

.NCF

3 OCH3I 11-92 F%7

HN

NO

2 11-95

HN

11-87

HN

OH

3 11-90 NQ(CFa 11,93 11-'F 110 -53- Va 0 0 ci 0 N F 11-97 HNr4

NCF

3 11-98 N F 11-99

CH

3

N

NCF

3

OH

3 N

HN

I .NCF 3 11-101 CI 0- 11-102 (9 tttN 00QF 3

CH

3

W

11-104

CH

3

HN

4 P-x St4 F 3

H

3 C

K

'I-los

C)

O. H 3

ANH

NCI

N

11-106 11-107 11-lOB -54- Va 0 0, ci

H

HN c IQ CF3 11-109

F

N

11-112 HN!2 I 1N CF 11-115

HN

NCI

11-110 hI-hi 11-113 11-114 HN29N 'N Cl 11-116 11-117 11-118 11-119 11-120 Va 0 0, ci

HN

F

1 11-123 11-121 11-122

F

HN

11-124 MeO 2

C

CF

3 11-125 11-126

'"N

11-129 11-127

NH

HN

F

3 C A 11-130 11-128

MHN

OhN 0 N

F

3

C

11-131 11-132 -56- Va 0 0, ci

CH

3 HN fJNH 11-133 11-134 11-,135 11-136 11-137 11-138 H Z

H

3 C

N

H

2 N

F

3

C

11-139 H3C

N~

AcNH 11-140

H

3 C

N

MeSO 2 NHJ C 11-141

WN

HNQN9

H

3 CC N j 0 11-144 11-142 11-143.

-57- Va

IN

CA

C)

11-145 11-146

H

HN ct N F 11-147 N ~N

CF

3 N t 11-150 111-149 H9N

N

NCF

I-1 2

N

11-153 11-151 11-152 -58- Va 0 0 ci 0 I.N'Me H9 HqN +IN

NCF

3 11-154

F

HNIt)I

CF

3 11-156

H-N

N--htN

CF

3

H

2 N

N

11-157 11-159

F

NCF

3 Nf Nj C F, Me-'N EtS-"N N') 11-160 11-161 11-162 Me HN 1-165 11-163 11-164 -59- Va 0 0 ci 0 11-166 11-167 11-168

H-

11-170 11-169 11-171 H9&H HaCA~NC 11-172

HN)--?N

Cbz.

H

11-175 AcNN CF, 11-173 11-174

HZ

H

2

N

11-176 If; i~ 11-177 11-178 11-179 1-8 11-180

IN

IND

MeO 2 Srt$)l

H

HN?(,tpH 11-182

H

3

C

HNZ

C

3 -rN& CAc 0 11-186 11-184 11-185

FNN

NN

CH> NF 11-189 11-187 11-188.

117191 II 190 11-192 i -61- N CF 11-193 H H MeNtN CF, 11-194 11-195 Va c Va tN C HI19 N CF 3 11-198

C)

11-197

F

HZ tp MeNC 11-200 HN2O Me )NCI H2N 2

SN

11-201 11-199 11-202 -11-203 11-204 -62- Va 0 0, ci 11-205

CH

3

,H

11-208

CH

3 HNt$

QN

311-23.3

JN

N

11-206

JH

HN

11-209 HNZ H 11-212 11-207 F

F

11-210 2N 11-213 1N 1 1-207 HN-'4" 11-214 11-215 -63- Va 0 0 ci 0 NC4 11-218 11-217 11-219 11-220 HP44 Q N C(O)NH 2 11-223

H?

11-221

HN

Me N) Me 11-224 HN2P

I

O~N

11-227 11-222 Me QLNMe 11-228 4, t 11-226 -64tN OMe .11-229 11-230 11-232 HC2P

H

kA~b

)NH

11-235

HN

Ott t-Bu IIt 2 3 3 IIN

NH

2

NO

11-236 11-231 Hu 11-234 11-237 HNt c46 .11-240

F?

ON NHZ 11-238 11-239 Va 0 c 0O Hg HN-24 'N N02 11-243 II-241 II-242 FyF (P:N C N N 6 II-244

MN

Ni> CN N CH3 11-245

HN

So 2

NH

2 11-248 11-246 F

F

H

HN

N S0 2

NH

2

N

11-247

H

PI N SO2N(Meh 1N II-249 H -nCF HN

_LX

HsC "N

CF

3 II-251 11-250 In another embodiment, this invention provides a composition comprising a compound of formula II and a pharmaceutically acceptable carrier.

-66-

IND

o One aspect of this invention relates to a 0 method of inhibiting GSK-3 activity in a patient, ccomprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula II.

Another aspect relates to-a method of treating IND a disease that is alleviated by treatment with a GSK-3 ninhibitor, said method comprising the step of oadministering to a patient in need of such a. treatment a therapeutically effective amount of a composition.' ocomprising a compound of formula II.

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

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

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

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora 0inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition Comprising a compound of formula I1. This method is 0* ci 10 especially useful for treating cancer, such as colon, o ovarian, and breast cancer.

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

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

Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity in a biological sample, which method comprises contacting the biological sample with the GSK-3 or Aurora inhibitor of formula 1I, or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3, Aurora or CDK-2.

-68- ND Each of the aforementioned methods directed to O the inhibition of GSK-3, Aurora or CDK-2, or the Streatment of a disease alleviated thereby, is preferably <carried out with a preferred compound of formula II, as described above.

Another embodiment of this invention relates to IND compounds of formula III: C R 2

R

S- t NH Va

HN

Rx

N

III

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

-R

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

R

x and R Y are taken together with their intervening atoms to form a fused, benzo ring or a 5-8 membered carbocyclo ring, wherein any substitutable carbon on said fused ring formed by R x and R Y is substituted by oxo or T-R3; T is a valence bond or a C,-4 alkylidene chain; -69r I D R2 and R 2 are independently selected from -T-W-R or 02 o 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 carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO 2 -R Or and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R 4 R' is selected from -halo, -OR, -CO 2

R,

o -COCOR, -COCH 2 COR, -N02, -CN, -S(0) 2 R, -SR.

-N(R

4 2

-CON(R')

2

-SO

2

N(R)

2

-N(R')COR,

-N(R

4 C02 (optionally substituted C1. aliphatic)., -N (R N(Rt) 2 -C=NN(Rt) 2 -C=N-OR, ;-N(R 4 ).CON(Rt) 2 -N(Rf)SO 2

N(R

4 2

-N(R

4

)SO

2 R, or 2 each-R is independently selected from hydrogen or an optionally substituted group selected from C-_ aliphatic, 06-10o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' 4 is independently selected from -R 7

-COR

7 -C02 (optionally substituted CI-6 aliphatic) -CON(R') 2 or -Sd2R', or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or.

heteroaryl ring; each R 5 is independently selected from halo, -OR,

-CO

2 R, -COCOR, -NO2, -CN, -SO2R, -SR,

-N(R

4 2

-CON(R

4 2

-SO

2

N(R')

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

-N(R')N(R

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

-N(R')SO

2 N(R4) 2

-N(R

4 )S0 2 R, Or -OC N 2; V is -S02-, -SO 2 -CO2-, IND -N (R6)CON (R6) -N (R')SO 2

-NRW)N(RW)-

O -C()N(R 6

-C(R'S)

2 o0-, 2

S-,

-LtC(R)2,S-, -U~CR) 2 flU-, -C(RC)2SU 2 t-CR)2L(C)

C(R')

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

-C(R

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

-C(R

6 2 N CON (R6) IND W~i is -C (R6) 2

-C(R

6 2 -C(R 6) 2 so-, -C(R'6h s0 2

-C(R

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

)AN(R

6

CO-,

V.0 10 -C(R 6 2

N(R

6 0

-C(R

6 2

N(R

6

)N(R

6

-C(R

6 2 N(R')so 2 Ci -C(R6} 2 N(R')CON(R6)-, or -CON(R 6 each R'6 is independently selected from hydrogen or an optionally substituted Ca1.4 aliphatic group, or two R6 groups on the same nitrogen atom 'are taken together with the-nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an optionally substituted C 1 _6 aliphatic group, or two R' on the same nitrogen are taken toget her with the nitrogen to form a 5-8 membered beterocyclyl or heteroaryl ring.

Preferred formula III Rinig D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings. Wh en two adjacent substituentS on Ring D are taken toge. ther to form a fused ring, the Ring D system is bicyclic. Preferred formula III Ring D bicyclic rings include 1,2,3,4tetrahydroisoquinolinyl, 1,2,3, 4-tetlrahydlroguinolinyl, 2,3 -dihYdro-1H-isoindolyl, 2, 3-dihydro-uf-indolyl, iLsoqJuinolinyl, quinolinyl, and naphthyl. Examples of* -71- IND more -preferred bicyclic Ring D systems include naphthyl O and isoquinolinyl.

k Preferred R s substituents on Ring D of formula III include halo, oxo, CN, -NO 2

-N(R

4 2

-CO

2 R, -CONH(R 4

-N(R

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

-N(R

4

)SO

2 R, -SR, -OR, or substituted or unsubstituted group. selected from 5-6 membered heterocyclyl, C6s-o aryl, or C1-6 aliphatic. More a preferred R 5 substituents include -halo, -CN, -oxo, -SR, -OR, -N(R 2, -C(0)R,_or a substituted or unsubstituted Ci 10 group selected from 5-6 membered heterocyclyl, C-o aryl, o or C1-6 aliphatic. Examples of Ring D substituents 0 CN include -OH, phenyl, methyl, CH 2 0H, CH 2

CH

2

OH,

pyrrolidinyl, OPh, CF 3 C=CH, C1, Br, F, I, NH 2 C(0)CH3, i-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene dioxy, and ethylene dioxy.

Preferred rings formed when the Rx and R groups of formula III are taken together to' form a fused ring include a or 7-membered unsaturated or partially unsaturated carbocyclo ring, wherein any substitutable carbon on said fused ring is substituted by oxo or T-R 3 Examples of preferred bicyclic ring systems are shown below.

R F

NH

HN N HN HN, III-A III-B III-C -72- HN HN cii 0 Ill11-F l- Pref erred substituents on the eR 1 /R fused ring of formula III include -oxo, halo, -OR, -00 2

R,

o -000CR, -NO 2 -ON, -SO 2 R, -SR, -N(R 4 2 -CON(Rl 2 ci-SO 2

N(R')

2 -Oo(=c4R, -N(R)0C0 2 (optionally substituted 01_6 a~liphatic) -N (R 4 N(W) 2

-C=NN(RW)

2 Ci-CZ=N-OR, -N(Rt)CON(Rt) 2

-N(R

4

)SO

2

N(R

4 2

-N(RW)SO

2 R, or OC (=O)N(R 4 2 wherein R and R 4 are as defined above.

More pref erred substituents on the RX/RY fused ring include halo, ON, oxo, C1.f6 alkyl, C16g alkoxy, (C3.alkyl) carbonyl, (C1..6 alkyl) suit onyl, mono- or dialkylamino, mono- or dialkylarninocarbonyl, mono- or 1S dialkylaminocarbonyloxy, or 5-6 membered beteroaryl.

Examples of such preferred substituents include methoxy, mty, isopropyl, methylsulf onyl, cyano, chioro, pyrrolyl, methoxy, ethoxy, ethylamino, acetyl, and acetamido Preferred R 2 subst'ituents of formula III include hydrogen, aliphatic, alkoxycarbofql, (on) substituted phenyl, hydroxyalicyl, alkoxyalkyl, ami nocarbonyl, monoor dialkylanlinocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and heterocyclyl) carbonyl. Examples of such preferred Rt 2 substituents include methyl, cyclopropyl, ethyl, isdpropyl, propyl, t-butyl, cyclopentyl, phenyl, CO 2

H,

~~CO

2

CH

3 011201, 01120013, 011201420120H, 0112012C200H13.

OH

2

CH

2

CH

2 00CH 2 Ph, 0H 2 011 2

CH

2

NH

2

CH

2

CH

2

CH

2 bIHCOO)C (013) 3, CONHON (013)2, CONHCH 2 01= CH 2

CONHCH

2 01200113, CONHCH 2 Ph, -73- INDCONH(cyclohexyl), CON(Et) 2

CON(CH

3

)CH

2 Ph, CONH(n-CH 7 o CON(Et)CHCH 2 CH 3

CONHCH

2

CH(CH

3 2 CON(n-CH7) 2 CO(3methoxymethylpyrrolidin-1-yl), CONH tolyl), CONH (4tolyl) -CONHCH 3 CO(morpholin-l-yl), CO (4-methylpiperazin- 1-yl), CONHCH 2 CH20H, CONH 2 and CO(piperidin-l-yl).

O2 When the R 2 and R 2 groups of formula III are taken together to form a ring, preferred k 2

/R

2 ring Va systems containing the pyrazole ring include benzo, 1 pyrido, pyrimido, 3-oxo-2H-pyridazino, and a partially C 10 unsaturated 6-membered carbocyclo ring. Examples of such preferred R 2 /R2' ring systems containing the pyrazole ring 0 include the following:

OH

H H H H rN H and H Preferred substituents on the R 2

/R

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

-C

1 4 alkyl, -C1-4 haloalkyl, -NO 2 -O(C.-4 alkyl), -CO2 (C.4 alkyl), -CN, -SO 2

(C

1 4 akyl), -S0 2

H

2

-OC(O)NH

2

-NHSO

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

-C(O)NH

2 and -CO(C.-4.alkyl)', wherein the (C.L- 4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C 1 4 alkyl) group is niethyl.

Preferred formula III compounds have one or more, and more preferably .all, of the features selected from the group consisting of: -74- Ring D is an optionally substituted ring 0

I

selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydrouinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or IDnaphthyl ring; RX and RY are taken together with their intervening atoms to form an optionally substituted benzo ring or a 5-7 membered carbocyclo ring; and

R

2 is hydrogen or methyl and R2 is T-W-R' or c R, wherein.w is 2 2

N(R

6 -C0 2 -C(R6) 2

N(R

6 2

N(R

6 )C(0)O or

-CON(R

6 and R is an optionally substituted group selected from C 1 aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstitutedbenzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula III have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; ReX and RY are taken together with their intervening atoms to form a benzo ring or a 5-7 membered carbocyclo ring optionally substituted with oxo, halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -S(O)R,

-SO

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

-CON(R

4 2

-SO

2

N(R

4 2

-OC(=O)R,

-N(R')COR, -N(R').CO 2 (optionally substituted C 1 6 aliphatic),

D-N(R)N(R')

2

-C=NN(R')

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

)CON(R

4 2 0 o -N(R)SO 2 N(Rt) 2

-N(R

4

)SO

2 R, or 2; and each RS is independently selected from halo, oxo, CN, NO 2

-N(R

4 2

-CO

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

)COR,

s -SO 2

N(R')

2

-N(R

4

)SO

2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-o aryl, or C1-6 aliphatic.

ON Even more preferred compounds of formula III have one or more, and more preferably all, of the 0 features selected from the group consisting of: RX and RY are taken together with their C- intervening atoms to form a benzo or '6-membered partially unsaturated carbocyclo ring optionally substituted with halo, CN, oxo, CI-6 alkyl, C1-g alkoxy, (C1.6 alkyl)carbonyl,

(C

16 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each Rs is independently selected from -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs- 0 o aryl, or aliphatic; and R2' is hydrogen and R 2 is selected from R 2 is hydrogen or methyl and R2.is T-W-R' or R, wherein W is

-C(R

6

-C(R

6 2 -C0 2 2 or -CON(R6)-, and R is an optionally substituted group selected from C1-6 aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms .to form a benzo, pyrido, or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, 2 -C1-4 alkyl, -C 1 -4R baloalkyl, -NO 2

-O(CI-

4 alkyl), -C0 2

(C

1 _4 alkyl), -CN, S02 (c.

4 alkyl), -SO 2

NH

2 -OC NH 2

-NH

2

SO

2

(C

1 -4 alkyl) -NHC (C1-4 alkyl) -76- Va 0 0, ci C N, or -CO(C3 4 alkyl) wherein the (CI.

4 alkyl) is a straight, branched, or cyclic alkyl group.

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

Table 2

III-'

HNH

GtN N4- Cl.

111-2 i-5 CH3

HN'*H

111-3

CH

3

N

111-4

CH

3

HN<H

ACNHJZI("".$

111-6

CH

3 J'eNH CH3

HN'*H

111-9 111-8 111-7

CH

3

HN.RH

111-10 1% "I-II III-i2 -77- Va 0 0 ci 0

OH

3 HN C<1' 111-13

OH

3 N Z

OH

3 ztN

CC)I

111-14

H

3 *H _N~

CH

3 O3 111-20 III-is

CH

3 I*

H

OH

3

OH

3 CH 3

HN~

111-19

'N

111-21

CH

3

NH.

H

3

CH

3

SQ

2 cWt ap 111-23

OH

3

HN<H

tN N't 111-24 111-22

HN<N*

NH

OH

3

IH

CH

3

HN<N

0 -78- 111-25 111-26 111-27

OH

3

HN<*

111-28 HN re;-31

CH

3 HNt 111-29

CH

3

HN<N

111-32 SCH3 HN 14N

H

111-30

CH

3

HN

111-33

CH

3

CH

3 I 4

'NH

111-34 111-35

OH

3

*HN

NH

OH

3

HN<N

N C 1 cl .111-36

CH

3

HN

111-39 111-37 111-38 -79- Va 0 0, ci

HNX?

111-40

CH

3

HN<J:I

0 111-43 CH3

OH

3 111-41

OH

3

HN<

11-N H 111-44 111-42

OH

3

HN<

111-45

CH

3

HA

CH

111-48 111-46 111-47

OH

3

HN<*

N H -111-49 III-so 111-51

CH

3

HA

111-52

OH

3 HN<N*1 1N1-H

OH

3

HA

111-54 111-54

OH

3

HN<*I

0tN H CH3 N" IH 3 IllS

OH

3 111-5611-5 111-57

OH

3 111-58

CH

3 HN4 111-59

OH

3

HA*

N11-H CH3 HN*t 111-60

H

1ll-61 HNQ t 111-64 I 3C

H

HNS

C a

N

ID N -0Z 111-63 Ill-E5 111-66 -81- 111-67 111-67 ~111-68 116 111-69 0

HNX?

111-70 C0 2

H

111-72 111-71 C 2

CH

3 HN 111-73 111-74 111-75 111-76 111-77 111-78 -rNH 2 HN 1 111-79 III-so 111-81 -82- Va 0 0 ci 0

CH

2

NN

111-82 0Q HN 4 111-85

OCH

3 o H-

NNH

111-83 *o

,-CH

H

NN-8 .111-84 111-87 01P 111-90 111-88 111-89

N

N

H

HNN

111-91 .111-93 -83o Q-CH 3 111-94 o ,CH 3 HAf 111-96 111-95 111-97 111-98 111-99 111-100 111-101 111-102

OH

3 HN~t

NH

111-104

OH

3 KNiN

NH

III-IDS

.111-103

NC

HNK

OH

OH

3 HN4* ONtH 3

OH

3

H

-84- 111-106 111-106 ~111-10711-0 111-108 0

CH

3

HNL$

H.

0Q--OH 111-109 111-110 HN4 NztJH

CH

3 HN<1

NH

CH

3 -0 111-112

CH

3

HN

HNS

HN

111-114

HNS

111-115 III- 117 Hi 11N-1H 111-119 111-120 Va 0 0, ci 111-121

CH

2 0H

HAN'

111-124

F

HN

1N

H

111-127 II-122

CONH

2

Z

HN

H

'N

N

111-125

F

3

HZ

N- H 111-128 0

N

HN4 111-123

CONH

2

HN

CrlN

H

111-126

HN

2 1

P-

111-129 HN2 113 111-132 I

F

HN

HiN 1H 111-131 111-130 111-133. 111-134 -86- 111-135 Va 0 c 111-136 0 ci @0

HNA

111-140 PhOa, 111-138 HN -4NH 111-141 111-139 Q.,s C Nt CH3 HN2N 111-142

H

~iNN>Me Me 111-145 111-143 111-144

HN

1, rj' N Me0o 111-146 -87- ND In another embodiment, this invention provides o a composition comprising a compound of formula III and a Ci Spharmaceutically acceptable carrier.

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

VO

C of formula III.

Another aspect relates to a method of treating C- 10 a disease that is alleviated by treatment with a GSK-3 o inhibitor, said method comprising the step of Cq administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula III.

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

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

Another aspect relates to a method of inhibiting the phosphorylation of p-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition -88- D comprising a compound of formula III. This method is oespecially useful for treating schizophrenia.

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

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

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

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

One aspect of this invention relates to a method of inhibiting Src. activity in a patient, -89- ND comprising administering to the patient a therapeutically 0effective amount of a composition comprising a compound _of formula III.

<Another aspect relates to:a method of treating a disease that is alleviated by treatment with a Src inhibitor, said method comprising the step of IND administering to a patient in need of such a treatment a ON therapeutically effective amount of .a composition en1 r comprising a compound of formula III. This method is N 10 especially useful for treating hypercalcemia, 0 osteoporosis, osteoarthritis, cancer, symptomatic Ci treatment of bone metastasis, and Paget's disease.

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

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

Compounds of formula III, wherein R12' is hydrogen and RI and R Y are taken together with the pyrimidine ring to form an optionally substituted quinazoline ring system, are also inhibitors of ERK-2 and AKT protein kinases.

Accordingly, another method of this invention relates to a method of inhibiting ERK-2 or AIKT activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition IND comprising a compound of formula III,, wherein R 2 is Shydrogen and R x and R Y are taken together with the pyrimidine ring to form an optionally substituted quinazoline ring system.

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

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

R

2 R NH

IV

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, 'heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or -91- IND heterocyclyl ring having 1-4 ring heteroatoms selected o from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or S-Rs, and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or o heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring. D;

\O

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

_R

Y are taken together with their intervening atoms to 0 form a fused, unsaturated or partially unsaturated, 5-8 o membered ring having 1-3 ring heteroatoms selected from i i 0 oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring is optionally and independently substituted by T-R 3 and any substitutable nitrogen on said ring is substituted by

R';

T is a valence bond or a C 1 -4 alkylidene chain;

R

2 and R' are independently selected from -T-W-R 6 or

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring containing 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein said fused ring is optionally substituted by up to three groups independently selected from halo, oxo, -CN, -NOa, -R 7 or -V-R6;

R

3 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

4 2 -SON(Rt 2

-N(R

4

)COR,

-N (R 4

CO

2 (optionally substituted Ci-_ aliphatic),

-N(R

4

)N(R

4

-C=NN(R

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

)CON(R

4 2

-N(R

4

)SO

2

-N(R')SO

2 R, or 2; each R is independently selected from hydrogen or an optionally substituted group selected from Cz- 6 -92aliphatic, aryl, a heteroaryl ring having 5-10 o ring atoms, or a heterocyclyl ring having 5-10 ring atoms;, each R4 is independently selected from -COR7, -CO2 (optionally substituted C 1 6 aliphatic) -CON (R 7 Or -SOR 7 or two R4 on the same nitrogen are taken IND together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, Va -CO2R, -COCOR, -CN, -SO2R,

-N(R

4

-CON(R

4

-SO,.N(R

4 -N(RflCOR, i-N (Rt)CO, (optionally substituted Cj 6 aliphatic), -N (R 4

N(R

4 2, -C=NN(Rt,,1 -0=11-OR, -N(Rt)CON(R'),

-N(R

4 )SO2N(Rl,, -N(R 4 )SOR, or--C=)(42 V is -N(R6)SO2-, -SON(R)- -NCR') -CO2-, -N CR6) 0(0)0-, -N(R'jN(R6)-, 1C N(R6) -OC N(Rr) -C(R6'hO-, -C(R'6)2so-, -C(a 6 2 so2-, -C(R')2SO2N(R6) or -cCR') 2 N CON W is -C(R")2SO2, -C(R')2SO2N(R)-, -C(R6)OC(O) -C(R')OC(O)N(R6) (R6) 00-, -C(R 6b=N(R), O -C(R6),N (R6) CON or -CON *each R6 is independently selected from hydrogen or an optionally substituted CI- aliphatic group, -ot two R'6 groups on the same nitrogen atom are taken together w7ith the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and -93- IDeach R' is independently selected from hydrogen or an optionally substituted C 16 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl ring or heteroaryl.

Preferred formula IV Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings. Preferred formula IV 0g 10 Ring D bicyclic rings include 1,2,3,4ci tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 0 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred Ring D bicyclic rings include naphthyl and isoquinolinyl.

Preferred substituents on Ring D of formula IV include halo, oxo, CN, -NO 2 4 2

CO

2 R, -CONH(R 4

-N(R

4 )COR, -SO 2

N(R

4 2 -N (R 4

)SO

2 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C 6 1 aryl, or C 1 1s aliphatic. More preferred R 5 substituents include -halo, -CN, -oxo, -SR, -OR, :N(R 4 2 or a substituted or unsubstituted group selected from'5-6 membered heterocyclyl, Cs-.o aryl, or C 16 aliphatic. Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 0H, CH 2

CH

2 0H, pyrrolidinyl, OPh, CF3, CiCH, Cl, Br, F, I, NH 2

C(O)CH

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

When the RX and R groups of formula rIV are taken together to form a fused ring, preferred R 1 /R rings include a or 8-membered unsaturated or partially unsaturated ring having. 1-2 heteroatoms. This provides a bicyclic ring system containing the pyrimidine -94- Va 0 0 ci 0 ring. Examples of preferred pyrimidine ring systems of formula Iv are the mono- axid bicyclic, systems shown below.

HN3' R

N'

TV-D

fl-H

IV-;

37- J fN~ fl-K TV- H TV- L Tv-N fl-N

HNN

NKN

IV-R

(N

HN;'

Nxt fls IV- 0 IV- T Va 0 0, ci

HN?

IVV

'V-v

HN<N

N N- Iv-w IV-U 3:VU

IV-

'v-Kr HN 377

N

Xes Noly

IV-AA

IV-Y

HN'Z

IV-BB

IV- z v-HNCC IV-cc H N

IV-DD

More preferred pyrimidine ring systems of formula IV include Iv-R, IV-G, IV-H, IV-J, IV-K, IV-L, tV-M, IV-T, and IV-U.

In the monocyclic pyrimidine ring system of formula IV, preferred RX groups include hydrogen, amino, nitro, alkyl- or dialkylamino, acetiamido, or a C 1 4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl. Preferred RY groups include T-R 3 wherein T is a valence bond or a methylene, and R 3 is -R, -96- ND or -OR. When R 3 is -R or -OR, a preferred R is 0 an optionally substituted group selected from C 1 -6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred R Y groups include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, O acetamido, optionally substituted phenyl such as phenyl, N t methoxyphehyl, trimethoxyphenyl, or halo-substituted phenyl, and methoxymethyl.

Ci 10 In the bicyclic pyrimidine ring system of o formula IV, the ring formed when Rx land R Y are taken Ci together may be substituted or unsubstituted. Suitable substituents include halo, -OR, -CO 2

R,

-COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2 -CON(R4) 2 -S02N(R 4 2

-N(R

4 )COR, -N(R 4 C0 2 (optionally substituted Ci-6 aliphatic), -N(R 4

)N(R

4 2

-C=NN(R

4 2 -C=N-OR, -N(R')CON(R 4 2 -N(R4)SO 2 N(R4) 2 -N(R4)SO2R, or

-OC(=O)N(R

4 2 wherein R and R 4 are as defined above for compounds of formula IV. Preferred RX/RY ring substituents include -halo, -OR, -COR, -C0 2

R,

-CON(R4)2, -CN, or -N(R 4 2 .wherein R is a substituted or unsubstituted C-.

6 aliphatic group.

The R 2 and R 2 groups of formula IV may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IV compounds having a pyrazole-containing bicyclic ring system: -97- Van 0

NH

HN h( FeN N N

N

RYX frNH H NH

NH

,and n Preferred substituents on the R 2

/R

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

-C.

4 alkyl, -Ca.4 haloalkyl, -NO 2 -O(CI.4 alkyl), -CO2(C.

4 alkyl), -CN, -S0 2 (C1-4 alkyl), -SO 2

NH

2

-OC(O)NH

2

-NH

2

SO

2

(C.

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

C(O)NH

2 and -CO(C2..4 alkyl), wherein the alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (01-4 alkyl) group is methyl.

When the pyrazole ring system of formula IV is monocyclic, preferred R' groups include hydrogen, a substituted or unsubstituted group selected from aryl, beteroaryl, or a C1_6 aliphatic group. Examples of such preferred R 2 groups include methyl, 't-butyl, -CH20CH3, cyclopropyl, furanyl, thienyl, and phenyl. A preferred R' group is hydrogen.

Preferred formula IrV compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; -98- D Rx is hydrogen or C1-4 aliphatic and R Y is T- O R 3 or R' and R y are taken together with their intervening k atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring heteroatoms; and

R

2 is hydrogen or methyl and R 2 is T-W-R 6 or \0 R, wherein W is -C(R 6 2

-C(R

6 2

N(R

6

-C

2

O-,

C -C(R' -C(R) 2

N(R

6 CO-, -C(R 6 2

N(R

6 or

S-CON(R

6 and R is an optionally substituted group 10 selected from C1-6 aliphatic or phenyl, or R 2 and R 2 are Staken together with their intervening atoms to form a C( substituted or unsubstituted benzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula IV have one or more, and more.preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; Rk is hydrogen or methyl and R Y is -R, N(R4)2, or -OR, or R x and R Y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, wherein said ring is optionally substituted with -R, halo, oxo, -OR, -CO2R, -COCOR, -NO 2 -CN, -S(O)R,

-SO

2 R, -SR, -N(R) 2

-CON(R')

2 -S0 2

N(R

4 2 -OC(=0)R,

-N(R

4 COR, -N(R')CO 2 (optionally substituted Ci-6 aliphatic), -N(R4)N(R 4 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 R, or -OC(=O)N(R 4 2 and -99- IND each R 5 is independently selected from halo, 0 o oxo, CN, N0 2 -N (R 4 2

-CO

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

)COR,

-SO

2

N(R

4 2

-N(R')SO

2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-30 aryl, or aliphatic.

Even more preferred compounds of formula IV INDhave one or more, and -more preferably all, of the features selected from the group consisting of: RX and RY are taken together. with their \O N 10 intervening atoms to form a 6-membered unsaturated or O partially unsaturated ring having 1-2 ring nitrogens, C optionally substituted with halo, CN, oxo, C-6 alkyl, C..6 alkoxy, (C 1 .C alkyl) carbonyl, (C1.-6 alkyl) sulfonyl, moho- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R 5 is independently selected from -halo, -CN, -oxo, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-.o aryl,. or C.1-6 aliphatic; and

R

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

-C(R

6 2 -C02-,r

-C(R

6 2 N(R)CO-, or and R is. an optionally substituted group selected from C1.,6 aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, oxo, -N(R 4 2 -CI4 alkyl, -C,.4 haloalkyl; -NO 2 alkyl), -COl(C4 alkyl), -CN,

-SO

2 (C2- alkyl), -S0 2

NH

2

-OC(O)NH

2 -NHaS0 2

(C

1 -4 alkyl) -NHC(0) (C1.4 alkyl), -C NH2, or -CO(Cl-4 alkyl), wherein the (C1.4 alkyl) is a straight, branched, -or cyclic alkyl group.

-100- Representative compounds of, formula. IV are set forth in Table 3 below.

Table 3.

IV -1 OMe IV- 2

CH

3 HN4 02Nt'N Nej Nv s

H

CH

3 AcNH~a

I

IV- 3

CH

3 H2Nt'N

IV-G

IV- 4 HN3 TV-*7 'V-a XV- 9 IV-11 IV- 12 -101- Va 0 0 ci 0 Va en 0 ci Va 0 0 ci IV-13 IV1-14

CH

3 HN IV- 16

H.

3 C N') I-19

CH

3

HN

IV- 17

CH

3 IV- 20

CH

3 IV-18

HNZC

>ZACHN

IV-21 .1

CH

3 HN JkH IV- 22 TV- 23 IV- 24 -102-

I

Va 0 0, ci CHs HN

H

H

3 C 1a iH3 HN9NH MeOJ IV-28

CH

3

HN

IV-26

CH

3

HNH

HN,,-

{J

N

KIN

IV-29

CH

3 HN

H

fN H C

CH

IV-27

CH

3

HN

4

AP

H

CH

3

CH

3 HJ H

H

HNA* HNN H HNN NN N N H IV-31 IV-32 IV-33 In another embodiment, this invention provides a composition comprising a compound of formula IV and a pharmaceutically acceptable carrier.

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a -103- IND therapeutically effective amount of a composition o comprising a compound of' formula 37.

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising 0 administering to said patient a therapeutically effective amount of a composition comprising a compound of formula

IND

IV. This method is especially useful for- diabetic patients.

c-i 1 Another aspect relates to a method of inhibiting the production of hyperphosphorylated Tau 0protein in a patient in need thereof, comprising administering to said patient a therapeutically effective .amount o f a composition comprising a compound of formula TV. This method is especially useful in halting or slowing the progression of Alzheimer's disease.

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

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora inhibitor., said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula Iv. This method is -104- Va D especially useful for treating cancer, such as colon, 0 ovarian, and breast cancer.

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

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

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

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

Another embodiment of this invention relates to compounds of formula V: -105- IN

R

2

SHN

RY Z v Sof

Z

I and Z' is nitrogen; G is Ring C or Ring D; Va Ring C is selected from a phenyl, p yridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents indeor a phaaceutically acceptable derivative or prodrugnonortho carbon position on Ring C is independently 0 Ring C are optionally taken together.with their intervening atoms to form a fused or unsaturatovidedthat o partially unsaturated, 5-6 membered ring having 0-3 Sof htroatond Z is nitrogen; said fused ring being optionally substituted by halo, G is Ring C or Ring D; Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicycic ring selected from a phenyprnyl, pyrimidinyl, heterocyclyl or carbocyclyl, said heteroaryl or Sheterocazinyl, pyrazinyl, or 1,2,4-triazinyl ringselected wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable nonfrom nitrogen, oxygesition or sulfur, wherein Ring C is independently substituted aby 5 and tto adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted ring nitrogen by halo, oxo, or -RB; provided thaRing D is a 5-7 membered monocyclic ring or membered 106bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable rin4 nitrogen by -R 4 provided that. when Ring D is a six-membered aryl or -106- D heteroaryl ring, -R 5 is hydrogen at each ortho carbon o position of Ring D; R is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 Smembered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci.e aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, r oxo, or -R 8 said C25- aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 10 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;

C

N

R

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

R

Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by RX and R Y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by R x and R y is substituted by R 4 T is a valence bond or a C 1 4 alkylidene chain;

R

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

R

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

-R

7 or

-V-R

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

R

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

R,

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

-N(R

4 2, -CON(R 7 -SO2N(R 7 2, -N(R COR, -107- IND -N (R 7 )C0 2 (optionally substituted C 1 c 6 aliphatic), o -N(R 4

)N(R

4 2

-C=NN(R

4 2 -CrN-OR, -N(R')CON(R) 2

-N(R

7

)SO

2

N(R

7 2

-N(R

4 )S0 2 R, or O=)NR2; each R is independently selected from hydrogen or an .optionally substituted group sele cted from C,> 6 0 aliphatic, C 6 10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R7. -COR', ci -C0 2 (optionally substituted C1..6, aliphatic), CO(' 2 1 NO 7,f oOr SO 2 R ,or two It' on the sane nitrogen are taken 0 together to form a 5-8 membered heterocyclyl or S heteroaryl ring; each Rt 5 is independently selected from -Rt, halo, -OR, C R, CO 2 COCOR, NO 2 -at S SO 2 R, -SRt, 2 -CONCR%), -S0 2

NCR

4 -OC -NCRt)COR, -N (R4) CO 2 (optionally substituted 6 aliphatic), -N(Rt)N(R') 2

-C=NN(R

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

SO

2 R, or NRW) 2 Or R 5 and an adjacent substituent taken togeth er with-their intervening atoms form said ring fused to Ring C; V is 1

-SO

2 -N S0 2

-SO

2

N(R)-

is1 7CO2-,' CON SO 2 N(It) -C(Rt) 2 2

S-,

-CCR')

2 S0-, -C(It') 2 S0 2 2 S0 2 NCR6)-, 2 N(R 2 -CCR 6) 2 -CCR') -C CR 6 2 -CCR') 2

SO

2 NCR6) or -C CR') 2 1T(R") CON CR)-; W is -C(It') 2

-CCR')

2 S0-, -CCR)bSO 2

-CCR')

2 S0 2 -C0 2 2

N(R')CO-,

-C CR') 2 C -C CR6) -CCR') -108- S-CC(R6) 2 N (R)N (R 6 -C (R) 2

N(R')SO

2 N o

-C(R

2 N (R CON(R 6 or -CON(R 6 Seach R 6 is independently selected from hydrogen, 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 IND heterocyclyl or heteroaryl ring; C each R 7 is independently selected from hydrogen or an optionally substituted C 1 -e aliphatic group, or two R 7 10 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or Sheteroaryl ring; each R 8 is independently selected from an optionally substituted C1-4 aliphatic group, -OR 6

-SR

6

-COR

6 -SO2R 6 -N(R6) 2 -N(R6)N(R 6 2 -CN, -NO 2

-CON(R')

2 or -C0 2

R

6 and Ra is selected from halo, -OR, -C0 2 R, -COCOR,

-NO

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

-CON(R)

2

-SO

2

N(R

4 2 COR, CO 2 (optionally substituted Ci-s aliphatic), -N(R 4 N 4 2

-C=NN(R

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

-N(R

4

)SO

2

N(R

4 2

-N(R

4 )SOzR, -OC(=0)N(R 4 or an optionally substituted group selected from Ci-6 aliphatic, Cs-3o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

Compounds of formula V may be represented by specifying Z 1 and Z 2 as shown below: -109- Va 0 0, ci Va Vb When the Rx and R Y groups of formula V are taken together to form a fused ring, preferred RX/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said RX/Ry ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Examples of preferred bicyclic ring systems of formula V are shown below.

R

2 HN N N G Va-A

HNA

Vb-A Vc-A

HN-

N

Va-B Vb-B Vc-B -110- HNiZ HN>?1

N~

<N

Z4

A

oVa-C vb-D ye-C RZ:HN>?7 HN3Z 4' HN3' 0 R4~NR41N Vb-D ye-B HN? HN-N HN Va-S vb-E Vc-E HN' Z? HN H'

N

N2>

(N

b-i ltc-J

HNAZ

Va-K HN

Z

HN3% Vb- L Vc-K Va- L Vc -L

HN-

vb-m Va-Id Vc-M

_N,

N,.

Va-N vb-Nq Va- 0 Vb -0 Vc-0 -112- Va HNt HN HNZ

NN

C

(CNX $J C o Va-P Vb-P Va-P N More preferred bicyclic ring systems of formula n 5 V include Va-A, Vb-A, Va-A, Va-B, Vb-B, Vc-B, Va-D, Vb-D, Vc-D,.Va-E, Vb-E, Vc-E, Va-J, Vb-J, Vc-J, Va-K, Vb-K, IDVc-K, Va-L, Vb-L, Vc-L, Va-M, Vb-M, and Vc-M, most C preferably Va-A, Vb-A, Vc-A, Va-B, Vb-B, and Vc-B.

In the monocyclic pyridine ring system of formula V, preferred RX groups include hydrogen, alkyl- or dialkylamino, acetamido, or a C1-4 aliphatic-group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl..

Preferred Ry groups include T-R 3 wherein T is a valence bond or a methylene, and R' is -N(R) 2 or -OR. When

R

3 is -R or -OR, a preferred R is an optionally substituted group selected from 01_6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred R include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl, and methoxymethyl.

In the bicyclic ring system of formula V, the ring formed when R'X and RY are taken together may be substituted or unsubstituted. Suitable substituents include halo, -OR, -C00 2 R, -COCOR, -NO 2

-CN,

-S -SO 2 R, -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 C1-6 aliphatic), 2

-C=NN(R

4 2

-C=N-OR,

-N(R')CON(R

4 2

-N(RRSON(R')

2 -N(R4)SO 2 R, or -113- IN 2 wherein R and R4 are as defined above.

0 o Preferred RXI/RY ring substituents include -halo, -OR, cii -COR, -C0 2 R, -CON(R) 2, CN, or 2 wherein R is an optionally substituted C 1 6 aliphatic group.

The R 2 and R 2 groups of formula v may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are 0 C 10 exemplified in the following formula v compounds having .a o pyrazole-containing bicyclic ring system: 0

NH

HNN

Z2 x z jNH NH NH 2 NH RY R'Z- N

N

,and Preferred substituents on the R 2

/R

2 fused ring of formula V -include one or more of the following: -halo, -N(R 2 4 alkyl, -C.

4 haloalkyl, -NO 2

-Q(C

1 4 alkyl), -C02(C1.4 alkyl), -CN, -S0 2

(C

1 4 alkyl), -SO 2

NH

2

-OC(O)NH

2

-NH

2 So 2

(C

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

When the pyrazole ring system is monocyclic, preferred R 2 groups include hydrogen, C.

4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (N- -114oN heterocyclyl)carbonyl. Examples'scprfre

R

2 o substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO 2

H,

*C0 2

CH

3

CM

2 OH, CH 2 700H 3 C2HRCE 2 O1 2 OH, O1 2 O1 2

CR

2 0CH 3 sCH, 2

CH

2

CH

2 OaH 2 Ph, CH 2 aI 2

CH

2

QH

2

CH

2 C11 2 0{ 2 NHCOOC (CH 3 3 CQNHCH (CH 3 2

CONH'CH

2

-H=CH

2

CQNHCH

2

CH

2

OCH

3

CQNRCH

2 Ph, IND CONH(cycloheXyl), CON(Et) 2

CON(CH

3

CJM

2 Ph, CONR(n-CgI 7 CON(Et)CH 2

OH

2 CH3, CONHCH 2 CH(11 3 2 CON(n-C 3 H74 2 CO(3- 10methoxymethylpvrrolidin-1.y1), CONH(3-tolyl), CONI{(4r0 toll C0NHO 3 CO (morpholin-1-yl), Co (4 -methylpiperazin- 1-yl) ICONHCH 2

CH

2 OH, CONH 2 and CO(piperidin-i-yl).

A

preferred R 2 group is hydrogen.' -More preferred ring systems of formula v are the following, which may be substitu Ited as described above, wherein R' and R 2 are taken t~ogether with the pyrazole ring to form an optionally substituted indazole ring; and RX and O' are each methyl, or RX and R T are taken together with the pyridine ring to form an optionally substituted quinoline, isoquinoline, tetrabydrogminolinje or tetrahydroisoquinoline ring:

ZI

z t ctH 3 C Z V-Aa V-B3a V-Ha When G is Ring C, Pref erred formufla V Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system.

Preferred fused .rings, include a benzd or pyrido ring.

-115- ND Such rings preferably are fused at ortho and meta o positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred RJ groups include -halo, an optionally substituted C-6 aliphatic group, phenyl, -COR, -OR, -CN, -SO 2

-SONH

2 o-N(R') 2 -CO2R 6 -CONH2, -NHCOR', -OC(O)NH 2 or -NHSO 2

R'.

When R' is an optionally substituted

C

1 6 aliphatic group, the most preferred optional substituents are halogen.

Examples of preferred R 1 groups include -CF 3 -Cl, -F, C 10 -CN, -COCH 3 -0CH 3 -OH, -CH 2

CH

3

-OCH

2

CH

3 -CH3, -CF 2

CH

3 C cyclohexyl, t-butyl, isopropyl, cyclopropyl, -0CH, c( -CC-CH3, -SO 2

CH

3

-SO

2

NH

2 -N(CH3) 2

-CO

2

CH

3

-CONH

2

-NHCOCH

3 -OC(0)NH 2

-NHSO

2

CH

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

R,

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

N(R

4 2 and -N(R')SO 2 R. More preferred R 5 substituents include -Cl, -CN, -CF3,

-NH

2

-NH(C

1 4 aliphatic), -N(C 1 4 aliphatic) 2

-O(C

1 -4 aliphatic), C 1 -4 aliphatic, and aliphatic).

Examples of such preferred R 5 substituents include -C1, -CN, -CF 3

-NH

2 -NHMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -CO 2 Et.

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

When two adjacent substituents on Ring D are taken together to form a fused ring, the Ring D system is bicyclic. Preferred formula V Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, qcuinolinyl, and -116-

IND

S naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

Preferred substituents on Ring D of formula V include one or more of the following: halo, oxo, CN, -N0 2 2

-CO

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

N(R)

2

-N(R

4

)SO

2

R,

-SR, -OR, or substituted or unsubstituted group \D selected from 5-6 membered heterocyclyl, C0lo aryl, or C.,s n aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl,. Cs..o aryl, or C1.- aliphatic.

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

CH

2 0H, pyrrolidinyl, OPh, CF 3 C=CH, C1, Br, F, I, NH 2 C(0)CH3, i-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene'dioxy, and ethylene dioxy.

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

-SO

2

NH

2

-N(R

6 2 C0 2

R

6

-CONH

2 -NHCOR6, -OC(O)NH2, or -NHSO 2

R

6 or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-H-isoindolyl, 2,3-dibydro-H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; -117- IND Rx is hydrogen or C 1 4 aliphatic and R Y is To R 3 or R x and R 7 are taken together with their intervening k atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; and

R

2 is hydrogen and R 2 is hydrogen or a substituted .or unsubstituted group selected from aryl, C heteroaryl, or a C1-6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a Ci 10 substituted or unsubstituted benzo, pyrido, pyrimido or

D(

0 partially unsaturated 6-membered carbocyclo ring.

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

R

1 is -halo, a C 1 haloaliphatic group, .a Ci-6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,.

1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; R" is hydrogen or methyl and R Y is -R,

N(R

4 or -OR, or R x and R y are'taken together with their intervening atoms to form a benzo ring or a 5-7 membered partially unsaturated carbocyclo ring,, said benzo or carbocyclo ring optionally substituted with halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2

R,

-SR, CON(R 4

-SO

2

N(R)

2

-N(R')COR,

-118oD -N C02 (optionally substituted C 1 aliphatic), o 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(R

4

)SO

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

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a CI-S aliphatic group, or R 2 and R 2 are taken together V\ with their intervening atoms to form a substituted or n unsubstituted benzo, pyrido, pyrimido or partially o unsaturated 6-membered carbocyclo ring; and Ring D is substituted by oxo or R 5 wherein Seach R 5 is independently selected from -halo, -CN, -NO C -N(R) 2 optionally substituted Ci- aliphatic group, -OR,

-CO

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

N(R

4 2 or

-N(R

4 S0 2

R.

Even more preferred compounds of formula V have.

one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R s wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and

R

1 is -halo, a C1-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl;

R

x is hydrogen'or methyl and R Y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or Rx and R y I are taken together with their intervening atoms to form a -119- IND benzo ring or a 6-membered partially.unsaturated D carbocyclo ring optionally substituted with halo, CN, Soxo, Ci-6 alkyl, Ci-s alkoxy, (CI-6 alkyl)carbonyl, (CIalkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

R

2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or Spartially unsaturated 6-membered carbocyclo ring C. 10 optionally substituted with -halo, N(R 4 2 -Ci- 4 alkyl,

S-CI-

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

NH

2 -OC(0)NH 2

-NH

2 SO2(Ci- 4 alkyl), -NHC(O) (CI-4 alkyl) -C(0)NH 2 or -CO(C 1 4 alkyl) wherein the (C

I

-4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -Cl, -CN, -CF 3 -NH2, -NH(CI-4 aliphatic), -N(CI-4 aliphatic) 2 -0(C.Ialiphatic), C 1 -4 aliphatic, and -CO 2 (Cx- 4 aliphatic).

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

Table 4.

4N F 3 t CF3 V-1 V-2 V-3 120- 2006201396 04 Apr 2006 z z /z 0

I

,Is C4 o cir

II

Q

Lu"I -n nz z z to

LO

Ci w I nn z C d ci Cd zill 0

$I

ti Va 0 0 ci 0

F

H

3

C

H

3 Ctkfl:%

F

3

C

V- 16 V-i19 V-17 V-18

F

3

C

V-20

HN

H

3 CN V-21 V-22 V-23 V-24 cIl V-27 V- 25 V-26 -122- Va 0 0 ci 0 V-28 .V-29 SV-31 V- 32 V-33 H N V-34 V- 35 V-36

F

3 c V-37

HN

V- 38 V-39 -12 3- HN H HZ V-41 V-42 H

H

F

3 C ci 3 V-43 V- 44

F

F

3 C ClF 3 0 V-46 Vr47 V-48

F

3 C F 3

C

V-49 V-50 V-53.

-124- Va 0 0 ci 0 cI-' V-52 V-53 V-54

N

F

3

CN

V- 55

HN

N

NH

2

F

3 V.-58

/N-

0IcN v-SE V-57

CH

3

HNJIH

F

3

C

V- 62

V-EO

V-El1 V-63 -125-

S

CH

3 CH3 N H NH H SHN HNN HNN TrNN HNI OI HNJ t V-64 V-65 V-66

F

H

SN H

F

3 0

F

3

C

V-67 V-68 In another embodiment, this invention provides a composition comprising a compound of formula V and a pharmaceutically acceptable carrier.

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

Another aspect relates to a method of treating a'disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to 'a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula V., Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose .in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula -126- INDV. This method is especially useful for diabetic o patients.

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

Another aspect relates to ,a method of,

IND

inhibiting the phosphorylation of j3-catenin in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula V. 1This method is especially useful. for treating schizophrenia.

One aspect of this invention relates to a method of -inihibiting Aurora -activity in a patient, comprising administering to the patient a therapeutically effective amnount of a composition comprising a compound of 'ormula V.

Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora.

inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula V. This method is especially useful for treating cance r, such as colon, ovarian, and breast cancer.

one aspect of this invention relates to a method of inhibiting CDK-2 activity in a patient, comprising administering to the patient a therapeutically eff ect ive amount of a composition coimprising a compound of formulla. V.

-127- IND Another aspect relates to a mecnoa or treating 0 o a disease that is alleviated by treatment with a CDK-2 ci Sinhibitor, said method comprising the step of 1 administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula V. This method is especially useful for treating cancer, Alzheimer's 0 disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, C1 i0 alopecia, and autoimmune diseases such as rheumatoid o arthritis.

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

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

Another embodiment of this invention relates to compounds-of formula VI: R 2 RX NH

HNN

N"2N

VI

-128- ND or a pharmaceutically acceptable derivative or prodrug O thereof, wherein: SG is Ring'C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents 0 5 independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with-their o intervening atoms to form a fused, unsaturated or Ci 10 partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R 8 Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said'heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

-R

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

R

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

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci-, aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or said Ci-6 aliphatic group optionally sibstituted with halo, cyano, nitro, or oxygen, or R 1 -129- ND and an adjacent substituent taken together with their o intervening atoms form said ring fused to Ring C;

R

y is T-R 3 T is a valence bond or a C 1 -4 alkylidene chain;

R

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

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or O partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each C- substitutable carbon on said fused ring formed by R 2 0 and R 2 is substituted by halo, oxo, -CN, -NO 2 -R1, or C- 10 and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R4;

R

3 is an optionally substituted group selected from CI-6 aliphatic, C3-.

0 carbocyclyl, C 6 -io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an .optionally substituted group selected from C 1 -6 aliphatic, Cs-i 0 aryl, a heteroaryl ring having 5-10 -ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -R 7

-COR

7 -C02(optionally substituted C-_s aliphatic) -CON(R 7 2 or -SD 2

R

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

-CON(R')

2

-SO

2

N(R

4 2

-N(R

4 C

OR,

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

-N(R')N(R

4 2

-C=NN(R

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

-N(R')SO

2

N(R')

2

-N(R

4

SO

2 R, or -OC(=O)N(R4) 2 or R s and -130- IDan adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is SO2-, -N(R')S0 2

-SO

2

N(R

6 -CO02-, S -N(R 6 -N(R6)SO 2

S-,

IND-C(R

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

-C(R)

2

SO

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

-C(R)

2 -C(R 6 -C(RPt 2 -C 2 N(R) S02N(R6) or -C 2 N (R 6 CON W is.-C(R') 2

-C(R

6 2 2 So-, 2

S

2 -c(R) 2 o 2

-C(R

6 2 -CO-,

-C(R

6

-C(R

6 2N(R 6

CO-,

-C(R 2

N(R)N(R

6

-C(R

6 ),N(R')S0 2 N(R6)-, or -CON(R 6 each R6. is independently selected from hydrogen, an optionally substituted CaL- aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R' is independently selected from hydrogen or an optionally substituted 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 each R is independently selected from an optionally substituted C.-4 aliphatic group, -OR 6

-COR,

-SO

2 2 2 CN, -NO 2

-CON(R')

2 or

-CO

2

R'.

Preferred R' groups of formula VI include T-R 3 wherein T is a valence bond or a methylene, and R3 is an optionally substituted group selected from Cj-6 aliphatic, -131- \Q C3-10 carbocyclyl, CG-.o aryl, a heteroaryl ring having 5-10 o ring atoms, or a heterocyclyl ring having 5-10 ring atoms. A preferred R 3 group is an optionally substituted group selected from C3-6 carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred R Y include 2-pyridyl, 4-pyridyl, piperidinyl, morpholinyl, cyclopropyl, cyclohexyl, and optionally C substituted phenyl such as phenyl or halo-substituted phenyl.

S. 10 The R 2 and R 2 groups of formula VI may be taken 0 together to form a fused ring, thus providing a bicyclic C 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 VI compounds having a pyrazole-containing bicyclic ring system: HN N iA N NH NH NH NH N G N N NN S, and Preferred substituents on the R /R 2 fused ring include one or more of the following: -halo, 2 -C1-4 alkyl, -CI-4 haloalkyl, -NO0, -O(C1.4 alkyl), -C02(C.-4 alkyl), -CN, -S02(Ci-4 alkyl), -S0 2 NH2, -OC(O)NH 2

-NH

2 S0 2 (Ci- 4 alkyl), -NHC(O) alkyi), -C(O)NH 2 and -CO(CI-4 alkyl), wherein the (C1-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (Ci.4 alkyl) group is methyl.

-132- IND When the pyrazole ring system is monocyclic, opreferred Rt 2 groups of formula VI include hydrogen, C.aliphatic, alkoxycarbonyl, (un)substituted phenyl, *hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoaljcyl, phenylaminocarbonyl, and (N- IND heterocyclyl)carbonyl. Examples of such preferred Rt 2 0" substituents include methyl, cyclopropyl, ethyl, o isopropyl, propyl, t-butyl, cyclopentyl, phenyl, 00211, 0020113, 011201, 01120013, 011 2 011 2 01 2 0H, 0112M120H20CH3, 0 ON~~C 2 C012 0 2 001 2 Ph, CH2 2 N2 N 2 011 2 011 2 0 2 NHC000 (OH3)3, Ci O~ONHCH (CH 3 2 001q1101 2 01=01 2

OONHCH

2

CH

2 00H.

3

OONHCH

2

PIJ,

OONH(cyclohexyl), OON(Et) 2

OON(CH

3 )CHPh, OONH(n-0 3

H

7 OON(Et)CH1201120113,

OONHOH

2 OH (013)2, CON(n-C 3 H,1) 2 00(3methoxymethylpyrrolidin-1-yl), CONH (3-tolyl), OONH(4tolyl), CONHOH 3 00 (morpholin-1-yl), 00 (4-methylpiperazin-.

1-yl), 00NH101 2 C1 2 0, 00N11 2 and 00(piperidin-1-yl).

A

p .referred R 2 group is hydrogen.

When G is Ring 0, preferred formula VI Ring C groups- are phenyl'and pyridinyl. Then two adjacent substituents on Ring 0 are taken together to form a fused ring, Ring C is contained in a bicyclic ring system..

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at ortho and meta positions of Ring 0. Examples of preferred bicyclic Ring C systems include naphthyl and isogainolinyl. Preferred

I

1 groups include -halo, an optionally substituted 0C...

aliphatic group, phenyl, -COR6, -01, -SRt, -SO 2

NH

2 -Nq(R6) 2 -0OR6, -COiN! 2 -NHCOR6, -OCOQ)N11 2 or -NHSO 2

R

6 When Rt' is an optionally substituted C3- aliphatic group, the most preferred optional substituents are halogen.

Examples of preferred R' 1 groups include -OF 3 -01, F,' -ON, -000113, -O013, -OH, 01120113, -00120113, 0113, -CF 2 0H 3 -133- ND cyclohexyl, t-butyl, isopropyl, cyclopropyl, -C-CH,

-CO-CH

3 -S0 2

CH

3 -S0 2

H

2

-N(CH

3 2 -02CH3, -CONH2,

-NHCOCH

3

-OC(O)NH

2

-NHSO

2

CH

3 and -OCF 3 On Ring C preferred R 5 substituents, when present, include -halo, -CN, -NO 2 2 optionally substituted C 2 -6 aliphatic group, -OR, -CO 2

R,

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

N(R')

2 and -N(R 4

)SO

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

-NH

2

-NH(C.

4 aliphatic), -N(C 1 4 aliphatic) 2

-O(C

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

Examples of such preferred R 5 substituents include -C1, ci -CN,.-CF 3

-NH

2 -NHMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -CO 2 Et.

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

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

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

-CO

2 R, -CONH(R 4

-N(R

4 )COR, -S0 2 2

-N(R

4

SO

2

R,

-SR, -OR, C(O)R, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C-o10 aryl, or C 1 6 aliphatic. More preferred Ring D-substituents include -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a substituted or unsubstituted group selected from 5-6 -134g membered heterocyclyl, C6-10 aryl, or. C1-s aliphatic.

o Examples of Ring D substituents include -OH,-phenyl, Smethyl, CH20H, CH2CH20H, pyrrolidinyl, OPh, CF 3 C=CH, Cl, -Br, F, I, NH 2

C(O)CH

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

Preferred formula VI compounds have one or IND more, and more preferably all, of the features selected from the group consisting of: 0 Ring C is selected from a phenyl or \0 10 pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a CI bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl' or isoquinolinyl .ring, and R 1 is -halo, an optionally substituted Ci-.

aliphatic group, phenyl, -COR 6 -OR6, -CN, -Sb2R 6

-SO

2

NH

2

-N(R

6 2 -C0 2

R

6 -CONH2, -NHCOR 6

-OC(O)NH

2 or -NHSO 2

R

6 or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyi, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indoiyl, isoquinolinyl, quinolinyl, or naphthyl ring;

R

Y is T-R3', wherein T is a valence bond or a methylene; and

R

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

More preferred compounds of formula VI have one or more, and more preferably all, of the features selected from the group consisting of: -135- \D Ring C is a phenyl or pyridinyl ring, o optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R, is -halo, a Ci-s haloaliphatic group, a CI-6 aliphatic 0 group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl,

VO

Ch piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, e 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- C- 10 tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-

VO

o dihydro-iH-indolyl, isoquinolinyl, quinolinyl, or C naphthyl; R is T-R 3 wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from Ci-s aliphatic, C3- 6 carbocyclyl, C 6 -i 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or .a CI-6 aliphatic group, or R 2 and R 2 are taken togetherwith-their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -halo, -CN, -NO 2 -N(R4) 2 optionally substituted'C 1 _6 aliphatic group, -OR, -CO2R, -CONH(R 4

-N(R

4 )COR,- -SO 2

N(R

4 2 or

SO

2

R.

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

R

Y is T-R 3 wherein T is a valence bond or a methylene and R 3 is an optionally substituted group -136- IDselected from C 1 4 aliphatic, C 3 6 catbocyclyl, phenyl, or o a 5-6 membered heteroaryl or heterocyclyl ring; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C.and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R is -halo, a CI-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4itetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl;

R

2 and R2' are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R 4 2

-C

1 4 aliyl, -Ci- 4 haloalkyl, -NO 2 -0 4 alkyl), -COC(C.-4 alkyl), -CN, -so02 (c-4 alkyl), -SO 2 NHa 2 -OC(0)NH 2

-NH

2 SO2 (C- 4 alkyl), -NHC(O) (C 1 4 alkyl), -C(0).NHa, or -CO(C 1 4 alkyl), wherein the (C 1 -4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or RS, wherein each R 5 is independently selected from -C1, -dN, -CF 3

-NH

2 -NH(C3, 4 aliphatic), -N(C3.4 aliphatic) 2 -0 (C 1 -4 aliphatic), C 1 -4 aliphatic, and -Co (C 1 -4 aliphatic).

Another embodiment of this invention relates to compounds of formula VIa: -137-

HNN

NN

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

-R

5 and at any substitutable ring nitrogen by provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; -138- D R 1 is selected from -halo, -CN, -N0 2

T-V-R

6 phenyl, 5-6 o membered heteroaryl ring, 5-6 membered heterocyclyl Sring, or C3.

6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R 8 said C.a- aliphatic group optionally \0 substituted with halo, cyano, nitro, or oxygen, or R 1 Sand an adjacent substituent taken together with their intervening atomsform said ring fused to Ring C; T is a valence bond or a C 1 4 alkylidene chain;

R

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

-R

7 or -V-R,6 and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R'; each R is independently selected from hydrogen or an optionally substituted group selected from C 1 -s aliphatic, Cs-Io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -COR 7

-CO

2 (optionally substituted C1-6 aliphatic), -CON (R 7 2 or -SO2R 7 or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -CO2R, -COCOR, -NO 2 -CN, -SO2R, -SR, 2

-CON(R

4 2 -SOaN(R') 2

-N(R

4

)COR,

-N(R')CO2 (optionally substituted CI.- aliphatic),

-N(R')N(R

4 2

-C=NN(R

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

)CON(R

4 2 -139-

I

IN SO, 2

N(R)

2 -N(R')S0 2 R, or -OC(=O)N(R) 2 or R 5 and o an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; to Ring C; Vis-0-,

-SO

2 -N(R)s0 2 -So 2 N(R6)-,

-N(R

6 C0, -N(R 6 o -N(R')CON(R 6

-N(R

6 )S0 2

-N(R')N(R

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

-C(R

6

-C(R

6 2

S-,

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

-C(R

6 2

N(R')SO

2

N(R

6 or -C (R 6 2 CON (R 6 W is -C(R 6 2 2 2 SO-, -C(R'),S0 2

-C(R)

2 SO2N(R 6

-C(R

6 2

-CO

2

-C(R

6

)OC(O)N(R

6

-C(R

6 2

N(R

6

)CO-,

-C(R6) 2 C(R')=NN(R 6 -C(R6) -C(R )2N(R)N(R6) -C(R6)2N(R) SO2N

-C(R

6 2

N(R

6

)CON(R

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

optionally substituted C 1 -6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each RB is independently selected from an optionally substituted C..4 aliphatic group, -OR, -COR 6 -S0 2

R

6 2 2

-NO

2

-CON(R)

2 or

-CO

2 R6..

Preferred rings formed by the R' and R 2 groups of formula Via include benzo, pyrido, pyrimido, and a -140-

VO

o partially unsaturated 6-membered carbocyclo ring. These C are exemplified in the following formula VIa compounds having a pyrazole-containing bicyclic ring system:

N

NN 0 H I3 H H Q NH I 5 ,and Preferred substituents on the R 2

/R

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

NH

2

-OC(O)NH

2 -NH2SO2(CI-4 alkyl), -NHC(O) (C 1 -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 (C 1 -4 alkyl) group is methyl.

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

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at ortho and meta positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred R' groups include -halo, an optionally substituted C 1 -6 aliphatic group, phenyl, -COR 6 -OR6; -CN, -SO2R 6

-SO

2

NH

2 2

-CO

2

R

6 -CONH2, -NHCOR 6

-OC(O)NH

2 or -NHSO 2

R

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

Examples of preferred RI groups include -CF 3 -Cl, -F, -141- IN -CN, -COCH 3 -OCH3, -OH, -CH2CH 3

-OCH

2 0H 3

-CH

3

-CF

2

CH

3 o cyclohexyl, t-butyl, isopropyl, cyclopropyl, -c, -CeC-CH 3 -S0 2

CH

3 -SO2NH 2 -N(CH3) 2 -C0 2

CH

3

-CONH

2

-NHCOC

3 -OC(0)NH 2 -NHSO2CH 3 and -OCF 3 On Ring C preferred R 5 substituents, when present, include -halo, -CN, -NO 2 2 optionally INDsubstituted CI-6 aliphatic group, -OR, -Co0 2

R,

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

N(R

4 and -N(R')So 2 R. More Spreferred R 5 substituents include -01, -cN, -CF 3 -NJH2, -NH(CI4 aliphatic), -N(CI-4 aliphatic)2, -0(CI.4 aliphatic), .4 aliphatic, and -CO2(C..4 aliphatic).

Examples of such preferred R 5 substituents include -Cl, -CN; -CF 3

-NH

2 -NNMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -C0 2 Et.

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

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

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

-NO

2

-N(R)

2

-CO

2 R, -CONH(R 4 COR, -SON (R' 4 2

-N(R

4

)SO

2 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-3o aryl, or CI-6 aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, -142- D -N(R4)2, or a substituted or unsubstituted group 0 selected from 5-6 membered heterocyclyl, Cs-3o aryl, or CI- Saliphatic. Examples of Ring D substituents include -OH, phenyl, methyl, CH2OH, CH 2

CH

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

ND Preferred formula Via compounds have one or c more, and more preferably all, of the features selected Sfrom the group consisting of: 10 Ring C is a phenyl or pyridinyl ring, Soptionally substituted by -R 5 wherein when Ring C and two CA adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is -halo, an optionally substituted C.- 6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2

R

6 "-SO0NHa, -N(R 6 2

-CO

2

R

6

-CONH

2

-NHCOR

6

-OC(O)NH

2 or -NHSO 2

R

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

R

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

More preferred compounds of formula VIa have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R s wherein when Ring C and two adjacent substituents thereon form a bicyclic ring -143- ND system, the bicyclic ring system is a naphthyl ring, and o R L is -halo, a Ci-G haloaliphatic group, a C 16 aliphatic Sgroup, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-iH-isoindolyl, 2,3- CA dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or M- naphthyl CA 10 R 2 and R 2 are taken together with their o intervening atoms to form a benzo, pyrido, pyrimido or C partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, 2

-C

1 4 alkyl,

-C

1 -4 haloalkyl, -NO2, alkyl), -CO 2 (CI-4 alkyl), -CN,

-SO

2 4 alkyl) -S02NH 2

-OC(O)NH

2 -NH2SO2(C-.

4 alkyl) -NHC(O) (C1- 4 alkyl), -C(O)NH 2 and -CO(C1.4 alkyl), wherein the (C 1 -4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -halo, -CN, -N0 2 -N(R4)2, optionally substituted C-6 aliphatic group, -OR, -C02R, -CONH(R 4

-N(R

4 )COR, -SO 2 or

SO

2

R.

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

R

1 is -halo, a C,-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, -144- Va o piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl;

R

2 and R' are taken together with their intervening atoms to form a benzo, pyrido, or partially INDunsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R 4 2 4 alkyl, -C 1 -4 haloalkyl,

-NO

2

-O(C

1 4 alkyl), -CO2(C..

4 alkyl), -CN, -so 2 4 alkyl), -S2NH 2 -OC NH 2 -NHASo 2

(C

1 -4 alkyl) -NHC(O) (C 1 -4 alkyl), -C(O)iNH 2 or -CO(C,-4 alkyl), wherein the (C-4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -C1, -CN, -CF 3

-NH

2

-NH(C

1 4 aliphatic),

-N(C

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

(C

1 4 aliphatic).

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

Table CH F 3 H H H HNk HN ZHHN Z NONN

N)N

VI-1 VI-2 VI-3 -145- ;0-

CH

3 N 6N VI -4

OH

3

N

CK

3 N VT-6 vi -5

VI-?

HNZH

N JN VI-11 Et

HAC-

VI -9 Pr

N~

VI -10 Bu N

J*N

VI-12 N 4N

N

VI -13 VI-1 4VT-is -146- Va 0 0 ci 0 VI -16 VI-17 18

F

HP

V:1-20

NA

VI -21 VI -19 V-I-22 VI-23

F,

HN HN A' N" N CI Q"NAIN A N HN2N7P

N

F

3

C

VI-24 N

VN

VI -27 VI -25 VI -26 -147- Va 0 0 ci 0 HN2N; N )-N

H

3 C-Cj0tW

F

3

C)

VI -28 VI -29 VI -31 N

C~N

VI -32 VI -35 HN2

HNJF

3

CA

VI HN2-

N

V-33 HN

J?

N -N VI -36 f

F$F

N

4

NZ

VI -37 VI -38 VI -39 -148- Va 0 0 ci 0 H4NX

F

3

C

VI -41

HN

NH

2 VI -42 VI -40 VI -43 Vi -44 (1) N J N VI

H

HNS

N N

NX)N

V Ia-3

H

KN

N'IN CF 8 VIa-6 Vla- 1 V~a-2 Vla-4 Vla-5 -149- HN H HN H CN N CN NNN Me N N o NHMe VIa-7 VIa-8 VIa-9 0 0 N~

N

SH H H HN H HN o N'N N N N'N NNMe N C ONH2 NHMe VIa-10 VIa-11 Via-12 In another embodiment, this invention provides a composition comprising a compound of formula VI or VIa and a pharmaceutically acceptable carrier.

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

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

Another aspect relates to a method of enhancing glycogen synthesis and/or 'lowering blood levels of glucose in a patient in need thereof, comprising -150- IND administering to said patient a therapeutically effective 0 amount of a composition comprising a compound of formula ci SVI or Via. This method is especially useful for diabetic Spatients.

Another aspect relates to a method of 0inhibiting the production of hyperphosphorylated Tau D protein in a patient in need thereof, comprising a administering to said patient a therapeutically effective Samount of a composition comprising a compound of formula Ci 10 VI or Via. This method is especially useful in halting Sor slowing the progression of Alzheimer's disease.

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

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

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

One aspect of this invention relates to a method of inhibiting CDK-2 activity in a patient, comprising administering to the patient a therapeutically -151- ND effective amount of a composition comprising a compound o of formula VI or Via.

ci c Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition 0 comprising a compound of formula VI or Vla. This method is especially useful for treating cancer, Alzheimer's Ci 10 disease, restenosis, angiogenesis, glomerulonephritis, o cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, 0q alopecia, and autoimmune diseases such as rheumatoid arthritis.

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

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

Another embodiment of this invention relates to compounds of formula VII: Fe

N>H

HN -N N-1

N

'r R Ve -152- ID vII ci Sor a pharmaceutically acceptable derivative or prodrug thereof, wherein: .G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, D pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from any substitutable non- S. ortho carbon position on Ring C is independently Ssubstituted by -R 5 and two adjacent substituents on Cq Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R a 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 beterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

-R

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

R

1 is selected from -halo, -CN, T-V-R 6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C 1 aliphatic group, said' phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to. three groups independently selected from halo, oxo, or said CI- 6 aliphatic group optionally -153- \D substituted with halo, cyano, nitro, or oxygen, or R

I

and an adjacent substituent taken together with their k intervening atoms form said ring fused to Ring C; L

R

Y is hydrogen or T-R 3 T is a valence bond, hydrogen, or a Ci-4 alkylidene chain; O

R

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

R

2 and R 2 are taken together with their intervening

VO

S atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having .0-3 ring heteroatoms C selected from nitrogen, oxygen, or sulfur, wherein each I substitutable carbon on said fused ring formed by R 2 0 10 and R 2 is substituted by halo, oxo, -CN, -NO 2

-R

7 or

-V-R

6 and any substitutable nitrogen on said ring formed by R2. and R 2 is substituted by R4;

R

3 is selected from an optionally substituted group selected from C 3 1 0 carbocyclyl, Cs-.0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an Soptionally substituted group selected from C 1 -s aliphatic, C6-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R 7

-COR',

-CO

2 (optionally substituted C 1 z- aliphatic), -CON(R 2 or -S0 2 or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R s is independently selected from halo, -OR, -CO2R, -COCOR, -NO2, -CN, -SOR, -SR,

-N(R)

2

-CON(R')

2

-SO

2

N(R)

2

-N(R')COR,

-N(R4) C0 2 (optionally substituted C.1- aliphatic),

-N(R

4

)N(R

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

)CON(R')

2 -154-

-INDSNR'

2

-N(R

4

)SO

2 R,'or or R 5 and o an adj acent substituent taken together with their intervening atoms form said. ring fused to Ring C; V is -S- 1 -SO2-, -N(RS)S0 2

-SON(R)-,

'4 S 0

-N(R

6 )S0 2 -C(R6) 2 2

S-,

2 so-, -C(R) 2 So 2 2 S0 2 C~1W is -C(R6) 2 2 -C(R'h2So-, 2 S0 2 -C(R6) 2 s0 2 N(R) -C(R6) 2 N(R 6 _C0 2

-C(R

6 )co -C(RbR )C, It -C (It) 2 NCR6) -CCR6)= -C (It) 2

-C(R)

2 N(t)CON(It')-, or -CON(R6) each R6' is independently selected from hydrogen, an optionally substituted C3-, aliphatic group, or two R6' -groups on the'same nitrogen atom 'are' taken together with the nitrogen. atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each Ri' is independently selected from hydrogen or an optionally substituted C 1 6 aliphatic' group, or two R7' on the sane nitrogen are tiaken together with the nitrogen, to form a 5-B membered heterocycly). or heteroaryl ring; each It 8 is independently selected from an optionally substituted C 1 4 aliphatic group, -OR, -CClt', -SOR', -NCR) 2 2 -aI -NO 2

-CON(R')

2 or -OR; and R9' is selected from -Rt, halo, -OR, R, -CO 2 R, -COCOa,

-NO

2 -az, -S0 2 R, -SR, -N(Rt 2

-CON(R')

2 -155- \D -SO 2

N(R

4 2

-N(R

4 COR, -N CO2 (optionally o substituted C 1 -s aliphatic), 2

-C=NN(R')

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

-N(R)SO

2

N(R

4 2 or -OC N(R) 2 Preferred R Y groups of .formula VII include T-R 3 0 wherein T is a valence bond or a methylene. Preferred R 3 groups include an optionally substituted group selected

VO

O from C3- 6 carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred RY OD I C- 10 include 2-pyridyl, 4-pyridyl, piperidinyl, cyclopropyl, and an optionally substituted phenyl such as phenyl or O halo-substituted phenyl.

The R 2 and R 2 groups of formula VII 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 VII compounds having a pyrazole-containing bicyclic ring system: Ry ~NH

N

H NH 1G N N -N

N

S, and Preferred substituents on the R 2

/R

2 fused ring include one or more of the following: -halo, 2 -C.-4 alkyl, -Ci-4 haloalkyl, -NO2, -0(C3.4 alkyl), -CO (CI-4 alkyl), -CN, -S0 2 (Ci.4 alkyl), -SO0NHa, -OC(O) NH 2

-NH

2 S0 2 (CI-4 alkyl), -NHC(O) (C 1 -4 alkyl), -C(0)NH 2 and -156- IND-CO (C1..4 alkcyl), wherein the 4 alkyl) is a straight, o branched, or cyclic alkyl group. Preferabfly, the (C 1 4 al~kyl) group is Methyl.

When the *pyrazole ring system of formula V3:3 is monocyclic, preferred R 2 groups include hydrogen, CI..4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, IND hydroxyalkyl, aljcoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, allcylamirioalkyl, dialkylaminoalkyl, phenylaminocarbonyl, an d (Nheterocycljrl)carbonyl. Examples of such preferred It 2 substituents include methyl,_-cyclopropyl,'*ethyl, Ci isopropyl, propyl, t-butyl, cyclopentyl, phenyl, C021,.

002 CH 3

CH

2 OH,. CH 2 0CH3, CR2 012 C1 2 011, CH 2

CH

2

CH

2 0CH 3

CH

2

CH

2

CH

2

OCH

2 Ph, CH2CH 2

CH

2

NH

2

CH

2

CH

2

CH

2 IlcoObC (CH) CONECH (0113)2, CONHC 2

CH=CH

2

CONHCH

2

CH

2 00H 3

CONHCH

2 Ph, CQNH(cyclohexylj, CON(Et) 2 CON(C11 3

)CH

2 Ph, CONH(n-C 3

H

7 CON (Et) C12C112C13, CONHCH 2 CH (Ob)2,_-CON (n-C 3

H

7 2 CO (3methoxymethyipyrrolidin-l-yl) CONH (3 -tolyl), CONH (4tolyl), CObIHCH 3 CO (iopholin-1-yl), Co (4-methylpipe'razin- 1-yl), CONHCH 2

CH

2 OH, CONE 2 and COipiperidin-l-yl).

A

preferred It 2 group is hydrogen.

When G3 is' Ring C, preferred formula VII Ring C groups arei'phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic. ring system.

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at ortho and meta positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred k' groups include -halo, an optionally substituted aliphatic group, pheny:l, -COR', -ORE, -CN, -SO 2 -S0 2 N11 2 2 -CO21I6, -CONH 2 -ERCORt', -OC N1, or -NHS%2R' When It' is an optionally -substituted aliphatic group, -157- IND the most preferred optional substituents are halogen.

o Examples of preferred R' groups include -CY 3 -Cl, -F, -01, -COCH3, -0013, -OH, -CH 2

CH

3

-OCH

2

O{

3 -Cf 3

-CF

2 01 3 cyclohexyl, t-butyI, isopropyl, crclopropyl, -CraCH, -~ca-cg 3 -so 2 cw 3 -S0 2 N11 2

I-N(CH

3 2 -co 2 cn 3 -coNcH 2

-NHCOCH

3 -OCc(a) i 2

-NHSO

2

CH

3 and -OCF 3 IND On Ring C preferred R5 substituents, when present, include -halo, -CN, -NO 2 -N(R0) 2 Optionally Cj~ aliphatic group, -OR; -CO 2

R,

1'-CONH(R 4

-N(R

4 )COR, -SO 2

N(R')

2 and -N(R*)SO 2 R. MoreC preferred It 5 substit-ients include -dl, -Cit CFa, Ci -H1 2

-NH(C

1 4 aliphatic), -N(c 1 4 aliphatic)2, -0OC 1 aliphatic), C 1 4 aliphatic, and -CO 2

(C

1 4 aliphatic).

Examples of such preferred It 5 substituents include -Cl, -CNt -C? 3 -NI1 2 -NHMe, -lime 2 -OEt, me thyl, ethyl, cyciopropyl, isopropyl, t-butyl, and -CO 2 Et.

When (3 is Ring preferred formula VIZ Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,. azepanyl, and morpholinyl rings.

When two adj acent substituents on Ring D) are taken together to form a fused ring, the Ring D system- is bicyclic.: Preferred formula VII Ring El bicyclic rings include 1,2,3 ,4-tetrahydroisoquinoli'-nyl, 1,2,3,4tetrahydroquinolinyl, 2, 3-dihydro-lH-isoindolyl, 2,3dihydro-lH-indolyl, isoquinolinyl, quinolinyl, and naphthlyl. -Examples of more preferred bicyclic Ring Dl systems include naphthyl and isoqluinolinyl.

Preferred substituents on 'Ring D include one or more of the following:- halo, oxo, CM, 1, -NCR 4 2 -00 2

R,

-CONH(R

4 -N(R)COR, -30 2

N(R)

2

-N(R')SO

2 R, -SR, -OR, C or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C 6 10 aryl,' or C 1 _6 -158- IDaliphatic. More preferred Ring D substituents include o -halo, -CN, -oxo, -SR, -OR, -N(R) 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C-.

0 aryl, or C3,- aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 0H, 0 2 CH2OH, pyrrolidinyl, OPh, CF 3 CECH, C1, INDBr, F, I, NH 2

C(O)CH

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

Preferred formula VII compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring, and R 1 is -halo, an optionally substituted C1- 6 aliphatic group, phenyl, -COR, -OR 6 -CN, -SOR', -SONH 2 -N(R6) 2

-CO

2 R6

-CONH

2 -NHCOR', -OC(O)NH 2 or -NHSO 2 R; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinoinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; RY is wherein T is a valence bond or a methylene; and

R

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

-159- ND More preferred compounds of formula VII have o one or more, and more preferably all, of the features Sselected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is;a naphthyl ring, and C R 1 is -halo, a C 1 haloaliphatic group, a C 1 aliphatic group, phenyl,. or -CN; or. Ring D is an optionally CA 10 substituted ring selected from phenyl, pyridinyl, Spiperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, C] 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl;

R

y is wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from C3-. carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring;

R

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

-N(R)

2 optionally substituted -C-6 aliphatic group, -OR,

-CO

2 R, -CONH(R 4 -N(R')COR, -S2N(RR) 2 or

SO

2

R.

Even more preferred compounds of formula VII have one or more, and more preferably all, of the features selected from the group consisting of: -160- IND(a) RY is wherein T is a valence bond or 03M o a methylene and R is an optionally substituted group selected from phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two IDadjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R' is -halo, a CI-.

4 aliphatic group optionally substituted with halogen, or CN; or Ring D is an optionally substituted ring selected from phenyl,. pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinqlinyl, or naphthyl; R' and are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, 2 -C3.

4 alkyl,

-C

1 2.

4 haloalkyl, 7NO 2

-O(C

1 4 alkyl), -CO2(C- 4 alkyl), -CN, -SO (C3.

4 alkyl), -S0 2

NH

2

-OC(O)NH

2 -NHaSO 2 (Cj.

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

4 alkyl), wherein the alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or Re, wherein each Rs is independently selected from -C1, F, -CN, -CF 3

-NH

2

-NH(C..

4 aliphatic), aliphatic) 2 aliphatic), C..

4 aliphatic, and -CO2 (C1- 4 aliphatic) Representative compounds of formula VII are set forth in Table 6 below..

-161- 2006201396 04 Apr 2006 0 0z

C)

C

oz L z -z J' \i' 1060 z 71 zt ko- Qz 9C)11 pz #-Z Va 0 0 ci 0 F' F HNQrN 1

J-'

VII -14 HN Z' VII

C'N'

HN2 VII -13 'VII -16

HN'

N 'jN VII -17 N N VII-20

CH

3 N I N V3I1-18

N

4

N

VII-19 HN24H 3 VII-21

HNI

NJ-N CF 3 >Z HN ,:CH3 VII -24 VII -22 VII-23 -163- HN

I,

NIN !CF 3 VII1-25 VII-28 VII-31 VII-34 0--N C

HN,

VII-26

CH

3

HN

NN

VII-29 HN9 N N C1 VI1-27

HNZ

N N VII-32

CH

3

HNJ*P

VII-33 Et

HNJH

N'6N

NWA

I

CH

3 HN 5JJH N 'N In another embodiment, this invention provides acomposition comprising a compound.of formula VI1 and a pharmaceutically acceptable carrier.

-164- ID One aspect of this invention relates to a O method of inhibiting GSK-3 activity in a patient, Scomprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VII.

Another aspect relates to a method of treating 0D a disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a C 10 therapeutically effective amount of a composition

NO

0 comprising a compound of formula VII.

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

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

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

One aspect of this invention relates to a method of inhibiting Aurora activity in a patient, -165- MD comprising administering to the patient a therapeutically o effective amount of a composition comprising a compound of formula VII.

Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora inhibitor, said method comprising the step of administering to a patient in need of such a treatment- a therapeutically effective amount of a composition -0 comprising a compound of formula VII. This method is Cq 10 .especially useful for treating cancer, such as colon, o ovarian, and breast cancer.

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

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

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

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

Another embodiment of this invention relates to compounds of formula VIII: 0 HN VIlz or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Z3 is N or CR 9

Z

2 is N or CH, and Z 3 is N or CR x provided that one of Z' and Z 3 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R 8 -167- ID Ring D is a 5-7 membered monocyclic ring or 8-10 membered o bicyclic ring selected from aryl, heteroaryl, Sheterocyclyl or carbocyclyl, said heteroaryl or' heterocyclyl ring having 1-4 ring heteroatoms-selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by halo, oxo, or -R 5 and at any substitutable ring nitrogen by provided that when Ring D is;a six-membered aryl or heteroaryl ring, -R s is hydrogen at each ortho C- 10 carbon position of Ring D; o0 Ri is selected from -halo, -CN, -NO 2 phenyl, 5-6 C membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -Re, said C, aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R

I

and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;

R

x is T-R 3 T is a valence bond or a C1-4 alkylidene chain;

R

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

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3.ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R and R 2 is substituted by halo, oxo, -CN, -NO2, -R 7 or

-V-R

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

R

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

R,

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

-CON(R

7 2

-SO

2

N(R

7 R, -N (R')COR, -168o-N (R 7 C2(optionally substituted Cl.

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

-C=NN(R)

2 -C=N-OR, -NCR 7

)CON(R

7 2 -N (0 7 )S0 2 2 -N (R4) So 2 a, or -C(O each R. is independently selected from hydrogen or an optionally substituted group.-selected from Cl..

aliphatic, C 6 10 aryl, a heteroaryl ring having -5-10 IND ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each e. is independently selected from -R 7, -COR., -CO? (optionally substituted' C..

6 aliphatic),-CNR).

or -SO 2 or two on the same -nitrogen are taken CI together to formn a 5-8 memberedheterocyclyl or S heteroaryl ring; each is indeiendently selected from halo, -OR, -CVcO)R# -C%2R, -COCOR, -NO 2 -QQa, -SO 2 R, -SR,

-NCR')

2

-CON(R')

2

-SO

2

NCR')

2 -NCR')COR,

-NCR

4

CO

2 (optionall:y substituted 6 aliphatic), 2 -C=NN(W4) 2 -C=N-OR, -flqP.') CON(R') 2 -NCR')S0 2 -N'(R')S0 2 R, or -OC(=O)N(R4) 2 or R.

5 and an adj acent substituent taken together with their intervening atoms fonm said ring fused to Ring C; V is

-SO

2 iS-N(R 6 C02-, -N(R 6 -N(R 6 CON -N S0 2 N(R6) N (R 6 )7, -co)2 6 -C W) 20-, -C 2

S-,

2 S0-, -C(R6) 2 3o 2

-C(R

6 2 80 2

-C(R

6 2

NVR)-,

NR0) C -C(R 6 2

-C(R

6 2 N(R')N(R 6

-C(R

6 2 Nq(R')S0 2 Or.

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

-C(R

6 2 -c(n6) 2 so-, -C(R6) 2 so 2

CCR")

2 S0 2

N(R

6 2 NtR 6 -C0 2 -C(R6)OCCO)

-C(R')OC(O)NCR

6

-C(R

6 2 Nq(PY) C-, -cC(R6) 2 N C -C CR 6 =fN -C -169- IN 2 N(R')S0 2 0 o 2 CON(R') or each is independently selected from hydrogen, an optionally substituted C 1 4 aliphatic group, or two R' 5 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered IDheterocyclyl or heteroaryl ring; each R7 is independently selected from hydrogen or an optionally substituted Cj-s aliphatic group, or two R' C 10 on the same nitrogen are taken together with the o nitrogen to form a 5-8 membered. heterocyclyl or- 0 heteroaryl ring; each Re is independently selected from an optionally sizbstituted C3-4 aliphatic group, -ORe, -COR',

-SO

2 2 -N(R6)N(R') 2 -CN, -NO 2

-CON(R')

2 or

-CO

2

R

6 and R9 is selected from halo, -OR, -CO2R, -COCOR,

-NO

2 -CN, -S02R, -SR, 2

-CON(R')

2

-SO

2

N(R')

2 C0 2 (optionally substituted CI-6 aliphatic) -N(R 2, 2, -C=N-OR, -N(R')CON(R) 2

-N(R')SO

2

N(R

4 2

-N(R)SO

2 R, or

-OC(=O)N(R

4 2 Accordingly, the present invention relates to compounds of formula VIIIa, VIIIb, VflIc and VIId as shown below: Fe Fe. FF Fe NH N HN H NH HN H' -NHN HN) N N N)"N N' G G

G

Sand -170- Villa VIIlb VfIIc VIlld SPreferred

R

1 groups of formula VIII include T-R' wherein T is a valence bond or a methylene and R 3 is CN, or -OR. When R 3 is preferred R 3 groups include an optionally substituted group .selected from aliphatic, \O phenyl, or a 5-6 membered heteroaryl or heterocyclyl Sring. When R 3 is -OR, preferred R groups include an Soptionally substituted group Ci-_ aliphatic group such as 10 alkyl- or dialkylaminoalkyl and aminoalkyl. Examples of preferred R include acetamido, CN, piperidinyl,

C

N piperazinyl, phenyl, pyridinyl, imidazol-1-yl, imidazol- 2-yl, cyclohexyl, cyclopropyl, methyl, ethyl, isopropyl, t-butyl, NH 2

CHCH

2 NH, and NH 2

CH

2 CH0O.

Preferred R 9 groups of formula VIII, when present, include R, OR, and N(R4) 2 Examples of preferred

R

9 include methyl, ethyl, NH 2

NH

2 CH2C 2 NH, N(CH3)2CH 2

CH

2

NH,

N(CH

3 2

CH

2 CH20, (piperidin-1-yl)

CH

2 CHO, and NH 2 2

CH

2

CHO.

The R 2 and R2" groups of formula VIII 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 VIII compounds having a pyrazole-containing bicyclic ring system: HN

N"

-2 fZ2 H H H H and -171o Preferred substituents on the f ormula V3:11

R

2

/R

2 fused ring include one or more of the following: -halo, -N(Rt 2 4 alkyl, -C 1 4 haloalkyl, -NC 4 alkyl),

(C

1 4 alkyl), -ai, -SO 2

(C

1 4 Salkyl), -SO 2

NH

2 0-OC N 2 -Ii 2

S%

2 4 alkyl) -NHC (CI-.

4 alkyl) -C (O)NH 2 and 4 alkyl) wherein the (C3p-, alkcyl) is a straight, branched, or cyclic alkyl, group. Preferably, the (C:L-4 alkyl) group is methyl.

When the pyrazole ring system of formula VIII.

NO

o is monocyclic,. pref erred R 2 groups include hydrogen, C.- 4 c-i aliphatic, alkoxycarbonyl, (un)subhatituted phenyl, hydroxyalkyl, 'alkoxyalkyl, aminoocarbonyl, mono or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl', dialkylamind'alkyl., phenylaminocarbonyl, and (N4heterocyclyl) carbonyl -'Examples of rsuch preferred Rt 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO 2

H,

00 2

CH

3

CH

2 OH, Cw 2 ocii 3

CH

2

CR

2

CN

2 OH, CH 2

CII

2

CH

2 0CH 3 Oi 2

CH

2

CH!

2 00H 2 Ph. CH 2

CH

2 (2 2

H

2

CH

2

CR

2

CH

2 NRCOOC (CH 3 3 cowHa &ZH 21 CONRHI 2 OI= H 2 CONHC2H 2 C)0H 3 COflHCH 2 Ph, CONlicycloheXYl), CON(Et) 2

CON(CH

3

)CH

2 Ph,,CONH(n-C 3

H

7

I

CON (Et) CU 2

CII

2 CH,; CONRCH 2 CH CON (n-C 3 H4) 2 CO (3methoxymethylpyrrolidin- l-yl), CONE (3 -tolyl), CONE tolyl), CONHCH 3 CO(morpholin--yl), CO(4-methylpiperazin- 1-fl), CONRCH 2

CH

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

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

Preferred fused rings include a benzo or. pyrido ring.

Such rings preferably are fused at ortho and meta -172positions of Ring C. ExamPles of preferred bicyclic Ring C. systems include napbthyl and isoquinolinyl. Preferred R" groups include halo, an optionally substituted C 1 6 aliphatic group, phenyl, -COat, -oR 6 -CN, -so 2 a 6 -So 2

NH

2 W(R6) 2 1, -CO 2

-CONH

2 -NUCOR', -oC(O)NH,, or -NHSO' 2

RK..

When R' is an optionally substituted C3.- 6 alipbatic group, the most preferred optional substituents are halogen.

Examples of preferred groups include -CF3, -Cl, -F, -CN, -COCH 3 -OCH,, -OH, -C11 2

CH

3

-OCH

2

CH

3 -Mb 1

-CP

2

CH

3 cyclohexyl, t-butyl, isopropyl, cyclopropyl, -Cin-CH,

-OSC-CH

3

-SGCH

3

-SO

2 NqH 2

-N(CH

3 h2, -0'02013, -COfi 2

-NHCOCH

3 -OC NH4 2

-NHSO

2

CH

3 and -QOCF 3 Oxi Ring C preferred R5~ substituents, when present, include -halo, -M -NO 2

-N(R

4 2 optionally s ubstituted.C 1 6 aliphatic group, -OR, -CO 2

R,

-COI4H(R 4

-N(R

4 )COR, -SO 2

N(R')

2 and -N(R)SO 2 R. More preferred R 5 subbtituents include -Cl, -CIA, -CF3,

-NH

2

-NH(C-

4 aliphatic), 4 aliphatic)2, 4 aliphatic), C 1 4 aliphatic, and -CO 2 (Cl..

4 aliphatic).

Examples of such preferied R 5 substituents include -Cl, -CN, -CF 3

-NH

2 -Nme, -NMe 2 -Ost, methyl, ethyl, cyolopropyl, i-Sopropyl, t-butyl, and -CO 2 Et.

When G is-Ring D, preferred formula VIII Ring fl monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpbolinyl rings.

When two adj acent substituents on Ring D are taken together to form a fused ring, the Ring 12 system is bicyclic., Preferred formula VIII Ring D bicyclic rings include 1,2,3,4-tetrahydroiSoquinfolifyl, 1,2,3,4tetrahydroquinolinyl, 2, 3-dihydro-1H-isoindolyJ., 2,3dihydro-lH-indolyl, isoquinolinyl, quinolinyl, and -173naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

Preferred R 5 substituents on Ring D of formula VIII include halo, oxo, CN, -NO 3 3

-CO

2

R,

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

N(R)

2

-N(R

4

)SO

2 R, -SR, -OR, o or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs- 1 o aryl,- or C 1 aliphatic. More preferred R 5 substituents include -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C-Lo 1 aryl, or C.- 6 aliphatic. Examples of o Ring D substituents include -OH, phenyl, methyl, CH2CH 2 0H, pyrrolidinyl, OPh, CF3, C=CH, Cl, Br, F, I, NH 2 C(b)CH 3 i-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene dioxy, and ethylene dioxy.

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

naphthyl, quinolinyl or isoquinolinyl ring, and. R. is -halo, an. optionally substituted C 16 aliphatic group, phenyl, -CORO, -CN, -SO 2 -S0o 2

NH

2 2

-CO

2

R',

-CONH2, -NHCOR', -OC(0)NH 2 or -NHSO32R; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2'3,4tetrahydroisoquinolinyl, 1, 3, 4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; -174- O R x is T-R 3 wherein T is a valence bond or a methylene; and S(c)

R

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

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

6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tettahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl; Rx is T-R 3 wherein T is a valence bond or a methylene and R 3 is CN, -R or -OR;

R

2 is hydrogen and R is hydrogen or a substituted or unsubstituted group selected from aryl, or a Ci- aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and each R S is independently selected from -halo, -CN, -NO 2 2 optionally substituted Ci- -175- INDaliphatic group, -OR, -CO0R, -CONH(R), -N(R')COR,

-SO

2 or -N(R)SO 2

R.

Even more preferred compounds of formula VIII have one or more, and more preferably all, of the features selected from the group consisting of: R is- T-R' wherein T is a valence bond or a methylene and R 3 is -R or -Ok'wherein R is an optionally substituted group selected from C 1 6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; C 10 Ring C is a phenyl or pyridinyl ring, D optionally substituted by -Rs, wherein when Ring C and two 0 adjacent substituents thereon form a bicyclic ring system, the bicyclic.ring system is a naphthyl ring, and

R

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

-C

1 4 haloalkyl, -NO 2

-O(C

1 4 alkyl), -COI(C.

4 alkyl), -CN,

-SO

2 (C3.

4 alkyl), -SO 2

NH

2 -OC(O) NH 2

-NH

2 S0 2

(C

1 4 alkyl), -NHC(0) (C 1 4 alkyl), -C(O)NH 2 or 4 alkyl), wherein the (Ca 4 alkyl) is -a straight, branched, or cyclic alkyl group; each R5 is independently selected from -Cl, -CN, -CF 3

-NH

2

-NH(C

1 -4 aliphatic), 4 aliphatic) 2 -O(CI-4 aliphatic), C.

4 aliphatic, and S-C0 2

(C

1 4 aliphatic); and -176- Va 0 0 ci 0 R9 is R, OR, Or N (R 4 2 Representative compounds of formula VIII are set forth-in Table 7 below.

Table 7s.

KNZH

VIII -1.

Me VIII- 3 VIII -2 Et

JH

VIII -4

HNZH

N

VIII-6 VIII -5 Bu

NN

VIII-7 .Pr

VIII-S

Pr VIII -9 .Me .N <)yy

O

HNJ$H~

N 4NN TtokN:N -177-

N-II

IDN

EZ-13:I t f N.M-II 10 N%,N

HZ

Nt 61-111A 0 Z- IIIA N-yN

NH

81-IIIA t d0N~N

HJ!

5 3 CON N14il NH-il K 3 STIIlA 111-IIIA lITA

NH

0 0 0 0 t 0 0 ZT-IIIA a- inr-llTA O-IIIA Va 0 0 ci 0

F

Iq-N N l 1% VIII -27 31111-25 VIII -26 V111-28 VIII1-31 VIII-29 VIII -32

HZ

Met VIII -35 Nt VIII -33

YN

Me-Nf Me VIII1-34 VIII-36 -179- Va 0 0 ci 0 Va en 0 ci Va 0 0 ci

HN

NA"N -Cl VIII -39 VIII-37 VII*I-38 VIII1-40 HN2-pH

NOC

VIII-41 F H VIII -44 r N.

VIII -42

H.

Ql% N or 3 VIII VIII -43 VIII -46 VIII -47 VIII-48 -180- H H H SCHN F N^ HN Cy1 HN

\O

ID

N CF N C I HN N OF 3 VIII-49 VIII-50 VIII-51 Me ci ko F

S

H N H N HN HN IY,!N CF, HN2a r N CF 3 VIII-52 VIII-53 VIII-54 VIII-55 VIII-56 VIII-57 In another embodiment, this invention provides a composition comprising a compound of formula VIII and a pharmaceutically acceptable carrier.

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 -181- ND inhibitor, said method comprising the step of o administering to a patient in need of such a treatment a ci therapeutically effective amount of a composition <comprising a compound of formula VIII.

Another aspect relates toga method of enhancing 0 glycogen synthesis and/or lowering blood levels of q glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective Samounit of a-composition comprising a compound of formula Ci 10 VIII. This method is especially useful for diabetic 0patients.

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

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora inhibitor, said method comprising the step of administering to a patient in need of such a treatment a -182- ND therapeutically effective amount of a .composition o comprising a compound of formula VIII. This method is Sespecially useful for treating cancer, such as colon, Sovarian, and breast cancer.

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

<C 10 Another aspect relates to a method of treating 0 a disease that is alleviated by treatment with a CDK-2 Ci inhibitor, said method comprising the step of administering to a patient in need of such'a treatment a therapeutically effective amount of a composition comprising a compound of formula VIII. This method is especially useful for treating cancer, Alzheimer's disease, restenosis,. angiogenesis, glomerulonepbritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

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

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

The above formula I compounds contain a pyrazole ring bearing the R 2 and R 2 substituents. In -183- ND their search for further inhibitors of the protein o kinases GSK and Aurora, applicants sought to replace the Spyrazole moiety of formula I with other heteroaromatic rings. One of the more effective pyrazole ring replacements was found to be a triazole ring. Inhibitors 0 having this triazole ring are otherwise structurally similar to the formula I compounds and are represented by Ch the general formula IX:

C-I

0

H

A

IX

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

1 is nitrogen or CR 9 and Z 2 is nitrogen or CH, provided that at least one of Z 1 and Z 2 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from any substitutable nonortho carbon position on Ring C is independently pubstituted by -R s and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, -184- IND said fused ring being optionally substituted by halo, O oxo, or -R; SRing D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected \D from nitrogen, oxygen or pulfur, wherein Ring D is Ssubstituted at any substitutable ring carbon by oxo or

S-R

5 and at any substitutable ring nitrogen by \C 10 provided that when Ring D is a six-membered aryl or, o heteroaryl ring, -R 5 is hydrogen at each ortho carbon Ci position of Ring D; R is selected from -halo, -CN, -NO 2 T-V-R6, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci- aliphatic 'group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -Re, said C 1 -s aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R x and an adjacent substituent 'taken together with their intervening atoms form said ring fused to Ring C; Rx and R Y are independently selected from T-R 3 or RX and

R

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

4 alkylidene chain;

R

2 is -R or--T-W-R 6 -185- IND R 3 is selected from -halo, -CO 2

R,

o-COCOR, -COCH 2 00R, -NO 2 -CNi -S{O) 2 R, -SR,

-N(R

4 2

-CON(R

7 2 -S%2N(R 7 2

-N(R')COR,

N (R 7

CO

2 (optionally substituted C 1 _6 aliphatic) 2 -C=NN(Rt) 2 -C=N-OR, _N (R7) CON (R 7 )2, -N SO 2

N(R')

2

-N(RW)SO

2 R, or OC NRW) 2 each R is independently- selected from- hydrogen or an.

optionally substituted group selected from C1-6 aliphatic, 0 s-lo aryl, a heteroaryl ring having 5-10 rigatoms,,P a heterocyclyl ring having 5-10 ring

IN

atoms-; CAeach R 4 is independently selected from -k 7

-COR

7

-CO

2 (optionally substituted 01.6 aliphatic.), -CON 2 or -SC or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -00 2 R, -COCOR, -NO 2 -CN, -S%2R, -SR, -N(R4) 2

-CON(R')

2 -80 2

N(R")

2

-N(R

4

)COR,

-N CR) C02 (optionally substituted C.-6s aliphatic), 2

-C=NN(R')

2

-NCR

4 CON (R 4 2

-N(R

4

)SO

2

N(R)

2

)SO

2 R, or -oc(=O)Nq(a 4 b, or R 5 and an adjacent substituent taken together with their.

intervening atoms form said ring fused to Ring C; V is -SO2-, -N(R 6 -S%2N(R 6 -COn-, N( CO-, -N -N (R')CON q S0 2 N -N -C(0)11(R 6 2

-C(R

6 2 2 S0-, -C(R 6 2 50O 2 2 S0 2 C(R'6)- 2 2 -C(R'bNN(R6)C(O)O-, -C(R6) 2

-C(R)

2

N(R)SO

2 or WCR) 2 N (R0)CON (R6)- -186- IND w is -C(R) 2 2 2 aso0-, 2 so 2 2 -C(R) 2 _CO 2R 2 -C(R 6 -C(R6)OC(O)N(R6)-, -C(R )wCR')co-, -C(R6)2N(R6)C(0)O-, S 2 N 2 so02N(R)-, 2 N(R6)CON(R) or IDeach R' is independently selected from hydrogen, an optionally substituted C- 4 aliphatic group, or two R' groups on the same nitrogen atom are taken together with the nitrogen atom to form a'5-6 membered heterocyclyl or heteroaryl ring; each R' is independently selected from hydrogen or an optionally substituted C1-s 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; each Ro is independently selected from an optionally.

substituted C 1 4 aliphatic group, -SR, -COR', -so2R6, 2

-N(R

6 2 -CN, -NO 2 -CON(R6) 2 or

-CO

2 Rk; and R9 is selected from halo, -OR, -CO2R, -COCOR,

-NO

2 -CN,

-SO

2 R, -SR, -N(Ri) 2

-CON(R')

2 -S0 2 -N(R')COR, -N (R')C0 2 (optionally substituted

C

1 -G aliphatic),

-N(R

4

)N(R)

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

N(R

4 2 -N(R)'S0O2R, or Compounds of formula IX may exist in alternative tautomeric forms, as in tautomers 1-3 shown below. Unless otherwise indicated, the representation of any of these tautomers is meant to include the other two.

-187gN

HN{N,

HN N HN H HN 1 2 3

HN

A Af A_" RY ZI .CI RY ZIRY z~ G G 1 2 3 Va The RX and RY groups of formula IX may be taken o 5 together to form a fused ring, providing a bicyclic ring IDsystem containing Ring A. Preferred RX/RY rings include a o or 8-membered unsaturated or.partially unsaturated ring having 0-2 heteroatoms, wherein said R/RY ring is optionally substituted. Examples of Ring A systems are shown below by compounds Ifx-A through fl-DD, wherein EZ is nitrogen or and Z 2 is nitrogen or C(H) N

H

HNN

HNHN

01 X CX fl-A IX-B IX-C HNI HN7 HN\ IX-D IX-E IX-W -188- Va 0 0 ci 0 ix- S Il-H Il-I H N>

IZ-L

5 ix- j 'i-x IX-M Il-bT HN31 S IZ-Qk Il-P Il-It

HN"N

Ilk-s.

1I-N7 II-T 12.-u -189- HN'3Z7 HNA HN' Va

N

IX-V 1 zz-W IX-z oHN HN H

\O

NN

Z1 <xtI Z oz IX_ z

IX-AA

HNA HN- H HN f 0 o r z2 IX-BB Il-CC IX-DD Preferred bicyclic Ring A:systems of formula IX include IX-A, IX-B, IX-C, Ix-D, IX-E, IX-F, IX-G, IX-H, IX-I, IS-J, Il-K, IX-L, and IS-M, more preferably IX-A, IX-B, XX-C, IX-F, and IS-H, and most preferably IX-A, IX- B, and I-H..

In the monocyclic Ring A system of formula Ix, preferred R groups include hydrogen, alkyl- or dialkylamino, acetamido, or a C 1 4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred RY groups, when present, include T-R 3 wherein'T is a valence bond or a methylene, and R 3 is 2 or -OR. Examples of preferred RY' include 2-pyridyl, 4pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl or halosubstituted phenyl, and methoxymethyl.

-19d- IND In the bicyclic Ring A system of formula IX, o the. ring formed by R t and RY taken together may be substituted or unsubstituted. Suitable substituents include halo, -OR,

-CO

2 -COCOR,

-ON,

1- 5 -80211, -SR, -N(R 4 2 -CON(Rt 2 -SO2N(R 4 )2,

-N(R

4 )COR, C0 2 (optionally substituted C1_G IND aliphatic), -N(R 4

)NVR)

2

-C=NN(R

4 2

-C-N-OR,

2

-N(R')SO

2

N(R')

2

-N(R

4 )S0 2 11, or -OC(=O)N(Rt) 2 wherein R and R4 are as defined above.

Prefrrred RZ/Ry ring subatituents iniclude -halo, -OR, o -COR, -CO 2 R, -CON(R 4 2 -CN, or 2 Whferein R is an Cioptionally- substituted C1.- aliphatic group;.

Preferred R12 groups of formula IX include hydrogen, C1..4 aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl', alkoxyalkyl, aminocarbonyl, monoor dialkylaminocarbonyl, aninoalkyl, alkylaminoalkyl, dialkylafiinoalkylr phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred 112 Bubstituents include methyl, cyclopropyl, ethayl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, 0'02,1 020H1, CH2QH, C0CH00, 03,03,C0311H, H2C2CH03,, CH2CH2CH2OOH2Ph, tH201,0iNH2, CH2CHtE,2NHCOOc (OH,) 3 COmlCn (03)2 ~'COmouH2H=Ca!, 1103,03,001,3, CONHCHPhy CONE (cyc lohesyl) CON (Et)2, 'CON ,01,P1I 001111(n-C03,-), CON (EtICHCH2301, 00111103,0(0%3),, CON CO (3methoxymetylpyrrolidin-1-yl)-, COM(3-tolyl), C0111(4tolyl), CONHCH,, CO (morpholin-l-yl), CO (4-methylpiperazinl-yl), CONHCHCHOH, CONE 2 and CO (piperidin-1-yl). A more preferred R2' group for fonmula IX compounds is hydrogen.

An embodiment that is particularly useful'for treating GSK3 -mediated diseases relates to compounds of formula K wherein ring A is a pyrimidine ring: -191- O ID

R

2 0

N

t e HN N

O

0 Va.

O x pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from any substitutable nonortho carbon position on Ring C is independently substituted by -R s and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially uisaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R R' is 'selected from -halo, -CN, -NO 2 T-V-R, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or CI, aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to. three groups independently selected from halo, oxo, or said CI-6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with"their intervening atoms- form said ring fused to Ring C; -192- IND e and RI are independently selected from .or R and o *RY. are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, S-B membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R and RY is IND substituted by oxo or T-R, and any substitutable S nitrogen on said ring formed by RI and RY is substituted by R; T is a valence bond or a C 1 -4 alkylidene chain; INDo S. R2 is -R or -T-W-R; C

R

3 is selected from -halo, -OR, -CO2R, -COCOR, -COcH 2 COR, -NO 2 -CN, -S(0) 2 R, -SR, -CON (R )2 SdN(P 2,

COR,

C0 2 (optionally substituted C3-s aliphatic), 2

-C=NN(R')

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

-N(R

7

)SO

2

N(R)

2

-N(R

4 )S2R, or -OC(=0)N(R)2; each R is independently selected from hydrogen or an optionally substituted group selected from CI- 6 aliphatic, C 6 s-16 aryl, a heteroaryl ring haying 5-10 ring atoms, or a heterocycly1 ring having 5-10 ring atoms; each R' is independently selected from R, -COR' 7

-CO

2 (optionally substituted C 16 aliphatic), -CON (Rt 7 2, or -SO 2

R

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

-CO

2 R, -COCOR, -NO; -CN< -SO2R, -SR, 2 -CON (R) 2

-SO

2

N(R')

2

-N(R')COR,

CO2(optionally substituted C 1 6 aliphatic), 2

-C=NN(R')

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

-N(R'))SO

2

N(R')

2 -N(R')SOR, or 2 -or IRs 5 and -193- IND an adjacent substituent taken together with their o intervening atoms form said ring,-fused to Ring C; eN]s -802-, -SO 2 S -N(R')SO 2 o C(O)N(R) -C(R6hO.-, -C{R 6 2

S-,

IND -C(R) 2 S0-, 2 Sc -C(Rr') 2 S0 2

-C(R)

2

N(RJ)-,

C>-C(R6) 2 -C(R6) =NN (R 6 2 -C(Rr)bN(R')S0 2 or 2 N (R')CON (R 6 oW is -CCR)hO-, 2 S0-, 7

C(R)

2 S0 2 ci -C{R6) 2 2

-CC

2

-C(R

6 -C(R'b2N(R 6)CO-, 2

C(R')

2 -C(R6) 2

N(R")SO

2 2 or each R6 is independently selected from hydrogen, an optionally substituted C 1 4 alipbatic group, or two R6 groupsq on the seine nitrogen atom, are taken -together with the nitrogen atom to form a.,5-6 membered heterocyclyl or heteroa-ryl ring; 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 form a 5-8 memnbered heterocyclyl or heteroaryl ring; and each R' is independently selected fron an optionally.

substituted C 1 4 aliphatic group, -SR 6

-COR'

SO

2 2 -N(R')N(R6) 2 -Cit. -NO 2 -CON(R6) 2 or -C0 2

,R

6 Compounds of formula X are structurally similar to compounds of formula II except for the replacement of the pyrazole ring moiety by the triazole ring moiety.

-194- ND Preferred 2

R

x RY and Ring C groups of formula X are as Sdescribed above for the formula II compounds. Preferred Sformula X compounds have one or more, and more preferably all, of the features selected from the group consisting.

t 5 of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring; o

R

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

R

1 is -halo, an optionally substituted C3-g aliphatic group, phenyl, -COR 6 -OR, -CN, -S02R 6

-SO

2 NH -N(R' 2, -C0 2 R, -CONH2, -NHCOR 6

-OC(O)NH

2 or -NHSO 2

R';

and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, -or a Ci-6 aliphatic group.

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

R

x is hydrogen or methyl and R y is -R, or -OR, or R X and R y are taken together with their intervening atoms to form a benzo ring or a 5-7 membered carbocyclo ring, wherein said ring formed by R x and R

Y

is -195- I\D optionally substituted with halo,. -OR, -CO 2

R,

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

-CON(R')

2

S-SO

2

N(R

4 -OC COR, -N(R 4 C0 2 (optionally substituted CI- 6 aliphatic),, -N (R 4 2 ,-C=NN (R' 2 5 -C=N-OR, -N(R')CON(R 4 2, SO2N(R 4 2 -N.(R4)SO2R, or -OC N 2;

R

1 is -halo, a Ci- baloaliphatic group, a C 1 Saliphatic group, phenyl, or -CN;

R

2 is hydrogen or a substituted or Cr 10 unsubstituted group selected from aryl or a C.-6 aliphatic o group; and Ci each R 5 is independently selected from -halo, -CN, -NO 2 -N(R' 2, optionally substituted Cialiphatic group, OR, -CO 2 R, -CONH(R'), N(R) COR,

-SO

2

N(R

4 2 or -N(R 4

)SOR.

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

R

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

Y

are taken together with their intervening, atoms to form an optionally substituted benzo ring or a 6-membered carbocyclo ring;

R

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

R

2 is hydrogen or a C 1 -6 aliphatic group; and -196- ND each R 5 is independently selected from -Cl, o -CN, -CF 3

-NH

2 -NH(CI-4 aliphatic), -N(C 1 -4 Saliphatic) 2 -0(C- 4 aliphatic), C,- 4 aliphatic, and -C02(Ci-4 aliphatic) Another embodiment of this invention relates to compounds of formula XI: eO m R 2 0

NH

IN HN':

XI

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

-R

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

R

X and R Y are taken together with their intervening atoms to form a fused benzo ring or 5-8 membered carbocyclo ring, wherein any substitutable carboh on said fused ring formed by R X and R y is substituted by oxo or T-R 3 T is a valence bond or a C 1 -4 alkylidene chain; R' is -R or -T-W-R6; -197-

IND

3 is selected from -halo, -OR, -C(stO)R, -COR, o-cOaO; -COCH 2 CORI, -wo0 2 -aM, -S(O)RZ, -s(O) 2

-SR,

2

CON(R')

2

-SO

2

N(R')

2

-N(R

4 )C0R,.

-N (R 4 )C0 2 (optionally substituted C 1 ~g al~iphatic), S-N(R')N(Rt) 2

-C=NN(R

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

)CON(R)

2 0-N(R 4

)SO

2

N(R')

2 -N(Re)S0 2 R, or -C=)(42 each Rt is independently selected from hydrogen or an

NO

a" optionally substituted group selected from C 1 6 aliphatic, C 6 1 aryl, a heteroaryl ring having 5-10 0 ring atoms, or a heterocyclyl ring having 5-10 ring'

IND

o atoms; 0each R! is independently selected from -R -COat -c0 2 {(optionally substituted C 1 6 aliphatic) -CON(RT) 2 or -S0 2 R, or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each Rt 5 is independently selected from -Rt, halo, -OR,

-CO

2 R, -cocoa, -NO 2 -01, -SO 2 R, -SR,

-N(R)

2

-CON(R')

2 -SO2N(R) 2

-N(R")COR,

-N(R)CO2 (optionally substituted C3 1 aliphatic-), -N(R')N(Rt) 2 -C =NN(Rfl 2

*-N(R

4

)CON(R

4 2

-NCR')SO

2

N(R')

2

-N(R

4 )SOR, or -OC(=0)N(R 4 2 V is -N(R')SOr, SO 2

N(R)-

-cc 2 Co-, -N(RG) C(O)Or,

-N(R')SO

2 OC(0)N(R 2 2 5 -C(R6) 2 S0-, -C(R 6) 2 SO2-, 2 S0 2 N(R6) C(R') 2 N(R) 2 -C(qY)=NN(Rr) 2 2

N(R')SO

2 or rC(R') 2 N(R')CON(R') W is 2 2

-CCR')

2 S0-, 2 S0 2 C(R6) OC(o)N(R C(R'h N (R'6)CO-, -198- IND

C(R')

2

-C(R

6

)=NN(R

6 -C(R6) N-0-, SR-C(R6) N (R 6 )N 6) SNC(R' 2 N S 2 -C 2 N (R)ON 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 IN with the nitrogen atom to form a 5-6 membered Sheterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an 10 optionally substituted C3-_ aliphatic group, or two R 7 o on the same nitrogen are taken together with the Ci nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.

Compounds of formula XI are structurally similar to compounds of formula IIX except for the replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred R 2 Re, R

Y

and Ring D groups of formula XI are as described above for the formula III compounds. Preferred formula XI compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring -selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, .azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-IH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

R

X and R Y are taken together with their intervening atoms to form an optionally substituted benzo ring or 5-7 membered carbocyclo ring; and -199- IO R' is hydrogen or a substituted or 0 o unsubstituted group selected from aryl, heteroaryl, or. a C 6 aliphatic group.

More preferred compounds of formula'XI have one or more, and more preferably all, of the features selected from the group conisisting of: Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4- N 10 tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinol1inyl, O 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, 0 isoquinolinyl, quinolinyl, or naphthyl; e and RY are taken together with their intervening atoms to form a benzo ring or 5-7 membered carbocyclo ring, wherein. said ring formed by I and RY is optionally substituted with oxo, halo, -OR,

-CO

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

-CON(R')

2

-SO

2

N(R')

2

-N(R)COR,

-N C02 (optionally substituted C3.

6 aliphatic),

-C=NN(R

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

-N(R')SO

2

N(R

4 2 -N(R')SO2R, or -OC(=O)N(R)2; R -is hydrogen or a substituted or unsubstituted group selected from aryl or a Ci- 6 aliphatic group; and each Rs is independently selected from halo, oxo, CN, NO, 2 -C0 2 R, -CONH(R'), -N(R')COR,

-SO

2

N(R

4 2

-N(R

4

)SO

2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs- 1 o aryl, or aliphatic.

Even more preferred compounds of formula XI have one or more, and more preferably all, of the features selected from the group consisting of: -200- ND

R

X and R Y are taken together with their Sintervening atoms to form a benzo ring or 6-membered Scarbocyclo ring, wherein said ring formed by R and RY is optionally substituted with halo, CN, oxo, C 1 i- alkyl, Ci-6 alkoxy, alkyl)carbonyl, 6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or *0 dialkylaminocarbonyloxy, or 5-6.membered heteroaryl; each R s is independently selected from S1 -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a cq 10 substituted or unsubstituted group 'selected from 5-6 0 membered heterocyclyl, Cs-io aryl, or Ci-. aliphatic; and C R 2 is hydrogen or a C3- aliphatic group.

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

NH

Re

N

XII

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Ring D is a 5-7 membered monocyclic- ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryi or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is.

substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or -201- \0 heteroaryl ring, -R s is hydrogen at each ortho carbon 0 0 position of Ring D;

SR

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

R

Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable S carbon on said fused ring is optionally and independently substituted by T-R 3 and any C- substitutable nitrogen on said ring is substituted by

\O

CD

R

4 Ci T is a valence bond or a C 1 .4 alkylidene chain;

R

2 is -R or -T-W-R6;

R

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

R,

-COCOR, -COCH 2 COR, -NO2, -CN, -S(O) 2 R, -SR, 2

-CON(R')

2

-SO

2

N(R

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

COR,

-N CO 2 (optionally substituted Ci-6 aliphatic),

-N(R

N

2

-C=NN(R

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

)CON(R')

2

-N(R

4

SO

2

N(R

4 2

-N(R')SO

2 R, or -OC(=O)N(R 4 )2; each R is independently selected from hydrogen or an optionally substituted group selected from C 1 -6 aliphatic, C-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 from -R 7

-COR

7 -CO2 (optionally substituted aliphatic), -CON(R 2 or -SO2R7, or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -CO2R, -COCOR, -N0O, -CN, -SOaR,- -SR,

-CON(R')

2 -SOaN(R4) 2

-N(R')COR,

-N(R' CO (optionally substituted C.-s aliphatic), -202-

IND-N(R')N(R')

2 -C=blN(R') 2 -C=N-OR, -N(R)CON(R 4 2 o-N4(Rt)SO 2 N(Rfl 2 -Nq(R')SO 2 R, Or 0OC(nO)N(R') 2 V is A -SO 2 N(R6)S0 2

-SO

2

N(R

6

-N(R

6 -C0 2 -Nq(RY)CO-, -N(RY)C(O)O-,

-N(R

6

)SO

2

N(R

6 C '-C{Rg) 2 -C(R6) 2

S-,

2 80 2 2 So 2 N (R 6 -C 2 N (R6)

-C(R

6 2 -C(R6) 2

N(R

6 )c(o *-C(R 6 -C(R'ktN-qO_, 2

N(R

6 2

N(R')SO

2 N(R) or -0 C (R 6 2 o is -C 2 CR)S- C -C(R")2S02N(R 6

-C(R

6 2 -co 2 -C0(R6) 2 N (R 6 C -C (R'6 =TI(R6) -c (R 6 C(R) 2 N N (a 6 Cd(R 6 2 N(R)S0 2 N (R6), -C(6)2(R)CO(R6-,or

-CON(R

6 each R 6 is independently selected from hydrogen or an optionally substituted C 1 4 aliphatic group, or two R 6 groups on 'the- same nitrogen atom 'are taken together with the nitrogen atom to form a'5-6 membered heterocycjlyl or heteroary3. ring; and each RW is independently selected from hydrogen or an optionally substituted C, 1 6 alipha tic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 menibered heterocyclyl ring or heteroaryl..

Compounds of formula XII are structurally similar to compounds of-formula IV except for the *replacement of the pyrazole ring moiet y by the triazolering moiety. Preferred Rt, e, Rb', and Ring D groups of formula X11 are as described above for the formula IV compounds.. Preferred formula XII compounds have one or -203- ND more, and more preferably all, of the features selected 0 from the group consisting of: S(a) Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- D tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3- C dihydro-1H-indolyi, isoquinolinyl, quinolinyl, or naphthyl ring; C 10 R X is hydrogen or C1-4 aliphatic and R is T- o R 3 or R z and RY are taken together.. with their intervening Cq atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring heteroatoms; and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci-6 aliphatic group.

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

R

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

N(R

4 2 or -OR, or R x and R Y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, wherein said ring is optionally substituted with -R, halo, oxo, -OR, -CO0R, -COCOR, -CN, -S(0)R, -SO2R, -SR, -CON(R')2, -SOaN(R')2, -OC(=O)R, -204- COR, C02 (optionally substituted C 1 6 aliphatic), 2

-C=NN(R')

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

N(R)

2

-N(R')SO

2 R, or -OC(=o)N(R)2; R2 is hydrogen or a substituted or unsubstituted group selected from aryl or a C 1 aliphatic group; and each R' is independently selected from halo, oxo, CN, NO 2 2 -C02R, -CONH(R), -N(R')COR, -S0 2

N(R')

2

-N(R')SO

2 R, -SR, OR, or a substituted or unsubstituted group selected from' 5-6 membered heterocyclyl, Cs-1o aryl, or C1-6 aliphatic.

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

R

2 and RY are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, optionally substituted with halo, CN, oxo, C3- 6 alkyl, C1-6.

alkoxy, -(C 1 6 alkyl) carbonyl, (C 1 6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocaronyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each Rs is independently selected from -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-3o aryl, or' C-s aliphatic; and R2 is hydrogen or a C1-.6 aliphatic group.

Anothet embodiment of this invention relates to compounds of formula XIII: -205c,,HN N

Z'

IND

or a pharmaceutically acceptable derivative or prodrug Ci thereof, wherein: O Z' is nitrogen, CR*, or CH, and Z 2 is nitrogen or CH; q provided that one of. Z' and 2 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C hasone or two ortho substituents independently selected from any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen,, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R 8 Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected.from aryl; heteroaryl,.

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

-R

s and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or -206- D heteroaryl ring, -R s is hydrogen at each ortho carbon o position of Ring D;

SR

1 is selected from -halo, -CN, -NO2, T-V-R 6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C 1 -s aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently 'selected from halo, oxo, or -R 8 said CI-.saliphatic group optionally Ssubstituted with halo, cyaho, nitro, or oxygen, or RI c 10 and an adjacent substituent taken together with their o intervening atoms 'form said ring fused to Ring C; C R" and R' are independently selected from TLR 3 or Rx and

R

Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R x and R y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by R X and Ry is substituted by R 4 T is a valence bond or a Ci-4 alkylidene chain; R' is -R'or -T-W-R 6

R

3 is selected from -halo, -OR, -CO2R, -COCOR, -COCH2COR, -NO2, -CN, -S(O) 2 R, -SR,

-N(R

2

-CON(R

2

-SO

2

N(R

2

-N(R

7

)COR,

-N C% (optionally substituted Ci-6 aliphatic),

N(R')

2

-C=NN(R'

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

)SON(R

7 2 -N(R')SOR, or each R is independently selected from hydrogen or an optionally substituted group selected from C 1 -s aliphatic, Cs-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -207- IND each it' is independently selected f rpm. 7k 7 -C!010, o -002(optionally substituted aliphatic), -CONCR'b2, Or SO 2 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heterdary. ring; 0 each R 5 is independently selected from halo, -OR, -C%2R, -COCOR, -No 2 -cN, -SO 2 R, -SR, 2, -CON(R') 2

-SO

2

N(R')

2 OCC=O)R, -N(R')COR, -N WR) CO 2 (optionally substituted C1_6 aliphatic),

-NC(R')N(R)

2

-C=NN(R')

2

-NCR')CON(R)

2 o -NCR')SO 2

N(R

4 2

-NCR

4

)SO

2 R, or or R5 -and c-i .an adjacent substituent taken together with their intervening atoms form sai& ring fused to Ring C;, V is -SO2-, -SO 2 N -N (R -N(R6)CO-, -N(R')CCO)o-, -N (R6) CONC(R -0(R6) 20, -C(R6) 2

S-,

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

-CCR')

2 S0 2 -C(R )bN(R -C(R 2 2 NC11)'s0 2 Or -C(WR2NRW) COXCRW)- W is -CCR 6) 2 -C(Rt) 2 -C(a 6 2 50-, -c(R 6 b2sc 2 S0 2 2 N -00-Co, -00C2, -CCR)OC -C NCR 6 1 C 2 2 -OCR6) -C CR.) N-O-, C W -CR2NC(R)N(R')- 2 S0 2

NC(R)-

2 N(R')CON(R6)-, or -0011CR')-'; each R6' is independently selected from hydktogen, an optionally substituted C3- aliphatic group, or two k6 groups on the same -nitrogen atom 'are taken together with the nitrogen atom to form a '5-6 membered heterocyclyl or heteroaryl ring; -208- INDeach 7 R' is independently selected from hydrogen or an o optionally substituted C3.- aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocycly1 or heteroaryl ring; 0 each R 8 is independently selected from an optionally substituted Cj-4 aliphatic group,

-COR,

-S%2R, 2 2 -CN, -NO2, -CON(R) 2 or -CO2R'; and CI 10 Ra is selected from halo, -OR, -CO 2 R, -COCOR,

-NO

2 -CN, -SO2R, -SR, -N(R 4 2

-CON(R)

2 C -SO2N(R 4 2 -OC(=9O)R, -N(R 4 )COR, CO02 (optionally substituted C.s aliphatic), 2 2 -C-N-OR, -N(R')CON(R') 2

-N(R')SO

2

N(R)

2

-N(R')SO

2

R,

2 or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

Compounds of formula xIII may be represented by specifying Z 1 and Z 2 as. shown below: N- N

NLH

HNA Hi HHNA

H

N N RY RY

R"

G G G and.

ZIIIa XIIIb ZIc Compounds of formula XIII are structurally similar to compounds of formhla V except for the replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred R 2 R, Y, a, and Ring G groirps -209- ID of formula XIII are as described above f6r the formula V O compounds. Preferred formula XIII compounds have one or Smore, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -RS, wherein when Ring C and two IND adjacent substituents thereon form a bicyclic ring C system, the bicyclic ring system is selected from a .naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is CN 10 -halo, an optionally substituted Ci-' aliphatic group, 0 phenyl, -COR, -CN, -SO 2

R

6

SO

2

NH

2

-N(R

6 -C0 2

R

6 C -CONH, -NHCOR, -OC(O)NH 2 or -NHSO 2

R

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

R

x is hydrogen or CI-4 aliphatic and R Y is T-

R

3 or RE and R

Y

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

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a

C

1 -6 aliphatic group.

More preferred compounds of formula XIII have one or more,-and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and- -210- IN R:is -halo, a C.-s haloaliphatic group,. a C., 6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1 2, 3, 4-tetrahydroisoquinolinyl, 1,2 3,4tetrahydroquinolinyl, 2, 3-dihydro-1H-isoindolyl, 2, 3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; R' is hydrogen or methyl and RY is N R') 2 or -OR, or R and RY are taken together with their o intervening atoms to form a benzo ring or a 5-7 membered Ci carbocyclo ring, wherein said ring formed by X and R T is optionally substituted with halo, -OR, -CO2R, -cocoR, -NoC, -CN,

-SO

2 R, -SR, 2

-CON(R')

2

-SO

2

N(R')

2 R, -N (R')COR,

CO

2 (optionally substituted

C

1 6 aliphatic),

-N(R')N(R

4 2

-C=NN(R')

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

-N(R')SO

2

N(R')

2 -N(R')SOi2R, or -OC N 2; R is hydrogen or a substituted or unsubstituted group selected from aryl, or a C3- 6 aliphatic group; and each Rs 5 is independently selected from -halo,, -CN, -N02, 2 optionally substituted

C

1 6 aliphatic group, -OR,

-CO

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

)COR,

-SO

2

N(R')

2 or -N(R')SO 2 R, and, when Ring G is Ring D, Ring D is substituted by oxo or RI Even more preferred compounds of formula XIII have one or more, and more preferably all, of the features selected from the group consisting of: x is hydrogen or methyl and RY is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or It and RY -211- I N are taken together iith their' intervening atoms to form a Sbenzo ring or a 6-membered carbocyclo ring wherein said ring formed by RZ and RY is optionally substituted with halo, CN, oxo, C1_6 alkyl, C 1 -s alkoxy, alkyl)carbonyl,

(C

1 6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; Ring C is a phenyl or pyridinyl ring, optionally substituted by -Rs 5 wherein when Ring C and two C 10 adjacent substituents thereon form a bicyclic- ring system, the bicyclic ring system is' a naphthyl ring, and 0 R is -halo, a C 1 -4 aliphatic group optionally substituted with halogen, or or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl,. quinolinyl,. or naphthyl;

R

2 is hydrogen or a. C,.s aliphatic group; and each Rs is independently selected from -C1, -CN, -CF 3

-NH

2

-NH(C-

4 aliphatic), -N(C-4 aliphatic) 2

-O(C

1 4 aliphatic), C1.4 'aliphatic, and -CO2(C 1 4 aliphatic), and when Ring b is Ring D, Ring D is substituted by oxo or R 5 Representative compounds of formula IX are shown below in Table 8.

Table 8.

CH

3 N H N- H N ;H H L oHN1 HNO t

H

3 N0 F -212- Va 0 0 ci 0 Va en IX- 1 IX-2

CH

3 N

H

IX- 3 H4CH 8 IX- 6 11-4 OtN CF 3 IX-7 Il-S IX- 8 IX- 9

CH

3 N >"H H CFP

CH

3

HN*P

N a N .0CF 3 IX-12 11-10

CH

3

NAH

ECkN

OH

3 N Il-is IX-13 IX-14 -213- Va 0 0 ci 0 Va en 0 ci Va 0 0 ci IX- 16 =x-17 tX-18

CH,

NA

HN~t HsC N4 XX- 19-

CH

3

HN%

I 'N

CF

3 N N -X -22

CH

3 HN W .N CF 8

-N

IX-20 HN*t IX- 21

CH

3

HN

4

P

H

5 C N

F

3 IX-24

HN$Y.

Mact-N

ON

H

3 CW 16 IX-27 IX- 23 K 3CH

NH

HN "4 HCtN Ci IX-26 IX- 25 -214- Va 0 0 ci 0 IX-28

H

3

HNZP

F

IX- 31

CR

3

N

IX- 34

HN'IP.

IX1-29

CH

3

N&OCHS

11-32

CR

3

N

HN

IN

0 1 N CH 3 11X-35

N'CH

3 HN t Al NCs IX- 33

OH

3

HN

4

P

N C- 36

CR

3 0&N~JCH3 IX-37

*CHS

HN

4 )6NCF 3 11X-38

N'CH

3 HN

NOH

I1-41

HN

4

P

QNCH2CHS IX-39

CH

3

HN*P

O~tNOCH2CHS

NI

IX-42 T1X-4b -215- Va 0 0 ci 0 Va en 0 ci Va 0 0 ci

HN'

N F IX-43

WN?

NCF

3 IX- 44

NH

HN P NCF 3

N

NCF

3

NH

HN

IX

OH

N

IX -48B

CH

3 IX- 51 IX-46 HN4 H N4 IX-49

HN

N C IX-52

OH

3 NkH IX-54 3--53 -216- Va 0 0 ci 0 HN P

N

IX-55

CH

2

N

Ix -58

OH

3 N A- IX-56

OH

3

NH

NCFS

H

3

C

I-X-59

OH

3 N

H

NO

2 IX- 62 CKs

NIL

NY 4 IXC-57

OH

3 N A N C' 'IX-

CH

3

HNAP

IX- 63 IX- 61

CH

3

N

IX- 64

OH

3

HNA$

IX-67

OH

3

HN

4

P

9 t5OF3

H

3

C

IX-166 IX-65

OH

3

N*

-FNCF

3 IX-68 -217- HNPNm 1 N OF 3 I2-69 Va 0 0 ci 0 Va en 0 ci Va 0 0 ci 2X-70 IX-71

*CH

3

NJ'NH

HN

NIt

F

3

C

73IX7 IX -72

CH

3

NA

IX- 74

CH

3 3

HN$

N N

H

2 Nj AcNH $0F IX-76 -IX-77

CH

3 HN

-WNN

HfC

N

MBS0 2 NH CI~N

CH

8 HNt

H

3 C NQ N 0.

ix-alI IX-?79 nc-so 218-.

Va 0 0 ci 0

CH

3 HNt IX- 82 C113

NHN

4

P

IX-84 TX- 83*

OH

3 C H 3 HNAXtp N:Jiht N CF 3

NY

I1X-86

OH

3 HNt

C

1 oe N CF 3 11-87 22- 85 P83

OH

'N CF 3 IX-88 I1-89 ix- CH3 Cbzv% 4 0 IX-91

H

2 N F IX-92 1X- 93 IX-94 IX-95 -219- IX- 96 Va 0 0 ci 0 Va en Me2SN.%QI$l 4N.

IX -97

OH

3

(H.

IX- 100 IX-98 IX-99 IX-101 IX-102 IX- 103 -Cs N N~

HN"

IX-104 IX -105

CHS

HNZ

IX- 106 I-108 -22 0- Va 0 0 ci 0 CH3

NH

IX- 109 CH3 HNVt ix- 111 h--lbo

HNZLS

N

IX-112.

CN

3

HNZ

(N

C(O)NH

2

NID

CH

3 cx~jH

CH

3 N

H'

CH

3

NA

4H%

HN

IX- 119

CH

3 HN~t IX- 114

CH

3

NA

Me N AO

CH

8 Nl-li IX -120 -221- Va 0 0 ci 0 Va en 0 ci Va 0 0 ci

CH

3 N

H

No IX- 121 pOhN Hs%

H

3 C OH, X-123 IX -122

NI

IX-124

CH

3 HN tI IX- 125 IX -126

CH

3

HN*

IX- 127

OH

3 IX- 129 IX- 12 8 I-X-130 O H 3

HN

4 I-X- 131

HNQ

"NH

IX-132 -222- Va 0 0, ci IX-133 IX-134

CH

3 AL. H IX-135 IX-136 IX-137

CH

Q-NH

Xt IX-140 IX-138 IX-139 IX-141

HN

IX-142 CHs HN %No N4- IX-144 IX -143

CH

3 HN AS

H

IX-146 IX-145 IX-147 -223- IX-148 IX-149'I,5 IX-:-150

INDN

00 0 r CHs o0 o H 3 HN HNA1 HN A0 N dH H! HN H 1--157 IX-152 IX-153 -224- Va 0 0 ci 0 IX -160 fl-i El IX- 162

CH

3

HNX

I-X- 165 IX-163 T1X-164 N

H'*

IX- 166 IX -167 IX-168 110 IX- 169

CH

3

N-IN

HNQ.

NZ

tX- 170 N~r

MNZ

02NtN IX- 173

CM

3 NkH HN I'

F

3

C

IX-171

O:H

3 IX-172 IX-174 -225oNH N H NN

OHN

N NN HNNHN N H

F

3

C

o IX-175 IX-176 IX-177 Va In another embodiment, this invention provides c 5 'a composition comprising a compound! of formula IX and a O pharmaceutically acceptable carrier.

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

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

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

Another aspect relates to a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula -226- SIX. This method is especially usefuil in halting or 0 slowing the progression of Alzheimer's disease. cii SAnother aspect relates to; a method of inhibiting the phosphorylation of p-catenin in a patient Q 5 in need thereof, comprising administering to said patient a therapeutically effective amount of a composition ND comprising a compound of formula iX". This method is n especially useful for treating schizophrenia.

0 One aspect of. this invention -relates to a N 10 method of inhibiting Aurora activity in .a patient, 0 Scomprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula IX.

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

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

Each of the aforementioned compositions and methods directed to the inhibition of GSK-3 or Aurora, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IX, as described above.

-227- i \D The. compounds of this invention may be prepared o as illustrated by the Synthetic.Methods below, by the C Synthetic Examples described herein and by general J methods known to those skilled in the art.

o General Synthetic Methods The general synthetic methods. below provide a

VO

I series of general reaction routes that were used to prepare compounds of this invention. Methods A-F below C 10 are particularly useful for preparing formula II Scompounds. In most cases, Ring C is drawn as a phenyl 0 ring bearing an ortho R 1 substituent. However, it will be apparent to one skilled in the art that compounds having other Ring.C groups may be obtained in a similar manner.

Methods analogous to methods A-F are also useful for preparing other compounds of this invention. Methods F-I below are particulary useful for preparing compounds of formula III or.IV.

Method A RR R 2 .(HO)2B R 1

R

I RNHNI HN F)I

N

'N

R

1 2 n Method A is a general route for the preparation of compounds wherein ring C is an aryl or heteroaryl ring. Preparation of the starting dichloropyrimidine 1 may be achieved in a manner similar ito that described in Chem. Pharm. Bull., 30, 9, 1982, 3121-3124. The chlorine in position 4 of intermediate i may be replaced by an aminopyrazole or aminoindazole to provide intermediate.2 -228- D in a manner similar to that described in J. Med. Chem., 38, 3547-3557 (1995). Ring C is then introduced using a boronic ester under palladium catalysis (see Tetrahedron, 48, 37, 1992, 8117-8126). This method is illustrated by the following procedure.

A suspension of lH-quinazoline-2,4-dione (10.0 \D g, 61.7 mmol) in POC13 (60 mL, 644 mmol) and N,Nc ~dimethylaniline (8mL, 63.1 mmol) is heated under reflux for 2 h. Excess POC 3 is evaporated under vacuum, the 10 residue is poured into ice, and the precipitate is o collected by filtration. The crude solid 2,4- (N dichloroquinazoline product may be used without further purification.

To a solution of 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 mL) is added methyl-1-pyrazol-3-yl amine (3.2 g, 32.9 mmol). The mixture is stirred at room temperature for 4 h, and the resulting precipitate is. collected by filtration, washed with ethanol, and dried under vacuum to afford (2-chloroquinazolin-4-yl) (5-methyl-lH-pyrazol-3-yl) -amine.

To a solution of (2-chloro-quinazolin-4-yl)-(5methyl-lH-pyrazol-3-yl)-amine (50 mg, 0.19 mmol) in DMF mL) is added the desired arylboronic acid (0.38 mmol), 2M Na2C03 (0.96 mmol), and. tri-t-butylphosphine (0.19 mmol). Under nitrogen, PdCl2(dppf) (0.011 mmol) is added in one portion. The. reaction mixture is then heated at 800C for 5 to 10 hours, cooled to room temperature, and poured into water (2 mL). The resulting precipitate is collected by filtration, washed with water, and purified by HPLC.

-229- P0 a. R 2 Rx NH R

P

Ca N R i R Pe RY N 3 4 I NH R 1 C 02H H N H 2 NH 0

OR

1 0 RI

NH

2 N (iii) 7 00 NH 2 Methods B through F describe routes where the pyrazole ring system is introduced after Ring C and the pyrimidine ring portion are first constructed. A versatile intermediate is the 4-chloropyrimidine 4, which is readily obtained from pyrimidindne 3 as shown in Method This reaction sequence is generally applicable for a variety of Ring C groups including aliphatic, aryl, heteroaryl; or heterocyclyl. See J.

Mled. Chem., 38, 3547-3557 (1995).

For qiinazoline ring systems (where R x and R are taken together to form a benzo ring), the useful intermediate 6 may be obtained by condensing an anthranilic acid or its derivative with a benzamidine as shown in Method B(ii) or by condensing a benzoylchloride with an anthranilamide as shown in Method B(iii) Many substituted anthranilic acid, anthranilamide, benzamidine and benzoylchloride starting materials may be obtained by -230- ND known methods. See Aust. J. Chem., 38, 467-474 and J.

o Med. Chem.,.38, 3547-3557 (1995). Method B(iii) is Sillustrated by the following procedure.

<To a solution of anthranilamide (33 mmol) in THF and CH 2 C1 2 70 mL) is added the desired benzoyichloride (33 mmol), and triethylamine (99 mmol) at D room temperature. The mixture is stirred for about 14 hours. The resulting precipitate is collected by filtration, washed with CH 2 C1 2 .and water, and dried under C 10 vacuum. The crude 2-benzoylaminobenzamide may be used Sdirectly for the next step without further purification.

Ci To a solution of the above crude product (13 rmmol) in ethanol (50 mL) is added NaOEt (26 mmol) at room temperature. The mixture is heated under reflux for 48 to 96 h. The solvent is evaporated and the residue is neutralized using concentrated HC1 to pH 7. The product is then collected by filtration and dried under vacuum to provide 2-phenyl-3H-quinazolin-4-one that may be used without further purification.

To a suspension of the above product (12 mmol) in POCl 3 (120 mmol) is added tri-n-propylamine (24 mmol).

The mixture is heated under reflux for h. After removalof the excess POCI 3 by evaporation, the residue is dissolved in ethyl acetate," and washed with IN NaOH (twice) and water (twice). The organic layer is dried over MgS04, the solvent is evaporated under vacuum, and the crude product is purified by flash chromatography (eluting with 10% of ethyl actetate in hexanes) to give 4-chloro-2-aryl quinazoline.

To a solution of 4-chloro-2-aryl quinazoline (0.16 mmol).in DMF (or TRF, ethanol) (1 mL) is added the desired .aminopyrazole or aminoindazole (0.32 mmol). The mixture is heated in DMF (or THF under reflux) at 100 to -231- ID 110°C for 16 h (or in ethanol at 130-160 0 C for 16 hours) C and then poured into water (2 mL). The precipitate is Scollected by filtration and purified by HPLC.

Method C NH R 1 O RY Ry C O2Et RriNH R 8 9

\O

H

2 11 RxACO2Et PRO5CO2Et S101 Methods C and D(i) above employ 0-ketoesters 8 and 10, respectively, as pyrimidinone precursors. The substitution pattern of the R and R Y groups on the pyrimidinone ring will be reversed if a chlorocrotonate 11 (Synth. Comm, (1986), 997-1002), instead of the corresponding p-ketoester 10,.is condensed with the .desired benzamidine. These methods are illustrated by the following general procedure.

To a solution of a 0-ketoester mmol) and amidinium chloride (5.7 mmol) in ethanol (5 mL) is added sodium ethoxide (7.8 mmol). The mixture is heated under reflux for 7-14 hours. After evaporation the resulting residue is dissolved in water, acidified with concentrated HCl to pH 6, and then filtered to obtain a solid product 2 -aryl-3H-pyrimidin-4-one .(yield 75-87%), -232which may be purified by flash column chromatography if needed. To this pyrimidinone (3.7 mmol) is added POC1 3 (4 mL) and n-Pr 3 N (1.4 mL). The mixture is heated under reflux for 1 hour. After evaporation of the excess POC1 3 the residue is dissolved in ethyl acetate, washed with IN NaOH solution (three times) and NaHCO 3 (once), and dried over MgSO 4 The solvent is removed iunder vacuum and the residue is purified by flash column, chromatography eluting with 10% of ethyl acetate in hexanes to give 2aryl-4-chloro-pyrimidine as a pale yellow syrup. This crude product may be treated with a 3-aminopyrazole or 3aminoindazole as described above.

Method D(ii) NH R 1 H2N' O POC 3

C.

0 O ''INH R nPr3N RX N RI EtO 2Et reflux N 1" 36 37 38 H

H

H

morpholine, CI H2N' MeOH N R 38 Sreflux -reflu 1 N 39 40 Method D(ii) above shows a general route for' the preparation of the present compounds, such as compound 40, wherein R Y is N(R) 2 See II Farmaco, 52(1) 61-65 (1997). Displacement of the 6-chloro group is exemplified here using morpholine. iThis method is illustrated by the following procedure.

To a solution of. 2-methylmalonic acid diethyl ester (5 mmol) and sodium ethoxide (15 mmol) is added the -233- ND appropriate amidine salt (5 mmol) in ethanol (10 mL) and o the reaction heated at reflux for 2-24 hours. The residue is dissolved in water and acidified with 2N HC1.

The resulting precipitate is filtered off and further purified by flash chromatography (yield 5-35%) to afford the pyrimidinedione 37. To 37 (1.6 mmol) is added POC1 3 (32 mmol) and tri-n-propylamine (6.4 mmol) and the C\ reaction refluxed is for.lh. After evaporation of excess POC1 3 the residue is dissolved in ethyl acetate, basified Ci 10 with IN NaOH, separated and the aqueous phase twice more o extracted with ethyl acetate. The combined organics are C dried (sodium sulfate) and evaporated. Purification by flash chromatography provides the dichloropyrimidine (38) as a yellow oil in 23% yield.

A solution of 38 (0.33 mmol) in methanol (5 mL) is treated with an amine, exemplified here using morpholine (0.64 mmoi) and refluxed 1 hour. After evaporation of solvent, the residue is purified by flash chromatography to provide the mono-chloropyrimidine 39 as a colorless oil in 75% yield.

The mono-chloropyrimidine, 39, (0.19 mmol) may be treated with a 3-aminopyrazole or 3-aminoindazole compound in a manner substantially similar those described above in Methods A and B.

Method E R' O 1 0 Y N=C=0 RY H NH R

NH

4 0Ac, RN' 12 AcOH, reflux 9 (R H) As shown by Method E, an acyl isocyanate 12 may be condensed with an enamine to provide pyrimidinone 9 -234o Org. Chem (1993),. 58, 414-418; J.Med.Chem., (1992), 0 35, 1515-1520; J.Org.Chem., 91967, 32, 313-214). This Smethod is illustrated by the following general procedure.

The enamine is prepared according to W. White, et al, J. Org Chem. (1967), 32, 213-214. The acyl isocyanate is prepared according to G Bradley, et al,. J I\D Med. Chem. (1992), 35, 1515-1520. The coupling reaction Cc? then follows the procedure of S Kawamura, et al, J. Org.

o Chem, (1993), 58, 414-418. To the enamine (10 mmol) in 10 tetrahydrofuran (30 mL) at OOC under nitrogen is added o dropwise over 5 min a solution of acyl isocyanate C nmmol) in tetrahydrofuran (5 mL) After stirring for h, acetic acid (30 mL) is added, followed by ammonium acetate (50 mmol). The mixture is refluxed for 2 h with continuous removal of tetrahydrofuran. The reaction is cooled to room temperature and is poured into water (100 mL). .The precipitate is filtered, washed with water and ether and dried to provide the 2-aryl-3H-pyrimidin-4-one.

Method F'

O

7Q 1 NH40H

NH

2 Heat W HN NH 16 13 14 Method F shows a general route for the preparation of the present compounds wherein R X and R Y are taken together to form a 5-8 membered partially unsaturated saturated or unsaturated ring having 1-3 heteroatoms. The condensation of a 2-amino-carboxylic acid, such as 2-amino-nicotinic acid 13, and an acid chloride 7 provides an oxazinone 14. Treatment of 14 with ammonium hydroxide will furnish the benzamide -235- \D which may be cyclized to a 2-(substituted)-pyrido[2,3o d] [1,3]pyrimidin-4-one 16. This method is illustrated by the following procedure.

2-(Trifluoromethyl)benzoyl chloride (4.2 ml, 29.2 mmol) is added dropwise to a solution of 2o aminonicotinic acid (2.04g, 14.76 mmol) in 20 ml of pyridine. The reaction mixture is heated at 158 C for Smin then cooled to room temperature. The reaction is poured into 200 ml of water and an oil forms which Ci 10 solidifies upon stirring. The solid is collected by

VO

o vacuum filtration and washed with water and diethyl 0 ether. The product is-dried to give 2-(2trifluoromethyl-phenyl) -pyrido oxazin-4-one (2.56 g, 60% yield) which may be used in the next step without further purification.

2-(2-Trifluoromethyl-phenyl)-pyrido[2,3d [1,3]oxazin-4-one (2.51g) is stirred in 30% ammonium hydroxide (25 ml) at room temperature overnight.' The resulting precipitate is filtered and rinsed with water and diethyl ether. The precipitate is dried under vacuum at 50 C overnight to give 2-(2-trifluoromethylbenzoylamino)-nicotinamide (850 mg,, 33% yield) 2.-(2-Trifluoromethyl-benzoylamino)-nicotinamide (800mg, 2.6mmol) is dissolved in 10ml of ethanol. Potassium ethoxide (435mg, 5.2mmol) is added to the solution which is heated to reflux for 16 h. -The reaction mixture is evaporated in vacuo to afford a gummy residue that is dissolved in water and acidified with sodium hydrogen sulfate to pH 7. The resulting precipitate is filtered and dried under vacuum at 50 C to give 2-(2-trifluoromethyl-phenyl)-3H-pyrido[2,3d] pyrimidin-4 -one.

-236- SMethod G is analogous to Method B(i) above.

This method is illustrated by the following general procedure.

o 5 2-(3,4-Dichloro-phenyl) -3H-quinazolin-4-one (Ig, 3.43 mmol) is suspended in phosphorus oxychloride (4 D mL) and the reaction mixture was stirred at 1100C for 3 C hours. The solvents are then evaporated and the residue o is treated carefully with an ice cold aqueous saturated s 10 solution of NaHCO 3 The solid is collected by filtration o and washed with ether to give 4-chloro-2-(3,5-dichlorophenyl)-quinazoline as a white solid (993 mg, 93%).

To 4-chloro-2-(3,5-dichloro-phenyl)-quinazoline (400mg, 1.29 mmol) in THF '(30 mL) is added methyl pyrazole (396 mg, 2.58 mmol) and the reaction mixture is heated at 65°C overnight. The solvents are then evaporated and the residue triturated with ethyl acetate, filtered and washed with a minimum amount of ethanol to give 12-(3,4-dichlorophenyl)-quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl)-amine as a white solid (311 mg mp 274°C; H NMR (DMSO) 8 2.34 (3H, 6.69 (1H, 7.60 (1H, 7.84 (1H, 7.96 (2H, 8.39 (1H, dd), 8.60 (IH, 8.65 (1H, 10.51 (1H, 12.30 (1H, IR (solid) 1619, 1600, '1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5 (M+H) The THF solvent used in the previous step may be replaced by other organic solvents such as ethanol, N,N-dimethylformamide, or dioxane.

Method H -237- HZ (HO) 2 B e Fe eRR~~~ P 0

R

17 18 RZ R 2 RrR HNH (CH))SI: H HN RN N OR N" CulFxNR (ii) 17 19 Method H shows routes in which a Ring D aryl group bearing a halogen (X is Br or I) may be converted to other formula III compounds. Method H(i) shows a phenylboronic acid coupling to Ring D to provide compound 18 and Method H(ii) shows an acetylene coupling to provide compound 19. Substituent I in compound 17 may be bromine or iodine. These methods are illustrated by the following procedures.

Method To a mixture of E2-(4-bromophenyl) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl) amine (196 ing, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol) in THF/water 4 mL) is added Na 2 CO (219 mg, 2.06 mmol), triphenylphosphine (9mg 1/15.mol%) and palladium acetate (1 mg, 1/135 molt). The mixture is heated at 80 0 C overnight, the solvents are evaporated and the residue is purified by flash chromatography (gradient of. d 2 C1 2 /MeH) to give (2-biphenyl-4 -yl-quinazolin-4-yl)- (5-methyl-2H-pyrazol-3-yl) -amine as a yellow solid (99 mg, 5%):1H NMR (DMSO) 2.37 (3H, 6;82 7a.39- -238-

I

ND 7.57 (4H, 7.73-7.87 (6H, 8.57 (2H, 8.67 (1H, O 10.42 (1H, 12.27 (1H, MS 378.2 (M+H) SMethod H(ii). To a mixture of [2-(4-bromo- <phenyl) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl) -amine (114 mg, 0.3 mmol), and trimethylsilylacetylene (147 rmg, mmol)in DMF mL) is added CuI (1.1 mg, 1/50 mol%), 0D Pd(PPh),CI, (4.2 mg, 1/50 mol%) and triethylamine (121 mg, S0.:36 mmol). The mixture is heated at 120 0 C overnight and o the solvent is evaporated. The residue is triturated in q 10 ethyl acetate and the precipitate is collected by o filtration.

S. To the above precipitate suspended in THF (3 mL) is added tetrabutylammonium fluoride (IM in THF, 3.leq). The reaction mixture is stirred at room temperature for two hours and the solvent is evaporated.

The residue is purified by flash chromatography (gradient.

of CH 2 C1 2 /MeOH) to give [2-(4-ethynylphenyl)-quinazolin-4yl]-(5-methyl-2H-pyrazol-3-yl)-amine as .a white solid (68 mg, 1 H NMR (DMSO) 6 2.34 4.36 (1H, 6.74 (1H, 7.55 (1H, 7.65 (2H, 7.84 (2H, 8.47 (2H, 8.65 (31, 10.43 (1H, 12.24 (1H, MS 326.1 Method I 2 R 2 R R2 R N

N

2 Method I above shows a general route for the preparation of the present compounds wherein ring D is a heteroaryl or heterocyclyl ring directly attached to the -239- I\D pyrimidine 2-position via a nitrogen atom. Displacement o of the 2-chloro group, exemplified here using piperidine, Ci Smay be carried out in a manner similar to that described in J. Med. Chem., 38, 2763-2773 (1995) and J. Chem. Soc., 1766-1771 (1948). This method is illustrated by the following procedure.

To a solution of (2-chl6ro-quinazolin-4-yl)-

VO

(1H-indazol-3-yl)-amine (1 equivalent, 0.1-0.2 mmol) in

C

N, N-dimethylacetamide (1 ml) is added the desired amine Ci 10 (3 equivalents). The resulting mixture is maintained at o 100°C for 6 h and then purified by reverse-phase HPLC.

Method J FF R RrFF (i) 21 22 Fe R2 CI H2N HN H 1 (ii) 23 24 Method J above shows the preparation of compounds of formula V via the displacement of a chloro group from an appropriately substituted pyridyl ring.

Method J(i) is a route for preparing compounds of formula Va (see Indian J. Chem. Sect.B, 35, 8, 1996, 871-873).

Method J(ii) is a route for preparing compounds of -240- O formula Vb (see Bioorg. Med. Chem.,6, 12, 1998, 2449- 0 2458). For convenience, the chloropyridines 21 and 23 k are shown with a phenyl substituent corresponding to Ring D of formula V. It would be apparent to one skilled in the art that Method J is also useful for preparing compounds of formula V wherein Ring D is heteroaryl, \D heterocyclyl, carbocyclyl or other aryl rings. Method J cn is illustrated by the following procedures.

SMethod (5-Methyl-2H-pyrazol-3-yl) f" 10 phenyl-quinolin-4-yl)-amine. To 4-chloro-2o phenylquinoline Het. Chem., 20, 1983, 121-128)(0.53g, 2.21 mmol) in diphenylether (5 mL) was added methylpyrazole (0.43g, 4.42 mmol) and the mixture was heated at 200 0 C overnight with stirring. To the cooled mixture was added petroleum ether (20 mL) and the resulting crude precipitate was filtered and further washed with petroleum ether. The crude solid was purified by flash chromatography (SiO 2 gradient DCM-MeOH) to give the title compound as a white solid: mp 242-244OC; 1H NMR (DMSO) 6 2.27(3H, 6.02(1H, 7.47(2H, 7.53- 7.40(2H, br 7.67(1H, 7.92(1H, 8.09(2H, d), 8.48(2H, 9.20(1H, 12.17(1H,'br IR (solid) 1584, 1559, .1554, 1483, 1447, 1430, .1389; MS 301.2 (M+H) Method J(ii). (5-Methyl-2H-pyrazol-3-yl) phenyl-isoquinolin-1-yl)-amine. To l-chloro-3phenylisoquinoline Het. Chem., 20, 1983, 121- 128)(0.33g, 1.37 mmol) in dry DMF.(5 mL) was added 3- (0.27g, 2.74 mmol) and potassium carbonate (0.57g, 4.13 mmol)and the mixture was heated under reflux for 6 hours. The mixture was cooled and the bulk of DMF was evaporated. The residue was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO 4 filtered and -241- ND concentrated. The crude was purified by flash o chromatography (SiO 2 gradient DCM-MeOH) to give the title c( S compound as a colourless oil; 'H NMR (MeOD) 8 2.23 (3H, 5.61 (1H, 7.41 (1H, 7.52(2H,.m), 7.62(1H, m), 7.81(1H, 8.07(1H, 8.19(2H, 8.29(1H, 8.54 (1H, d);-MS 301.2

\O

Method K R R a a 2

H

N N N NN H 2 CVcta C t RY \N 25 26 27 Method K shows a route for the preparation of compounds of formula VI. A versatile starting material is 2,4,6-trichloro- [1,3,5]triazine 25 in which the chlorine substituents may be sequentially displaced. The displacement of one of the chlorines by an aryl Grignard reagent or an aryl boronic acid is described in PCT patent application WO 01/25220 and Helv. Chim. Acta, 33, 1365_ (1950). The displacement of one of the chlorines by a heteroaryl.ring is described in WO 01/25220; J. Het.

Chem., 11, 417' (1974); and Tetrahedron 31, 1879 (1975).

These reactions provide a 2,4-dichloro-(6substituted) [1,3,5]triazine 26 that is a useful intermediate for the preparation of compounds of formula VI. Alternatively, intermediate 26 may be obtained by constructing the triazine ring by known methods. See US patent 2,832,779; and US patent 2,691020 together with J.

Am. Chem. Soc. 60, 1656 (1938). In turn, one of the chlorines of 26 may be displaced as described above to provide 2-chloro- (4,6-disubstituted) triazine 27.

-242- The treatment of 27 with an appropriate aminopyrazole provides the desired compound of formula VI.

Method L urea CF POC1 (400 y I^0 O N NH N N o CI 28 29 SFeR 2 H NH HN HN N

SNN

31 Method L shows a route for preparing compounds of formula VII. For illustration purposes the trifluoromethylchalcone 28 is used as a starting material; however, it would be apparent to one skilled in the art that other rings may be used in place of the.

trifluoromethylphenyl and phenyl rings of compound 28.

Substituted chalcones may be prepared by known methods, for example as described in the Indian J. Chemistry, 32B, 449' (1993). Condensation of a chalcone with urea provides the pyrimidinone 29, which may be treated with POC13 to give the chloropyrimidine 30. See J. Chem. Eng.

Data, 30(4) 512 (1985) and Egypt. J. Chem., 37(3), 283 -243- 0D (1994). In an alternative .approach to compound 30, one o of the aryl rings attached to the pyrimidine is introduced by displacement of of the 4-chloro group of 9 2,4-dichloro- (6-aryl)-pyrimidine by an aryl boronic acid using a palladium catalyst such as (Ph 3

P)

4 Pd in the 0 presence of a base such as sodium carbonate as described in.Bioorg. Ned. Lett., 1057 (1999). Displacement

NO

Sof the chlorine of compound 30 by an appropriate Saminopyrazole provides compounds of this invention, such C 10 as 31. The last step of this method is illustrated by o the following procedure.

C (4-Methylpiperidin-l-yl)-pyrimidin-2-yl]-(5methyl-2H-pyrazol-3-yl)-amine. To a solution of 2chloro-4- (4-methylpiperidin-1-yl) -pyrimidine (prepared using a procedure similar to the one reported in Bur. J.

Med.. Chem.,.26(7) 729(1991)) (222 mg, 1.05 mmol) in BuOH mL) was added 3 -amino-5-methyl-2H-pyrazole (305mg, 3.15 mmol) and the reaction mixture was then heated under reflux overnight. The solvent was evaporated and the residue dissolved in a mixture ethanol/water 4 mL).

Potassium carbonate (57mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water twice and rinsed with ether twice to give the title compound as a white solid (143mg, mp 193-195°C; 'H NMR (DMSO) 8 0.91 (3H, 1.04 1.67 (3H, m), 2.16 (3H, 2.83 (2H, 4.31 (2H, 6.19 (2H, m), 7.87 (1H, 8.80 (1H, br 11.71.(1H, IR (solid) 1627, 1579, 1541, 1498, 1417, 1388, 1322, 1246; MS 273.3(M+H) Method M -244- Va 0 0, ci n2n VIIIa VIIIb

CI.

N

G

Na 34 a

NN

k, VIIIc VIIId Method M provides routes for obtaining compounds of formula VIII. A general procedure for displacing the chlorine of a 4-chloro-6-substitutedpyridazine, 32, with an appropriately substituted pyrazole 'to provide VIIla is described in J. Het. Chem., 1473 (1983). Analogous reactions may be carried out as.follows: with 33,-.to provide VIIIb is described in J. Med. Chem., 41(3), 311 -(1998); with 5-chloro-3-substituted- -245- [1,2,4]triazine, 34, to provide VIIl is described in o Heterocycles, 26(12), 3259 (1987); and with 3-chloro- 5-substituted-[1,2,4]triazine, 35, to provide VIIId is described in Pol. J. Chem., 57, 7, (1983); Indian J.

Chem. Sect. B, 26, 496 (1987); and Agric. Biol. Chem., 54(12), 3367 (1990). An alternative procedure to compounds of formula VIIIc is described in Indian J.

.Chem. Sect. B, 29(5), 435 (1990).

SCompounds of formula IX are prepared by methods c- 10 substantially similar to those described above for the

NO

o pyrazole-containing compounds of formula I. Methods A-J C- may be used to prepare the triazole-containing compounds of formula IX by replacing the amino-pyrazole compound with an amino-triazole compound.. Such methods are specifically exemplified by Synthetic Examples 415-422 set forth below. The amino-triazole intermediate may be obtained by methods described in J. Org. Chem. USSR, 27, 952-957 (1991).

Certain synthetic intermediates that are useful for preparing the protein kinase inhibitors of this invention are new. Accordingly, another aspect of this invention relates to a 3-aminoindazole compound of formula A:

H

Rio

NH

2

A

where R 10 is one to three substituents that are each independently selected from fluoro, bromo, Ci- 6 haloalkyl, nitro, or 1-pyrrolyl. Examples of such compounds include the following: -246- Va 0 0, ci

H

F l NH2 Al

H

F N

NH

2 A2 F

H

NH2 A3 FF F H H F2 NHBr NH2 NH 2 H H Br F NH2

NH

2 A7 AS

H

O2N

N

NH2

AD

H

N NH 2 Another aspect of this invention relates to a- 4-chloropyrimidine compound of formula B: C3a F R'N

R!

RY N

B

wherein R x and R Y are as defined above; R 1 is selected from Cl, F, CF 3 CN, or NO 2 and is one .to three substituents that are each independently selected from H, Cl, F, CF3, NO2, or CN; provided that R 1 and R s are not simultaneously Cl. Examples of'compounds of formula B are shown below: C1 Mef N

CI

MeN B2 -247- Va 0 0, Met

N

Me NSy B6 Ci 6 Cl N CF 3 %Q N1

CI

F 1 ~N CF

C

2%N

CF

3 35N1141

CLC.

F

'N N;F 312

BI

CI

CF

3 B13 -314 316 317 B18

CI

CF

3 MeOK 319 Cl N~ CN 320 -248- Va 0 0, ci Another aspect of this invention relates to compounds of formula C:

H

HN

R I Ry W--Cl'

C

wherein R 1 Ry, R 2 and R 2 are as defined above, Examples of compounds of formula C are shown below:

H

HctN C1

H.

HN%

C4

F

HZH

HNt,- C7

H

HN

C2 HN 2 C5

H

HN

Ca

CH

3

H*H

HN

C3 H301

N

HN2

H

3 C'6N

CG

C9 -249- Va k eD 0 ci 0 Va

C

Vt 0 ^sD a> 0 ci

<D

0D 0q

CH

3

H

C1a

HN

C13

F

CHN4H

HN

C1

H

HN t. C14

HNZ

C12 Me

HN

K Yet 'another aspect of this invention relates to compounds of formula D: 0 RX/ NH CFs

D

where R 5

R

x and R Y are as defined above. Examples of formula D compounds and other useful pyrimidinone intermediates are shown below: D2 O HsC NH

CI

-250- Va 0 0, ci 0 0.

F NH CF, NH CFs D8 D9 0 0 N' NH CI NH Br N 3 U N Y D11 D12 D13 D14 0 NH CF3 D18 Di6 D17 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.

-251- I

VO

0 SYNTHETIC EXAMPLES SThe following HPLC methods were used in the analysis of the compounds as specified in the Synthetic 5 Examples set forth below. As used herein, the term "Rt" refers to the retention time observed for the compound using the HPLC method specified.

\O

HPLC-Method A: C1 10 Column: C18, 3 um, 2.1 X 50 mm, "Lighting" by Jones 0 Chromatography.

Ci Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) over 4.0 min, hold at 100% acetonitrile for 1.4 min and return to initial conditions, Total run time min. Flow rate: 0.8 mL/min.

HPLC-Method B: Column: C18, 5 um, 4.6 X 150 mm "Dynamax" by Rainin Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) over 20 min, hold at 100% acetonitrile for 7.0 min and return to initial conditions. Total run time 31.5 min. Flow rate: 1.0 mL/min.

HPLC-Method C: Column: Cyano, 5 um, 4.6 X 150 mm "Microsorb" by Varian.

Gradient: 99% water TFA), 1% acetonitrile (containing 0.1% TFA) to 50% water 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.

-252- I"

VO

HPLC-Method D: Column: Waters (YMC) ODS-AQ 2.0x50mm, SS, 120A.

Gradient: 90% water Formic acid), acetonitrile .(containing 0.1% Formic acid) to water formic acid), 90% acetonitrile IND (containing 0.1% formic acid) over 5.0 min, hold for 0.8 mini and return to initial conditions. Total run time 7.0 min.

0 Flow rate: 1.0 mL/min.

Ci HPLC-Method E: Column: 50x2.0mmO Hypersil C18 BDS;5 pm Gradient: elution 100% water TFA), to 5% water TFA), 95% acetonitrile (containing 0.1% TFA) over 2.1 min, returning to initial conditions after 2.3 min.

Flow rate: 1 mL/min.

ExaTle-1. (2-Clorophenyl) -5,6-dimethylpyrimidin-4-yl] (5-Xethyl-2H-pyrazol-3-yl)-amine 'HNMR (500 MHz, DMSO-d6) 810.4 br, 1H), 7.74 2H), 7.68 1H), 7.60 1H), 6.39 1H), 2..52 13H), 2.30 3H), 2.22 3H); MS 314.1 Exaple [2-(2-Chloro-phenyl) -6,7,8,9-tetrahydro-5Hcycloheptapyrimidn-4-yl] (1'-indazol-3-yl) -amine (11-2): Prepared in 30% yield. 'HNMR (500MHz, DMSO-d6) 8 1.72 (m, 4H), 1.91 2H), 3.02 4H), 7.05 IH), 7.33 (t, 7.39 IH), 7.47 1H), 7.55 3H), 7.59 (d, 1H), 10.4 1I), 13.11 (br. s, IM); EI-MS 390.2 HPLC-Method A, Rt 2.99 min.

-253- IND Example 3 (5-Fluoro-1B-indazol-3-y1)- trifluoromethyl-phenyl)-5,6,7, 8-tetrahydro-pyrido 3,4d]pyrimidin-4-yl]-amine CompoundII-18B (90 mg, 0.17 mmol) was treated with an.equal weight of Pd/C in 4.4% formic acid in MeOH at-room temperature for 14 h.

The mixture was filtered through celite, the filtrate was evaporated, and.crqde product was purified by HPLC to provide.18 mg of the desired product as pale yellow solid. 'HNMR. (500 MHz, DMSO-ds) 812.9 1H), 9.51 (s, Cl 10 1H), 9.26 2H), 7.72 1H), 7.63 1H), 7.58 (t,

N

oH 7.49 2H); 7.21 (td, 1H), 7.15 (dd, IH), 4.24 (s, c 2H), 3.56 295 2H) ppm. MS m/e= 429z22 HPLC-Method A, Rt 2.88 min.

.Exdaple A (2-Chloro-phenyl) -6,7,8,9-tetrahydro-5Hcyclohebaptapyrimidin-4-yl (7-fluoro-i-indaol-3-yl) amine Prepared in 52% yield to afford a white solid. 1 HNTR (500MHz, DMSO-d6) 8 1.72 4H), '1.92 (m, 2H), 3.00 4H), 7.02 (td, 1H), 7.20 (dd, 1H), 7.40 (m, 1H), 7.42 1H), 7.52 3H), 10.5 11), 13.50 (br.

s, 1H); EI-MS 408.2 HPLC-Method A, Rt 3.00 min.

EAamle 5 -[2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-s5Hcycloheptapyrimidin-4-yl]-(5-fluoro-JM-indazol-3-yl)amine Prepared in 51% yield. HNMR (500MHz, DMSOdG) 8-1.71 4H), 1.91 2H), 3.01 4H), 7.24 (td, 1H), 7.41 2H), .7.54 4H), 10.5 1H), 13.1 (br.

s, 1H); EI-MS 408.2 HPLC-Method A; Rt 3.05 min.

ExamiC 6 [2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-SHcyaloheptapyrimidin-4-yl] -(5,7-difluoro-1B-indaaol-3-yl)amine Prepared according to Method C in 72% yield. XHNMR (500MHz, DMSO-d6) 6 1.72 4H), 1.91 (m, -254- IND 2H), 3.01 (Mn, 4H), 7.31 (mn, 2H), 7. i41 (in, 1H), 7.54 (tn, o 3H), 10.5 (in, .1H) 13.6 (br. s, 111)'; El-MS 426.2 (M+*EI HPLC-Method A, Rt 3.21 min.

Eiamn2&.J (7-Fluoro-JM-indazol-3-yl) (2- 0 trifluoromethyl-phenyl) 8-tetrahydroquinazolin-4l yl-ainine Prepared in 62%- yield;- 3 HENMR (500 MHz, ON flMSQ-d6)' 813.5 br, I11), 10.1 br, 1H), 7.75 (mn, 104H), 7.33 I11), 7-17 (dd, -111), 7..00 (td, 1H), 2.80 (mn, 2H), 2.71 (in, 2H1), 1.89 (br, 4H) ppm; LC-MS 428.44

IND

o(14+1), 426-43 CM-H); HPLC-Method A, Rt 3.02 min.

Ex~l (5-Fluoro-1Hf-indazol-3-yl)- (2triflucromethyl-phenyl) 8-tetrahydroqninazoliLn-4 ylJ -amine (11-8) Prepared in 53% yield. 'flHIR. (500 M4Hz, DMSo-dE) 813.1 1H), 10.2 br, 110, 7.75 (mn, 4H), .7.50 (cia, 11), 7.27 (dci, 1I1), 7.21 1H1), 2.80 (mn, 2H),.2.72 (mn, 2H), 1.88 4H) ppm; MS (ES5+) 428.43 (14tH)', 426.43 WPLC-Metbed A, Rt 3.01 ii.

Examle 9C5 1 7-Difluoro-Jz-indazol-3-yl).- (2trifluoromethyl-phenyl) 8-tetrahydroquinazolin-4yl]-ainine (11A9): Prepared in 37% yield. 1 3HNIIR (500 MHz, DMSO-dE) 813.7 IH), 10.2' br, 1WN), 7.80 (di, iH), 7.76 IN), 7.6.9 (mn, 2H), 7.31 Ct, 110, 7.1.8 1W), 2.81 Ct, brt 2W), 2.72 Ct, br, 2H),-1.90 4H1) ppm; MS 446.42 (14+11), 444.37 HPLC-MethodA, Rt 3.'05 man.

Exmo1 (5-Trifluoromiahyl-1a-indazol-3-yl) 2- trifluoroinethyl-phenyl) 6,7, 8-tettahydroqunazoln-4.

yil-amne(11-10): Prepared by Meth~d C in elthanol in yield. 'IWI4 (500 14Hz, DM50-dG) 81-3.2 11), 10.1 -255- IND s, br, 11), 8.01 Cs, 1H); 7.76 1H), 7.66 4H), 7.57 1H), 2.2.9 Cm, 2H), 2.73 Cm, 2H), 1.89 4-H) ppm.-MS 478.45 47.6.42 HPLC- Method A, Rt 3.21 min.

0xa nre 1l (5,7-difl'uoro- 1E-indazol'-3-yl) 2- (2trifluoromethyl-phenyl) -tetrbydro- SHcycloheptapyrimitdin-4-ylJ-amine 11-11): Prepared in yield. White solid. HNMR (SOOMHz, DMSO-dG) 8 t.72 (m, 4H), 1.91 21), 3.01 41), 7.15 Cdd, 1H), 7.30 (td, 1H), 7.66 Cm, 7.72 Ct, 1H), .278 1H), 10.2 Cm, Ci lH), 13.5 (br. 1H); El-MS 460.2 CM+H); KPLC-Method A, Rt 3.13 min.

Exmp-t 1i (6-Benzyl-2-(2-trifluoromethyl-phenyl)- 5,6,7,8-tetrahydro-pyrido[4, 3-dpyrimidin-4-yl)-(5fluoro-1E-indazol-3-yl) -amine (11-12): Prepared in 49% yield. 'HNMR (500 MHz, DMSO-d) 812.8 Cs, 111), 9.11.Cs, IN), 7.68 Cd, iNH), 7.58 Ct, 1H), 7.53 Ct, 1H), 7.44 Cm, 4H), 7.37 Ct, 2H), 7.29 Ct, 1H), 7.19 Cm, 2H), 3.78 Cs, 2H), 3.61 Cs, 2H), 2.81 Cs, br, 4H) ppm; LC-MS (ES+) 519.24 UPLC-Method A, Rt 3.11 min. ZMnale JL, (1H-Indazol-3-yl).- (2-trifluoromethylphenyl) 6, 7, 8, 9 tetrahydro 59- cycloheptapyrimidin- 4 -yl amine (11-13):L.repared in 40% yield. '2QMR CSOOMHz, DMSO-dS) 8 1.70 4H), 1.90 2H), 3-.00 4H), 7.01 Ct, IR), 7.30 (td, 11), 7.44 1H), 7.49 1H), 7.68 3H), 7.77 13), 10.01 Cm, 1H), 12.83 Cs, lIH; El- MS 424.2 HPLC-Method A, Rt 3..17 min.

&;pMzgLe j (7-Fluoro-1.r-i'ndazol-3-y1) trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-SE- -256- \o cyclobeptapyrinidin-4-yl]-amine Prepared in 78% 0 yield. 1HNMR (O50MHz, DMSO-dg) 6 1.71 4H), 1.91 (m, 2H), 3.00 4H), 6.98 (td, 1H), 7.16 (dd, 12), 7.31 (d, 1H), 7.68 3H), 7.77 1H), 10.25 13.40 S (br. s, 1H); Ei-MS .442.2 HPLC-Method A, Rt 3.12 min.

Va Ch CC) Exame 15 (5-Pluoro-1E-indazol-3-yl) o trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H- 10 cycloheptapyrimnidin-4-yl]-mine (11-15): Prepared in 63% o yield. 'HNMR (500MHz, DMSO-d6) 8 1.71 4H), 1.91 (m, 3.00 4H).,-7.20 (td, 1H), 7.25 (dd, 1H), 7.49 (dd, 1H), 7.69 (br. t, 2H), 7.74 1H), 7.79 1H), 10.35 1H), 13.00 (br. s, 1H); EI-MS 442.2 HPLC-Method A, Rt'3.21 min.

Example 16 (5-Fluoro-1&-indazol-3-yl) (2trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3djpyrimidin-4-yll 1-amine (11-16): A solution of compound 11-12 (45mg, 0.087 mmol) in methanol HCOOH) was treated with an equal weight of Pd/C at room temperature for 14 h. The mixture was filtered through celite, the filtrate evaporated, and the crude product was purified by preparative HPLC to.provide 15 mg (41%) of the desired product as yellow solid..' 'HNMR (500 MHz, DMSO-d) 812.9 1H), 9.52 1H), 9.32 TFA- 0H), 7.72 1H), 7.59 2H), 7.49 2H), 7.21 (m, 1H), 7.15 1H), 4.31 2H), 3.55 2H), 3.00 (m, 2H) ppm;. LC-MS 429.20 HPLC-Method A, Rt 2.79 min.

Example 27 (1H-indazol-3-yl)-[2-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine (11-17): -257- IND Prepared in 58% yield. '2HMR (500 MHz, DMSO-d) 813.0 21), 10.3 hr, IH), 7.74 4H), 7.51 1H), 7.47 IH), 7.32 1H), 7.03 11), 2.82 21), 2.73 21), 1.90 4H) ppm; LC-MS 410.21 HPLC-Method A, Rt 2.99 min.

INDnpExaln (7-Benzyl-2- (2-trifluoromethyl-phenyl) 5,6,7,8-tetrahydro-pyrido[4,3-d pyrimidin-4-y) fluoro-JM-indazol-3-yl)-anmlne (11-18): Prepared from compound li in 92% yield. 1 HNMR (500 1Sz, DMSO-d6) o 812.9 1H) 10.5 br, 1H), 9.58 -IH -TPA-OR) 7.71 11H), 7.52 (in, 9H),.7.19 21), 4.57 211, 4.20 (in, 21), 3-.70 21), 3.00 2H) ppm; tO-MS AES+) 519.23 HPLC-Method A, Rt S.23 min.' Example 19 (1N-Indazol-3-yl)- [6-methyl-2- (2tri fluor-oiethyi-phenyl) -pyriiidin- 4 -yl I amine (11-19): Prepared in 42% yield. Melting point 235-237OC; 1

HNMR

(500 MHz, DMSO) 8 2.44 (31, 7.09 (11, aT=7.5 Hz, t), 7.40 (11, J=7.1 Hz, 7.49 (1H, J=8.3 Hz, 7.70 (3H, 7.79 (1H, 3=7.3 Hz, 7.87 (11, J=8.3 Hz, 8.03 (1H, J=7.7 Hz, 10.3 (11, 12.6 (11, a) ppm; HPLC- Method A, R: 2.958 min; MS (FIA) 370.2 Exnznlt 22 (1f-Indazol-3-yl)- C6-phenyl-2- (2trifluoromethyl-phenyl) -pyrimidin-4-yl] -a mine (11-20): Prepared in 32; yield. 'HMR (500 MHz, DMSO) 8 6.94 (IH, J-=7.4 Hz, 7.24 (111, J-7.4 Hz, 7.33 (1H, 37=8.4 Hz, (43H, 7.57 (11, J=7.3 Hz, 7'.68 (21, m), 7.75 (in, J=7;9 Hz, 7.93 (3H1, i),'8.18 (11, br a), 10.45 br 12.5 (IR, br a) ppm; HPLC-Method A, Rt min;. MS 432.2 -258- Va oXalP.e 21 (h-Indazol-3-y1) (pyridin-4-yl) (2- 0 trifluromethyl-phenyl) -pyrimidin-4Lyl] -amine (11-21): Prepared in 12W yield. 'HNMR (500 MHz, DMSO) 8 7.16 (11, e, '46 (IH, J=7.6 Hz, t)' J=7.4 Hz, 7.46 (iM, J=7.6 Hz, 7.56 (IH, J-8.3 Hz, o 55 7.80 (1H, J=7.2 Hz, 7.90 (2H, 7.97 (1H, J=7.8 Hz, 8.09 (IH, br), 8.22 (2H, J=4.9 Hz, 8.45 (111, Va br 8.93 (2H, J-4.8 Hz, 10.9' (Ii, br 12.8 (IH, br s) ppm; HPLC-Method A; Rt 3.307 min; MS (FIA) 433.2 o IN oxamp l- (3f-Indazol-3-yl)- (pyridin-2-yl)-2- (2trifluoromethyl-phenyl)-pyrimidin-4-yl)-amine (11-22): Prepared in 42% yield. 'IIM (500 MHz, DMSO) 8 7.07 (111, J=7.4 Hz, 7.36 (iH, T=7.4 Hz, 7.46 (UI, J.7.4 Hz, 7.53 (1H, J=5.0 Hz, 7.70 (1H, J=7.4 Hz, 7.79 (in, J=7.1 Hz, 7.83 (11, .7=7.4 Hz, 7.88 (1H, J=7.8 Hz, 7.97 J=7.7 Hz, 8.02 (1H, J=5.5 Hz, hr 8.36(11, =7.8 Hz, 8.75 (2H, =4.1 Hz, d), 10.5 (11, br 12.7 (1H, hr s) ppm; HPLC-Method A, Rt 3.677 min; MS (FIA) 433.2 amtle 23 (2-Chiorophenyl) (2-trifluoromethylphenyl) -pyrimidin-4-yll-( 1-indazol-3-yi) -amine (11-23): Prepared in 44% yield; 'HNMR (500 MHz, DMSO) 8 :7.08 (IR, J77.5 Hz, 7.37 Hz, 7.45 (IH, J=8.4 Hz, 7.51 (2H, 7.61 (iH, J=7.4, 1.9 Hz, dd), 7.69(2H, 7.79 (2H, J=4.0 Hz, 7.86 (31, .7=7.8 Hz, 8.04 (2H, J=6.2 Hz,. hr 10.7 (1H, br 12.6 (1H, br a) ppm; HPLC-Method A, Rt 3.552 min; KS (FIA) 466.2 Exg-gle _24 15,6-Dimethyl-2- (2-trifluoromethyl-phenyl)pyrimidin. 4-yll- (1-indazol-3-yl)-amine (11-24): Prepared in 35W yield; nip 183-186W; lHNMR (500 MHz, DMSO) 8 2.14 -259- IND(31, 2.27 (31, 6.85 (IH, J=7.5 Hz, 7.15 (1 J7.6 Hz, 7.32 7.38 (11, J=7.5 Hz, t) 7.42 H(11, J=7.4 Hz, 7.53 (11, J=7.6 Hz, 8.88 (11, a), 12.5 (1H, a) ppm; KPLC-Method A, Rt.2.889 min.; MS (FIA) 384.2 (M+HY'.

jpJl 2 5, 6-Diiethyl-2- (2-trifluoromethyl-phenyl) pyrinidin-4-yl]- (5-fluoro-a-idazol-3-yl)-amine (11-25): Prepared in 44% yield. Melting point l60-163 0 C 'INMR (500 MHz, DMSO) 8 2.27 (3M, 2.40 (3H, 7.16 (2H,' 7.44 (21, 7.52 (IH, J=7.4 Hz, 7.57 (1H, .=7.4 Cl Hz, 7.67 (21, Hzy'd), 9.03 (32, 12.75 (1H, a) ppm; HPLC-Method A, Rt 2.790 min; MS (Fm-A) 402.2

(M+H)

4 Exaumle 21 (2-cblorophenyl) 6-dimethyl-pyriiidin-4ylJ-(1B-indazol3k1) -'amine (11-26): Prepared in yield. 'HNMR (500 -MHz, DMSO) 8-2.14 2.33 (3H,.

6.84 (1H, J=7.4 Hz, 7.13 J=;7.4*Hz, 7.19 J=6.9 Hz, br (11, J=7.4 Hz, 7.32 (3R, br 7.37 (11, J=7.1 Hz, 10.01 (12, br), 12.8 (1H, br s) ppm; 8 2.919 min; MS. (FIA) 350.1 (M+H) t Examle .27 6-Dimethyl-2- (2-trifluoroiethyl-phanyl) pyriiidin-4-ylJ- (7-fluoro-3A-indazol-3-yl) -amine .Prepared in 92% yield. JNMR (500 MHz, DMSO) 6 2.33 (3H, 2.50 (3H, 6.97 (11, 1.15 (11, 7.30 Hz, 7.65 (3H, 7.76 J-=7.5 Hz, d), 10.0 (lI, 13.4 a) ppm; IPLC-Method A, Rt 3.053 min; MS (PTA) 402.2 (M.H)t BXrle 231 (5,7-Difluoro-la- indazol-3-y) 6-Dimethyl- 2- (2-trifluoromethyl-phenyl) -pyrimidin-4-yl] -amine (II- -260-

I

IN

28): Prepared in SQ* yield. HDNMR (500 MHz, DMSO) 8 2.42 c- (3H, 2.63 (3H, 7.22 (iF, J=7.6 Hz, 7.38 (1H, J=9.3, 1.7 Hz, dt), 7.71 7.75 (1H, J=7.0 Hz, d), 7.79 (lH, J=6.7 Hz, 7.86 (11, J=8.0 Hz, 10.0 (1H, 13.2 S) ppm; HPLC-Method A, Rt 3.111 min; MS (FIA) 420.2 (M+H) 4 __xample-22 [2 (2 -Chiorophenyl) 6 dimethyl -pyrimidin-4 o ylJ (5,7-dtLfluoro-Na-indazol-3-yl) amine (11-29): c Prepared in 58% yield. 'LHNMR (500 MHz, DMSO) 8 2.47 (3H, sLO2.66 (3H, 7.44 (2H, 7.53 (in, 7.64 (3H, 10.4 (IH, 13.8 (11, br a) ppm; HPLC-Method:A, Rt 2.921 min; MS (FIA) 386.1 (M+H) 4 Exa2p. 3Q (2-Chlorophenyl) 6-dimethyl-pyriidin-4yl] (7-fluoro-f-indazol-s-yl) -amine Prepared in yield. 1 NMR (500 MHz, DM50) 512.35 (3H, 2.51 (3H, 7.03 (1HI 4.4 Hz, dt), 7.22 (1H, 7.33 (111, 3=7.4 Hz, 7.42 9.19 JH, 13.3 (3.H, s) ppm; HPLC-Method A, Rt 2.859 min; MS (FIA) 368.2 Exagle 1 (2-Chiorophenyl) 6-dimethyl-pyrinidin-4 ylt-(5-fluoro-1Kf-indazol-3-yl)-amine* (11-31): Prepared in 86% yield. 'HNMR (500 MHz, DMSO) $'2.49 (3H, 2.68 (31, 7.38 (1H, 3=9.0 Hz, 7.54 (211, 7.67 (4H, 10.5 (II, br), 13.2 (11, br a) ppm; HPLC-Method A, Rt 2.850 min; MS (PTA) 368.1 Eamtj 32 [2-(2,4-Dichiorophenyl)-5,6-aimethylpyrimidin-4-ylJ (1--indazol-3-yl) -amine (11-32): Prepared in 521 yield. 'HNMR (500 MHz, DMSO) 5 2.46 (3H, 2.64 -261- IND(3H, 7.16 (1H, J=7.5 Hz, 7.46 (3H, 0=7.6 Hz, t), 7.61 (2H, 7.68 (2H, 3=8.2 Hz, 7.82 10.2 (131, br), 13.'0 br S) ppm; HPLC-Method A, Rt 2.983 min; MS (FMl) 384.1 0 tn~le 33 (5-Methyl-2H-pyrazol-3-yl)-12-(2methylphenyl)-quinazolin-4-yl]-enin'e (11-33): 1 HNMR (DMSO) 1.21 (3H,s),-2.25 (3H, 6.53 (11, 7.38 (4H, m), 7.62 7.73 (1W, 7.81 (13, 7.89 (13, t), 8.70 (111, 12.20 (1H, MS 316.3 Hxalle '34 (2-(2,4-Difluorophenyl)-quinazolin-4-y1]-(5 methyl-2H-pyrazol-3-yl)-anine (11-34): 'HNMR (500 MHz,- DMSO-d6) 812.4 (br a, 131), 10.8 (br s, 8.58 1H1), 7.97 1H), 8.3'6 1H), 7.85 1H), 7.60 1H), 6.62 1H), 2.30 3H); MS 338.07 Eample 35 (2,5-Diiethoxyphenyl) -quinazolin-4-ylJ 3.

iethyl-2H-pyrazol-3-yl)-amine (11-35): 'NMR (500 MHz, *DMSO-d6) 812.5 (br s, 1H), 8.68'(br, 13), 7.92 J Hz, 1H), 7.86 J 8.2 Hz, 13), 7.65 Hz, 13), 7.45 1H), 7.14 Cm, 2H), 6.51 1H), 3".79 3H), 3.67 3H), 2.14 3H); MS 362.2 £xamnle 36 [2-(2-Chiorophenyl) -quinazolin-4-ylI- methyl-20-pyrazol-3-yl)-amine (11-36): 'IHNMR (500 MHz, DMSO-dE) 511.8 (br, 13), l80 3 8.3 Hz, 13), 8.00 Ct, 3 7.6 Hz, 13), 7.82 J 8.3 Hz, 1H), 7.78 (m, 7.67dd 3 7.8 Hz, 13), 7.61 J =7.0 Hz, 13), 7.55 1 7.4 Hz, 13), 6.56 lk), 2.18 3H); MS 336.1 -262- Va oN 1xamle 37 (2 -Methoxyphenyl) -quaazolin-4-ylJ 0~ methyl-25-pyrazol-3-yl)-&mine (11-37): 'HNR (500 Hz, DMSO-d) 88.78 br, IH), 8.00 J 7.4 Hz, IH), .7.90 2H), 7.74 J 7.5 Hz, IH), 7.63 Ct, J 7.3 Hz, 7.30 Cd, J 8.4 Hz, 1H), 7.18 J 7.5 Hz, 1H), '6.58- br, IH, 3.90 3H), 2.21 Cs, 3H); MS IND .332.1 o rnJ.e 3 6-Dimethylphenyl) -quinazolin-4-yl] IND 10 methyl-23-pyrazol-3-yl)-amine. (11-38): HNMR (500 MHz, DMSO-d6) 812.2 br, 2H), 8.88 J7 7.7 Hz, 1H), 8.05 J 7.7 Hz, 1H), 7.80 7.37 J 7.6 Hz, 1H), 7.21 J 7.7 Hz, 2H), 6.36 11), 2.16 (s, 3H), 2.15 6H); MS 330.1 Example 39 [2-(2-Acetyiphenyl) -qiinazolin-4-yl]- methyl-2H-pyrazol-3-yi)-amine (11-39) IHfMR. (500 MHZ, DMSO-dG) 512.35 br, 110, 8.93 Cd, J 8.4 Hz, 1), 8.37 J 8.6 Hz, IH), 8.20 3 Hz, 1H), 8.11 J 8.0 Hz, 2H), 7.89 Cm, 2H), 7.77 2H), 6.93 Cs, 11), 2.33 3H), 2.04 3H) MS 344.1 Bgpje 4Q (2,3-Dimethyiphenyl) -quinazolin-4-yl]- CSmethyl-2H-pyrazol-3-yl)-amine (11-46): 1 HNMR (500 MHz; DMSO-d) 812.6 Cs, br, 1H), 12.1 br, 11), 8.91 J- 7.7 Hz, 1H), 8.14 Ct, OT 7.2 Hz, 1H), 7.95 8.4 Hz, 1H), 7.89 Ct, J7 7.7 Hz, 1H), 7.58 J 7.6 Hz, 1H), 7.53 Cd, J 7.0 Hz, 1K), 7.42- Ct, J 7.6 Hz, 1H), 6.60 11), 2.43 Cs, 31), 2.35 Cs, 31), 2.32 3H); MS 330.1 ExamJle&1 C5-Ethyli-2H-pyrazol-3-yl)-[2-(2trifluoromethylphenyl) -quinazoiin-4-yl -amine (11-41): -263- I'1flHM (500 MHz, DMSO-d6) 812.3 1H), 10.5 s, 1K), o 8.77 8.2 Hz, 1H), 7.92 2H), 7.85 3H), 7.56' J 8.1 Hz, 110, 7.67 J 7.4 Hz, 1K), 6.63 1H), 2.27 3H); MS 370.1L(M+H).

Ep~Mle 42 (2-Ethyiphenyl) -quinazolin-4-yll 2O 2H-pyrazol-3-yl)-azdne (11-42): -'HNKI (500 MHz, DMSO-dE) 8.8.80 1K), 8.02 br, 7.82 J 8.4,Hz, 1 7.77 1K), 7.62 Cd, 7.6* Hz, 1H), 7.54 (m, INO 10 7.41 Cm, 2H), 6.40 1H), 2.75 c, J 7.1 Hz, 2H), 2.17 0.99 CtJ =7.5 Hz, MS 330.1 Exnn&..a 43 (2-Biphenyl-2-yl-quinazolin-4-yl).-(5-methyl- IS 20-pyrazol-3-yl)-amine (11-43): 1 }HM4 (500 1Hz, DMSO-d6) 5'8.76 J= 7.6 Hz, IH), 8.04 Cm, 1K), 7.75 Cm, 6H), 7.30 Cm, SH), 5.34 1H), 2.14 3H); MS 378.2 ]-Rxarmp2&,44 (2-Hydxioxypheny1) -quinazolin-4-yl] Methyl-2H-pyrazol-3-yl)-amine (11-414): 1 fflMR (500 MHz, DMSO-d6) 510.9 Er, 1K), 8.62 J 8.2 Hz, .1H), 8.28 J 7.9 Hz, 1K), 7.87 7.60 J 7.9 Hz, 11), 7.37 Ct, J 7.8 Hz, IH), 6.92 im, 2H), 6.45.Cs, 1H), 2.27 3);LMS 318.1 Znmpln 45 [2-(2-Ethoyphenyl) -quinazolin-4-ylJ- Kthyl-2H-pyrazol-3-y1) -amine (11-45): 3RN1' (500 MHz, DMSO-dE) 812.1 Er, 1H), 8.75 Cd, J 8.3 Hz, 1H) 7.97 J 7.8 Hz, 1H),,7.82 J 8.3'Hz, 1K), 7.78 7.5,Hz, 1K), 7.70'(t, J 7.8 Hz, 1K), 7.56 Ct, 3 7.8 Hz, 1H), 7.22 d, 3 8.4 Hz, 1H), 7.12 Ct, J =7.6 Hz, 1K),6.55 Cs, 1K), 4.11 J 6.9 Hz, 21), 2.16 Cs, 3H), 1.22 Ct, J 6.9Hz, 3H); MS 346.1.CM+H).

-264- 0 ~SMSi2§hA46 (Thiophen-2-yl) -25-pyrazal-3-ylJ (2tl~aJUmuaty.lpaenyl) -qwxnazoL2n-4 'y31-amine (11-46).: 1 'jWpM (500 MHz, DMSO-dS) 88.04 J 8,.3 Hz, 1H), 8.05 (dd, J 8.2 Hz, IH), 7.93 J 6.5 Hz, 111), 7'.81 (mn, SH) 7. 34 J 5.0o Hz, 1W) 7. 25 (mn, 1W), 7. 00 (mi, IND IH), 6.87 1W); MS 438.1 (14+1).

o Exampl4 (Th~iophen-2-yl) -2RT-pyrazol-3-ylJ (2- IND 10 trifluoromethylphenyl) -qiazolin-4- yl] -amiLne (11-47): o Prepared according to-method.B. 'HMqlg (500MHz, 3DMSOr'dG) a 6.97 (in, iN); 7.08 (mn, iN), 7.27 iN), 7.36 (In,1), 7.66 (in, 2H), 7.77 (in, 3W), 7.83 lW), 8.00 (i,1H), 8.18 111), 8.62.(d, J 8.2 Hz, 1H), 10.7 IW); El-MS 438.1 HPLC-Method A, Rt 2.97 min.

B~amlJ&48 (4-Phenyl-23-pyrazoi-3-yl) (2trifluoromethyiphenyl) -quiinazolin-4'-ylJ -amine (11-48): Prepared according to Method B. 1 WNNR,(50014Hz, DMSO-d6) 8 7.05 (br. a, 1W), 7.14 7.8 Hz, 1H), 7.25 (in, 3H), 7.43 (mn, 2H), 7.60 (mn, 2H1), 7.73 (mn, 2H1), 7.80 111), .7.95 (mn, 8.12 (br. s, 1W), 8.60 (mn, 1W) 10. 6 (br.

s, 1WH); El-MS 432.2 HPLC-Method A, Rt 3..04 mnin.- BxamnpJ&49- (5-tert-Eutyl-23-pyrazol-3-yl) (2trifluoromethyl-phenyl) -quinazoltn-4-yiJ -amine (11-49)- 1 1NR@H (500 MHz, DMSO-dE) S 8.76 J 8. Hz, 1W) 7.94 (i2H1), 7. 79 (mn, 4H), 7. 70 1 7. 6.Hz, 1W), 6. 51 (a, IW) 1. 16. 910; MS 412.2 (Mi-f) -Pxa..iQ 5 (5-Phenyl-2H-pyrazol-3-fl) (2trifluoronethyiphenyl) -quinazoliLn-4 -yll -amine (11-50): 'HNMR (50014Hz, DMSO-dE) 8 7.09 iN), 7.36 (td, J 7.8, -265- IND 1.1 Hz, 1H), 7.46 Ct, J 7.8 Hz, 2H) 7.65 (br. d, J 8.1 Hz, 2H), 7.78 Cm, 2H), 7.90 Cm, 4H), 7.95 Cd, J 7.7 Hz, AH), .8.00 t, J .7.8 Hz, 1K), 8.81 Cd, J 8.6 Hz, 1H), 11.29 Cbr. s, 1K); El-MS 432.J HPLC-MethodA, Rt 3.24 min.

oje 5 (4,5-Diphenyl-20-pyrazol-3-yl) (2trifluoromethylphenyl) -quinazolin-4-yl -amine (11-51):

H

1 6mq (5001Hz, DMSO-d) 8 7.13 111), 7.18 5H), 7.36 Cm, 51), 7.62 7.73 Cm, 7.85 1K), 8.48 J Hz, 11), 10.02 Cs, lH), 13.19 IH); El-MS Ci 508.2 HPLC-Method A, Rt 3.39 min.

nct.=12 52 (4 -Carb amoyl-2Hf-pyrazol-3-yl) (2- 'trifluoromethyphenyl) -quinazolin-4-yl]-amine (11-52): Prepared in 40% yield. 'HNMR (50OMHz., fMSO-dE): 8 12.85 12.77 iN), 11.80 1K), 10.80 1), 8.35-7.42 9H); MS 399.13 (M+H)Y HPLC-Metbod A, Rt 2.782 rin.

Exapw 53 (20-Pyrazol-3-yl) 12- (2trifluoromethylpheny) -quinazolin-4-ylJ -amine (11-53): Prepared in 38% yield. 'HNMR (500 MHz, DMSO-d) 8 12.52 1K), .10.65 1H), 8.75 1K), 7.91-7.68 Cm, 8H), 6.87 Cs, 1H). MS: CM+H) 356.17. HPLC-Method A, at 2.798 min.

nri..e 54 (5-Hydroy-2-pyrasol-3-yl)-[2-(2 trifluoromethyphenyl)- qunazolin-4-ylJ-aine (11-54): Prepared in 36% yield; t HIIR (500 Mz, DMSO-d6) 8 10.61 Cs, iN), 8.75 Cs, 110, 8.03-7.75 9H), 5.97 1H); MS 372.18 HPLC-Method 2.766:min -266-

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o xauDe 5 (5-Cyclopropyl-2-pyrazol-.3-yl) (2- 0~ trifluoromethyl-phenyl) -quinazolin-4-ylJ -amine .(11-55): Prepared in 30% 'yield. 1 }fNMR (500 MHz, DMSO-dl 812.21 IS, iM), 10.45 la), 8.68. 7.89-7.45 Cm, OH), 6.48 1H), 0.89 Cm, 2H); 0.62 Cs, 2H). MS 396.18 HPLC-Method A, Rt 3.069 min.

Va enxtle 56 (5-Metboxymethyl-2H-pyrazol-3-yl) (2trifluoromethyl-phenyl) -quinazolin-4-y1 -amine 1-56): IND 10 Prepared in 33W yield; 1NMR. (500 MHz, DMSO-d) 8 12.51 o Cs, 1H), 10.48 Cs, 8.60 111), 7.81-7.55 Cm, 6.71 1H), 4.28 Cs, 2H), 3.18 Cs,-3H). MS 400.19 HPLC-Method A, Rt 2.881 min.

E2le 52 (lf-indazol-3-yl) 12- (2-trifluoromethylphenyl) -quinazolin-4-yl] -amine (11-57): Prepared to afford 51 mg (78% yield) as pale yellow solid. fHNMR (500 MHz, DMSO-d) 812.7 1H), 10.4 1H), 8.55 1H), 7.81 IN), 7.71 Cd, 32), 7.61 1N), 7.58 IN), 7.46 4H), 7.36 1d, 11), 7.22 Ct, 1H), 6.91 IN) ppm; LC-MS (ESi) 406.16 (MtH), 404.19 HPLC- Method A, Rt 3.00 min.

Exampte 5 (4-Chloro-1B-undazol-3-yl)- (2trifluoromethyl-phdnyl) -qulnazolin-4-yl -amine (11-58): Prepared in DMF (70% yield) as pale.yellow solid. 'HNMR (500 MHz, DMSO-d) 813.3 Cs, br, 11), 10.9 br, 1H), 8.60 11), 7.97 1H), 7.81 (d 1H), 7.75 iN), 7.67 1H), 7.63 (dA, 1H), 7.57 Cm, 7.43 Cd, 1N), 7;28 (dd, iN), 7.08 Cd, IN) ppm; LC-MS (ESt) 440.10 CM+H), 438.12 HPLC-Method A, Rt 3.08 min.

-267- Ramolo- (5-Fluoro-1H-indaol-3-yl).- (2trifluoromethyl-pheiayl) -quinazolin-4-ylJ -amine (11-59): Prepared in DMF (34W yield) as pale yellow solid. 'H)ZMR (500 MHz, DMSO-d6) 813.0 3H), 10.6 1H), 8.72 (d, S iN), 7.99 Ct, 1W), 7.89. d, 1W), 7.79 Id, 7.75 Ct, 1H), 7.68 3H), 7.56 (dd, 7.39 iH), 7.28 (t, in) ppm; LC7MS 424.12 r/em 422.13 (M- HPLC-Method A, Rt 3.05'min.

Eraj le SQ (7-Fluoro-1-indazol-3-yl) (2trifluoromethyl-pbanyl)-qninasolin-4-yl-amine (11-60): Prepared in DMF (51% yield) as yellow solid. 'fMR (500 MHz, DMSO-dE) 813.4 1W), 10.6 Cs, 13), 8.68 1H), 7.95 t, 11),7.85 lW), 7.72 2H), 7.63 2H), 7.58 7.43 7.18 (dd, 1W), 7.00 1H) ppm; LC-MS (ESi) 424.11 CM+H), 422.15 WPLC- Method A, Rt 3.06 min.

Examnp I1 (5-Kethyl-lH-indazol-3-yl) (2trifluoromethyl-phenyl) -quiniazolin-4-yl] -amine (11-61): Prepared in DMF (811 yield) as yellow solid. 1HNMR (500.

MHz, DMSO-d) 81310 br, 3H), 8.79 Cbr, 6.11- (br, 13), 7.96 3W), 7,82 5H), 7.4t 7.41 (d, 1H), 7.20 13), 2.33 3H) ppm;'MS.ESt) 420.15 CM+H), 418.17 HPLC-Metbod A, 'Rt 3.07 min.

ianlte 62 6-Dichloro-phenyl)-quinazolin-4-yll fluoro-1H-indazol-3-yl)-amine (X1-62): PrepareO in DM (37% yield) as yellow solid. tffljy (500 MHz, DMSO-G6) 813.0 1H), 10.8 iN), 8.72 7.97 1W), 7.90 110, 7.75 IW), 7.53 Cm, 3H), 7.43 1H), 7.35 1H), 7.23 Ct, 1H) ppm; LCMS (ESt) 424.08 422.10 HPLC-Method'A, Et 3.06 min.

-268- Va o Exame-3 (2-Chloro-phenyl) -quinazolin-4-ylI indazol-3-yl)rmine (11-63): Prepared in 91W yield. 1HNMR 4 (500MHz, DMSO-d6) 8 7.06 t, 7.36 t, lIH, 7.39 (t, 1H), 7.52 (tm, 3H), 7.62 Cd, IN), 7.'72 1H), 7.82 (m, iN), 7.90 1H), 8.05 iN), 8.76 iN), 11.5 (m, IND 1H), 13.02 1H); El-MS 372.1 (M NPLC-Method A, Rt: 0\ CC) 2.93 min.

10 Exap.le 64 (5-Trifluoromethyl-1a-indazol-3-yl)-[2-(2trifluoromethyl-phenyl) -qnnazolin-4-yl amine (11-64): Prepared in flMF'(57% yield) as yellowsolid. "HNMR (500 MHz, DMSO-dC) 813.4 br, 1H), 11.4 (br, IH), 8.72 (a, 1H), 8.12 Cs, 11), 7.98 t, 3H, 7.83 iH), 7.76 (d, lH), 7.73 (dd, 1H), 7.60 4H), 7.52 1H) ppm; LC-MS 474.12 (MiH), 472.17 HPLC-Method A, Rt 3.25 min.

Exaple (5 (4-Trifluoromethyl-1l-indazo1-3-y1) trifluoromethyl-phenyl)-quinazolin-4-yl] -amine (11-65): Prepared in DMP yield) as yellow solid., 'NNMR (500 MHz, DMSO-d) 813.7 br, 1H), 11.2 Cbr, 1H), -8.70 (d, 1H), 8.05 110, 7.85 3H), 7.65 4H), 7.51 Cm, 2H) ppm; LC-MS'(ES+) 474.13 472.17 CM-H); HPLC-Method A, Rt 3.15 min.

Enam e 6[ 12- (2,6-Diclloro-phenyl) -quinazolin-4-yl]- (Xindazol-3-yl) -amine (11-66): Prepared in DMP (30% yield) as yellow solid. lHM14 (500 MHz, DMSO-d6) 812.9 11), 11.1 Cs, I-1, 8.69 1H), 7.95 7.82 1), -7.73 Ct, 110, 7.56 Cd, 1j, 7.47 Cs, 11), 7.45 21), 7.39 7.26 lH), 6.92 Ct, 1H) ppm; LC-MS (ES+) -269- IO 406.11 404.12 HPLC-Method A; Rt 3.00 imin.

xample 67 (H-indasol-3-yl)-[2- (2-methyl-phenyl) quinazolin-4-yl] -amine (11-67): Prepared in 55% yield.

0 1 EMRe (500MHz; DEMSO-d6) 6 2.15 (8s, 3H), 7.09 1H), 7.26 IND IH), 7.31 1H), 7.39 1H),7.42 In), 7.55 C (d IH), 7.64 7.74 1H), 7.89 1H), 7.96 21), 8.10 1H), 8.81.(d, 1H), 12.0 1H), 13.18 1i); EI-MS 352.2 HPLC-Method A, Rt 2.93 min.

NO'

c kxample s68 (7-Trifluoromethyl-1s-indazol-3-y) 2-(2trifluoromethyl-phenyl)-quinazolin-4-ylJ-amine. (11-68): Prepared in DMF (75% yield) as yellow solid. mfHNMR (500 MHz, DMSO-d 813.5 br, 1i), 11.2 br, IH), 8.68 Cd, 1i), 7.97 1H), 7.92 1H), 7.82 7.74 1H), 7.70'(d, 1H), 7.68 1H), 7.64 2H), 7.57 1H), 7.14 1K) ppm; LC-MS 474.11 472.14 .HPLC-Method A, kt 3.24 min.

Rxa=mle 69 (6-Trifluoromethyl-1a-indazol-3-yl) trifluoromethyl-phenyl)-quinazolin-4-yl -amine (11-69): Prepared by Method B in DMF (78% yield) as yellow solid.

1 HNR (500 MHz, DMSO-d6) 8 13.4 br, 1H), 11.1 br, 1i), 8.67 1H), 7.95 1H), 7.82 3H), 7.72 (m, 2H), 7.63 Am, 2H), 7.57 1H), 7.23 1H) ppm; LC-MS 474.12 472.15 HPLC-Method A, Rt 3.28 min.

Examlte 70 (5-Nitro-1l-indazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yl]-amine (11-70): Prepared in.DMF (82% yield) as yellow solid. 1 HNMR (500 MHz, DMSO-d6) 813.6 br, 1H),11.4 br, 1K), 8.75 -270- Va o 1H), 8.72 iH), 8.09 (dd, 111), 7.98 7.83 0 1H), 7.75 1H), 7.70 (in, 2H), 7.61 3H) ppm; LC-MS 451.14 449.12 HPLC-Method A, Rt 3.02 min.

0S xample 71 (5,7-Difluoro-1a-indazol-3-yl)-[2-(2- ID trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (11-71): CC) Prepared in DMF (60% yield) as yellow solid. 'IfMR (500 o MHz, DMSO-d6) 813.7 br, 1H), 11.2 br, 1H), 8.73 ID 10 Cd, 1H), 8.03 IE), 7.88 1H), 7.80 2H), 7.70 3H), 7.32 2H) ppm; LC-MS 442.14 (ES- 440.14 HPLC-Method A, Rt 3.11 min.

Bmale 722 (4-Pyrrol-1-yl-2- indazol-3-yl) trifluoromethyl-phenyl) -quinazolin-4-yl] -nine (11-72): Prepared in DMF (33% yield) as yellow solid. 'lMdR (500 MHz, DMSO-d6) 813.4 br, 1H), 11.0 br, lH), 8.53 IH), 7.98 11), 7.75 4H), 7.62 2H), 7.52 11H), 7.43 1H), 7.05 1H), 6.80(s, 21), 5.61 2H) ppm; LC-MS (ES+).471.18 469.18 (M- HPLC-Method A, Rt 3.12 min.

Examle 73 (5-Aipno1-if.ndazol:-3-yl)- [2 (2trifluoromethyl-phenyl) -quinazolin-4-yl amine (11-73): A solution of compound 1-1-70 (70 mg, 0.16 rmiol) in MeOH (2 mL) was treated with Raney Ni until solution was colorless (about 1.5 g Raney Ni was added). After stirring at room temperature for 40 mit, the mixture was filtered through celite, the resulting celite was washed with MeOH (5 times), and the solvent was evaporated in vacuo to provide a crude.product that was then purified by HPLC to give the title compound as a yellow solid mg, m.p. 221-223C; 1 HNMR (500 MHz, DMSO-d6) -271- 813.2 Cs, br, IH), 10.7 br, 1H),.9.80 2H), 8.68 o Cd, IH), 7.97 Ct, in), 7.87 Cd, 7.75 Cm, 2H), 7.65 Cm, 5H), 7.30.(d, 1H) ppm; MS CES4) 421.16 (ES-) '419.17 HPLC-Metod A, Rt 2.41 min.

Eimtle 74 12- (2-Chloro-phenyl) -quinazolin-4-yl] fluoro-22-indazol-3-yl) -amine (11-74): Prepared in DMF.

(351 yield) as yeilow solid. 'HMqm (500 MHz, DMSO-d6) 813.7 1H), 11.7 Cs, br, lI), 8180 IH), 8.15 (t, lH), 7.99 7.88 1H),,7.68 Cd, 7.60 f o 2H), 7.53 t, 1H), 7.46 1H), 7.25 dd, 1H), 7.04 (m, CiH) ppm; LC-MS 390.16 HPLC-Metbod A, Rt 3.00 min.

xamp1e5 12- (2-.Chioro-phenyl) -quinazolin-4-yl (5 fluoro- f2-indazol-3-yl) -amine (11-75): Prepared in DM1.

HN MR (500 MHz, DMSO-d6) 813.2 Cs, lU), 11.7 br, 1H), 8.80 iH), 8.10 Ct, 1H), 7.91 Cm, 2H), 7.70 IH), 7.58 41), 7.50 t, 1H), 7.29 t, I11) ppm; LC-MS CES+) 390.17 HPLC-Method A, Rt 3.00 min.

Exn Le 2j 2- (2-Chioro-phenyl) -qunazoli-4-ylJ difluoro-lH-indazol-3-yl) -amine (11-76): Prepared in DM' yield)-as yellow solid. 'mD&R (500 MHz, DMSO-d) 813.8 3H),f11.5 br, IH), 8.76 iN), 8.08 1N), 7.93 1H), 7.84 Ct, LU), 7.64 Cd,.1H), 7.55 (d, 1H), 7.50 Ct, IHf, 7.44 2H), 7.36 1H) ppm; LC-MS CES+) 408.15 406.17 HPLC-Method A, Rt 3.08 min.

iExailte 77 2-Chlbro-phenyl) -quinazolin-i-yi]- trifluorometbyl-1H-indazol-3-yl) -amine (11-77): Prepared in DM1 (66% yield) as yellow solid. 1HN1R (500 MHz, DMSO- -272-

IN

d6) 813.5 111), 11.4 br, .8.79 1H), 8.29 0 1H), 8.07 7.93 7.84 iN), .7.72 1H), 7.63' d, 2H), 7.53 7.48 Ct, 1M),'7.36 111) ppm; LC-MS m/e= 440.16 m/e= 438.18 CM-H); HPLC-Method A, Re 3.22 min.

a ~swRaIul 78 [2 -(2-cyano-phenyl) -quinazolin-4-yl]- (1n findazol-3-yl)-amine Prepared in 13% yield. '1- NW (500 MHz, DM80) 8 12.9 (br, 1H1), 10.8 (br, 11), 8.73 (br a, H) 7.97 Cm, 4H), 7.74 1H), 7.5 4H), 7.42 o Cm, 7.08 lH) ppm; MS (PtA)'363.2 HPLC- Method A, -Rt 2.971 min.

Exam2e 79 (5-Broio-1E- indazol-3-yl) (2trifluoromethyl-phenyl). -quinazolin-4-jrl] -amine (11-79): Prepared in DMF (64% yield) as yellow solid. 'HNMR (50.0 MHz, DMSO-d6) 813.4 1H), 11.6 Cs, br, 1W), 8.93 (d, iH), 8.21 1H), 8.14 Cs, in), 8.05 1H, 7.95 (m, 4H), 7.86 Ct, l2), 7.65 1H), 7.59 Cd, 1W) ppm; MS (ES) 486.10 CM+H), 484.09 HPLC-Method A, Rt 3.22 min.

Examle 80 (G-Chloro-1I-indazol-3-yl)- trifluoromethyl-phepyl) -,quinazdlin-4-yl -amine. (11-80) r Prepared in DMF (94% yield) as yellow solid. 1 INMx (500 MHz, DMSO-dE) 813.1 1W), 11.2 Cs, br, 1H), 8.73 (d, 1H), 8.03 Ct, 11), 7.87 1H), 7.79 2H), 7.73 (m, 2H), 7.67 211), 7.58 Cs, 1W), 7.04 (dd, 1H) ppm. LC-MS (ES) 440.14 438.16 CM-H); WPL-Method A, Rt 3.25 min.

BXxmV-f& 81 (7-Fluoro-6-trifluorometlhyl -1f-indazol-3-yl)- (2-trifluoroiethyl-phenyl) -quina.olin-4-yll -amine (I- -273- IND 81): Prepared in DMP (30% yield) as yellow solid. 'HNMR o (500 MHz, DMSO-d) 813.9 11), 11.0 br, 1H), 8.64 11) 7.94 1H), 7.81 111), 7.71 Cm, 2H), 7.60 4H), 7.20 (dd, 11) ppm. LC-MS 492.18 490.18 CM-H); HPLC-Method A, Rt 3.44 min.

I NDn J&.a8 (6-Eromo-1a- ndazol-3."yl) (2trifluoromethyl-phenyl) -quinazolin-4-ylJ -amine (1-82): Prepared in DMF (40% yield) as yellow solid. 1 HMR 3.o MHz, DMSO-d6) 513.1 11), 11.2 S. br, IH), 8.73 (d, o 1H), 8.03 1H),.7.87 lH), 7.80 21), .7.73 (m, 3H), 7.67 1H), 7.61 1H), 7iS (dd, 11) ppm; MS 486.07 H PLC-tethod A, at 3.28 min.

ExamnTlei E2- (2,4-Bis-trifluoromethyl-phenyl) quinazolin-4-yl (5,7-difluoro-1H-iiadazol-3-yl) -amine (11-83): Prepared in DMP in 28% yield. 'Hl (500MHz, MeO%-d4) 'S 8.81 J=8.4Hz, 1H), 8235-8.20 3H), 8.19-7.96' 31), 7.40-7.34 Cm, 11), 7.29-7.14 Cm, IH); LC-MS (ESi) 510.14 (MiH); HPLC-Method C, at 8.29 min.

mxapJ 84 (5,7-Difluoro-1B-indazol-3-yl) (4-fluoro-2trifluoromethyl-phenyl) -quinazolin-4-ylJ -amine (11-84): Prepared in 48% yield. 1 HNMR (500MHz, MeOH-d4) 88.74- 8.63 Cm, 11), 8.23-8.10 11), 7.99-7.90 21), 7.89- 7.80 1H), 7.71-7.61 7.61-7.50 11), 7.24- 7.15 IN), 7.14-7.02 (76, 11); LC-,MS 460.14 HPLC-Method C, Rt 7.59 min.

92arle Q-5 (2-Bromo-phenyl) -quinazblin-4-y13 (5,7 difluoro-1E-indazol-3-yl)-amine Prepared in THY (21% yield). 1 HjNM (500MHz, MeOH-d4) 68.81 d, J=8.4Hz, I1), 8.35-8.20 C Am, 8.19-7.96 31), 7.40-7.34 (m, -274iH), 7.29-7.14 Cm, 1H); LC-MS (ESt) 510.14 (M+H);.HPLCo Method C, R 8.29 min.

Ex&te §6 (5,7-Difluoro-1H-indazol-3-yl) (5-flnoro-2trifluorometbyl -phenyl)-guinazolin- yll amine (11-86): Prepared in THF (26% yield). 'MM a (500MHz, MeOH-d4) IND88.62 Cd, J=8.4Hz, IN), 8.16-8.02 1H), 7.96-7.73 (m, 3H), 7.59-7.48-m, 1H), 7.48-7.35 1H), 7.21-7.09 (m, o 11), 7.09-6.89 111); LC-MS 460.16 HPLC- Method C, R 7.28 min.

Examle (2,4-Dichioro-phenyl) -quinazoiin-4-yiJ (5,7-Difluoro-iEF-indazol-3-yl) -amine (11-87): Prepared' in TH' (16% yield), 'IVNMR (500MHz, MeOH-d4) 88.81 (d, J=8.4Hz, 1H), 8.35-8.20 3H), 8.19-7.96 3H), 7.40- 7.34 7.29-7.14 iii); LC-MS 510.14 HPLC-Ijethod C, Rt 8.29 man.

ltie 88 [2-(2-Chloro-5-trifluoroiethyl-phenyl)quinazolin-4-ylJ 7-Difluoro- L-indazol-3 -yl) -amine Prepared in THE' (33% yield). 1 HNMR (500MHz, fMSO-dg) 8 10.76 1H), 8.66 J=B.31z, 1H1, 8.06- 7.84 3H), 7.81-7.63 3H), 7.48-7.16 2H); L;C-MS (ESi) 476.16 HPLC-Method C, Rt 19.28 min.

Pxamle 89- (4-Fluoro-I.H-indazol-3-yl) (2trifluoroiethyl-phenyl) -quinazolin-4-ylJ-amine (11-89): Prepared in NMP (79W yield) as yellow solid. HNMR (500 MHz, DMSO-d) 813.2 Cs, 1H), 10.8 br, UH), 8.63 (d, 7.97 11), 7.85 7..74-m, 21), 7.64 (t, 11), 7.57 21), 7.32 2H), 6.82 11) ppm; LC-MS' 424.17- NPLC-Method A, Rt 3.14 min.

-275- IND kxaMp1_e.2Q(1Ei-Indazal-3-yl) [-methoxy-2- o trifluoromethyl-phenyl) -guinazolin-4-ylJ -amine (11-90): PrepaLred using TEE as solvent to afford the title compound as a TEA salt (23% yield). HPLC-Method A, Rt 2.97 min 1 m-HR (DISO-dE, 500.14112)8 12.9 (111, ba), 11.0 0 10.7(1H,.bs), 8.25 (1H1, in), 7.75-7.50 (811, 7.30 (in, in), 6.90 (I rn) 1 4.0 !MS 436.2 o J. Examl 91 (5-Fluoro-l.H-indazol-3-yi).- [B-methoxy-2- (2trifluoromethyl-phny1)-ainazojn-4.ylp-aming (11-91): o ~~~Prepared using TEA. as solventtoafrthtil ci compound as a TEA salt'(23%; yield). HPLC-Method A, Rt 3.10- mi. (.99W) '1H2U (DMSO-dG, 500, Mflz): 13. 0 (1H1, bs), 11.0 -10.7(111, bs), 8.25 (IH, in), 7.75-7.50 17H1, mn), 7.35 (iii, mn), 7.25 (IN, in), 4-.0 (311, MS 454.2 (M+aH).

Exwle9 (7-Fluoro-J1n-indazoi-3-yl) -C8-iethoxy-2- (2triLfiuoromethyl-phenyl) -quinazolin-4-yi] -amine (11-92): Prepared using THE as solvent to afford the title compound as a TEA salt (98 mng, 58% yield). HPLC-Method A, Rt 3.20 min (92W); 'HNI4R (DMSO-d,. 500 MU~z) 813.45 (111, bs),.11.0 10.7(111, bs),.8.25 (iH, in), 7.75-7.60.

(SH, mn), 7. 50 (111, in), 7.40 (111, 7.15 (111, in), 6.95 (IN1, mn) 4.0 (3H1, MS 454.2.(M+H).

Eample.9Z (5,7-Difluoro-ln-indazol-3-yl) -[8-inethoxy-2- (2-trifluoromethyl.-phenyl) -quinazolin-4-y3ll-amine.

(I-

93): Prepared using THE as solvent to afford the title compound'as a TPA salt (36% yield). 'HPLC-Method A, Rt 3.27 min. (95t); 'IMR (DMSo-d6, 500.MHz): 13.65 (121, bs), 11.0 -10.7(111, bs), 8.22 (1H1, mn), !,.75-7.60 (5H1, mn), -276- Va 7.40 (lB, 7.35 (lI, 7.19 4.0 (3H, MS 0~ 472.2 £xamole 94 (2-Chloro-pyridin-3 -yl) -quinazolin-4-yl]- (5,7-D:Lfluoro-1H-indazol-3-yl)-amine (11-44): Prepared in DMF. 1 LHNMR (5001Hz, DMSQ-d6) 8 13.62 (br s, 11.06-.

IND10.71 1H), 8.16-7.70 4H), 7.60-7.09 31); LC- MS 409.14 EPLC-Method A, Rt 2.89 min.

92paDe 2a (2-Chloro-4-nitro-phenyl) -quinazolin-4-yl] (5,7-difluoro-1H-indazol-3-yl) -amine (11-95): Prepared in THF. HNMR (5001Hz, DMSO-dE) 8 13.35 1H1), 10.74 (s, 1H), 8.67 J8.4Hz, lH), 8.29 J=2.OSHz, 1H)j *8.18- 8.08 1H), 8.07-7.60 4H), 7.53-7.10 2H). LC-, MS 453.15 (M+H) 7 HPLC-Method D, Rt 3.63 min.

Exmpje 96 12- (4 -Amino-2 -chioro-phenyl) -quinazolin-4 -yll (5,7-Diflnoro-1M-indazol-3-yl)-amine (11-96): A solution of compound 11-95 (8mg, 0.Ol8mmol) and-tin chloride dihydrate (22mg, 0.limol) in ethanol (2mL) was heated at 100CC for 24h. The reaction was diluted with EtOAc (lOmL, washed with IN NaOH solution (2xlOiL), brine, and dried over nhydrous sodium Buif ate to afford the crude product. Purification was achieved by flash chromatography on silica gel (eluting with 1-3% MeOH in

CH

2 C1 2 The title compound was isolated as pale yellow solid (1.2mg, 16% yield). LC-MS 423.12 HPLC-Method C, at 13.78 min.

Exa=e 22 (4,5,6,7-Tetrahyro-1 -indazol-3-yl) -[2-(2-trifluoromethyl-phnyl) -quinazolin-4-yl]-amine (11-97):..Prepared in 34W yield. '1HNMR (5001Hz, DMSO-d6) S 1.58 1.66 2.24 21), 2.54 (in 2H), -277- IND 7.63 3H), 7.71 IN), 7.75 1H), 7.78 1K), o 7.85 Ct, 1H), 8.53 1H), 9.99 CB, 1H), 12.09 1H); EI-MS 410.2 KPLC-Mettod A, Rt 3.05 min.

nxamvje 9 (I-Pyratolo pyridin-3-yi) (2trifluoromethy1-phe~yl) -quinazolin-4-yl1-amine (11-98): O Prepared in DM1' (37% yield) as yellow solid. '-HNMR (500 MHz, DMSO-d) 813.1 br, 1H), 11.2 br, 8.73 8.54 (da, 8.12 1K), 8.06 Ct, lB), 7.90 1H), 7.84 Ct, 1K), 7.75 IN), 7.69 2K), 7.65 1H), 7.47 (dd, 11) ppm; C-MS 407.18 CM+H); ci HPLC-Method A, Rt 2.77 min.

Exa=ie t (1-Pyrazolo pyridin-3-yl) (2trifluoromethyl-phenyl) -quinazolin-4.-ylJ -amine (11-99): Prepared in DM (45% yield). 1 KNMR (500 MHz, DMSO-d) 813.5 br, 11.3 Cs, br, JH), 8.78 1H), 8.49 8.17 iH), 8.03 Ct, 1K) 7.89 7.80 2N), 7.74 2H), 7.68 1K), 7.08 (dd, 1H) ppm.

MS 407.16 405.16 CM-N); KPLC-Method A, Rt 2.80 min.

Exampla00 (6-Methyl-LE-pyrazolo[3,4-b pyridin--y) [2- (2-trifiuoromethyl-phenyl) -quinazoiin-4-yl] -amine (II- 100)1: Prepared in DM (11% yield). 1 NNMR (500 MHz, DMSOd6) 813.2 Cs, br, 1K), 10.8 Cs, br, 1H), 8.57 1H), 7.95 1H), 7.82 Cd, 1H), 7.72 Ct, iN), 7.65 2H), 7.58 Cm, 2K), 2.44 Cs, 3H, buried by DMSO), 2.20 3H) ppm. LC-MS 435.22 433.25 CM-K); KPLC- Method A, It 2.94 min.

Rxnpim I 101 (6-Oxo-5-phenyl-s, 6-dihydro-E-pyrazolo [4,3clpyridazin-3-yi)-[2-(2-trlfluoroethyl-phenyl)- -278oquinazolin-4-yl] -amine 11-101:- Prepared in D?'F (6% ci yield). 'HW4R (500 M4Hz, DMSO-d6) 812.6 111), 11.0 a br, 11) 8.60 111), 7.95 IN), 7.88 1H1), 7.80 1H) 7.6.8 (in, 4H1), 7.40 3H), 7.22 211), 6.61.

111) ppm. IC-MS 500.21: 4.98.16 (N- HPLC-Nethod A, Rt 3.00 mini.

en ExampleJ~ 13[6-Methyl-2- (2-trifluoromethory-phenyl) o pyrimidin-4-yl (5-pheniyl-2a-pyrazoi-3-yl) -nine (II- No 10 103): MS 412.13 (141); HPLC-Method H Rt 1.248 mini.

Sxanmn2&JLQ (5-Furan-2-y1-2H-pyrasol-3-yl)- [6-methyl-2- (2 -trifluormetoxy-phenyl) -pyrimidLn- 4-yl] -nine (II- 104), MS 402.12 (14+1) HPLC-Method E, Rt 1.188 mini.

E~~e 0 (6-Ethyl tri fluoromethoxy-phenyl) pyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl) -nine -(XI- 105) MS 364.14 HPLC-Method E, Rt 1.112 mini.

Exampi~l 2- (2-Chioro-phenyl) -pyrido [2 ,3-dJ pyrimidin- 4-yl (5-methyl-2H-pyrazol-3-yl) -amine (11-106): 'HNNR (500 MHz,. DM50) 612.23 111), 10.78 111), 7.73-7.47 (in, 7H1), 6.72 114), 2.21 3H). MS: (M4.1) 337.02.

HPLC-Method. Rt 2.783 min.

amlt.2QZ .(5-Fluoro-1-i-ndazcl-3-yl) (2trifhuoromethyl-phenyl) 7-dlihydro-SEcyalopentapyrinidin-4-ylJ -amine (11-107). Prepared in 68W yield. 1 H1NR (50014Hz, DMS0-dg) 8 2.16 2H1), 2.88 (m, 211), 2.98 Ct, 211), 7.21 (td, 111), 7.29 (dd, 1H1), 7.50 (dd, 3M), 7.65 7.67 111), 7.73 Ct, 111), 7.79 111),,10.22 (br. s, 111), 12.99 (br. 1H1); El-MS 414.2 (14+1) HPLC-Metbhod A, Itt 2.92 miii.

-279- Zm ae 0 (2B-Indazol-3-yl) (2-trifluoromethylpheanyl) -pyrido 3-dJ pyrimidin-4-ylJ -amine (11-108): HPLC-Method A, Rt 2.78 mini. (95W) 1 mqNMR (D)MSO-ds, 500 MHz): 12.95 (1H, be), 11.45 8 11.1.5(1H1, be), .9.20 (2H1, in), 7.85-7.70 (2H1, mn), 7.70-7.55 (4H1, in), 7.50 (1H1, in), 7.35 (111, mn), 7.05 (3-H mn); KS (m/z)'407.03 (Mi-H).

tio trifluorornethyi-;henyl)-;yriaow:3-4]ya 2-

IND

o amine (11-109): Yellow, di-TFA salt (25% yield). HPLC ci (Method A) 3.10 mini. 'IWMR (DMSO-d6, SOO4Uiz): 13.8-13.6 (lx, bs), 11.4 -11.2(111, be), -9.15 (211, in), 7.95-7.7S (2H1, mn), 7.75-7.62 (3H1, 7.32 (2H1, in); KS 442.98 (Mi-H).

Exml 11(2- (2-Chioro-phenyl) -pyrido [2,3-d!]pyriinidin- 4 -yl]-(1B-indazol-3-yl)-amine (11-110): Prepared from 2- -ainuonicoti-nic acid and 2 -cblorobenzoyl chloride afforded the title compound as a di-TPA saltl(28% yield). HPLC- Method A, Rt 2.85 mini. 'HNMR (DMSO-dE, 500 M4Hz): 12.90 (iH, 11.10 10.90 (11H, be), 9.05 (2H, in),, 7.75-7.60 (2H1, mn), 7.51 (111, in), 7.45-7.25 (Sn, mi), 6.95 (1IN, in); MS 372.99(M+fl.

Exsi-le-J1f (5-Fluoro-1H-4-ndazol-3-y) (2trifluoromethyl-phenyl) -5 1 6 1 7,8,94L0-hexahydrocyclooctapyrindiun-4-ylJ -amine (XI-111). Prepared in 43% *yield. 1 Jfq'Nf (500MHz, DMSO-dG) 8 1.46 (rp, 2H) 1.53 (mn, 211), 1.77 (in, 411), 2.95 (mn, 21), 3.04.(mn, 211), 7.22 (in, 211) 7.50 (dd, 111), 7.72 (mn, 3H), 7.80 111), 10.5 in 111), 13. 05 (br e, El-MS 456.2 HPLC-Metbod C, *Rt 11. 93 muin.

-28o-

NO

0 sEampe 112 (2-Chloro-phenyl) -6,7-dibydro-SHcyclopenttpyrmidin-4-yl] (5-flioro-11- indazol-3-yl) amine (11-112): Prepared in 67% yield. 'INM (500MH, DMSO-dG) 82.18 Cm, 2H), 2.89 Cm, 3.02 Ct, 2H), 7.24 (td, 1H), 7.42 2H), 7.49 (td, 7.52 Cdd, 11), 7.54 1H), 7.57 (dd, 1H), 10.50 s, 1H), 13.06 en, (br. s, 1H); El-MS 380.1 HPLC-Method C, Rt 9.68 min.

IND Exampb. 113 (E-Indazol-3-yl) (2-trifluoromethylphenyl) -6,7 dhydro-51-cyclopentapyrimidin-4 -yl] -amine (11-113): Prepared in 37% yield. 1 1-HNMR (500MHz, DMSO-dS) 82.65 Cm, 21), 2.85 21), 2.99 Ct, 2H), 7.02 Ct, 11), 7.32 11), 7.47 12), 7.55 Cd, IH), 7.68 t, 3-H), 7.74 1H), 7.80 1H),*10.37 (br. 12.91 Cbr.

s, 1H); ElI-MS 396.1 HPLC-Method B, Rt 9.88 min.

xaLe 114 (7-Fluoro-1H-indazol-3-yl)r[2-(2trif luoromethyl -phenyl) 6, 7 dihydro cyclopentapyrimidin-4-yl) -amine (11-114)': Prepared in yield. 1 HNMR (500MHz, DMSO-d6) 8 2,i5 Cm, 2H), 2.87 (m, 2.97 t, 2H), 6.99.- (td, IH) .7.17 Cdd,. 1H), 7 .38 (d, 11), 7.65 Cm, 2H), 7.71 1H), 7.78 Cd, 11), 10.21 (br.

a, 11), 13.40 Cbr. a, 1H); E-MS 414.1 HPIC-Method C, Rt 9.99 ain.

pxamale i (5,7-Difluoro-1E-indazol,.3-yl) (2ttifluorozethyl-phenyl)-6,7dihydro-5Rcyclopentapyrimidin-4-yl] -amine (11-115): Prepared according to Method C in 52% yield. 'HNMR (SOOMHz, DMSOd6) 8 2.16 2H), 2.89 2H), 2.97 Ct, 21), 7.19 (dd, 1H), 7.29 (td, 1H), 7.63 Ct, 1H), 7:.66 1H), 7.71 Ct, -281- IND lW), 7.78 11), 10.16 (br. e, 1H), 13.55 (br. s, 1H); EI-MS 432.1 HPLC-Method C, Rt 10.09 min.

ExamPJ&JJ& 12-(2-Chioro-phenyl) ayclopentapyrimidin-4-ylj (T-indazol-3-yl) -amine (11- 116): Prepared in 56% yield. 1iMe4 (500MHz, DMSO-dG) 82.16 2H), 2.85 2H), 3.01 2H), 7.06 1H), 7.34 11), 7.40 1H), 7.48 2H), 7..53 1H), 7.56 1H), 7.63 1H), 10.39 (br. s, 1H), 12.91 (s, El-MS 362.1 HPLC-Method A, Rt 3.09 min.

Ci B &amjle 117 2- (2-Chloro-phenyl) -6,.7-dihydro-5Hcyclopentapyrimidin- 4-yll fluoro- 10- indazol -3 -yl) amine (11-117): Prepared in 63%V yield. 'HNNR DM-d6) 2.15 2H), 2.87 2H), 3.00 2H), 7.01 (td, 1H), 7.19 (dd, 11), 7.39 IH), 7.45 21), 7.51 11), 7.55 1H), 10.35 (br. a, 11), 13.45 (br. a, 1H); El-MS 380.1 HPLC-Method A, Rt Rt 3.15 mim.

xam2le 12- (2-Chloro-phenyl) -6,7-dihydro-50cyclopentapyrimidin-4 -yl] difluoro- 10- indazol-3 -yl) amine (11-118): Prepared in 60% yield. 1 N4M (SOOMHz, DMSO-dE) 2.18 2H), 2.91 2H), 3.01 2H), 7.32 1H), 7.33 (td, 1W), 7.41 7.48 7.53 7.55 (dd, 1H), 10.35 a, 13.45 (br. a, 1H); El-MS 398.1 IPLC-Method A, Rt Rt 3.24 min.

Er 1. (1H-Indazol-3-yl)- (2-trifluoroiethyl phenyl) -5,6,7,B,9,1O-hexahydro-cyciooctapyrinidin-4-y1amine (11-119): Prepared'in-36% yield. 1 HNMR (500Mz, DMSO-dE) 81.47 2H), 1.53 2H), 1.78 4H), 2.96 2H),.3.06 2H), 7.03 7.47 1W), 7.72 11), 7.73 1W), 7.72 3H), 7:81 11), 10.52 -282- (in, 1H), 12.97 (br. a, 1H); El-MS 438..2 HPLCo Method A, Rt 3..37 min.

gp.mflQ 2 7 -Fluoro-IE-indazol-3-ya) 2- (2- .4 5 trifluoromethyl-phenyx) -5,6,7,8,9,10-hexahydro- 0 cyciooctapyrimin-4-yl3 -amine (11-120): Prepared in yield. '1HNMRk (50014Hz, DMSO-d6) 8 1J 46 2H), 1.52 (mn, 2H), 1.77 (mn, 4K), 2.94 (mn, 2H), 3.04 2H), 7.00 (td, 7..17 (da, 7.30 1W), 7.70- (in, 3H), 7.79 Ci 10 23), 10.5 (mi 13.49 (br s, El-MS 456.1 (Mi-H);

IND

o HPIC-Method A, Rt 3.43 mini.

EJajle 11(5,7-Difluoro-1H-indazo1-3-y1) (2trifluoromethyl-phenyl) 6,7,8,9,10-IhezAhydrocyclooctapyrimidin-4-ylI -amine (11-121): Prepared in 48% yield, 1 HIUMR (50014Hz, DMSO-dE) 8 1.46 2H), 1.52 (in, 2H), 1.77 4H), 2.95-Cm 2K), 3.03 (in, 2H), 7.14 (d, 1H), 7.30 1H), 7.73 C,3H), 7.80 .10.5 (m, In), 13.62 (br. s, 1H); El-MS 475.1 HPLC-Method A, 2 t 3. 52 min.

Examle 12[6-Cyclohexyl-2- (2-tritluoroiethyl-phenyl) pyrimidin-4-;ylJ (1H-undazbl-3-yl) -amne (11-122): Prepared in 45W yield. 'HNMM (500 mHz, CZDC13) 8 1.30 (2H, mn), 1 .46 (2H, in), 1.65 (2H, mn),-1.76 42H, in), 1.91 (2H, mn), 2.61 (1H, br in), 7.08 (111, t, J=-7.4 Hz), 7-.27 (1W, d, Hz), 7.35 (1W, t, J- 7.1 Hz) 7.50 t, JT=7.O Hz), 7.58 (Iii, t, J=7.4 Hz), 7.66 (3H, mn), 1.72 (1H, d, J-~7.B Hz), 8.0 (1K, br), 9.87 (1W, br) ppm,;HPLC-Method D, Rt 3.57 MIni LC-MS 438.17 (14tH) t gxm* 12[6- C2-Pluoro-phenyl) (2-trifluoroinethylphenyl) -pyriiin-4-yi]- (1H-indazol-3-yl) -aminxe (11-123): -2 83- NO Prepared in 8% yield, 1 IHNMR (500 MHz, CDC1) 8 7.18 o (3H, 7.37 (1H, m),-7.43 (1H, t, J=7.9 Hz), .7.51 (1H, d, J=7.9 Hz), 7.55 (1H, t, J-7.6 Hz), 7.65 t, J=7.4 Hz), 7.79 (1i, d, J=7.9 Hz), 7.85 ad, J='7.6 Hz), 8.19 (2H, mi), 8.70 (1i, d, J=8.5 Hz) ppm; HPLC-Method D, Rt 4.93 min; LC-MS 450.13 (M+H) 4 Va Example 124 (6-Fluoro-1E-indazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yll-amine (11-124).

Ci 10 Prepared in DMF (87% yield) as yellow solid. 'iHNMR (500 MHz, DMSO-ds) 813.0 11.1 br, 1lH), 8.66 (d, C 1H), 7.95 1H), 7.80 1H), 7.72 21), 7.62 (m, 4H), -7.21 (dd, 1H), 6.84 (td, 1H) ppm. LC-MS 424.15 HPLC-Method A, Rt 3.05 min.

xampe 125 3-12-(2-Trifluoromethyl-phenyl)-quinazolin-4ylamino] -1-indazole-5-carboxylic acid methyl ester (II- 125):. To a solition of compound II-79 (100 mg 0.21 mmol) in DMF (2 mL) was added MeOH (1 mL), DIEA (54 uL, 0.31 mmol) and PdCl 2 (dppf) (4 mg, 0.005 mmol). The flask was flushed with CO three times and then charged with a CO balloon. The reaction mixture was heated at 80 0 C for 14 h then poured into water. The resulting precipitate was collected and washed with water. The crude product was then purified first by flash column (silica gel, ethyl acetate in hexanes) then by preparative HPLC to to afford 11-125 as yellow solid. IHNMR (500 MHz, DMSO-d) 813.3 1H), 11.3 br, 1H), 8.70 1H), 8.36 1H), 7.97 1iH), 7.82 2H), 7.71 3H), 7.58 2H), 7.51 1),.3.75 3H) ppm; LC-MS (ES+) 464.13 (MiHI); HPLC-Method A, Rt 3.12 min.

-284- IND XnMIe..208 (5-Methyl-2H-pyrazol-3-yl) (2-naphthyl-1..

o yl) -quinazolin-4-yl -amine (11-208):: '1D0R (500 MHz, DMS0dE) 8 8. 92 11H) 8. 73 (in, 8.3 9 8. 0 9 2H1), 7.95 Cmn, 3H1), 7.62 Cm, 3H1), 6.78 Cs, lIH), 2.32'(s, 311); MS 352.2 (14+1).

IND gxpt-lzn2 (2-Chioro-phenyl) -pyrido [2,3-lpyrimidin- (7-fluoro-1E-indazol-3-yl)-am ine 1-214): Prepared o ~from t-Chloro-2- (2-chioro-phenyl) -pyrido [2,3-c)pyrimidine ci 10 (100 mg, 0.36xmnol) and 7-Fluoro-1H-indazol-3-ylanine o (108mg, 0.721mmol). Purification by' preparative EPLO' Ciafforded the title compound as'a yellow, di-TFA salt (93 mng, 46t yield). HPLC-Method A, 3.04 mint; 'H NMR (DMSO, .500 M41z): 13.67 (1H1, 11.40-11.25 ClIH, be), .9.35- 9.25 (211, in), 7.95 (1H1, mn), 7.80-7.47 (SH, mn), .7.35(11,' mn), 7.fS MS MW 391.1.

Example22i (2 -Chioro-phenyl) -pyrido pyrimidin- 4-yl] -(5-fluoro-2B-indazol-3-yi) -aminei (11-215): Prepared from 4-Chl.oro-2- (2-chloro-phenyl) -pyrido pyriinidine (100 mg, 0.3Emnol) and 5-Flnoro-1H-indazol-3ylamine (108mg, 0.72mmo1). Purification by preparative HPLC afforded the title com~pound as a yellow, dii-TPA salt ing, 22% yield) HPLC-Method A, Rt 3.-00 mint; iH NMR (DM50, 500 MHz): 8 1.3.0 (1H1, a),f 10.90(111, bs), 9.15-9.05 (2H, in), 7.70 (1H1, in), 7.60-7.30 (6H1, mn), 7.20 (11, in); MS VW' 391.1.

gX~wp211f (2-Chloro-phenyl) -pyrido [2,3-lpyriinidin- 4-yl]-(5,7-difluoro-3B-4indazol-3-yl) anine -(11-216): Prepared from 4 -Chloro-2- (2-chioro -phenyl) -pyride [2,3d~pyriinidine (100 mug, 0.3Einmol) and 7-Dfitluoro-1Hindazol-3-ylanine (112mg, 0.E6imaol). Purification by -285- NOpreparative HPLC afforded the titlecmon as a yellow, odi-TFA salt (130 ing, 62% yield). HPLC-Method A, Rt 3.12 mini; -H NMM (DM60, 500 M4Hz): 13.80-13.60 (174, bs), 11.30- 11.10 (174, be), 9.20-9.10 (233, in), 7.80 mn), 7.60- 7.30 (6i, in); MS MW 409.1.

Ml [U 2- (2 .Chloro -phenyl) -pyrido [3,4 -dl pyriiin- 4 -rll-OIfu-indazol-3-y)-am4ne (11-2 17): Prepared from 4- Chloro-2-.(2-cbhloro-phenyl) -pyrido~i,4-dlpyrimidine (100 0 10 mug, 0.3Suimol) and iH-u-ndazol-3-ylaaine (88mg, 0.E6mmol) oN Purif ication by preparative. HPhC af forded the title 0 compound as a yellow, di-TPA salt (72 rng, 33W yield)., EPLO-Method Rt 3.21 mini; 'H NMR (DM50, 500 MHz): 12.95 (174, 10.90 (174, 9.25 (133, 8.75 (1H4, in), 8.55- (13, in), 7.65 in), 7.55 (174, in), 7.50-7.30 (574, in), 7. 0 0(17, mn); MS z) 14W 3 73. 1.

ZwnpLt--21a (2-Cliloro-phenyl) -pyrido[3,4-djpyrinidin- 4 -yll (7 -f luoro -JMH-indazol -3 -yl) am3.;ne'(11-218): Prepared from 4-dfloro-2 -chloro-phenyl) -pyrido [3,4 -di]pyriiine (100 mug, 0. 3Simol) and 7-Fluoro-1H-u-nd9azol-3-ylamunme (108mg, 0. 72rnrol) Purification by' preparative HPLC.

af forded the title compound as a yellow,- di-TFA salt (48.7 tug, 22% yield). HPLC-Metbod* ARt L3.35 mini; 'H NR (nMSo, 5 00 M4Hz): 8 12.95 (133, 10.90 (17, be), 9.25 (14, s) 8. 75 (174, in), 8.55 (111, in), 7.70-7.35 (574, in), 7.25(174, in), 6.95 (1Hi, MS 14 331.08.

xP1Q...214 (2 -Chloro-phenyl) -pyrido [3,4 -di]pyrimidin- 4-yll-(5-fluoro-1K-Lndazqol-3-yl)-amine (11-219): Prepared from. 4-chl-oro-2- (2-chloro-5-fluoro-1H-indiazol-3-ylaiine (108mg, 0.72minol) Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt -286- (57.2 mg, 26% yield). HPLC-Metbod R, 3.27 min; 'H NMR (DMSO, 500 MHz): 8 13.05 (1H, 10.95 (1H, 9.25 (1H, 8.75 (1S, 8.55 (IN, 7.60 (11, 7.55 (iH, 7.50-7.30 (Sn, 7.25(IH m) MS xW 391.1.

Exampe 22a (2-chloro-phenyl) -pyrido (3,4-dlpyrimidin- 4-ylJ (5,7-difluoro-1E-indazol-3-yl) -mine (11-220): Prepared from 4-chloro-2- (2-chloro-7-difiuoro-1H-indazol- 3-ylamine (112mg, O.66imol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (57.2 mg, 26% yield). HPLC-ethod A, Rt 3,45 min; 2H NMR (DMSO, 500 MHz): 8 13.65 11.0 9.25 (1H, .8:80 (lH, 8.50.(1H, 7.60 (1H, 7.55 (IH, 7.50-7.30 (5H, MS 409.1.

Exap2&.21. 6 6-Fluoro-iH-indazol-3-ylamine 1HNM (500 MHz, DMSO-d) 811.4 1H), 7.68 (dd, 1H), 6.95 (dd, iN), 6.75 (td, 1H), 5.45 2H) ppm; LC-MS (ES+) 152.03 HPLC-Method A, Rt 2.00 min.

xa~mJ 217 5-Fluoro-J.-ind&zol-3-ylamine

HNMR

(500 MHz, DMSO-dE) 811.3 7.43 1H), 7.22 7.08 1H), 5.29 2H) ppm; LC-MS 152.01 HPLC-Method A, Rt 1.93 min.

Examle 218 5 7 -Difluoro-N-indaazoi-3 -yl-amine 'NMR (500 MHz, CD30D) 67.22 (dd, J-2.0, 8.45Hz, 11), 7.04-6.87 1H); LC-MS 169.95 HPLC-Method C, Rt 2.94 min xamRt2.219 7-Fluoro-iH- indaol-3-ylamine '1NMR (500 MHz, DMSO-dE) 811.8 7.42 1H), 6.97 3-H), -287- IND 6.78 1H), 5.40 21) ppm; LCMS 152.01 HPLC-Method A, Rt 2.00 man.

SExa=3.e 22, 7-Fluoro-6-trifluorometyyl-IH-indazol-3ylamie (AS5): 'KH-NMR (500 MHz, DMSO) 8 12.5 1R), 7.75 1H), 7.25 1H), 5.85 1H) ppm; MS (FIA) 220.0 HPLC-Method A, Et 2.899 min.

9&=le 221 6-Eroio-1N-indazol-3-ylamune 'H-NMR (500 Cl 10 MHz, DMSO) 8 11.5 11), 7.65 11), 7.40 Cs, 1H), 7.00 (Id, 1H), 5.45 Cbr s, 1H) ppm; MS (PA) 213.8 Ci !PLC-Method A, Rt 2.441 min.

Exa le 222 4-Flu'oro-1E-ndazol-3-ylamine 1L -NMR (500 Mz, DMSO) 8 11.7 1K), 7.17 7.0s (d, 1H),-6.7 (br, 1H),'6.60 (dd, 11), 5.20 (br s, 2H) ppm; MS (FIA) 152.0 Method A, Rt 2.256 min.

xanw-e 23 5-Bromo-1E-'ndazol-3-ylamite 1 1-NMR (500 MHz, DMSO) 8 11.55 (br s, 1H), 7.95 1H), 7.30 (d, 1K), 7.20 1H), 5.45 (br s, 2H) ppm; MS (P11) 213.8 Method A, Rt 2.451 min.

Example 22j 5-Nitro-1 i-u ndazol-3-ylamine 1 K-NIR (500 MHz, DMSO-dG) 8 9.00 1H), 8.20 1H), 7.45 1H), 6.15 (br a, 1H) ppm; Method A, Rt 2.184 min 9amng.p-e 225 4-Pyrrol-1-yl-1H- indaoi-3-ylamine (AlO):H- NMR (506 bMz, DMSO) 8 7.20 Cs, 2K), 7.00 2K), 6.75 1H), 6.25 2H), 4.30 11) ppm; Method A, Et 2.625 min.

-288- ND Exampl 226 4-Chloro-5,6-dimethyl-2-(2-trifluoromethylo phenyl)-pyrimidine Prepared to afford a colorless oil in 75% yield. 1H-NMR (500 MHz, CDC13) 7.70 (d, J=7.8 Hz, 1H), 7.64 J=7.6 Hz, 1H), 7.55 J=7.6 Hz, 1H), 7.48 J=7.5 Hz, 11), 2.54 3H), 2.36 3H) ppm; MS (PIA) 287.0 HPLC-Method A, Rt 3.891 min.

Va SExamnple 227 4-Chloro-2- (2-chloro-phenyl) 6-dimethylpyrimidine (3B2): Prepared to afford a ye.1ow-orange oil in 71% yield. 'H-NMR (500 MHz, CDC13) 8 7.73 1H), S7.52 11), 7.39 2H), 2.66 3H) ppm; MS (FIA) 253.0 HPLC-Method A, Rt Rt 4.156 min.

Examle 228 4-Chloro-6-methyl-2-(2-trifluoromethylphenyl) -pyrimidine Prepared to afford a pale yellow oil in 68% yield. 1H-NMR (500 MHz, CDC13) 8 7.72 (d, J=7.8 Hz, 11), 7.65 J=7.9 Hz, 1H), 7.57 J=7.5 Hz, 1H), 7.52 J=7.8 Hz, 1H), 7.16 1R), 2.54 3H) ppm; MS (FITA) 273.0. HPLC-Method.A, Rt 3.746 min.

Examle 229 4-Chloro-6-cyclohexyl-2-(2-trifluoromethylphenyl)-pyrimidine Prepared to afford a yellow oil in 22% yield. 'H-NMR (500 MHz, CDC13) 8 7.70 2H), 7.57 J=7.5 Hz, 1H), 7.50 J=7.5 Hz, 1H), 7.19 (s, lH),.2.65 1H), 1.9 2H), 1.8 2H), 1.5 2H), 1.3 21), 1.2 2H) ppm; MS (FIA) 341.0 Zxample.230 4-Chloro-6-phenyl-2-(2-trifluoromethylphenyl)-pyrimidine Prepared to afford a yellow oil in 53% yield. 'H-NM (500 MHz, CDC13)8 8.08 (dd, J=7.9, 1.6.Hz, 7.80 J=7.6 Hz, 1H), 7.77 J=7.8 Hz, 7.67 1H), 7.61 J=7.5 Hz, 11), 7.54 J=7.6 -289- Hz, 7.47 3H) ppm; MS (FIA)' 335.0 HPLCo Method A, Rt 4.393 min.

0 Example 231 4-Chloro-2-(2,4-dichloro-phenyl)-5,6dimethyl-pyrimidine Prepared to afford a white o solid in 91% yield. 'H-NR (500 MHz, CDCl3) 0 7.62 (d, J=8.3 Hz, iH), 7.43 J=7.0 Hz, 1H), 7.27 (dd, J=8.3, Va Hz, 1H), 2.55 3M), 2.35 (s,!3H).ppm; MS -(PIA) 287, 289 HPLC-Metlod A, R 41j140 min.

Exampe 232 4-Chloro-6-(2-chloro-phenyl)-2-(2- S trifluoromethyl-phenyl) -pyrimidine Prepared to affod a yellow oil in 52% yield. 'H-NMR (500 MHz, CDC13) 8 7.75 3H), 7.65 2H), 7.53 7.44 1H), 7.36 2H) ppm; MS (PFA) 369.1 HPLC-Method A, Rt 4.426 min.

Exam.a 233 4-Chloro-6-(2-fluoro-phenyl)-2-(2trifluoromethyl-phenyl)-pyrimidine Prepared to afford a yellow oil in 95% yield. 'H-NMR (500 MHz, CDC13) 6 8.24 J=7.9 Hz, 1H), 7.84 1H), 7.78 J=7.7 Hz, 1H), 7.76 J=8.0 Hz, 7.60 J=7.5 Hz, 1H), 7.53 J=7.6 Hz, 1H), 7.43 1H), 7.23 J=7.6 Hz, 7.13 1H) ppm; MS (FlA) 353.0 Example 234 4-Chloro-6-pyridin-2-yl-2-(2-trifluoronethylphenyl)-pyrimidine Prepared to afford a pale yellow solid in 50% yield. 2-NMR (500 MHz, CDC13) 8 8.68 (m, 1H), 8.48 J=7.9, 0.8 Hz, 1H), 8.38 'J=2.3 Hz, 1H), 7.84 3H), 7.62 J=7.6 Hz, 1H), 7.55 J=7.6 Hz, 1H), 7.38 1H) ppm; MS (FIA)0336.0 HPLC- Method A, Rt 4.575 min.

-290o pheny)=56,7,8-etrahydro-pyridoE4,3..;]pyrimiaine 1 HNMRq (500 MHz, CDcl 3 87.70 11', 7.2(d, 110 7.5 Ct, Ill), 7.48 Ct, IN), 7.32 CM, 4H), 7.25 Cm, 111), 3.74 CS, 2H1), 3.66 Cs, 210, 2.99 Ct, 2k), 2.80 Ct, 2H1) ppm; WAMS (ESi-) 404. 17 (74+1) HPLO-Method A, Rt 3.18S mini.

Exal-eZ167-Benzyl-4-chloro-2- (2-trifluoromethylphenyl) 8-tetrahydro-pyrido[34-dlpyrimidine (B11): IND 10 ?HNMR (SOO MHZ, CC1 3 67.69 1H1), 7.60 Cd, *7.54' o 1H),.7.47 Ct, 111), 7.28''Cm, 411),'7.20 Cm, 1H), 3.68 Cs, 2H), 3.67 2H), 2.86 Ct, 2H), 2.79 2H1) ppm. MS 404.18 H-PLC-Metbhod A, Rt 3.12 muin.

Exanit..an 4-Chloro-2-(4-fluoro-2-trifluoromethylphenyl)-qnunazoline (B12): 3 1 HMR C500MHz, CD3OD) 8 8.43 Cd, J=B.1Wz, 1H1), 8.20-8.05 Cm, 211);' 8.05-7.82 Cm, 2H), 7.71-7.51 2H1). LC-MS 327.09 WPLC-Method D, Rte 4. 56 ruin.

Exmr:2t3& 4-Chloro-2- (2-chloro-S-trifluoromethylphenyl)-quiunazoline (B13): LC-MS CES+) 342.97 CM-iH).' WPLC-Method D, Rt 4.91 mini.

Ea~pe..a2 4-Chloro-2- chloro -4 -nitro -phenyl) quunazoline CR14): LC-MS 319.98 CM-iH). WPLC-Method D, Rt 4. 45 mini.

ExaImlIA24 4-Chloro-2- (2-trifluoromethyl-phenyl) quinazoline (B15) Prepared in 57% yield. White solid.

'HNVR (500MHz,- DMSO:-dS) *8 7.79 Ct, 111), 7.86 Ct, 111), .7.94 C,311,8.15 Cdd, 111), 8.20 Ctd, iH), 8.37 Cm, 11) El- MS 30B.9 -291-

IN

Szmle24 4-.Chloro-2- (2-trifluoromethyl-phenyl) -6,7- (316): Prepared in 22% yield. 'HbDIIR (50OMHZ, MSO-d)6S 2.19 3.01 (t, 21), 3.08 2H), 7.49 IH), 7.55 Ct, IH), 7.62 (4, 01), 7.71 1H). El-MS' 299.0 (Mdi).

Example 242 4-Chloro-2-(2-c hloro-phenyl)-6,7,s8,9 tetrahydro -3H- cycloheptapyrimidine Prepared according to Method C in 82% yield to afford a white

NO

o solid. 1HNMR (SOOMHZ, cDCl 3 8.1.67 (m 4H), .1.87 (m 2H), Cl 3.02 (m 4H), 7.28' 7.40 1H), 7.65 EI-MS 293. 0 BZapI. 243 4-Chloro-2- (2-trifluoromethyl-phenyl) 5,6,78,9,10-hexahydro-cycloctapyrmicine

(BIB):

Prepared in 38% yield to afford a brown oil. 'HNMR (SOOM14z, CDC1 3 8 1.35 (m 2R), 1.41, (m 2H), 1.76 (m 4H), 2.96 4H), 7.48 t, 1R), 7.56 Ct, 11), 7.66 1H), 7.70'Cd, 1H); El-MS 341.0 ExanP& 244 4-Chloro-B-methosy-2-(22-trifluoromethyl-.

phenyl)-quinazoline (B19): Prepared from 8-methoxy-2-(2trifluoromiethyl-phenyl) -3H-quinazolin-4 -one 3.l2mnol), triethylamine hydrochloride (472mg, 3.43mol), and POC1 3 Purification by flash chromatography afforded a white solid (89W yield). HPLC-Method A, Rt 4.10 min, (98W), MS 258.08 Axamne 245 2- 4 -Chloro-quinazolin-2-yl) -beazonitrile Prepared to afford a yellow solid in 1.5% yield.

'H-NMR (500 MHz, CDC13) 8 8.47 1H), 8.24 3H), 8.16 Cd, 1H), 8.07 (imp-urity), 7.94 11), 7.92 (impurity), -292- IND7.86 1H), 7.68 2H), 7.65* (impurity), 7.54 o (impurity), 7.49. 11), 4.2 (impurity), 1.05 (impurity) ppm; MS (LC/MS) 266.05 HPLC-Method A, Rt 3.88 min.

kxanl1 2i 6-Methyl-2- (2 -trifluoromethyl-phenyl) -3Hpyrimidin-4-one Prepared to afford a yellow solid in 50% yield. 'H-NMR (500 MHz, DMSO-d) 5 12.7 (br s, 1H), 7.9 114), 7.8 2H), 7.7 6.3 11), 2.21 3) ppm; MS (FIA) 255.0 HPLC-Method A, Rt 2.578 min.

Cl Example 241a 6-Cyclohezyl-2- (2-trifluoromethyl-phenyl) pyrimidin-4-one Prepared to afford an off-white solid in 54% yield. 'H-NMR (500 MHz, DMSO-d6) 8 12.9 (br s, 1H), 7.9 4H), 6.3 11), 2.5 11), 1.9 Cm, SH), 1.4 5H) ppm; MS (PIA) 323.1 HPLC-Method A, Rt 3.842 min.

Exaoe 2A 2- (2-Chloro-5-trifluoromethyl-phenyl) -3Hqninazoli-4-one (D10): 1'HNMR (50MHz, D30D) 8 8.32-8.25 11), 8.01 11), 1.91-7,72 1H), 7.66-7.55 (m, 1H). LC-MS 325.01 HPLC-Method D, Rt 3.29 min.

&r&p1e 2A2 2 4 -Fluoro-2-trifluorometlaya-pkenyl)-3nT- -quinazolin-4-one (D14): 'IHNMR (500MHz, CD3OO) 5 8.28 .d, 8.OHz,1H) 7.94-7.84 1H), 7.84-7.77 11), 7.76- 7.67 2H), 7.65-7.53 L-MS 309.06 HPLC-Method D, Rt 2.88 min.

EKe 259 2-(4-Nitro-2-chloro-phenyl)-3H-quiunazolin-4one LC-MS- ES+ F'o2. 03 HPLC-Method D, Rt 2.81 min.

-293- Va oB==In 251 2-(5-Fluoro-2-trifluornethyJ-pheyl).-3H.

qinazolin-4-one (D17): IEIk (SOOMHz, CD 3 OD) 8 8.28 (d, Rt 3=8.,05Hz, 11), 7.96 (dd, J=5.05,: 8.55Hz, 11), 7.89 (t, J=7.9Hz, 7.78-7.69 7.66-7.46 3H). LC-MS 309.14 HPLC-Method f, Rt 2.90 min.

ExNg pj 252, (1&-Indazol-3-yl) (2-phenyl-quinazolin-4-yl) amine Prepared by Method A, in DMF to afford 0~ 10 mg (50% yield) as pale yellow solid. 'H NMR (500 MHz, ci SDMo-dS) 813.1 Cs, br, iH), 8.48 1H). 7. 91Cd, 2H), 7.76 Cbr, 2H), 7.45 21), 7.36 21), 7.20 Cm, 4H), 6.86 1H) ppm. MS 338.07 336.11 (M- HPLC-Method A, at 2.88 min.

xa~mle 253 (5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-5, 6,7,8tetrahydroqinazolin-4-yl) -amine (111-7): Prepared according to Method A. H NMR (500 MHz, DMSO-d) 812.1 br, 1H), 8.70 hr, 8.37 J 6.7 Hz, 2H)), 7.54 31), 6.67 111), 2.82 Cm, 2H), 2.68 Cm, 21), 2.37 Cs; 3H), 1.90 Cs, br, 4H); MS 306.1 (1iH).

Example 254 (5-Methyl-2H-pyrazol-3-yl)- (.2-henyl-6,7,8,9tetrahydro-5E-cycloheptapyrimidin-4 -yl) -amine (111-8): MS 320.48 HPLC-Method E, Rt 1.124 min.

Ea=-Inp 255 (5-Methyl-2Ef-pyrazol-3-yl) (2Zpyridin-4 yl- .quinazolin-4-yl)-amine (111-9): Yellow aolid,'mp 286- 289 0 C, 'H MR (DMSO) 8 2.35 (3H, 6.76- (12, 7.61 (11, 7.89 (2H, 6.32 (2H, 8.70 (11, 8.78 C(2H, 10.56 br 12.30 (114, hr Ia (solid) 1620, 1598, 1571, 1554, 1483, 1413, 1370, 1328; MS 303.2

(M+H)V

-294- EKane 256 (7-Chloro-2-pyridin-4-yi-quinazolin-4-yl) methyl-2H-pyrazol-3-yl) -amine (111-28): 1H NMR (fMSO-d6) S 2.35 6.75 (11, 7.65 (1W 7.93 (1K, 8), 8.30 (2H, 8.73 (1Hi 8.79 10.69 (IH, s), 12.33 (1H, MS m/z 337.2 ExamP. 257 (6-Chloro-2-pyridin-4-yl-quinazlin-4-yl) methyl-2-pyrazol-3-yl)-amine (3:11-29): 'H flMR (fMSO-dG) 8 2.31 (31, 6.74 7.89 (1W, a) 8.30 (2H, d), 8.80 (2H, d) 8.91 (1H, 10.63 (1H, 12.29 a); MS 337.2 (M+I-H) xample 258 (2-Cyclohexyl -qninazoliia-4-yl) (5-methyl-25pyrazol-3-yl)-amine (111-301: 'H iMR.(DMSO) 8 2.35 (3H, 1.70 1.87 (2W, 1.99 (2H, 2.95 (11, 6.72 (1H, 7.75 (111, 7.88 7.96 (1H,: 8.83 (11, 11.95 (11, 121.70 (11, MS 308.4 Example 259 (5-Mehy1-2H-pyrazol-3-yl) (2-phenylquinazolin-4-yl) -amiine (111-31): mp; 246 0 C; 'H NMR (400MHz) 8 2.35 (3H, 6.70'(1H, br.s), 7.51-7.57. (4H, 7.83- 7.84 (2H, 8.47-8.50 (2H, 8.65 (1H, 10.4 (1-H, 12.2 (1H, be); ID (solid) 3696,13680, 2972, 2922, 2865; MS 302.1 E le-260 12- (4-lodophenyl) -quinazolin-4-yl] 2H-pyrazol-3-yl)-amine (111-32): HINM (DMSO-d6) 8 2.34 (3H, 6.72 (3H, 7.56 (1H, 7.84 (2H, 7.93 (211, 8.23 (2H, 8.65 (23, 10.44 (JR, 12.24 (1H, MS 428.5 -295- Examp 261 (3,4-Dichlorophenyl) -quinazolin-4-yll o methyl-2H-pyrazol-3-yl) -amine (III-33): A suspension of C 2- 4-dichloro-phenyl) -3H-quinazolin-4-one (1g, 3.43 e, mmol) in phosphorus oxychloride (4 mL) was stirred at 110 0 C for 3 hours. The solvent was: removed by evaporation o and the residue is treated carefully with cold aqueous, saturated NaHCO 3 The resulting solid was collected by filtration and washed with ether to affotd 4-chloro-2en (3,5-dichloro-phenyl)-qninazoline as a white solid (993 mg, To the above compound (4o00mg, 1.29 mmolY in Ci OTHP (30 mL) was added 3-amino-5-metyl pyrazole (396 mg, o 2.58 mmol) and the.resulting mixture heated at 65 0

C

overnight. The solvents were evaporated and the residue triturated with ethyl acetate, filtered-, and.washed with the minimum amount of ethanol to afford compound 111-33 as a white solid (311 mg mp.274 0 C; IH NMR (DMSO) S 2.34 (3H, 6.69 7.60 (1H, 7.84 (1H, d), 7.96 (2H, 8.39 (1H, dd), 8.60 (iH, 8.65 (1H, d), 10.51 (1H, 12.30 (11, IR (aolid) 1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5 Exampe 262 (4-Bromophenyl) -quinazolin-4-yl] methyl-2r-pyrazol-3-yl)-amine -(111-34): mp 262'265C; 11H NME (DMSO) 8 2.34 (35, 6.73 (1H, 7.55 (1H, m), 7.74 (2H, 7.83 (2H, 8.40 (2H, 8.65 (1H, d), 10.44 (1H, 12.25 (1H, IR (solid) 1603, 1579, 1546, 1484, 1408, 1365; MS 380.1/382.1 Exale 253 [2-(4-Chlorophenyl)-quinazolin-4-yl]-(5methyl-2H-pyrazol-3-yl)-amine (II-3S): mp >300 0 C; 1H NMR (DMSO) 8 2.34 (3H, 6.74 7.53-7.62 (3H, m), 7.84 (2H, 8.47 (2H, 8.65 (11R, 10.44 (1H, s), -296- I N 12.26 (1H, IR (solid) 1628, 1608, 1584, 1546, 1489, o 1408, 1369, 1169; MS 336.2 Examl2642 (3,5-Dichlorophenyl)'-quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-amine (III-36): mp 228oC; 1H NMR (DMSO) 8 2.34 (3H, 6.69 7.96 (1H, 8.21 IND(3H, 8.56 (iM, 8.60 (2H, 10.51 (1H, 12.30 S(1H, IR (solid) 1546, 1331, 802, 763, 729, 658, 652; MS 370.5 010 Examnle 25 (4-Cyanophenyl) -quinazolin-4-yll cA methyl-2H-pyrazol-3-yl)-amine (111-37): mp 263CC; 3'H NMR (DMSO) 8 2.34 (3H, 6.72 (1H, 7.61 (1H, 7.88 (2H, 8.04 (2H, 8.63 (2H, 8.67 (1H, 10.52 (1H, 12.27 IR (solid) 1739, 1436, 1366, 1229, 1217; MS 327.? Example 266 [2-(3-lodophenyl)-quinazolin-4-ylj- 2-pyrazol-3-yl)-amine (111-38): mp 234-235 0 C; 'H NMR (DMSO) 8 2.35 (3H, 6.73 (11, 7.35 (11, 7.56 7.85 (3H, 8.47 (Li, 8.65 (1H, 8.86 (1H, 10.49 (11, 12.28 (1H, br IR (solid) 1560, 1541, 1469, 1360; MS 428.1 Examlte 267 12-(4-Ethylsulfanylphenyl)-quinazolin-4-yl (5-methyl-2E-pyrazol-3-yl)-amine (111-39): mp 229-231OC; 'H NMR (DMSO) 8 1.29 (3H, 2.35 (3H, 3.07 (2H, q), 6.76 (1H, 7.43 (2H, 7.51 (1H, 7.81 (2H, m), 8.41 (2H, 8.64 (1H, 10.38 (1H, i2.24 (1H, br IR (solid) .1587, 1574, 1555, 1531, 1484, 1412, 1369; MS 362.1 -297-

I

IND RxamDlg -8 (5-Cyclopropyl -20-pyrazIol-3 -yl) 2-phenyl- Squinasolin-4-yl)-amine (111-40): np 218-219 0 C; 'H NMR (DMSO-d6) 8 0.70-0.80(2, 0.90-1.00 (2H, 6.70 (1H, 1.45-7.55 (4H, 7.80-7.85 (2H, 8.45-8.55 (2H, 8.65 (11, 10.40 12.27 (1H, MR o (solid) 1624, 1605, 1591, 1572, 1561, 1533, 1479, 1439, 1419, 1361, 1327, 997, $28, 803, 780, 762, 710; MS' 328.2 IND 0 10 Example, 26 (4-tert-Eutylphenyl),-quinazolin-4-ylJ-(s- *methyl-2H!pyrazol-3-yl) -amine- (111-41): mp >300WC; 3H NMR (DMSO-d6)8 1.35 (9H, 2.34 (31, f.79- (1H, a), 7.55 (3H, .7.85 (2K, 8.39 (211, d),.8.62 (1H, d), 10.35 (1H, 12.22 IR (solid) 1603, 1599, 1577, 1561, 1535,-1481, 1409, 1371, 1359, 998, 841, 825, .766, 757; MS 358.3 Exanie 22Q (4-Chiorophenyl) -quinazolin-4-ylJ cyclopropyl-2H-pyrazol-3-yl) -amine :(111-42): 1 N'IRMM (DMSOd6) 5 0.77 (4H, br m) ,2.05 (1H, 6.59 (11, 7.60 (1H, 7.85 (2H1, 7.91 (2H, 8.22 8.65 10.51 12.33 MS 362.1 (M+H) 4 Exaxnple 271 (2-Benzo[1,i3Jdioxol-5-yl-qinazolin-4-yl)-(5methyl-2E-pyrazol-3-yl)-amine (111-43): 'H NMR (DMSO) S 2.33 (3H, 6.13 6.78 7.11 d), 7.80 (11j, 7.94 (11, 8.09 (3H, 8.25 (1H, d), 10.34 (11, 12.21 (1H, MS 346.5 gxaj1=e 2_2 [2-(4-Diettylannophenyl)-qinazolin-4-yl]- .(5-ethyl-2H-pyrazol-3-yl) -amine (111-44): 'H NMR (DMSOdS) 8 2.02 (6H, 2.39 (3H, 6.83 (1H, s),'7.711 (H, -298- 7.98 (2H, 8.04 (2H, 8.33 8.67 (1H, 11.82 (1H, 12.72 (1H, MS 345.3 ample 27l [2-(3-Methoxyphenyl)-quinazolin-4-yll methyl-20-pyrazol-3-yl)-amine (111-45): mp 226C; -3H NMR (DMSO) .8 2.34 3.92 (3H, 6.72 (1H, 7.21.

(1H, 7.57 (1H, 7.79 (1H, 8.02 (3H, 8.14 (1H, 8.79 10.39 12.22 (1H, IR (solid) 1599, 1572, 1538, 1478, 1427, 1359, 833, 761, 661; MS 332.2 (M+H)t.

Bxanple 275 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4dichlorophenyl)-quinazolin-4-yl -amine (111-46): IH NM4R (DMSO-d6) 6 0.86 (2H, 1.62 (2H, 1.69 (1H, m), 6.56 (1H, 7.57 (1H, 7.84 (4H, 8.40 (1H, d), 8.58 (1H, 8.64 (1H, 10.53 (1H, 12.36 (1H, a); MS 396.0 Example 276 (2-Biphenyl-4-yl-quinazolin-4-yl)- 2H-pyrazol-3-yl)-amine (111-47): To a mixture of bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pytazol-3yl)-amine (111-34) (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol) in THF:water 4 mL) was added Na2CO, (219 mg, 2.06 mmol), triphenylphosphine (9mg, 1/15 molt) and palladium acetate (1 mg, 1:135 molt). The resulting mixture was heated at 80 0 C overnight, the solvents were evaporated and the residue purified by flash chromatography (gradient of dichloromethane:MeOH) to afford. 111-21 as a yellow solid (99 mg, 1H NMR (DMSO0) 8 2.37 (3H, 6.82 (1H, 7.39-7.57 (4H, m), 7.73-7.87 (6H, 8.57 (2H, 8.67 (1H, 10.42 (1H, 12.27 (1l, MS 378.2 I -299- IN EXamle 2227 (4-Ethynylphenyl) -quinazolin-4-yll 0 o methyl-2-pyrazol-3-yl)-amine (11I-48): To a mixture of E2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2pyrazol-3-yl)-amine (111-34) (114 mg, 0..3 mmol), and trimethylsilylacetylene (147 mg, 1.5 mmol)in DMP (2 mL) was added CuI (1.1 ng, 1:50 molt), Pd(PPhl),C1, (4.2 mg, 1:50 mol%) and triethylamine (121 mg, 0.36 mmol). The Va Sresulting mixture was heated at 1200C overnight and the solvent evaporated. The residue was triturated in ethyl C- 10 acetate and the resulting precipitate collected by Va o filtration;. The collected solid was suspended in THF (3 SmL) and TBAP (M in THFP, l.leq) was4 added. The reaction mixture was stirred at room temperature for 2 hours and the solvent evaporated. The residue was purified by flash chromatography (silica gel, gradient of DCM:MeOH) to afford III-48 as a white solid (68 mg, 1'H NMR (DMSO) 6 2.34 (3H, 4.36 6.74 7.55 (1i, 7.65 (2H, 7.84 (2H, 8.47 (2H, 8.65 (1H, 10.43 12.24 (iH, MS 326.1 Examle 228 12- (3-Ethynylphenyl) -quinazolin-4-yl] methyl-20-pyrazol-3-yl)-amine (111-49): np 204-207 0 C; 1H NMR (DMSO) 8 2.34 (3H, 4.28 (1H, 6.74 (11, s), 7.55-7.63 (3H, 7.83-7.87 (2H, 8.49 8.57 (1H, 8.65 (iH, 10.46 (1H, 12.27 (IH, IR (solid) 1598, 1574, 1541,-1489, 1474, 1422, 1365; MS 326.1 Example 279 (3-Methylphenyl)-quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-amine (I111-50): A suspension of 1H.quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POC1 3 mL, 644 mmol) and N,N-dimethylaniline (8maL, 63.1 mmol) was heated under reflux for 2 h. The excess POC1 3 was -300- DO removed in vacuo, the residue poured into ice, and the C resulting precipitate collected by filtration. The crude Ssolid product 2,4-dichloro-quinazoline (6.5 g, 53% yield) was washed with water and dried under vacuum for next step use without further purification. To a solution of the 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 mL) was added 5-methyl-1H-pyrazol- C 3-yl amine (3.2 g, 32.9 mmol)and the resulting mixture was stirred at room temperature for:4 hours. The Cq 10 resulting precipitate was collected by filtration, washed

ID

o with ethanol, and dried under vacuum to afford 4.0 g (93% C- yield) of (2-chloro-quinazolin-4-yl)-(5-methyl-lHpyrazol-3-yl)-amine which was used in the next step without further purification. To a!solution of the (2chloro-quinazolin-4-yl) (5-methyl-lH-pyrazol-3-yl) -amine mg, 0.19 mmol) in DMF.(1.0 mL) was added m-tolyl boronic acid (0.38 mmol), 2M Na 2

CO

3 1(0.96 mmol), and trit-butylphosphine (0.19 mmol). The flask was flushed with nitrogen and the catalyst PdCl 2 (dppf) (0.011 mmol) added in one portion. The reaction mixture was then heated at 0 C for 10 hours, cooled to room temperature, and poured into water (2 mL). The resulting precipitate was collected by filtration, washed with water, and purified by HPLC to afford III-50 as a pale yellow solid (61mg, 'H NMR (500 MHz, DMSO-d6) 612.3 (br s, 1H), 10.4 (br s, 1H), 8.75 1H), 8.30 1H), 8.25 1H), 7.78 2H), 7.55 1H), 7.45 7.35 1H), 6.80 1H), 2.47 3H), 2.30 3H); MS 316.1 Example 280 [2-(3,5-Difluorophenyl)-quinazolin-4-yl]-(5methyl-2H-pyrazol-3-yl)-amine (III-51): 'H NMR (500 MHz, DMSO-d6) 812.3 (br s, 1H), 10.8 (br's, 1K), 8.63 1H), -301- 7.95 7.85 2H), 7.58 Ct, IH), 1.41 Ct, 1H), 6.59 12), 2.27 3H); MS 338,.1. CM+H).

gamle 2i81 (3-chloro-4-fluorophenyl),-qinazolin-4yl]-(5-methyl-2-pyrazol-3-yl)-amtne (311-52): 'HN 1 (500 MHz, DMSO-d6) 812.4 (br s, IN), 10.8 Cbr s, 1H), 8.65 (d, 1H),.8.50 Cd, IH), 8.36 IH), 7.85 1H), 7.60 (m, 1H), 6.62 iN), 2.30 Cs, 3H); MS354.1 CM+H).

C' 10 9an =le 2n a (5-Methyl-2H-pyrazol-3-yl)-[2-(3o trifluoromethyphenyl) -quinazolin-4-ylJ -amine (111-53): 'H NMR (500 MHz, DMS-d)' 812.2 Cbr, 10 .45(br, iN), 7.53 lI), 7.43 Cd, J 7.2 Hz, 1H), 7.06 J 8.2 Hz, 6.65 Cd, J 8.3 Hz, 3H), 6.57 Ct, 7.6 Hz, 1H), 6.51 Cd, J 7.8 Hz, IH), 6.43 J =7.8 Hz, 1H)), 6.32 Ct, J 7.6 Hz, 1H), 5.51 Cs, 1H), 2.03 3H); MS 370.2 Examiple 283 [2-(3-Cyanophenyl) -quinazoiin-4-yiJ- methyl-2Hf-pyrazol-3-yl)-amine (111-54): 'H NMR (500 MHz, DMSO-dE) 89.01 Cs, 1H), 8.96 Cm, 8.8 J 7.3 Hz, 1H), 8.16 br, 2H), 8.06 Ct, J 7.8 Hz, 7.88 Cm, 11), 6.96 11), 2.58 3H); MS 327.1 92Ple 284 (3-Isopropylphenyl) -quinazolin-4-yl meth;yl-2H-pyrazol-3-yl)-amine (111-55): 'H NHR (500 MHz, DMSO-d6) 88.89 J' 7.5 Hz, 1H) 8.37 Cs, 11), 8.26 11), 8.08 Cm, 211), 7.81 t, br, 1H), 7.67 2H)), 6.88 'Cs, 1H), 3.12 iH), 2.40 Ca, 3H), 1'.38 3 i 6.9 Hz, 6H); MS 344.2 =xantle 2k (5-Methyl-2H-pyrazol-3-yl) -(2-pyridin-3-ylcunazolin-4-yl) -amine (111-56): '22 NMR (500 M4Hz, DMSO-d6) -302- Cs, IH), 8.84 J 7.3 Hz, 1H), 8.80 J 4.4 o Hz, 8.66 C(d, J 8.2 Hz, in), 7.87 2H), 7.77 (m, W1H), 7.60 t, J 7.2 Hz, IH), 6.67: (s 1W), 2.28 (s, 3H); MS 303.1 (MiH).

Exampe 286 [2-(3-Acetyiphenyl) -quinazolin-4-ylJ methyl-2H-pyrazol-3-yl)-amine (111-157): 'H MR (500 MHz, ON DMSO-d) 8.80 8.55 J 7.7 Hz, 1W), 8.42 od, J 7.6 Hz, 1H), 8.00 Cd, J 7.0'Hz, 11), 7.76 (m, ci 10 2H), 7.58 J 7.7 Hz, 7.48 Cs, br, 1H),j6.60 (9, 2.49 Cs, 3H), 2.03. 3H); MS 344.1 CM+H).

BXple 2a7 4 -ylj (5-iethyl-2-pyrazol-3-y) -amine (111-58)': 1 H NMR (500 MHz, DMSO-d) 510.7 Cs, br, 1W), 8.95 Cs,- 21), 8.63 -Cd,'J 8.2 Hz, 1W), 8.25 Cs, 1H), 7.86 21),'7.58 (t, J 6;9 Hz, 1W), 6.62 Cs, 1H), 2.26 3H); MS 438.1 (M+11).

nm~E e2B2 (3-Hydroxymethylphenyl)-quinazolin-4-yj- (5-methyl-2-pyrazoi-3-yl)..amine (111-59): 'H NMR (500 MHz, DMSO-d6) 8 8.74 Cd, J 7.9 Hz, 11), 8.33 1W), 8.17 br, 1H), 7.95 Cs, br, 11), 7.89 br, 1H), 7.62 3H), 6-12 Cs, 1) 5'.53 s, n, 4.60 2W), 2.28 31); MS 332.1 MaIDml.. 28§l (5 :Xethy1-2H-prrazol-3 phenoxyphenyl)-quinazolin-4-yll p-ine (111-60): mp 231- 2320c; '11 NMR CDMSO-d6) 8 2.21 (3H, 6.59 (1H, 7.10-7.22 7.41-7.45 C2H, 7.54-7.59 (2H, m), 7.81 (2H, 8.09 (1H, 8.27 C1Wjm), 8.64 (1W, n), 10.40 (11, 12.20 (1H, IR (solid); Th (solid) 1589, 1560, 1541, 1536, 1484, 1360, 1227; MS 394.7 (M -303- ~Exiale 290 (5-Cyclopropyl-23-pyrazol-3-yl) E2'-(3phenoxyphenyl) -quiazolin-4-yl -amine (111-61): mp 193- 19500; 'H NMR (DMSO-d6) 0.67 (2H, 0.93 (2H, m),1.87 6.56 (13, 7.06-7.20 (4H, 7.40-7.43 (2H, 7.55-7.59 (2H, 7.81 (23, 8.11 (13, s),'8.27 (13, 8.63 (13, rn) 1 10.43 (iN, 12.26 (13, II

NO

(solid); IR (solid) 1589, 1574, 1527, 1483, 1369, 1226; MS 420.7 CM+H)+.

010

INDI

Exame 291 (5-Methyl-2H-pyrazol-3 (2-thiophen-3 -ylquinasolin-4-yl)-amine (111-62): 'HNMR (500 MHz, DMSO-dE) 811.78 br, IH), 8.75 J 8.1 Hz, 1H), 8.68 (s, 1H), 7.98 (dd, *J 7.9, 7.5 Hz, 13), 7.89 2H), 7.81 Cm, 7.68 Ct, J 7.5 Hz, 13), 6.69 13), 2.30 Cs, 3H); MS 308.1 Exanmre 292 (2-Phenyl-quinazolin-4-yl) (2H-pyrazol-3-yl) amine (111-63): mp 247-249-C; 'H NMR (DMSO) 8 6.99 (1H, br 7.49-7.58 (5H, 7.81 (1H, b 7.83 (2H, m), 8.47-8.49 (2H, 8.66 (1H, 10.54 (1H, 12.59 C1H, IR (solid) 3145, 2922, 1622, 1597; 'MS 288.2' Example 222 (2-Pyrazol-3-yl) -pyridin-4-yl-quinazolin- 4-yl)-aiine (111-64): tp 285-28SOC;1 'H NMR (DMSO) 8 6.99 (1H, br 7.65 (1H, 7.81-7.94 8.3-8.35 (2H, 8.73 (1H, 8.84-8.90 (23, 10.76 (13, s), I.2.6 m- (solid) 3180, 2972, 1600, 1574; MS 289.2 xamtle 2 5-Ethyl- 2H-pyrazol-3-yl) (2-phenylquinazolin-4-yl)-amine (111-65): mp 221-222-C; 'H NME -304- (DMSO) 6 1.31 (3H, 2.68 (211, 6.80 (1H, 7.50- 7.60 (4H, 8.45-8.55 (2H, 8.65-8.75 (1H, 10.44 12.27 IR (solid) 3190, 1622, 1595, 1575, 1533, 1482, 1441, 1420, 1403, 1361, 758, 711; MS 316.2 \O Examle 295 (2-Phenyl-quinazolin-4-yl) (5-propyl-2H- Cc, pyraol-3-yl)-amine (111-66): np 204-205OC; 'H NMR (DMSOo d6) 8 1.02 (3H, 1.66-1.75 (2H, 2.69 (2H, 6.80 10 (13, 7.45-7.60 7.80-7.88 (2H, 8.45-8.50 o 8.65 (11, 10.39 (1H, 12.25 (11, s);-IR (solid) 1621, 1560, 1572, i533, 1479, 1441, 1421, 1363, 1328, 999, 827, 808, 763, 709, 697; MS 330.2 Example 22J (5-Isopropyl-2-pyrazol-3-yl)- (2-phenylquinazolin-4-yl)-amine (111-67): mp 218-219oC; 3H NMR (DMSO-d6) 8 1.36 (6H, 3.05 6.86 (13, P), 7.48-7.59 (4H, 7.80-7.88 (2H, 8.49-8.58 (211, m), 8.66 (13, 10.47 (1H, 12.30 (1H, IR (solid) 3173, 2968, 1619, 1593, 1573, 1533, 1478, 1438, 1413, 1398, 1363, 1329, 995, 822, 798, 761, 707, 666,.659; MS 330.2 xaimptle 297 (5-tert-Butyl-2H-pyrazol-3-yl) (2-phenylquinatolin-4-yl) -amine (111-68): mp' 136-137 0 C; "H NMR (DMSO-dS) 8 1.38 (9H, 6.87 (1H, br 7.51-7.57 (4H, 7.84-7.85 (2H, 8.49-8.51 (2H, 8.65 d), 10.43 (13, 12.21 (1H, br IR (solid) 3162, 2963, 1621, 1590, 1572; MS 344.2(M+H).

Exampl 298 (5-tert-Butyl-23-pyrazol-3-yl)-(2-pyridin-4yl-quinazolin-4-yl)-amine (111-69): MP >300C; 13H NMR (DMSO) 8 1.38 (93, 6.82 (1H, br 7.63 (1H, m), -305- IN 7.86-7.91 (2H, 8.32-8.33 (2H, 8.69 (1H, d), o 8.75-8.76 (2H, 10.60 (1H, 12.31 (1H, br IR (solid) 3683, 3149, 2963, 1621; MS1345.2(M+H).

Example 229 (5-Cyclopentyl-2-pyrazol-3-yl) (2-phenylquinazolin-4-yl)-amine (111-70): mp 240-241oC; 1H NMR.

(DMSO-d6) 6 1.68-1.89 (6H, 2.03-2.17 (2H, 3.14-.

3.22 (1H, 6.80 (1H, 7.50-7.60 (4H, 7.80-7.89 (2H, 8.45-8.52.(2H,'m), 8.67 (1H, 10.52 (1H, s), CA 10 12.26 IR (solid) 2957, 1621, 1591, 1571, 1531, Va o 1476, 1438, 1405, 1370, 1325, 999, 951, 801, 775, 761, Ci 747, 710695, 668, 654; MS 356.2(M+H)+.

Example 300- (5-Phenyl-2H-pyrazol-3-yl) 2-phenylguinazolin-4-yl)-amine (111-71): mp 207-209 0 C; 1H NMR (DMSO) 8 7.38-7.40 (11, 7.50-7.58 (61R, 7.82-7.88 (4H, 8.51 (2H, 8.67.(1H, 10.58 13.11 (11, br IR (solid) 3345, 3108, :1627, 1612; MS 364.2 Example 301 (5-Carbozy 2-pyrazol- 3 -yl) (2-phenylquinazolin-4-yl)-amine (111-72): (5-Methoxycarbonyl-2Hpyrazol-3-yl) (2-phenyl-quinazolin-4-yl)-amine (111-73) (345mg, 1 mmole in THF, 6 mL) was treated with NaOH (1M, 4.0 mL), stirred at 50 0 C for 5 hours,. cooled to room temperature, and neutralised with M HC1. The mixture was concentrated in vacuo to remove THF then diluted with water and the resulting precipitate filtered. The residual solid was dried at 800C under vacuum to afford 111-72 as an off-white solid (312 mg, mp 289-2910C 1'H NMR (DMSO) 6 745 (1H, br 7.50-7.60 7.80-7.88 (2H, 7.40-7.50 (2H, 8.60-8.70 (1H, 10.70 (1H, 13.00-13.80 (2H, br IR (solid) -306- N 1699, 1624, 1607, 1570,1539, 1506, 1486, 1398, 1333, S1256, 1177, 1004, 827, 764, 705; MS 332.3(M+H) Example 302 (5-Methoxycarbonyl-2H-pyrazol-3-yl)- (2phenyl-quinazolin-4-yl)-amine (III-73): mp 271-273C; 1

H

NMR (DMSO) 8 3.95 (3H, 7.50-7.65 (5H, 7.80-7.98 (2H, 8.40-8.50 (2H, 8.65-8.73 (1H, 10.80 (1H, Om 13.80 (1H, IR (solid) 3359, 1720, 1624, 1597, o 1561, 1538, 1500, 1475, 1435, 1410, 1358, 1329, 1283, 0 10 1261, 1146, 1125, 1018, 1010, 944, 827, 806, 780, 763, o 703, 690,.670; MS 346.3(M+H) Example 303 (5-Hydroxymethyl-2H-pyrazol-3-yl) (2-phenylquinazolin-4-yl)-amine (III-74): A solution of Methoxycarbonyl-2H-pyrazol-3-yl) (2-phenyl-quinazolin-4yl)-amine (III-73) (345mg, Immol) in anhydrous THF was treated with lithium borohydride (125mg, 5.75 mmol) at 65 0 C for 5 hours. The mixture was cooled to room temperature then combined with 2M HC1 and ethyl acetate.

Solid sodium hydrogen carbonate was; added to achieve pH 8 and the resulting mixture extracted with ethyl acetate.

The extracts were dried over magnesium sulphate and concentrated. Purification by flash chromatography (SiO 2 methanol-dichioromethane gradient) afforded III-74 mg, 30%) as an off-white solid: mp 238-239 0 C; 1H NMR (DMSO) 6 4.58 (2H, d, CH2), 5.35 (1H, s, OH), 6.94 7.50-7.60 (4H, 7.85-7.90 (2H, 8.48-8.54 (2H, 8.69 (IH, 1H), 10.40 (1H, 12.48 (1H, IR (solid) 1652, 1621, 1603, 1575, 1558, 1539, 1532, 1480, 1373, 1320, 1276, 1175, 1057, 1037, 1007, 951, 865, 843, 793, 780, 7124; MS 318.2(M+H) -307- 1I IO xample 304 (5-Methoxymethyl-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl) -amine (111-75): tnp 190-191 0 C; 'H NMR (DMSO) 6 3.34 (3H, 4.45 (2H, 7.00 7.50- 7.62 (4H, 7.82-7.90 (2H, 8.45-8.52 (2H, 8.65 (1H, br 10.50 (1H, 12.30 (1H, IR (solid) 3177, 1606, 1589, 1530, 1479, 1441, 1406, 1374, 1363, 1329, .1152, 1099, 999,.954, 834, 813, 766, 707, 691; MS 332.3(M+H)+.

N 110 xamler 30a [5-(3-Hydroxyprop-1-yl)-2s-pyrazol-3-yl]-(2- phenyl-quinazolin-4-yl)-amine (III-.76): A solution of c- benzyloxypropyl -72H-pyrazol-3-yl) -(2-phenyl -quinazolin-4-.

yl)-amine (111-78) (200mg, 0.46mmol) in toluene (4mL) and acetonitrile (8mL) was stirred with trimethylsilyl, iodide (0.64ml, 4.6mmol) at 55 0 C for 3 hours to afford an amber coloured solution. This mixture was diluted with ethyl acetate and aqueous sodium hydrogen' carbonate. The resulting layers were separated, the organic layer was dried over magnesium sulphate and concentrated in vacuo.

Purification by flash chrominatography (Sio 2 methanoldichloromethane gradient) affords a yellow oil (115mg).

Trituration with dichloromethane affords 111-76 as an off-white solid dried at 75 0 C under vacuum (83mg, mp 164-165 0 C; 1H EMR (DMSO) 6 1.80-1.90 (2H, 2.70-2.80 (2H, 3.50-3.60 (2H, 4.59 (1H, 6.80 (1H, s), 7.50-7.60 (41, 7.82-7.90 (2H, 8.48-8.53 (2H, m 8.63 (1H, 10.40 (1H, 12.25-(1, IR (solid) 1622, 1587, 1574, 1562, 1528, 1480, 1440, 1421, 1368, 1329, 1173, 1052, 1030, 1006, 952, 833, 762, 734, 706, 690, 671, 665; MS 346.0(M+H)+.

zjamjle 306 [5-(3-Methosyprop-1-yl)-2E-pyrazol-3-ylJ phenyl-quinazolin-4-yl)-amine (111-77): mp 169-170 0 C; 'H -308- INDMR (DMSO-d6) 8 1.86-1.97* (2H, 2.75 (2H, 3.30 (3H, 3.45 (2H, 6.80 (1H, 7.50-7.60 (4H, 7.80- 7.90 (2H, 8.45-8.55 (2H, 8.67 (1H, 10.30 (1H, 12.25 (1H, IR (solid) 1620, 1591, 1572, 1532, 1476, 1425, 1408, 1373, 1326, 1117,. 1003, 831, 764, 714, 695; MS 360.3(M+H).

Va E Iamle 307 3 -Benzyloxyprop-1-yl)-2H-pyrazol-3-yl]- (2-phenyl-quinazolin-4-yl)-amine (I1I-78): mp 177-178* 0

C;

10 H NMR (DMSO) 8 1.92-2.03 (2H, 3.76-3.85 (2H, m), 3.52-3.62 (2H, 4.51 (2H, 6.82 (11H, 7.28-7.40 cl (5H, 7.46-7.58 (45, 7.80-7.85 (2H, 8.47-8.52 (2H, 8.661(1H, 10.45 (1H, IR (solid) 1621, 1591, 1562, 1532, 1479, 1454, 1426,.1408, 1374, 1101, 1006, 835, 766, 738, 712, 696; MS 436.3(M+H).

Example 308 [5-(3-Aminoprop-l-yl)-2H-pyrazol-3-ylJ-(2phenyl-quinazolin-4-yl)-amine (111-79): A solution of (3-tert-butoxycarbonylaminoprop-l1-yi)-2H-pyrazol-3-yl]- (2-phenyl-quinazolin-4-yl)-amine (111-80) (250mg, 0.56mmol), in dichloromethane (3mL) at 0 0 C was treated with TFA (2mL). The mixture was warmed to room temperature then concentrated in vacuo. The residue was triturated and concentrated from dichloromethane and ether, then triturated with dichloromethane to crystallize the TFA salt. The resulting solid was collected by filtration and dissolved in a mixture of ethanol (3mL) and water-(3mL). Potassium carbonate was added in portions to achieve pH 8 then the mixture allowed to crystallize. The product was collected by filtration and dried at 80 0 C under vacuum to afford 111-79 as an off-white powder (122mg, 63): mp 205-207C; 1 H NMR (DMSO) 8 1.68-1.83 (2H, 2.65-2.80( 4H, 6.80 (11, -309- IN 7.50-7.60 (4H, 7.80-7.90 (2H, 8.45-8.53 8.65 (1H, 10.45 (1H, -br IR (solid) 1621, 1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 951, 830, 776, 764, 705, 677; MS 345.3(M+H)*.

SExamle 309 [5-(3-tert-Butoxycarbo ylaminopopp-1-y1)-2Hpyrazol-3-yl] (2-phenyl-quinazolin-4-yl)-amine (111-80): mp 199-200OC; 'H NMR (DMSO) 8 1.37 (9H, 1.71-1.82 2.67 (2H, 3.00-3.11 (2H, 7.81 (1H, s), C 10 7.99 (1H, 8),.7.50-7.60 (4H, 7.80-7.85 (2H, 8.48o 8.52 (2H, 8.63 (1H, 10.40 12.26 (1H, m); ciIR (solid):2953, 1687, 1622, 1594, .1573, 1535, 1481, 1441, 1419, 1364, 1327, 1281, 1252, 1166, 1070, 1028; 998, 951, 848, 807, 768, 740, 728, 710,693; MS 445.3 Baample 310 5-Isopropylcarbamoyl-2H-pyrazol-3-yl) (2phenyl-quinazolin-4-yl)-amine (II-81): H NMR (500MHz, DMSO-d6) 6 1.20 J 6.6 Hz, 6H), 4.13 1H), 7.42 (br. s, 1H), 7.61 (dd, J 7.0, 7.7 Hz, 2H), 7.66 J 7.1 Hz, 1H), 7.71 1H), 7.99 21H), 8..39 1H), 8.42 J =7.1 Hz, 21), 8.74 J 8.2 Hz, 11), 11.41 (br. s, 1H); EI-MS 373.2 HPLC-Method C, Rt 14.09 nmin.

92ampe 311 (5 -Ally1carbamoyl-2E-pyrazol-3-yl) (2-phenylquinazolin-4-yl)-amine (111-82) 'HINMR (500MHz, DMSO-d6) 4.02 2H), 5.15 1H), 5.23 1H), 5.94 1H), 7.45-(br..s, 1H), 7.60 J 6.9 Hz, 2H),-7.64 11), 7.72 7.98 2H), 8.43 8.72 J 8.2 Hz, 1H), 8.84 (br. s, 11), 11.34 (br. s, 1H); EI-MS 371.2 HPLC-Method C, Rt 13.67 min.

-310- NDtExg 312 15- (2-Metoxyethylaarbamoyl) -20-pyrazol-3yll-( 2 -phenyl-qainazolin-4-y1) -amine (111-83): 'H NM S(500MHz, DMSO-dg) 8 3.32 31), 3.48 41), 7.36 (br.

s, 1H), 7.62 2H), 7.63 1H), 7.71 (im, 1K), 7.98 21), 8.41 (dd, J 1.4, 7.0, 2H), 8.70 2H), 11.30 (br. s, 1K); El-MS 389.2 EPLO-Method C, Rt 12.37 IND min.

o saule 313 (5-Benzylcarhamoyl -2H-pyrazol-3-yl)- (2- IND 10 phenyl-qninazolii-4-y1)-amjne (111-84): 'H IMR (500MHz, DMSO-d6) 8 4.52 J 6.0 Hz, 7.29 1H1), 7.38 J 4.2 Hz, 41), 7.58 J 7.5 Hz, 21), 7.63 (m, 7.72 1H), 7.98 2H), 8.43 J 7.7 Hz, 2H), 8.72 J 7.5 Hz, 11), 9.23 (hr. s, 2K), 11.34 (br. s, 11); El-MS 421.2 HPLC-Method c, Rt 16.76.

maLn.

Exaple 314 Cyclohexylcarbamoyl-2-pyrazol-3-yl)- (2phenyl-qu~nazolin-4-yl) -amine (111-85): 'H NMR (500OMHz, DMSO-d) 8 1.16 1H), 1.34 Cm, 4H), 1.62 J 2.6 Hz, 1H), 1.76 2H), 1.85 2H), 3.79 11), 7.43 1H), 7.60 J 7.2 Hz, 2H), 7.65 J 7.1 Hz, 1H), 7.71 (ddd, 2.2, 5.4, 8.2 7.98' 2H)', 8.35 8.43 (dd, J 7.2 Hz, 21), 8.72 Cd, 3 8.2 Hz, 1H), 11.34 (br. s, 1K); El-MS 413.5 HPLC-Method C, Rt 17.18 min.

Exaple 315 (5-Diethylcarbaoyl-a.-pyrazo..3-yl),- (2phenyl-quinazolin-4-yl)-amine (111-86): 'H NMR (5001Hz, DMSO.-d) 8 1.18 (br. s, 311), 1.25-Cbr.-a, 3K), 3.49 (hr.

B, 2H), 3.69 2H), 7.21 Cs, 1H), 7.'59 6.9 Hz, 2H),.7.62 Cm, 11), 7.70 1H), 7.96 2H), 8.39 -311- N J =7.1 Hz, 2H), 8.74 J 8.4 Hz, 1W), 11.37 (br.

s, 1H); EI-MS 387.2 HPLC-Method C, It 14.50 min.

9Kamgje2-3Jj (Benzyl-methyl-carbamoyl).-20-pyrazol-3 ylI (2 -phenyl-quinazolin-4 -yl) -samt ne (111-87): 'H MR (5001Hz, DMSO-dE) 8 3.33 3H), 4.75 2H), 7.26 Cm, 1H), 7.31 1H), 7.38 Cm, 4H), 7.58 2H), 7.70 Cm, No 1H), 7.95 3H), 8.26 Cm, 1H), 8.40 Cd, J 7.8 Hz, 2H), 8.75 1H), 11.2 (br. s, 1W); El-MS 435.2 (tM+H); C HrC-Method C, Rt 16.77 min.

Example 317 (2-Phenyl-quinazolin-4-yl) prpylcarbamoyl-2H-pyrazol-3-yl) -amine (111-88): IH NMR (5001Hz, DMSO-AG) 8 0.94 J 7.3 Hz; 3H), 1.57 (m, 21), 3.24 3 Hz, 2H), 7.39 (br. as 7.60 (t, J 7.3 Hz, 2H), 7.64 1K), 7.71 (br. t, J 6.5 Hz, 1H), 7.98 Cm, 2H),'8.42 J 7.2 Hz, 2H), 8.61 (br. s, 1KH) 8.72 J 8.5 Hz, 1H), 11.34 Cbr. a, 1W); EI-MS 373.3 HPLC-Method C, Rt 13.51 min.

Exaue 318 CEthyl-isopropyl-carbamoyl) -2E-pyrazol-3ylJ- (2-phenyl-quinazolin-4-yl) -amine (111-89): 'H NuvIR (500MHz, DMSO-d6) 80.92 t, J 7.4 Hz, 6H), 1.52 Cm, 2H), 1.59 1H), 3.79 Cm, 2H), 7.53 Cbr. a, IH), 7.57 t, J 7.5 Hz, 2H), 7.65 Ct, J 7:2 Hz, 1H),-7.71 (m, 1K), 7.99 2H), 8.23 (br. d, J 8.8 Hz, 1H), 8.46 (d, J 7.5 Hz, 2H), 8.74 J 8.4 Hz, 1K), 11.34 Cbr. a, 1H); El-MS 401.2. HPLC-Metbod'C, Rt 15.51 min.

an l2 31 (5-Cyclopropylcarbazoyl-25-pyrazol-3-yl) (2pheayl- inasolin-4-yl)-amine (111-90): 'H Ni (SOOMHz, DMso-d).8 0.60 Cm, 2H), 0.74 2H), 2.86 Cm, 1H), 7.34 (br. s, 7.62 Cm, 3H), 7.70 Cm, 11), 7.97 Cm, 2H), -312- IN B.41 J 7.9 Hz, 2H), 8.63 (br. s, 1H), 8.72 J 7.8 Hz, 1H), 11.35 (br. s, IH); El-MS 371.2 (MiH); HPLC- Method C, R 12.64 min.

gQxa=e 320 (SIsobutylcarbamoyl -25-pyrzol-3-yl)-(2pbenylqainazoli-4 -yl)-amine (11-91): 'H NMR (500MHz, INDDMSO-dE) 0.94 J 6.7 Hz, 6H)' 1.88 11), 3.12 ON J 6.4 Hz, 2H), 7.45 (br. IH), 7.58 J 7.2 Hz, 3H), 7.64 Js 7.1 Hz, 11), 7.71 1H), 7.98 (m, Cl 10 2H), 8.44 (dd, LT 1.3, 7.9 Hz, 2H), 8.62 (br. s, 1H), Va o 8.72 J 8.3 Hz, 1H), 11.33 (br. s, 11); El-MS 387.2 HPLC-Method C, Rt 14.70 min.

Exare 321 {5-((39)-3-Methoxymethyl-pyrrolidine-icarbonyll -2-pyrazol-3-yl}- (2-phenyl-quinazolin-4-yl) amine (111-93): 'H NMR (SO0Hz, DMSO-dE) 8 2.00 2R), 2.12 1M), 3.29 3H), 3.45 Ct, J 8.7 Hz, UH), 3.57 (dd, J 3.2, 9.3 Hz, 11), 3.86 1H), 3.92 (m, 4.36 2H), 7.45 (br. s, 1H), 7.59 J 7.2 Hz, 7.63 iH), 7.69 11), 7.97 21), 8.40 L Hz, 2H), 8.74 J 7.6 Hz, 11.38 Cbr. s, El-MS 429.2 ;IJfPLC-Hethod C, Rt 13.84 min.

Exsample 322 (2-Phenyl-qunazolin-4-yl)- (3-mtolylcarbamroyl-23-pyrazol-3-yl) -amiie (111-94): '1 NMR (5007Hz, DMSO-d6) 8 2.33 3H), 6.97 J 7.5 Hz, 7.27 Ct, J 7.8 Hz, 11), 7.62 7H), 7.72 (m, 7.98 Cm, 2H), 8.46 Cdd, J C 2.0, 7.9 Hz, 2H), 8.71 Cm, 10.29 11), 11.31 (br. a, 11); El-MS 421.2 HPLC-Method C, Rt 17.11 min.

£axa=3-tf23 (2-Phenyl-quinazolin-4-yl)-(5.,p-.

tolylcarbamoyl-2H-pyrazol-3-yl) -amine (111-95): 1H NMR -313n~c- llr~ 1r- IND(5001Hz, DMSO-d6) 8 2.30 3H), 7.20 J 8.3 Hz, 2H), 7.62 SE), 7.68 J 8.3 Hz, 2H), 7.72 (m, 7.98 2H), 8.46 (dd, J 1.8, 7.0 Hz, 2H), 8.72 lI), 10.31 1H), 11.36 (br. s, 1H); El-MS 421.2 HPLC-Method C, Rt 16.95 min.

E C 5-324- (5-ethylcarbamoyl-2H-pyrazol-3 phenyl-quinazolin-4-yl) -amine (111-96) 'H NMR (5001Hz, DMSO-dE) S 2.82 J 4.6 7.31 Cbr. s, 11), 7.62 7.69 1H), 7.97 2H), 8.42 Cd, J= o 7.1 Hz, 2H), 8.59 Cbr. a, 8.71 J 8.0 Hz, 11), Ci 11.30 (br. 111); El-MS 345.1 HPLC-Metbod.C, Rt 11.02 min.

Examp3, [-355- (Xorpholine-4-carbonyl) -2H-pyrazol-3-yl (2-phenyl-quiazolin-4-yl)-amine (111-97): 1H NMR (500MHz, DMSO-dE) 8 3.33 4H), 3.83 (m 4H), 7.34 (br. 11), 7.53 41), 7.86 21), 8.43 2H), 8.67 J= 8.6 Hz, 1H), 10.70 1H), 13.56 IH); EI-MS 401.2 HPLC-Metbod A, Rt 2.68 min.

[xamle 326,15- (l-Methylpiperazine-4-cabonyl) pyrazol-3-yl] (2-phenyl-quinazolin-4-yl) -amine (131-98): 'H NMR (SOOMHz, DMSO-d) 8 2.25 13H), 2.43 4H), 3.87 (m 41), 7.33 (br. a, 1H), 7.53 Cm, 41), 7.87 (m, 2H), 8.45 Cm, 2H), 8.67 J =7.6 Hz, 1H), 10.70 (s, 11), 13.30 1K); El-MS 414.2 HPLC-Metbod A, R- 2.38 min.

xamle 3.22 2 -Eydroxyethylarbamoyl-2a-pyrazo2.-.3-yl (2-phenyl-quinazolin-4-yl)-amune 'LH NMR (500MHz, DMSO-d6) 8 3.36 Cm, 211); 3.52 2H), 4.79 11), 7.50 Cm, 5H), 7.83 8.50 4H), 10.52 (br. a, 1K), -314-- 13.25 1H); EI-MS 375.1 HPLC-Method A, Rt 2.51 o min.

Ble 328 (5-Carbamoyl-2BH-pyrazol-3-yl) -(2-phenylquinazolin-4-yl)-amine (III-100): To a solution of 5-(2phenyl quinazolin- 4 -ylamino) 1H-pyrazole-3-carboxylic INDacid 2,5-dioxo-pyrrolidin-1-yl ester (270 mg, 0.63 mmol) C*N in DMF .(20 ml) was added a solution of ammonia in 1,4dibxan 10 ml). The resulting mixture was stirred at room temperature.for 24 h. After

IND

concentration of the solvents, the residue was added to CA water (20 ml). The resulting precipitate was collected to afford III-100 (168 mg, 80%)as a yellow solid. 1H NMR (500MHz, DMSO-d6) 8 7.77-7.51 6H), 7.86 (br s, 2H), 8.11 8.50 2H), 8.63 11), 10.52 1H), 11.25 1H); EI-MS 331.1 HPLC-Method A, Rt 2.52 man.

Example 329 (4-Bromo-2B-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (III-101): Prepared according to Method A to afford a yellow solid, rnp 189 0 C; 'H NMR (DMSOd) 8 7.44-7.46 (3H, 7.58 (1H, 7.87 (2H, 8.15 (3H, 8.31-8.34 (2H, 8.49 (1H, 10.08 (1H, s), 13.13 (1H, IR (solid) 3286, 2969, 1738, 1632; MS 366.2/368.2(M+H)+.

Example 330 4 -Bromo-5-methyl-2-pyrazol-3-yl) (2-phenylquinazolin-4-yl)-amine (111-102): mp 183-185 0 C; 'H NMR (DMSO) 8 2.33 (3H, br 7.44-7.46 (3H, 7.57 (1H, .7.84-7.87 (2H, 8.31-8.34 8.48 (1H, d), 10.05 12.91 (1H, br IR (solid) 3362, 3065, 2831, 1619, 1578; MS 380.2/382.2(M+)+.

-315- INDmDzfl331 (4-Cyano-2N9-pyrazol-3-yl) (2-plenylquinazolin-4-yl) -amine (111-103): MP >250cC; '1 N? m (DMSO) 8 7.47-7.49 7.64 (1H, 7.91 (2H, 8.40- 8.43 (2H, 8.53 (1H, 8.7-1 10.61 (3M, s), 13.60 (1H, IR (solid) 3277, 3069, 2855, 2231, 1625; 0 MS 313.2(MiH) 4 Exime 332 (5-Methyl-2H-pyrazol-3-yl)-(2-morpholin-4-ylquinazolin-4-yl)-anine (111-104): mp 223-224W; 'HKNMR (DMSO) 5 2.26(3H, 3.65(4H, 3.75(4, 6:44(l1f, 7.12(1K, 7.33(1H, 7.56(3-, 8.37(11, d), 10.01(1, 12.13(1, hr s),.IR (solid) 1621, 1578, 1537, 1475, 1434, 1385; MS 11.0 (M+H) 4 EmB2&2. 333- (5-Methyl-2H-pyrazol-3-yl) -(2-piperazin-1-ylquinazolin-4-yl) -amine (111-105): nip 179-181OC; 1 NMR (DMSo) 8 2.26(3H, s),,2.74 (4H, hr 3.71(4, hr a), 6.43(1l, 7.08(1!, 7.30(1K, 7.53(11, t), 8.34(1W, 9.50(1, 12.08(11!, hr R (solid) 2853, 1619, 1603, 1566, 1549, 1539; MS 310.0 Rrgjje 334 (4-Methylpiperidin-1-Tyl) -qutnazolin-4-ylJ (5-msthyl-2-pyrazol-3-yl) -amine (11-106): np 148-150-C; 1H NMR (DMSO) 8 1.06(3H, 1.03(2K, 1.51-1.70(3H, 5 2.26(3H, 2.86(2, 4.73(2H, 6.44(1K, a), 7.06(1!, 7.29(11!, 7.52(11, 8.32(1H, dl, 9.92(1K, 12.09(IH, br IR (solid) 2917, 2840, 1629, 1593, 1562, 1546, 1486; MS323.0 Exanml'335 (4-Methylpiperazin-1-yl) -quinazolin-4-yl (5-methyl-2E-pyrazol-3-y1) -amine (111-107): np 105-107OC; 11! NMR (DMSO) 8 2.21(31, 2.26(3H, 2.34(4H, m), 3.75(4H, 6.45(11!, 7.09(1H, 7.31(1H, d), -316- ID7.54(1H, 8.34(1H, 9.96(1H, 12.12(1H, br s); IR (solid) 2934, 2844, 2804, 1620, 1593, 1572, 1536, 1476; MS 324.0 Example 336 (5-Methyl-2-pyrazol-3-yl)-(2-piperidin-1-ylquinazolin-4-yl) -amine (111-108): mp 294oC; HI NMR (DMSO) IN 8 1.45-1.58 (4H, 1.63 (21, 2.26 (3H, 3.79 S(4H, 6.45 (1H, br 7.06 7.29 (1H, d), 7.52 (11, 8.33 (1H, -9.92 (1H, 12.11 (1H, br ci 10 IR (solid) 2929, 2847, 1632, 1591, 1500, 1482, 1437, 1382; MS 309.3 Examle 337 (2-Azepan-1-yl)-quinazolin-4-yl] 2H-pyrazol-3-yl)-amine (111-109): mp 269 0 C; 'H NMR (DMSO) 8 1.50 (4H, br 1.76 (4H, br 2.25 (3H, 3.78 (4H, 6.55 br 7.03 7.28 (1H, d), 7.50 (1H, .8.33 (1H, 9.92 12.09 br IR (solid) 3427, 2963, 2927, 2909, 2872, 2850, 1623, 1595, :1586, 1568, 1504, 1486, 1468, 1386, 1427; MS 323.3 Exapl 13e-38 2- (4-(2-Hydroxyethylpiperidin-1-yl)quinazolin-4-yl] -(5-methyl-23-pyrazol-3-yl)-amine

-(III-

110): mp 175C; 1H NMR (DMSO) 8 1.08 (2H, rh), 1.38 (2H, 1.57-1.83 (3H, 2.26 (3H, 2.85 (2H, 3.47 (2H, 4.38 (1H, 4.75 (2H, 6.45 (1H, br s), 7.06 (1H, 7.29 7.52 (1H, 8.32 (1H, d), 9.93 (1H, 12.12 (1H, br IR (solid) 3365, 3073, 2972, 2868,- 1622, 1604, 1586, 1568, 1486, 1463, 1440, 1394; MS 353.2 Example 339 (5-Cyclopropyl-25-pyrazol-3-yl) methylpiperidin-1-yl) -quinazolin-4-yl -amine (III-111): -317- IND To a solution of (5-cyclopropyl-1H-pyrazol-3-yl)-(2chloro-quinazolin-4-yl)-amine (118 uig, 0.41 mmol) in tert-butanol (3.0 mL) was added 4-m ethylpiperidine (0.49 mL, 4.1 mmol) and the reaction.mixture heated at reflux overnight. The reaction mixture was concentrated in o vacuo and the residue dissolved in 'a mixture EtOH:water 4 nL). Potassium carbonate (57mg, 0.41 mmol) was Va added and the mixture stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water and rinsed with Et 2 0 (x2) to afford III- IN 111 as a white solid (123mg, mp 190C; 1H IMR (DMSO) 6 0.66 (2H, 0.93 (58, br 1.07 (2H, 1.66 (3H, 1.91 (1H, 2.85 (2H, 4.72 (2H, 6.33 (1H, 7.06 (1H, 7.29 (1H, 7.52 8.31 (1H, 9.95 (1H, 12.18 (1H, br IR (solid) 2925, .2852, 1622, 1590, 1581, 1558, 1494, 1481, 1453, 1435, 1394; MS 349.2 Exampl 340 (1,4-Dioxa-8-aza-spiro 14, 5]dec-8-yl) quinazolin-4-yl (5-methyl-2H-pyrazol-3-yl)-amine (III- 112): mp 191oC; 1H NMR (DMSO) 8 1.65 (41H, 2.26 (3H, 3;90 (4H, 3.93 (41, 6.43 (1H, br s),:7.09 (1H, 7.32 (1H, 7.54 (11, 8.35 (1H, 9.99 (1H, br 12.13 (1H, br IR (solid) 3069, 2964, 2927, 2868, 1618,1581, 1568, 1540, 1495, 1481, 1435, 1390; MS 367.3 Examle 341 [2-(4-Cyclopentylamino-piperidin-1-yl)quinazolin-4-yll- (5-methyl-2H-pyrazol-3-yl) -amine (III- 113): mp 191 0 C; 'H iMR (DMSO) 8 1.33 (2H, 1.65 (4H, 1.87 (2H, 2.20 (1H, 2.26 (3H, 2.49 (2H, 3.00 (21, 3.36 (2H, 4.61 (2H, 6.45 (1H, br 7.07 (1H, 7.31 (1H, 7.52 (1H, 8.33 -318- Va d),'9.94 (lH,.br 12.12 (1H, br IR (solid) 0 3371, 2943, 1622, 1600, 1581, 1545, 1509, 1463, 1440, 1390; MS 378.2 (M+H) 4 Ejmnple 342 (4-Eydroxypiperidin-1-yl) -quinazolin-4yl] (5-methyl-20-pyrazol-3-yl) -amine (111-114): mp 123OC; O 1H NMR (DMSO) 81.34 (2H, 1.80 (2H, 2.26 (3H, a), C) 3.24 (2H, 3.72 (1H, br 4.39 (2H, 4.70 (1H, o 6.44 (1K, br 7.07 (1H, 7.30 7.53 IND 10 8.33 (1i, 9.94 (1H, brs), 12.11 (1H, br s); o IR (solid) 3265, 3151, 2927, 2863, 1622, 1600, 1572, 1540, 1504, 1476, 1440, 1390, 1349, 1066, 1098; MS 325.3 Exaple 343 (5-Cyclopropy1-23-pyrazol-3-yl) hydroxy-4-phenylpiperidin-1 -yl) -quinasolin-4-yl] -amine (III-115) mp 131oC; 'H NMR (DMSO) 8 0.64 (2H, 0.93 (2H, 1.68 (2H, 1.83-1.97 in), 3.20-3.45 (2H, 4.69 (2H, 5.11 (1i, 6.37 (1H, br 7.08 (1H, 7.20 7.31 (3H, 7.49 (2H, 7.53 (in, 8.33 9.98 (1H, br 12.18 (1H, br s); IR (solid) 3362, 2952, 2934, 2911, 2870, 2825, 1618, 1584, 1570, 1559, 1536, 1481, 1459,.1431, 1372, 1336, 1213, 994; MS 427.6 Example 344 (5-Cyclopropyl-2H-pyrazol-3-yl) dihydro-isoindbl-2-yl)-quinazolin-4-yll-amine (I1I-116): Prepared according to Method E-I to affdrd an off-white solid, mp-237 0 C; 1 NMR (DMSO-d) 5 0.79 (2H, 1.00 (2H, 1.99 (iH, 4.92 (4H, 6.72 (1K, br a), 7.13 7.33 (2H, 7.30-7.48 (3H, 7.58 (1K, 8.40 (1K, 10.12 (1H, 12.17 (1s, IR (solid) 3449, 3318, 2850, 1623, 1595, 1577, 1541,1509, -319- ND 1482, 1432, 1391, 1359, 1141, 1027, 877, 814; MS 369.4 o Exmle 345 (2-Azepan-1-yl) -quinazolin-4-y13 cyclopropyl-20-pyrazol-3-yl)-amine (1III-117): bip 199- 200 0 C; 1H NMR (DMSO-d6) 8 0.60-0.70 0.90-1.00 ID(2H, 1.45-1.57 (4H, 1.70-1.85 (4H, 1.88-1.97 S(1H, 3.75-3.87 (4H, 6.42 (1H, 7.02 t), 7.27 (1H, 7.49 (1H, 8.29 9.91 s), 10 12.19 (11, bt IR (solid) 2929, 1624, 1595, 1581, IND I 1563, 1542, 1498, 1482, 1440, .1426, 1397, 1356, 1305, 1000, 825, 754; MS 349.2 Ejamle 346 (5-Cyclopropyl-2-pyrazol-3-yl) C[2-(3,4dihydro 1-isoquinolin- 2-yl)-quinazolin-4-yl] amine (III- 118): mp 182-184OC; "H NMR (DMSO) 8 0.75 (2H, 1.02 (2H, 1.96 (1H, 2.89 (2H, nm) 4.05 4.94 (2H, 6.46 (1H, 7.10 (1H, 7.21 (4H, 7.37 7.55 (1H, 8.36 (1H, d),.10.05 (1H, 12.23 (1H, br IR (solid) 1621, 1581, 1560, 1537, 1479, 1456, 1426, 1396, 1374, 1341, 1222; MS 383.3 .Exa2pe 347 (5-Cyclopropyl-2a-pyrazol-3-yl) dihydro-indol-1-yl)-quinazolin-4-yl] -amine (111-119): mp.

150-153OC; 'H NMR (DMSO) 8 0.74 0.98 (2H, d), 1.96 3.15 (2H, 4.25 (21, 6.45 (1H, br 6.88 (1H, 7.09 (1H, 7.20 (2H, 7.53 (1H, 7.65 (1H, 8.43 (2H, br 10.09 (1H, 12.28 (1H, br IR (solid) 1621, 1588, 1577, 1564, 1537, 1487, 1455, 1425, 1386, 1259; MS 369.3 Examle 348 (5-Cyclopropyl-2H-pyrazol-3-yl) hydroxymethylpiperidin- l-yl) -quinazolin-4-y1 -amine (III- -320- Va 120): mp 142 0 C; 1 H NMR (DMSO) 8 0.67 (2H, -0.96 (2H, 0 1.10 (2H, 1.55-1.70 1.91 2.85 (2H, 3.28 (2H, 4.48 (11, 4.76 (2H, 6.34 7.06 (1H, 7.30 (1H, 7.52 8.31 (1H, 9.96 (1H, 12.19 (1H, IR (solid) 3363, 3000, 2927, 2854, 1618, 1604, 1573,11536, 1509, 1477, ID1436, 1395, 1354, 1314, 1241, 1186, 1091, 995, 941, 823; ern MS 365.8 IN 10 Erampt 349 (5-Cyclopropyl-2E-pyrazol-3-yl)-[2-(3,4dihydro-2H-quinolin-1-yl)-quinazolin-4-yl -amine (III- 121): mp 137-145 0 C; 1H NMR (DMSO-d6) 8 0.55 (21, 0.88 (2H, 1.78 (1H, i.92 (2H, 2.75 (2H, 4.04 (2H, 6.20 (11H, br 6.97 (11, 7.14 (1H, m), 7.19 (1Hi, 7.42 (1H, 7.61 (1H, 7.67 (1H, d), 8.43 (1H, 10.64 (1H, 12.21 (1H, br sj; IR (solid) 1622, 1572, 1539, 1493, 1454, 1420, 1373, 1249; MS 383.3 Example iQ (5-Methoxycarbonyl-23-pyrazol-3-).- [2- (piperidine-1-yl)-quinazolin-4-yl -amine (III-122): 1I NMR (500MHz, CDC1 3 8l.7-1.8(6H, 8 3.8 (4H, 83.9 (3H, 8 5.5 (1H, 8 7.15 (1H, 57.4 (11, 8 7.6 (1H, 8 8.0 (1H, HPLC-Method B, (starting with H20) Rt 7.4 min; MS 353.24 ExamJle 351 (Piperidine-1-arbonyl) -2H-pyrazol-3-yl] [2-(piperidine-1-yl)-quinazolin-4-yl -amine (11-123): HPLC-Method B, (starting with.95% H20:0.1% TFA) Rt min; MS 406.30, 404.30.

Example 352 (5-Hydroxymethyl-2a-pyrazol-3-yl) [2- (piperidin-1-yl)-quinazolin-4-yl -amine (III-124): To a -321- IN solution of 111-122 (10.0 mg, 0.028mmol) in THF mL) at ambient temperature was slowly added a lM solution of LiAH 4 in THF (0.05 mL, 0.05 mmol). After 15 minutes the solution was quenched with water and IN HC1. The product was extracted from the aqueous layer with EtOAc. The oorganic layer was dried over MgSO 4 filtered, and concentrated in vacuo. The residue was purified by Va preparatory HPLC to afford 111-124 (4.0 mg, HPLC- Method B, (starting with 95% H 2 0:0.1% TFA) Rt 6.1 min; MS 10 325.13 323.13 0g Example 353 (5-Carbamoyl-2a-pyrazol-3-yl) 2-(piperidinl-yl)-quinazolin-4-yl] -amine (111-125): A solution of III-122 (1.5 g, 4.3 mmol) in 2.0 M NH 3 /MeOH (100 mL) was heated at 110 0 C for 2 days. The daik brown reaction mixture was concentrated in vacuo to afford a viscous oil which was purified by column chromatography to yield 0.7 g of 111-125. 1H NMR (500MHz, CD30D-d 3 81.6 (4H, 8 1.7 (2H, 5 3.3 (1H, 6 3.8 (4H, 8 (13, 8 7.15 (1H, 8 7.45 (1H, 8 7.55 (13, 8 (1H, HPLC-Method B, (starting with 95% H 2 0:0.1% TFA) Rt 5.9 min; MS 338.13, 336.15. Hxample 354 (5-Carbamoyl-2U-pyrazol-3-yl)-[2-(4methylpiperidin-1-yl) -quinazolin-4-ylJ -amine (II-126): HPLC-Method B, (starting with 95% H20:0.1% TFA) Rl 6.4 mi;'MS 352.19, 350.20.

Exanple 355 (5,7-Difluoro-1R-indazol-3-yl) -(2-phenyl- 5,6,7,8-tetrahydroquinazolin-4-yl)-amine (111-127): 1H IM.

(500 MHz, DMSO-d) 813.7 1H), 10.3 br, 13), 7.90 2H), 7.52 1H), 7.45 7.26 2.99 -322- D(Mi, 2H), 2.75 2H), 1.95 (br, 4) ppm; MS 378.24 o 376.23 CM-H); HPLC-Metbod A, Rt 3.04 min.

Example 356 2 -Phenyl-56,7, 8-ttrahydroquinazolin-4-yl) (S-trifluoromethy-2.s-indazol-3y1)' amine (111-128): 'H NMR (500 MHz, DMSO-d6) 813.4 11), 10.2 Cs, br, 1H), IND8.13 1N), 7.86 7.78 1H), 7.69 en 7.50 1N), 7.35 (dd, 2H), 2.89 Cm, 2H), 2.72 2H), 1. 90 br, 4H) ppm; MS (ESi) 410.24 405.23 c C HPLC-MethodA, Rt 3.19 min.

xale 357 (7-Fluoro-t&-indazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-129): 'H NR (500 MHz, DMSOd6) 813.6 iH),ii1.i br, 1N), 8.65 8.03 2H), 7.95 Cs, 2H), 7.67 in), 7.45 2H), 7.33 2H), -7.22 (dd, 1H1), 6.99 (td, 11I) ppm. MS m/e= 356.20 HPLC-Metod A Rt 3.00 min.

Smamle 3tS (5-Fluoro---indazol-3 (2-phenylquinazolin-4-yl) -amine (111-130): 'H NMR (500 MHz, DMSOd6) 813.2 Cs, 1N), 11.3 Cs, br, in), 8.67 1W), 8.04 2H1); 7.96 2H), 7.70 Cm, 11), 7.58 (dd, 11), '7.43 4H), .7.28 Ctd,. IN) ppm. lMS 356.20 CM+H); HPLC- Method A, Rt 3.00 min.

E~arle 359 (5,7-Difluoro-3x-indazoi-3-y) (2-phenylquinazolin-4-yl) -amine (111-131): 'H NMR '(500 MHz, DMSOd6) 513.7 1H), 8.65 11), 8.04 2H), 7.95 (s, 2H), 7.68 11), 7.45 (mi IN), 7.35 4H) ppm. MS r/es 374.17 HPLC-Method'A, Rt 3.07 min.

BKO~le jQ0 (2-Indazol-3-yl)- (3.trifluoromethylphenyl) -quinazolin-4-yll -amjne (III132) 'H NMR (5001Hz, -323- IND DMSO-d6) 7.06 Ct, 3H), 7.42 Ct, 12), 7.59 1H), 7.63 o Ct, 1H), 7.66 Cd, 1H), 7.71 1H), 7.80 7.98 2H), 8.33 Ii), 8.46 1H), 8.71 Cd, 12), 11.04 Cbr. a, 12.97 11); El-MS 406.1 HPLC- Method A, .Rt 3.15 min.

IND Exaa 361 (2-Phenyl-quinazolin-4-yl) (1ff-pyrazolo [4,3blpyridin-3-yl) -amine (111-133): 'H N2MR (500 MHz, DMSO-d6) 13.3 Cs, br, 1H) 11.4 Cs, bi, 1H), 8.78 1H), 8.58 (dd, 8.24 Cd, 1H), 8.10 Cm, 2H), 7.95 Cd, 2H), 7.86 \O 1) ot, N) 7.56 2H) 7.44 2H) ppm. MS 339.11 HPLC-Method"A, Rt 2.63 min.

ExanWle 362 [5-(3-Methoxy-phenyl) -oxo-S ,'-dibydro-13pyrazolo 3-cl pyridazin-3 -yl] (2 -phenyl-quinazoliln-4yl)-amine (111-134): 1H NMR (500 MHz, MeOH-d4) 88.65 (d, IH), 8.17 8.10 1H), 7.90 15), 7.75 Ct, 1H), 7.58 21), 7.25 Ct, 1H),6.95 Cm, 22), 6.85 (d, 1H), 6.80 Cs, 1H), 3.64 3H) ppm. MS mle= 462.2(M+H).

Examptle 363 (6-Oxo-5-phnyl-5,6-dihydro-1H-pyrazolo[4,3clpyridazin-3-yl)- (2-phenyl-quinazolin-4-yl) -amine CIXi- 135): NMR (500 MHz, MeOH-d4) 58.61 1H), 8.13 (m, 3H), 8.05 11), 7.85 Ct, IH), 7.70 Ct, IH), 7.58 (m, 2H), 7.32 Cm, 52), 6.79 Cs, 12) ppm. m/e= 432.2(MH).

lxupRmj 364 15-(4-Methoxy-phenyl)-6Aoxo-5,6-dihydro-1Hpyrazolo4,3-clpyridazin-3-yl] (2-phenyl-quinazolin-4yl)-amine (111-136): MS 462.2(M+2).

-324- INDkBXgp1.e 36.5 (2,4-Diahioro-phenyl) o-5, 6-dihydrolE-pyrazolo C4,3 -cjpyridazin-s-ylJ (2-phenyl-quinazolin-4yl)-amine (111-137): 'H 1Th (500 MHz, MeOH-d4) 88.63 (ca, cr41H), 8.17 4H), 7.89 1H),.7.-73 1H), 7.61 (t, 2H), 7.57 1H), 7.32 12), 7.21 12), 6.84 (s, 12) ppm. MS m/e= S0o.1(M+i).

IND

Iat~gi 36 [6-Oxo-5- (3-trifluoromethyl-phenyl) -5,6dihydro-1H-pyrazolo pyridazin-13-yJ (2-phenyl- 11-3) HNR(0 ~,MOo d4) 88.55 1H1), 8.19 2H), 7.92 Cm, 2H), 7.65 Cm, 3M), 7.45 2H), 7.25 Ct, 12), 7.13 Ct 1 12), 7.05 Ct, 12), 6.75 1K) ppm. MS m/e= 500.2 CM-eM).

Am&Wneta5J2 [6 -Oxo-5- Phenosy-phenyl) -5,6 -dlhydro ipyrazolo pyridazin-3 -yl] (2-phenyl-qudinazolin-4yl)-amine (111-139): MS 524.3CM-H).

Mm-l [6 5- (4 -c~horo-pheny1) -6 -oso-5,6 -dihydro -13pyrazolo pyridazin-3 -yl] -(2-pbheny1-quinato1Jn-4- *yl)-asine (111-140): MS 466.2CM+K).

Mamlet.2.Qa (2-imdazol-1-yl-qinazonin-4-yl) indazol-3 -amine (111-141): '.3H ISIIR (50014Hz, DMO-dE) 8 7.10 Ct, 1K), 7.44 12), 7.50 Cbr. s, 1H), 7.60 (d, 1H), 7.72 2K), 7.77 1K), 7.88 1K), 7.98 C(t, 12), 8.73 8.96 1H), 11.23 Cs, 1H), 13.06 1H); El-MS 328.1 CM-I); HPLC-Method A, Rt 2.93 min.

kamplt3-U (JS-Indazol-3-yi) -[2-42-"methyl-imidazol-i-ylquinazolini-4-ylJ -amine (111-142): 3.NR(0M~,DS-6 8 2.48 7. 10 110, 7.43 Ct,, 12), 7.57 .11), 7.60 12), 7.S67 Cd, 1H) 7. 76 (tdl 12) 7. 86 Cd, In) -325- IN 7.91 iN), 8.01 td, IN), 8.72 1H), 11.15 111), 13.10 1H); El-MS 342.1 HPLC-Method A, Rt 3.06 min.

Zxamprle 371f (1E-Indazol-3-yl)- (2-piperidin-1-ylquinazolun-4-yl)-amlne (111-143): 1 H NMR (5001Hz, DMSO-d6) IND8 1.48 3.60 Cm, 4H), 7.11 Ct, IH), 7.52 Ct, 1H), ON 7.55 lI), 7.64 1H), 7.69 Cd, 1H), 7.75 1H), 7.90 Ct, 8.58 1H), 11.82 sr. s, 1H), 13.25 (s, lIH); El-MS 345.1 HPLC-Method'A, Rt 3.03 min.

c ram2e 372 (1-undazol-3 -yl) (octahydro-quinolin- 1yl) -quinazolin-4-yl] -amine (111-144): 'H NMR DMSO-d6).8 0.6-1.9 13 3.15 ii), 3.25 IR)., 4.0 Cm, 1H), 7.10" 0.5H), 7.12 Ct, 0.5H), 7.55 (m, 2H), 7.66 0.5 7.69 0.5 7.77 7.91 11), 8.55 0.5 8.59(d, 0.5 11.46 11.54 Cs, 0.5 11.78 0.5 11.84 0.S H), 13.10 Cs, 0.5 13.12 Cs, 0.5 El-MS 399.3 HPLC-Method A, Rt 3.37 min.

Exaale 373 (1-hndazol-3-yl)-[2-(2, 6-dimethyl--morpholun- 4-yl) -quinazolu-4-y13 -amine (111-145): 1 H I NMR (SO0Hz, DMS-dE) 8 1.0 Cm, EN), 4.0 61),-7.12 Ct, iN), 7.41 (td, 11), 7.56 7.58 Cd, iN), 7.68 Cdd, 11), 7.77 1H), 7.93 1H), '8.60 11.69 13.16 iN); El-MS 375.3 HPLC-Method A, Rt 2.93 min.

EJxane 374 (5-Methy-2-pyrazol-3-yi) (2-phenylpyrtmidin-4-yl) -amine vp 245-246WC; H1 NMR (DMSO) 8 2.26 6.32 (1H1, br 7.07 (iH, br 7.48- 7.54 C3H, 1:33-8.39 (3H, 9.87 (1k1, 12.03 iH, -326- O S8); IR (solid) 1628, 1589, 1579, 1522, 1479, 1441, 1393, O 1336; MS 252.2 Example 375 (4-Acetamidophenylsulfanyl) -2-phenylpyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl)-amine (IV-3): A suspension of Fenclorim (4,6-dichloro-2- NO phenylpyrimidine) (O.1g, 0.44 mmol), methylpyrazole (0.045 g, 0.47 mmol), N, N- S. diisopropylethylamine (0.08 ml, 0.47 mmol) and sodium SC 10 iodide (0.067 g, 0.44 mmol) in n-butanol (5 ml) were Sheated at 117 °C for 18 hours. The solvent was removed in vacuo and the crude product purified by flash chromatography (silica gel, 3:2 Petrol:EtOAc)-to afford 0.037 g (29 yield) of (6-Chloro-2-phenyl-pyrimidin-4yl)-(5-methyl-2H-pyrazol-3-yl)-amine as a off-white solid. A suspension of the above pyrimidine (0.037 g, 0.13 mmol) and thioacetamidothiophenol (0.108 g, 0.64.

mmol) in tert-butanol was heated at 85 °C under nitrogen for 2 days. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The concentrate was dissolved in EtOAc, and washed with NaHCO (sat, The organic layer is concentrated in vacuo, and the crude product by preperative HPLC. The residual disulfide that still remained in the mixture after HPLC may be removed by precipitation from EtOAc and filtration. The mother liquor was concentrated to afford IV-3 (7mg, 13 yield) as an off-white solid: mp 235- 236 0 C; 'H NMR (DMSO) 8 2.10 (3H, 2.21 (3H, 6.33 (1H, br 7.50 (3H, 7.7-7.59 (2H, 7.76-7.78 (2H, 8.25 (2H, 9.72, 10.26 and 11.93 (3 H, 3 x br IR (solid) 1669, 1585, 1551, 1492, 1392, 1372, 1312, 1289, 1259, 1174, 1102, 1089, 1027, 1015, 984; MS 417.3 -327- Va Example 37 [2 (4-Methylpiperidin-1-yl) -pyrimidin-4-yl] (5-methyl-2E-pyrazol-3-yl)-amine mp 215-2160C; 'H NMR (CDO 3 D) 6 0.96 (3H, 1.16 (2H, nm), 1.66 (3H, n), 2.27 (3H, 2.86 (2H, 4.58 (2H, 4.78 (2H, exch.protons), 6.13 (2H, 7.83 (1K, IR-(solid) 1593, 1550, 1489, 1436, 1331, 1246, 1231; MS 273.1 en Sxample 377 [2-(4-Methylpiperidin-1 7 4-yl]-(5-methyl-2H-pyrazol-3-yl)-aiine mp 185- O .1870C; 1 H NMR (DMSO) 8 0.93 (3H, 1.06-1.18 (2H, m), Cl 1.68-1.80 (3H, 2.26 (3H, 3.01-3.12 (2H, 4.63 (1H, 4.80 (1H, 6.39 (1H, 9.00 (1K, 10.41 12.3.6 (1H, IR (solid) 1589, 1517, 1479, 1446, 1346, 1317, 1246, 1222, 1055; MS 318.2 Example 378 15-Amino-2-(4-Methylpiperidin-1-yl)pyrimidin-4-yll (5-methyl-2H-pyrazol-3-yl)-amine (IV-6): To a solution of IV-5 (48 mg, 0.151 mmol) in ethanol mL) was added tin dichloride dihydrate (171 mg, 0.756 mmol) and the resulting mixture heated at reflux for 3 hours. The reaction was cooled to room-temperature and poured onto a mixture of 1M NaOH:dichloromethane:propanol (18:8:4mL) and stirred for 15.minutes. The layers were separated and the aqueous layer extracted twice with dichloromethane. LThe combined organic layers were concentrated in vacuo and the residue purified by flash chromatography (silica gel, gradient dichloromethane:MeOH) to afford IV-6 as a grey solid (27mg, 1'H NMR (DMSO) 8 0.88-1.04 (5H, 1.55-1.62 (3H, 2.21 (3H, 2.70 (2H, 3.36 (2H, 4.40 (2H, m),.6.37 (1K, 7.49 (11, 8.40 (11, 11.92 (1H, br MS 288.2 -328oxml 37 [5-Amino-6-methyl-2 (4-methylpiperidin-1-yl)pyrimidin-4-yll -(5-methyl-23-pyrazol-3-yl) -amine (IV-7): mp 172-3175cC; 'LH WM (flmSO) 8 0. 90 (3H1, d) 1. 03 (2H1, in), 1.52-1.62 (311, mn). 2.13 (3H1, (311 a 2.69 (211, mn), 3.92 (211, br 4.44 (2H1, 6.35 (111, 8.41 I(1ND 11.85 (111, bras); IR (solid) 161-2, 1589, -1489, 1446, 1317; MS 302.5 IND 10 Eample2 6-Methyl-2- (4-methyl-phenyl) -pyrimidin-4o yll-(5-phenyl-2H-pyrazol-3-yl)-amine (27-1O): MS 342.34 HPLC-Method Rt 1.334 min.

xamnet381 Chloro -phenyl) -6-methyl -pyrimidin- 4ylJ- (5-furan-2-y1-2H-pyrazol-3-yl) -amine (IV-11): MS 352.11 (Mdl); HPLC Method E, Rt 1.1-94 min.

Exaaup2i 5-P'uran-2-yl-2H-pyrazol-3 -yl) -(6-inethyl-2 phenyl-pyrimiditn-4-yl) -amine (IV-12): MS 318.21 (Mdli); HPLC-Method E, 1.192 mini.

B---ma 8 [6-Methyl-2- (4-trifluoromethyl-phenyl) pyriLmidin-4-yl] -(5-phenyl-2-yl-2H-pyrazol-3,-yl) -amine (IV-13) MS 396.24 RPLC-Metbod E, Rt 1. 419 mini.

Exatpf384 Puran- 2-yl 2-pyrazol-3 -yl) -methyl -2- (4 -tri fluoramethyl -phenyl) -pyrimidin-4 -yl 1-amine (IV-14):.

MS 386.08 (Mdl); HPLC-Method E 1.347 mini.

Zample 3M [2-(2,3-Dihydro-benot,4)diozin-2-yl)-6meth yl-pyriiin-4-yl (5-furan-2-yl-2H-pyrazol-3-yl) MS 376.18 (Mdl) EPIC-Method R, Rt 1.181 min.

-329o Znp1~~A386 (2,3-Dhdo-eol4]diosin-2-yl) -6ethyl -pyrimidin- 4-yl] -(5-methyl -2H-pyrazol-3 -yl) -amine (ZV-16): MS 338.17 HPLC-Method E, Rt 1.082 min.

0m l 387pi±~i (6-Hthyl-2-phenyl-pyrimic'ttn-4-yl) 2H-pyrazcl-3-yl)-amine (IV-17): MS 280.18 (M+H);-HPLC- Method E, at 1.024mi-.

Lnpat.2e 3i (6-Methy-2-phenyl-pyriiadin-4-yl)-(5-pheny1- 2H-pyrazol-3-yl).-am4une MS 328.51 HPLC- 0 Method E, Rt 1.192 mini.

8 [6-Ethyl-2- (4-trifluoromethyl-phenyl) pyrimidin-4-yl] (5-methyl-2x-pyrazol-s-yl) -amine (3Iv-20):% MS 348.5 HPLC-Metbhod E, at 1.224 mini.

Exaple390 (S-Puran-2-yl-ZH-pyrazol-3-yl) -[6-methyl-2- (4 -=ethyl -phenyl) -pyr-imidin-4-yl] -aimine (IV-21): MS 332.23 HPLC-Method-E, at 1. 139 miii.

Example 391 (6-Xethoziymethyl-2-phenyl-pyrimidin-4-yl) methyl-2H-pyrazol-3-yl) Lamine (IV-22): MS 296.31 HPLC-Method E, It~ 0.971 mini.

MmanTh.2a (5,6 -Dimethyl -2 -phenyl-pyrimidin-4-yl) methyl-.2R-pyrazo.-3-y)-ainune (XV-23): MS 280.2 HPLC-_Method E, Rt 0.927-miii.

Exa.Iaa32 (6-Methyl-2-phenyl-pyrimidn4yl) 2H-pyrazol-3-yl)-amine.(Iv-24): MS 26.6.18 1{PLC- Method H, R, 0. 925 mini.

-33 0- Examle 94[6-Ethyl-2- (4-m'etbyl-phenyl) -pyrimidin-4-y1J 0 (5-methyl-25-pyrazol-3-yl)-.-amime (ZV-25): MS 294.46 HPLC-Method E, Rt: 1.174 min.

Ex~e3- [2 (4 -Chloro-phenyl) 6 -ethyl -pyrimidin-;4-yl] (5-methyl-23-pyrazol-3-yl)-amine (IV-26): MS 314.42 HPLC-Mettod E Rt 1. 213 nan.

o xx~E np~t..396 (5-Methyl-1H-pyrazol-3-yl) -(6-methyl-2-ptolyl-pyrimidin-4-yl) -amne,(xV-27): MS 280.45 HPLC-Method BE, Rt 1.135 min.

E~pjle 3j7 (1&-Indazol-3-yl) -(6-methosymethyl-2-phenyl-.

.pyrimidin--4-yl)-amine (IV-28): 1H NNR (500 MHz, 3.57 (3H1, 4.65 (2H, 7.23 (111, J=7.5 Hz, 7.52- (111, J=7.6 Hz, 7.63 7.75 (111, br), 8 .13 (111, Hiz, br 8.44 (1H1, J=5.7 Hz, br 10.6 (1H, br), 12.8 (1H, br s) ppm; HPLC-Method A, Rt 2.944 min; MS (PTA) 332.1 Exme 9 (5-Methyl-2H-pyrazol-3-yl) -(2-pyridin-4-ylthienoC3,2-dlpyrimidin-4-yl)-emine CIV-29):- NMR 82.34 6.66 (111, 7.53'(111, 7.84 (1H1, d), 8.32 (2H1, 8.70 (2H1, MS 309.6 Examle3Q9 (5-Methyl-2H-pyrazol-3-yl) -(2-phenyl., pyrido[j3, 4-dJ pyrimidin -4 -y1) -amine (IV-3 mp 225 0 C; "H NMR (DM80) 5 2.35 (3H, 6.81 (1H1, s),-7.50-7.63 (3H1, in), 8.45-8.52 (2H1. in), 8.54 (111, 8.62 (111, 9.20 (11, 10.79 12.38 (111, br 111 (solid) 2958, 2917, 2852, 1593, 1565, 1524,',1467, 1450; MS 303.2 -331- ND Ex lamle 400 (5-Methyl-23-pyrazol-3-yl) (2-phenylpyrido[2,3-d] pyrinidin-4-yl)-amine (IV-31): To a solution of 4-chloro-2-phenyl-pyrido[2,3djpyrimidine Pharm. Belg., 29, 1974, 145-148) (109mg, 0.45 mmol) inTHF (15 mL) was added pyrazole (48 mg, 0.5 mmol) and the tesulting mixture heated at 65 oC overnight. The mixture was cooled to room temperature and the.resulting suspension was filtered and washed with Et 2 O. The solid was dissolved in a mixture C 10 EtOH:water and the pH adjusted to pH 7. The aqueous was o extracted twice with ethyl acetate and the combined C- -organic layers were dried (MgS0 4 filtered, and concentrated in vacuo. The residue was'purified by flash chromatography (Sioz 2 DCM-MeOH gradient) to afford IV-31 as an off-white solid (69 mg, imp 2340C; 'H NMR (DMSO) 8 2.14 (3H, 5.99 (1H, 7.20-7.40 (3H, 7.40-7.50 (3H, 8.60 d),.8.79 (IH, 12.82 (1H, br IR (solid) 2957, 2921, 2857) 1644, 1560, 1459, 1427; MS 303.2 XaMlt 401 (5-Cyclopropyl-2-pyrazol-3-yl) (2-phenylpyrido[3,4-d]pyrimidin-4-yl)-amine (IV-32): off-white solid, mp 232-2330C; 1 H NMR (DMSO) 5 0.70-0.85 (2H, m), 0.90-1.05 (2H, 1.05-2.07 (1H, 6..75 (1H, 7.50- 7.75 (3H, 8.40-8.70 (4H, 9.20 (1H, 10.80 (1H, 12.41 IR (solid) 3178, 1601, 1573, 1532, 1484, 1452, 1409, 1367, 1328, 802, 781, 667; MS 329.2 (M+H) t Jap 4 t2-(4-Methylpiperidin- methyl-2H-pyrazol-3-yl)-amine (IV-33) To a suspension of 2,.4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 nt) was added 5-methyl-iH-pyrazol-3-yl amine (2.05 g, 21.2 mmol). The resultinginixture was stirred -332-

I

IN at room temperature for 48 h. The resulting precipitate, o was collected by filtration, washed with ethanol, and dried under vacuum to afford 1.524 g (58% yield) of (2chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used in.the next step without further purification.

To a,solution of (2-chloro-purin-4-yl) (5-methyl-1H- INDpyrazol-3-yl)-amine (200 mg, 0.80 mmol) was added 4methylpiperidine (4 mL, 8.01 mmol) and the reaction mixture heated at reflux overnight. The solvent was evaporated and the residue dipsolved in a mixture EtOH:water 4 mL). Potassium carbonate (57mg, 0.41 c- mnol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (x2) and rinsed with Et20 (x2) to afford IV-33 as a white solid (225mg, 901): mp >3000C; 1 NMR (DMSO) 8 0.91 (3H, 1.10 (2H, nm), 1.65 (3H, m), 2.24 (3H, 2.84 (2H, 4.60 (2H, 6.40 (1H, s), 7.87 (1H, 9.37-9.59 (1H, 12.03-12.39 (2H, IR (solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3 ExaB le 403 (5-Cyclopropyl-2B-pyrazol-3-yl)-[2-(4methylpiperidin-1-yl) -pyrrolo[3,2-d]pyrimidin-4-yll-amine (IV-34): white solid; 11H NMR (DMSO) 8 0.65 (2H, 0.91- 0.96 (5H, 1.08 1.58-1.64 (3H, 1.89 (1H, nm), 2.77 (2H, 4.57 (2H, 6.09 (1H, 6.38 (1, 7.33 (11, 9.42 (1H, 10..65 (11, 12.02 (1H, br MS 338.3 Exa1pe 4A04 6 -Benzyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-d pyrimid:in-4-yl (5-fluoro-1E-indazol-3-yl)amine 1H NMR (500 MHz, DMSO d) 813.0 1H), 10.4 br, 11), 9.73 1H, TFA-OH), 8.00 2H), -333- QD 7.64 2H), 7.59 (dd, IH), 7.52 3H), 7.41 1H), o 7.31 3H), 7.14 (dd, 1H), 4.58 2H), 4.35 (br, 2H), 3.74 2H), 3.17 2H) ppm. MS m/e= 451.30 HPLC-Method A, Trt 2.96 min.

SExample 405 (5-Fluoro-1H-indazol-3-yl)- (2-phenyl-5,6,7,8tetrahydro-pyrido[4,3-d]pyrimidin-4-yl) -amine (IV-36):

VO

Prepared from IV-35 (0.13 mmol) by treatment with an equal weight of Pd/C in 4.4% HCOOH in MeOH at room C 10 temperature for 12 h. The mixture was filtered through.

Scelite, the filtrate was evaporated, and crude product (C was purified by HPLC to afford IV-36 as yellow solid in yield. 'H NMR (500 MHz, DMSO-d6) 612.9 1H), 9.06 1H), 7.99 2H), 7.57 (dd, 1H), 7.34 1H), 7.28 3H), 7.22 1H), 3.83 2H), 3.05 2H), 2.72 2H) ppm. MS m/e= 361.20 HPLC-Method A, Trt 2.68 min.

Example 06 (5-Methyl-2H-pyrazol-3-yl) (3-phenylisoquinolin-l-yl) -amine To a solution of 1-chloro- 3-phenylisoquinoline Het. Chem., 20, 1983, 121- 128)(0.33g, 1.37 mmol) in DMP (anhydrous, 5 mL) was added (0.27g, 2.74 mmol) and potassium carbonate- (0.57g, 4.13 mmol)and the resulting mixture was heated at reflux for 6 hours. The reaction mixture was then cooled and solvent removed in vacuo. The residue was extracted twice with ethyl acetate and the combined organic layers washed with brine, dried (MgSO), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO 2 gradient DCM-MeOH) to afford V-l as a colourless oil; 1H NMR (MeOD) 8 2.23 (3H, 5.61 (1H, 7.41 (1H, 7.52(2H, m), -334- ID 7,62(1H, in), 7.81(1H,.m), 8.07.(1H, 8.19(2H, m), o 8.29(IH, 8.54 (2E, MS 301.2 ExamPle (1H-Indazol-3-yl) -[3-(2-trifluoromethylphenyl)-isoquinoline-1-yl]-amine (V A solution of 1chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (100 mg, IND0.326 mmol) and I.-indazol-3-ylamine (86-mg, 0.651 mmol) O in ethanol (3 nL) was heated at 160 C and the solvent evaporated with a stream of nitrogen. The remaining oil Ci 10 was then heated at 160 C for 18 hours under nitrogen.

Va o The resulting melt was dissolved in Ci methanol:dichloromethane (50 washed with saturated aqueous sodium bicarbonate.(l x 25 mAL) then dried over magnesium sulfate. Purification by silica gel chromatography (25% to 50% hexane:ethyl acetate) afforded V-2 as a yellow solid (35 mg, 1H NMR (500 MHz, DMSO) 8 9.78 (br s, 1H), 8.62 1H), 7.9-7.85 1H), 7.78-7.72 1H), 7.70-7.68 7.65-7.62 1H), 7.60-7.55 1I), 7.52-7.45 3H), 7.41-7.38 1E), 7.28-7.25 l1), 7.18 in), 6.95-6.92 lH), 5.76 1H); LC-MS m/e= 405.18 HPLC-Method D Rt 2.74 min.

Exaimn 408 (5,7-Difluoro-1&-indazol-3-yl)-[3-(2trifluoromethyl-phenyl)-isoquinolin-1-yll -amine Prepared from 5,7-difluoro-1H-indazol-3-ylamineto afford compound V-3 as a yellow solid (90 mg, "H NMR (500 MHz, d-DMSO) 8 13.25 1H), 9.92 (br s, 8.61 (d, I1), 7.9 1H), 7.81-7.49 7.26-7.2 2H), 7.12-7.10 1H); LC-MS m/e= 441.16 HPLC- Method D, Rt 3.58 min.

-335- Exale 40g (5-Methyl-2K-pyrazol-3-yl)-(2-phenylo quinolin-4-yl)-amine To a mixture of 4-chloro-2- N phenylquinoline Net. Chem., 20, 1983, 1 21-1 2 8)(0.53g, 2.21 mmol) in diphenylether (5 mL) was added methylpyrazole (0.43g, 4.42 mmol) and the resulting mixture heated at 200 0 C overnight with stirring. The reaction mixture was cooled to ambient temperature then petroleum ether (20 mL) was added and the resulting r precipitate was isolated byfiltration. The crude solid 0 10 was purified by flash chromatography (siO,, gradient DCMci o MeOH) to afford V-4 as a white solid: mp 242-244 0 C; H.NMR 0 (DMSO) 8 2.27(3H, 6.02(1H, 7.47(2H, 7.53- 7.40(2H, br 7.67(1H, 7.92(11, 8.09(2H, d), 8.48(2H, 9.20(1H, 12.17(1H, br IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 (M+H)4.

Example 410 (1&-Indazol-3-yl)-(2-phenyl-quinolin-4-yl)amine H NMR (500 MHz, d-DMSO) 8 12.78 1H), 9.50 1H), 8.65 1H), 8.15 1H), 8.04-7.98 (mn, 3H), 7.94 7.78-7.75 7.60-7.40 6H), 7.15-7.10 1H). LC-MS m/e= 337.11 HPLC- Method D, Rt 2.10 min.

Examwle A411 (2-Phenyl-quinolin-4-yl), (1-pyrazolo[4,3blpyridin-3-yl)-amine 1H NMR (500 MHz, DMSO-d6) 813.6 IH), 11.4 8.94 1H), 8.61 (dd, 1H), 8.23 1H), 8.16 (dd, 1H), 8.12 1H), 7.89 1H)., 7.86 1H), 7.65 41H), 7.54 1H), 7.52 (dd, 1H) ppm. MS mr/e= 338.11 HPLC-Methd A, HPLC- Method D, Rt 2.91 min.

EmB e 412 (1E-Indazol-3-yl) [2-(2-trifluoromethylphenyl)-quinolin-4-yl-amine 1H NMR (500 MHz, d- -336- Va o DMSO) 5 12.68 1H), 9.51 1H), 8.7 1H), 7.95- 7.89 2H), 7.83-7.70 3H), 7.68-7.62 2H), 7.60 1H), 7.55-7.52 1H), 7.49-7.45 1K), 7.40-7.37 1H), 7.12-7.09 LC-MS m/en 405.15 HPLC-Method D Rt 2.25 min.

Example Sa (5,7-Difluoro-Is-indazol-3-yl) e trifluoromethyl-phenyl) -quinolin-4-yl] -amine 1H NMR S(500 MHz, d-DMSO) 8 13.31 1H), 9.49 1H), 8.70- Va 10 8.67 1K), 7.96-7.92 1H), 7.85-7.66 (mi, 7H), 7.63o 7.60 1K), 7.42-7.40 1H).LC-MS m/e= 441.18 HPLC-Method D Rt 2.39 min.

Example 14 [2-(2-trifluoromethyl-phenyl)-quinolin-4-ylJ (1B-pyrazolo[4,3-b]pyridin-3-yl)-amine 'H NMR (500 MHz, DMSO-d6) 513.6 1H), 11.6 br, 1K), 8.98 (d, 1H), 8.57 (dd, IH), 8.12 3H), 7.97 2H), 7.86 (m, 3H), 7.49 (dd, 1H), 7.23 1K) ppm. MS m/e= 406.20 HPLC-Method A R, 2.91 min.

Exmale 41S (2-Phenyl quinaolin-4-yl) (2- [1,2,4Jtriazol-3-yl)-amine (11-154): off-white solid, mp 266-2267C; 'H NMR (DMSO) 8 7.50-7.70' (4H, 7.85-8.00 (2H, 8.15-8.25 (21, 8.37-8.45 (2H, 8.58 (1H, 13.90 (1K, br IR (solid) 3344, 3059, 1630, 1609, 1570, 1557, 1543, 1501, 1495, 1445, 1411, 1355, 1326, 1267, 1182, 1053, 1038, 760, 676, 667, 654; MS 289.2 Exam1e 416 (5-Methyl-2H-11,2,4]triaodl-3-yl)-(2-phenylquinazolin-4-yl)-amine (11-155): 1'H'NMR (500 MHz, DMSOds) 88.59 1H), 8.42 J 6.7 Hz, 2H), 7.79 (m, -337-

II

IN 4H), 8.03 2H), 7.74 4H), 2.151 3M)Y ppm. MS 0I m/e= 303.08 HPLC-Method A, Rt 2.64 min.

RX=Ie 4171 (2H-11, 2,41-Triazol-33-ll) (2 trifluoromethylphenyl) qinazolin-4 -yl3 -amine (11-47): Pale yellow solid (521 yield). H IMR (500 MHz, DMSO-d) 88.54 1H), 8.15 br, 1H), 7J91 11), 7.85 Cm, 2H), 7.76 3H), 7.66 Ct, H) ppm. MS r/e.

357.1W (ES-):3m5.e= is715 HPLC-Method A, Rt 2.81 min.

0 Example -428 (5-ethyl-2-{ 1,2,4Jtriazol-3-yl)- trifluoromethylphenyl) -qunazolin-4 yll -amine (11-38) Pale yellow solid yield). 3I* NMR (500 MHz, DMSO-d6) 58.44 br, 1H), 7.92 Cm, 3H), 7.184 Cm, 7.77 (m, 2H), 7.68 Ct, 11), 2.28 3H) ppm. MS m/e= 371.14 m/e= 369.18 (M HPLC-Method A, Rt 2,89 min.

Example 419 (5-Methylsulfanyl-2H- [1,2, 4 ltriazol-3-yl) [2- (2-trifluoromethylphenyl) -quinazolia-4-yl -amine (3x- 156): Pale yellow solid (65% yield). 'H NMR (500 MHz, DMSO-d6) 88.56 (br, M11), 7.90 1W, 7.84 2H), 7.78 7.67 2H), 2.51 3H, buried by fMSO) ppm.

MS (ESt): m/e= 403.12 m/e= 401.16 -HPLC-Method A,'Rt 3.20 min.

Exam&Ae 420 (lH- f1,2,4] Triaol--yl) (2 trifluoromethyl-phenyl) -isoqninolinl-yl] -amine (IX-175): A solution of 1-chloro-3- (2-trifluoromethyl-phenyl) isoquinoline (0.326 imol) and 1H- [11,2,4 jtriazol-3-ylamine (0.651 mmcl) in ethanol (3 mL) was heated at 1600C and the solvent evaporated with a stream of nitrogen. The -338- ND remaining oil was then heated at 1600W for 18 hours under o nitrogen. The resulting melt was dissolved in metbanol/dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1 x 25 mL) then dried over S' magnesium sulfate. Purification by silica gel chromatography afforded IX-175 as a colorless oil (4% INDyield). 3H NMR (500 MHz, CDC13) 6 -9.18 1H), 8.82 (s, 1H), 7.90 1I1), 7.85-7.75 3H), 7.71-7.62 3H), 7.60-7.55 2H), 4.42-4.35 LC-MS 356.16 HPLC-Method D, Rt 3.55 min..

Ci Egample 421 (2-Phenyl-quinolin-4-yl)-(Lj- [1,2,4]triazol- 3-yl)-amine (1X-176): Pale yellow solid (30% yield). 'H NMR (500 MHz, d-DMSO) 8 13.82 1H), 9.91 1H), 8.80 1H), 8.70-8.65 1H), 8.55 11), 8.15-8.12 2H), 8.03-7.98 1H), 7.75-7.72 1H), 7.57-7.49 3H). LC-MS 288.11 HPLC-Method D, Rt 1.55 min.

Example 422 (1iH-[1,2,43triazol-3-yl)- trifluoromethyl-phenyl)-quinolin-4-yl]-amine (X-177): Pale yellow solid (46% yield). 1H NR (500 MHz, d 6

-DMSO)

8 13.70 11), 9.98 8.70 1H), 8.49 (s, 1H), 8.30 1H), 7.94-7.88 2H), 7.80-7.68 7.64-7.56 2H). LC-MS m/e= 356.18 HPLC- Method D, Rt 1.68 min.

xampe 423 (1-H-Indazbl-3-yl)- [5-methyl-6-morpbolin-4yl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine (11-251): Colorless film; 2 yield; 'H-iNMR (500 MHz, *CDOD) 8 7.84 2H), 7.71 7.41 2H), 7.14 1H), 3.74 4H), 3.69 1.24 ppm; HPLC-Method A Rt 3.26 min; MS (FIA) 455.1 -339-

VO

0 BIOLOGICAL TESTING The activity of the compounds as protein kinase J inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine O inhibition of either the phosphorylation activity or ATPase activity of the activated protein kinase.

VO

Sh Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase. Inhibitor C 10 binding may be measured by radiolabelling the inhibitor o prior to binding, isolating the inhibitor/protein kinase 0 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 DETERMINATION FOR THE INHIBITION OF GSK-3 Compounds were screened for their ability to inhibit GSK-3p (AA 1-420) activity using a standard coupled enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). Reactions were carried out in a solution containing 100 mM HEPES (pH 10 mM MgC12, 25 mM NaC1, 300 /M 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 (HSSPHQS(P3H 2 )EDEEE, American Peptide, Sunnyvale, CA).

Reactions were carried out at 30 °C and 20 nM Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 pM NADH, 30 pg/ml pyruvate kinase and i pg/ml lactate dehydrogenase.

-340- NO An assay stock buffer solution was prepared Scontaining all of the reagents listed above with the Sexception of ATP and the test compound of interest. The assay stock buffer solution (175 Al) was incubated in a 96 well plate with 5 Cl of the test compound of interest at final concentrations spanning 0.002 AM to 30 pM at O O°C for 10 min. Typically, a 12-point titration was conducted by preparing serial dilutions (from 10 mM Scompound stocks) with DMSO of the test compounds in .c 10 daughter plates. The reaction was initiated by the addition of 20 Il of ATP (final concentration 20 pM).

C

N Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 min at OC. The. Ki values were determined from the rate data as a function of inhibitor concentration..

The following compounds were shown to have Ki values less than 0.1 pM for GSK-3: compounds II-1, II- 105, II-33, 11-34, 11-36, 11-39, 11-38, 11-39, 11-40, II- 41, 11-42, 11-46, 11-57, 11-59, II-60,.11-61, 11-62, II- 63, II-64, 11-66, 11-67, 11-69, 11-70, 11-53, 11-71, II- 99, 11-73, 11-74, 11-75, 11-76, 11-77, 11-7, 11-8, 11-9, 1-10, 11-24, 11-19, 11-78, II-54, 11-79, Il-80, II-81, 11-82, 11-83, 11-84, 11-56, 11-86, 11-20, 11-25, 11-26, 11-85, 11-21, 11-27, 11-28, 11-87, 1-88, 11-29, II-11, 11-12, 11-30, 11-31, 11-13, 11-14, 11-15, 11-16, 11-17, I1-18, 11-79, 11-23, 11-2, 11-90, 11-91, 11-92, 11-93, II-3, 11-4, 11-5, -11-6, 11-94, II-95, 11-96, 11-107, II- 108, 11-109, 1-110, 11-124, II-125, II-111, 11-112, II- 113, 11-114, 1-115, 11-116, 11-117, 1-118, 11-119, II- 120, 11-121, 11-208, III-8, III-7, III-9, III-37, III-38, III-39, 111-40, III-42, III-45 III1-46, III-47, III-48, III-49, III-51, III-52, II-53, III-54, 111-55, III-56, III-57, III-58, III-59, III-60, III-61, III-62, III-63, -341- IND 111-30, 11-65, 111-66, 111-67, 111-70, 111-73, 111-31, o 111-75, 111-76, 111-77, 111-33, 111-34, 111-106, 111-108, 111-109, 111-111, 111-35, l1-116, III-117, 111-118, III- 119, 111-120, 111-121, III-127,- III1-128, III-141, III- 130, II1-131, V-15, IV-16, IV-17, IV-20, IV-25, IV-26, IV-34, V-3, and IX-47.

INDThe following compounds were shown to have K1 values between 0.1 and 1.0 pM for GSK-3: compounds II- 103, 11-104, 11-35, -11-44, 11-45, 11-49, 11-50, 11-97, 0 10 II-101, II-22, 11-32, 111-41, III-43, 111-44, 111-28, o 111-50, 111-29, 111-64,.III-71, 111-74, 111-78, 111-82, II-88, 111-90, III-102, 111-105, III-107, III-110,III- 112, 111-114, III-115, 111-122, 111-124, 111-124, IV-1, 111-1, 111-138, 111-140, 111-142, 111-129, 111-132, III- 134, III-135, 111-136, V-1, TV-10, IV-11, IV-12, IV-13, IV-14, IV-19, IV-21, IV-22, IV-23, IV-24, IV-3, IV-4, IV- 6, IV-7, IV-8, IV-29, IV-31, IV-32, IV-33, IV-36, V-2, V- 7, IX-38, IX-154, and IX-177.

The following compounds were shown to have K values between 1.0 and 20 pM for GSK-3: compounds II-43, 11-48, 11-47, II-51, 11-68, II-52, 11-72, 11-100, II-98, 11-89, 111-68, 111-81, 111-83, 111-91, III-94, 111-95, 111-96, 111-97, III-98, 111-99, II1-100, III-101, 111-103, 111-123, III-137,- III-139 III-143, 111-145, 111-146, IX-156, and IX-176.

BIOLOGICAL TESTING EXAMPLW 2 K DETERMINATION FOR THE INHIBITION OF AURORA-2 Compounds were screened in the following manner for their ability to inhibit Aurora-2 using a'standard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249).

-342- D To an assay stock buffer solution containing O 0.1M HEPES 7.5, 10 mM MgC1 2 1 mM DTT, 25 mM NaCi, 2.5 mM k phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and 800 pM peptide (LRRASLG, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present ND invention to a final concentration of 30 pM. The resulting mixture was incubated at 30 C for 10 min. The reaction was initiated by the addition of 10 AL of Cq 10 Aurora-2 stock solution to give a final concentration of o 70 nM in the assay. The rates of reaction were obtained Ci by monitoring absorbance at 340 nm over a 5 minute read time at 30 OC using a BioRad Ultramark plate reader (Hercules, CA). The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 pM for Aurora-2: compounds 11-33, II-34, 11-36, 11-37, 11-40, 11-41, 11-55, III-7, III-9, III-37, III-38, III-39, III-40, III-41, III-42, III-44, III-45, III-46, III-47, III-48, III-49, III-50, III-51, III-52, 1-53, III-54, III-55, III-56, III-57, III-59, III-61, III-63, III-30, III-65, III-66, III-67, 111-31, III-76, III-77, III-78, III-80, III-32, III-33, III-34, III-106, III-108, III-109, III-110, III- 111, 11-112, III-114, III-35, III-115, 111-116, III-117, III-118, III-119, II-120, III-121, IV-7, IV-30, IV-32, and IV-34.

The following compounds were shown to have K values between 0.1 and 1.0 1M for Aurora-2: .compounds II- 1, 11-105, 11-35, 11-38, 11-39, 11-42, 11-64, 11-70, II- 53, 11-99, 11-77, 11-79, 11-86, 11-20, 11-93, 1-94, III- 28, III-58, III-64, III-71, III-73, 111-74, III-75, III- -343- ND 102, III-105, III-107, III-113, III-124, III-i, III-130, o IV-1, IV-3, IV-4, IV-6, IV-29, IV-33, and V-4.

The following compounds were shown to have Ki values between 1.0 and 20 1M for Aurora-2: compounds II- 103, II-104, 11-57, 11-59, 11-61, 1-63, 11-67, 11-69, 11-75, 11-76, 11-10, 11-19, II-78, II-54, 11-80, 11-82, 11-21, II-90, 11-91, 11-96, 11-107, III-68, III-79, III- ON 82, II-101, III-103, 1-127, III-141, III-129,.II1-132, SIV-31, V-2, IX-47, IX-154, and IX-177.

(C 0 BIOLOGICAL TESTG EXAMPLE 3 C( CD3K-2 INHIBITION ASSAY Compounds were screened in the following manner for their ability to.inhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgC12, I mM DTT, 25 mM NaCI, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and 100 p.M peptide (MAHHHRSPRKRAKK, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 M.

The resulting mixture was incubated at 30 oC for. 10 min.

The reaction was initiated by the addition of pL of CDK-2/Cyclin A stock solution to give a final concentration of 25 nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over a 5-minute read time at 30 oC using a BioRad Ultramark plate reader (Hercules, The Ki values were determined from the rate data as a function of inhibitor concentration.

-344- "O BIOLOGICAL TESTING EXAMPLE 4 O ERK INHIBITION ASSAY SCompounds were assayed for the inhibition of <ERK2 by a.spectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay, a fixed concentration of activated ERK2 (10 nM) was incubated \D with various concentrations of the compound in DMSO n for 10 min. at 30 0 C in 0.1 M HEPES buffer, pH Scontaining 10 mM MgC1 2 2.5 mM phosphoenolpyruvate, 200 ci \D 10 PM NADH, 150 ug/mL pyruvate kinase, 50 pg/mL lactate Sdehydrogenase, and 200 jM erktide peptide. The reaction was initiated by the addition of 65 pM ATP. The rate of decrease of absorbance at 340 nM was monitored. The ICso was evaluated from the rate data as a function of inhibitor concentration.

The following compounds were shown to have a Ki value of <1IM for ERK-2: III-109, III-111, III-115, III- 117, III-118, III-120, and IV-4.

The following compounds were shown to have a Ki value of between IpM and 12pM for ERK-2: III-63, and III-108.

BIOLOGICAL TESTING EXAMPLE ART 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 NaC1 1 mM DTT and 1.5% DMSO. Final substrate.

concentrations in the assay were 170 MM ATP (Sigma Chemicals) and 200 PM peptide (RPRAATF, American Peptide, Sunnyvale, CA). Assays were carried out at 30 C and nM AKT. Final concentrations of the components of the -345- ND coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 AM NADH, 30 pg/ML pyruvate kinase and 10 pg/ml Cq lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of the reagents listed above, with the o exception of AKT, DTT, and the test,compound of interest.

56 1l of the stock solution was placed in a 384 well plate followed by addition of 1 pl of 2 mM DMSO stock containing the test compound (final compound 0 10 concentration 30 pM). The plate was preincubated for I about 10 minutes at 30 C and the reaction initiated by o 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 ICso values.

BIOLOXICAL TESTING EXAMPLE 6 SRC INHIBITION ASSAY The compounds were evaluated as inhibitors of human Src kinase using either a radioactivity-based assay or spectrophotometric assay.

Src Inhibition Assay A: Radioactivity-based Assay The compounds were assayed as inhibitors of full length recombinant human Src kinase (from Upstate Biotechnology, cat. no. 14-117) expressed and purified from baculo viral cells. Src kinase activity was monitored by following the incorporation of "P from ATP into the tyrosine of a random poly Glu-Tyr polymer substrate of composition, Glu:Tyr 4:1 (Sigma, cat. no.

P-0275). The following were the final concentrations of the assay components: 0.05 M HEPES, pH 7.6, 10 mM MgCI 2 2 -346- *mM DTT, 0.25 mg/ml BSA, 10 yM ATP (1-2 Ci 33P-ATP per o reaction), 5 mg/ml poly Glu-Tyr, and 1-2 units of k 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 ND give a final DMSO concentration of The assay plate was incubated at 30 OC for 10 min before initiating the Sreaction with "P-ATP. After 20 min of reaction, the \0 10 reactions were quenched with 150 pl of Strichloroacetic acid (TCA) containing 20 mM Na 3 PO0. 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 PO41 and then 4 times with methanol. 200-1 of scintillation fluid was then added to each well. The plates were sealed and the amount of radioactivity associated with the filters was quantified on a TopCount scintillation counter. The radioactivity incorporated was plotted as a function of the inhibitor concentration. The data was fitted Ito a competitive inhibition kinetics model to get. the Ki for the compound.

Src Inhibition Assay B: Spectrophotometric Assay The ADP produced from ATP by the human recombinant Src kinase-catalyzed phosphorylation of poly Glu-Tyr substrate was quanitified using a coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). .In this assay one molecule of NADH is oxidised to NAD for every molecule of ADP produced in the kinase reaction. The disappearance of NADH can be conveniently followed at 340 nm.

-347- IND The following were the final concentrations of the assay components: 0.025 M HEPES pH 7.6, 10 mM MgC12, C( 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 o phosphoenolpyruvate, 200 AM NADH, 30 pg/ml pyruvate kinase and 10 pg/ml lactate dehydrogenase.

NO In a typical assay, all the reaction components Swith the exception of ATP were pre-mixed and aliquoted into assay plate wells. Inhibitorsi dissolved in DMSO ND were added to the wells to give a final DMSO concentration o 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: III-31, III-32, III-33, III-34, III-47, III-65, III-66, III-37, III-38, III-39, III-40,-11I-42, III-44, III-48,. III-49, I-70, III-78, III-76, and IV- 32.

-The following compounds were shown to have a Ki value of between 100nM and 1pM for SRC: III-63, III-71, III-73, 111-72, 111-74, III-80, III-50, -The following compounds were shown to have a Ki value of between IpM and 6pM for SRC: III-79, IV-1, and IV-31.

While we have hereinbefore presented a number of embodiments of this invention, it is apparent that our basic construction can be altered to provide other embodiments which utilize the compounds and methods of -348- 00 this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the a appended claims rather than by the specific embodiments which have been represented by way of example.

The term "comprise" and variants of the term such as "comprises" or "comprising" are used herein to denote IN the inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, unless in the context or usage an exclusive IN interpretation of the term is required.

Any reference to publications cited in this specification is not an admission that the disclosures constitute common general knowledge in Australia.

-349-

Claims (25)

1. 2. The composition according to claim 1, wherein said compound has one or more features selected from the group consisting of: Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic -353- 00 ring system, the bicyclic ring system is selected from a Snaphthyl, quinolinyl or isoquinolinyl ring, and R1 is Q^ -halo, an optionally substituted Ci-6 aliphatic group, phenyl, -COR 6 -OR 6 -CN, -SO 2 R 6 -SO 2 NH 2 -N(R 6 -CO 2 R 6 -CONH 2 -NHCOR 6 -OC(0)NH 2 or -NHSO 2 R 6 or Ring D is an optionally substituted ring selected from a phenyl, ND pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, a thienyl, azepanyl, morpholinyl, 1,2,3,4- 0 tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, ID 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, Sisoquinolinyl, quinolinyl, or naphthyl ring; Rx is hydrogen or Ci-4 aliphatic and R y is T- R 3 or R x and R y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; and R 2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1-6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring.
2. 3. The composition according to claim 2, wherein: Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is -halo, an optionally substituted Ci-6 aliphatic group, phenyl, -COR 6 -OR 6 -CN, -SO 2 R 6 -SO 2 NH 2 -C0 2 R 6 -CONH 2 -NHCOR 6 -OC(O)NH 2 or -NHSO 2 R6; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, -354- 00 thienyl, azepanyl, morpholinyl, 1,2,3,4- Stetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, Q 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, )isoquinolinyl, quinolinyl, or naphthyl ring; M Rx is hydrogen or Ci- 4 aliphatic and R y is T- R 3 or Rx and R Y are taken together with their intervening IN atoms to form an optionally substituted 5-7 membered c unsaturated or partially unsaturated ring having 0-2 ring Snitrogens; and ID R 2 is hydrogen and R is hydrogen or a Ssubstituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 -6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring.
3. 4. The composition according to claim 2, wherein said compound has one or more features selected from the group consisting of: Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R 1 is -halo, a C 1 -6 haloaliphatic group, a C1-6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; RX is hydrogen or methyl and R y is -R, N(R4)2, or -OR, or RX and R y are taken together with their intervening atoms to form a 5-7 membered unsaturated or -355- 00 partially unsaturated carbocyclic ring optionally Ssubstituted with halo, -OR, -CO 2 R, -COCOR, (N S-NO 2 -CN, -SO 2 R, -SR, -N(R 4 2, -CON(R) 2, 4 4 4 -SO 2 N (R -N(R')COR, -N (R )C0 2 (optionally M! substituted C1-6 aliphatic), -N(R 4 )N(R 4 -C=NN(R')2, \O -OC(=O)N(R 4 )2; ¢C R is hydrogen and R is hydrogen or a substituted or unsubstituted group selected from aryl, or \D a Ci-6 aliphatic group, or R 2 and R 2 are taken together Swith their intervening atoms to form a substituted or (N unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -halo, -CN, -NO 2 -N(R 4 optionally substituted Ci-6 aliphatic group, -OR, -CO 2 R, -CONH(R 4 -N(R 4 )COR, -SO 2 N(R 4 or -N(R 4 SO0 2 R. The composition according to claim 4, wherein: Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R 1 is -halo, a C1-6 haloaliphatic group, a C1-6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3- dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl; R x is hydrogen or methyl and R Y is -R, N(R4)2, or -OR, or Rx and R y are taken together with their -356- 00 intervening atoms to form a 5-7 membered unsaturated or Spartially unsaturated carbocyclic ring optionally Q substituted with halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, 2, -CON(R) 2, m -SO 2 N(R4)2, -N(R4)COR, -N(R4)C02(optionally substituted C 1 -6 aliphatic), -N(R 4 )N(R 4 -C=NN(R 4 )2, IN -C=N-OR, -N(R 4 )CON(R 4 -N(R 4 )SO0 2 N (R 4 2, -N(R 4 )SO 2 R, or m -OC(=O)N(R 4 )2; 0 R 2 is hydrogen and R 2 is hydrogen or a ND substituted or unsubstituted group selected from aryl, or Sa Ci-6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -halo, -CN, -NO 2 -N(R 4 optionally substituted C1-6 aliphatic group, -OR, -CO 2 R, -CONH(R 4 COR, -SO 2 N(R 4 or -N(R 4 )SO 2 R.
4. 6. The composition according to claim 4, wherein said compound has one or more features selected from the group consisting of: Rx is hydrogen or methyl and R y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or Rx and R Y are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated carbocyclic ring optionally substituted with halo, CN, oxo, C1-6 alkyl, C1-6 alkoxy, (Ci-6 alkyl)carbonyl, (C0-6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; -357- 00 Ring C is an optionally substituted ring 0 selected from phenyl or pyridinyl, wherein when Ring C r and two adjacent substituents thereon form a bicyclic )ring system, the bicyclic ring system is a naphthyl ring, M^ and R 1 is -halo, a C1-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an IN optionally substituted ring selected from phenyl, C pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, 0 morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- ND tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or Snaphthyl; R 2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -C1-4 alkyl, -Ci- 4 haloalkyl, -NO 2 -O(C1-4 alkyl), -CO2 (C 1 -4 alkyl), -CN, -SO 2 (C 1 4 alkyl), -SO 2 NH 2 -OC(O)NH 2 -NH 2 SO2 (C1- 4 alkyl), -NHC(O) (Ci- 4 alkyl), -C(O)NH 2 or -CO(C1-4 alkyl), wherein the (Ci-4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -Cl, -CN, -CF 3 -NH 2 -NH(C1-4 aliphatic), -N(CI-4 aliphatic)2, -O(Ci-4 aliphatic), C1-4 aliphatic, and -C02(C1-4 aliphatic).
5. 7. The composition according to claim 6, wherein: Rx is hydrogen or methyl and R y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or Rx and R Y are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated carbocyclic ring optionally substituted with halo, CN, oxo, CI-6 alkyl, Ci-6 alkoxy, (Cl-6 alkyl)carbonyl, (Ci-6 -358- 00 alkyl)sulfonyl, mono- or dialkylamino, mono- or 0 dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, Q or 5-6 membered heteroaryl; Ring C is an optionally substituted ring Sselected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic IN ring system, the bicyclic ring system is a naphthyl ring, c and R is -halo, a C1-4 aliphatic group optionally Ssubstituted with halogen, or -CN; or Ring D is an ND optionally substituted ring selected from phenyl, Spyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; R 2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -N(R 4 -C1-4 alkyl, -C1-4 haloalkyl, -NO 2 -O(C1-4 alkyl), -C02(C 1 -4 alkyl), -CN, -SO 2 (CI-4 alkyl) -SO 2 NH 2 -OC(O)NH 2 -NH 2 SO 2 (C1- 4 alkyl) -NHC(O) (CI-4 alkyl), -C(O)NH 2 or -CO(C1-4 alkyl), wherein the (Ci- 4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -Cl, -CN, -CF 3 -NH 2 -NH(C1-4 aliphatic), -N(C1-4 aliphatic)2, -O(Ci-4 aliphatic), C1-4 aliphatic, and -CO2(C1-4 aliphatic).
6. 8. The composition according to claim 7, wherein said compound is selected from the following compounds: -359- 00 OH 3 H N V -1 OH 3 HN ffj~NH 'N v-4 HN F C I F HN V-2 V-3 HN AN HN V-5 V- 6 HN CF3 NI -N 4 H HN v- 7 v-8 V- 9 HN A N NIN F 3 CN OH 3 HN aN l "I v-11 V-12 H 3 C- H 3 C' H 3 C INZ H 3 CNA V-13 V- 14 -360- 00 F HN N H 3 C H 3 CN N, F 3 C V-16 24 H H NN H 3 CN V-19 F P HN H 3 C H 3 CNA ci V- 17 F HN N H 3 C N A F 3 CN V-20 V-i18 HN H 3 CNA V- 21 V-22 V-23 2H HN N" N F 3 CN V-2 6 V-24 NoH HN N AN ci V-27 -361- 00 I-F c-i H F- HNH HN"N H N0' NZ- NN N F 3 C CI F 3 0 V-28 V-29 F H NY H N~ H N Y H 3 C 1 N H 3 C H 3 C 1 N H 3 C -H 3 C HC F 3 C N 3 C V-31 V-32 V-33 F CH 3 HN dHHN< HN O"N C, "N H3CtN H 3 C V-34 V-35 V-36 F H N HjH HNN" HN HNN "N N "N H 3 C H 3 C H 3 C V-37 V- 38 V- 39 -362- 00 V-41 V- 42 V-43 V-44 V-46 V- 47 V- 48 V-49 V- 50 V-51 -3 63- 00 cIHN H N 7- H N~ N N N CI" F 3 C F 3 C V-52 V-53 V-54 r4NHN N9-N HN 2 -JI N 'N 'N F 3 C F 3 C H.>F 3 C V-56 V-57 HN 9 H N9 H HN9-t4H N 'N HN 0'' F/ FCN F 3 C N N c- NH 2 NH 2 V-58 V-59 Q H 3 H N N H IN r F 3 C "-F 3 C HN F 3 C V- 61 V- 62 V-63 -364- 00 CH 3 CH 3 CHN H H HNN HN N SI Y r^i 'iQ^ H NN N HN HNJ F 3 C F 3 C F 3 C V-64 V-65 V-66 <h SF -OH 0 HN H H N F IC F 3 C V-67 V-68.
7. 9. The composition according to any one of claims 1-8 further comprising a second therapeutic agent. A method of inhibiting GSK-3 or Aurora activity in a patient in need thereof comprising the step of administering to said patient a therapeutically effective amount of the composition according to any one of claims 1-9.
8. 11. The method according to claim 10, wherein said method inhibits GSK-3 activity in a patient.
9. 12. A method of treating a disease in a patient that is alleviated by treatment with an GSK-3 inhibitor, said method comprising the step of administering to said patient in need thereof a therapeutically effective amount of the composition according to any one of claims 1-8. -365- 00 13. The method according to claim 12 further comprising the step of administering to said patient a second therapeutic agent. M14. The method according to claim 12, wherein said disease is diabetes. The method according to claim 12, wherein said disease is Alzheimer's disease. IND
10. 16. The method according to claim 12, wherein said disease is schizophrenia.
11. 17. A method of enhancing glycogen synthesis in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of the composition according to any one of claims 1-9.
12. 18. A method of lowering blood levels of glucose in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of the composition according to any one of claims 1-9.
13. 19. A method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of the composition according to any one of claims 1-9. A method of inhibiting the phosphorylation of 1- catenin in said patient in need thereof, which method comprises the step of administering to said patient a -366- therapeutically effective amount of the composition according to any one of claims 1-9.
14. 21. A method of treating a disease in a patient that is alleviated by treatment with an aurora inhibitor, which method comprises the step of administering to said patient in need thereof a therapeutically effective amount of the composition according to any one of claims 1-8.
15. 22. The method according to claim 21, further comprising the step of administering to said patient a second therapeutic agent.
16. 23. The method according to claim 21 wherein said disease is cancer.
17. 24. A compound of formula V: R 2 R 2' Rx- Z2 I R Y Z 1 1 )G V or a pharmaceutically acceptable derivative or prodrug as hereinbefore defined, wherein: Z 1 is N, CRa, or CH, and Z 2 is N or CH, provided that one of Z 1 and Z 2 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents -367- 00 independently selected from -R 1 any non-ortho carbon Sposition on Ring C is optionally and independently Q^ substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their r intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 0) heteroatoms selected from oxygen, sulfur or nitrogen, Mr said fused ring being optionally substituted by halo, 8 0 oxo, or -RS; \M 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 Ring D is substituted at any substitutable ring carbon by oxo or -R 5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; R 1 is selected from -halo, -CN, -NO 2 T-V-R 6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C 1 -6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R 8 said C1-6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; Rx and R Y are independently selected from T-R 3 or Rx and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by Rx and R y is -368- r 00 substituted by oxo or T-R 3 and any substitutable Snitrogen on said ring formed by Rx and R y is Q substituted by R 4 T is a valence bond or a C1- 4 alkylidene chain; R 2 and R 2 are independently selected from -T-W-R 6 or R 2 and R 2 are taken together with their intervening I\ atoms to form a fused, 5-8 membered, unsaturated or cpartially unsaturated, ring having 0-3 ring heteroatoms Sselected from nitrogen, oxygen, or sulfur, wherein each \D substitutable carbon on said fused ring formed by R 2 Sand R 2 is substituted by halo, oxo, -CN, -NO 2 -R 7 or (NI 6 -V-R and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R 4 R 3 is selected from -halo, -OR, -C02R, -COCOR, -COCH 2 COR, -NO 2 -CN, -S(0) 2 R, -SR, -N(R 4 2 -CON(R) 2 -SO 2 N(R 7 2 -N(R )COR, -N(R C02(optionally substituted C 1 -6 aliphatic), -N(R)N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 7 )CON(R 7 2 -N(R 7 S 2 N(R 7 2 -N(R 4 )S0 2 R, or -OC(=O)N(R 7 2 each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R 7 -COR 7 -CO2(optionally substituted C1-6 aliphatic), -CON(R )2, or -S0 2 R 7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 -CON(R -S0 2 N(R 4 -N(R 4 )COR, -N(R 4 C02 (optionally substituted C1-6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 -C=N-OR, -N(R 4 CON(R 4 2, -369- I 00 -N(R SO 2 N(R 2, -N(R )SO 2 R, or -OC N 2 or R 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -S02-, -N(R )SO 2 -SO 2 -N(R -C02-, -N(R 6 -N(R 6 -N(R )CON(R') -N SO 2 N -N IND-C(0)N(R) -OC N (R -C (R -C(R 2 S-, 66 6 6 6 6) -C(R 2 SO-, -C(R )2S2-, -C(R 2 SO 2 NRP -C(R 2 N (R 0 -C (R 2 N(R6) C -C 2 N(R C -C(R6)=NN(R 6), IN -C (R -C (R 2 N(R -C (R 2 SO 2 N(R or -C(R 2 N(R )CON(R W is -C (R 6 2 -C (R 6 )2SO-, -C (R 6 2 S0 2 -,r -C(R 2 SO 2 N -C(R 2 N(R -C02-r -C(R -C -C(R) 2 N (R6)CO-, -C(R 2 N(R C -C (R 6)=NN(R6) -C (R -C(R 2 N(R 6)N(R) -C 2 N SO 2 N -C (R 2 N (R CON(R or -CON(R) each R is independently selected from hydrogen, an optionally substituted C1-4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R 7 on the same nitrogen are optionally taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; each R8 is independently selected from an optionally substituted C1-4 aliphatic group, -OR 6 -SR 6 -COR 6 -SO 2 R -N(R )2r -N(R )N(R )2r -CN, -NO2r -CON(R or -C0 2 R and Ra is selected from halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 -CON(R 4 )2, -SO 2 N (R4 -N(R 4 )COR, -N(R 4 C02 (optionally -370- 00 substituted C1-6 aliphatic), -N 2 -C=NN (R 2 -C=N-OR, -N(R 4 CON(R 2, -N(R 4 SO 2 N(R 2, -N SO 2 R, -OC(=O)N(R4 or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; IDprovided that when Z 2 is nitrogen and G is selected from c imidazol-2-yl, thiazol-2-yl, oxazol-2-yl, 1,2,4-triazol-5-yl, 1,2,4-thiadiazol-5-yl, (1,2,4- ND oxadiazol)-5-yl, 1,2,4-triazol-3-yl, 1,3,4-thiadiazol-2- yl, 1,3,4-oxadiazol-2-yl, or 4,5-dihydro-oxazol-2-yl, at least one of RX, RY, R 2 and R 2 is other than hydrogen, C1 4 aliphatic, or C1-4 haloalkyl, or at least one of RY, and Ra is other than halo, C1-4 aliphatic, CI-4 haloalkyl, C 1 4 alkoxy, CN, or NO 2 The compound according to claim 24, wherein said compound has one or more features selected from the group consisting of: Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is -halo, an optionally substituted C1-6 aliphatic group, phenyl, -COR 6 -OR 6 -CN, -S0 2 R 6 -SO 2 NH 2 -N(R 6 2, -C0 2 R 6 -CONH 2 -NHCOR 6 -OC(0)NH 2 or -NHSO 2 R 6 or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; -371- 00 R x is hydrogen or C1- 4 aliphatic and R Y is T- 0 R 3 or Rx and R y are taken together with their intervening Satoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring Snitrogens; and R 2 is hydrogen and R 2 is hydrogen or a IN substituted or unsubstituted group selected from aryl, c heteroaryl, or a C 1 -6 aliphatic group, or R 2 and R 2 are Staken together with their intervening atoms to form a \D substituted or unsubstituted benzo, pyrido, pyrimido or Spartially unsaturated 6-membered carbocyclic ring.
18. 26. The compound according to claim 25, wherein: Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is -halo, an optionally substituted C 1 -6 aliphatic group, phenyl, -COR 6 -OR 6 -CN, -S0 2 R 6 -SO 2 NH 2 -N(R 6 -CO 2 R 6 -CONH 2 -NHCOR 6 -OC(O)NH 2 or -NHSO 2 R6; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; Rx is hydrogen or C1-4 aliphatic and R y is T- R 3 or Rx and R Y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; and R 2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, -372- 00 heteroaryl, or a C1-6 aliphatic group, or R 2 and R 2 are Staken together with their intervening atoms to form a Q substituted or unsubstituted benzo, pyrido, pyrimido or j partially unsaturated 6-membered carbocyclic ring.
19. 27. The compound according to claim 25, wherein NO said compound has one or more features selected from the c group consisting of: S(a) Ring C is an optionally substituted ring (N DO selected from phenyl or pyridinyl, wherein when Ring C 0 and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R 1 is -halo, a Ci- 6 haloaliphatic group, a C 1 -6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; Rx is hydrogen or methyl and R y is -R, N(R 4 or -OR, or Rx and R y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated carbocyclic ring optionally substituted with halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 -CON(R 4 )2, -SO 2 N(R -N(R 4 )COR, -N(R 4 )C02 (optionally substituted C1-6 aliphatic), -N(R 4 )N(R 4 2, -C=NN(R 4 2 -C=N- OR, -N(R 4 )CON(R 2 -N(R 4 )SO 2 N(R 4 2 -N(R 4 )SO 2 R, or )N(R 4 )2; R 2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a C1-6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or -373- 00 unsubstituted benzo, pyrido, pyrimido or partially 0 unsaturated 6-membered carbocyclo ring; and Q^ Ring D is substituted by oxo or R 5 wherein j) each R is independently selected from -halo, -CN, -NO 2 C r -N(R optionally substituted Ci-6 aliphatic group, -OR, -C0 2 R, -CONH(R 4 -N(R 4 )COR, -SO 2 N(R 4 or -N (R 4 SO 2 R. S28. The compound according to claim 27, wherein: ND Ring C is an optionally substituted ring Sselected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R 1 is -halo, a C 1 -6 haloaliphatic group, a C 1 -6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3- dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl; R x is hydrogen or methyl and R y is -R, N(R 4 or -OR, or Rx and R Y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated carbocyclic ring optionally substituted with halo, -OR, -C02R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 -CON(R 4 )2, -SO 2 N(R 4 -N(R 4 )COR, -N (R 4 C02 (optionally substituted Ci-6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 4 CON(R 4 -N(R 4 )SO 2 N(R 4 -N(R4)SO 2 R, or -OC(=O)N(R 4 )2; R 2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a Ci-6 aliphatic group, or R 2 and R 2 are taken together -374- 00 with their intervening atoms to form a substituted or Sunsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and S(d) Ring D is substituted by oxo or R wherein C each R 5 is independently selected from -halo, -CN, -NO 2 -N(R 4 optionally substituted C1-6 aliphatic group, -OR, \D -CO 2 R, -CONH(R 4 -N(R 4 C OR, -SO 2 N(R 4 or -N(R )SO 2 R. \D 29. The compound according to claim 27, wherein Ssaid compound has one or more features selected from the group consisting of: RX is hydrogen or methyl and R y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or Rx and R y are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated carbocyclic ring optionally substituted with halo, CN, oxo, C1-6 alkyl, Ci-6 alkoxy, (Ci-6 alkyl)carbonyl, (C 1 -6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R 1 is -halo, a C1-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; -375- 00 R 2 and R 2 are taken together with their Sintervening atoms to form a benzo, pyrido, pyrimido or Q partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -N(R -C 1 -4 alkyl, M -C1- 4 haloalkyl, -NO z -O(Ci-4 alkyl), -C2 (C1-4 alkyl), -CN, -SO 2 (C 1 4 alkyl) -SO 2 NH 2 -OC(0)NH 2 -NH 2 S02(C1- 4 alkyl) \0 -NHC(O) (C 1 4 alkyl), -C(O)NH 2 or -CO(Ci-4 alkyl), wherein c the (Ci-4 alkyl) is a straight, branched, or cyclic alkyl Sgroup; and \O Ring D is substituted by oxo or R wherein Seach R is independently selected from -Cl, -CN, -CF 3 -NH 2 -NH(C1-4 aliphatic), -N(C1-4 aliphatic)2, -O(Ci-4 aliphatic), CI-4 aliphatic, and -C02(C1-4 aliphatic). The compound according to claim 29, wherein: R x is hydrogen or methyl and R Y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or Rx and R y are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated carbocyclic ring optionally substituted with halo, CN, oxo, C1-6 alkyl, CI-6 alkoxy, (CI-6 alkyl) carbonyl, (Ci-6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R 1 is -halo, a C1-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, -376- 00 morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; 2 2' R and R are taken together with their M intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring INDoptionally substituted with -halo, -N(R 4 0C1-4 alkyl, -C1-4 haloalkyl, -NO 2 -0(C1-4 alkyl), -C02(C01-4 alkyl), -CN, -SO 2 (01-4 alkyl) -SO 2 NH 2 -OC (O)NH 2 -NH 2 SO2 (C1- 4 alkyl), ND -NHC(O) (C01-4 alkyl), -C(O)NH 2 or -CO(C1-4 alkyl), wherein the (C 1 4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -Cl, -CN, -CF 3 -NH 2 -NH (C1-4 aliphatic), -N(Cl-4 aliphatic)2, -O(C1-4 aliphatic), C1-4 aliphatic, and -C02 (C1-4 aliphatic)
20. 31. The compound according to claim 30, wherein said compound is selected from the following compounds: H3 FS F F V-1 V-2 V-3 H V5 V-6 OH 3 N N, CN CF" HN N V-4 V-5 V-6 -377- 00 HN HN V- 7 HN N HN v-8 V- 9 v- 10 v-11 OH 3 A NH N- NA F 3 C IN V- 12 H Nq 4H H 3 C N H 3 CN A-- 24 H H NN H 3 CN H 3 C NA F 3 CN V- 13 V-1 4 -tN >jH H 3 CN H 3 CN A 1 F 3 CN V-i16 F P-4H H N H 3 CN H 3 C'NA N I H 3 C' N Al1 F 3 CN V-i17 V-18 -378- 00 H NrNH H 3 0 N c I' V-19 F-NI HN H 3 C N V-20 'N H 3 CN- ci V-21 F. V-22 V-23 V-24 HNN N F 3 C H NN 'N I V-27 V- 25 V-26 H NNH y 'N F 3 V- 28 V-29 -37 9- 00 H N H NNfN HC 1 N H 3 C H H H H3C N N 3 C H 3 C H 3 C -H 3 C F C" CI V-31 V-32 V CH 3 IN HHN'N H N jf H N H c-I N H3 CI3 V-34 V-35 F HN~~ HN.H N H H H3 N H 3 C ~NH 3 C' 3 C -l F V-37 V-38 V Fp Fp HN HN H H 3 C NZ" CI CI V-41 V -33 -36 -39 CIl -42 -380- 00 F Cl H b.J\H H H AN/' 'N N 'N FC CI 3 V-43 V-44 F HN HNH9H HN N N N F 3 C CI F 3 C V-46 V-47 V-48 F OH HH N 'N '-N F 3 C NCI'- F 3 CN V-49 V-50 V-51 HN~ HN 2 HN 2 -NN N -N N CI F 3 C F 3 C V-52 V-53 V-54 -381- 00 H N N N F 3 C V- 55 24 H H NN 'N H N (~F 3 G' NH 2 HN9- V-56 V-57 F 3 C NH 2 V- 59 V-58 OH 3 H N rNH CH 3 H N NH V- 61 V-62 V- 63 OH 3 HN rN H OH 3 H N N* V-64 V-65 V66 -382- 00 F O CK H H H N H H N N N N N N F 3 C 3 C V-67 V-68
21. 32. A method of treating Alzheimer's disease in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective Samount of a compound according to any one of claims 24-31.
22. 33. A method of treating schizophrenia in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to any one of claims 24-31.
23. 34. A method of treating diabetes in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to any one of claims 24-31. A method of treating cancer in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to any one of claims 24-31.
24. 36. A method of treating a disorder of the central nervous system, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 24-31. -383- 00 37. The method of claim 36, wherein the disorder of the central nervous system is selected from the group consisting of manic depressive disorder, d) C) neurodegenerative diseases, and cardiomyocete Shypertrophy. NO 38. A compound of formula V as defined in claim 1 and Ssubstantially as described in at least one of the accompanying examples. \O
25. 39. A pharmaceutical composition comprising the compound of claim 38 and a pharmaceutically acceptable carrier. A method of inhibiting GSK-3 or Aurora activity in a patient in need thereof comprising the step of administering to said patient a therapeutically effective amount of the compound according to claim 38 or the composition according to claim 39. Dated this 3 rd day of September 2008 Vertex Pharmaceuticals Incorporated By their Patent Attorneys CULLEN Co. -384-