AU2006201265B2 - Pyrazole Compounds Useful As Protein Kinase Inhibitors - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name of Applicant: Address for Service: Invention Title: Vertex Pharmaceuticals Incorporated CULLEN CO Patent 6 Trade Mark Attorneys, 239 George Street Brisbane QId 4000 Australia Pyrazole Compounds Useful As Protein Kinase Inhibitors The following statement is a full description of this invention, including the best method of performing it, known to us:

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ci 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 o extracellular and other stimuli cause a variety of C- cellular responses to occur inside the cell. Examples of Ssuch stimuli include environmental and chemical stress signals osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H202), cytokines (e.g.

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

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

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

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

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o et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et C al., J. Biol. Chem., 1997, 272, 13766-13771.

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

Ci GSK-3 has been implicated in various diseases including Sdiabetes, Alzheimer's disease, CNS disorders such as ci D 10 manic depressive disorder and neurodegenerative diseases, 0 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-i, c-Jun, c-Myc, c-Myb, CREB, and CEPBa. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.

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

The inhibition of GSK-3 leads to.increased glycogen synthesis aid glucose uptake [Klein et al., PNAS, 93,

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o 8455-9 (1996); Cross et al., Biochem. 303, 21-26 Ci (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); t Massillon et al., Biochem J. 299, 123-128 (1994)].

SHowever, in a diabetic patient where the insulin response p 5 is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood )n levels of insulin. This leads to abnormally high blood

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C- levels of glucose with acute and long term effects that o may ultimately result in cardiovascular disease, renal \D 1 0 failure and blindness. In such patients, the normal o 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 phosphorylated on abnormal sites.

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

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

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

C 5 As a result of the biological importance of GSK-3, there is current interest in therapeutically t effective GSK-3 inhbitors. Small molecules that inhibit Cl GSK-3 have recently been reported [WO 99/65897 (Chiron) o and WO 00/38675 (SmithKline Beecham)].

For many of the aforementioned diseases Sassociated with abnormal GSK-3 activity, other protein ci kinases have also been targeted for treating the same diseases. However, the various protein kinases often act through different biological pathways. For example, certain quinazoline derivatives have been reported recently as inhibitors of p38 kinase (WO 00/12497 to Scios). The compounds are reported to be useful for treating conditions characterized by enhanced p38-a activity and/or enhanced TGF-O activity. While p3 8 activity has been implicated in a wide variety of diseases, including diabetes, p38 kinase is not reported to be a constituent of an insulin signaling pathway that regulates glycogeh synthesis or glucose uptake.

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

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

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

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: 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: R' N a N eN e N N d I Ry JNA a a N N

N

4-

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CN N and R i- G is Ring C or Ring D; C 5 Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, o pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, \wherein said Ring C has one or two ortho substituents o independently selected from any substitutable non- "C ortho 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 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; 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 s 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-.s aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo,

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C oxo, or -R

B

said C 1 -6 aliphatic group optionally C< substituted with halo, cyano, nitro, or oxygen, or R 1 Sand an adjacent substituent taken together with their 1 intervening atoms form said ring fused to Ring C; Cq R* and R Y are independently selected from T-R 3 or R X and

R

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

-V-R

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

R

3 is selected from -halo, -OR, -C02R, -COCOR, -COCHCOR, -NO2, -CN, -S(O)aR, -SR, -N(R 2, -CON(R' -SO (R 7 2, -OC(0) -N(R 7

COR,

-N(R CO2(optionally substituted C 1 -6 aliphatic),

-N(R

4

)N(R

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

-N(R

7 )S02N( 7 7 -N(R')SO2R, or -OC(=O)N(R 2; each R is independently selected from hydrogen or an optionally substituted group selected from C-a 6 aliphatic, C6-IO aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -8each R4 is independently selected froin R7, -COC, aliphatic), -CON(R 7 2 or -S0 2

R

7 or two R 4 on the same nitrogen are taken together to form a-S-8 membered, heterocyclyl or heteroaryl ring; c- 5 each R 5 is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO 2 -CN, -S0 2 R, -SR, 2 -CON(R)i, -SO 2 N(Rfl 2 -N(0')COR,

-N(R

4 )C0 2 (optionally substituted 6 aliphati),

-N(R

4

-C=NN(R

4 2 -C=N-OR, -N(R 4 )CoN(R 4 2 ci 10 -N(R)SO 2 N(R 2

-N(R')SO

2 RI or or R 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -N(R6)S0 2

-SO

2

N(R

6

)-S

-N(R6)CO-, -NCR 6

-N(R

6 )CON (R 6

-N(R

6

)SO

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

-C(R)

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

-C(R

6 2 C(R6) 2

N(R

6

-C(R

6 )cNN(R)-, -C(R6)nN-O-, -C(R 6 2 N(R6)N(R 6 -C(R6) 2 N(R6)sO 2 or C 2N (R6) CON(R6) W is -C(R6) 2 2

-C(R

6 -C(R6) 2 s0 2 -C(R6) 2 S0 2 -C0 2

-C(R

6

-C(R

6 OC(0)N(R 6

-C(R

6 2

N(R

6

)CO-,

-C(R

6 2

N(R

6

-C(R

6 )=bN(R 6

-C(R

6 hd

-C(R)

2

N(R")N(R

6 -C(R2K(R6)SONR

-C(R)

3 or -CON(Rfl-; each R 6 is independently selected from hydrogen or an optionally substituted C,- 4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; &.ch A 7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the -9-

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D nitrogen to form a 5-8 membered heterocyclyl or C heteroaryl ring; Seach R e is independently selected from an optionally C substituted Ci-4 aliphatic group, -SR6, -COR 6 -S0 2 3

-N(R)N(R

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

-CO

2

R

6 and in R 9 is selected from halo, -OR, -CO 2 R, -COCOR,

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CN -NO 2 -CN, -SOzR, -SR, 2

-CON(R')

2 o -SO 2

N(R

4 2

-N(R

4 )COR, CO 2 (optionally OD 10 substituted Ci- aliphatic), -N(R 4 2 -C=NN(R')2, o -C=N-OR, CON(R') 2

-N(R

4

SO

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

SO

2 R, or -OC(=0)N(R 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 t(un)substituted." i 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.. C-Cu hydrocarbons which are completely saturated or which contain one or.

more units of unsaturation but which are not aromatic.

For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl) alkyl or (cycloalkyl)alkenyl. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety shall include both 00 -11- 0

C

N straight and branched chains containing two to twelve carbon Satoms. The term "cycloalkyl" used alone or as part of a CI larger moiety shall include cyclic C 3

-C

12 hydrocarbons which

C<N

are completely saturated, but which are not aromatic.

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

The term "heteroatom" means nitrogen, oxygen, or sulfur and 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 Va o five to fourteen members; such as phenyl, benzyl, 0g phenethyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2anthracyl. The term "aryl" also refers to rings that are optionally substituted. The term "aryl" may be used interchangeably with the term "aryl ring". "Aryl" also includes fused polycyclic aromatic ring systems in which n an aromatic ring is fused to one or more rings. Examples C include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2anthracyl. Also included within the scope of the term "aryl"', as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring., The term "heterocycle", "heterocyclyl", or "heterocyclic as used herein includes non-aromatic ring systems having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, 0, or S, Examples of heterocyclic rings include.3-1Hbenzimidazol-2-one, (1-siibstituted)-2-oxo-benzimidazol-3yl, 2-tetrahydrofuranyl, 3-tetraydrofuranyl, 2tetrahydropyranyl, 3-tetrahydropyranyl, 4tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl, (1,3-dioxanyl, 2-tetrahydrothiophenyl, 3tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4thiomorpholinyl., 1-pyrrolidinyl, 2-pyrrolidinyl, 3pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, and benzothianyl. Alsoincluded within the scope of the term -12- Va 'heterocyclyll or "heterocyclic, as it is used herein, is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as in-an indolinyl, chromanyl, S phenanthridinyl, or tetrahydroguinolinyl, where the radical or point of attachment. is on the non-aromatic heteroatom-containing ring. The term "heterocycle, C( "heterocyclyl", or "heterocyclic whether saturated or o partially unsaturated, also refers to rings'that are ID 10 optionally substituted.

o The term "'heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to heteroaromatic ring groups having five to fourteen members. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2imidazolyl, 4-imidazoly, 5-imidazolyl, 3-isoxazolyl, 4isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2- PYrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2triazolyl, 5-triazolyl, 2-thienyl,..3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, 'indolyl, isoindolyl, acridinyl, or benzoisoxazolyl. Also included within the scope of the term "heteroaryl", as it is used herein, is a group in which a heteroatomic ring is fused to one or more aromatic or nonaromatic rings where the radical or point oflattachment is on the heteroaromatic ring. -Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[3,4-d pyrimidinyl.

The term "heteroaryl also refers to rings that are optionally substituted. The term "heteroaryl' may be -13- Va o used interchangeably with the term "heteroaryl ring" or 0q the term "heteroaromatic.

An-aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of IND an aryl, heteroaryl, aralkyl, or heteroaralkyl group Sinclude a halogen, -RO, -ORO, -SRO, 1,2-methylene-dioxy, IN 10. 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl o substituted Ph, substituted -O(Ph),

-CH

2 substituted -CH2 -CR 2

H

2 substituted

-CH

2 cH 2

-NO

2 -cN, -NR 0 C(O)RO, -NR 0

C(O)N(RO)

2 -NRC0o 2 RO, -NRONROC R, -NRNROC N(R 0 2, -NRONROCO 2

R

O

-C(O)C((0o)RO,

-C(Q)CH

2 C()RO, -C02RO,

-C(O)N(RO)

2 -OC(O)N(R) 2 -S(0) 2 R, -SO 2 N (R) 2 R, -NROSO 2

N(RO)

2

-NR

0

SO

2 RO, 2 2 -(cH 2 YNHC(o) R 0 (CH2) yNHC CH wherein RO is. hydrogen, a substituted or unsubstituted aliphatic.group, an unsubstituted heteroaryl or heterocyclic ring, phenyl substituted Ph, substituted -O(Ph),

-CH

2 or substituted -CH 2 y is 0-6; and V is a linker group. Examples .of substituents-:on. the'aliphatic group or the phenyl ring of R* include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonryl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy; haloalkoxy, or haloalkyl.

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

Examples of suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclie -14--

IO

D ring include those-listed above for the unsaturated Ci carbon of an aryl or heteroaryl group and the following: S=00, =mNHR, -NN(R*) 2 .NNHC(0)R*, nNNHC2 (alkyl),

S=NNHSO

2 (alkyl),. or where each R' is independently Ci 5 selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of fn substituents on the aliphatic group include amino,

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Ci alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, o alkylaminocarbonyl, dialkylaminocarbonyl, \D 10 alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, o nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

Suitable substituents on the nitrogen of a nonaromatic heterocyclic ring include 2 -CO2aR, -C(O)CH 2 C(O)R, -S0 2 -S0 2

N(R)

2 2 and -NR S0R+; wherein R* is hydrogen, an aliphatic group, a substituted aliphatic group, phenyl substituted Ph, substituted CH 2 substituted CH 2 (Ph), or an unsubstituted heteroaryl or heterocyclic ring.

Examples of substituents on the aliphatic group or the phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, -hydroxy, haloalkoxy, or haloalkyl.

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

Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as -CHa-, -C(O)NH-, or'a chain of atoms, such as an alkylidene chain. The molecular mass of a linker is typically in the range of about 14 to 200, preferably in the range of 14 to 96 with D a length of up to about six atoms. Examples of linkers o include a saturated or unsaturated C 1 6 alkylidene chain which is optionally substituted, and wherein one or two Ssaturated carbons of the chain are optionally replaced by -CONH-, -CONHNH-, -CO2-, -NHC02-, -NHCONH-, OC(0)NH-, -NHNH-, -NHCO-, -S02-, -S02NH-, or -NHSO 2 ND The term "alkylidene chain" refers to an Soptionally substituted, straight or branched carbon chain that may be fully saturated or have one or more units of ounsaturation. The optional substituents are as described Ci 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 OC or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a uC- or "C-enriched carbon are within the scope of this invention.

-16-

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ID

0 Compounds 'of formula I or salts thereof may be C formulated into compositions. In a preferred embodiment, t 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 _C invention and pharmaceutical compositions thereof, which O comprise an amount of the protein kinase inhibitor Io 10 effective to treat or prevent a GSK-3-mediated condition o 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), multiple sclerosis schizophrenia, cardiomycete hypertrophy, reperfusion/ischemia, and baldness.

One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the -17- CD phosphorylation of P-catenin, which is-useful for C( treating schizophrenia.

ct Another aspect of the invention relates to inhibiting GSK-3 activity in a biological sample, which p 5 method comprises contacting the biological sample with a GSK-3 inhibitor of formula I.

V Another aspect of this invention relates to a Ci method of inhibiting Aurora-2 activity in a patient, o which method comprises administering to the patient a QD 10 compound of formula: I or a composition comprising said 0 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 method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula'I or a pharmaceutical composition thereof.

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

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

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

Another aspect of this invention relates to a method of treating or preventing a CDK-2-mediated -18o diseases with a CDK-2 inhibitor, which method comprises CN 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.

C 5 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 C( role. The term "CDK-2-mediated condition" or "disease" o also means those diseases or conditions that are ID 10 alleviated by treatment with a CDK-2 inhibitor. Such o conditions include, without limitation, cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, 'cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis. See Fischer, P.M.

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

Another aspect of the invention relates to.

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

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

The term "ERK-mediated condition", as used herein means any disease state or other deleterious -19-

VO

CD condition in which ERK is known to play a role. The term Ci "ERK-2-mediated condition" or "disease" also means those c diseases or conditions that are alleviated by treatment Swith a ERK-2 inhibitor. Such conditions include, without limitation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Vn Alzheimer's disease, cystic fibrosis, viral disease,

NO

C( autoimmune diseases, atherosclerosis, restenosis, o psoriasis, allergic disorders including asthma, ID 10 inflammation, neurological disorders and hormone-related 0 diseases. The term "cancer" includes, but is not limited to the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, -lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colonrectum, large intestine, rectum,,brain and central nervous system, and leukemia. ERK-2 protein kinase and its implication in various diseases has been described.

(Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478; Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al.

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

210, 162; Moodie et al., 1993, Science 260, 1658; Frey

ID

and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, t Am. J. Respir. Cell Mol. Biol. 16, 589].

Another aspect of the invention relates to rC 5 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 CN comprising said compound.

o Another aspect of this invention relates to a Ci ND 10 method of treating or preventing an AKT-mediated diseases o 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 "AXT-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a ART inhibitor. ART-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders. The association of AKT, also known as protein kinase B, with various diseases has been described [Khwaja, Nature, pp. 33-34, 1990; Zang, Q. et al, Oncogene, 19 2000; Kazuhiko, et al, The Journal of Neuroscience, 2000].

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

Another aspect of this invention relates to a method of treating or preventing a Src-mediated disease -21-

VO

D with a Src inhibitor, which method comprises Cq 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,"Src-mediated condition", as used herein means any disease state.or other deleterious in condition in which Src is known to play a role. The term C- "Src-mediated condition" or "disease" also means those 0 diseases or conditions that are alleviated by treatment \O 10 with a Src inhibitor. Such conditions include, without Slimitation, hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and Paget's disease. Src protein kinase and its implication in various diseases has been described [Soriano, Cell, 69, 551 (1992); Soriano et al., Cell, 64, 693 (1991); Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli, Drugs of the Future 2000, 25(7), 717, (2000); Talamonti, J. Clin. Invest., 91, 53 (1993); Lutz, Blochem. Biophys.

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

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

The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and -22-

VO

o which does not destroy the pharmacological activity thereof.

SThe term "patient" includes human and veterinary subjects.

C( 5 The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts n thereof; preparations of an enzyme suitable for in vitro CN assay; biopsied material obtained from a mammal or O extracts thereof; and blood, saliva, urine, feces, semen, i \S 10 tears, or other body fluids or extracts thereof.

The amount effective to inhibit protein kinase, for example, GSK-3 and Aurora-2, is one that measurably 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, for example, the Biological Testing Examples described below.

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

The compositions of the present invention may be administered orally, parenterally, by inhalation -23- O spray, topically, rectally, nasally, buccally, vaginally C or via an implanted reservoir. The term "parenteral" as t used herein includes subcutaneous, intravenous, Sintramuscular, intra-articular, intra-synovial, rC 5 intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

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

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

o These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride 'solution. In.

addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic monoor di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceuticallyacceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers -24-

ID

o which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other t dosage forms may also be used for the purposes of.

formulation.

C( 5 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 o the case of tablets for oral use, carriers commonly used ND 10 include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.

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

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

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

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

Topically-transdermal patches may also be used.

cFor topical applications, the pharmaceutical compositions may be formulated -in a suitable ointment y 5 containing the active component suspended or dissolved in .one or more carriers. Carriers for topical In administration of the compounds of this invention Ci include, but are not limited to, mineral oil, liquid o petrolatum, white petrolatum, propylene glycol, ID 10 polyoxyethylene, polyoxyprppylene compound, emulsifying o wax and water. Alternatively,. the pharmaceutical compositions. can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or;more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

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

.The pharmaceutical compositions of this invention may also be administered .by nasal aerosol or inhalation. Such compositions are. prepared according to 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, -2u-

VO

CD fluorocarbons, and/or other conventional solubilizing or Ci dispersing agents.

c In addition to the compounds of this invention, Spharmaceutically acceptable derivatives or prodrugs of C- 5 the compounds of this invention may also be employed in compositions to treat or prevent the above-identified tf diseases or disorders.

VO

Ci A "pharmaceutically acceptable derivative or o prodrug" means any pharmaceutically acceptable salt, *s 10 ester, salt of an ester or other derivative of a compound o of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

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

Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, 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, -27-

VO

CD fumarate, glucoheptanoate, glycerophosphate, glycolate, CI hemisulfate, heptanoate, hexanoate, hydrochloride, t hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, Slactate, maleate, malonate, methanesulfonate, 2q naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, VS phosphate, picrate, pivalate, propionate, salicylate, C succinate, sulfate, tartrate, thiocyanate, tosylate and o undecanoate. Other acids, such as oxalic, while not in \0 1 0 themselves pharmaceutically acceptable, may be employed Sin the preparation of salts useful as intermediates in.

obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal sodium and potassium), alkaline earth metal magnesium), ammonium and N'(C 14 alkyl) 4 salts. This invention also. envisions the quaternization of any basic nitrogen-containing groups of the- compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

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

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

It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity-of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and -28-

O

D the judgment of the treating physician and the severity C( of the particular disease being treated. The amount of t the inhibitor will also depend upon the particular Scompound in the composition.

SC Depending upon the particular protein kinasemediated condition to be treated.or prevented, additional V therapeutic agents, which are normally administered to

NO

C treat or prevent that condition, may be.administered o together with the inhibitors of this invention. For

(N

sO 10 .example, in the treatment of diabetes other anti-diabetic o agents may be combined with the GSK-3 inhibitors of this invention to treat diabetes. These agents include, without limitation, insulin or insulin analogues, in injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonyl ureas.

Other examples of agents the inhibitors of this invention may also be combined with include, without limitation, chemotherapeutic agents or other antiproliferative agents such as adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives; antiinflammatory agents such as corticosteroids, TNF blockers, IL-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 -29-

VO

C for treating liver disease such as corticosteroids, (1 cholestyramine, interferons, and anti-viral agents; 3 agents for treating blood disorders such as C corticosteroids, anti-leukemic agents, and growth C- 5 factors; and agents for treating immunodeficiency disorders such.as gamma globulin.

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

ID 10 Alternatively, those agents may be part of a single O dosage form, mixed' together with the protein kinase inhibitor of this invention in a single composition.

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

R

2

R

2 A G 1 2 RX and RY (at positions Z 3 and Z 4 respectively) may be taken together to form a fused ring, providing a bicyclic ring system containing Ring A. Preferred RX/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R/RY:'ring is optionally substituted.

Examples of Ring A systems are -shown below by compounds I-A through I-DD, 'wherein Z' is nitrogen or C(R 9 and Z 2 is nitrogen or C(H).

H$f$ HNV> HI' ciN I-A I-B I-C VaHN7 HIN -7 HNt17 0 j

Z

2 .N X t r-fl I-I HN Z HN3Z? HN Me me Z22 HN-3 HN)?HN3t I-rI-K I-L HN Z MN-NZ HN3% UN

N

IS I-V I-N -31-

I-P

HN-s

I-S

1-0

HN?

I-T

3-W

XR

1-U .131? I-V I-x lay 1-4 I-Ak

I-BE

I -CC I -DD Preferred bicyclic Ring A I-B, I-C, I-D, I-B, I-F, 1-0, I-H, and Il-M, more preferably I-A, I-B, most preferably I-A, I-B, and I-H.

systems include I-A, I-C, I-F, and I-H, and -32-

VO

o In the monocyclic Ring A system, preferred Rz groups, when present, include hydrogen, alkyl- or t dialkylamino, acetamido, or a CI-4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Ci 5 Preferred R Y groups, when present, include T-R 3 wherein T is a valence bond or a methylene, and R 3 is -N(R4)2, \Q or -OR. Examples of preferred R Y include 2-pyridyl, 4c pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, o isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, ND 10 optionally substituted phenyl such as phenyl or haloo substituted phenyl,, and methoxymethyl.

In the bicyclic Ring A system, 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, -COCOR, -NO 2 -CN, -SO2R, -SR, -N(R 4 2

-CON(R

4 2

-SO

2

N(R

4 2

-N(R

4

)COR,

-N(R CO2 (optionally substituted C 16 aliphatic)

-N(R

4 2

-C=NN(R')

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

-N(R

4

)SO

2

N(R

4 2

-N(R

4

)SO

2 R, or -OC(=0)N(R 4 2 wherein R and R' are as defined above. Preferred RX/R Y ring substituents include -halo,' -OR, -COR, -CO 2

R,

-CON(R4) 2 -CN, or -N(R 4 2 wherein R is hydrogen or an optionally substituted C.:aliphatic group.

R

2 and R 2 may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring, wherein said fused ring is optionally substituted. These are exemplified in the following formula I compound: having a pyrazole-containing bicyclic ring system: -33-

IND

0N 0Z ciN Van Preferredsubstituents on the R 2

/R

2 fused ring 0include one or more of the following: -halo, -N(R 4 2 alkyl, -C 1 3 haloalk-rl, -NO 2 -0 (C 1 3 alkyl, -CO 2 (Ca-3 0 alkyl), -ON, So 2 (Cl 1 3 alkyl), -SO 2

NN

2

-OC(O)NH

2

NH

2 S0 2

(C

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

When the pyrazole ring system is monocyclic, preferred R 2 groups:" include hydrogen, C 1 4 aliphatic, alkoxycarbonyl, (uz) substituted phenyl., hydroxyalcyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkyLaminalcyl, dialkylaminoalkyl, henylaminocarbonyi, and (Nheterocyclyl) carbonyl1. Examples of'such preferred R 2 substituents-include methyl, cyclopropyl, ethyl., isopropyl, propyl, t-butylr cyclopentyl, phenyl, CO2H, C0 2

CH

3

'CH

2 OH, Ca 2 oC'i 3

CH

2

CH

2

CH

2 0H, CH 2

CHCI{

2 Oai 3

CH

2

CH

2

CH

2

OCH

2 Ph, CH 2

CH

2

CH

2

NH

1

CH

2

CH

2

CH

2 NHCOOC (053)3, COIQHCH (CHS) 3

CDNHCH

2

CH=CH

2

CONIIOH

2 aI 2 00H 3 CONHaI 2 P~i, CONEcycloheXYl),. CON(Et) 2 CON(C11 3

)CH

2 Ph, 'CONH(n-C 3

H

7 CON(Et) OH 2

CH

2 CH3, CONECH 2 CS (CI3)2, CON (n-C: 3 3 7 2 00(3methoxymethylpyrrolidin-l-yl), CONS (3 -tolyl), 00141*(4tolyl), CONHCH 3 CO:(morpholin-1-yl), Co (4 -methylpiperazinl-yl), CO NHCN 2 CRsOH, CONS 2 and CO(piperidin-1-yl). A'pref erred R 2 group is hydrogen.

-34- 0 An embodiment that is particularly useful-for treating GSK3-mediated diseases relates to compounds of Sformula

II:

R

2 0H

HN

R

I N

II

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

R

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

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or CI-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R 8 said Ci-s 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;

VO

C R z and R Y are independently selected from T-R 3 or R x and C R Y are taken together with their intervening atoms to t form a fused, unsaturated or partially unsaturated, 5-8 Smembered ring having 0-3 ring heteroatoms selected from C- oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R X and R Y is v B substituted by oxo or T-R3, and any substitutable CN nitrogen on said ring formed by R" and R Y is o substituted by R'; ND T is a valence bond or a Ca-4 alkylidene chain;

SR

2 and R 2 are independently selected from -T-W-R 6 or R' and R 2 are taken together .with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms' selected from nitrogen, oxygen, or sulfur, wherein each substitutable 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';

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

-SO

2

N(R

7 -N (R )COR, 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 -N (R 7 S0 2 N (R 2 OC N (R 2; each R is independently selected from hydrogen or an optionally substituted group selected from C 1 6 aliphatic, C 6 -i0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring Satoms; each R 4 is independently selected from -R 7

-COR,

-CO

2 (optionally substituted -C- 6 aliphatic), -CON(R 2 or -SO2R 7 or two. R 4 on the same nitrogen are taken -36- Va o together to form a 5-8 membered heterocyclyl or heteroaryl ring; ct each R5 is independently -selected from halo, -OR, -C0 2 R, -CO0R, -N0 2 -CN, -SO 2 R, -SR, S -N(R 4 2

-CON(R')

2

-SO

2 N(Rt) 2

-N(R')COR,

-N 02 (optionally substituted C.6 aliphatic), -N N(R4 2

-C=NN(R)

2 -C=N-OR, -N(R')CON(R') 2 -N (R)so0 2 N W) 2 -&(R4)SO 2 R, or -OC(=0)NR) 2 or R 5 and an adj&cent substituent taken together with their intervening atoms form said ring fused to Ring C; V is _SO20, -N(R 6 )S0 2

-SO

2 ,-1(R 6 -COn-, -fl(R 6

-N(R

6

-N(R

6

)SO

2

-N(R

6 2 -C(R6) 2

S-,

-C(R

6 2

-C(R)

2 50 2 2

SO

2 2

N(R

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

-C(R

6 2 -C(R6) 2 N(R)S0 2 or -C(R6) 2

N(R'}CON(R)-;

W is -C(R6) 2 -C(R6)2S-, 2 S0-, 2

SO

2

-C(R

6 2 S0 2 -C(R'b2N(R6)-, -C02-, -c(R6)Oc -C(a')OC(O)N(R 6 -OCR6) 2 N(1R) CO- -0(R 6 ,N -C(R6) rN-O-, 2 N (R6) N -C(R 2

N(R)SO

2 N -C(R6) 2 N(R6)CON( or -CON(R)- 1 each R6 is independently selected from hydrogen, an, optionally substituted C1-4 aliphatic group,. or two R' groups on the same nitrogen atom are taken together with the nitrogen. atom to form a 5-6 membered beterocyclyl or heteroaryl ring; each- R is independently selected from hydrogen or an optionally substituted. Cj-_ aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or beteroaryl ring; and -37-

VO

each R 8 is independently selected from an optionally substituted Ci- 4 aliphatic group, -OR 6

-SR

6

-COR',

S-SO

2

R

6

-N(R

6 2

-N(R

6

)N(R

6 2 -CN, -N0 2

-CON(R)

2 or -COaR 6 C 5 When the Rx and R Y groups of formula'II are taken together to 'form a fused ring, preferred RX/RY rings Sinclude a or 8-membered unsaturated or CA partially unsaturated ring having 0-2 heteroatoms, o wherein said RX/RY ring is optionally substituted. This

CA

ID 10 provides a bicyclic ring system containing a pyrimidine O ring. Examples of preferred pyrimidine ring systems of CAl formula II are the mono- and bicyclic systems shown below.

R

2 SHN- Ei t II-A II-B II-C HN HN- HN RN 4_N N! II-D II-E II-F HN3 HN HN' H Me II-G II-H fI-I -38-

VO

ID

S HN- HN3 HNm N 01, N N N II-J II-K

II-L

ci

IND

HN-Z HN- HN" II-M II-N II-O HNk

II-P

More preferred pyrimidine ring systems of formula II include II-A, II-B, II-C, II-P, and II-H, most preferably II-A, II-B, and II-H.

In the mpnocyclic pyrimidine ring system of.

formula II, preferred RX groups include hydrogen, alkylor dialkylamino, acetamido, or a C 1 4 aliphatic group such.

as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred R Y groups include T-R 3 wherein T is a valence bond or a methylene, and R 3 is N(R 4 2 or -OR. When

R

3 is -R or -OR, a preferred R is an optionally substituted group selected from C-6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred R y include. 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyciopropyl, isopropyl, t-butyl, alkyl- or dialkylamino,.acetamido, optionally substituted phenyl -39- Va o such as phenyl or halo-substituted phenyl, and 0 methoxymethyl.

In the bicyclic pyrimidine ring system of formula II, the ring formed when RX and a are taken S together may be substituted or unsubstituted. Suitable substituents include.,-R, halo, -OR, -C(s0)R, -CO 2

R,

In -COCOR, -NO 2 -CN, -SO2R, -SR, -N1(R') 2

-CON(R)

2 e -SOzN(R) 2

-N(R

4 )COR, -N(R)C0 2 (optionally substituted C, aliphatic), -N(R 4 N 21 CNN(R) 2 -C=N-OR, -N(R)CON(R 4 2

-N(R')SO

2

N(R

4 2 -N(Rt)SO 2 R, or o wherein R and R 4 are as defined above.

Preferred RX/RY ring substituents include -halo, -OR, -COR, -CO 2 R, -CON(R 4 -CN, or -N(R 4 2 wherein R is an optionally substituted C1-6 aliphatic group.

The R 2 and R' 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:

NH

Fix HN N N NN INH NH NH H

NNN'N

and I Preferred substituents on the Ra/R' 1 fused ring of formula II include one or more of the following: -halo, -N(R 4 2 -C1-4alkyl, -C1- haloalkyl, -NO 2 -0(Cl-4 alkyl), -C0 (C14 alkyl), -CN, -502 (C-4 alkyl), -SO 2

NHA

2 -0c (0)N 2

-N

2 so 2

(CI-

4 alkyl) -NHC(O) alkyl),

VO

O -C(0)NH 2 and -CO(C-.

4 alkyl), wherein the (C1- 4 alkyl) is a

C

N straight, branched, or cyclic alkyl group. Preferably,, the (C 1 -4 alkyl) group is methyl.

When the pyrazole ring system of formula II is Cl 5 monocyclic, preferred R 2 groups include hydrogen, a substituted or unsubstituted group selected from aryl, Sheteroaryl, or a Cz- 6 aliphatic group. Examples of such Cl preferred R 2 groups include methyl, t-butyl, -CH 2

OCH

3 o cyclopropyl, furanyl, thienyl, and phenyl. A preferred IO 10 R 2 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 R and R Y are each methyl, or R x and R Y are taken together with the pyrimidine ring to form a quinazoline or.

tetrahydroquinazoline ring: N H H NH HN HN HN 0 .N H 3C

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- is halo, methyl, or trifluoromethyl.

Preferred formula II Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system. Preferred fused rings include a benzo or.pyrido ring. Such rings -41- Va C preferably are fused at ortho and meta positions of Ring ci C. Examples of preferred bicyclic Ring C systems include naphthyl, quinolinyl and isoquinolinyl.

An important feature of the formula II compounds is the R 1 ortho substituent on Ring C. An ortho position on Ring C or Ring D is defined relative to the position where Ring A is attached. Preferred R1 groups y include -halo, an:optionally substituted C1_G aliphatic o group, phenyl, -COR', -OR 0 -CN, -S0 2

R

6

-SO

2

NH

2

-N(R

6 2

-CO

2

-CONH

2

-NHCOR

6 -OC(0)NH1 or -fNHS0 2 R. When R is an optionally substituted C.6 aliphatic group, the most preferred optional substituents are halogen.- Examples of preferred RA' groups include -CF 3 -C1, -CN, -COCH3, -OCH3, -OH, -CH2C13, -OCH1CH3, -CH3, -CF2Ca,, cyclohexyl, tbutyl, isopropyl, cyclopropyl, -OcaH, -C-CHa 3

-SO

2

CH

3

-SO

2

NH

2 -N (CH3) 2

-CO

2 04, -CONH, -NHCOCM -OC(O)NH2, -NHS02OH3, and -OCF 3 On Ring C of formula II, preferred R substituents, when present, include -halo, -CN, -NO 2 2 optionally substituted C1-6 aliphatic group, -OR,

-CO

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

N(R')

3 and

-N(R

4 )SOR. More preferred R 5 substituents include -CI, -CN, -CF3, -NH 2 -NH(C1-. aliphatic), -N(C3.

4 aliphatic) 2 aliphatic), aliphatic, and -CO2 (C.4 aliphatic). Examples of such preferred Rs substituents include -Cl, -CN, -CF, -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: Ring C is a phenyl or pyridinyl ring, optionally substituted by -Rs, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring -42-

VO

system, the bicyclic ring system is selected from a C naphthyl, quinolinyl or isoquinolinyl ring; S(b)

R

x is hydrogen or C 1 4 aliphatic and RY is T-R or R x and R Y are taken together with their Cr 5 intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; cI R I is -halo, an optionally substituted Ci- O aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SOR 6 -SO0NHa, O 10 -N(R 6 2

-CO

2 R, -CONHa, -NHCOR 6

-OC(O)NH

2 or -NHSO 2 R6; C and c-I

R

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

More preferred compounds of formula 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), 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, -COaR, -COCOR,

-NO

2 -Cf, -SOaR, -SR, -N(R) 2 -CON(R4) 2 -SON (R 4 2 COR, CO2 (optionally substituted C 1 i- aliphatic), -N(R4)N(R 4 -C=NN(R" 2, -C=N-OR, -N(R)CON(R) 2

-N(R

4

)SO

2

N(R)

2

-N(R

4 SOaR, or -OC(=0)N(R)2; -43-

VO

D R is -halo, a C..

6 haloaliphatic.group, a Ci Ci-6 aliphatic group, phenyl, or -CN; S(d) R 2 is hydrogen and R 2 is hydrogen or a G substituted or unsubstituted group selected from aryl, or a C.-6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or tl ursubstituted benzo, pyrido, pyrimido or partially

\O

Cq unsaturated 6-membered carbocyclo ring; and o each R s is independently selected from \D 10 -halo, -CN, -NO 2

-N(R

4 2 optionally substituted C 1 i- s :aliphatic group, -OR, -CO 2 R, -CONH(R 4

-N(R

4

)COR,

-SOaN(R 4 or -N(R)SO 2

R.

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 .is hydrogen or methyl and R Y is methyl, methoxymethyl, ethyl, 'cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or RX and R

Y

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

R

1 is -halo, a C1-. aliphatic group optionally substituted with halogen, or -CN;

R

2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R4) 2 -CI-4 alkyl, -C .4 haloalkyl, -NO 2 -0(CI- 4 alkyl) -C2 (Ci-4 alkyl), -CN, -S02 (CI-4 alkyl), -SO 2

NH

2

-OC(O)NH

2

-NH

2 S02 (C-4 alkyl), -NHC(O) (C3-4 alkyl), -C(0)NHa, or -CO(C1-4 alkyl), wherein -44-

IND

Va 0

CA

the 4 alkyl) is a straight, branched, or cyclic alkyl group; and each R 5 is independently selected from -C1, -CN, -CF3, -NH 2

-NH(C..

4 aliphatic), -N(CI-4 S aliphatic) 2 -O(CJ4 aliphatic), C 1 aliphatic, and -C0 2

(C

1 4 aliphatic).

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

Table 1.

CHS

OH

H N

CI

H304NOll

F

H

II-2 FZ

H

HN

HN

11-3 F

F

H

II-6 F ZF

H

II-9 11-4 11-5

F

HH

N-CF

8 N1- II-7

IND

IN

N

F

F

C

F

3 C NilF

F

NCF

3 11-12 11-10 11-13

F,

HN~H

'I-is 11-14

F]H

'I-isOF 11-17

H-N

11-20 11-21 11-19 -46- 11-22 11-23 11-24

FF

HNZ

H

a$ HN H3C1N' C1 11-26 11-27 11-28 11-29 11-30 11-31 CHs

HN

4 N F

N

11-34 H3C9 11-32

HN.

N OCH3 cx>0H 3 11-35 CH3 IN CH.,I 11-33 OM3 HNg*H

N

11-36 -47-

OH

8

-VH

N

OH

8 HNf-t

H

3

C~

11-38 OHs HN f 11-37 11-39

CH

3 HN* Hjf c 9 N H 3 I CF 3 CH c ,N1

CH

3

HNV*

11-40 11-41 11-42

HN

4

PH

CH-l

HN

OH

*CM

3 EXZtN OCH2CH3 Nlb 11-43 11-44 11-45

N

11-46 tIN

NCF

3 MN JJ

NV

11-47 .11-48 -48-

H

HN

11-49 0 N p 11-52 N F 11-55

HN

NI-Se HN2S PO 4 NCF 3

HNW

N

'I-so 'I-si

HN-JQ-JH

NCF

3

OH

H-tv ro iN F 11-53 11-54

CF

3

N-CF

3 11-59

HN

N

11-57

H?

HN

11-60 -49- Va 0 0 ci ci

H

3

C

H9H

HN

11-61

F

3

C

1~H

HN

11-64 HNY

H

X, QN Cl 11-62 H

H

NCF

3 11-65 HN2Nt

N

11-63

N

11-66 Nd 11-67 0 2

N

HN

11-70 11-68

CF

3 11-69

N

Il 72 ,11-71 11-73 g;H 11-76 Br fcI N CF 3 11-79 Br H Z

N

11 -82

F

LC.I

11-74

F

8

C

HN

NCI

11-75

)N

11-77 11-78 cl

HZ

N.CF

3

CF

8

HN

HN

Il-so 11-81 ltN CF 8 11-83 N F 11-84 -51- 11-85

F

cCN

F

@0 11-89

HN

11-87

NCI

CF

9 11-91

N

11-91 11-90 11-92

F]Z

H

r4NO 2

F

11-93 tLH 2 N C 11-96 -52-.

11-97

OH

3

HN

HNf*& 9, N CF 3 11-98

HN

HN

2 OHi

N

11799 11-102 CH3 H 3 C-t 11-103 11-104 11-105

OH

3 11-106

H?

NCF

3 11-208 11-107 -53- F F HN

XH

'4QON GF3

N

HN?

ii-itLo Il-ill

F

a Na 11-112 5., 11-113 11-114 r

HN

1111

HN

CrI .N

CI

11-117 11-115

HN

117118 11-129 11-120 -54- Va 0e2C

HN'H

NCF

3

P

Cl~

'IN

11-121 11-122 11-123 Cl F a MO HN 2

'NN

P QN Cg NCF 3 tN CF 3 511-124 11-125 11-126 FFF F HNT4HP

H

N (NN 11-127 11-128 11-129 F

F

F F 3 Co 11-130 11-131 11-132

OH

9

F

3

C

II -:133

HN

F

3 0C 11-134 11-135 11-136 11-137 11-138

H

3 C

N

H

2 NJ; lF 11-139

H

3 0 MeSO 2 NH cl 11-140 .11-141 11-142 11-143 11-144 -56- Va 0

IN

cIN Ni li-14S 11-146 I-ZCF3

N

11-148 11-147 01j HN 0 k,,N po0 11-149

N.

H

2

N

11-153 1-151 11-152 HNMeHN H?

HN

11) N CF31N-CF, 11-154 11-155 11-156 -57- H H N

HGFZ

11-157

F

N

CF,

11-160

N

1Y-16 C 11-159 11-162 me

HN*P

NCF

8

NWY

11-165, 11-163 11-166 11-164 11-167 11-168 -58-

N

11-169 11-172 11-170 00HNH Q,,P H i HsGHt N CFs IX-173

HN

2

N

H2N NFb 11-176

HNP-)M

Cbz11 11-179 11-171 11-174 CbzNN---A

H

11-175 11-177 7N CF 3

HNP-

11-180 11-178 -59-

HN

2

H

MeOASNII Nd il:-iei11-182 .11-183

I

11-184 11-185 11-186 11-187 11-188 3:1-189 it, HN2i 11-192 11-190 11-191

NCF

8 Nw 11-193 .e N 11-196 11-194 11-195 11-197 11-198

F

HNZ

M N C I Me 11-200 11-199

IHN

9 J-4N Me Y

K

2 N0 2 $A N 11-201 11-204 HN 2P 11-202 11-203 -61- Ci

ON

11-205

OHS

11-208

CH

8 HN 4 4H C *l II-21

F

~LN-N

HN

SI-

11-206

FN

4 11-209

QN

11-212

F

NIH

11-215 11-207 11-210 OlNt 11-213

N

11-216 1 11-214 .62-

H.

HN*~

HN1 N Ci 11-217 11-218

F

HN

N cl 11-219 N 11-222 11-220 11-221 ON C(O)NH 2

N

11-223

HN

Me Me 11-224 11-225 HNt 11-227 11-226 11-228 -63- 11-229 11-230

H.~

11-231 11-234 F Hr

HNP

~NII

Q1-23 11-237 t-8u'k, 11-232 11-233 OtN C(O)NH2 11-235 7N NH2 N- NH2 11-236

F

NH

2 11-239 11-238 11-240 -64-

H

I*K2 'xt6 II-241 II-242 II-243 II-244 F

H

II-247

F

H

HNZ

Pjj.NSO 2 N(Me) 2 II-250 HNtH

N&CN

II-245

H

HNT-2 -N

SO

2

NH

2 11-248 HtH HCI-N

CF

3 c NO 11-251 11-246

FIZ

H

N N0 -S02N(Me)49 11-24.9 In another embodiment, this invention provides a composition comprising a compound of formula I 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 t of formula II.

S

Another aspect relates to a method of treating C- 5 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 therapeutically effective amount of a composition o comprising a compound of formula II.

\D 10 Another aspect relates to a method of.enhancing o 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, comprising administering.to the patient a therapeutically effective amount of a composition comprising a compound of formula II.

-66-

ID

0 Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora iinhibitor, said method comprising the step of Sadministering to a patient in need of such a treatment a C 5 therapeutically effective amount of a composition comprising a compound of formula II. This method is IND especially useful for treating cancer, such as colon, ovarian, and breast cancer.

q One aspect of this invention relates to a N 10 method of inhibiting CDK-2 activity in a patient, Scomprising 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, 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 II, or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3, Aurora or CDK-2, or the treatment of a disease alleviated thereby, is preferably -67-

VO

O carried out with a preferred compound of formula II, as C( -described above.

SAnother embodiment of this invention relates to compounds of formula III:

NH

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

R

2 and R 2 are independently selected from or

R

2 and R 2 are taken together with their intervening atoms to form a .fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each -68- Va o substitutable carbon on said fused ring formed by R 2 and R2' is substituted by halo, oxo, -CN, -N02, or and any substitutable nitrogen on said ring formed by'R2 and Ra 2 is substituted by R'; N 5. R 3 is selected from -halo, -OR, -CO 2

R,

-COCOR, -COCHaCOR, -NO 2 CN, -S(o)2R, -sR, -N 2 -CON(Rf) 2

-SO

2

N(R')

2 -ii(R 4

)COR,

-N C02 (optionally substituted C1-6 aliphatic),

-N(R

4

)N(

4 2

-C=NN(R')

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

)CON(R')

2 -N(Rt)SO 2

N(R

4 2

-N(R)SO

2 R, or -OC(=O)N(Rt)2; Seach R is independently selected from hydrogen or an optionally substituted group selected from C 1 -6 aliphatic, C6s-o10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -COR7, -COS2 (optionally substituted C.-6 aliphatic.), -CONI(R 7 2 or -So 2 or two R' 4 on the same nitrogen are taken together to form a 5-8 menbered heterocyclyl or heteroaryl ring; each Rs is independently selected from halo, -OR, -COaR, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N 2, -CON(R) i -O 2

N(R'Y

2

-N(R')COR,

-N(R)CO

2 (optionally substituted C1-6 aliphatic),

-N(R')N(R

4 2

-C=NN(R)

2 -C=N-OR, -N(R')CON(R') 2 SO02N(R') 2

SO

2 R, or -OC N(R V is -SO2-, -SOaN(R')-,

-N(R

6

-N(R')SO

2 2 2

S-,

2S-0, -C(R) 2 N aN(R')SON(R)- or 2 N (R)CO -C(RN(R6)C(0)0 C(R6)NN(R6)- q-0.r, -C(R6)2N(R6)S02N (R6)-,.orr C 29 CON -69- Va W is -C(R) 2 o0-, -C(R6) 2

-C(R

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

N(R

6 -o0 2 OC N (R 6 2

N(R

6

CO-,

-C(R

6

-C(R

6 2 N N aN S0 2

N(R

6 -C (R(R 6 2 N(R')CON or -CON(R) IC each R 6 is independently selected from hydrogen or an Va C( optionally substituted C 1 4 aliphatic group, or two R 6 o groups on the same nitrogen.atom are taken together ID 10 with the nitrogen atom to form.a 5-6 membered o heterocyclyl or heteroaryl ring; and each R' is independently selected from hydrogen or an optionally substituted C1- 6 aliphatic group, or two R on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.

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

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

-CO

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

N(R')

2

-N(R

4 )SO0R, -SR, -OR, or substituted or unsubstituted group -selected from 5-6 membered heterocyclyl, C6-1o aryl, or C1-, aliphatic. More preferred R5 substituents include -halo, -CN, -oxo, -SR, Va o -OR, -N(R 4 2 or a substituted.or unsubstituted group selected from 5-6 meibered heterocycly, C 6 aryl, G or C 1 -6 aliphatic. Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 OH, pyrrolidinyl, OPh, CF 3 CiCH, Cl, Br, F, I, NH 2

C(O)CH

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

Preferred rings formed when the RX and RY groups Sdf formula III are taken together to form a fused ring ci include a or 7-membered unsaturated or partially 0 unsaturated carbocyclo ring, wherein any substitutable carbon on said fused ring is substituted by oxo or T-R.

Examples of preferred bicyclic ring systems are shown below.

S2 HN NHN HN'3' III-A III B III-C HN>? HN>? III-F IfI-I Preferred substituents on the RX/RY fused ring of.formula III include oxo, halo, -OR, -COR, -COCOR, -NO 2 -CN, -S0 2 R, -SR, -N(R 4 2

-CON(R

4 )2, -SO2N(R') 2 -N(R)COR, -N(R 4

)CO

2 (optionally substituted C 16 aliphatic),'-N(R') N 2 -CcNN(R -CaN-OR, -N(R')CON(R') 2

-N(R')SO

2

N(R

4 2 -N(R')SO2R, or -71- -OC (R 4 2 wherein R and R 4 are as def ined above'.

ci More preferred substituents on the RX/RY fused ring include halo, GN, oxo, C 1 6 alkyl, C 1 alkoxy, (C 1

L-

6 alkyl) carbonyl, (C 1 6 alkyl) suit ony., mon o- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 memnbered heteroaryl.

Examples of such preferred substituents include methoxy, CA methyl, isopropyl, methylsulfonyl, cyano, chjloro, o pyrrolyl, inethoxy, ethoxy, etbyJlamino, acetyl, and IND 10 acetamido.

8 Preferred R 2 substituents of formula III include hydrogen, C 1 4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl,. monoor dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbor. yl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO 2

H,

CO

2

CS

3 C01i, 01 2 O0ZH 3

OH

2

CH

2

CR

2 OH, OHC

H

HO

2 OCH3,

CH

2

CH

2

CH

2

OCI

2 Ph;' Cni 2 2 2 CH,2CU 2

CE

2 NUCOOC (Cl! 3 3 CONHCH (oH) 2

CQNHCII

2 CH= 012, CONHCH 2

CH

2 0CH 3

CONHCH

2 Ph, CONH(cyclohexyl), COP(Et) 2 CON(01 3

H

2 Ph, CONH(II-C 3 11 7 CON (Et) Cl{2011203, CONHC3{ 2 01 2 CON (n-C 3 1 7 2 CO (3 methoxymethylpyrrolidin-l-yl), CONH (3 -tolyl), CON!!(4tolyl), CO1*1013, Co(morpholin-l--yl), C0(4-methylpiperazin- 1-yl) CONHCE 2

CH

2 OH, CONH 2 and CO(piperidin-1-yl).

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

/R

2 ring systems containing the pyrazole ring include benzo, pyrido, pyrimido, 3 oxo-2H-pyridazino, and a partially unsaturated 6-mewbered carbocyclo ring. Examples of such preferred eR 2 2 ring systems containing the pyrazole ring include the following: -72- I I I FN H, and H Preferred substituents on the R 2 fused ring of formula III include one or more of the following: -halo, -N(R 4 2, -C 1 4 alkyl, haloalkyl, -NOa, O(C.-4 alkyl), -C2(C0.4 alkyl), -CN, -SO 2 (C-4alkyl), -SONHR 2 -OC(O)NH2, -NH2S02(C1-4 alkyl), -NHC(O) (C1- alkyl), -C(0)NH2, and -CO(C..4 alkyl), wherein the alkyl) is a straight, branched, or cyclic alkyl group.. Preferably, the (C1.4 alkyl) group is methyl.

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

R" 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' is hydrogen or methyl and R2 is T-W-R6 or R, wherein W is 2 2 CO-, -CO-, 2 CO-, 2 or -CON(R)-,:and R is an optionally substituted group' -73- Va selected from C1_ aliphatic or phenyl, or R 2 and are taken together with' their intervening atoms to form a substituted or unsubstitutedbenzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring.

c] 5 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 o selected from phenyl, pyridinyl, piperidinyl, ID 10 piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4o tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; ax and RY are taken together with their intervening atoms to form a benz6ring or a 5-7 membered carbocyclo ring optionally substituted with oxo, halo, -OR, -CO 2 R, -COCOR, -N02, -CN, -S(O)R,

-SO

2 R, -SR, -N(R 4 2 -CON(R4)t 2

-SO

2

N(R')

2 i COR, CO, 2 (optionally substituted C 1 -6 aliphatic),

-N(R

4

)N(R

4 2

-C±NN(R)

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

)CONW(R)

2

-N(R')SO

2

N(R')

2

-N(R)SO

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

-N(R

4 2, -CO 2 R, -CONH(R 4

-N(R)COR,

-SO

2

N(R

4

-N(R

4 )S0R, -SR, -OR, or a substituted or unsubstituted group, selected from 5-6 membered heterocyclyl, Cs-o 1 aryl, or C 1 aliphatic.

Even more preferred compounds of formula III have one or more, and more preferably all, of the features selected from the group, consisting of: Rx and RY are taken together with their intervening atoms to form a benzo or 6-membered partially unsaturated carbocyclo ring optionally substituted with halo, CN, oxo, CZ-. :alkyl, C 1 alkoxy, (C 1 6 alkyl)carbonyl, (C3_ 6 alkyl)sulfonyl- mono- or dialkylamino, mono- or -74- Va dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R 5 is independently selected from -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a Ci 5' substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-lo aryl, or C1-6 aliphatic; and Ra 2 is hydrogen and R 2 is selected from R 2 is hydiogen or methyl and R' is T-W-R 6 or R, wherein W is 2 -C(R6)N(R 6 -CO2-, -C(R 6 or -CON(Rc)-, and R is an optionally o substituted group selected from C3._ aliphatic or phenyl, or R' aid 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, -N(R) 2 -C13 alkyl, -C3-4 haloalkyl, -NO 2 -O(C1.4 alkyl), -C03 (C 1 4 alkyl), -CN, -802(C.4 alkyl), -SO 2

NH

2 -OcC(0)NH 2

-NH

2

SO

2

(C

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

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

Table 2

CM

3 HNH HN dH

H

HNH HN* 0 a CI~ae III-1 111-2 I11-3

CH

3 CH0

N

HN

3 111-4 111-77

CH

3 Ha

OH

3

HN

OCFHg 111-13 111-5

HN<P

l-

OH

3 111-14

OH

3 HN(

*H

111-9 "I1-6

OH

3 111-12 III-is 111-17 cANN 0 1-1 111-16 -76-

HNH

NN

CH

3

HN

H

3 C.<~ittH3 C1133 HN111-25

OH

3

OH

3 0j I 111-20

OH

3 HN

J*H

111-23 111-21

OH

3

HN

111-24

OH

3

LIH

111-26 111-27

OH

3

NH

111-28

CH

3

HA

111-31

OH

3 111-29

OH

3

HA

tN

H

111I-32 C H 3 HA 111-30

OH

3

H

111-33 -77-

OH

3 HN *t 111-34

H

3 tN

H

~CIL

111-35

OH

3

HA"

111-38

OH

3 HN< .t H 111-36

OH

3

HN

tN 111-37

HNS

111-40

OH

3 HN<P1 111-43

HNS

111-46 111-39

H

3

OH

3

H

N~e

OH

3

CH

111-41

H

111-42 111-45 111-46 -78-

CH

3

I-

111-49 013

HN$

-a 111-52

OH

3 HN OhH

NK

7 111-50

OH

3 HN4* l~t ,,0F3 111-53 111-51 111-54

OHS

4,* 111-55 111-56 CH3 0 111-57

CH

3

HAN'

III-GO

CH

3

.H

111-58 HNO3

HN

111-59

OH

3 HN4

\N

111-62 111-61 111-63 -79- HN N.

NH

HN

CH

2

OH

2

HN

OH

8

HN

otH 111-65 111-66 CH3

CH,

HN jl.,

H

N

111-67 111-68 111-69 111-70

HX

111-71

CH

2 0H HN4*

-NH

111-74 C0 2

H

HN*t 111-72 00CH 3

HN

N4K III773 111-75

HNXII

uN

H

111-76

OCH

HNtP ro-'

H

111-77 111-78 111-79 111-80 111-81 001% 0 r 111-83 111-82 111-84

HNS

QN H-8 o ,-CH 3

N-

1 %t1-86

H

tN

H

III-87 -81- .66-I1l1 L6-111 96-Ill S6-111 fr6-lII

JNH

0zo, C4HT4H

CHO

E-Ill ESIl I-Ill N~Y NSGN H H SHNHN NH0 6 H3l 00- Q.

CHO EH 06-11l 68-Ill 8-l HHNI HN 9

Y

pNAH

NH

o N H 0 0

H

NH

111-100 111-101

CH

3 *HN4* a..H 111-104 Br

OH

3 111-102

CH

3

HN

NH

111-105 HN4O

-N

111-108 111-203 &H3 111-106 HN4

HA

111-119

OH

3 .HN4* O.NCH3 111-107

CH

3 HN4 111-113 III-ill

CH

3

HA*

&-:OH

111-114 -83 HN$4

NCO

*111-115 HN4

HZ

HN4 111-121

HZ

C'Nt (N1-_1N 11I-119

HZX

111-117.

HZ1 111-120

HN$

11.1-123

CONH

2

HN

NH

3 111-126 111-122

CONH

2 HN' rl$

H

111-125

F

HN

111-127 111-128 111-129 -84-

F

KN1 111-131 111-130 111-132 111-133 111-134 MeO

HH)

1"1-01t 111-136 111-135 flo

F

3 CIat

A

HNZ

111-138 111-137 cl 0.

HNA' NN 111-140 111-141 111-139 b HNN HN HN N, HN 0 N H Me N Me Me: III-145 III-146 In another embodiment, this. invention provides a composition comprising a compound of formula III and a pharmaceutically acceptable carrier.

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

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

Another aspect relates to a method of enhancing glycogen.synthesis and/or lowering blood levels of glucosein a patient in need thereof, comprising administering to said patient a .therapeutically effective amount of a composition comprising a compound of formula -86-

VO

I0 II1. This method is especially useful for diabetic patients.

t Another aspect relates to a method of inhibitingthe production of hyperphosphorylated Tau C( 5 protein in a patient in need thereof, comprising administering to said patient a therapeutically effective q\ amount of a composition comprising a compound of formula III. This method is especially useful in halting or 0 slowing the progression of Alzheimer's disease.

NO 10 Another aspect relates to a method of Sinhibiting the phosphorylation of -catenin 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 treating schizophrenia.

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

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

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

-87-

ND

o Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 t inhibitor, said method comprising the step of administering to a patient in need of such a treatment a q 5 therapeutically effective amount of a composition comprising.a compound of formula III. This method is n especially useful for treating cancer, Alzheimer's

VO

C( disease, restenosis, angiogenesis, glomerulonephritis, o cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis,

(N

ID 10 alopecia, and autoimmune diseases such as rheumatoid 0 o arthritis.

(N

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

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

Each of the aforementioned methods directed to the inhibition of GSK-3, Aurora, CDK-2, or Src, or the -88- Va

IND

0 o treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula III, as t described above.

_Compounds of formula III, wherein R 2 is C( 5 hydrogen and RX 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 D 10 relates to a method of inhibiting ERK-2 or AKT activity o in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula III, wherein R 2 is hydrogen and R and R Y are taken together with the pyrimidine ring to form an optionally substituted quinazoline ring system.

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

Another embodiment of this invention relates to compounds of formula IV: -89- I 2 R 2

HN

N

IV

CI or a pharmaceutically acceptable derivative or prodrug o thereof, wherein: ID 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; 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 membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring is optionally and independently substituted by T-R 3 and any substitutable nitrogen on said' ring is substituted by R4; T is a valence bond or a Ci-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 containing 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, Va wherein said fused ring is optionally substituted by up to three groups independently selected from halo, oxo, -CN, -NO 2 -R7, or -V-R6

R

3 is selected from -halo, -OR, -COR, -COCOR, -COCH 2 COR, -CN, -S(O)2R, -SR, 2 CON(R')2, -SON(R4),, -N (R 4

)COR,

-N C0(optionally substituted C 1 6 aliphatic), 2-N('R 4 -C=N-OR, -N(R 4

)CON(R

4 o

-N(R

4 )SO0N( -N(Rt)SO 2 R, or -OC J 2 IND each R is independently selected from hydrogen or an o optionally substituted group selected from C 1 6 aliphatic, C6.10 aryl, a heteroaryl ring having 5-10 ring atoms, or aheterocyclyl ring having 5-10 ring atoms; each R' is independently selected from-R', -COR 7 -oC02(optionally substituted C 1 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, -C(0O)R, -CO 2 R, C OCOR, -N02, -CN, _S02R, -SR,

-N(R

4 2 -CON(R')2, -S0 2

N(R

4

-N(R')COR,

-N(R

4 )'CO(optionally substituted 01-6 aliphatic), 7N(R 4 )N(R)2 -C=NN(R0l 2 -C=N-OR, -N(R 4

)CON(R')

2

-N(R

4

)SON(R')

2

-N(R

4 )SOR, or V is -N{R6)S0 2 -SO2N(R)-,

-N(R

6 -002-, -N(R 6 -N(R6)S0N(R6)-, -N(R6)1q(k6)-, -C(R6'bO-, -C(i6)2S-, -C(RqhsO-, -C(R')2S0 2 -C(R)2,SON(R0)-, -C(R 6 -0(R 6 )2N(R6)N(R6)-, -C or

-(R

6 2N CON (R 6 -91- Va W is 2 aS-, -C(R) 2 SO-, -C(R')aSO 2

-C(R)

2

SO

2

-C

0 0

-C(R

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

N(R

6 S0 2 C(R6)2N(R') or. -CON(R6) Va each R'.is independently selected from hydrogen or an Cl optionally substituted C1..4 aliphatic group, or two R 6 o groups on the same nitrogen atom are taken together ID 10 with the nitrogen atom to form a 5-6 membered o 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 together with the nitrogen to form a 5.-8 membered heterocyclyl ring or heteroaryl.

Preferred formula IV Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings. Preferred formula IV Ring D bicyclic rings include 1,2,3,4tetrahydroisoquinolinyl, 1,2,.3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-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 2

-CO

2 R, -CON(R),

-N(R

4 )COR, -SO 2

N(R)

2

-N(R')SO

2 R, -SR, -OR, -C R, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, 'C6,o aryl, or C1-. 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, Cs-uo aryl, -92-

VO

or C 1 aliphatic. Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 0H, CH 2 Spyrrolidinyl, OPh, CF 3 CCH, Cl, Br, F, I, NH 2

C(O)C,

I-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene dioxy, (N 5 and ethylene dioxy.

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

HN3 HNA HN NR4,N RMe N IV-D IV-E IV-G HN3 HN -N- Me C IV-H IV-J J IV-K HNHN' HNe N I INN rN

N

IV-L IV- IV-N -93- ~HN37

NN/

iv- o HN

Z

ITV- S HN3L 'v-v HN31

IV-Q

3V-T

HN

rv-w 'v-ti HN37 'v-s

N

N'

'V-AA

HNA

N

fl-BE N

N

Nt z HNxtk ':V-cc -94- Hg HN3% Va

NN

oo c~K IV-DD IN More preferred pyrimidine ring systems of formula IV include IV-E, IV-G, IV-E, IV-J, IV-K, IV-L, 0 IV-M, IV-T, and IV-U.

ci In the monocyclic pyrimidine ring system of o formula IV, preferred RX groups include hydrogen, amino, nitro, alkyl- or dialkylamino, acetamido, or a C 14 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, or -OR. When R is -R or -OR, a preferred R is an optionally substituted group selected from C 1 -s aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocycly1 ring. Examples of preferred RY groups include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl, methoxyphenyl, trimethoxyphenyl, or halo-substituted phenyl, and methoxymethyl.

In the bicyclic pyrimidine ring system of formula IV, the ring formed when RX and RY are taken together may be substituted or unsubstituted. Suitable substituents include halo, -OR, -CO 2

R,

-COCOR, -10 2 -CN, -S0 2 R, -SR, 2 -CON(Rt) 2

-SO

2 N(R)2, -OC(cO)R, COP, -N(R)CO 2 (optionally substituted C 1 -s aliphatic), 2

-C=NN(R')

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

N(R)

2 -N(R)SOR, or -OC(=o)N(Ra') 2 wherein R and R' are as defined above for compounds of formula IV. Preferred R 2 /RY ring

NO

D substituents include -halo, -OR, -COR, -C02R, Ci -CON(R') 2 -CN, or -N(R 4 2 wherein R is a substituted. or cunsubstituted C 1 aliphatic group.

SThe 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 V3 rings include benzo, pyrido, pyrimido, and a partially C- unsaturated 6-membered carbocyclo ring. These are Sexemplified in the following formula IV compounds having \D 10 a pyrazole-containing bicyclic ring system: HN H IX N N Ry NH H NH NH R andN Preferred substituents on the R 2

/R

2 fused ring of formula IV include one or more of the following: -halo, -N(R 4 2 -Ci- 4 alkyl, -C 1 3- haloalkyl, -NO 2 -O(Ci.

4 alkyl), -CO2(C 1 4 alkyl), -CN, -SO2(Cl-4 alkyl), -SO2NHa, -OC ()NH 2 -NHaSO 2

(CI-

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

-C(O)NH

2 and -CO(C.

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

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

R

2 group is hydrogen.

-96- 0 Preferred formula IV compounds have one or more, and more preferably all, of the features selected t from the group consisting of: Ring D is an optionally substituted ring C 5 selected from a phenyl, pyridinyl, piperidinyl, .piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- CN tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3o dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or D 10 naphthyl ring; o R x is hydrogen or C-1, aliphatic and R Y is Tor 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 1-2 ring, heteroatoms; and

R

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

-C(R

6 2

N(R

6 -C0 2 -C(R -C(R')2N(R 6

-C(R

6 2

N(R

6 or -CON(R6)-, and R is an optionally substituted group selected from C1- aliphatic or phenyl, or R' and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring..

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

R

x ishydrogen or methyl and R' is -R, N(R4)2, or -OR, or R

X

and R

Y

are taken together with their -97-

VO

CD intervening atoms to form a 5-7 membered unsaturated or C partially unsaturated ring having 1-2 ring nitrogens, Swherein said ring is optionally substituted with -R, Shalo, oxo, -OR, -C0 2 R, -COCOR, -NO 2 -CN, -S(O)R, C 5 S0 -SO 2 R, -SR, -CON(R) 2

-SO

2

N(R

4 2

-OC(=O)R,

-N(R

4 COR, C2 (optionally substituted C-e6 aliphatic), iCn

-N(R

4

N(R

2

-C=NN(R

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

\O

q -N(R 4

SO

2

N(R

4 2 -N (R)SO 2 R, or -OC(=0)N(R 4 and o each R s is independently selected from halo, \0 10 oxo, CN, NO 2

-N(R

4 3 -COaR, -CONH(R 4

-N(R

4

)COR,

S-SOaN(R') 2

-N(R')SO

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

Even more preferred compounds of formula IV have one or more, and more preferably all, of the features selected from the group consisting of: Rx and R Y are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, optionally substituted with halo, CN, oxo, C-6 alkyl, C 1 -s alkoxy, (Ci-.

6 alkyl)carbonyl, (C1-s alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R 5 is independently selected from -halo, -CN, -oxo, -SR, -OR, -N(R) 2 C(O)R, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-o aryl, or C1i- aliphatic; and

R

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

-C(R

6 2

N(R

6 -CO2-,

-C(R

6

-C(R

6 2 N(R)CO-, or -CON(R 6 and R is an optionally substituted group selected from C1-. 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 -98osubstituted with -halo, oxo,' -N(R 4 2

-C

1 4 alkyl, -C3..

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

(C

4 alkyl), -C04, Ct-SO 2

(C

1 4 alkyl), -30 2

NH

2 -OC (O)NH 2 -NHA*202M( 1 4 aliyl), _-NHC (C 1 4 alkyl) C(0) NH 2 or -CO (C 1 4 'alkyl) wherein CI 5 the (C 1 4 alkyl) is a straight, branched, or cyclic alkcyl group.

R Representative compounds of formula IV are set

IND

c-I forth in Table 3 below.

Table 3.

OH

3

CH

2

OH

3 AcNHa

L

Ne I P MN S N OMe IV-1 IV-2 IV-3

CH

3

OH

3

OH

3

HN

4 *H HN& erp

HN

4

V

02N I WN H2Nt'N

OH

3 CCH NO L-tH3 IV-4 IV-5 IV-6

CM

3 C0 2 Me OH H~rHN*HN 4 IV-7 IV-S IV-9 -99-

HN

H

3 0 N$O IV-11 IV-l0

HN

IV-12

HN#@

tN

H

8 C INkQ 0 IV- 13 IV-14

HAS

N2 H3Cd I-t IV-1

CH

3

H

3

C

14~ IV-17 CH3

N&

IV- 20 IV-18 IV- 21 -100-

CH

3

HN

4

H

MeO IV-22

CH

3

HN

HC~~,O CH 3 H

I-IN

MeO IV- 28 IV-23 IV-24 CHs

HN

H

N

IV-26 CH3

NIV-

IV-29 IV-27

CH

3 HN P IV-31

HN

IV-32 IV-32

CHS

H

H HN-t IV-33 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 -101-

VO

o effective amount of a composition comprising a compound C of formula IV.

c Another aspect relates to a method of treating Sa disease that is alleviated by treatment with a GSK-3 c- 5 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a i) therapeutically effective amount of a composition Ci comprising a compound of formula IV.

o Another aspect relates to a method of enhancing ID 10 glycogen synthesis and/or lowering blood levels of o glucose 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 diabetic patients.

Another aspect relates to a method of inhibiting the production of hyperphosphorylated Tau.

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

Another aspect relates to a method of inhibiting the phosphorylation of 0-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.

-102-

ID

0 .Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora Sinhibitor, said method comprising the step of administering to a patient in need of such a treatment a (C 5 therapeutically effective amount of a composition comprising a compound .of formula IV. This method is especially useful for'treating cancer, such as colon, ovarian, and breast cancer.

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

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 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 -103-

VO

CD carried out with a preferred compound of formula IV, as 0C described above.

SAnother embodiment of this invention relates to Scompounds of formula V:

R

2 H NH C HNRY

V

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

1 is N, CRO, 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 independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo,.or -R 8 Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected -104from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

S-R

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

T-V-R

6 phenyl, 5-6 (c membered heteroaryl ring, 5-6 membered heterocyclyl o ring, or Ci-, aliphatic group, said phenyl, heteroaryl, ID 10 and heterocyclyl rings each optionally substituted by o up to three groups independently selected from halo, oxo, or said Ci-e 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;

R

1 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 R 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 R4; T is a valence bond or a Ci- 4 alkylidene chain;

R

2 and R 2 are independently selected from or

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring 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, -NO2, -R 7 or and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R4; -105-

IND

o R3 is selected from -halo, -OR, -CO 2

R,

ci-COCOR, -C0CH 2 C0R, -NO 2 -S -S (O) 2 R, -SR,

-NCR

4 2 -CON(R 7 2

-SO

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

)COR,

-N(RW)C0 2 (optionally substituted C 1 6 aliphatic),

-N(R

4

)N(R

4 2 -C=blN(R 4 2 -C=N-OR, -NCR 7 CON 2 -N (R 7S0 2

NCR

7 2 rN(RtSO 2 R, Or C=ONP)2 V) each R is independently selected from hydrogen or an'

IND

c-i optionally substituted group s~lected from C..

6 o aliphatic, Cs_3 10 aryl, a' heteroaryl ring having 5-10 IND ring atoms, or a heterocyclyl ring having 5-10 ring o atoms; *each. R 4 is independently 'selected f rom '-COL' -002 (optionally substituted C16r aliphatic), -CON(R'7) 2 or -SO 2 or two RL 4 on the same nitrogen are taken together to form a 5-8 membered .heterocyclyl or heteroaryl ring; each R5 is independently selected from -RL, halo, -OR,

-CO

2 R, -COCOR, -NO 2 -ON, -sO 2 R, -R

-NCR

4 2 -CON(Rt 2

-SO

2

N(R)

2

-N(R

4

)CO,,

-NCR') C0 2 (optionally substituted C1_6 aliphatic), -Nq(R 4

)N(R

4 2

-C=NN(R)

2 -C=N-OR, -N(R 4 CON (0L) 2 -N(R')S0 2

N(R')

2 -N(R')S0 2 R, or -OC( =O)N (R 4 2 orR 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -SOs2-, -N(R)80r-, -SO 2 N(R'h-, -COn-, -N(R6)C(O)O-,

-N(R

6 N1(R6)s0 2

-N(R')NC(R

6 -OC(O)N(R6) -cCR6)20-, -C C) 2S-,

-C(RS)

2 so-, 2 80 2 2 S0 2 2 -C (RE) 2 NO(R) C C 2 N(RW) C(0) 0- -CRW) =VN 2

_C(RZ

6 2 N (R6)80 2 or 2 so 2 2 -C0 2 -106- S-C OC OC N (R 6 2N (R 6

CO-,

2

N(R

6 C -C =NN (R 6 -c eN-O-, S -C(R" 2 N

(R

6

)N(R

6

-CN()

2

N(R)SO

2

N(R

6

-C(R

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

-SR

6

-COR

6 -S0 2

R

6

-N(R

6

-N(R')N(R

6 2 -CN, -NO 2

-CON(R

6 2 or

-CO

2

R

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

-NO

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

-CON(R

4 2 -S0 2

N(R

4 2

-N(R

4 )COR, -N(R 4

CO

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

-C=NN(R

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

)SO

2

R,

-OC or an optionally substituted group selected from C1- 6 aliphatic, C6-3o 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: -107-

A

2 YR:tNH

VC

When the R x and R Y groups of formula V are taken together to form a fused ring, preferred RX/R Y rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R/R 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 HE& H N HN.N Va-A

HN

h vb-A HNNt Vo-A

HN

Q N

-I

Va-B Vb-B Va-B -108-

HCN

3z7 V C Vb- C Va -C tIN31 Va-D Vb-D Va-fl R4,, Q N SSO- Va-Z VB- K Va Va- r vb- F Va

HN

N N

VAM-

vb Ve-J -109- HN

Z

Yb -K A 'N Va-K V K HN Z

HN

Vsb L Va-L Yb -M Vo -M Va-N rNN Yb-N HN3%

N-

Yb-o Va-Nq Va-C Vc-O -110- HN Z7 HN HN N Va-P Vb-P Vc-P ND More preferred bicyclic ring systems of formula 5 V include Va-A, vb-A, Va-A, Va-B, Vb-B, Va-B, Va-D, Vb-D, 0 Vc-D, Va-E, Vb-E, Vc-E, Va-J, Vb-J, Va-J, Va-K, Vb-Z, N Va-K, Va-L, Vb-L, Va-L, Va-M, Vb-M, and Vc-M, most 0 preferably Va-A, Vc-A, Va-B, Vb-B, and Va-B.

In the monocyclic pyridine ring system of formula V, preferred RX groups include hydrogen, alkyl- or dialkylamino, acetamido, or a C 1 4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred R 7 groups include T-R wherein T is a valence bond or a methylene, and R' is -N(R 4 2 Or -OR. When R3 is -R or -OR, a preferred R is an optionally substituted group selected from C3. aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred RY include 2-pyridyl, 4-pyridyl,.piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as.phenyl or halo-substituted phenyl, and mnethoxymethyl.

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

-CN

-SO

2 R, -SR, 2

-CON(R)

2

-SO

2

N(R

4 2 -N(R*)COR, -N(R)CO 2 (optionally substituted C.

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

-C=N-OR,

CON(R) 2

SO

2

N(R)

2

-N(R')SO

2 R, or

-OC(=O)N(R

4 2 wherein R and are as defined above.

-111-

VO

C Preferred Rx/RY ring substituents include -halo, -OR, Cl -COR, -CO 2 R, -CON(R 4 -CN, or -N(R' 2 wherein R is an optionally substituted C1-6 aliphatic group.

1 The R' and R 3 groups of formula V may be taken C- 5 together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused V rings include benzo, pyrido, pyrimido, and a partially CA unsaturated 6-membered carbocyclo ring. These are o exemplified in the following formula V compounds having a ID 10 pyrazole-containing bicyclic ring system:

NH

R H N N N H NH H H and Preferred substituents on the Ra/R 2 fused ring of formula V include one or more of the following: -halo,

-N(R

4 2 -C1-4 alkyl, -Ci3. haloalkyl, -N02, -0(C1-4 alkyl), -CO2 alkyl), -SO (Ci.4 alkyi), -SO2NHa, -OC(O)NH2, -NHaSQo (CI-4 alkyl), -NHC (C2.4 alkyl), NH 2 and -CO(C.-4 alkyl), wherein the (C1.

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

When the pyrazole ring system is monocyclic, preferred R 2 groups include hydrogen, C1-4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, -112- Va isopropyl, propyl, t-butyl, cyclopentyl, phenyl, C0 2 00 2

CH

3

CH

2 0OH, CH20CH3, CH 2 CH2CH20H, CH 2

CH

2

C

2 0CH 3

CH

2

CH

2 CH20CH 2 Ph, CH 2

CCH

2 0 2 CH2CH 2

CH

2 NHCOOC (CE,) 3 CONHCH(CH3) 2 CONHCH2C=CH 2

CONHCH

2

COCH

3

CONHCH

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

CON(CH

3

)CH

2 Ph, CONK(n-C 3

H

7 CON(Et)CHaCH2C 2 1 3

CONHCH

2 CHCH3) 2 CON(n-C 3 H7) 2 CO(3methoxymethylpyrroiidin-1-yl), CONH(3-tolyl), CONH(4tolyl), CONHCH 3 CO(morpholin-1-yl), CO(4-methylpiperazin- 1-yl), CONHCH 2

C

2 OH, CONH 2 and CO(piperidin-1-yl). A IN 10 preferred R 2 group is hydrogen.

o More preferred ring systems.of formula V 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 optionally substituted indazole ring; and Ra and RY are each methyl, or RX and Ry are taken together with the pyridine ring to form an optionally substituted quinoline, isoquinoline, tetrahydroquinoline or tetrahydroisoquinoline ring: NH NH NH HN HN HN Ot%K4OHSHCg -11-0 H 3 0 V-Aa V-Ba V-Ha When aG-is Ring C, preferred formula V Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system.

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at ortho and meta positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred -113oN RI grusicue-do, an optionally substituted 6 ci aliphatic group, phenyl, -COR 6 -OR1: 6 -CR,'3R, -S02NA 2 Ct 2 -C0 2

R

6

-CONH

2 -NHCOR', -OC(O)NH 2 or -NHSO 2

R

6 When R 1 is an optionally substituted CI-6'aliphatic group, S the most preferred optional substituents are halogen.

Examples of preferred R 1 groups include -CF, -C1, -F, CN, -00CR 3

-OCH

3 -OR, -CH 2

CH

3

-OOI

2 CH,, -CR 3

-CF,CH

3 ci cyclohexyl, trbutyl, isopropyl, cyclopropyl, -CmMC, o -020-CH 3

-SO

2

CH

3

-S%,NR

2 -br(at) 2

-CO

2

CH

3 -comH 2 IND 10 -NHCOCH 3 -OC(O)N1 2

-HHSO

2 C%3, and -OCF 3 o On Ring C preferred R 3 substituente, when present, include -halo, -Oil, -NO 2

-N(R

4 optionally substituted C 1 6 aliphatic group, -OR, -CO 2

R,

-CONH(R'), *-N(R 4 )COR, arid -N(R 4

)SO

2 R. More preferred R 5 substituents include -Cl, -Vii, -C, aliphatic), C._ 4 aliphatic, and -C0 2 4 g aliphatic).

Examples of such preferred R 5 substitnents include -Cl, -Cli, -CF3, -Nil 2 -NMe, -MMe 2 -0EV, methyl, ethyl, cyclopropyl,' isopropyl, t-butyl, and -CO 2 Et.' When G is Ring D, preferred formula V Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl,.piperazinyl, pyrrolidinyl, thienyl1, azepanyl, and morpholinyl. rings.

when two adjacent substituents on Ring D2 are taken together to form a- fi:'sed ring, the Ring D system is' bicyclic.. Preferred,formula V Ring 12 bicyclic ringw include 1,2,3,4-tetrahydroisoquinolinyl., 1,2, 3,4tetrahydroquinolinyl, 253 -dihydro-1E-isoindoiyl,,2,3-, dihydro-1H-indolyl, is oquinotinyl, quinolinyl,, and naphtbyl. Examples of more preferred bicyclic Ring fl systems include naphthyl and isoquinolinyl.

Pref erred substituents on Ring D2 of formula V include one or more of the following: halo, oxo, ON, 4102, -114- Va o -COaR, -CONH(R), -N(R 4 )COR, -SO 2

N(R

4 2

-N(R

4

)SO

2

R,

CI -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-1.o aryl, or C 1 6 aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, -N(R'1 2 or a substituted.or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-.o aryl, or C 1 -s aliphatic.

Examples of Ring D substituents include -OH, phenyl, Smethyl, C0 2 0H, CH 2

CH

2 OH, pyrrolidinyl, OPh, CF 3 CMCH, C1, 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 V compounds have one ormore, 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 Snaphthyl, quinolinyl or isoquinolinyl ring, and R is -halo, an optionally substituted Ci-s aliphatic group, phenyl, -COR', -OR 6 -CN, -S0 2

R

6

-SO

2

NH

2 2 -C0 2

R

6

-CONH

2 -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-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; RX is hydrogen or C 1 4 aliphatic and R is T- R, or R and RY are.taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; and -115-

VO

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

i) More preferred compounds of formula V have one

VO

C- or more, and more preferably all, of the features o selected from the group consisting of: c\ 10 Ring C is a phenyl or pyridinyl ring, Soptionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and

R

1 is -halo, a CI- 6 haloaliphatic group, a C 1 -6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, 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)2, or -OR, or R x and R Y are taken together with their intervening atoms to form a benzo ring or a 5-7 membered partially unsaturated carbocyclo ring, said benzo or carbocyclo ring optionally substituted with halo, -OR, -C0R, -COCOR, -NO 2 -CN, -SO 2

R,

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

N(R

4 2 -N(R)COR, -N (R 4 C0 2 (optionally substituted .CI- aliphatic), -N(R4)N(R4) 2 -C=NN(R4) 2 -C=N-OR, -N(R4)CON(R4) 2 -N(R4)SO 2

N(R

4

-N(R

4 )S02R, or 2

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a C 1 -6 aliphatic group, or R 2 and R 2 are taken together -116-

VO

C .with their intervening atoms to form a substituted or CA unsubstituted benzo, pyrido, pyrimido or partially Sunsaturated 6-membered carbocyclo ring; and Ring D is substituted by oxo or R 5 wherein C- 5 each R s is independently selected from -halo, -CN, -NO 2

-N(R

4 2 optionally substituted C 1 6 aliphatic group, -OR, -COaR, -CONH(R 4 -N(R')COR, -SO 2

N(R')

2 or Ci

SO

2

R.

O Even more preferred compounds of formula V have ID 10 one or more, and more preferably all, of the features o 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 CI-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphtbyl; R* 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" and R

Y

are taken together with their intervening atoms to form a benzo ring or a 6-membered partially unsaturated carbocyclo ring optionally substituted with halo, CN, oxo, Ci,- alkyl, CI-e alkoxy, (C16 alkyi) carbonyl, (Cizalkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; -117o R' and R 2 are taken together with their 0 N intervening atoms to Iform a benzo, pyrido, pyrimido or t partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R 4 2

-C

1 4 alkyl, C- 5 -C 1 4 haloalkyl, -NO 2

-O(C

1 z-4 alkyl), -C02 (C 1 4 alkyl) -CN,

-SO

2

(C-

4 alkyl), -SO 2 VNR, OC NI, -NH 2

SO

2

(C

1 4 alkyl), -NHC (C 1 -4 alkyl) -C(O)NH 2 or -CO(C. alkyl), wherein (N the (C, 4 alkyl) is a straight, branched, or cyclic alkyl o group; and IN 10 Ring D is substituted by oxo or Rs, wherein 0 O each R5 is independently selected from. -Cl, -CN, -CF 3

-NH

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

(C

1 4 aliphatic).

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

Table 4.

F

CHs F H H

H

HNf_ HtP H bCF3..N OF3, 'V-1 V-2 V-3

NIV

H H Ha H V-4 V- V-6 -116- H N V-7 V-8 VI-9 V-11 V-i12

C

3 V- 13

H

3

C

F

3

C

V-1s

I

H

3

CXA,-

V- 14

F

HZ

H

3 CXN N e V-17

H

3

C

v-Is' 10 -119-

H

3

CN

V-203

H

3

C

V-21 v-i19 V-22 V-23 v-24 V-26 V-27 F0 H-2

F

3

C

V-29 -120- HN

HN)

HC H3Ct. N H 3

C

F

3 C H C!H

F

3

C

V-31 V-32 V-33 VaH HN~ aH SV-34 .V-35 V-36

HN

9 d HN 9

HNI

H3CHSCHsCt

LH

3 -1

F

3 C clFa0 V-37 V-38 V-39 FFp HN Hr.

5 -NN IH C V- 40 V-41 V-42 -121- V-43 V-44 V4 V-45 V- 46 V- 47 V- 48 V-49 V-s0 v-51 V-52 V-53 V-54 -122ciHN HN; H

F

3 C HNQ F 3

C'

V-56 V-57 IC-Ha'4 HN 0N ci or

F

3 0CF

NH

2 NH 2 S V-58 V-59 V-SO

CH

3

HN

2 J HFN H N

OH

3

F

3 C NQF 3 0 V-61 V-62 V-63 -123-

ID

0F NOH

H

H HN 2 N

N

SF3C^ '3

C

SV-67 V-68 Va

IN

a In another embodiment, this invention.provides a composition comprising a compound of formula V and a Spharmaceutically acceptable carrier.

C 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 V. 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 -124- Va D oD V. This method is especially useful in halting or slowing the progression of Alzheimer's disease.

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

ci One aspect 6f this invention relates to a o 10 method of inhibiting Aurora activity in a patient, 0comprising 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-'an Aurora inhibitor, said method comprising the-step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula V. This method is especially useful for treating cancer, such as colon, ovarian, and breast cancer.

One aspect of this 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 V.

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 V. This method is especially useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, -125- 0 cytomegalovirus, HIV, herpes; psoriasis, atherosclerosis, C alopecia, and autoimmune diseases such as rheumatoid Ct arthritis.

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

(N

Ms 10 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 V, as described above.

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

'H

N'N

VI

or a pharmaceutically acceptable derivative or prodrug thereof,.wherein: G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their -126- Sintervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 Sheteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, N( 5 oxo, or -RO; Ring D is a 5-7 membered monocyclic ring or 8-10 membered \q bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or Sheterocyclyl ring having 1-4 ring heteroatoms selected IND 10 from nitrogen, oxygen or sulfur, wherein Ring D is Ssubstituted 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.i- aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or said aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;

R

y is T-R3'; T is a valence bond or a Ci-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 -127- Va and any substitutable nitrogen on said ring formed by R2 and R 2 is substituted by R';

R

3 is an optionally substituted group selected from C1.6 aliphatic, Cs-.

10 carbocyclyl, Cs-to aryl, a heteroaryl C- ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10.ring atoms;.

each R is independently selected from hydrogen or an

NO

(N optionally substituted group selected from C 1 6 aliphatic, C 6 10 aryl, a heteroaryl ring having 5-10 IND ring atoms, or a heterocyclyl ring having 5-10 ring o atoms; each R' is independently selected from -R7, -COa7,

-CO

2 (optionally substituted C 1 6 aliphatic), -CON(R')2, or -SO 2 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,

-CO

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

-N(R

4 2

-CON(R')

2 -SO2N(R 4 2

-N(R')COR,

-N C 2 (optionally substituted C 1 aliphatic), 2

-C=NN(R')

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

SO

2

N(R)

2

-N(R')SO

2 R, or 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(Rr)SO-, -S0 2

N(R

6

-N(R

6 -C0 2

-N(R

6

CON(R

6 S0ON (R 6

-N(R

6

)N(R

6

-C(R)

2 2

S-,

-C(R)

2 SO0-, -C(R) 2

SO

2

-C(R

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

-C(R

6 2

-C(R

6 2

(R

6 C -C(R 6 -c(R 6 2

N(R')N(R

6 2

N(R

6

)SO

2

N(R

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

-C(R

6

-C(R

6 2 SO-, -C (R 6 2 S0 2 2SO 2 N(R) -C(R 6 2 -C0 2 -128- -C (R' -C(R 6

)OC.(O)N(R

s -C (R 2

N(R

6

)CO-,

S_-C 2 N(R)C

S-C(R

6 2 N -C(R 6 2

N(R')SO

2

N(R

6 C(R)2N (R 6 CON(R) or -CON(R 6 C( 5 each R 6 is independently selected from hydrogen, an optionally substituted CI- 4 .aliphatic group, or two R' groups on the same nitrogen atom are taken together _c with the nitrogen atom to form a 5-6 membered o heterocyclyl or heteroaryl ring; Va 10 each R 7 is independently selected from hydrogen or an Soptionally substituted Ci-6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to formia 5-8 membered heterocyclyl or heteroaryl ring; and each R e is independently selected from an optionally substituted C1-4 aliphatic group, -OR 6

-SR

6

-COR',

-SO

2

R

6 -N(R 2

-N(R')N(R

6 2 -CN, -NO 2

-CON(R

6 or

-CO

2

R

6 Preferred R y groups of formula VI include T-R 3 wherein T is a valence bond or a methylerie, and R 3 is an optionally substituted group selected from C_-6 aliphatic, C3-3o carbocyclyl, Csg-o aryl, a heteroaryl ring having 5-10 ring atoms, or a beterocyclyl ring having 5-10 ring atoms. A preferred R 3 group is an optionally substituted group selected from C3- carbocyclyl, phenyl, or a 5-.6.

membered heteroaryl or heterocyclyl ring. Examples of preferred R Y include 2-pyridyl; 4-pyridyl, piperidinyl, morpholinyl, cyclopropyl, cyclohexyl, and optionally -substituted phenyl such as phenyl or halo-substituted phenyl.

The R 2 and R 2 groups of formula VI may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially -129-

IND

unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula VI compounds havin~g ct a pyrazole-containing:,bicyclic ring system: NA N NM4N oH ANHH.m and Preferred gubstituents on the R 2

/R

2 fused ring include one or more of the following: -halo, -NCR 4 2

-C

1 4 alkyl, 4 haloalkyl, -NO 2 -0 c 1 4 alkyl),. -C02 (C 1 4 alkyl), -S0 2 (C3,- 4 alkyl), -SO 2

NH

2 -OC(0)NH 2

-NH

2 80 2 alkyl), -NRC (0)(C 1 4 alkyl), -C(O)NH4 2 and -C C.

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

When the pyrazole ring-system is monocyclic, preferred. R' groups of formula VI include hydrogen, C 1 4 *aliphatic,-alkoxycarbonyl, (un)substituted phenyl, *hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalcyl, alkylaminoalkyl, dialkylaminoalkyl, phenylsiminocarbonyl, and (Nheterocyclyl) carbonyl. Examples of such pref erred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyciopentyl4 phenyl, CO 2

H,

0 2

CR

3

CH

2 OE, CR 2 00H3,, CR 2

CH

2

CH

2 OH, CE 2

CH

2

CH

2 0CH 3

CH

2

CH

2

CS

2 00H 2 Ph, CE 2

CH

2

CH

2 1VH2, CH 2

CE

2

CH

2 NHCOOC(CHli,, CON HCE (cH4 CONRCR 2

CR=CH

2

CONHCH

2

C

2 00R,, coN}TcH 2 Pb, 00NR(cyclohexyl), CON(Et) 2 ,0 CON(CH4CH 2 Ph, CONE Cn-C3H 7 CON CEt) ObH2CH, *CONH01,0E (01, V, 1 CON (n-C3H 7 CO (3methoxymethypyrrolidin-l-yl), CONR3-tolyl), CoNB(4- -130- Va Stolyl), CONHCH, CO(morpholin-l-yl), CO(4-methylpiperazin- 1-yl), CONHCH2CH 2 0H, CONH 2 and CO(piperidin--yl). A preferred R 2 group is hydrogen.

When G is Ring C, preferred formula VI Ring C N 5 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.

0- Such rings preferably are fused at ortho and meta positions of Ring C. Examples of preferred bicyclic Ring o C. systems include naphthyl and isoquinolinyl. Preferred R groups include -halo, an optionally substituted C 1 -s aliphatic group, phenyl, -COR', -CN, -SO 2

-SO

2

NH

2 2

-CO

2 -CONH2, -NHCOR', -OC(O)NH 2 or -NHSO 2

R'.

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

Examples of preferred R' groups include -CF3, -CI, -F, -cN, -COCH 3 -OCH3, -OH, -CH 2

CH

3 -OCHCH, -04, -crcHn, cyclohexyl, t-butyl, isopropyl, cyclopropyl, -CCH,- -C=C-0C1, -SO 2

CH

3

-SON-

2

-N(CH

3 -CO2C0i, -CONH 2

-NHCOCHI

3

-OC(O)NH

2 -NHS0 2

CH

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

R,

-CONH(R

4

-N(R

4 )COR, -SO 2

N(R')

2 and -N(R)SOaR. More preferred R5 substituents include -Cl, -CN, -CF 3

-NH

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

-O(C.

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

4 aliphatic).

Examples of such preferred R' substituents. include -Cl, -CN, -CpF,, -NHi, -NHMe, -NMea, -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, -131- Va 0 pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.

CA When two adjacent substituents on Ring D are taken t together to form a fused ring, the Ring D system is bicyclic. Preferred formula VI Ring D bicyclic rings Ci 5 include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-H-isoindo)yl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and CA naphthyrl. Examples of more preferred bicyclic Ring D o systems include naphthyl and isoquinolinyl.

ID 10 Preferred substituents on formula VI Ring D Co include one or more of the following: halo, oxo, CN, -No 2 2 -C0 2 R, -CONH(R'), -N(R 4 )COR, -SO 2

N(R)

2 -N(R')SOaR, -SR, -OR, orsubstituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-1o aryl, or C 1 aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-.o aryl, or C1- 6 aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 OH, CH2CH 2 0H, pyrrolidinyl, OPh, CF 3 C-H, 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 more, and more preferably all, of the features selected from the group consisting of: Ring C is selected from a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or iboquinolinyl ring, and R' is -halo, an optionally substituted C 1 -6 aliphatic group,. phenyl, -COR, -CN, -SOR', -SONHa, 2 -C0 2

R

6

-CONH

2 -NHCOR', -OC(O)N 2 or -NISOiR'; or Ring D is an optionally substituted ring selected from a -132-

VO

o phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4- G tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, S2,3-dihydro-1H- isoindolyl, 2,3-dihydro- 1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

R

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

R

2 is hydrogen and R 2 is hydrogen or a C substituted or unsubstituted group selected from aryl, cO heteroaryl, or a CI-_ aliphatic group, or R' and R 2 are 0 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: 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 -6 haloaliphatic group, a Ci-e 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-IH-isoindolyl, 2,3-.

dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl;

R

Y is T-R 3 wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from Ci-s aliphatic, C3- carbocyclyl, C-io 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -133-.

siwiPi

VO

R

2 is hydrogen and R 2 is hydrogen or a CN substituted or unsubstituted group selected from aryl, or t a C 1 -6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or C- 5 unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo. ring; and S(d) Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -halo, -CN, -NO 2 o -N(R 4 2 optionally substituted C-s6 aliphatic group, -OR, 1D -CO 2 R, -CONH(R 4

-N(R

4 )COR, -SO 2

N(R)

2 or S-N (R 4 S0 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: RY is T-R 3 wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from CI- 4 aliphatic, C 3 6 carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and

R

1 is -halo, a Cl.

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

R

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

4 alkyl, -Ci-4 haloalkyl, -NO 2 -O(C1-4 alkyl), -CO2(C1-4 alkyl), -CN, -134- -S02 4 alkyl), -SO 2

NH

2 -OC (0)NH 2

-NH

2 SO (C 1 i- alkyl) -NHC(O) (Ca-4 alkyl), -C(O)NHa, or -CO(C..4 alkyl), wherein Sthe (.C 1 -4 alkyl) is a straight, branched, or cyclic alkyl group; and C 5 Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -Cl, -CN, -CF 3

S-NH

2 -NH(Ci.

4 aliphatic), -N(C1- 4 aliphatic) 2 -O(Ci-4 C aliphatic), C-.

4 aliphatic, and -CO 2

(CI.

4 aliphatic) O Another embodiment of this invention relates to ND 10 compounds of formula Via: cR

NH

HN

NN

Via or a pharmaceutically acceptable derivative or prodrug thereof, wherein: G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, 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 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; -135-

VO

o Ring D is a 5-7 membered monocyclic ring or 8-10 membered o bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or Sheterocyclyl 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 NO provided that when Ring D is a six-membered aryl or Sheteroaryl ring, -R 5 is hydrogen at each ortho carbon C 10 position of Ring D; 0 RI is selected from -halo, -CN, -NO2, T-V-R 6 phenyl, 5-6 C1 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R 8 said 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; T is a valence bond or a Ci-4 alkylidene chain;

R

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

-V-R

6 and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R4; each R is independently, selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, Cs-i. aryl, a heteroaryl ring having 5-10 ring atoms, or a.heterocyclyl ring having 5-10 ring atoms; -136each R 4 is independently selected from -k7, -COR"I -C0 2 (optionally substituted C3._6 aliphatic), -CON 2 ct or -S0 2

R

7 or twd R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring;, each R 3 is independently selected from halo, -OR, R, -CO 2 R, .1COCOR, -NO 2 -CN, -S -SO 2 R, -SR, _N -NR) 2 -CON(Rt 2

-SO

2 N (R4) 2 -OC R, -N(Rt4COR, o -N (R 4 C02 (optionally substituted -C 1 -6 aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R

4 2 -N(R')CON(Rt) 2 o-N (R 4 SO2N (R 4 2 -N (R 4

)S

2 R or' -OC N(R4) 2 or R 5 and An adjacent substit uent taken together with-their intervening atoms f orm said ring. fused to Ring C; V is -802-, -N(R 6 )S0 2 -50 2 N (R 6

-N(R

6

-CO

2 1

-N(R

6 -Nq(R 6

-N(R

6 5)CON(R 6

-N(R')SO

2

-N(R')N(R

6

-C(O)N(R

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

-C(R

6 2 s0-, -C(R 6 2 S0 2

-C(R

6 2 So 2 -c(R 6 2

N(R

6

-C(R

6 2 N (RrC -C(R 6 2

-C(R

6

)=NN(R

6 -CR) 2N(R0) N (R 6 -C(RW) 2 N 6 S0 2 N or -C (R 6 )2N (R 6 )dog (R 6 W is -C(R 6 2

-C(R

6 2

-C(R

6 2 s0-, -C(R 6 2 S0 2

-C(R

6 2 s0 2

N(R

6

-C(R

6 h2N(R 6 -00,2-1 -C (R 6 OC -C (R.

6 )OC -C(R 6 2 N(RC0- -C (R6) 2 N (R 6 -C0(R 6 =NN -C -(R 6 2

N(R')N(R

6

-C(R

6 2

N(R')SO

2 N3(R'6)-,

-CON(R

6 each R6 is independently selected from hydrogen, an optionally substituted C1-4 aliphatic group, or two R6 groups on the same nitrogen atom ate taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R 7 isrindependently selected from.hydrogen or an optionally subst ituted aliphatic group, or two R'7 -137o on the same nitrogen are taken together with the Cq nitrogen to form a 5-8 membered heterocyclyl or Sheteroaryl ring; and each R 8 is independently selected from an optionally 5 substituted Ci-4 aliphatic group, -OR, -SR 6

-COR

6

-SO

2

R

6

-N(R

6 2

-NCR

6

)N(R

6 2 -CN, -NO 2

-CON(R

6 2 or f -COR 6

VO

C- Preferred rings formed by the R2 and R 2 groups o of formula Via include benzo, pyrido, pyrimido, and a ID 10 partially unsaturated 6-membered carbocyclo ring. These o are exemplified in the following formula Via compounds C having a pyrazole-containing bicyclic ring system: HNN NNN-N N 'N ,N 1 /1 KNk >i'.NH NH- H 2

NH

and Preferred substituents on the R 2

/R

2 fused ring include one or more of the following: -halo, 2 -C1- 4 alkyl, -Ci-4 haloalkyl, -NO 2 -0(CI-4 alkyl), -CO2 (C1-4 alkyl), -CN, -So 2 (Ci-4 alkyl) -S0 2 NHa, -OC(0)N 2 a,

-NH

2

S

2

(C-

4 alkyl), -NHC (CI- 4 alkyl), -C(O)NH 2 and -CO (CI-4 alkyl), wherein the (CI- 4 alkyl) is a straight.

branched, or cyclic alkyl group. Preferably, the (CI-4 alkyi) group is methyl.

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

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at ortho and meta -138positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred RI groups include -halo, an optionally substituted CI-..

6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2

-SO

2

NH

2 2

-CO

2

-CONH

2 -NHCOR', -OC(O)NH 2 or -NHSO 2

R'.

When R' is an optionally substituted C..

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

Examples of preferred R 1 groups include -CF, -C1, -F, -CN, -COCH3, -OCH3, -OH, -CH2CH, -OCH2CH3, -CF 2 CH3, cyclohexyl, t-butyl, isopropyl, cyclopropyl, -COC, -CC-CH3, -S02CH31, -SO 2

NH

2 -N(CH3) 2 -C02CH3, -CONH 2 -NHCOCH3, -OC(O)NH 2 -NHS0 2 CH, and -C003.

On Ring C preferred R 5 substituents, when present, include -halo, -CN, -NO 2 2 optionally substituted C1-6 aliphatic group, -OR, -CO 2

R,

-CONH(R

4 -N(Rt)COR, -SON(R 4 and -N(R 4 )SOR. More .preferred R 5 substituents include -C1, -CN, -CF3, -NH2, -NK(C4 aliphatic), -N(C.4 aliphatic)2, aliphatic), -aliphatic, and -CO(C4 aliphatic) Examples of such preferred R 5 substituents include -C1, -CN, -CF3, -NHa,' -NHMe, -NMe2, -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -COEt.

When G is Ring D,.preferred formula VIa Ring V 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, 2,3-.

dihydro-ur-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring.D systems include naphthyl and isoquinoliny.

.4 -139- Preferred substituents on the formula Via Ring D f include one or more of the following: halo, oxo, CN,

-NO

2 -N 2

-CO

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

-N(R

4

)SO

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

CH

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

Preferred formula VIa 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 16 aliphatic group, phenyl, -COR 6 -OR, -CN, -SOR, -SONH 2

-N(R

6 2 -CO2R', -CONH, -NHCOR 6

-OC(O)NH

2 or -NHSO2R; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl,.1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, -quinolinyl, or naphthyl ring; and

R

2 and R 2 are taken together with their.

intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6membered carbocyclo ring.

-140- More preferred compounds of formula VIa have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -RS, 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.-6 haloaliphatic group, a C 1 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

2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionalijsi@tued4 with. -halo, NR 4 2 -Ci.

4 alkyl, -CI-4 haloalkyl, -NOa, -0(C -4 alkyl), -C0 2 (CI-4 alkyl) -CN, -S02 (CI-4 alkyl), -SOaNH 2

-OC(O)NH

2

-NH

2 SO2 (C 1 -4 alkyl), -NHC(O) (C 1 -4 alkyl), -C(O)NH 2 and -CO(C.-4 alkyl), wherein the (Ci-4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R s is independently selected from -halo, -CN, -NO 2 2 optionally substituted Ci-6 aliphatic group, -OR, -COaR, -CONH(R 4 -N(R')COR, -SO 2

N(R')

2 or

-N(R

4 )S0 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 -Rs, wherein when Ring C and two -141- Va adjacent substituents thereon form a bicyclic ring C( system, the bicyclic ring system is a naphthyl ring, and

SR

1 is -halo, a C 1 4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, S 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- C- tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or o naphthyl; ID 10 R" and R2' are taken together with their o intervening atoms to form a benzo, pyrido, or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, 2

-C

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

-O(C

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

-SO

2

(C

1 1 4 alkyl), -802NH2, -OC(0)NH 2

-NH

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

-NH

2 -NH(CI-.4 aliphatic), -N(C 1 4 aliphatic) 2

-O(C

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

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

Table

CH

3 H H

H

HN

4 HNZ

HNZ

N-N N'N

N-N

Vx-1 VI-2 VI-3 -142-

N,

4 VI -4

OH

8

HN

N H3 Pr HNgPH N J-N W" Me vi -11 HNAIt VI -6 Et HNg N Y.N .VI -9 VI-? IPr VI -10 Eu N4N v-

N

VI -13 VI -14 VI -143-

H

VI-17 VI -16 VI -18 HN4H F 3

C

Vi -19 VI -20 VI -21 VI -22 F VI -23

F

N J'N C4 VI -26 1)

F

3

C

VI -24 N 'jN VI -27 -144- VI-28

F

H

N -N CNAN)Y)e VI -29 F

H>?

VI -32

MN?

N

HN

F

3 0 VI N F3N VI -33 VI-31 VI-34 VI-35

NN

VI -38 VI -36 HN Zf N .N VI -39 VI-37 1-145- VI -40

HN

N -L-N

FC

VI -43 N 'IN VI-41

H

NN

VI -44 VI-42

NN

FC

3 0 VI -VIa-1 VI a-2 Vla -3

N"NON

Vla-4 N JN Me .Vla-5

N

IH

HN%

A

N QN CF 3 VIa-6 146-

VO

HN

H H H SHN9; HN HN SN' ON N NN Me N 4

N

NHMe i VIa-7 VIa-8 VIa-9

VO

HNH

0 H HN H 0HN 1 HN HN NN NN N N ONNH2 NHMe VIa-10 VIa-ll VIa-12 In another embodiment, this invention provides a composition comprising a compound of formula VI or VIa and a pharmaceutically acceptable carrier.

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

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

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective -147-

IO

O amount of a composition comprising a compound of formula C VI or Vla. This method is especially useful for diabetic Spatients.

SAnother aspect relates to a method of c- 5 inhibiting the production of hyperphosphorylated Tau .protein in a patient in need thereof, comprising l administering to said patient a therapeutically effective Ci amount of a composition comprising a compound of formula o VI or Via. This method is especially useful in halting ci IND 10 or slowing the progression of Alzheimer's disease.

SAnother aspect relates to a method of ci inhibiting the phosphorylation of 0-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 methodis .especially useful for treating schizophrenia.

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

Another aspect relates to a method of treating a disease 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 effective amount of a composition comprising a compound of formula VI or VIa.

-148- Va

ID

0 Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 t inhibitor, said method comprising the step of administering to a patient in need of such a treatment a C 5 therapeutically effective amount of a composition comprising a compound of formula VI or Via. This method ~Q is especially useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, 0 cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, IND 10 alopecia, and autoimmune diseases such as rheumatoid 0 arthritis-. ci 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:

R

2

NN

VINi R y

VII

-149-

VO

D or a pharmaceutically acceptable derivative or prodrug 0 C thereof, wherein: c G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, r pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents iV 5 independently selected from -R 1 any substitutable non- Ci ortho carbon position on Ring C is independently o substituted by R s and two adjacent substituents on \D Ring C are optionally taken together with their Sintervening atoms to form a fused, unsaturated or -c 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 -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

s 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 16 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 RI and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C, -150-

VO

ID

o

R

y is hydrogen or T is a valence bond, hydrogen, 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 ^C atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms IQ 5 selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R 2 0 and R 2 is substituted by halo, oxo, -CN, -N0 2

-R

7 or o -V-R 6 and any substitutable nitrogen on said ring o formed by R 2 and R 2 is substituted by R 4

R

3 is selected from an optionally substituted group selected from C3- 10 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.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 -R 7

-COR

7 -COz (optionally substituted C 1 i- aliphatic), -CON (R 7 2 or -SO 2 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, -C(0O)R, -C02R, -COCOR, -N02, -CN, -SO2R, -SR,.

-N(R

4 2

-CON(R

4 2

-SON(R

4 2

-N(R

4

COR,

-N(R C0 2 3(optionally substituted Ci-± aliphatic),

-N(R

4

)N(R)

2

-C=NN(R')

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

)CON(R*)

2

-N(R')SO

2

N(R)

2

-N(R

4

)SO

2 R, or 2 or R 5 and an adjacent substituent-taken together with their intervening atoms form said ring fused to Ring C; -151- Va V is -SO2-, -N(R 6

)S

2

-SO

2 N(R6)-, C~ -C02_1 -N(R6)CO-, -N(R6)C(0)0-,

-N(R

6 -N(R")80 2 -OC(O)N(R6) 2 C(R 6 2S-, C- 5 2 S0-, 2 S0 2 -C(R6) 2

SO

2

-C(R

6 2

N(R

6 -C(IZ6)21(Rq)CO)r -C(R6)2NIk6C(O)O-, 2

N(R

6

-C(R')N(R

6 )SON(R6)-, or -C(R6) 2 N (R6) CONR6)- W is 2

-C(R'

2

-C(R

6 2 SO-, 2 S0O 2 -C(R6) 2

SO

2

-C(RZ)

2 -002-,

CR

6

-C(R

6 2-C(R 6

)N(R

6 C C (R) 2

N(R

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

-C(R

6

A(R

6

)SS

2

-C(R

6 2

,N(R

6 or -CON(R 6 each R6 is independently selected from hydrogen, an optionally substituted C 1 4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R 7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two .R7 on the same nitrogen are taken together with the nitrogen to form a 5- membered heterocyclyl or heteroaryl ting; each I 8 is independently selected from an optionally substituted 01-4 aliphatic group, -QR 6 -SR, -COlt 6

-SO

2 R6, -N(R6) 2 2 -cN, -NO 2

-CON(R)

2 or

-CO

2 R; and

R

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

-NO

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

-CON(R

4 2 -S0 2

N(R

4 2

-N(R

4 )COR, -NCR)C0 2 (optionally substituted C aliphatic), -N(R)N(R) 2 -C=N(RW2,

-N(R

4

)CON(R

4 2 -N(R4)SO 2

N(R)

2

-N(R

4

)SO

2 R, or -00 C=O)N( 4 2 -152- VO ID S Preferred R Y groups of formula VII include T-R 3 wherein T is a valence bond or a methylene. Preferred R 3 t groups include an optionally substituted group selected from C3-6 carbocyclyl, phenyl, or a 5-6 membered C( 5 heteroaryl or heterocyclyl ring. Examples of preferred R

Y

include 2-pyridyl, 4-pyridyl, piperidinyl, cyclopropyl, 4\ and an optionally substituted phenyl such as phenyl or halo-substituted phenyl.

0 The R 2 and R 2 groups of formula VII may be taken together to form a fused ring, thus providing a Sbicyclic 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:

,NH

HN N N

N--N

RyNaH H H H R and Preferred substituents on-the R2/R 2 fused ring include one or.more of the following: -halo, -N(R 2 -CI-4 alkyl, -C 1 -4 haloalkyl, -NO 2 -O(CI4 alkyl), -CO2(C,.4 alkyl), -CN, -S02 (C- 4 alkyl), -SO 2

NH

2

-OC(O)NH

2 -NH2SO 2 (C3-4 alkyl), -NHC(O) alkyl), -C(O)NHa, and -CO (Ci- alkyl), wherein the (C-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C-4 alkyl) group is methyl.

When the pyrazole ring system of formula VII is monocyclic, preferred R 2 groups include hydrogen, C1-4 -153-

IND

o aliphatic, alkoxycarbonyl, (un)substituted phenyl, 0 hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,, phenylaminocarboby.,'and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl,!t-butyl, cyclopentyl, phenyl, CO 2

M,

Va ~CO 2

CH

3

CM

2 OH, C2 2

CH

3 CH2 2

C

2 0H, CH2 CH 2

CH

2 0CM 3 oCH 2

CHCH

2

OCE

2 Ph, CK 2

CH

2

CH

2

NH

2 C2HC2HOCC33 IND 10 COrNICH (CHO} 2 consai2ca=ca 2

CONHCII

2

CH

2 OCH4 3

CONHCH

2 Pt±, o CONP(cyclohexyl), CON(Et) 2

CON(CII,)CH

2 Pb, CONM(n-C 3 CON(Et) CH 2

CH

2 CH3, CONHCM 2 CM (CH 3 2 CON(n-C 3 Ib) 2 C0C3methoxymethylpyrrolidin-1-yl), CONK (3 -tolyl)', CONK (4tolyl), COWICR.

3 Co (morpholin-1-yl), Co (4 -metbylpiperazin-

CONECE

2

CH

2 OH, CONE 2 and CO(piperidin-1-yl). A preferred R 2 group is hydro gen.

When G is. Ring C, preferred formula VII Ring C groups are phenyl and pyridinyl. Then two adj acent substituents on Ring C are taken together to form a fused ring, Ring C is conitained in a bicyc .lic 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 aliphatic group, ph~nyl, -COR 6 -0RC, -CN, -80 2 R6, -S0 2

NH

2 t

-N(R)

2 -C0 2

R

6

-CONH

2 -NHCOR', -OC(O)NE 2 or -NIISO 2

R

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

Examples of preferred R' groups include -C7 3 -Cl, -F, -ON, -COCH 3 -0CM 3 -OH, -CH 2

CH

3

-OCE

2

CM

3

'-CH

3

-CF

2

CH

3 Cyclohexyl, t-butyl,, isopropyl, cyclopropyl, -OsGIH,

-C-C-CH

3 _S0 2

CM

3

-SO

2

NH

2

-N(CH

3 2 -C0 2

CM

3

-CONH

2 -NIICOa! 3 -OC (0)NH 2 -NIES0 2

CH

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

R,

-CONH -N(R')COR, -SO 2 N (R4) 2 and -N(R.')SO 2 R. More C 5 preferred R 5 substituents include -Cl, -CN, -CF 3

-NH

2

-NH(CI.

4 aliphatic), aliphatic) 2

-O(C-

aliphatic), C1.4 aliphatic, and -C02(C.4 aliphatic).

c Examples of such preferred Rs 5 .substituents include -Cl, o -CN, -CF 3

-NH

2 -NHMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl', and -CO 2 Et.

o .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 VII Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetraydroquinolinyl, 2,3-dihydro-IH- isoindolyl, 2,3dihydro-1l-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring b systems include naphthyl and isoquinolinyl.

Preferred substituents on Ring D include one or more of the following: halo, OXo, CN, -NO 2 -N(Rf)2, -CO 2

R,

-CONH(R), -N (R')COR, -S0 2 1N(R') 2

-N(R')SO

2 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-io aryl, or Cj-e 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 aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 0H, CH2CH 2 0H, pyrrolidinyl, OPh, CF3, C=CH, C1, -155-

VO

C Br, F, I, NH 2

C(O)CH

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

Preferred formula VII compounds have one or more, and more preferably all, of the features selected c 5 from the group consisting of: Ring C is a phenyl or pyridinyl ring, i) optionally substituted by -R 5 wherein when Ring C and two

VO

Ci adjacent substituents thereon form a bicyclic ring o system, the bicyclic ring system is selected from a \D 10 naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is S-halo, an optionally substituted C1- aliphatic group, CI phenyl, -COR 6 -CN, -SO 2

R

6

-SO

2

NH

2

-N(R

6 2

-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, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

R

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

R

2 is hydrogen and R 2 is hydrogen or a' substituted or unsubstituted group selected from aryl, heteroaryl, or a C2-6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula VII have one or more, and more preferably all, of.the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and -156-

VO

o R I is -halo, a haloaliphatic group, a C 1 aliphatic group, phenyl, or -CN; or Ring D is an optionally t substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, Cl 5 i,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- V) dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; 0 R Y is T-R 3 wherein T is a valence bond or

N

D 10 a methylene and R 3 is an optionally substituted group O selected from C3- 6 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 C 1 -6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and Ring D is substituted by. oxo or R 5 wherein each R 5 is independently selected from -halo, -CN, -NO 2

-N(R

4 2 optionally 'substituted Cz-6 aliphatic group, -OR,

-CO

2 R, -CONH -N(R 4 )COR, -S0 2

N(R')

2 or -N (R 4 S0 2

R.

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

R

y is'T-R 3 wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and -157- SR1 is -halo, a C.4 aliphatic group optionally substituted C with halogen, or -CN; or Ring D is an optionally t substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, c 5 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or V3 naphthyl; Cn t R" and R" are taken together with their o intervening atoms to, form a benzo, pyrido, pyrimido or IN 10 partially unsaturated 6-membered carbocyclo ring o optionally substituted with -halo, -N(Rt) 2 -C1.4 alkyl, -C1-4 haloalkyl, -NO, -O(C1-4 alkyl), -C02(C-4 alkyl), -CN, -802(C 1 4 alkyl), -S0 2

NH

2 -OC(0)NH2, -NHE2S0 2

(C

1 4 alkyl), -NBC(O) alkyl) -C(0)NH2, or -CO (cl.

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

(C

1 aliphatic).

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

Table 6.

F

9 -H HN HN. HN N kN N% N N4N .VII-1 VII-2 VII-3 -158- VI14 VII-s vil-5 VII-6

N

4 6N VI 1-9 VI 1-7 HN?4 N N viI VII-12. VII-12

HNZ~

N ~N

F

3

C

CN'

HN%,)

VII -13 VII -14 -159- Fr1 c VII-lE

F

3 C

N

CH

3

N'

VII-17' VII-18 HN2 N N VII -20 VII -21 VII -19 VII1-22 VII1-23 VII-24 >c 'i4

HN

N AlN OFa VII -25 HN _zX

N

t -N Cl VII -26 HN t

N

4 N C1

A-

N

N

VII1-21 -160-

CH

3 HNr

H

VII1-28 CH3 HN

H

N0N VII-29

HN

'NN

HN

NN VII31 VII-31 VII-32 CHs

HNJ*

H

NN

VII-33 Et HN f-

H

N 'N VII-36

CH

HN

H

NVI34N VII-34 CHs HN 1

H

N

t

N

VII-35 In another embodiment, this invention provides a composition comprising a compound of formula VII and a pharmaceutically acceptable carrier.

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a -161-

VO

D therapeutically effective amount of a composition 0 comprising a compound of formula VII.

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

q 10 Another aspect relates to a method of 7 8 inhibiting the production of hyperphosphorylated Tau ci 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 0-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of .a composition comprising a compound of formula VII. This method is especially useful for treating schizophrenia.

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula VII. This method is -162- Va

D

o especially useful for treating cancer, such as colon, ovarian, and breast cancer.

i One aspect of this invention relates to a method of inhibiting CDK-2 activity.in a patient, C 5' comprising administering to the patient a therapeutically effective amount of.a cbmposition .comprising a compound of formula VII.

Another aspect relates to a method of treating 0 a disease that is alleviated by treatment with a CDK-2 1 0 inhibitor, said method comprising the step of Va 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, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

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

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

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

VO

o 2

INH

fz cq or a pharmaceutically acceptable derivative or prodrug O thereof, -wherein:- C ZX is N or CR 9

Z

2 is N or CH, and Z 3 is N or CR x provided that one of Z 1 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 -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 ting or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by halo, oxo, or -R 5 and at any substitutable ring nitrogen by

-R

4 provided that when Ring D is a six-membered aryl ,-164-

VO

o or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; t R 1 is selected from -halo, -CN, -NO 2 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl C( 5 ring, or Ci-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by q\ up to three groups independently selected from halo, .oxo, or -R 8 said Ci- 6 aliphatic group optionally 0 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; Rx 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 2 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 R4;

R

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

-N(R

4 2

-CON(R

7 2

-SO

2 N(R7) 2

-N(R')COR,

C0 2 (optionally substituted C-6 aliphatic),

-N(R)N(R

4 2

-C=NN(R

4 -C=N-OR, -N(R')CON(R 7 )2, -N (R SON (R 7 2 -N (R SO 2 R, or 2; each R is independently selected from hydrogen or an optionally substituted group selected from Cialiphatic, C6- 10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -165- O ~~each R 4 is independently selected from-R,-R' ci-C0 2 (optionally substituted C 1 .6 aliphatic)., -CON(R.) 2 Or SO 2 or two 'R 4 on the same nitrogen are taken together to form a S-8 membered heterocyclyl or c-i 5 heteroaryl. ring; each R 5 is independently selected from halo, -OR, -00 3 Ri, -OOR, -NO 2 -ON, -SO 2 R, -SR, v.0 -N(R 4 2

-CON(R

4 2

-SO

2

N(R

4 2

-N(R')COR,

o -N (at002 (optionally substituted 0i_6 aliphatic), 1N 0 -N(Rt)NCRt 2 2 -C-N-OR, -N(Rt)CON(Rt) 2 i) o-N(R 4

)SO

2

N(R

4 2 -N(R4)SO 2 or -OCrO)N(R) 2 or A 5 and (N an adjacent substituent-taken together with their intervening atoms form said ring fused to Ring C; V is 1 -N(R6) S0 2 S0 2 N -N (R 6 -C02-, -N(R)00, -N(R)C(O)O,

-N-(RY)SO

2

-N(R

6 -0 -OC -cCR 6 20O -C (R)bS-, -ORit 2 SO-, -C{R6' 2 S0 2 -CR'z) 2

SO

2 NCRt)-, 2 -C(R6) 2

N(R

6 -C (R6) 2

N(R

6 C -cCR 6 NN(R')

-C(R

6 -0(R 6 2

N(R')N(R

6 -C -0( 6 2 NCR') S0 2 or -C CRg) 2 N CON(a)- W is -C(R6) 2 2 2 S0-, -C(R6) 2 S0 2 C-0) 2

SO

2 N(R -C(R'6) 2 -C0 2 -0'(Rr bN(R')OO-,- -C (R 6) 2 NCR)C(O)O-, -C(R6) 2 2

N(R')SO

2 2

N(R)OONC(R

6 or -001(R)-; each R 6 is independently selected from hydrogen, an optionally substituted 01-4 aliphatic group, or two R groups on the same nitrogen atom at e taken together with the nitrogen atom to form. a 5-6 membered heterocyclyl or heteroaryl ring; each R7 is independently selected from hydrogen or an optionally substituted 01.,6 aJ~aphatic group, or two R7 -166- Va on the same nitrogen are taken together with the C nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ringi each R 9 is independently selected from an optionally substituted C 1 4 aliphatic group, -OR 6 -SR, -COR', -SO2R', -N-R 6 2 -NO, -CON(R') 2 or

-CO

2 and RP is selected from R, halo, -OR, -CO 2 R, -COCOR, o -NO 2 -CN, -SO2R, -SR, -CON(R) 2 a 10 -S0 2

N(R)

2 -N(R)COR, -N(R)CO2(optionally 0 o substituted C 1 aliphatic), -N(R 4

)N(R

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

-N(R')SO

2 R, or Accordingly, the present invention relates to compounds of formula VIIIa, VIZIb, VIlla and VIId as shown below: R2 2 r 2

R

2 NH NH H HN'< HNX HN .1N N N' N N N4t® and N G G ad VIIIa VIIb VIla VIII Preferred R 2 groups of formula VIII include T-R' wherein T is a valence bond or a methylene and R3 is CN, or -OR. When R is preferred R3 groups include an optionally substituted group selected from CL-6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. When R' is -OR, preferred R groups include an optionally substituted group C 1 aliphatic group such as alkyl- or dialkylaminoalkyl and aminoalkyl. Examples of -167preferred RX include acetamido, CN, piperidinyl, piperazinyl, phenyl, pyridinyl, imidazol-1-yl, imidazol- 2-yl, cyclohexyl, cyclopropyl, methyl, ethyl, isopropyl, t-butyl, NH2CH2C!H2N, and NH2CH 2 Preferred R' groups of formula VIII, when .present, include R, OR, and N(R 4 2 .Examples of preferred R9 include methyl, ethyl, NH 2

NH

2

OCH

2

CH

2 NH, N(CH 3 2

CH

2

CH

2

N,

N(CH3)2CHzCH 2 0, (piperidin-1-yl) CH2cHo, and NH 2

CHCH

2 0.

The R 2 and R 2 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:

NH

ND.C NH A NH NH NHnd Zi CNN N 'N ,and Preferred substituents on the formula VIII

R

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

-CI-.

4 alkyl, -CI.4 haloalkyl, -NO 2 -0 (CL.

alkyl), -C02(C14 alkyl), -CN, -S0 2

(C

1 4 alkyl), -SO 2

NH

2

-OC(O)NH

2

-NH

2 S0 2 4 alkyl), -NHC(0) alkyl),

-C.(O)NH

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

When the pyrazole ring system of formula VIII is monocyclic, preferred.R 2 groups include hydrogen, C1-4 -168o aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl', mono- or dialkyJlaminocarbonyl,-amninoalkyl, alkylaminoalkyl, dialkylaxuinoalkyl, phenylaminocarbonyl, and (N- (N 5 heterocyclyl)carbonyl. Examples of such preferred R substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, e-butyl, cyclopentyl, phenyl, CO 2

H,

CO

2

CH

3

CH

2 OH, CH 2 OcRI 3

CH

2

CH

2

CH

2 OH, CH 2

CHCH

2

OCH

3 0 CH 2

CH

2

CH

2 OcR 2 Ph,'CH 2

CH

2 cHNH 2

OR

2

CH

2

CH

2 NHCOOC (OR 3 3 IN 10. CONHCH (CH 3 2

CONHCH

2

CH=CH

2

COWACU

2

CH

2

QCA

3

CONHCH

2 Pb, o CONH(cyclohexyl), CON(Et) 2 CON(CH4 3

)CH

2 Ph, CONH(n-C 3

H

7 cC oN(Et)cw 2 cs 2

CH

3 cONHcH 2 CH(cH 3 2 CON(n-C 3

HI)

2 CO(3methoxymethylpyrrolidin-1-yl), CONfI I(3 -tolyl), CONH (4tolyl), CONiWH 3 CO (rorpholin-l-yl), CO (4-methylpiperazinl-yl) CONSCH 2

CH

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

When G is iRing C, preferred formula Vill Ring C groups are~ phenyl and iyridinyl. When two adjacent substituents oih Ring C are taken together to form a fused ring, Ring c'is contained in a -bicyclic ring system.

Preferred fused ring s include a benzo or pyrido ring.

Such rings preferably are fus~d at. ortho and metea positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred include -halo, an optionally su bstituted C 1 6 aliphatic group, phenyl, -COR', -OR 6 -dN, -S0 2

R

6

-SO

2

NH

2 -N(R6) 2 -00 2 R6, -CON! 2

-NHCOR

6

-OC(O)NH

2 j or -NHSO 2 Rr.

When'R' is an optionally substituted aliphatic group, the most preferred optional substituents are halogen.- Examples of. preferred R 1 groups include -Cl, -CRK, -OCH,, OH, 1

-CEI

2 CH3, -OCH 2 CH3, -Cli,, -CF 2

CH,

cyclohexyl, t-butyl,. isopropyl, cyclopropyl, -CsCH, -iC-c, S 2

R,-ON

2 -N(CH3P 2 -C0 2 CH3, -CONS 2 -NHCOCH,, -OC (O)NH 2 -NHS0 2 CH3, and -16 9- On Ring C preferred R 5 substituentsi when 0 present, include -halo, -CN, -NOz, optiIonally substituted CI-6 aliphatic group, -OR, -CO 2

R,

-CONH(R'), -N(R')COR, -SO 2 N(R)2, and -NA4)SO 2 R. More preferred R 5 substituents include -Cl, -CN, -CF 3 -NH2, -NH(C.-4 .aliphatic)., N(C1.4 .aliphatic)2, -0(C:-4 n aliphatic), C,.

4 .aliphatic, and -C0 2 (C2.

4 aliphatic).

p Examples of such preferred R5 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 VIII 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 VIII Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1&-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

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

-N(R

4 2

-CO

2

R,

-CONH(R'), -N(R 4 )COR, -SO 2 N(R6) 2 -N(R')S0 2 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C 1 s-io aryl, or C 1 6 aliphatic. More preferred R 5 substittients include -halo, -CN, -oxo, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-.to aryl, or C 1 6 aliphatic. Examples of Ring D substituents include -OH, phenyl, methyl, CHAOH, Ca 2

CH

2 H, pyrrolidinyl, OPh, CF, CCH, Cl, Br, F, I, NH 2 -170- VO ID o C(O)CH 3 i-propyl, tert-butyl, SEt, OMe, N(Me)2, methylene dioxy, and ethylene dioxy.

Preferred formula VXII compounds have one or more, and.more preferably all, of the features selected C( 5 from the group consisting of: Ring C is a.phenyl or pyridinyl ring, V' optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring 0 system, the bicyclic ring system is selected from a ND 10 naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is o -halo, an optionally substituted Ci-6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SOR 6

-SO

2 NH, -N(R 6 2 -CO2R 6 -CONH2, -NHCOR 6 -OC(O)NHa, 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-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

R

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

R

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

More preferred compounds of formula VIII have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and -171- CD R is -halo, a C-.

6 haloaliphatic group, a C- 1 aliphatic C group, phenyl, or -CN; or Ring D is an optionally Ssubstituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 5 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dibydro-1H-isoindolyl, 2, 3dihydro-1H-indolyl,:isoquinolinyl, quinolinyl, or eC naphthyl; o Rx is T-R 3 wherein T is a valence bond or a 10 methylene and R 3 is 'CN, -R or -OR; C) S(c) R' 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 intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring;.and each R 5 is independently selected from -halo, -CN, -NO 2

-N(R

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

-SO

2 N(R4) 2 or -N(R 4 )SOaR.

Even more preferred compounds of formula VIII have one or more, and more preferably all, of the features selected from the group consisting of: RX is T-R 3 wherein T is a valence bond or a methylene and R 3 is -R or -OR wherein R is an optionally substituted group selected from CI-. aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and

R

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, -172- Va o piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; Cl 5 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 CI optionally substituted with -halo, -N(R) 2 alkyl,

S-C..

4 haloalkyl, -NO 2 -0 (Q4 alkyl), -C02 (C 1 4 .alkyl), -CN, -02 (C 1 4 alkyl), -SO 2

NH

2 -OC(O)NH, -NH 2 SOn (C 1 4 alkyl), S-NHC (C.

4 alkyl), C-C(O)NH 2 or -CO(C 1 -4 alkyl), wherein the -(C 1 4 alkyl) is a straight, branched, or -cyclic alkyl group;' each R 5 is independently selected from -C1, -CN, -CF 3

-NH

2

-NH(C

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

-O(C

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

(C

1 -4 aliphatic); and, R9 is R, OR, or N(R) 2 Representative compounds of formula VIII are set forth in Table 7 below.

Table 7.

Me Me VIII-1 VII-2 VIIH-3 HN HNf HNf .VIII-1 VIII-2 VIII-3 -173- Etf* VIII -4 .VIII-5 Su

HN<*H

N 6N Vill Me HNf*t VI 11-10 VIII -6 IPr HNgP1.

VI 11-9 HN: ~Me

N

4

N

VIII1-12 G0 VIII -8

H-NS

N

VIII -11o 101 HN2P_4 VIII1-14

HKN

Vill-is Vi 11-13 -174- VIII -16 9H N IN CF 3

H

2

NZZO

VIII-19

N.

M4e VIII-17

H

N-J-N CF 3 Me VIII -20 HNr N J'N CI' VIII -23 N 14N -OF 3 VIII-21.

VI 11-24 VIII -18 VI 11-22

H

NJ-N CN 9H HN N J N CA VIII -26 FZ

H

HN

NON CI VIII -27 -175- VIII1-28 VIII -31 VXI -29 HN2V VIX-32 VIII Hg VII1I-33 0 VIII -34

H~

N-

VII-35 Hg N-t-N CF 3 Me .N-.%JNO M~e VIII -38 VIII1-36 VIII-37 VIII-39 -176-

HNHN

2 Me HNt N CF3 CI MeYl-N CF3 VIII-41 VIII-42 AHN

-NX"HNAN

Nl CFS K flN CF 8 N 'k CF 3 VIII-43 VIII-44 HN HNHNJ ?rO 07.NCF 3

CFS

VIII-46 VIII-47 VIII-48 CF3 A-N sNHF KNA F VIII-49 VIXI-50 VhSl-Si -177- ID F Hq H h f H N HN

N

"HNO iHN' Vak QIN CF N I N CF

H

VIII-52 VII-53 VIII-54 0H H H i HNNO', HN" HN 0 S CF3 HNN°rN CF3

C)

H2 NttJ 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 therapeuticaliy effective amount of a composition comprising a compound of formula VIII. Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula VIII.

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula -178-

VO

o VIII. This method is especially useful for diabetic

C

N patients.

t Another aspect relates to a method of inhibiting the production of hyperphosphorylated Tau Cl 5 protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula c_ VIII. This method is especially useful in halting or o slowing the progression of Alzheimer's disease.

NO 10 Another aspect relates to a method of o inhibiting the phosphorylation of P-catenin in a patient in need thereof, comprising administering to said patient 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 therapeutically effective amount of a composition comprising a compound of formula VIII. This method is especially useful for treating cancer, such as colon, ovarian, and breast cancer.

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

-179- Another aspect relates to a method of treating (C a disease that is alleviated by treatment with a CDK-2 Sinhibitor, 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 c-q disease, restenosis, angiogenesis, glomerulonephritis, o cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid "9 O 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 CDKr2, 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 R2' substituents. In their search for further inhibitors of the protein kinases GSK and Aurora, applicants sought to replace the pyrazole moiety of formula I with other heteroaromatic rings. One of the more effective pyrazole ring replacements was found to be a triazole ring. Inhibitors having this triazole ring are otherwise structurally similar to the formula I compounds and are represented by the general formula IX: -180-

VO

I

N

N

Ax H N SR

Z

1 IND IX C] or a pharmaceutically acceptable derivative or prodrug S. thereof, wherein: Cq 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 Sindependently 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, S-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 -Rs, and at.any substitutable ring.nitrogen by -R 4 provided that when Ring D is a six-membered aryl or -181- Q heteroaryl ring, -R 5 is hydrogen at each ortho carbon C position of Ring D;

SR

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

T-V-R

6 phenyl; 5-6 Smembered heteroaryl ring, 5-6 membered heterocyclyl S ring, or C- 6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by Sup to three groups independently selected from halo,

VO

C- oxo, or -R 8 said Ci-6 aliphatic group optionally o substituted with halo, cyano, nitro, or oxygen, or R" 10 and an adjacent substituent taken together with their S- intervening atoms form said.ring fused to Ring C;

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 R and RY is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by Rx and R Y is substituted by R 4 T is a valence bond or a Ci-4 alkylidene chain;

R

2 is -R or'-T-W-R 6

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, -SO2N(R') 2

-N(R

7

)COR,

-N (R 7 )C0 2 (optionally substituted Ci- aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R')

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

)CON(R')

2

S

O

N

(R

7 2

-N(R

4 )S02R, or -OC(=0)N(R 7 3 each R is independently selected from hydrogen or an optionally substituted group selected from Ci.aliphatic, Cs- 0 o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -182- Va each R4 is independently selected from -R 7 -COR7, -CO(optionally substituted C 1 6 aliphatic), -CON (R7) 2 or -SO 2 R7, or two R4 on the same nitrogen are taken together to forma 5-8 membered heterocyclyl or (N 5 heteroaryl ring; eachR 5 is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, 2-NCR 4 2 -CON(Rt) 2 -S0 2 N(Rf, -N(R"COR, 0 -N CO 2 (optionally substituted C 1 6 aliphatic), o 10 N(R 4

)N(R

4 2

-C=NN(R

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

)CON(R')

2 o -N(R 4

)SON(R)

2

_N(RN)SO

2 R, or 2 or R 5 and an adjacent substituent taken together with their intervening atoms form said ring, fused to Ring C; V is -502-, -N(R')SO 2 -s0 2 -C0 2 -N(RG)CO-, -N(R6)C(O)O-,

-N(R)SO

2

-C(O)N(R

6

-OC(O)NCR

6 -C(R6) 2

-C(R

6 2

S-,

2 SO-, -C(R6) 2 sSO 2 -C(R'S0 2 2 -C(R6) 2 N(R6)C(0) -D -C(R 6 2 =NN(R6) -C(R0) 2 N(R6)N(R6)- -C(R'hN(R6)SON(R)-, or -C (R 6 2 N (R6) CON( R 6 W is -C(R6) 2 -C(R6) 2 2 S0-, -C(R) 2

SO

3 W C(RSO 2 -C0 2 OC(O)N(R6)-, 2

CO-,

-C(R)

2 -CCR6)=N-O-, 2 -C(R6) 2

N(R

6

)SO

2 N(R6)-, 2 N CON(R)- or -CON(R)-; each R6 is independently selected from hydrogen, an optionally substituted C 1 4 aliphatic group, or two R6 groups on the samie nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R7 is independently selected from hydrogen or an optionally substituted C 16 aliphatic group, or two R 7 -183-

\O

0. on the same nitrogen are taken together with the 0< nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; Seach R 8 is independently selected from an optionally substituted aliphatic group, -OR 6

-SR

6

-COR',

-SO

2

-N.(R

6 2 -CN, -NO 2

-CON(R)

2 or

-CO

2 R; and

R

9 is selected from halo, -OR, -CO 2 R, -COCOR, o -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2

-CON(R

4 2 -SON 2, -N(R 4 COR, -N(R C02 (optionally o substituted Ci-6 aliphatic), 2

-C=NN(R

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

)CON(R

4 2

-N(R

4

)SO

2 N(R) 2

-N(R

4

)S

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

R2 R2 A2 N N HN HNJ HN N

HN

R HtZ 2 Rx

R

y RY Z1'o RY Z 1 2 3 The RX and R Y groups of formula. IX may be taken together to form a fused ring, providing a bicyclic ring system containing Ring A. Preferred RX/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said Rx/RY ring is optionally substituted. Examples of Ring A systems are shown below by compounds IX-A through IX-DD, wherein Z I is nitrogen or C(R 9 and 22 is nitrogen or

C(H).

-184- Va 0 0 ci ci

N

HNN

z 2

HN

4 3- R I4-,N IX-B Ix- C IS-E Il-F Il-0

IS-N

N

Il-I HN37 Ix-J HN, 1 N !%X4Zl

IX-L

HN3 YNik 11-0

IS-M

-185- HzNstN Il- Il-P HN-37 Ix -7 S .z y Is-vZI nX-a

IX-T

HNA?

4

R

Ix-w Il-U Ix-I f Ix-y Ix-z zr-a IX -BE Is-cc IS- DD Preferred bicyclic Ring A systems of formula IX include'IX-A, IS-B, IS-C, IX-D, Il-B, Il-F, Ix-G, IS-N, IX-I, IX-a, 11-X, fl-L, and Il-K, more preferably IS-A, -186- Va IX-B, IX-C, IS-F, and IX-H, and most preferably IX-A, IX- 3, and IX-H.

In the monocyclic Ring A system of formula IX, preferred RX groups include hydrogen, alkyl- or c 5 dialkylamino, acetamido, or a C1_4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred R 7 groups, when present, include T-R' wherein T (N is a valence bond 6r a methylene, and R 3 is 2 o or -OR. Examples of-preferred R' include 2-pyridyl, 4- ID 10 pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, o isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl or halosubstituted phenyl, and metboxymethyl.

In the bicyclic Ring A system of formula-IX, the ring formed by RX and RY taken together may be substituted or unsubstituted. Suitable substituents include halo, -OR, -CO 2 R, -COCOR, -NO, -CN, -S R, -SOR, -SR, 2 -CON(R') 2 -S0o 2 N 2 -N(Rt)COR, -N(R)C0 2 (optionally substituted Cl-_ aliphatic), -NRi 4 )N(R4) 2 -C4NN(R') 2

-C=N-OR,

-N CON (R 4 2

SO

2 N(R) 2

-N(R')SO

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

Preferred RX/RY rizig substituents include -halo, -OR, -COR, -C0 2 R, -CON(R)2, -CN, or 2 wherein R is an optionally substituted C.,6 aliphatic group.

Preferred i 2 groups of formula IX include hydrogen, C..

4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, monoor dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl) carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl., isopropyl, propyl, t-butyl, cyclopentyl, phenyl, COIH, C02CHa 3 CHO20H, CH 2 OCH CH2

C

O

2

CH

2 0H, CHCH2CH 2 0CH 3 -187- Va

CH

2

CC

H

2H20CH 2 Ph, CH 2

CHCHNH

2

CH

2

CH

2

CH

2 NHCOOC (CH 3 3, CONHCH (CH 3 2, coNcc=c 2

CONCH

2

HCHCHCH

2

OC

3

CONHCH

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

CON(CH

3

)CH

2 Ph, CON (n-C 3 H) CON(Et)CH 2

CH

2

CH

3

CONHCH

2

CH(CH

3 2 CON(n-C3%7) 2 CO(3methoxymethylpyrrolidin-l-yl), CONEH(3-tolyl), CONH(4tolyl), CONRCH 3 CO(morpholin-l-yl), CO(4-methylpiperazin- 1 CONHCHLCH 2 O0H, CONH 2 and CO(piperidin-1-yl). A more preferred R 2 oup for formula IX compounds is hydrogen.

An embodiment that is particularly useful for treating GSK3-mediated diseases relates to compounds of CR formula X wherein ring A is a pyrimidine ring: R2 HNtkNHM Nx N

JA'E

RY N N

X

x or a pharmaceutically acceptable derivative or prodrug thereof, wherein;.

Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently -selected from any substitutable nonortho carbon position on Ring C is independently substituted by -Rs, 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, -188-

VO

said fused ring being optionally substituted by halo, C] oxo, or -R 8 SR' is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl C( 5 ring, or C1- 6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings.each optionally substituted by up to three groups independently selected from halo, CN oxo, or -Re, said aliphatic group optionally O substituted with halo, cyano, nitro, or oxygen, or R

I

ID 10 and an adjacent substituent taken together with their Sintervening 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, 5-8membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R x and R' is substituted by oxo-or T-R 3 and any substitutable nitrogen on said ring formed by R z and R Y is substituted by R 4 T is a valence bond or a C 1 -4 alkylidene chain;

R

2 is -R or -T-W-R 6

R

3 is selected.from -halo, -OR, -C02R, -COCOR, -COCH 2 COR, -NO 2 -CN, -SR,

-N(R

4 2

-CON(R

2 -SOaN (R 7 2,-OC -N(R7 COR, -N(R')CO (optionally substituted C-6 aliphatic), -N(R N(R 4 2

-CNN(R

4 -C=N-OR, -N(R 7 )CON(R')2, -N(R)S0 2 N (R 7 2

-N(R

4 )SOaR, or 2; each R is independently selected from hydrogen or an optionally substituted group selected from Ci-6 aliphatic, Cs-0o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -189-

IO

o each R 4 is independently selected from -COR', CA -C0 2 (optionally substituted C 1 6 aliphatic), -CON(R 7 2 ct or -SO 2 R, or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or S heteroaryl ring; each RY is independently selected from halo, -OR, In -C(r0)R, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR; -N (i 4 2 -CON(R')2, -S0 2 N(Rb, -N(Rt)COR,

-N(R

4 C0 2 (optionally substituted C.6 aliphatic), NO 10 2

-C=NN(R')

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

-N(R

4

)SO

2

N(R

4 2

-N(R

4

)SO

2 R, or -OCC=O)N(R) 2 or R 5 and an adjacent. substituent taken together: with their intervening atomsform said ring fused to Ring C; V is -S- 1 -502-, -N(R6)S0 2 -S0 2

-N(R

6 -N(R CO-, N(R')C(OO-,

-N(R

6

)CON(R

6

-N(R

6 )S0 2

-OC(O)N(R

6

-C(R

6 2 2

S-,

-C(R

6 2 so-, -c(R6) 2

SO

2

-CCR

6 2 80 2

-C(R

6 2 N(R6)-, C (R6) 2 N(R6)C ()C(R 6 b N(R 6 )C(O)0 -C(R 6 )nNN(R6),

-C(R

6 -C(R6) 2

N(R

6 2

N(R)SO

2 N or -c (R6) aN (R6) CON WR')tq is 2 2 2 S0 2 2 60 2 2 N(R -CO, -C02-, 6) N(R')CO-_ -C(R6) 2 N(R6)C(0)0-,

N-O-,

-C(R6) 2 N(R -C(R6) 2 N(R6)SO 2 N(R6)-, -C(R6) 2 N(R6)CON(R)-, or -CONR')-; each R' is independently selected from hydrogen, an optionally substituted CI- aliphatic group, or two I' 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.. aliphatic group, or two R7.

-190-

VO

I0 o on the same nitrogen are taken together with the C nitrogen to form a 5-8 membered heterocyclyl or i heteroaryl ring;,and each R" is independently selected from an optionally 5 substituted Ci-4 aliphatic group, -OR 6

-SR

6

-COR

6

-SO

2

R

6

-N(R

6 2 2 -CN, -NO 2

CON(R

2 or Io

-CO

2 R6.

-c 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.

o Preferred R 2 R, RX, and Ring C groups of formula X are as described above for the formula II compounds. Preferred formula X 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;

R

x is hydrogen or C 1 -4 aliphatic and R is T-

R

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

R

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

-OR

6 -CN, -SOR 6 -SOaNI2, -N (R 2

-CO

2

R

6

-CONH

2

-NHCOR

6 -OC(0)NH 2 or -NHSOaR 6 and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, beteroaryl, or a

CI-

6 aliphatic group.

-191-

VO

C More preferred compounds of formula X have one Cr or more, and more preferably all, of the features Sselected from the group consisting of: S(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by -Rs,.wherein when Ring C and two adjacent substituents thereon form a bicyclic ring 3 system, the bicyclic ring system is a naphthyl ring;

VO

Cq R x is hydrogen or methyl and R Y .is -R, O or -OR, or R x and R Y are taken together with their \D 10 intervening atoms to form a benzo ring or a 5-7 membered O carbocyclo ring, wherein said ring formed by R x and R Y is optionally substituted with halo, -OR, -CO 2

R,

-COCOR, -NO 2 -CN, -SO 2 A, -SR, -N(R 4 2

-CON(R)

2 a, -SOaN(R 4 2 -N (R)COR, -N(R 4

C

2 (optionally substituted CI-6 aliphatic), -N(R)N(R 4 a, -C-NN(R) 2 -C=N-OR, -N(R CON 2

SO

2 N(R) 2 -N(R SOR, or -OC (R 2;

R

1 is -halo, a C 1 -6 haloaliphatic group, a C 1 6 aliphatic group, phenyl, or -CN;

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl or a C 1 aliphatic group;.and I each R 5 is independently selected from -halo, -CN, -NO 2

-N(R

4 )a 2 optionally substituted Ci- 6 aliphatic group, -OR, -CO2R, -CONH(R 4

-N(R

4

)COR,

-SO2aN(R 4 or -N(R')S02R.

Even more preferred compounds of formula X have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring; -192-

VO

§0 R" is hydrogen or methyl and R

Y

-is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, Salkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or Rx and R y (C 5 are taken together with their intervening atoms to form an optionally substituted benzo ring or a 6-membered \D carbocyclo ring; S(c) R 1 is -halo, a CI-. aliphatic group o optionally substituted with halogen, or -CN; IO 10 R 2 is hydrogen or a Ci-6 aliphatic group; and S(e) each R 5 is independently selected from -Cl, -CN, -CF3, -NH 2

-NH(C

1 4 aliphatic), -N(C 1 4 aliphatic)2, -0(CI-4 aliphatic), C1-4 aliphatic, and -C02(CI-4 aliphatic).

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

R

2 HN HN RY N 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, and at any substitutable ring nitrogen by -R 4 -193- Va o provided that when Ring D is a six-membered aryl or (N beteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D;

R

1 and RY are taken together with their intervening -atoms to form a fused benzo ring or 5-8 membered carbocyclo ring, wherein any substitutable carbon on said fused In ring formed by RX and R 7 is substituted by oxo or T-R3; Va Ci T is a valence bond or a CI.

4 alkylidene chain; R is-R or -T-W-R 6 R' is selected from -halo, -OR, -CO 2

R,

-COCOR, -COCHaCOR, -NO 2

-S(O)

2 R, SR,.

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

-S

2 OaN(R') 2 -OC R, -N(R')COR, -N C0 2 (optionally substituted C 1 6 aliphatic), -N (R 4 N -C=NN 2 -C=N-OR, -N (R')CON 2

N(R)SO

2

-N(R

4

)SO

2 R, or -OC(=O)N(Rt) 2 each R is independently selected from hydrogen or an optionally substituted group selected from C1-s aliphatic, Cs-.

10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring 'atoms; each R is independently selected from -R 7

-COR',

-CO2(optionally substituted C 1 6 aliphatic), -CON(R) 2

L

or -S02R', or two R' on the same nitrogen are takeh together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -COaR,. -COCOR, -NO 2 -CN, -SO 2 R, -SR,

-N(R

4

-CON(R')

2 -So 2

N(R

4 2 -N(Rt)COR, -N (R')CO 2 (optionally substituted Cj-g aliphatic),

-N(R

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

SO

2 N 2 -N(R SO 2 R, or -OC N 27 V is -So0-, -N(R 6 )S0 2 -S0 2

(R

6 -CO2-, -N(R" 6 N(R)SOaN(R-,N(R) N(R')N(R 6 -194o -C(0)N(R 6 2 C~1-c(R 6 2 s0-, -C(R 6 2 50 2 -C(R'6) 2 S0 2

-C(R

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

-C(R

6 1

U(R

6

-C(R

6 2

N(R

6 )S0.

2

N(R

6 or C -(R 6 N (R 6 C01N(R) W is -C(R 6 2 7 C(R'b So-, -C(R 6 2 80 2 2 S0 2

-C.(R

6 2

N(R

6 CO-, -03-, o-C (R'6) 2 N 0(0)0-;f =NN(Y) -C(R 6 0 0 -cR) 2

-C(R

6 2

N(R)SO

2 o -c(R) 2

N(R

6 or -CON(R)-; each R' is independently- selected from hydrogen'or..an optionally'substituted 1- aliphatic group, or two R groups on the same nitrogen atom are taken together IS with the nitrogenatom to f 'orm a-5-6 memibered heterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an.

optionally, substituted C1.6, aliphatic group, or two R on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or 'heteroaryl ring.- Compounds of formula XI are structurally similar to compounds of formula III except f or the replacement of the pyrazole ring moiety by-the triiazole ring moiety. Preferred R2, V 2 aY, and Ring D groups of fo rmula. X1 are as described above for the formula III compounds. Preferred formula XI compounds have one or more, and more prefeihbly all, of the features selected from th~e group consisting of: Ring D,is an optionally'substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,- azepanyl, morpholinyl, l,2,3,4-;tetrahydroisoquinolilyl, 1,.2,3,4tetrahydroquinolinyli 2 ,3-dihydro-lH-isoindolyl, 2,3 -195dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or.

naphthyl ring; Rx and RY are taken together with their intervening atoms to form an optionally substituted benzo ring or 5-7 membered carboeyclo ring; and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C.s aliphatic group.

More preferred compounds of formula KI have one or more, and more preferably all, of the features selected from the-gioup consisting of: Ring D is an optionally substituted ringselected from phenyl, pyridinyl,- piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4tetrahydroisoqu.inolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; RX and RY are taken together with their intervening atoms to,form a benzo ring' or 5-7 membered carbocyclo ring, wherein said ring formed by RX and RY is optionally substituted with oxo, halo, -OR,

-CO

2 R, -COCOR, -N0 2 -CN, -SO 2 R, -SR, 2

-CON(R

4 2 -SOaN(R) 2

-N(R')COR,

-N(R

4

)CO

2 (optionally substituted C 16 aliphatic),.

-N(R)N(Rt) 2

-C=NN(R)

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

SO

2

N(R

4 2 -N(R4)SO 2 R, or -OC(cO)N(R')2; R' is hydrogen or a substituted or unsubstituted group selected from aryl. or a C.-6 aliphatic group; and each R5 is independently selected from halo, oxo, CN, NO 2 2

-CO

2 R, -CONE(R), COR,

-SO

2

N(R')

2

-N(R.)SO

2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C 6 -o aryl, or C 1 6 aliphatic.

-196-

VO

o hv Even more preferred compounds of formula XI cq have one or more, and more preferably all, of the Sfeatures selected from the group consisting of:

R

X and R Y are taken together with their C( 5 intervening atoms to form a benzo ring or 6-membered carbocyclo ring, wherein said ring formed by R x and R Y is S optionally substituted with halo, CN, oxo, CI- 6 alkyl, C 1 -6 c alkoxy, (Ci- 6 alkyl) carbonyl, 6 alkyl) sulfonyl, mono- or o dialkylamino, mono- or dialkylaminocarbonyl, mono- or 10 dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; o each R 5 is independently selected from -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-lo aryl, or CI-6 aliphatic; and

R

2 is hydrogen or a C- 6 aliphatic group.

Another embodiment of this invention relates to compounds of formula XII: FA NNH

XII

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -197- Q -R s and at any substitutable ring nitrogen by -R 4 0 provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon Sposition of Ring D; SRx 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 o oxygen, sulfur, or nitrogen, wherein any substitutable c a carbon on said fused ring is optionally and C.

o independently substituted by T-R 3 and any Ci substitutable nitrogen on said ring is substituted by

R

4 T is a valence bond or a Ci-4 alkylidene chain;

R

2 is -R or -T-W-R 6

R

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

R,

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

-N(R

4 2 -CON(R' 2, -SbN (R 4 2 R, -N(R 4

COR,

-N(R'CO

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

)SO

2

N(R

2

-N(R

4 )SO2R, or -OC N(R 4 2; each R is independently selected from hydrogen or an fi optionally substituted group selected from C.1aliphatic, C6-i0 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',

-C02 (optionally substituted C1-6 aliphatic), -CON(R')2, or -SO 2

R

7 or two 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, -C0 2 R, -COCOR, -NO 2 -CN, -SO2R, -SR,

-N.(R

4

-CON(R')

2

-SO

2

N(R

4 2 -OC -N(R')COR, -198- Va C0 2 (optionally substituted C 1 aliphatic), CA -N(R')N(Rt) 2

-C=NN(R

4 2 -CnN-OR, -N(R2CON(R#) 2

-N(R)SON(R

4 2 -N(R')SO0 2 R, or 2 V is -SO 2 -S0 2

N(R

6 -C0 2

-N(R

6

-N(R

6 -N(R)CON(RJ-,, N(R')SO 2 -oc(o -C(R) 2 2

S-,

NO

-C(R)

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

-C(R

6 2 SO2N(R)-, -C(R 6 )2N(R 6 2N(R 6 C -C 2 -C (R 6 )=NN -C (R 6 2 N(R) -C(R 6 )3N(R 6 SO2N(R') or O -C 2 N CON (R 6 W is -C(R 6 2 2

-C(R

6 2 SO-, -C(R 6 2

SO

2

-C(R

6 2 S0 2 1N(R 6

-C(R

6 2 -COZr-,

-C(R

6 )OC -C(R 6

').OC(O)N(R

6 2

N(R')CO-,

-C(R

6 3

N(R

6

-C(R

6

-C(R

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

N(R

6 )SON(R)

-C(R

6 2

N(R

6 o -CON(R each R 6 is independently selected from hydrogen or an optionally substituted C.

4 aliphatic, group, or two R6 groups on the same nitrogen atom are taken together 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,-s aliphatic group, or two R' on the same nitrogen.are taken together with the nitrogen to form a 5-8 membered heterocyclyl ring or heteroaryl.

Compounds of formula XII are structurally similar to compounds of formula IV except. for the.

replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred R2., RI, Ri, and Ring D groups of formula XII are as described above for the formula IV compounds. Preferred formula XII compounds have one or -199- Va o more, and more preferably all, of the features selected 0 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, 1,2,3,4kn tetrahydroquinolinyl, 2, 3-dihydro-1H-isoindolyl, 2,3- C dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or o naphthyl ring; RX is hydrogen or C.- 4 aliphatic and RY is T- R3, or Rx and Ry are taken together .with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring heteroatoms; 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 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, .1,2,3,4tetrahydroisoquinoiinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; R is-hydrogen or methyl and RY is -R, W(R)2, or -OR, or RX and R. are taken together with their intervening atoms toform 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, -C(nO)R, -CO 2 R, -COCOR, -NO 2 -CN, -S(O)R,

-SO

2 R, -SR, 2

-CON(R

4 2

-SO

2

N(R')

2

-OC(=O)R,

-N(R')COR, -N(R')CO0 2 (optionally substituted aliphatic), -200-

VO

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

-C=NN(R

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

SO

2 N (R 2, -N(R 4

SO

2 R, or -OC 2;

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl or a Ci-6 aliphatic C( 5 group; and each R 5 .is independently selected from halo, S0Xo, CN, NOa, -N(R 4 2 -CO0R, -CONH(R 4

-N(R

4

)COR,

_c -S0 2 N(R4) 2

-N(R')SO

2 R, -SR, or a substituted Sor unsubstituted group, selected from 5-6 membered 10 heterocyclyl, Cs-io aryl, or Ci.- aliphatic.

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

R

x and R Y are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, optionally substituted with halo, CN, oxo, C1-6 alkyl, C2-6 alkoxy, alkyl) carbonyl, (CI-6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R s 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, C6-io aryl, or C1i- aliphatic; a..nd

R

2 is hydrogen or a C1-s aliphatic group.

Another embodiment of this invention relates to compounds of formula XIII: -201- I ND 2 1 11 \o

NHN

o or a pharmaceutically acceptable derivative or prodrug Cq thereof, wherein:.

SZ

1 is nitrogen, CR a or CH, and Z 2 is nitrogen 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 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 i heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -Re; Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring beteroatoms 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 -202-

VO

o heteroaryl ring, -R 5 is hydrogen at each ortho carbon CI 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 C 5 ring, or C 1 -6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally .substituted by Sup to three groups independently selected from halo, C oxo, or -Re, said Ci- aliphatic group optionally Ssubstituted with halo, cyano, nitro, or oxygen, or R 1 D 10 and an .adjacent substituent taken together with their o intervening atoms form said ring fused to Ring C;

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 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 CI 1 4 alkylidene chain;

R

2 is -R or -T-W-R6;

R

3 is selected from -halo, -OR, -COaR, -COCOR, -COCH2COR, -NO 2 -CN, -S(0) 2 R, -SR,

-N(R

4 2

-CON(R')

2

-SON(R

7 2 R, -N (R COR, -N (R 7 )C0 2 (optionally substituted aliphatic), -N (R 4

)N(R

4 2

-C=NN(R

4 2 -C=N-OR, -N(R 7 CON 2 -N (R SON (R 7 2 -N (R 4 )SOR, or -OC(=O)N(R 2; each R is independently selected from hydrogen or an optionally substituted group selected from C-s aliphatic, Cs- 10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -203each R' is independently selected from -COR 7 O7 0 -C0 2 (optionally substituted C 16 aliphatic), -CON(R 7 2 Sor -50 2

R

7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered-heterocyclyl or heteroary1 ring; each Rs.is independently selected from halo, -OR,

-CO

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

\O

-N(R)

2

-CON(R')

2 -S02N(R 2

-N(R

4

)COR,

-N(R')C02 (optionally substituted C 16 aliphatic), 010 -N(R')N(R 4 2

-C=NN(R')

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

S-N(R')SO

2

N(R)*

2

-N(R

4

)SO

2 R, or -OC(=O)N(Rt1 2 or R 5 and an adjacent substituent taken together with their intervening atoms fonrm said ring fused to Ring C; V is -SO2-, 7 N(R')S0 2 -S02N(R')-, -CO2-, CON(R) SON(R') 20-, S-, 2 SO-, -C(RY) 2

SO

2 2 S0 2 2 2 N(R)C(O) C(R') 2 C(0) -C 2 N(R6) SO 2 N or -C 2 N (R')CON W is 2 2 2 SO-, -C(R)2SO 2 -,l -C (R 280N(R) -C(R)2NW(R -CO2-, 2

N(R')CO-,

-C aN C -C =NN -C -C 2 N -C 2 N SO 2 -C(R')2N(R6)CON(R"), or -CON(R')each R' is independently selected from hydrogen, an optionally substituted CI-.4 aliphatic group, or two R' groups on the same nitrogen atom are taken together with the nitrogen'atom to form a 5-6 membered heterocyclyl or -heteroaryl ring; each R 7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R 7 -204- Va on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or C heteroaryl ring; each R' is independently selected from an optionally substituted C 1 4 aliphatic group, -OR 6 -SRI, -COR',

-S

2 OaR 6

-N(R

6 2

-N(R')N(R

6 2 -CN, -NO 2

-CON(R)

2 or ID-C0 2 R; and

R

8 is selected from :halo, -OR, -CO 2 R, -COCOR, 0 -NO 2 -CN, -SO 2 R, -SR, 2

-CON(R')

2 o 10 -SO 2 -N(R')COR, -N(R)CO 2 (optionally o substituted C 1 6 aliphatic), 2

-C=NN(R')

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

N(R)

2 -N )SO 2

R,

-OC(tO)N(R') 2 or an optionally substituted group selected from CT.

6 aliphatic, Cs-o 0 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: P R2 R2 N1\ N N N Rx N NgX RX N R' RY and XIIa X111b XSIle Compounds of formula XIII are structurally similar to compounds of formula V except for the replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred R2, Re, RY, Ra, and Ring 0 groups of formula XIII arelas described above for-the formula V compounds.. Preferred formula III compounds have one-or -205- D more, and more preferably all, of the features selected C from the group consisting of: 3 Ring C is a phenyl or pyridinyl ring, E optionally substituted by -R 3 wherein when Ring C and two c 5 adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a In naphthyl, quinolinyl or isoquinolinyl ring, and R is C -halo, an optionally substituted CI-6 aliphatic group, O phenyl, -COR 6

-OR

6 -CN, -SO0 2

R

6

-SONH

2

-N(R

6 2 -C0 2

R

6 \D 10 -CONH 2

-NHCOR

6 -OC(0)Na 2 or -NHSO 2

R

6 or Ring D is an 0 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-1K-isoindolyl, 2,3-dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

R

X is hydrogen or .C.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 or a substituted or unsubstituted.group selected from aryl, heteroaryl,- or a C.-s 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 R' is -halo, a Ci-6 haloaliphatic group, a Ci-6 aliphatic group, phenyl, or -CN; or Ring.D is an optionally substituted ring selected from phenyl, pyridinyl, -206- Va piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, CA 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinoliny4 2,3-dihydro-1H-isoindolyl, 2,3dihydro-iH-indolyl, isoquinolinyl, quinolinyl, or naphthyl; RX is hydrogen or methyl and Ry is -R, or -OR, or RX and Ry are taken together with their Va intervening atoms to form a benzo ring or a 5-7 membered o carbocyclo ring, wherein said ring formed by IR and RY is ID 10 optionally substituted with halo, -CO2R, o -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2 -CON(R4)2,

-SO

2

N(R

4 2

-N(R

4 COR, C0 2 (optionally substituted C1-6 aliphatic), 2 -CmNN(R) 2 -C=N-OR, CON(R) 2 -N (R 4

SO

2 2

-N(R)SO

2 R, or -OC N 2;

R

2 is hydrogen or a substituted or unsubstituted group,selected from aryl, or a C1.6 aliphatic group; and each R 5 is independently-selected from -halo, -CN, -NOz, 2 optionally substituted C-.6 aliphatic group, -OR, -CO 2 R, CON(R), -N(R')COR, -SO2N(R4)2, or '-N(R')SOZ 2 R, and, when Ring G is Ring D, Ring D is substituted by oxo or R 5 Even more preferred compounds of formula XIII have one or more, and more preferably all, of the features selected from the group consisting of: RXI 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 RX and R are taken together with their intervening atoms to form a benzo ring or a 6-membered carbocyclo ring wherein said ring formed by R" and RY is optionally substituted with halo, CN, oxo, C 1 6 alkyl, C1-6 alkoxy, (C 1 6 alkyl) carbonyl, -207- Va o 6 alkyl)sulfonyl, mono- or dialkylamino, mono- or 0 dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; 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 Va Cq R1 is.-halo, a C 1 4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally cic substituted ring selected from phenyl, pyridinyl, o piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinalinyl, quinolinyl, or naphthyl;

R

2 is hydrogen or a C-6 aliphatic group; and each Rs is independently selected from -Cl, -CN, -CF 3

-NH

2

-NH(C

1 4 aliphatic), -N(C.-4 aliphatic) 2 4 aliphatic), C14 aliphatic, and -COa 2 (C.1- 4 aliphatic), and when Ring 0 is Ring D, Ring D is substituted by oxo or R 5 Representative compoundsof formula IX are shown below in Table 8. .:77 Table 8.

CHs

N

HN H HN tH HNN H H3C -1 HIX HNI->t3C) IX-1 IX-2 IX-3 -208-

CH

3 NX

HNPX

IX- 7 HN P IX-lo IX-5

IX-E

Ix- 8 IX-9

NCF

8 Ix-li Cl-la N-pH IX-12 IX-13 IX-14 IX -209- Va 0 0 ci ci N HN L--dlm 0 N N CF3 rc N' Z

I

IX -16 IX-17 IX -18

OH

3 HNMIPrX

>#N

.IX-19 IX-20

SH

IX- 21- O H

HN

4

P

HaC.tN F3

OH

3

NA

-N

IX -22 tEX-23 IX -24

HNS

HS0tN

OF

3

H

3 0C H O0 Ha v~N 01H 1116 IX- 26

HNS

HsCX 4 N ON H40 IX -27 -210- HN

APH

HSCrI.N Ci It0

OH

3 NH

H

IX-28 IX- 29

OH

3

HN

IX-31 HN N tCH3

OH

3 HN

IP

O~tCH 3 IX-32

OH

3 N

WH

HN*1 O;N H 3 H3

C.

N OH 3

HNZ

N

IX-33' HN -%rp

N

IX-34 IX -35 IX- 36

OH

3

NHA

N

TX-37

OH

3 N

HII

NCF

3 IX-38

OH

3 HN

;VNH

po NOH N4 b

OH

3 Q N H 2 CH3 IX-39

OH

3

HNA

.0%

HNAI

N 5 H2H3 IX -41 IX -42 -211-

N"

IX-43 Nt

N

IX-46 N H IX-49 2, HN A&p .N

C

IX-52

HN?

N H

RN

Po N

CF

3 IX-44 N

H

HN*

.4NCF 3 Ix-so IX

OH

NH

HN

N C IX-48S N HNI% IX -51 H 3

C"%

HN tV

NC'

IX-53

OH

3 8 N4 IX-54.

-212- HN P

N

OH

3 HN Jd-t

N

Q(iNC3 IX-58

OH

3 HNAJ'-q

N

ciN 1 IX-6

OH

3 HN &p

NCF

3

IX-SE

IX -57

CM

8

NCF

3

H

3 CJZ4N IX-59

OH

3 LHNAIV: 0 IX- 62 OH3'

N

HN

IX-

OH

3 HN~t IX- 63

N

CH

IX- 64

HOH

3 IX-66 IX -65

OH

8 HN V-d' IX-67'

OH

tON

F

3 IX -68

HNA

zN CFS

NY

IX-69 -213- Va 0 0 ci ci

HNN

IX- 71

CH

3 HNAX-r

N

F

3 Co IX- 74 IX-72

G

IX-73

CH

3

N-

4

H

3

C

H3 0-

H

2

N

IX -76 HNAI4NH

H

3 C AONH

F

3 IX- 77 O H 3

N-(

HN !tNNH

H

3 C II .MeSO 2 NHJ~ w~ IX-78 IX- 79 IX- 80 8 1 -224- N O H 3 HNAXtp IX- 82

OH

3

NCF

3 Me IX-83

OH

3 0 HN IL-dq aO N CF'3

N:

IX-84

OH

3 HN kt NjjN CF 3 IX-86

NH

HN'

1 EN

CF'

3 IX-87 Ix-as 4

A

IX-88

OH

3

N

4 HN AN-rNH

NCF

3 Ht IX-g1 IX-89

OH

3

N-

4 HNk__NNH H1 2 N e I StCF IX-92.

OH

3

N

4

A

A* N CF 3 HN 0 IX-93

OH

3

HN~H

Ac. N CF' 3 Ht IX -94

OH

3

N

4

A

HN

J,,

4

NH

~N CF 3 IlC-95 IX -96 -215- HN4 MveO2S.NNC, e)O, IX-97

OH

3 N NA THNA

N

Nx-il

N

1 m IX-98 UX-99

OH

3

N

4

A

HN-i-N HN),N CF 3 IX-101 IX-102 01%

IJJH

IX -103

OH

3

HN

4

I

IX-106 IX-104 MN HS3

CN-

IX- 107

H

3 C 3 IX-105 0%N' IX-108 (1) -216o xi I tT- XI yNH

CHOY

VIT-XI

HP

6li-XI 8TT-XI

NN

CHO

CHO

91t-XI yN.

y

N

H

s*r-xH 0

HO

grr-xi 0 0

ON'

0

ON

TTI-XI

~4 k,N yN OT XI rN

"YIN

SOT-fl

QN

yN

CHO

OH

3 HNAJ'd NOMe IX-121

S

H.

IX- 125

OH

3

HNZ

OhN

H

3 %i I- H 3 IX-123

OHS

HN

NH

2 IX-126

CH

3 IX-124

C)

OH3

HN~

HN

IX -127

OH

3 HNt~ IX-130

OH

3

N

HN

H3CQPiJ$ IX-133 HNA- HNAPt I"N SO 2 N4(Me) 2

NC

Ib IX- 12 8

OH

3

HN

Ni "m IX- 134 IX-129 IX-132 IX-13S -218t3li-xi L.PT-X sf-xI SII-fl Ny HN4 N tr

NH

tLN

I"V-XI

9 H0 I I-XI Zirt-XI fTV,-XI 0ovi-XI GET -XI

GHQ

HN.1O

H"Y

NH

8 H3

HNI

N'tr

NH

LET -XI 0 0 0

BET-XI

9 VT-XI ~QrNQO-

H

wlNH Nt HN j1 IX -151 IX-149 Ix-iso o r-CHs H

H'

IX -152 HNt IX-153

OH

3 N HN Ado Nt IX- 155 IX-154 IX-156 C0 2

H

3 HN Ad

N'H

QQ&1NQ

NC

HNX

IX-159 IX- 157 IX-16O, IX -161 IX-162 -22o- N

H

CH3

J)--NH

IX-163 IX-164 IX -165 HN nNH

N

IX- 166

KNNH

IX- 167 HN NzrH

HN)

IX -168

OH

3

HN

C:N N

HNI

N

.6 IX-170 IX-1E9 IX-171

OH

3 CH 3 N-

H

OH

3

HNP

H2N

IN

N O

H

3 1X-174 IX-172 .IX-173

HN

IX- 176 IX-17S IX-177 -221- Va

IND

c- In another embodiment, this invention provides ta composition comprising a compound of formula IX and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, Vcomprising administering to the patient a therapeutically

IN

c-i effective amount of: a composition comprising a compound o of formula IX.

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

Another aspect relates to a method of inhibiting the phosphorylation of P-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition -222-

IND

comprising a compound of formula IX. This method is ciespecially Useful for treating schizophrenia.

Ct 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 kn of formula IX.

(N Another aspect relates to a method of treating oa disease that is alleviated by treatment with an Aurora inhibitor, said method comprising the step of oadministering toapatient in need of such a treatment a (N 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 GSIC-3 or Aurora activity in a biological sample, which method comprises conta cting the biological sample with the GSK-3 or Aurora inhibitor of formula IX, or a pharmaceutical composition thereof; in an amount effective to inhibit GSK-3 or Aurora.

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

The compounds of this invention may be prepared as illustrated by the Synthetic Methods below, by the Synthetic Examples. described herein and by general methods known to those skilled in the-art.

General Synthetic Methods The general synthetic methods below provide a series of general reaction routes that were used to -223- D prepare compounds of this invention. Methods A-F below are particularly useful for preparing formula II compounds. In most cases, Ring C is drawn as a phenyl 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 eC preparing other compounds of this invention. Methods F-I below are particulary useful for preparing compounds of formula III or IV.

CI Method A

R

2

F

1 R ir 2 (HO)2

B

R y N

C

1 x N Pd N R1 1 RAN CI R N 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 to that described in Chem. Pharm. Bull., 30, 9, 1982, 3121-3124. The chlorine in position 4 of intermediate 1 may be replaced by an aminopyrazole or aminoindazole to provide intermediate 2 in a manner similar to that described in J. Med. Chem., 38, 3547-3557 (1995). Ring C is then introduced using a boronic ester under palladium catalysis (see Tetrahedron, 48, 37, 1992, 8117-8126). This method is illustrated by the following procedure.

A suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POC1 3 (60 mL, 644 mmol) and N,Ndimethylaniline (8mL, 63.1 mmol) is heated under reflux -224-

IO

for 2 h. Excess POC13 is evaporated under vacuum, the CA residue is poured into ice, and the precipitate is Ccollected by filtration. The crude solid 2,4dichloroquinazoline product may be used without further Ci 5 purification.

To a.solution of 2,4-dichloro-quinazoline (3.3 Sg, 16.6 mmol) in anhydrous ethanol (150 mL) is added CA methyl-IH-pyrazol-3-yl amine (3.2 g, 32..9 mmol). The o mixture is stirred at room temperature for 4 h, and the ID 10 resulting precipitate is collected by filtration, washed o with ethanol, and dried under vacuum to afford (2-chloroquinazolin-4-yl)- (5-methyl -1H-pyrazol-3-yl) -amine; To a solution of (2-chloro-quinazolin-4-yl)-(5methyl-1H-pyrazol-3-yl)-amine (50 mg, 0.19 mmol) in DMF (1.0 mL) is added the desired arylboronic acid (0.38 mmol), 2M Na2C03 (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). Under nitrogen, PdCla(dppf) (0.011 mmol) is added in one portion. The reaction mixture is then heated at 80°C for 5 to 10 hours, cooled to room temperature, and poured into water (2 mL). The resulting precipitate is collected by filtration, washed with water, and purified'by HPLC.

Method B o0 CI R' NH R 1

POC

1 3 Ry N P R 1 2

N

RY N RY N P 3 4 NH R O S H2N NH N (ii) S 6 -225- 0 O R C 0NH 2 r 4' 0 NH 2 (iii) 7 t Methods B through F describe routes where the CA S pyrazole ring system is introduced after Ring C and the o pyrimidine ring portion are first constructed. A \D versatile intermediate is the 4-chloropyrimidine 4, which o is readily obtained from pyrimidinone 3 as shown in Cl Method This reaction sequence is generally applicable for a variety of Ring C groups including aliphatic, aryl, heteroaryl, or heterocyclyl. See J.

Med. Chem., 38, 3547-3557 (1995).

For quinazoline ring systems (where R X and R y are taken together to form a benzo ring), the useful intermediate 6 may be obtained by condensing an anthranilic acid or its derivative with a benzamidine as shown in Method B(ii) or by condensing a benzoylchloride with an anthranilamide as shown in Method B(iii). Many substituted anthranilic acid, anthranilamide, benzamidine and benzoylchloride starting materials may be obtained by known methods. See Aust. J. Chem., 38, 467-474 and J.

Med. Chem., 38, 3547-3557 (1995). Method B(iii) is .illustrated by the following procedure.

To a solution of anthranilamide (33 mmol) in THF and CH 2 C1 2 70 mL) is added the desired benzoylchloride (33 mmol), and triethylamine (99 mmol) at room temperature. The mixture is stirred for about 14 hours.. The resulting precipitate is collected by filtration, washed .with CH 2 C1 2 and water, and dried under vacuum. The crude '2-benzoylaminobenzamide may be used directly for the next step without further purification.

-226- To a solution of the above crude product (13 mmol) in ethanol (50 mL) is added NaOEt (26.mmol) at room 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 POC13 (120 mmol) is added tri-h-propylamine (24 mmol).

The mixture is heated under reflux for lh. After .removal of the excess POC13 by evaporation, the residue is dissolved in ethyl acetate, and washed with N .NaOH (twice) and water (twice). The organic layer is dried over MgSO, the solvent is evaporated under vacuum, and the crude product is purified by flash chromatography (eluting with 10% of ethyl actetate in hexanes) to give 4-chloro-2-aryl quinazoline.

To a solution of 4-chloro-2-aryl quinazoline (0.16 mmol) in DMF (or THF, ethanol) (1 mL) is added the desired aminopyrazole or aminoindazole (0.32 mmol). The mixture is heated in DMF (or THF under reflux) at 100 to 110 0 C for 16 h (or in.ethanol at 130-160°C for 16 hours) and then poured into water (2 mL). The precipitate is collected by filtration and purified by HPLC.

Method C NH R 1 H2N' 0 0 1^ RX y CO 2 Et NObANH R 1 8 R 9Y 8 9 -227- SMethod D(i) C\ NH R 1 0 C1 HaNY tx )yC0 2 Et P x rCOEt 10 11 N Methods C and D(i) above employ A-ketoesters 8 and 10, respectively, as pyrimidinone precursors. The C- substitution pattern of the Rx and R y groups on the o pyrimidinone ring will be reversed if a chlorocrotonate C 11 (Synth. Comm, (1986), 997-1002), instead of the corresponding A-ketoester 10, is condensed with the desired benzamidine. These methods are illustrated by the following general procedure.

To a solution of a P-ketoester (5.2 mmol) and amidinium chloride (5.7 mmol) in ethanol (5 mL) is added sodium ethoxide (7.8 mmol). The mixture is heated under reflux for 7-14 hours. After evaporation the resulting residue is dissolved in water, acidified with concentrated HC1 to pH 6, and then filtered to obtain a solid product 2-aryl-3H-pyrimidin-4-one (yield 75-87%), which may be purified by flash column chromatography if needed. To this. pyrimidinone (3.7 mmol) is added POC13 (4 mL) and n-Pr 3 N (1.4 mL). The mixture is heated under reflux for 1 hour. After evaporation of the excess POCI 3 the residue is dissolved in ethyl acetate, washed with IN NaOH solution (three times) and NaHCO, (once), and dried over MgSO 4 The solvent is removed under vacuum and the residue is purified,by flash column chromatography eluting with 10% of ethyl acetate in hexanes to give 2aryl-4-chloro-pyrimidine as a pale yellow syrup. This crude product may be treated with a 3-aminopyrazole or 3aminoindazole as described above.

-228- Va 0 CA Method D(ii) NH R 1 SH2N 0 POCIs, C1 0to C02 RxC-tNH

R

1 nPr 3 N R N R JN6 reflux N CI jn 36 37 38

(N

t2

R

2 2 9 4 2' Method D(ii) above shows a general route for the preparation of the present compounds, such as compound 40, wherein R y is N(R4)2. See II Farmaco, 52(1) 61-65 (1997). Displacement of the 6-chloro group is exemplified here using morpholne. This method is illustrated by the following procedure.

To a solution of 2-methylmalonic acid diethyl ester (5 mmol) and sodium ethoxide (15 mmol) is added the MeOH re1luR Cl 38 -NI I N 39 appropriate amidin e sahows a generanl (10outemL) and the reaction ofheated at resentflux for 2-24 hours. The compound 40, wherein RY is l(R 4 2 See 11 Farmaco,'52(l) 61-65 (197).15 residue is dissolved in water and acidified with 2N Cis The resulting precipitate is filtered off anmethod further illustrated by flash chromatography (yieldure.5-35%) to afford To a solution of 2-methylmalonic acid diethyl the pyri mmol) anidinedione 37. To 37 (1.6 mmol) is added Pthe app(32 ropriateol) ad tri-n-propylamine (6.4 mmhanol) and(10. the) and t2 reaction heated at reflued is forh. After evaporation of excess POC, the residue is dissolved in ethyl acetater and acidified with 2 HC The resulting precipitated and the aqueous phase twice more purified-by flash chromatography (yield-5-3S%) 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 reaction refluxed is for lh. After evaporation of excess POCl 3 the residue is dissolved in ethyl acetate, basified with i LNaOH, separated and the aqueous phaie twice more extracted with ethyl acetate. The combined organics are dried (sodium sulfate) and evaporated. Purification by -229-

VO

D flash chromatography provides the dichloropyrimidine (38) C as a yellow oil in 23% yield.

A solution of 38 (0.33 mmol) in methanol (5 mL) Sis treated with an amine, exemplified here using morpholine (0.64 mmol) and refluxed 1 hour. After evaporation of solvent, the residue is purified by flash Schromatography to provide the mono-chloropyrimidine 39 as IND a colorless oil in 75% yield.

The mono-chloropyrimidine, 39, (0.19 mmol) may C 10 be treated with a 3-aminopyrazole or 3-aminoindazole Scompound in a manner substantially similar those Ci described above in Methods A and B.

Method G R. N ,R RoR 0

R

O C H H NH R 1

NH

4 OAc, RYN'- 12 AcOH, reflux 9 (Rx As shown by Method E, an acyl isocyanate 12 may be condensed with an enamine to provide pyrimidinone 9 Org. Chem (1993), 58, '414-418; -J.Med.Chem., (1992), 35, 1515-1520; J.Org.Chem., 91967, 32, 313-214). This method is illustrated by the following general procedure.

The enamine is prepared according to W. White, et al, J. Org Chem. (1967), 32, 213-214. The acyl isocyanate is prepared according to G Bradley, et al, J Med. Chem. (1992), 35, 1515-1520. The coupling reaction then follows the procedure of S Kawamura, et al, J. Org.

Chem, (1993), 58, 414-418. To the enamine (10 mmol) in tetrahydrofuran (30 mL) at 0°C under nitrogen is added dropwise over 5 min a solution of acyl isocyanate mmol) in tetrahydrofuran (5 inL). After stirring-for h, acetic acid (30 mL) is added, followed by ammonium -230-

VO

o acetate (50 mmol). The mixture is refluxed for 2 h with continuous removal of tetrahydrofuran. The reaction is t cooled to room temperature and is poured into water (100 mL). The precipitate is filtered, washed with water and C 5 ether and dried to provide the 2-aryl-3H-pyrimidin-4-one.

Vf' Method F 0 0o S7

NH

4 0HN Heat H H 'N 16 ci 13 1415 R 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-amiino-nicotinic acid 13, and an acid chloride 7 provides an oxazinone 14. Treatment of 14 with ammonium hydroxide will furnish the benzamide which may be cyclized to a 2-(substituted)-pyrido[2,3d] [l,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 2aminonicotinic acid (2.04g, 14.76 mmol) in 20 ml of pyridine. The reaction mixture is heated at 158 C for min then cooled to room temperature. The reaction is poured into 200 ml of water and an oil forms which solidifies upon stirring. The solid is collected by vacuum filtration and washed with water and diethyl ether. The product is dried to give 2-(2trifluoromethyl-phenyl)-pyrido [2,3-d oxazin-4-one -231-

NO

o (2.56 g, 60% yield) which may be used in the next step C without further purification.

t 2-(2-Trifluoromethyl-phenyl)-pyrido 2,3dl1[l,3]oxazin-4-one (2.51g) is stirred in 30% ammonium 5 hydroxide (25 ml) at room temperature overnight. The resulting precipitate is filtered and rinsed with water V and diethyl ether. The precipitate is dried under vacuum

VO

C< at 50 C overnight to give 2-(2-trifluoromethylbenzoylamino)-nicotinamide (850 mg, 33% yield) \O 1 0 2-(2-Trifluoromethyl-benzoylamino)-nicotinamide f o (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.

Method G Method G is analogous to Method B(i) above.

This method is illustrated by the following general procedure.

2-(3,4-Dichloro-phenyl)-3H-quinazolin-4-one (ig, 3.43 mmol) is suspended in phosphorus oxychloride (4 mL) and the reaction mixture was stirred at 110 0 C for 3 hours. The solvents are then evaporated and the residue is treated carefully with an ice cold aqueous saturated solution of NaHC0 3 The solid is collected by filtration and washed with ether to give 4-chloro-2-(3,5-dichloroi! phenyl)-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 -232-

VO

o methyl pyrazole (396 mg, 2.58 mmol) and the reaction Ci mixture is heated at 65°C overnight. The solvents are t then evaporated and the residue triturated with ethyl acetate, filtered and washed with a minimum amount of Ci 5 ethanol to give [2-(3,4-dichlorophenyl) -quinazolin-4-yl] (5-methyl-2H-pyraz6l-3-yl)-amine as a white solid (311 mg !S mp 274 0 C; H NMR (DMSO) 6 2.34 (3H, 6.69 (1H, 7.60 (1H, 7.84 (1H, 7.96 (2H, 8.39 (1H, 0 dd), 8.60 (1H, 8.65 (1H, 10.51 (1H, 12.30 (1H, IR .(solid) 1619, 1600, 1559, 1528, 1476, 1449, S1376, 1352, 797, 764, 738; MS 370.5 4 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 H 'l 5 Rr NZ$ (H0) 2 B HNZ$

HNCN

N H "0 HN i" N p 0 N.

R4t X 17 18 CHNl-1 i(CHa)-SI-- HN- Method H shows routes in which a Ring D aryl group bearing a halogen (X is Br or I) may be converted to other formula III compounds. Method H(i) shows a phenylboronic acid coupling to Ring D to provide compound 18 and Method H(ii) shows an acetylene coupling to provide compound 19. 'Substituent X in compound 17 may be -233- S* bromine or iodine. These methods are illustrated by the o following procedures.

Method To a mixture of [2-(4-bromophenyl) -quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl) -amine 5 (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol) in THF/water 4 mL) is added Na 2

CO

3 (219 mg, 2.06 mmol), triphenylphosphine (9mg, 1/15 mol%) and ID palladium acetate (I mg, 1/135 mol%). The mixture is heated at 80°C overnight, the solvents are evaporated and cq 10 the residue is purified by flash chromatography (gradient (I O of CH 2 Cl 2 /MeOH) to give (2-biphenyl-4-yl-quinazolin-4-yl)- C (5-methyl-2H-pyrazol-3-yl)-amine as a yellow solid (99 mg, 51%) :H NMR (DMSO) S 2.37 (3H, 6.82 (1H, 7.39- 7.57 (4H, 7.73-7.87 (6H, 8.57 (2H, 8.67 (1H, 10.42 (1H, 12.27 (1H, MS 378.2 Method H(ii). To a mixture of [2-(4-bromophenyl) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl) -amine (114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, mmol)in DMF (2 mL) is added Cul (1.1 mg, 1/50 mol%), Pd(PPh 3 ),C1 2 (4.2 mg, 1/50 mol%) and triethylamine (121'mg, 0.36 mmol). The mixture is heated at 120°C overnight and the solvent is evaporated. The residue is triturated in ethyl acetate and the precipitate is collected by filtration.

To the above precipitate suspended in THF (3 mL) is added tetrabutylammonium fluoride (1M in THF, 1.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, 1H NMR (DMSO) 5 2.34 (3H, 4.36 (1H, 6.74 (1H, 7.55 (1H, 7.65 (2H, 7.84 (2H, 8-.47 -234-

O

o (2H, 8.65 d) 10.43 (1H, 12.24 (1H, s) MS 326.1 Method I J H Hj HN

H

-;N

SR

Y I R N 0 5 2 Ci Method I:above shows a general route for the preparation of the present compounds wherein ring D is a heteroaryl or heterocyclyl ring directly attached to the pyrimidine 2-position via a nitrogen atom. Displacement of the 2-chloro group, exemplified here using piperidine, may be carried out in a manner similar to that described in J. Med. Chem., 38, 2763-2773 (1995) and J. Chem. Soc., 1766-1771 (1948). This method is illustrated by the following procedure.

To a solution of (2-chloro-quinazolin-4-yl)- (1H-indazol-3-yl)-amine (1 equivalent, 0.1-0.2 mmol) in N, N-dimethylacetamide (1 ml) is added the desired amine (3 equivalents). The resulting mixture is maintained at 100 0 C for 6 h and then purified by reverse-phase HPLC.

Method J R RFe Ri H2N H

H^

21 22 -235- O R2 (Ri) R 23 24 C Method J above shows the preparation of compounds of formula V via the displacement of a chloro \O group from an appropriately substituted pyridyl ring. SMethod J(i) is a route for preparing compounds of formula Ci Va (see Indian J. Chem. Sect.B, 35, 8, 1996, 871-873).

Method J(ii) is a route for preparing compounds of formula Vb (see Bioorg. Med. Chem.,6, 12, 1998, 2449- 2458). For convenience, the chloropyridines 21 and 23 are shown with a phenyl substituent corresponding to Ring D of formula V. It would be apparent to one skilled in the art that Method J is also useful for preparing compounds of formula.V wherein Ring D-is heteroaryl, heterocyclyl, carbocyclyl or other aryl rings. Method J is illustrated by the following procedures.

Method (5-Methyl-2H-pyrazol-3-yl)-(2phenyl-quinolin-4-yl)-amine. To 4-chloro-2phenylquinoline Het. Chem., 20, 1983, 121-128)(0.53g, 2.21 mmol) in diphenylether (5 mL) was added methylpyrazole (0.43g, 4.42 mmol) and the mixture was heated at 200 0 C overnight with stirring. To the cooled mixture was added petroleum ether (20 mL) and the resulting crude precipitate was filtered and further washed with petroleum ether. The crude solid was purified by flash chromatography (SiO 2 gradient DCM-MeOH) to give the title compound as a white solid: mp 242-244C; 'H 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), -236-

VO

o 8.48(2H, 9.20(1H, 12.1.7(1H, br IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 (M+H) 4 G .Method J(ii). (5-Methyl-2H-pyrazol-3-yl)-(3phenyl-isoquinolin-l-yl)-amine. To l-chloro-3- C 5 phenylisoquinoline Het. Chem., 20, 1983, 121- 128)(0.33g, 1.37 mmol) in dry DMF (5 mL) was added 3- 9\ amino-5-methylpyrazole (0.27g, 2.74 mmol) and potassium carbonate (0.57g, 4.,13 mmol)and the mixture was heated 0 under reflux for 6 hours. The mixture was cooled and the IND 10 bulk of DMF was evaporated. The residue was extracted o twice with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO 4 filtered and concentrated. The crude was purified by flash chromatography (SiO 2 gradient DCM-MeOH) to give the title compound as a colourless oil; 'H NMR (MeOD) 8 2.23 (3H, 5.61 (1H, 7.41 (1H, 7.52(2H, 7.62(1H, m), 7 8.07(1H, 8.19(2H, 8.29(1H, 8.54 (1H, MS 301.2 (M+H) Method K

R

2 CI CI CI H NN N N N N H2N .26 27 Method K shows a route for the preparation of compounds of formula VI. A versatile starting material is 2,4,6-trichloro-11,3,5]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.

'V

-237-

NO

o Chem., 11, 417 (1974); and Tetrahedron 31, 1879 (1975).

(C 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 5 VI. Alternatively, intermediate 26 may be obtained by constructing the triazine ring by known methods. See US V patent 2,832,779; and US patent 2,691020 together with J.

\O

IC Am. Chem. Soc. 60, 1656 (1938). In turn, one of the chlorines of 26 may be displaced as described above to O 10 provide 2-chloro-(4,6-disubstituted)[1,3,5]triazine 27.

The treatment of 27 with an appropriate aminopyrazole C1 provides the desired compound of formula VI.

Method L YCF urea

PC

O N NH N.N 0 CI 28 29

R

2

R

2 R 21 N tN H t NH

H

2 N NHN'

N

31 Method L shows a route for preparing compounds of fornmula 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 -238-

VO

o trifluoromethylphenyl and phenyl rings of compound 28.

Substituted chalcones may be prepared by known methods, t for example as described in the Indian 7. Chemistry, 32B, 449 (1993). Condensation of a chalcone with urea C( 5 provides the pyrimidinone 29, which may be treated with POC1 3 to give the chloropyrimidine 30. See J. Chem. Eng.

SData, 30(4) 512 (1985) and Egypt. J. Chem., 37(3), 283 (1994). In an alternative approach to compound 30, one Co of the aryl rings attached to the pyrimidine is O .10 introduced by displacement of of the 4-chloro group of S2,4-dichloro-(6-aryl)-pyrimidine by an aryl boronic acid using a palladium catalyst such as (Ph 3

P)

4 Pd in the presence of a base such as sodium carbonate as described in Bioorg. Med. Lett., 1057 (1999). Displacement of the chlorine of compound 30 by an appropriate aminopyrazole provides compounds of this invention, such as 31. The last step of this method is illustrated by the following procedure.

[4-(4-Methylpiperidin-1-yl)-pyrimidin-2-yl] methyl-2H-pyrazol-3-yl)-amine. To a solution of 2chloro-4- (4-methylpiperidin-l-yl)-pyrimidine (prepared using a procedure similar to the one reported in Eur. J.

Med. Chem., 26(7) 729(1991))(222 mg, 1.05 mmol) in BuOH mL) was added 3-amino-5-methyl-2H-pyrazole (305mg, 3.15 mmol) and the reaction mixture was then heated under reflux overnight. The solvent was evaporated and the residue dissolved in a mixture ethanol/water 4 mL).

Potassium carbonate (57mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water twice and rinsed with ether twice to give the title compound as a white solid (143mg, mp 193-195 0 C; H NMR (DMSO) 8 0.91 (3H, 1.04 (2H, 1.67 (3H, m), 2.16 (3H, 2.83 (2H, 4.31 (2H, 6.19 (2H, m), -239j S 7.87 (1H, 8.80 (1H, br 11.71 (1H, IR (solid) C- 1627, 1579, 1541, 1498, 1417, 1388, 1322, .1246; MS 273.3(M+H) Method M S1

N'

N H 2

N

Ni

G

I. VIIIa N N INI VI I I 33 01

VI

I I C 34.

Cl N N V i lld 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 -240-

VO

o pyrazole to provide Villa is described in J. Het. Chem., C< 20, 1473 (1983). Analogous reactions may be carried out c_ as follows: with 33, to provide VIIb is described in J. Med. Chem., C 5 311 (1998); with 5-chloro-3-substituted- [l,2,41triazine, 34, to provide VIIIc is described in S.Heterocycles, 26(12), 3259 (1987); and with 3-chloro- Cl 5-substituted-[l,2,4]triazine, 35, to provide VIId is o described in Pol. J. Chem., 57, 7, (1983); Indian J.

D0 10 .Chem. Sect. B, 26, 496 (1987); and Agric. Biol. Chem., o 54(12), 3367 (1990). An alternative procedure to compounds of formula VIIIc is. described in Indian J.

Chem. Sect. B, 29(5), 435 (1990).

Compounds of formula IX are prepared by methods substantially similar to those described above for the pyrazole-containing compounds of formula I. Methods A-J may be used to prepare the triazole-containing compounds of formula IX by replacing the amino-pyrazole compound with an amino-triazole compound. Such methods are specifically exemplified by Synthetic Examples 415-422 set forth below. The amino-triazole intermediate may be obtained by methods described in J. Org. Chem. USSR, 27, 952-957 (1991).

Certain synthetic intermediates that are useful for preparing the protein kinase inhibitors of this invention are-new. Accordingly, another aspect df this invention relates to a 3-aminoindazole compound of formula A:

H

NH

2

A

where R" is one to three substituents that are each independently selected from fluoro, bromo, C 1 -6 haloalkyl, -241o nitro, or 1-pyrrolyl. Examples of such compounds include C the following:

FH

NH

2

NH

2

NH

2

NH

2 Al A2 A3 A4 cF F H H H H SF Br yr 0

NH

2

NH

2

NH

2 NH2 0 AS A6 A7 A8 SH

H

02N

NH

2 N NH 2 A9 Another aspect of this invention relates to a 4-chloropyrimidine compound of formula B: Cl F R'NN

R

1

N

B

wherein R X and R Y are as defined above; R' is selected from Cl, F, CF3, CN, or NO 2 and is one to three substituents that are each independently selected from H, Cl, F, CF 3 NO0, or CN; provided that R 1 and R 5 are not simultaneously Cl. Examples of compounds of formula B are shown below: CI CI CI Me N CF 3 Met N Cl N CF Me N Me N' Me, Nb B1 B2 B3 -242cl MetIN

CI

Me N B6 R4 B8 B9

C

CF

3

N

-V

IF

Eli B12 O tN CI

CF

3 313

AN

2 B14

-V

N CI

~ON

317 316 318

CF

N-

Me B19 2CN -243- I

VO

0

O

cO I Va cIN

IN

CA

Another aspect of this invention relates to compounds of formula C: Rr N H Fix

N%

C

wherein RX, RY, R, and R 2 are as defined above. Examples of compounds. of formula C are shown below:

F

Ma Cl

HP

NC

C4

H

HN tP

NL~

C2 HN2

CS

05 ~'C

CH

3

HN

4

H

C3 ,tv

H

HN

HC NCI

C.

C7 -244-

IN

0

*CH

3

H

HN N J, cia

CI

C13

F

HN 4H

HN

Cli N2 C14 HN H C12 Me HN

H

Cis Yet another aspect of this invention relates to, compounds of formula D: 0 NH

CF

3 Fy teN~\ Fi'

D

where Rs, R and Ra are as defined above. Examples of formula D compounds and other useful pyrimidinone intermediates are -shown below:

O

DHC l D1 0 NH CF 3

DN

D6 D4 DS -245- S0 0 0 l N Fa F fCNH CF iNHCF CM D7 D8 D9 CQ NH CI NHC1 NHBr o 5

CF

3 o ,10 D11 D12 cM o o 0 NHCI N NHCF "NH CI N NN 1 NO D13 D14 NHCF3 NH"Q NNHCF3 D16 D17 DI8 0 1 NH CF 3 In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

-246- VO ID SYNTHETIC

EXAMPLES

G The following HPLC methods were used in the analysis of the compounds as specified in the Synthetic C( 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.

ci 0 HPLC-Method A: Column: C18, 3. urn, 2.1 X 50 mm, "Lighting" by Jones 0 Chromatography..

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.

-247- Va HPLC-Method D: 0 Column: Waters (YMC) ODS-AQ 2.0xSOmm, S5, 120A.

Gradient: 90% water Formic acid), acetonitrile (containing Formic acid) to S water formic acid), 90% acetonitrile (containing 0.1% formic acid) over 5.0 min, hold for va 0.8 min and return to initial conditions. Total run IN time 7.0 min.

Flow rate: 1.0 mL/min.

HPLC-Method

E:

Column: 50x2.Omm Hypersil CS18 BDS;5 gm Gradient: elution 100% water TFA), to 5% water TFA), 95% acetonitrile (containing 0.1% TFA) over 2.1 min, returning tb initial conditions after 2.3 min.

Flow rate: 1 mL/min.

Example 1 2-(2-Clorophenyl)-5,6-dimethylpyrimidin-4-yiJ .(5-Methyl-2-pyrazol-3-yl)-amine 'HNMR (500 MHz, DMSO-d6) 810.4 br, 1H), 7.74 21), 7.68 1M), 7.60 1H), 6.39 13), 2.52 3H), 2.30 3H), 2.22 3H);MS 314.1 Example 2 12 2 -Chloro-phenyl) 6,7,8, 9 cyoloheptapyrimidin-4-yll-(1H-indazol-3-yl)-amine (ZI-2): Prepared in 30% yield. 'nMMR (500MHz, DMSO-d6) 8 1.72 (m, 4H), 1.91 2H),.3.02 4H), 7.05 1H), 7.33 (t, 1H), 7.39 7.47 1R), 7.55 i(m, 3H), 7.59 (d, 10.4 1H), 13.11 (br. a, 1H); EI-MS 390.2 HPLC-Method A, Rt 2.99 min.

Example. 3 (5-Fluoro-15-indazol-3-yl)- t2-(2trifluormethyl-phnyl) 6,7,8-tetrahydro-pyrido [3,4- -248- Va o dlpyrimidin-4-yll-amine Compound 11-18 (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 (N 5 evaporated, and crude product was purified by HPLC to provide 18 mg of the desired product as.pale yellow solid. 3inMR (500 MHz, DMSO-d6) 812.9 9.51 (s, 1H), 9.26 2H), 7.72 1H), 7.63 1H), 7.58 (t, C( 1H), 7.49 2H), 7.21 (td, 11H), 7.15 (dd, 1H), 4.24 (s, o 10 21), 3.56 2H),.2.95 2H) ppm. MS m/e- 0 429.22 HPLC-Method A, Rt 2.88 min.

Example 4 [2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5Ecycloheptapyrimidin-4-yll-(7-fluoro-1H-indazol-3-yl) amine Prepared in 52% yield to afford a white -solid. 'EumR (500MHz, DMSO-d6) 6 1.72 4H), 1.92 (m, 2H), 3.00 4H), 7.02 (td, 1H), 7.20 (dd, l1), 7.40 (m, 1H), 7.42 1H), 7.52 3H), 10.5 13.50 (br.

s, 1H); EI-MS 408.2 HPLC-Method A, Rt 3.00 min.

Example 5 (2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5Scycloheptapyrimidin-4-yl (5-fluoro-1H-indazol-3-yl) amine Prepared in 51% yield., HNMR (500MHz, DMSOd6) 1.71 4H), 1.91 2H), 3.01 4H), 7.24 (td, 11), 7.41 2H), 7.54 4H), 10.5 1H), 13.1 .(br.

s, EI-MS 408.2 aPLC-Method A, Rt 3.05 min.

Example 6 12-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-Sacycloheptapyrimidin-4-yl-(5,7-difluoro-1H-indazol-3-yl)amine Prepared according to Method C in 72% yield. 'iUNR (500MHz, DMSO-d6) 8 1.72 4H), 1.91 (m, 21H), 3.01 (min, 4H), 7.31 21), 7.41 1H), 7.54 (m, 3H), 10.5 1H), 13.6 (br. s, 1H); EI-MS 426.2 RPLC-Method A, Rt 3.21 min.

-249- Va c- Example 7 (7-Fluoro-1H-indazol-3-yl)-12-(2trifluoromethyl-phenyl) 8 -tetrahydroquinazolin-4 yll-amine (11-7) Prepared in 62* yield. 'HNMR (500 MHz, DMSO-d) 813.5 br, JR), 10.1 br, 11), 7.75 (m, 4H), 7.33 1H), 7.17 (dd, 1H), 7.00 {td, i1), 2.80 (m, 2H), 2.71 2H), 1.89 (br, 4H) ppm; LC-MS (ESi) 428.44 C- 426.43 HPLC-Method A, Rt 3.02 min.

0 IND 10 Example 8 (S-Fluoro-1H-indazol-3-yl)-(2-(2trifluoromethyl-phenyl) 6,7, 8 -tetrahydroquinazolin-4 yl]-amine Prepared in 53* yield. l-HNMR (500 MHz, DMSO-dG) 813.1 11), 10.2 br, 1H), 7.75 4H), 7.50 (dd, IN), 7.27 (dd, 1H), 7.21 (td, 1H), 2.80 (Im, 21), 2.72 2H), 1.88 41) ppm; MS (ESt) 428.43 426.43 EPLO-Method A, Rt 3.01 min.

Example 9 (5.7-Dlfluoro-1H-indazol-3-yl)-(2-(2trifluoromethyl-phenyl) 6,7, 8 tetrahydroquinazolin-4 yll-amine Prepared in 37% yield. 1 HNMR (500 MHz, DMSO-dE) 513.7 1H) 10.2 br, 1H), 7.80 11), 7.76 IH), 7.69 2H), 7.31 11), 7.16 1H), 2.81 br, 2H), 2.72 br, 2H) .1.90 4H). ppm; MS 446.42 444.37 EPC-Method A, Et 3.09 min.

Example 1 0 (5-Trifluoromethyl-1H-indasol-3-yl) E2-(2trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4yl]-amine (11-10): :Prepared by Method C in ethanol in 35% yield. -DNMR (500 MHz, DMSO-dS) 513.2 1R), 10.1 br, 11), 8.01 11), 7.76 1H),.7.66 41), 7.57 11), 2.79 21), 2.73 21), 1.89 4H) ppm. MS 478.45 476.42 (M-H);.HPLC- Method A, Rt 3.21 min.

-250- Va ci Example 11 C5,7-difluoro-1E-indazol-3-yl) (2trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5Hcycloheptapyrtmidin'-4-yl -amine (I1-11t:' Prepared in yield. White solid. 'HNMR'(500MH, DMSO-d) 8 1.72 Cm, 4H) :1.91 2H) 3.01 4H) 7.15 (dd, 1H) 7.30 (td, 1H), 7.66 2H), 7.72 Ct, 7.78 11), 10.2 Cm, (N 11), 13.5 Cbr. s, 1H); El-MS 460.2 HPLC-Method A, o 'R 3.13 min.

fi C ExoQle 12 (6 -Benzyl-2 trifluoramethyl-penyl) 5,6,7,8-tetrahydro-pyridof4,3-:dpyrimidin-4-yl)-(5fluoro-1H-indazol-3-yl) -amine (11-12): Prepared in 49% yield. 'HNMIR (500 M4Hz, DMSO-dE) 812.8 Cs, 1H), 9.11 Cs, 1H), 7.68 11), 7.58 Ct, 7.53 Ct, 1111, 7.44 Cm, 4H), .7.37 Ct, 21), 7.29 Ct, 1N), 7.19 2m, 21), 3.78 Cs, 2H), 3.61 2H), 2.81 Cs, br, 41) ppm; LC-MS (ES+) 519.24 HPIC-Method.A, Rt 3.11 min.

Example 13 C1H-Indazol-3yl)-[2-(2-trifluoromethylphenyl) -6,7,8,9-tetrahydro-SE-cycloheptapyrimidin-4-ylJ amine (11-13):Prepared in 40% yield. 1 fflMR (500MHZ, DMSO-dG) S 1.70 Cm, 4H), 1.90 2H), 3.00 Cm, 4H), 7.01 Ct, 7.30 (td, 7.44 1H), 7.49 1H), 7.68 Cm, 3H), 7.77 11), 10.01 (in, 1H), 12.83 1M); El- MS 424.2 CM+H); HPLC-Method A, Rt 3.17 min.

Example 14 (7-Fluoro-13-indazol-3-yl) 12- (2trifluoramethyl-phenyl) 9-tetrahydro-SEcycloheptapyrimidin-4-ylJ-amineC- I-14) Prepared in 78% yield. 1 HNM (500MHz, DMSO-d) 8 1.71 4t), 1.91 (m, 2H), 3.00 Cm, 4H), 6.98 (td, 7.16 Cdd, 1H), 7.31 (d, 1H), 7.68 3H), 7.77 11), 10.25 Cm, 13.40 Cbr. a, 11); El-MS HPLC-Method A, Rt 3.12 -2521- ID min.

SExample 15 (5-Pluoro-1H-indazol-3-yl)- trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5scycloheptapyrimidin-4-yl]-amine (11-15): Prepared in 63% yield. 'HNMR (500MHz, DMSO-dS)- 1.71 4H), 1.91 (m, q 3.00 4H), 7.20 (td, 1H), 7.25 (dd, 1H), 7.49 IN (dd, 1H), 7.69 (br.t, 2H), 7.74 31H), 7.79 10.35 IH), 13.00 (br. s, EI-MS 442.2 c. 10 HPLC-Method A, R 3.21 min.

Ci Example 16 (5-luoro-1E-indazol-3-yl)-[2-(2trifluoraomethyl-phenyl)-5,6,7,8-tetrahydro-pyrido [4,3d]pyrimidin-4-yl]-amine (11-16): A solution of compound 11-12 (45mg, 0.087 mmol) in methanol HCOOH) was treated with an equal weight of Pd/C at room temperature for 14 h. The mixture was filtered through celite, the filtrate evaporated, and the crude product was purified by preparative HPLC to provide 15 mg (41%) of the desired product as yellow solid. 1 LNMR (500 MHz,.

DMSO-d6) 512.9 9.52 1H), 9.32 2H, TFA- OH), 7.72 1H), 7.59 2H), T.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 17 (1H-indazol-3-yl)- [2-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydroquinazolin-4-ylJ-aaine (11-17): Prepared in 58% yield. 'HNMR (500 MHz, DMSO-d6) 513.0 11), 10.3 br, 1H), 7.74 4H), 7.51 1H11), 7.47 1H), 7.32 1H), 7.03 111), 2.82 2H), 2.73 2H), 1.90 4H).ppm; LC-MS 410.21 HPLC-Method A, Rt. 2.99 min.

-252- Va cl Example 18 (7-Benzyl-2-(2-trifluoromethyl-phenyl)- 5,6,7,8-tetrahydro-pyrido( 4, fluoro-1E-indazol-3-yl)-amine (11-18): Prepared from compound E11 in 92% yield. 'NMR (500 MHz, DMSO-d6) 812.9 1W), 10.5. br, 9.58 1N,. TFA-OH), 7.71 7.52 sW), 7.19 2H), 4.57 2H), 4.20 2H), 3.70 2W), 3.00 2H) ppm; LC-MS (ES+) o 519.23 HPLC-Method A, Rt 3.23 min.

010 Example 19 (1-Indazoi-3-yl) [6-methyl-2- (2trifluoromethyl-phenyl) -pyrimidin-4-ylI -amine (11-19): Prepared in 42% yield. Melting point 235-237CC; 'HNM (500 MHz, DMSO) S2.44 (3W, 7.09 (1W,-J=7.S Hz, t), 7.40 37.1 Hz, 7.49 (1H, J=8.3 Hz, 7.70 (3H, 7.79 (1W, J=7.3 Hz, 7.87 (1W, 3=8.3 Hz, 8.03 (1W, 3=7.7 Hz, 10.3 (1W, 12.6 (1H, a) ppm; HPLC- Method A, at 2.958 min; MS (FnA) 370.2 Example 20 (1H-Indazol-3-yl)-[6-phenyl-2-(2trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine (11-20): Prepared in 32% yield. 1 HNMR (500 MHz, DMSO) 6.94 (1W, J=7.4 Hz, 7.24 (1W, J=7.4 Hz, 7.33 (1W, L=8.4 Hz, 7.42 (3H, 7.57 (1W, J=7.3 Hz, 7.68 (2H, m), 7.75 (1W, J=7.9 7.93 (3H, 8.18 br a), 10.45 (1H, hr 12.5 (1W, br a) ppm; WPLC-Method A, Rt min; MS (FIA) 432.2 Example 21 (1E-Indazcl-3-yl)- 16-(pyridin-4-yl)-2-(2trifluoromethyl-phenyl) -pyrimidin-4-yl -amine (11-21): Prepared in 12% yield. 'HNMR (SOO MHz, DMSO) 8 7.16 (1, J=7.4 Hz, 7.46 (1W, 3=7.'6 Hz, 7.56 (1W, J=8.3 Hz, 7.80 (1W, J=7.2 Hz, 7.90 (2H, 7.97 (IS, LT=7.8 -253- Va oN Hz, 8.09 (1H, br), 8.22 L=4.9 Hz, 8.45 (lH, br 8.93 (2H, 1=4.8 Hz, 10.9 (11, br 12.8 (IH, br s) ppm; HPLC-Method A, Rt 3.307 min; MS (PIA) 433.2 (M+uH) Rx mple 22 (lH-Indzol-3-yl)-(6-(pyridin-Z-yl)-2-(2_ V')trifluoromethyl-ph enyl) -pyrimidin-4-ylJ -amine (11-22) Prepared in 42% yield. HNMR (500 MHz, DMSO) 7.07 (IH, J=7.4 -Hz, 7.36 (1K, Hz, 7.46 (IH, .1=7.4 Hz, IN 10 7.53 J=5.0 Hz, 7.70 (1H, Hz, 7.79 (in, T=7.1 Hz, 7.83 (11, J=7.4 Hz, 7.88 (1H1, J=7.8 Hz, 7.97 J=7.7,Hz, 8.02 (1K, J-5.5 Hz, br'd), 8.36 (1K, Hz, 8.75 (2H, .1=4.1 Hz,'d), 10.5 (I1, br 12.7 (1K, br s) ppm; HPLC-Method A, Rt 3.677 min; MS (FIA) 433.2 Example 23 (6-(2-Chorophenyl) (2-trifluoramethylphenyl) -pyrimtdin-4-yil (1H-indazol-3-yl) -amine (11-23): Prepared in 44% yield; 1HNp (500 MHz, DMSO) S 7.08 (11, J=7.5 Hz, 7.37 J-7..5 Hz, 7.45 (il, J=8.4 Hz, 7.51 (2H, 7.61 (1H, J=7.4, 1.9 Hz, dd), .7.69 (2H, 7.79 (2H, J=4.0 Hz, 7.86 (3H, J=7.8 Hz, 8.04 (2H, LT-6.2Hz, br 10.7 (1H, br 12.6 (iN, br a) ppm; HPLC-Method A, Rt 3.552 min MS (FZA) 466.2 Example 24 (5,6-Dimethyl-2-(2-trifluoromethy1-phenyl)pyrmidin-4-yl].- (1-indazol-3-yl) -amine (11-24): Prepared in 35% yield; np 183-186 0 C; 1HNMR (500 MHz, DMSO) 8 2.14 (3H, a) 2.27 s) 6.85 (is, J=7.5 Hz, t) 7.15 (1H, J=7.6 4z, 7.32 7.38 (15, J-7.5 Hz, 7.42 (lE, J7.4 Hz, 7.53 (1H, J-7.6 Hz, 8.88 (1K, 12.5 (1K, a) ppm; HPLC-Method A, Rt 2.889 min.; MS (FIA) 384.2 (M+KY'.

-254- Va ci ~i~Exale 2 5 5,6 -Dimsthyl-2- (2-trifluoromethyl-phenyl) pyrimidin-4-yll- (S-fluoro-1H-indazol 3-yl)-amine (11-25): Prepared in 44% yield. Melting point 16-163 0 C; 1 HNMfrj C- 5 (500 MHz, DMSO) 8 2.27 (3H, 2.40 7.16 (21, m) 7. 44 m) 7..52 J= 7. 4 RZ, t) 7 57 (1H, J= 7. 4 Hz, 7.67 (1H, J=7.8 Hz, 9.03 (1H, 12.75 (1H, (N a) ppm; HPLC-MethodA, R 2.790 min; MS (FI) 402.2

(M+H)

4 IND o Example 26 (2-Chiorophenyl) 6-dimethyl-pyrimidin-4yll-.(1H-indazol-3-yl)-amine (11-26): Prepared in yield. IHNMr (500 MHz, DMSO) 8 2.14 (31, 2.33 (3W, 6.84 (1W, J=7.4 Hz, 7.13 (1H, J=7.4 Hz, 7.19 011, .1=6.9 Hz, br 7.27 (iN, J=7.4 Hz, 7.32 (3H, br 7.37 (iN, J-7.1 Hz, 10.0 (is, br), 12.8 (1, br B) ppm; 8 2.919 min; MS (FIA) 350.1 (M+HP.

Example 27 6-Dimethyl-2- (2-trifluoromethyl-phenyl) pyrimidin-4-yl (7-fluoro-1f-indazol-3-yl) -amine (11-27): Prepared in 92% yield. 'HNMR (500 MHz, DMSO) 8 2.33 (3H, 2.50 6.97 (1H, 7.15 (Ia, 7.30 (1W, J=B. 1 Hz, 7.65 (31, 7.76 (1H, J=7.5 Hz, d), 10.0 (IH, 13.4 (1H, s) ppm; SPLO-Method A, Rt 3.053 min; MS (VIA) 402.2 Examnle 2 8 (5,7-Difluoro-uH-indazol-3-yl)- [5,6-Dimethyl- 2-(2-trifluoroinethyl,phenyl)-pyrimidn-4-ylI-amine

(II-

28): Prepared in 50% yield. 1 HNMR (500 MHz, DMSO) 8 2.42 -(311, 2.63 (3H, 7.22 (1H, J=7.6 Hz, 7.38 (iN, J=9.3, 1.7 Hz, dt), 7.71 (1H, 7.75 (1W, J= 7.0 Hz, d), 7.79 (15, J=6.7 Hz, 7.86 0 Hz, 10.0 (iH, -255- Va o)1 13.2 (13, e) ppm; HPLC-Method A, 'Rt 3.111 min; MS 0~ (FIA) 420.2 Example 29 C2-(2-Chlorophenyl) -S,6-dimethyl-pyrimidin-4yil (5,7-difluoro-1W-indazol-3-yl) -amine (11-29): Prepared in 58% yield, 'HNMR (50.0 Mz, DMSO) .8 2.47 (3H, 2.66 (33, 7.44 (211, 7.53 (11, 7.64 (3H, Ci in), 10.4 (1H, br), 13.8 (iH, br a) ppm; HPLC-Method'A, Rt 2.921 min; MS (FIA) 386.1 IND Example 30 (2-Chiorophenyl) 5, -d-dmethyl-pyrimidin-4 yl] (7-fluoro-1H-indazoi-3-yl) -amine (11-30) Prepared in yield. 1 'HJNfl (500 MHz, DMSO) 8 2.35 (3H, 2.51 (33, 7.03 (13, J=7.8, 4.4 Hz, dt), 7.22 (13, 7.33 II, Jn7.4 Hz, 7.42 (1H, 9.19 (11, 13.3 (1H, a) ppm; RPLC-Method A,,Rt 2.859 min; MS (FIA) 368.;2 Eniple 31 (2 -Chiorophenyl) -56 -dimethyl-pyrirnidn-4 yl]-(5-fluoro-1H-indazol-3-yl)-amine (11-31): Prepared in 86% yield. 'HNMR (500 MHz, DMSO) 8 2.49 (3H, 2.68 (3H, 7.38 (13, 3=9.0 Hz, 7.54 (2H, 7.67 (4H, 10.5 (1H, br), 13.2 (13, br a) ppm; HPLC-Method A, Rt 2.850 min; MS (FIA) 368.1 Example 32 (2,4-Dichiorophenyl) 6-dimethylpyrimidin-4-ylJ- (L-indazol-3-yl) -amine (11-32): Prepared in 52% yield. 1 HNMR (500 Mz, DMSO) 6 2. 46 (33, 2.64.

(33, 7.16 (13, J=7.5 Hz, 7.46 J=7.6 Hz, t), 7.61 (23, m) 7.68 (2H, J=8.2 Hz, 7.82 (IH, 10.2 br), 13.0 br a) ppm; HPLC-Method A, Rt 2.983 min; MS (FIA) 384.1 -256- Va Example 33 (5-Xethyl-22-pyrazol-3-y1)-[2-(2mathyiphenyl) -quinazolin-4-yl] -amine (11-33): 'HNMR (DMSO) 8 1.21. 2.25 3H, 6.53 (11, 7.38 (4H, m), 7.62 (1W, 7.73 (1H, 7.81 7.89 (1W, t), 8.70 (IS, s),12.20 (1W, MS 316.3 Va c xample 34 [2-(2,4-Difluorophenyl) -qtdnazolia-4-yl] o methyl-2n-pyrazol"-3-yl)-amine (11-34): 'HNMR (500 MHz, VO 10 DMSO-dE) 812.4 br a, IW), 10.8 Cbr s, IN), 8.58 1W)., 7.97 Cm, 11), 8.36Cm, IN), 7.85 Cm,'1W), 7.60 1W), 6.62'(s, 1H), 2.30 Cs, 3H); MS 338.07 Example 35 £2-(2,.5-Dimethoxyphenyl) -quinazolin-4-yl]- CSnethyl-2H-pyrazol-3-yl)-amine (11-35): 1 KNMR (500 MHz, DMSO-d6) 812.5 Cbr a, 1W), 8.68 (br, IH), 7.92 Ct, J Hz, IN), 7.86 J 8.2 Hz, 1H), 7.65 J Hz, in), 7.45 1W), 7.14 Cm, 2H), 6.51 Cs, XW), 3.79 Cs, 3H), 3.67 Cs, 3H), 2.14 MS 362.2 CM+H).

Example 36 [2-(2-Chiorophenyl) -quinazolin-4-ylJ methyl-25-pyrazol-3-yl)-aaine 'LHNMR (500 MHz, DMSO-d) 611.8 (br, iN), 8.80 J 8.3 Hz, 8.00 Ct, 7.6 Hz, 11), 7.82 Cd, 3 8.3 Hz, 7.78 (m, 2H); 7.67 Cd, J 7.8 Hz;- 1H), 7.61 Ct, J 7.0 Hz, 1H), 7.55 Ct, J 7.4 Hz, 6.56 Cs, 1W), 3.18 Cs, 3H) MS 336.1 CM+H).

Example 37 (2-Methoxyphenyl) -quinazolin-4-yll-( inethyl-23-pyrazol-3-yl)-amine (11-37): 1 HNMR (500 MHz, DMSO-dG) 88.78 Cs, br, 1H), 8.00 Ct, J.t 7.4 Hz, iI), 7.90 2H), 7.74 J.7= 7.5 Hz, 1H), 7.63 t, J 17.3 Hz, lW), 7.30 3 8.4 Hz, 1W), 7.18 J 7.5 Hz, -257- Va 1, 6.58 br, 1H), 3.90 3H1), 2.21 3H); MS 0~ 332.1 Example 38 .12-(2,6-Dimethylphenyl) -quinazolin-4-yl]- methyl-2K-pyrazol-3-yl)-amine (11-38): 1}HNM (500 MHz, DMSO-dE) 612.2 br, 2H), 8.88 Cd, J 7.7 Hz, IH), kn 8.05 J 7.7 Hz, 1H), 7.80 2H), 7.37 J 7.6

IN

Ci Hz, 1H), 7.21 J a 7.7 Hz, 214), 6.36 Cs, 1H), 2.16 (s, 3H), 2.15 6H); MS 330.1 IN Example 39 [2-(2-Adetylpbenyl) -quanazolin-4-yl2- methyl-2H-pyrazol-3-yl) -amine (11-39): 2HNMR (500 MHz, DMSO-d6) 812.35 Cs,' br, 11), 8.93 J 8.4 Hz, 11), 8.37 J 8.6 Hz, 11), 8.20 J 7.6 Hz, 1H), 8.11 Ct, J 8.0 Hz, -7.89 Cm, 211), 7.77 2H), 6.93 Cs, 11), 2.33 Cs, 3H), 2.04 Cs, 3H) MS 344.1 Example 40 [2-(2,3-Dimethylphenyl)-quinasolin-4-ylJ nethyl-2K-pyrazol-3-yl)-amine lHINMR (500 M4Hz, DMSO-dG) 512.6 br, 1H), 12.1 br, 8.91 Id, J 7.7 Hz, 11), 8.14 Ct, OT 7.2 Hz, 1H), 7.95 J r- 8.4 Hz, 11), 7.89 7.7-Hz, 11), 7.58 LT 7..6 Hz, 11), 7.53 J 7.0 Hz, 1H), 7.42 Ct, J 7.6 Hz, 111), 6.60 1H), 2.43 3H), 2.35 3H), 2.32 3H); MS 330.1 Examle 41 (5-Methyl-2E-pyrazol-3-yl) 12- (2trifluoromethylphenyl)-qinazoliu-4-yl]-amine (11-41): HNI4R (s0o MHz, DMSOd6) 512.3 Cs, 10.5 Cs, IH), 8.77 J 8.2 Hz, 1H), 7.92 Cm, 2H), 7.85 3H), 7.56 8.1 Hz,, 1H), 7.67 Ct, J 7.4 Hz', 11), 6.63 1H), 2.27 Cs, 3H); MS 370.1 -258- Va i bEample 42 (2-Ethirlphenyl) -quinazolin-4-y13 CS-Methyl- 2H-pyrazol-3-yl)-amin, (11-42): 1 HNMR (500 MHz, DMSO-d) 88.80 Cm, iH), 8.02 br, 1H), 7.82 J 8.4 Hz, 7.77 1H), 7.62 J 7.6 Hz, iN), 7.54 (m, 1H),-7..41 Cm, 2k-) 6.40 1H), 2.75 J 7.1 Hz, 2.17 3M), 0.99 J 7.5 Hz, 3M); MS 330.1

CM+H).

Example 43 2 -Biphenyl-2-yl-quinaolin-4..yl)-(s.methylo 2 -pyrazol-3-yl)-amine 'HNMR (500 MHz, DMSO-dG) 8 8.76 J= 7.6 HZ, 1H), 8.04 1 7.75 Cm, 6H), 7.30 SN), 5.34 Cs, 1W), 2.14 Cs,. 3H); MS 378.2 Example 44 (2-Nydroxyphenyl) -quinazolin-4-ylJ Methyl-2E-pyrazol-3-yl)-amine (11-44): lHNMR (500 M'z, DMSQ-d6) 810.9 br, 11), 8.62 J 8.2 Hz, 1H), 8.28 L 7.9 Hz, IH), 7.87 2H), 7.60 J 7.9 Hz, 11), 7.37 J 7.8 Hz, 1H), 6.92 Cm, 2H), 6.45 (s, IH), 2.27 3H); MS 318.1 CM+H).

Example .45 (2-Ethoxyphenyl) -quinazolin-4-yll Nethyl-23-pyrazol-3 yl)-amine (11-45): 1 HNMR (500 MHz, DMSO-d6) 5812.1 br, 1H), 8.75 J n 8.3 Hz, 11), 7.97 J 7.8 Hz, iN), 7.82 Cd, J 8.3 Hz, 11), .7.78 Cd, J 7.5 Hz, 1H), 7.70 Ct, J n 7.8 Hz, 7.56 Ct, J 7.8 Hz, iH), 7.22 J 8.,4 Hz, 1H), 7.12 Ct, J 7.6 Hz, 11), 6.55 IH), 4.11 J 6.9 Hz,.2H), 2.16 (s, 3H), 1.22 Ct, 7 6.9 Hz, 3H); MS 346.1 CM#H).

Example 46 E5- (Thiophen-2-yl) 2 H-pyrazal-3-yl] (2trifluoramethyiphenyl)-quinazolin-4-yl]-amine (11-46): HNNMR (500 MHz, DMSO-d6) 88.04 T5- 8.3 Hz, 1H), 8.05 -259- Va N (dd, J 7.3, 8.2 Hz, 7.93 J 6.5 Hz, 1H), 7.81 Cm, SH), 7.34 J Hz, 1H), 7.25 iH), 7.00 (m, 1H), 6.87 iH); MS 438.1 Example 47 (Thiophen-2-yJ.) -20-pyrazol-3-yl] (2trifluoromethylphenyl)-quinazolin-4-yl]-axine (11-47) V')Prepared according to Method B. 'HNMR (500MHz, DMSO-d) 8 Va Ci 6.97 Cm, iH), 7.08 1H), 7.27 Cm, iR), 7.36 In)', 7.66 Cm, 2H), 7.77 3H), 7.83 iS), 8:'00 1H), 8.16 Cs, 1H), 8.62 J 8.2 Hz, IH), 10.7 (br. s, 13); El -MS 438.1-(M+H); HPLC-Method A, at 2.97 -min.

Example 48 (4-Phenyi-20-pyrazol-3-yl)-[2-(2trifluoromethyphenyl) -quinazolin-4-yl -amine (11-48): Prepared according to Method B. 'HNMR (500MHz, DMSO-d6) S 7.05 (br. s, 13), 7.14 J 7.8 Hz, 1H), 7.25 Cm, 3H), 7.43 2H), 7.60 2H), 7.73 7.80 il), 7.95 iN), 8.12 (br. s, IN), 8.60 10.6 (br.

S, 13); El-MS 432.2 HPLC-Method'A, Rt 3.04 min.

Example 49 (5-tert-Eutyl-2H-pyrazol-3-yl)-[2- (2trifiuoromethylpheny)-quinazolin..4-yll-amine (11-49): '3H)4 (500 MHz, DMS6-dE) 8 8.76 J 8.3 Hz, 1H), 7.94 Zn), 7.79 4H), 7.70 J 7.6.Hz, in), 6.51 2 5 13), 1.16 9H); MS 412.2 Example So (S-Phenyl-2H-pyrazol-3-y)- trifluoromethyiphenyl)-quinazolin-4-yll-amine (11-50).

1 HNa .(500MHz, DMSO-d6) 8 7.09 Cs, 1H), 7.36 (td, J 7.8, 1.1 Hz, iH), 7.46 t, J 7.8,Hz, 2H), 7.65 (br. d, J 8.1 Hz, 2H), 7.78 Cm, 2H), 7.90 7.95 J 7.7 Hz, 13), 8.00 Ct, J 7.8 Hz, 1H), 8.81 J 8.6'Hz, 1H), 11.29 (br. s, 13); El-MS 432.1 HPLC-Method A, Rt 3.24 min.

-260trifluoromethylphenyl) -quinazo±n4.}r13-amine (11-51): 'iNMa (500MHz, DMSO-d6) 8 7.13 (in, lB), 7.18 (iS) .36 c-i S 7.62-(M, 3H), 7.73 (in, 2H), 7.85 (in, IB), 8.4.8 uT 8.7 Hz, 10.02 1H), 13.19 1H); HI-MS 508.2 (M+H) 1 HPLC-Method A, Rt 3.39 min.

cIN o Example 52 (4-Carbiazoyl-2x-pyrazol-3-y1) (2- IND 10 trifluoromethylphenyl) -quinazolin-4:-yl3 -amnine (11-52): Prepared in 40% yield. 'KHNMR (500MHz, DMSO-dE): 8 12.85 12.77:(B, IN), 11.80 1IN), 10.80 1K), 8.35-7.42 9H); M1S 399.13. HPLC-Method A, St 2.782 muin.

Example 53 (2H-Pyrazol-3-yl)-(2-(atrifluoromethylphenyl) -quinazclin-4-ylI -amine (11-53): Prepated in 38% yiel d. 'MOMpf (500 MHz', DMSO-d6) 8 12.52 lW), 10.65 1H1), 8.75 id, 1K), 7.91-7.68 8H), 6.87 1K). MS: 356.17. HPLC-Method A, St 2.798 min.

Example 54 (5-Hydrory-2H-pyrazol-3-yl) (2trifluoromnethylphenyl) -quinazolin-4- yLl-amine (11-54): Prepared in 36%'yield; 1 HNMR (500 MHz, DI4SO-d6) 5 10.61 1K), 8.75 1K), 8.03-7.75 (in, 9H),.5.97 1H); MS 372.18 HPLC:-Method A, Rt 2.766 min.

(S-Cyclopropyl-2a-pyao'l (2trifluoromethyl.phenyl)- ±nazolin-4.yl..amine (11-55): Prepared'in 30% yield. 1 HmR~ (500 mHz, DMSO-dE) 612.21 (sH1), 10.45 1H), 8.68 lB), 7.89-7.4.5 BK), -261- Va oND 6.48 IH), 0.89 21), 0.62 MS 396.16 CM+H); HPLC-Method A, Rt 3.069 min.

Exampla 56 (5-Metboxymethyl-2E-pyrazol-3-yl) S trifluoromethxyl-phenyl) -quinazolin-4-ylJ -amine (11-56): Prepared in 33% yield; 'HNMR (500 MHz, DMSO-d) 8 12.51 Vn Cs, 111), 10.48 1H), 8.60 Cs, 11), 7.81-7.55 7H),

IN

C-I 6.71 1H), 4.28 2H), 3.18 Cs, 3H). MS 400.19 HPLC-Method A, Rt 2.881 min.

IND o, Examrle 57 (1H-indazol-3-yl)- (2-trifluoromethylphenyl)-quinazolin-4-ylJ-amine (11-57): Prepared to afford 51 mg (78% yield) as pale yellow solid. lfHMR (500 MHz, DMSO-dE) 612.7 1H), 10.4 1H), 8.55 IH), 7.81 Ct, 1H), 7.71 1H), 7.61 1H), 7.58 Ct, 1H), 7.46 AH), 7.36 (di 11), 7.22 (ti, 1H), 6.91 Ct, IH) ppm; LC-MS 406.16 404.19 CM-H); HPLC- Method A, Rt 3.00 min.

Example 58 (4-Chloro-1H-indasol-3-yl) trifluoromethyl-phenyl) -quinazolin-4-ylJ -amine (11-58): Prepared in DM2 (70t yield) as pale yellow solid. 'HNMR (500 MHz, DMSO-d) 813.3 Cs,.br, 1H), 10.9 Cs, br, 1H), 8.60 UI),'7.97. t, 11), 7.81,(d, 11), 7.75 1H), 7.67 1H), 7.63 Cdd, IH), 7.57 Cm, 2H), 7.43 Cd, .3i), 7.28 (dd, 1W), 7.08 1H) ppm; LC-MS (ESt) 440.10 438.12 HPLC-Metbod A, Rt 3.08 min.

Example 59 (5-Fluoro-lH-±ndazol-3-yl)-E2-(2trifinoromethyl-pheyl) -quinazoliu-4-yl] -amine (11-59): Prepared in -DM2 (34% yield) as pale yellow solid. lIflitM (500 MHz, DMSO-d6) 813.0.(s, 11), 10.6 1H), 8.12 (d, 11), 7.99 111), 7.89 1H), 7.79 1W), 7.75 Ct, 1H), 7.68 3H), 7.56 (dd, 1H), 7.39 IH), 7.28 (t, -262- Va 1K) ppm; LC-MS 424.12 m/e= '422.13 (1M- HPLC-Method A, Rt 3.05 min.

Example 60 (7-Fluoro-1R-indazol-3-yl)-[2-(2- C 5 trifluoromethyl-phenyl)-quinazolin-4-yll -amine (11-60): Prepared in DMF yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 813.4 1H), 10.6 1H), 8.68 1H), 7.95 1H) 7.85 i) 7.72 2H), 7.63 (in, 2H), 7.58 1H), 7.43 1H), 7.18 (dd, 1H), 7.00 1H) ppm; LC-MS 424.11 422.15 HPLCo Method A, Rt 3.06 min.

Example 61 (5-Methy-1ZE-indazol-3-yl)-12-(2trifluormethyl-phenyl)-quinazolin-4-yl]-amine (11-61): Prepared in DMF (81% yield) as yellow solid. 'EIMR (500 MHz,.DMSO-d6) 813.0 br, 1H), 8.79 (br, 8.11 (br, 1H), 7.96 1H), 7.82 5H), 7.46 1H), 7.41 (d, 1H), 7.20 IH), 2.33 3H) ppm; MS 420.15 418.17 HPLC-Method A, Rt 3.07 min.

Example 62 12-(2,6-Dichloro-phenyl)-quinazolin-4-yll-(5fluoro-1z-indazol-3-yl)-amine (11-62): Prepared in DMF (37% yield) as yellow solid. 'IHNMR (500 MHz, DMISO-d6) 613.0 1H), 10.8 1H), 8.72 1H), 7.97 1H), 7.90 1K), 7.75 1H), 7.53 3H), 7.43 1I), 7.35 1H), 7.23 1R) ppm; LCMS 424.08 (M+H)i 422.10 HPLC-Method A, Rt 3.06 min.

Example 63 [2-(2-Chloro-phenyl)-quinazolin-4-yl-(15indazol-3-yl)-amine (11-63): Prepared in 91% yield. IHNMFR (500MHz, DMSO-d6) 8 7.06 1H), 7.36 1H), 7.39 (t, 1H), 7.52 3H), 7.62 1H), 7.72 7.82 (m, 1N), 7.90 8.05 IH), 8.76 11.5 (m, 1H), 13.02 1H); EI-MS 372.1 HPLC-Method A, Rt -263-

VO

o 2.93 min.

Example 64 (5-Trifluoromethyl-1H-indazol-3-yl)- (2trifluoromethyl-phenyl) -quinazolin-4-yl -amine (1-64): Prepared in DMF (57% yield). as yellow solid. IHNMR (500 1MHz, DMSO-d6) 813..4 br, IH), 11.4 (br, IH), 8.72 (d, 1H), 8.12 Is, 1H), 7.98 1H), 7.83 1H), 7.76 (d, Ci 1H), 7.73 (dd, IH), 7.60 4H), 7.52 1H) ppm; LC-MS o 474.12 472.17 HPLC-Method A, Rt OD 10 3.25 min.

Example 65 (4-Trifluoromethyl-lB-indazol-3-yl) (2trifluoromethyl-phenyl)-quinazolin-4-yl]-amine (11-65): Prepared in DMF yield) as yellow solid. EHNMR (500 MHz, DMSO-d6) 813.7 br, iH), 11.2 (br, 1H), 8.70 (d, IH), 8.05 1H), 7.85 3H), 7.65 4H), 7.51 (m; 2H) ppm; LC-MS 474.13 472.17 HPLC-Method A, Rt 3.15 min.

Example 66 (2,6-Dichloro-phenyl) -quinazolin-4-yl] (1Hindazol-3-yl)-amine (II-66): Prepared in DMF (30% yield) as yellow solid.. WHNMR (500 MHz, .DMSO-d6) 8.12.9 1H), 11.1 1H), 8.69 1H), 7.95 1H), 7.82 1H), 7.73 1H), 7.56 1H), 7.47 IH), 7.45 1H), 7.39 2H), 7.26 IH), 6.92 IH) ppm; LC-MS 406.11 404.12 HPLC-Method A, Rt 3.00 min.

Example 67 (IH-indazol-3-y)-[2- (2-methyl-phenyl)quinazolin-4-yl]-amine (II1-67): Prepared in 55% yield.

1 HNMR (500MHz, DMSO-d6) 8 2.15 7.09 1H), 7.26 1H), 7.31 1i), 7.39 1H), 7.42 1H), 7.55 (d IH), 7.64 1H), 7.74 1H), 7.89 1H), 7.96 -264- Va 1H), 8.10 1H), 8.81 1d, 1K), 12.0 Cm, 1Kbi 13.1B N 1H); E-MS 352.2 HPLC-Method A, Rt 2.93 min.

Example 68 (7-Trifluoromethyl-l-indazol.3..yl) (2- C- 5 trifluoromethyl -phenyl) -quinazolin-4-yl -amine (11-68).

Prepared in DMF (75% yield) as yellow solid. 'IflMR (500 MHz, DMSO-d) 813.5 br, 1H), 11.2 br, IH), 8.68 1H), 7.97 1H), 7.92 Cd, 13), 7.82 13), 7.74 ot, 13), 7.70 1H), 7.68 Cd, IN), 7.64 Cm, 2H), 7.57 7.14 Ct, 1H) ppm; DC-MS 474.11 472.14 X-H);'PLC-Method A,*Rt 3.24 min.

Example 69 (6-Trifluoromethyl-1z-indazol-3-yl)-[2-(2trifluoromethyl-phenyl) -qanazolin-4-y3-nine (11-69): 'Prepared by Method B in DMF (78% yield) as yellow solid.

'HNMR (500 MHz, DMSO-dE) 8 13.4 Cs, br, 13), 11.1 Cs, br, 1K), 8.67 Cd, 1H), 7.95 7.82 Cm, 31),.7.72 (m, 2H), 7.63 Cm, 2H), 7.57 Ct, 13), 7.23 Cd, 1) ppm; LC-MS 474.12 472.15 HPLC-Method A, Rt 3.28 rin.

Example 70 (5-Hitro-1s-indazol-3-yl) (2trifluoromethyl-phenyl) -qainazolin-4-yl -amine (11-70): Prepared in DMF (82% yield) as yellow solid. 1HNMR (500 MHz, DMSO-d) 813.6 Cs, br, 1H), 11.4 br,AH), 8.75 Cs, IH), 8.72 8.09 Cdd, 1K), 7.98 Ct, 1K), 7.83 1H), 7.75 t, 1H), 7.70 7.61 Cm, 3H) ppm; LC-MS 451.14 449.12 CM-H); HPLC-Method A, Rt 3.02 min.

Example 71 (5,7-Difluoro-H-indasol-3-yl)-[2-(2trifluoromethyl-phenyl) -quinazolin-4-ylJ -amine (11-71): Prepared in DMP yield) as yellow solid. 1 !HIR (500 MHz, DMSO-d6) 813.7' br, 11), 11.2 br, 110, 8.73 -255-.

Va oN 1I), 8.03 1K), 7.88 1K), 7.80 7.70 0g 3H), 7.32 2H) ppm; LC-MS 442.14 (ES- 440.14 HPLC-Method A, Rt 3.11 min.

Example 72 (4-Pyrrol-1-yl-1E-indazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yll-amine (11-72): ~fl Prepared in DMF (33% yield) as yellow solid. 1 HJNIR (500 Va C MEHz, DMSO-d) 813.4 br, 1K), 11.0 br, 1H), 8.53 o 1H), 7.98 iN), 7.75 4H), 7.62 2H), 7.52 1H), 7.43 IH), 7.05 1H), 6.80 2H), 5.61 S(s, 2H) ppm; LC-MS 471.18 469.18 (Mc HPLC-Method A, Rt 3.12 min.

Example 73 (5-Amino-1E-indazol-3-yl)- trifluoromethyl-phenyl)-quinazolin-4-yl]-amine (11-73): A solution of compound 11-70 (70 mg, 0.16 mmol) in MeOH (2 mL) was treated with Raney Ni until solution was colorless (about 1.5 g Raney Ni was added). After stirring at.room temperature for 40 min, the mixture was filtered through celite, the resulting celite was washed with MeOH (5 times), and the solvent was evaporated In vacuo to provide a crude product that was then purified by HPLC to give the title compound as a yellow solid ig, m.p. 22i-223oC; 1 HNMR (500 MHz, DMSO-d6) 613.2 br, IH), 10.7 br, N1H), 9.80 (br, 2H), 8.68 1N), 7.97 1H), 7.87 7.75 2H), 7.65 5H), 7.30 IH) ppm; MS 421.16 (ES-) 419.17 HPLC-Method A, Rt 2.41 min.

Example 74 [2-(2-Chloro-phenyl)-quinazolin-4-yl]- (7fluoro-iH-indazol-3-yl)-amine (11-74): Prepared in DMF yield) as yellow solid. HNMR (500 MHz, DMSO-d6) 813.7.(s, 1H), 11.7 br, IN), 8.80 iN), 8.15 (t, 7.99 1K), 7.88 1K); 7.68 iN), 7.60 (m, -266- 2H), 7.53 11), 7.46 1H), 7.25 (dd, 11), 7.04 (m, 11) ppm; LC-MS (ESt) 390.16 EPLC-Method A, Rt 3.00 min.

S Example- 75 t2-C2-Chloro-pbenyl)-quinazolin-4-yl]-(5f2uoro-IH-indaol -3 -yl) -amine .(II-75) Prepared in DMF.

'I NMR (500 MHz, DMSO-d) 813.2 Cs, 111), 11.7 Cs, br, IH), 8.80 1H) 8.10 11), 7.91 Cm, 2H), 7.70 11), 7.58. 4H), 7.50 C(t, 11), 7.29 Ct, 1) ppm; LC-MS CES+) 390.17 HPLC-Method A, Rt 3.00 min.

ExM22e 76 [2-(2-Chloro-phenyl) -qinazolin-4-yl]-(5,7difluoro-1H-indazol-3-yl) -amine (11-76): Prepared in DMF yield) as yellow solid. 'HNMR (500'MHz, DMSO-d6) 813.8 1H), 11.5 Cs, br, 1H), 8.76 1H), 8.08 Ct, 11), 7.93 1H), 7.84 Ct,- IH), 7.64 1H), 7.55 Cd, 1H) 7.50 31I) 7.44 7.36 1H) ppm; LC-MS 408.15 406.17 CM-H); UPLC-Method A, Rt 3.08 min.

Example 77 [2-(2-Choro-phenyl) -quinazolin-4-yl] trifluoromethyl-LH- indazol-3-yl)-amine (11-77): Prepared in DMF (66% yield) 'as yellow solid. HNMR (500 MHz, DMSOdE) 813.5 Cs, 11), 11.4 br, 11), 8.79 1R), 8.29 Cs, 11), 8.07 Ct, 11), 7.93 111), 7.84 Ct, 7.72 d, 1iH), 7.63 2H), 7.53 1H), 7.48 Ct, 1H), 7.36 1H) ppm; LC-MS. m/e= 440.16 CM+H); m/e= 438.18 HPLC-Method A, Rt 3.22 min.

Example 78 t2-(2-cyano-phezyl) -quinazolin-4-yl]- (1idazolj-3-yl)- amine (11-78): Prepared iii 13* yield. 1'H NMR (500 MHz, DMSO) 8 12.9 Cbr, 1H), 10.8 (br, 11), 8.73 (br s, 1H), 7.97 Cm, 4H), 7.74 11), 7.5 Cm, 4H), 7.42 '-267- Va IH), .7.08 Cm, 1W) ppm; MS (FIA) 363.2 CM+H); HPLC- CI Method A, at 2.971 min.

Example 79 (5-Eromo-1H-indazol-3-yl)-(2-(2- Cl 5 trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (11-79) Prepared in DMF (64% yield) as yellow solid. 1 HNMR (500 tf MHz, DMSO-d) 513.4 Cs, 1W), 11.6 Cs, br, 11), .8.93 (d, Va Cl 111), 8.21 Ct, In), 8.14 Cs, lW), 8.05 Cd, 1H), 7.95 (m, o 7.86. Ct, lW), 7.65 iN), 7.59 Cd, in) ppm; MS IN 10 (ES+i) 486.10 CM+H), 484..09 CM-H); HPLC-Method A, Rt y) 0 3.22 min.

Example 80 (6-Chloro-1R-indazol-3-yl) (2trifluorome thyl -phenyl)-q uinazolin-4-yl-amine (11-80): Prepared in DMF (94% yield) as yellow solid. 1HNIR (500 MHz, DMSO-d6) 813.1 Cs, 1H), 11.2 br, 1W), 8.73 (d, 1W), 8.03 in), 7.87 1H), 7.79 Cm, 2H), 7.73 (m, 2H), 7.67 2H), 7.58 iN), 7.04 {dd, IN) ppm. LC-MS CES+) 440.14 438.16 CM-H); HPLC-Method A, Rt 3.25 min.

gmple 81 (7-Fluoro-6-trifluoromethyl-1H-indazol-3-yl)- (2-trifluoromethyl-phenyl) -quinazolin-4-yl] -amine .(Ii- 81):,Prepared in DMP (30% yield) as yellow solid. 1NM (500 MHz, DMSO-d) 813.9 Cs, 11), 11.0 Cs, br, 1W), 8.64 (d,1IH), 7.94 Ct, iR), 7.81 Cd, iN), 7.71 2H), 7.60 m, 4W), 7.20 Cdd, 1H) ppm. LC-MS CES+) 492.18 490.18 CM-H); HPLC-Method A, Rt 3.44 min.

Example 82 (6-Bromo-1E-indazol-3-yl)-[2-(2trifluorcmethyl-phenyl)-quinazolin-4-yl]7amine (11-82): Prepared in DMF yield) as yellow solid. NMR (500 MHz, DMSO-dE) 813.1 Cs, 11), 11.2 br, 1H), 8.73 (d, 1W), 8.03 Ct, 1H), 7.87 1W), 7.80 Cm, 2H), 7.73 (m, -268- 7.67 7.61 -7.1t (dd, 1H!) ppm; MS (N (ES+e) 486.07 HPLC-Method A, Rt 3.28 min.

__Example 83 (2,4-Bie-trifluoromethyl-phenyl) c-i 5 quinazolin-4-ylJ -(5,7-difluoro-1E-indazo1-3-y1) -amine (11-83); Prepared in DME in'.28% yield. I HNMR (500MH~z, MeOH-d4) 8 8.81 Jm8.4Hz, 8.35-8.20 3H!), 8.19-7.96 Cm, 7.40-7.34 7.29-7.14 (in, 1H!); 0 LC-MS (ES+i) 510.1 4 HPLC-Method C, Rt 8.29 'mini.

IN 0 Example 84 (5,7-Difl~noro-1H-indzo..-.y1) 2- (4-f luoro-2trifluorcinethy1-phmy1) -quinazolin-4-yl] -amine (11-84)-: Prepared in 48% yield. 2 XNMR (500MHz, MeOH-d4) 88.74- 8.63 (mn, 1H), 8.23-8.10 7.99-7.90 (mn, 2H),-7.89- 7.80 7.71-7.61 7.61-7.SO (mn, 7.24- 7.15 7.14-7.02 (mn, 111); LC-MS 460.14 HPLC-Method C, Rt 7.59 min.

(2-Bromo-phenyl) -qtzinazolin-4-yi] difluoro-1z-indazol-3-yl)-amine (11-85): Prepared in THF- (21% yield). 1 imNi (500MHz, MeOH-d4) td, J=8.4Riz, 8.35-8.20 8.19-7.96 7.40-7.34 (in,.

7.29-7.14 LC-MS (ES+Y 510.14 HPLC- Method C, -Rt 8.29 min.

ExaInp1h 86 (S,7-Difluoro-1B -indazol-3-yl)-(2-(s-fluoro-2trif luoroinethyl-ph.enyl) -qninazolin-4 -ylJ -nmine (18) Prepared in THfF (26% yield). HM (500MHz,. MeDH-d4) 88.62 11R), 8.16-8.02 7.96-7.73 (m, 7.59-7.48 (mn, 7.48-7.35 (mn, 7.21-7.09 (in, 11!)f 7.09-6..9 (mn, 13); LC-MS (ES+)-460.1.6

HPLC-

Method C, Rt 7.28 mini.

-269- Example 87 [2-(2,4-Dichloro-phenyl) -quinazolin-4-yl]- 5 ,7-Difluoro-1a-indazol-3-yl) -amine (11-87): Prepared in THP 16% yield). 'HNMR (500MHiz, MSOH-d4) 88.81 (d, J=8.4Hz, 1H), 8.35-8.20 31), 8.19-7.96 311), 7.40- 7.34 1H), 7.29-7.14 IN); LC-MS 510.14 HPLC-Method C, at 8.29 min.

Example 88 qninazolin-4-yll- (5,7-Difluoro-1H-indazol-3-yl) -amine (11-88): Prepared in THFl (33% yield). 'HNMR (SOOMHz, 10.76 12), 8.66 'J=8.31z, 1H), 8206- 7.84 3H), 7.81-7.63 3H), 7.4'.-7.16 22); LC-MS 476.16 HPLC-Method C, Rt 19.28 min.

Example 89 (4-Fluoro-1&-indazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-ylJ-amine (11-89): Prepared in IMP (79% yield). as yellow solid. 3'HNM (500 MHz, DMSO-dj) 813.2 Cs, 1H), 10.8 br, lIH, 8.63 (d, 12), 7.97 12), 7.85 11), 7.74 2H), 7.64 (t, 7.57 2H), 7.32 2H), 6.82 12) ppm; LC-MS (ESt) 424.17 HPLC-Method A, Rt 3.14 min.

Example 90 (1H-Indazal-3-yl)- [8-methozy-2- (2trifluornethyl-phenyl)-quinazolin-4-y13-amine (11-90): Prepared using THF as solvent to afford the title compound as a TFA salt (23% yield). HPLC-Method A, at 2.97 min mHNP. (DMSO-dE, 500 MHz) 12.9 (1H, be), 11.0 10.7(12, be), 8.25 (11, 7.75-7.50(SH, 7.30 (114, 6.90 (1H, 4.0 MS 436.2 Example 91 (S-Fluioro-1E-indazol-3-yl) CS-methosy-2- (2 trifluoraiethyl'henyl)-quinazolin-4-yll-amine (11-91): Prepared using TFA as solvent to afford the title compound as a TFA salt (23% yield). HPLC-Method A, Rt -270o3. 10 -min. (9 1 HNMR (DMSO-dE, 50 0 MHz) :13. 0 (1W, be) Cl 11.0 1O.7(lIH, be), .8.25 (111, in), 7.75-7.50 (7H, mn), 7.35 (111, in), 7.25 (1W, Mn), 4.0 MS 454.2 Example 92 (7-Fluoro-IH-±ndazol.-3-yi)- t8-methoqxy-2- (2trifluoroiethyi-phenyl) -quinazolin-4-yl] -amine (i1-92): Cl Prepared using TIIF as. solvent to afford the title 0 compound as a TFA salt (98 mag, 58% yield). HPLC-Method.

ol1 A, -Rt 3.20 min 'HNMR (DMSO-dG, 500 M4Hz) 8 13 0 (111, be), 11.0 10.7(111, be), 8.25 (1H, mn), 7.75-7.60 in), 7.50 (Ili, in), 7.40 (1H1, in), 7.15 (1H1, in), 6.95 (1H, in) 4. 0 (311, s) MS 454.2 (M+iH).

Example 93 (5,7-Difluoro-1z7-indazol-3-yi) (-methoxy-2- (2 -trifjluoroinethyl-phenyl) -quinazolin-4-yll -amine (II- 93): Prepared using TH' as solvent-to afford the title compound ,as a TFA salt (36% yield). EPLO-Method A, R 3.27 min. 1 MR (DMSO-d6, 500 M4Hz) .13.65 (1H1, bs) 11.0 10.7(1W, be), 8.22 (111, mn), 7.75-7.60 (51, in), 7A40 (111, in), 7.35 (1W; in), 7.19 (1H, rn), 4.0 MS 472.-2 Example 94 (2-Chiloro-py-ridin-3-yl) -quinazolin-4-yl] (S,7-Difiuorc-tH-. indazol'-3 -yl)-aaine (11-94): Prepared in D14F. 'flNR (500MHz, DMSO-dE) 8 13.62 (br s, 1H1, 11.06- 10.71 (mn, iN), 8.16-7.70 (mn, 4H1), 7.60-7.09 (mn, 3W); LC- KS 409.14 HPLC-Method A, Rt 2.8.9 rain.

Ex l 95(2- (2-Chloro-4-nitro-phenyl) -qninazolin-4-yll (5,7-dif-luoro-1s-indazol-3-yl)-azine (11-95). Prepared'in THE'. HN~MR (SOOrHz, DMSO-dE) 6 13.35 1H1), 10.74 (s, 1H), 8.67 J=8.4Hz, 1H), 8.29 Ju2.O5Hz, 111), 8.18- -271- IND 8.08 1I), 8.07-7.60 4H), 7.53-7.10 2H). LC- MS 453.15 HPLC-Method D, Rt 3.63 min.

Example 96 (4-Amino-2-chloro-phenyl) -quinasolin-4-yll (5,7-Difluoro-1l-indazol-3-yl)-amine (11-96): A solution of compound XI-95 (8mg, 0.018mmol) and tin chloride dihydrate (22mg, 0.lmmol) in ethanol (2mL) was N heated at 100 6 C for 24h. The reaction was diluted with EtOAc (10mL), washed with 1N NaOH solution (2x10mL), brine, and dried over anhydrous sodium sulfate to afford the crude product. Purification was achieved by flash Schromatography on silica gel (eluting with 1-3% MeOH in

CH

2 C1 2 The title compound was isolated as pale yellow solid (1.2mg, 16% yield). LC-MS 423.12 HPLC-Method C, Rt 13.78 min.

Example 97 (4,5,6,7-Tetrahydro-a-indazol-3-yl) -12-(2-trifluormethyl-phenyl)-quinazolin-4-y1]-amine (11-97): Prepared in 34% yield. 1 RNMR. (500MHz, DMSO-dG) S 1.58 2H), 1.66 2H), 2.24 2H), 2.54 (m 2H), 7.63 3H), 7.71 1i), 7.75 1H), 7.78 1H), 7.85 1H), 8.53 1H), 9.99 11), 12.09 11); EI-MS 410.2 HPLC-Method A, Rt 3.05 min.

Example 98 (lH-Pyrazolo[4,3-b]pyridin-3-yl)- 2-(2trifluorbmethylphenyl)-quinazolin-4-yll-amine (II-98): Prepared in DMF (37% yield) as yellow solid. l1JLNMR (500 MHz, DMSO-d6) 813.1 br, 1H), 11.2 br, 8.73 an), 8.54 (dd, 1iH), 8.12 11), 8.06 1H), 7.90 iN), 7.84 is), 7.75 1i), 7.69 2H), 7.65 1H), 7.47 (dd, 1i) ppm; LC-MS 407.18 HPLC-Method A, Rt 2.77 min.

-272- Va Example 99 (1H-Pyrazolo(3,4-b pyridin-3-yl) (2- Cl trifluoromethyl-phenyl) -quinazolin-4-yll-amine (11-99): Prepared in DMF (45% yield). 2 Z1Ma (s00 MHz, DMSQ-d6) 813.5 br, 1HY', 11.3 br, 110, 8.78 lH), 8.49 8.17 1H), 8.03 Ct, 1N), 7.89 1N), 7.80 Cm, 2H), 7.74 7.68 7.08 (dd, 1H) ppm.

MS 407.16 CM+H), 405.16 HPLC-Method A, Ca 2.80 min.

IND 10 Example 100 (6-Hethyl-lH-pyrazolot3,4-blpyridn-3-yl) o (2-trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (II- 100): Prepared in DMF (11% yield). THNMR (500 MHz, DMSOd6) 813.2 br, 15), 10.8 br, 8.57 Cd, 7..95 11), 7.82 7.72 15), 7.65 Cm, 2H), IS 7.58 2H), 2.44 Cs, 3M, buried by DMSO), 2.20 Cs, 3H) ppm. LC-MS 435.22 433.25 SPLC- Method A, Rt 2.94 min.

Example 101 (6-Oxo-5-phenyl-5,6-dihydro- az-pyrazolol4,3cjpyridazin-3-yl) [2-(2-trifluoromethl-phenyl)quinazolin-4-yl] -amine 11-101: Prepared in DMF (6% yield). 'ENMR (500 MHz, DMSO-d6) 512.6 15), 11.0 Cs, br, 1H), 8.60 7.95 Ct, 7.88 1H), 7.80 Is), 7.68 Cm, 4H), 7.40 7.22 2H), 6.61 1H) ppm. LC-MS 500.21 498.16 (M- HPLC-Method A, Rt 3.00 min.

Example 10 3 [6-Methyl-2- (2-trifluoromethoxy-phenyl) pyrimidin-4-yll- (5-phenyl-23-pyrazol-3 -yl) -amine (II- 103): MS-412.13 MPLC-Method E Rt 1.248 min.

Example 104 (5-Furan-2-yl-21-pyrazol-3-yl)-[6-methyl-2tri fluoromethoxy-phenyl) -pyrimidin- 4-yl I amine (II- 104) MS 402.12 (MH) HPLC-Nethod E, Rt 1.188 min.

-273c-I fale 105 [6-Etbyl-2- (2-trifluoromethoxy-phenyl) pyrimidin-4-ylJ -'(5-methyl-2H-pyrazol-3-yl) -mine. (11- 105) MS 364.14 HPLC-Method E, Rt 1.112 mini.

Example 106 (2-Chioro-phenyl) -pyrido[2,3-d]pyriaidin- 4 -yl3-(5-methyl-25-pyrazol-3-yl)-mne (11-106): 'HNNR Cl (5oc MHz, DM50) 812.23 10.76 7.73-7.47' o (in, 6.72 (al 1H1), 2.21 3H). MS: (M4.1) 337.02.

IND 1-0 HPLC-Method A, Rt 2.783 min..

jx~l 07 (5-Fluoro-1EH-±ndazol-3-yl) 2- (2trif luoromethyl-phenyl) -6,7 -dihydro-Saayclopentapyrimidin-4-ylJ-aaune (11-107): Prepared in 68%t yield. '1PEMR (500MHz, DMSO-dE)52.16 2H), 2.88 (mn, 2H1), 2.98 7.21 (td, in), 7.29 (ad, 1H), 7.50.

(dd, 7.65 7.67.(t, 18), 7.73 l1H), 7.79 1.0.22 (hr. s, 12.99 (br. S, 1H); EI-MS 414.2 PLC-Method A, Rt 2.92 mtin-.

Example 108 (12-Indazol-3-yl) (2-trifluoromethylphenyl) -pyridot2,3-dlpyrinidin-4-ylJ -amine (11-108): HPLC-.Method A, Rt 2.78 min. (95);l tr (DMSO-dE, 500 MHz): 12.95 be), 11.45 8 11.15(11*, be), 9.20 (2H*, in), 7.85-7.70 in), 7.70-7.55 mn), 7.50 (1H, in), 7.35 (1H, mn), 7.05 (1H1, mn); MS 407.03 Example 109 (5,.7-Difluoro-1H-indazol-3-yl) (2trifluoromethyl-phenyl) -pyridotZ,3-dlpyrimidin-4-yl] amine (11-109): Ytellow, di-TFAasalt (25% yield). HPLC (Method'A) 3.10 min. 1 mq~mR (DMSO-dE, 500 MHz): 13.8-13.6 (1H, be), 11.4 be), 9.15 (2H, in), 7.85-7.75 mn), 7.75-7.62 in), 7.32 in); MS 442.98 (M+eH).

-274- Va Example 110 2 2 -Chloro-phenyl)-pyridoEC2,3-dpyrimidin 4-ylJ -Q-&H-indazol-3-yl) -amine (Ii-110): Prepared from 2aminonicotinic acid and 2-chlorobenzoyl "chloride afforded ri 5 the title compound as a di-TFA salt (28* yield). HPLC- Method A, Rt 2.85 min. IHNR (DMSO-dE, 500 MHz): 12.'90 (1H, 11.10 10.90 (1H, be), 9.05 (2H, m), 7.75-7.60 (2H, 7.51 (1H, 7.45-7.25 (5H, 6.95 o (1H, MS (i/z).372.99(M+H).

0O o Example 111 (5-Fluoro-H-indazol-3-yl)- trifluoromethyl-phenyl)-5,6,7,8,9,10-henhydrocyclooctapyriin4din-4-yl]-amine (11-111). Prepared in 43% yield. 1 HNMR (5001Hz, DMSO-d) 8 1.46 2H, 1.53- (m, 2H), 1.77 4H), 2.95 2H), 3.04 21), 7.22 (m, 2H), 7.50 (dd, 7.72 3H), 7.80 11), 10.5 (m, 1H), 13.05 (br s, 1H); El-MS 456.2 HPLC-Method C, Rt 11.93 min.

Example 112, 2- (2-Chloro-phenyl) -6,7-dihydro-5Hcyclopentapyrimindin-4.yl]-(5-fluoro-1H-indazol-3-yl)amine (11-112); Prepared in 67% yield. 1 HNMfR (SOOMHz,.

DMSO-d6) 8218 2H), 2.89 2H), 3.02 Ct, 2H), 7.24 (td, 1H), 7.42 Cm, 2H), 7.49 1H), 7.52 (dd, 1H), 7.54 11), 7.57 (dd, 11), 10.50 Cbr. s, 1H), 13.06 (br. s, 1H); EI-MS 380.1 HPLC-Method C, Rt 9.68 min Example 13 (1B-Indazol-3-yl)-£2-(2-trifluoronethylphenyl) dihydro-5E-cyclopentapyrimidin-4-y1] -amine (11-113): Prepared in 37%..yield. '4ZAp (500M1Hz, DMSO- d) 82.65 2H), 2.85 2H), 2.99 2H), 7.02 1H), 7.32 Ct, 1H), 7.47 IH), 7.55 1R), 7.68 Ct, IH), -275- Va 7.74 t, 111, 7.80 Cd, IH), 10.37 (br. a, 1W); 1?.91 (br.

a, 1H); El-MS 396.1 WPLC-Method B, Rt 9.88 min.

Ex pe 114 (7-Fluoro-1H-indazol-3-yl) tri fluoromethyl -phenyl) -6,7 -dihydro Oyclopentapyrimidin4-y1-amine (II-114): Prepared in n yield. 'BNMR (500MHz, DMSO-d) 82.15 2H), 2.87 (m,

IN

cl 2H), 2.97 2W), 6.99 (td, 1H), 7.17 (dd, IN), 7.38 (d, 7.65 2H), 7.71 1H), 7.78 Cd, 1H), 10.21 Cbr.

IND 10 s, 1W), 13.40 (br. s, iN); El-MS 414.1 HPLC-Method C, Rt 9.99 min.

Example 115 (5,7.7Difluro-1H-indazoi-3-yl) (2trifluoromethyl-piayl)-6,7-dihydro-SHcyclopentapyrimidin-4-y1 -amine (11-115): Prepared according to Method C in 52k yield. 'hNMR (50014Hz, DMSOdE) 8 2.16 2H), 2.89 Cm, 2H), 2.97 2H), 7.19 (ad, IR), 7.29 (td, 1H), 7.63 1H), 7.66 1H), 7.71 (t, lW), 7.78 Cd, 1H), 10.16 Cbr. a, iN), 13.55 (br. a, 1W); BI-MS432.1'.M+H), HPLC-Method C, Rt 10.09 min.

Example 116 (2-Chioro-phenyl) -6,7-dihydro-Sacyclopentapyrimidin-4-yll-(1-indazol-3-yl)-anine (1I- 116): Prepared in 56% yield. 1 HNMR (SOOMHz, DMSO-d6) 52.16 Cm, 2H), 2.85 2H), 3.01 Ct, 2H), 7.06 Ct, IN), 7.34 1H), 7.40 Ct, 15), 7.48 2W), 7.53 IH), 7.56 iN), 7.63 1W), 10.39 (br. a, 1H), 12.91 (s, IH); El-MS 362.1 HPLC-Method A, Rt 3.09 min.

Examle 117 (2-Chioro-phenyl) -6,7-dihydro-SHcyclopentapyrlnidin-4-yl3-(7-fluoro-H-indazol-3-yl)amine (11-117): Preparedin 63% yield. INMR (500MHZ, DMSO-E) 82.15 .2.87 2W), 3.00 0t, 2W), 7.01 Ctd,'1H), 7.19 Cdd, iN), 7.39 1H), 7.45 2H), 7.51 -276- Va od, 1H), 7.55 11), 10.35 Cbr. s,1fH), 13;45 (br. a, Ili); El-MS 380.1 HPLC-Method A, Rt Rt 3.15 min.

Example 118 (2 -Chloro-phenyl) -6 1 7-dihydro-Sa- C-i 5 cyclopetapyrmidin.4.ylJ -(5,7-difluoro-IHndazol.3-yl)amine (11-118): Prepared in 60% yield. lIR4mp (SOoM1z, DMSO-dE) 82.18 Cm, 2H), 2.91 21), 3.01 Ct, 2H), 7.32 Ct, IH) 1.33 (td, 11) 7.41 1H), 7.48 Ct, 1H), .7.53 1R), 7.55 (dd, 1H), 10.35 Cbr. s, IN), 13.45 (br. a, ci 11); EI-MS 398.1 HPLC-Method A, Rt R 3.24 min.

Example 119 (1H-Indazol-3-yl)- (2-trifluoromethylphenyl)-5,6, 7 ,8, 9 ,10-hexahydro-cyclooctapyridin.4.yjjamine (11-119): Prepared in 36% yield. 1 HNMR (5001Hz, DMSo-d) 8 1.47 Cm, 2H), 1.53 2H), 1.78 Cm, 4H), 2.96 Cm, 2H), 3.06 Ct, 21), 7.03 Ct, 11), 7.47 Ct, 11), 7.72 Cd, 11), 7.73 1H), 7.72 Cm, 3H), 7.81 1H), 10.52 Cm, 1H), 12.97 Cbr. a, 1H); El-MS 438.2 CM+1); HPLC- Method A, Rt 3.37 min.

Example 120 (7-Yluoro-1E-indazol-a-yl)-£2- (2trifluoromethyl.-phenyl)-5,6,7,S,9,10-hexahydrocyclooctapyrimii n-4-yll -amine (11-120): Prepared in yield. 1 HN1R C5OOMHz,.DMSO-d6) 8 1.46 2H), 1.52 (m, 21), 1.77 4H), 2.94C-m, 2H), 3.04 cm, 2H), 7.00 Ctd, iS), 7.17 (dd, 11), 7. 30 cd, 1H), 7.70 31H), 7.79 (d; 11), 10.5 cm, 11), 13.49 Cbr a, 11); El-MS 456.1 HPLC-Method A, Rt 3.43 min.

Examle 121 (S,7-Difluoro- 1-inazol-3-yl)-r2...(itrifluoromethyl-henyl)-5,6,7,8,9,10-hesahydro- Cycloootapyrimidin-4-y] -amiine Prepared in 48% yield. 'mNmR (50Maz, DMSO-d6) 8 1.46 Cm, 21), 1.52 Cm, 2H), 1.77 4H), 2.95 Cm, 2H), 3.63 Cm, 2H), 7.14 (d, -277-

IN

oH), 7.30 lU), 7.73 3W), 7.80 1W), 10.5 (m, Ci 11H), 13.62 (br. a, 1H); El-MS 475.1 HPLC-Method A, Rt 3.52 min.

Ex p le 122 [6-Cyclohexyl-2- (2-trifluoromethyl-phenyl) pyrimidin-4-yll- (1H-indazol-3-yl) -amine (3:1-122): Prepared. in 45% yield. 'HNMR (500 MHz, CDC13) 5 1.30 (2H, Cl in), 1.46 (2H, 1.65 (2H, 1.76 (2H, 1.91 (2H, o in), 2.61 (1H, br 7.08 (1H, t, .1=7.4 Hz), 7.27 (1H, d, ~1? J=8.0 Hz), 7.35 (iH, t, J=7.1 Hz), 7.50 (11, t, 1=7.0 Hz), 7.58 (1H, t, Hz), 7.66 7.72 (1W, d, J=7.8 Hz), 8.0 (1H, br), 9.87 (1H, br) ppm; HPLC-Method D, Rt 3.57 min; LC-MS 438.17 (M+H) 4 fxamle 123 Fluoro-phenyl -2-(2-trifluoroiethylphenyl) -pyrimidin-4-yl]-(1H-indazol-3-yl)-amine (11-123): Prepared in 8% yield. 1 HMR (500 MHz, CDC1 3 8 7.18 (3M, 7.37 (1H, 7.43 (1H, t, LT=7.9 Hz), 7.51 (1H, d, J=7.9 Hz), 7.55 (iR, t, J=7.6 Hz), 7.65 (iN, t, J=7.4 Hz), 7.79 (iH, a, t7.9 Hz), 7.85 (i1H, d, J- 7.6 Hz), 8.19 (2H, 8.70 (iN. d, J= 8.5 Hz) ppm; HPLC-Method D, Rt 4.93 min; LC-MS 450.13 Example 124 (G-Fluoro-LE-indamol-3-yl)-[2-(2trifluoroiethyl-phenyl) -quinazolin-4-yl -amine (11-124).

Prepared in DMF' (87% yield) as yellow solid. -IHNM (500 MHz, DMSO-d6) 513.0 11.1 br, 1W), 8.66 (d, iN), 7.95 t, 1H), 7.80 1H), 7.72 21), 7.62 (m, 4H), 7.21 IN), 6.84 (td, iN) ppm. LC-MS CES+) 424.15 HPLC-Method A, Rt 3.05 min.

Example 125 3-[2-(2-Trifluoromethyl-phenyl) -quinazolin-4acid methyl ester (II- 125): To a solution of compound 11-79 (100 mg 0.21. mmol) -278- Va in DMF (2 mL) was added MeOK (1 mL), DIEA (54 uL, 0.31 mmol) and PdC2la(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 o afford II-125 as yellow solid. 'HNMR (500 MHz, DMSO-d6) 813.3 l1), 11.3 br, 1H), 8.70 1K), 8.36 1H), 7.97 1H), 7.82 2H), 7.71 3H), 7.58 2H), 7.51 1H), 3.75 3H) ppm; LC-MS (ES+) 464.13 HPLC-Method A, Rt 3.12 min.

Example 208 (5-Methyl-2H-pyrazol-3-yl)-[2-(2-naphthyl-1yl)-quinazolin-4-yll-amine (II-208): 1 HNMR (500 MHz, DMSOd6) 88.92 1K), 8.73 8.39 11), 8.09 (m, 2H), 7.95 7.62 3H), 6.78 1H), 2.32 (s, 3H); MS 352.2 Example 209 (2-Chloro-phenyl)-pyrido2,3-dpyrinidin- 4-yl] (7-fluoro-lH-indazol-3-yl)-aamine (11-214): Prepared, from 4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d pyrimidine (100 mg, 0.36uimol) and 7-Fluoro-1H-indazol-3-ylamine (108mg, 0.72mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (93 mg, 46% yield). HPLC-Method A, Rt 3.04 min;'H NMR (DMSO, 500 MHz): 8 13.67 (1K, 11.40-11.25 (1K, bs), 9.35- 9.25 (2H, 7.95 (1H, 7.80-7.47 7.35(1K, 7.15 MS MH* 391.1.

Example 210 [2-(2-Chloro-phenyl)-pyrido[2,3-djpyrimidin- 4-yl] (5-fluoro-IH-indazol-3-yl) -amine (11-215): Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido(2,3-d -279pyriinidine (100 mg, 0.3Einiol) and 5-Fluoro-1H-indazo.-3- CI ylamine (108mg, Otl72iniol) Purification by preparative Ct HRPLC af forded the'; title compound as -a yellow, di-TFA salt rug, 22W yield) WPLC-Method A, Rt 3.00 mini; 1H NI'& (DMSo, 500 ME-z): 8 13.0 (1W, 10.90(1W, be), 9.15-9.05 (2H, in), 7.70 (1H. mn), 7.60-7.30- (EH, mn), 7.20 (1W, MS rMgr 3.91.1.

cIN 0 Examle 211 (2-Chioro-phenyl) -pyrido.[2,3-dlpyrimidin- IND1 4-yl]-(5,7-difluoro-1H-ndazol-3-yl)-aAine. (11-216): o Prepared from '4-ChJloro-2- (2 -chlororphenyi) -pyrido 12,3-_ dlpyrimidine (100 mug, 0.3Emmol) and 7-Difluoro-1Hindazol-3-ylamine (112mg, O.E6mmol). Purification by preparative WPLC afforded. the title compound as a yellow, di-TFA salt (130 mg, 62% yield). WPLC-Method A, at 3.12 mini; 'H NMR (DM50, 500 M4Hz):. 13.80-13.60 (1H, be), 11.30- .11.10 (1W, bs), 9.20-9.10 (2W, at), 7.80 (1W, mn), 7.60- 7.30 (6H, in); MS MH* 409.1.

Example 21.2 12- (2-Chloro-phenyl) -pyridol3,4-djpyr-imidin- 4-ylJ-(1t-indazol-3-yl)-amine (11-217): Prepared from 4- ChLoro-2- (2-chioro-phenyl) -pyrido 4-djpyrimidune (100.

tag, 0.3Einmol) and 1H-indazol-3-ylaiine (88mg, 0.G6rnmol) Purification by preparative HPLC afforded the tit-le .compound as a yellow, di-TFA salt (72. mng, 33% yield).- HPLC-Method A, Rt,.3.21 min; 'H NY4R (DMSO, .500 MHz): 12.95 (1WE, 10.90 (1W, be), 9.25 (1H, s),'8.75 (1W, (1W, 7.65 (1W, mn), 7.55 (1H, mn), 7.50-7.30 (SH, Mn), 7. 00 (1W, mt) MS z) ME+ 3 73. 1.

Example 213 12- (2-Chiloro-phenyl) -pyride (3,4-dipyrimidin- 4-yl (7-fluoro-1H-indazol-3-yl)-nmine (11-218): Prepared from 4-Chloro-2- (2-chloio-phenyl) -pyrido pyriiine (100 mg, O.3Einmol) and 7-Fluoro-1H-indazol-3-ylamine -28.0- Va o(108mg, 0.72mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt G (48.7 mg, 22% yield). HPLC-Method A, Rt 3.35 min; 211 NMR (DMSO, 500 MHz): 8 12.95 (1H, 10.90 (1H, bs), 9.25 (1H, 8.75 (1H, 8.55 (IH, 7.70-7.35 (5H, m), 7.25(1H, 6.95 MS MH 391.08.

Va Example 214 [2-(2-Chloro-phenyl)-pyrido 3,4-djpyrimidin- 0g 4 -ylJ-(5-fluoro-1b-indazol-3-yl)-amine (11-219): Prepared o 10 from 4-chloro-2-(2-chloro-5-fluoro-1H-indazol-3-ylamine S(108mg, 0.72mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (57.2 mg, 26% yield). HPLC-Method A, Rt .3.27 min; 1 H NMR (DMSO, 500 MHz): 8 13.05 (lH, 10.95 (1H, 9.25 8.75 (1H, 8.55 (1Hi; 7.60 (1H, 7.55 7.50-7.30 (5H, 7.25(1H, MS MH* 391.1.

Example 215 [2-(2-Chloro-phenyl)-pyrido 3,4-d pyrimidin- 4 -yl]-(5,7-difluoro-1H-indaol-3-yl)-knine (11-220): Prepared from 4-chloro-2-(2-chloro-7-difluoro-1H-indazol- 3-ylanine (112mg, 0.66mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (57.2 mg, 26% yield). HPLC-Method A, Rt 3.45 min; 'H NMR (DMSO, 500 MHz): 8 13.65 (1H, 11.0 9.25 (1H, 8.80 8.50 (1H, 7.60 (11, 7.55 (1H, 7.50-7.30 (5S, MS MW* 409.1.

Example 216 6-Fluoro-1H-indazol-3-ymine HfNMR (500 MHz, DMSO-d6) 811.4 1H), 7.68 (dd, 1H), 6.95 (dd, 1H), 6.75 (td, 1H), 5.45 2H) ppm; LC-MS (ES+) 152,03 HPLC-Method A, Rt 2.00 min.

-281- Va UExale 217 S-Fluoro-1H-indazol-3-ylamine lHNMR (500 MHz, DMSO-d6) 811.3 1H), 7.43 1H), 7.2 (m, 1H), 7.08 Cm, IH), 5.29 2H) ppm; tC-MS 152.01 CM+H); HPLC-tethod A, Rt 1.93 min.

C

Example *218 i5,-7-Dffluoro-1-indazol-3-yl-amnle (A3) lHNMRt V) (.00 MHz, CD 3 OD) 67.22 Cdd,=2.0,. 8.45Hz, IH), 7.04-6.87 Cm, IB); LC-MS CES+) 169.95 HPLC-Metbod C, R. 2.94 min

C

NO o Example 219 7-Fluoro-1H-indazol-3-ylamine 1 HNMR (500 M4Hz, DMSO-d) 811.8' IH), 7.42 1H), 6.97 Cm, iN), 6.78 Cm, 111), 5.40 Cs, 2H) ppm; LOMS 152.01 HPLC-Method A, Rt 2.00 min.

is Example 220 7-Fluoro-6-trifluoromethy1-1f-iidazo1-3ylamine H-NMR (50014Hz, DMSO) 8 12.5 111), 7.75 1H), 7.25 Cm, 1H), 5.85 1H) ppm; MS (FIA) 220.0 HPLC-Method A, Rt 2.899 min.

Example 221 6-Bromo-1H-indazoi-3-ylamine 1 H-NMR (50,0 MHz, DMSO) 5 11.5 IH), 7.65 1H), 7.40 iH), 7.00 iH), 5.45 (br a, IN) ppm; MS (FIA) 213.8 HPLC-Method A, Rt 2.441 min.

txample 222 4-Fluoro-1s-indazol-3-ylamine 1

H-NMR

(500 MHz, DMSO) 8 11.7 11), 7.17 1H), 7.05 (d, iH), 6.7 Cbr, 1H), 6.60 (dd, 5.20 (br a, 2H) ppm; MS (FIA) 152.0 Method A, Rt 2.256 min.

Example 223 5-Bromo-1H-indazol-3-ylamine 'H-NMR (500 MHz, DMSO) 8 11.55 Cbr a, 1H), 7.95 1H), 7.30 (d, -282- Va o 7.20 1W), 5.45 (br s, 2H) ppm; MS (FIA) 213.8 Method A,.Rt 2.451 min.

Example 224 5-Nitro-1B-indazol-3-ylamine IH-NMR (500 MHz, DMSO-d6) 8 9.00 1H), 8.20 1i), 7.45 1W), 6.15 -(br 1H) ppm; Method A, Rt 2.184 min Va SExample 225 4-Pyrrol-1-yl-ll-indazol-3-ylamine Cl NMR (500 MHz, DMSO) 8 7.20 2W), 7.00 2H), 6.75

NO

o 10 1H), 6.25 2H), 4.30 1H) ppm; Method A, Rt Cl 2.625 min.

Example 226 4-Chloro-5,6-dimethyl-2-(2-trifluoromethylphenyl)-pyrimidine Prepared to afford a colorless oil in 75% yield. 1H-NMR (500 MHz, CDC13) 8 7.70 (d, J=7.8 Hz, IH), 7.64 J=7.6 Hz, 1H), 7.55 J=7.6 Hz, 1W), 7.48 J=7.5 Hz, 1H), 2.54 3H), 2.36 3H) ppm; MS (FIA) 287.0 HPLC-Method A, Rt 3.891 min.

Example 227 4-Chloro-2- (2-chloro-phenyl)-5,6-dimethylpyrimidine Prepared to afford a yellow-orange oil in 71% yield. 'H-NMR (500 MHz, CDC13) 8 7.73 iH), 7.52 1H), 7.39 2H), 2.66 3H), 2.45 3H) ppm; MS (FIA) 253.0 HPLC-Method A, Rt Rt 4.156 min.

Example 228 4-Chloro-6-methyl-2-(2-trifluoromethylphenyl)-pyrimidine Prepared to afford a pale yellow oil in 68% yield. 'H-NMR (500 MHz, CDC13) 8 7.72 (d, J=7.8 Hz, 1H), 7.65 J-7.9 Hz, 1H), 7.57 Jc7.5 Hz, 1H), 7.52 T=7.8 Hz, 1H), 7.16 1H), 2.54 3H) ppm; MS (FIA) 273.0 HPLC-Method A, Rt 3.746 min.

-283- Va o Example 229 4 -Chloro-6-cycloexyl-2-(2-trifluormethyl- C- phenyl)-pyrimidine Prepared to afford a yellow oil in 22% yield. 1H-NMR (500 MHz, CDC3) 5 7.70 2H), 7.57 J=7.5 Hz, 1H), 7.50 J=7.5 Hz, 18), 7.19 (s, S 1H), 2.65. 1H), 1.9 2H), 1.8 2K), 1.5 2H), 1.3 2H), ppm;--MS (FA) 341.0 Va Example 230 4-Chlore-6-phenyl-2-(2-trifluoromethylo phenyl)-pyrimidine Prepared to afford a yellow oil 010 in 53% yield.. 'H-NMR (500 MHz, CDC13) 6 8.08 (dd, J=7.9, 1.6 Hz, 2H), 7.80 J=7.6 Hz, 1H), 7.77 J=7.8 Hz, 1K), 7.67 13), 7.61 J=7.5 Hz, 1H), 7.54 J=7.6 Hz, 1H), 7.47 3H) ppm; MS (FIA) 335.0 HPLC- Method A, Rt 4.393 min.

Example 231 4-Chloro-2-(2,4-dichloro-phenyl)-5,6dimethyl-pyrimidine Prepared to afford a white solid in 91% yield. 'H-NMR (500 MHz, CDC13) 8 7.62 (d, J=8.3 Hz, 1iH), 7.43 J=7.0 Hz, 1H), 7.27 (dd, J=8.3, 2.0 Hz, 11), 2.55 3H), 2.35 3H) ppm; MS (FIA) 287, 289 HPLC-Method A, Rt 4.140 min.

Example 232 4-Chloro-6-(2-chloro-phenyl)-2-(2trifluoramethyl-phenyl)-pyrimidine Prepared to affod a yellow oil in 52% yield. H-NMR (500 MHz, CDC13) 6 7.75 3H), 7.65 2H), 7.53 1H), 7.44 1K), 7.36 2H)'ppm; MS (FIA) 369.1 HPLC-Method A, Rt 4.426 min.

Example 233 4-Chloro-6-(2-fluoro-phenyl)-2-(2trifluoromethyl-phenyl) -pyrimidine (B8) :-Prepared to afford a yellow oil in 95% yield. 'H-MR (500 MHz, CDC13) 6 8.24 J=7.9 Hz, 7.84 1H), 7.78 J-7.7 -284- Va Hz, 1H), 7.76 J=8.0 Hz, 1W), 7.60 J=7.5 Hz, 1H), 7.53 J=7.6 Hz, iH), 7.43 1H), 7.23 J=7.6 Hz, in), 7.13 Cm, 1) ppm; MS (FIA) 353.0 CM+H).

(N 5 Example 234 4-Chloro-6-pyridin-2-yl-2-(2-trifluoroethylphenyl) -'pyrimidine Prepared to afford a pale yellow solid in 50% yield. 'H-NMR (500 MHz, CDC13) 8 8.68 (m, 1H), 8.48 Cdd, J=7.9; 0.8 Hz, 1W), 8.38 Hz, 0 111), 7.84 Cm, 7.62 J=7.6 Hz, 7.55 J=7.6 Hz, 11), 7.38 1H) ppm; MS (FIA) 336.0 HPLC- 0~ Method A, Rt 4.575 rin.

Example 235 6-Eenzyl-4-chloro-2-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydxo-pyrido[4,3-dlpyrinidine 1 H3MR (500 MHz, CDC1 3 87.70 11), 7.62 1H); 7.55 1H), 7.48 Ct, 1H), 7.32 Cm, 4H), 7.25 IH), 3.74 2H), 3.66 Cs, 2H), 2.99 2H), 2.80 2H) ppm; LCS (ES4) 404.17 HPLC-Method Rt 3.18 min.

Example 236 7-Benzyl-4-chloro-2- (2-trifuoromethyl-, phenyl) 8-tetrahydro-pyrido[3,4-dlpyrimidine (B11): 1 HNJ4R (500 MHz, CDC 3 67.69 1W), 7.60 1H), 7.54 Ct, 1H), 7.47 Ct, 1H), 7.28 Cm, 4H), 7.20 Cm, 1H), 3.68 Cs, 2H), 3.67 2H), 2.86 Ct, 2W), 2.79 2H) ppm. MS 404.18 HPLC-Method A, Rt 3.12 min.

Example 237 4-Chloro-2-(4-fuoro-2-trifluoronethylphenyl)-quinazoline (B12): HISMR (50014Hz, CD30D)6 8.43 Cd, .=8.1Hz, 1W), 8.20-8.05 Cm, 2W), 8.05-7.82 Cm, 2H), 7.71-7.51 Cm, 2H). LC-MS (ES) 327.09 CM+H). HPLC-Method D, R, 4.56 min.

-285oN Ex~ale 238 4 -Chloro 2-.(2-ch:loroes-ttrifluoreehy..

0 phenyl)-quinazoine (313): LC-MS 342.97 (14+1).

HPLC-Method D, Rt 4.91 min.

Exarppie 239 4 -Chloro-2-(2-chloro-4-nitro.phenyl).

quinazoline (314) :jj.C-MS 319. 98 -HPLC-Method DRt 4. 45 min.

ExaM2jQ24 4-Chloro.-2- (2-trifluoromethyl-phenyl) quinazoline (315): Prepared in 57% yield. White solid. o tbtHvR (500M~z, DMSO-dE) 8 7.79 1H), 7.86 13), 7.94 Cm, 3H), 8.15 (dd, in), 8.20 (td, in), 8.37 IH); SI- MS 308.9 (M4).

.Exa mple 241 4-Chloro-2- (2-trifluoromethyl-lanyl) -6,7- (316): Prepared in 22% yield. 13NMR (50014Hz, DMSO-dE) 8 2.19 3.01 Ct, 3.08 213), 7.49 13), 7.55 113), 7.62 (d, 13), 7.71 13). El-MS 299.0 Example 242 4-Chloro-2- (2-ahioro-phenyl) -6,7,8,9tetrahydro -53-cycloheptapyrizmidine' (317): Prepared accordling to Method C in 82% yield to afford a white solid. ',Nmm (50014z, ODcd 3 6 1.67 (M 4H), 1.87 (m 23), 3.02 (m 43), 7.28 Cm, 2H), 7.40. 7.65 1H); El-MS 293.0' (M+i1).

Example 243 4-Chloro-2- (2-trifluoroznethyl-phenyl) 5,6,7, S8,lO1-hexahydro-cyclooctapyrimidine (318): Prepared in .3 8% yield. to af ford a brown oil. YNMR (500MHZ,. ODC 3 8 1.35 (m 2H) 1.41. (m 2H), 1.76 (m 4H) 2.96 Cm, -4H1), 7. 48 1R) 7. 56 C t, ID), 7.6 9 d, 1H) 7.70 1W) EI-14MS 341. 0 (14+1).

-286- Va Example 244 4-Chloro-8-methoxy-2-(2-trifluoramethylphenyl)-quinazoline (319): Prepared from 8-methoxy-2-(2trifluoromethyl-phenyl) -3H-quinazolin-4-one 3.12mmol), triethylamine hydrochloride (472mg, 3.43mmol), and POC1. Purification by flash chromatography afforded a white solid (89% yield). HPLC-Method A, Rt 4.10 min, V' MS 258.08 ci o Example 245 2- (4-Chloro-quinazolin-2-yl) -benzonitrile IN 10 (B20): Prepared to afford a yellow solid in 1.5% yield.

o 'H-NNR (500 MHz, CDC13) 8 8.47 11), 8.24 1H), 8.16 8.07 (impurity), 7.94 1H), 7.92 (impurity), 7.86 1H), 7.68 2H), 7.65.(impurity), 7.54 (impurity), 7.49 1H), 4.2 (impurity), 1.05 (impurity) ppm; MS (LC/MS) 266.05 HPLC-Method A, Rt 3.88 min.

Example 246 6-Methyl-2-(2-trifluoromethyl-phenyl)-35-.

pyrimdin-4-one Prepared to afford a yellow solid in 50% yield. 'H-NMR (500 MHz, DMSO-d) 6 12.7 (br a, 1H), 7.9 1H), 7.8 2H), 7.7 11), 6.3 2.21 3H) ppm; MS (FIA) 255.0 HPLC-Method A, Rt 2.578 min.

Example 247 6-Cyclohexyl-2- (2-trifluoromethyl-phenyl) -3Hpyrimidin-4-one Prepared to afford an off-white solid in 54% yield. 1 H-NMR (500 MHz, DMSO-d6) 8 12.9 (br 1H), 7.9 4H), 6.3 1H), 2.5 1.9 (m, 1.4 5H) ppm; MS (FIA) 323.1 (M+H);HPLC-Method A, Rt 3.842 min.

Example 248 2-(2-Chloro-5-trifluoramethyl-phenyl)-3Hquinazoli-4-one nmiR (500MHz, CD30D) 8 8.32-8.25 1R), 8.01 7.91-7.72 1H), 7.66-7.55 (m, -287- Va LC-MS 325.01 HPLC-Method'D, Rt 3.29 min.

Example 249 2- 4 rrluoro-2-trifluormsthyl-phenyl) -3Hquinazoln-4-oe: (D14): 'HNMR (SOOMHz, CD0D) 6 8.28 (d, 1H) 7.94-7.84 1H), 7.84-7.77 11), 7.76n 7.67 2H), 7.65-7.53 2H). LC-MS CES+) 3.09.06 Va Ci HPLC-Method D, Rt 2.88 min.

NO 10 Example 250 2- (4,Nitro-2-chloro-phenyl) -3H-quinazolin-4one (D1S)± LC-MS 302.03 HPLC-Method D, Rt 2.81 min.

ExaIph 251 2-(S-Fluoro-2-trifluoromethyl-phenyl)-3Kquinazolin-4-vne (D17): 1 HNMR (500MHz, CDOD) 8.28 Cd, ,Rt J=8.05Hz, lH), 7.96 (dd, J=5.05, 8.55Hz, 1H), 7.89 (t, JT=7.9Hz, 1H), 7.78-7.69 7.66-7.46 C(m, 3H). LC-MS CES+) 309.14 HPLC-Method D, Rt 2.90 min.

Example 252 (1Z-Indazol-3-yl) (2rphenyl-quinazolin-4-yl) amine Prepared by Method A in DMF to afford mg (50% yield) as pale yellow solid. 1H NMR (500 MHz, DMSO-d) 513.1 br, fl), 8.48 1H), 7.91 2H), 7.76 (br, 2H), 7.45 2H), 7.36 1H), 7.20 Cm, 4H), 6.86 Ct, 1H),ppm. MS CES+) 338.07 (MiH); 336.11 (M- HPLC-Method A, Rt 2.88 min.

Example 253 (5-Methyl-2H-pyrazol-3-yl)- (2-phenyl-5,6,7,8tetrahydroquinazo'in-4 -yl)-amine Prepared according to Methiod A. NNR (500 MHz, DMSO-d) 812.1 Cs, br, 1H), 8.70 br, 1H), 8.37 Cd, J 6.7 Hz, 2H), 7.54 3H), 6.6.7 Cs, 1H), 2.82 Cm, 2H), 2.68 2H), 2.37 3H), 1.90 br, 4H); MS 306.1 -288- Example 254 (S-Methy1-2H-.:yrazo1-3-y1) -(2-phenyl-6,7,s,9ter(dr-Ncylhp.prmdi- l)aie (111-8): MS 320.48 HPLC-Method E, Rt 1.124 min.

Exarpe2s. (5-Methyl-23-,pyrazo-3.yl) -(2-pyridin-4-ylquinazolin-4-yl):-amine, (111-9): Yellow solid, mp 286kn 289 0 C, 'H NNR (DM50) B 2.35 6.76 7.61 (11!H, 7.89 mn), 8.32 6.70 dl, 6.78 0 d) 10.55 (1H, -br s) 12.30 br IR (solid) 1620,.1558, 1571, 1554, 1483, 1413, 1370, 1328; MS 303.2 Example 256 (7-Chloro-2-pyri~in-4yl-qunazoln4yl) flethy1-2S-pyrazol73-y1) -amine (111-28): 'H NMR (DMSO-dE)B 2.35 6.75: s) 7.65 7.93 (11, s), 8.30 8.73 8.79 10.69 (in, s), 12.33'(1H!, MS m/z 337.2 Example 257 (6-Chlorc-2-pyridin-4-yl-quinazolin4.yl) Methy 1-2E-pyrazo-3-y).aaine (111-29): 'H NMR (D)MS0-d6l a 2.31 (31, 6.74 7.89 (III, 8.30 d), 8.80 8.91 10.63 12.29 s); MS 337.2 (M+H)t.

Examle 258 (2-Cyolohexyl-quiLnazoln-4.yl) (-methyl-2Hpyrazol-3-yl)-amine (111-30): 'H NMR (IDM50) 8.2.35 (3H!, 1.70 1.87 1.99 dl, 2.95 (1H, 6.72 7.75 7.88 7.96 (18, 8.83 1.1.95 (111, 12.70 (1H, MS 308.4 Rxampl& 259 (5-Methyl-20-pyrazol-3-yl) -(2-phenylquinazolin-4-yl)-amine (111-31): mp 246 0 C; 1H NMR (400MHZ) -289- O 8 2.35 (3H, 6.70 (1H, br 7.51-7.57 (4H, 7.83- 7.84 (2H, 8.47-8.50 (2H, 8.65 (1H, 10.4 (1H, 12.2 (1H, bs); IR (solid) 3696, 3680, 2972, 2922, 2865; MS 302.1 C( Example 2 60 .[2-(4-lodophenyl) -quinazolin-4-yl S2H-pyrazol-3-yl)-amine (III-32): H NMR (DMSO-d6) 8 2.34 C- (3H, 6.72 (1H, 7.56.(1H, 7.84 (2H, 7.93 C (2H, 8.23 (2H, 8.65 (1H, 10.44 (1H, 12.24 (1H, MS 428.5 Example 261 (3,4-Dichlorophenyl) -quinazolin-4-yl methyl-2H-pyrazol-3-yl)-amine (III-33): A suspension of 2-(3,4-dichloro-phenyl)-3H-quinazolin-4-one (1g, 3.43mmol) in phosphorus oxychloride (4 mL) was stirred at 1100C for 3 hours. The solvent was removed by evaporation and the residue is treated carefully with cold aqueous, saturated NaHC03. The resulting solid was collected by filtration and washed with ether to afford 4-chloro-2- (3,5-dichloro-phenyl)-quinazoline as a white solid (993 mg, To the above compound (400mg, 1.29 mmol) in THF (30 mit) was added 3-amino-5-methyl pyrazole (396 mg, 2.58 mmol) and.the resulting mixture heated at overnight. The solvents were evaporated and the residue triturated with ethyl acetate, filtered, and washed with the minimum amount of ethanol to afford compound II-33 as a white solid (311 mg mp 274°C; 1H NMR (DMSO) 2.34 (3H, 6.69 (1H' 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 IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797,.764, 738; MS 370.5 -290- Va Example 262 [2-(4-Bromophenyl)-quinazolin-4-yll-(5methyl-2H-pyrazol-3-yl)-amine (111-34): mp 262-265 0

'H

wMR (DMSO) 5 2.34 (S38, 6.73 (iH, 7.55 (i1H, m), 7.74 (2H, 7.83 (2H, 8.40 (2H, 8.65 d), 10.44 (1I, 12.25 (1H, IR (solid) 1603, 1579, 1546, 1484, 1408,.1365; MS 380.1/382.1 Va Example 263 [2-(4-Chlorophenyl)-quinazolin-4-yl]-(5- 0 methyl-2-pyrazo-3-yl)-amlne (II-35): mp >3000C; 1 NMR Cl o 10 (DMSO) 8 2.34 (3H, 6.74 (1H, 7.53-7.62 (3H, m), 0g 7.84 (2H, 8.47 (2H, 8.65 (1W, 10.44 (1i, a), 12.26 (1W, IR (solid) 1628, 1608, 1584, 1546, 1489, 1408, 1369, 1169; MS 336.2 Example 264 [2-(3,5-Dichlorophenyl)-quinazolin-4-yl]-(5methyl-2H-pyrazol-3-yl)-amine (111-36): mp 228 0 C; 1'H NM (DMSO) 8 2.34 (3H, 6.69 (1H, 7.96 (1H, 8.21 (3H, 8.56 (1H, 8.60 (2H, 10.51 (1i, 12.30 IR (solid) 1546, 1331, 802, 763,.729, 658, 652;.

MS 370..5 Example 265 [2-(4-Cyanophenyl)-quinasolin-4-yl] methyl-2B-pyrazo-3-yl)-amine (111-37): mp 263WC; 'H NMR (DMSO) 8 2.34 (3H, 6.72 7.61 (iH, 7.88 (2H, 8.04 (2H, 8.63 (2H, 8.67 (1H, 10.52 (1H, 12.27 (1H, IR (solid) 1739, 1436, 1366, 1229, 1217; MS 327.2 Example 266 [2-(3-lodophenyl)-quinazolin-4-yll-(5-methyl- 2 H-pyrazol-3-yl)-amine (111-38): mp 234-235C; H NMR (DM0) 8 2.35 (3H, 6.73 (1H, 7.35 (1H, 7.56 (in, 7.85 (3H, 8.47 (1H, 8.65 (1W, 8.86 -292- Va o (1K, 10.49 12.28 br IR (solid) 0 '1560, 1541, 1469, 1360; MS 428.1 Example 267 (4-Ethylsulfanylphenyl)-quinazolin-4-yll- (S-methyl-2-pyrazol-3-yl)-amine (111-39): mp.229-231OC; 1H NMR (DMSO) 8 1.29 (3H, 2.35 (3H, 3.07 (2H, q), In 6.76 (1H, 7.43 (2H, 7.51 (1H, 7.81.(2H, m), Va C] 8.41 (25, 8.64 (1H, 10.38 12.24 (15, br SS8); IR (solid) 1587, 1574, 1555, 1531, 1484, 1412, 1369; ND 10 MS 362.1 Example 268 (5-Cyclopropyl-2r-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-40): mp 218-219*C; 1H NMR (DMSO-d6) 8 0.70-080(2H, 0.90-1.00 (2H, 6.70 (11, 7.45-7.55 (45, 7.80-7.85 (2H, 8.45-8.55 (2K, 8.65 (11, 10.40 (1H, 12.27 (1H, IR (solid) 1624, 1605, 1591, 1572, 1561, 1533, 1479, 1439, 1419, 1361,1327, 997, 828, 803, 780, 762, 710; MS 328.2 Example 269 [2-(4-tert-Butyphenyl)-quinazolin-4-ylJ-(5methyl-2H-pyrazol-3-yl)-amine (II-41): mp >300*0; 'H NMR (DMSO-d6) 8 1.35 (91, 2.34 (3H, 6.79 (11, s), 7.55 (3H, 7.85 (2H, 8.39 (2H, 8.62 (15, d), 10.35 (15, 12.22 (1H, IR (solid) 1603, 1599, 1577, 1561, 1535, 1481, 1409, 1371, 1359,. 998, 841, 825, 766, 757; MS 358.3 Example 270 [2-(4-Chlorophenyl) cyclopropyl-25-pyrazol-3-yl)-aine (111-42): 1H NMR (DMSOd) 8 0.77 (4H, br m) ,2.05 (11, 6.59 (15, 7.60 (1H, 7.85 (25, 7.91 (2H, 8.22 (2H, 8.65 (1H, 10.51 12.33 MS 362.1 -292- Va Example 271 (2-Benzo(1,3]dioxo-5S-yluinazo1±n -4.y1) methyl-25-pyrazol-3 -yl) -amine (111-43): 1 H NMR (DMSO) S 2.33 6.13 (2H, 6.78 7.11 (iN, d), 7.80 (iN, 7.94 (1H, 8.09 (3H, 8.25 (i1H, a), 10.34 (111, 12.21 (1H, MS 346.5 Example 272 (4 -Dime thylaminophenyl) -quinazolin-4-yl -methyl-2H-pyrazol-3 -yl) -aine (II.144) 1 H NMR (DMSO- 0 d) 8 2.02 (6H, s),'2.39 6.83 (i1H, 7.71 (iF, 7.98 8.04 (2H, 8.33 (2H, 8.67 (iN, 0a), 11.82 (1H, 12.72 (iN, MS 345.3.(M+H)+.

Example 273 (3-Methozyphenyl) methyl-23-pyrazol-3-yl)-amine (111-45): mp 226WC; 'H NMR (DMSO)-8 2.34 3.92 (3H, 6.72 (iN, 7.21 (1H, 7.57 AlI, 7.79 (1H, 8.02 (3H, 8.14 (iN, 8.79 (IN, 10.39 12.'22 (1H, IP (solid) 1599, 1572, 1538, 1478, 1427, 1359, 833, 761, 661; MS 332.2 Example 275 (5-Cyclopropyl-2f-pyrazol-3-yi)-[2-(3,4dichiorophenyl) -quinazolin-4-yl] -amine (111-46): 1 N NMR (DMSO-ds) 8 0.86 (2H, 1.02 (2H, 1.6. m), 6.56 (iN, 7.57 7.84 (4H, .8.40 d), 8.58 (11, s)i 8.64 (iN, 10.53 12.36 (111, a); MS 396.0 Examfle 276 (2-Diphenyi-4-yl-quinazolin-4-yl)-(5-methyl- 2H-pyrazoi-3-yl)-amine (111-47)': To a mixture of broio-phenyl)-quinazolin-4-ylJ- (5-iethyl-2H-pyrazol-3yl)-amine (111-34) (196 mg, 0.51 mml) and phenylboronic acid (75 mg, 0.62 mmcl) in THF:water 4 mL)'was added Na 2

CO

3 (219 nig,'2.06 mmcl), triphenyiphosphine (9mg, 1/15 mol%) and plladium acetate (1 mg, 1:135 molt'). The -293-

IN

o resulting mixture was heated at 800C overnight, the C- solvents were evaporated and the residue purified by cflash chromatography (gradient of dichloromethane:MeOH) Sto afford III-21 as a yellow solid (99 mg, ,H NMR 5 (DMSO) 6 2.37 (3H, 6.82 (1H, 7.39-7.57 (4H, m), -7.73-7.87 (6H, 8.57 8.67 (1H, 10.42 (1H, g 8s), 12.27 (1H, MS 378.2 o Example 277 [2-(4-Ethynylphenyl)-quinazolin-4-yl]- \D 10 methyl-2H-pyrazol-3-yl)-amine (III-48): To a mixture of S[2 (4-bromo-phenyl) -quinazolin-4-yl] (5-methyl-2Hpyrazol-3-yl)-amine (III-34) (114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, 1.5 mmol)in DMF (2 mL) was added Cul (1.1 mg, 1:50 mol%), Pd(PPh 3 2 C1 2 (4.2 mg, 1:50 mol%) and triethylamine (121 mg, 0.36 mmol). The resulting mixture was heated at 1200C overnight and the solvent evaporated. The residue was triturated in ethyl acetate and the resulting precipitate collected by filtration. The collected solid was suspended in THF (3 mL) and TBAF (1M in THF, 1.leq) was added. The reaction mixture was stirred at room temperature for 2 hours and the solvent evaporated. The residue was purified by flash chromatography (silica gel, gradient of DCM:MeOH) to afford III-48 as a white solid (68 mg, H NMR (DMSO) 5 2.34 (3H, 4.36 (1H, 6.74 (1H, 7.55 (1H, 7.65 (2H, 7.84 (2H, 8.47. (2H, 8.65 (1H, di, 10.43 (1H, 12.24 (1H, MS 326.1 Example 278 (3Ethynylphenyl)-quinazolin-4-yl]- methyl-2H-pyrazol-3-yl)-amine (III-49) mp 204-2070C;. H NMR (DMSO) 6 2.34 (3H, 4.28 (IH, 6.74 s), 7.55-7.63 (3H, 7.83-7.87 (2H, 8.49 (1H, 8.57 (1H, 8.65 (1i, 10.46 (1H, 12.27 (1H, IR -294- VO ID o (solid) 1598, 1574, 1541, 1489, 1474, 1422, 1365; MS 326.1 Example 279 (3-Methylphenyl)-quinazolin-4-yl]- N 5 methyl-2H-pyrazol-3-yl)-amine (III-50): A suspension of 1H-quinazoline-2.,4-dione (10.0 g, 61.7 mmol) in POC13 D mL, 644 mmol) and N,N-dimethylaniline (8mL; 63.1 mmol) was heated under reflux for 2 h. The excess POC13 was Cq removed in vacuo, the residue poured into ice, and the o 10 resulting precipitate collected by filtration. The crude 0 solid product 2,4-dichlbro-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- 3-yl amine (3.2 g, 32.9 mmol)and the resulting mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 4.0 g (93% yield) of (2-chloro-quinazolin-4-yl) pyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of the (2chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine mg, 0.19 mmol) in DMF (1.0 mL) was added m-tolyl boronic acid (0.38 mmol), 2M Na 2

CO

3 (0.96 mmol), and trit-butylphosphine (0.19 mmol). The flask was flushed with nitrogen and the catalyst PdCl 2 (dppf) (0.011 mmol) added in one portion. The reaction mixture was then heated at 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 I-50 as a pale yellow solid (61mg, 'H NMR (500 MHz, DMSO-d6) 812.3 (br s, 1H), 10.4 (br s, 1H), 8.75 1H), 8.30 1H), 8.25 IH), -295- Va 7.78 2H), 7.55 Cm, 1H), 7".45 Cm, 15), 7.35 6.80 15), 2.47 3H), 2.30 Cs, 35); MS 316.1 C1+H).

C

Eaple 280 12-(3,5-Dif lu'rpey)-unz~a4y] =S ethyl -2-pyazol-3 -yl -amine (111-51) H NMR (50 0 MHz, flMSO-d6) 812.3 Cbr s, 10.8 (br a, 8.63 7.95 2H), 7.85 2H), 7.58 Ct, 11), 7.41 6.59' 1) 2.27 35); MS 338.1 Example 281 12-(3-Chloro-4fluoropheyl)-quisazoli-4ylJ (5-methyl-2-pyazol-3-yl) -amine (111-52): NIR (500 MHz, DMSO-dS) 812.4 (br'a, IH), 10.8 (br a, 15), 8.65 (d, 1H), 8.50 15), 8.36 m, 7.85 Cm, 15), 7.60 Cm, 1H), 6.62 15), 2.30 3H); MS 354.1 Example 282 (5-Methyl-2H-pyrazol-a-yl)-(2- (3trif luoromethylphenyl) -quinazolin-4-ylJ -amine (111-53) NMR (500 MHz; DMSO-d) 612.2 (br, 11), 10.45(br, IH), 7.53 15), 7.43 Cd, j 7.2 Hz, 15), 7.06 Cd, J- 8.2 Hz, 1H), 6.65 Cd, J 8.3 Hz, 1H), 6.57 J 7.6 Hz, 1H), 6.51 J 7.8 Hz, 1H), 6.43 Ct, J 7.8 Hz, 6.32 Ct, J 7.6 Hz, 1H), 5.51 1H), 2.03 35); MS 370.2 Example 283 (3-Cyanophenyl) -quinazolin-4-yl] methy-2H-razol..3-yl)-amine (111-54): 'H NMR (500 MHz, DMSO-de) 89.01 Cs, 1H), 8.96 Cm, 2H), 8.28 'J 7.3 Hz,1H), 8.16 br, 2H), 8.06 Ct, J 7.8 Hz, 1H), 7.88 Cm,lH), 6.96 CS, 1H), 2.58 Cs, 3H)fMS 327.1 Ex ple 284 C2- 3-Isopropylphenyl) methyl-2a-pyrazo..-yl) -aimine (111-55): 'H NMR (500 MHz, DMSO-d6) 8.89 J =7.5 Hz, IH), 8.37 1H), 8.26 -296- Va 8.08 (in, 2H), 7.81 br, 2, 7.67H 210, Cl 6.88 Cs, 1H), 3.12 1f1), 2.40 3H), 1.38 Cd, 3 6.-9 Hz, 6H); MS 344.2 Ci 5 ExM2je 285 (5-Methyl-2H-,pyrazol-3-yl) (2-pyridin-3-ylquinazli-4-yl)-amine (111-56): 1 NR (500 .Mz, DM50-d6) Ss.so 1H), 8.84 J 7.3 Hz, 1H), 8.80 J 4'.4 Hz, 1H), 8.66 J 8.2 Hz, 1H), 7.87 2H), 7.77 (m, 0 1H), 7.60 J 7.2 Hz, 1H), 6.67 Cs, 1I), 2.28 (s, 3H); MS 303.1 (M4H)).

Example 286 [2-(3-Acetylphenyl) methyl-2H-pyrazol-3-yl)-amine (111-57): 'H NMR (500 MHz, DMSO-d) 88.80 1K),.8.55 Cd, J 7.7 Hz, 8.42 J 7.6 Hz, 11), 8.00 J 7.0 Hz, 111), 7.76 (m, 7.58 Ct, J 7.7 Hz, 1H), 7.48 br, 1H), 6.60 Cs, 1I), 2.49 3A1), 2.03 31); MS 344.1 Example 287 (tS-Ditrifluoromethylpheyl) -quinazolin- 4-yll-(5-methyl-23-pyrazol-3-yl)-amine (111-58): 'H NR (500 MHz, DMSO-d6) 810.7 br, 110, 8.95 2H), 8.63 J 8.2 Hz, 1H), 8.25 1H), 7.86 Cm, 2H), 7.58 (t, 3 6.9 Hz, 1H), 6.62 1H), 2.26 Cs, 3H); MS 438.1 Example 288 (3-Hydroxyiethylphenyl) -quinazolin-4-ylJ (5-methyl-20-pyrazol-3-yl)- amnne (ii-5 'H NMR (500 MHz, DMSO-d6l 88.74 7 7.9 Hz, 11), 8.33 1), 8.17 br, 1H), 7.95- br, 1H), 7.89 br, 1K), 7.62 Cm, 3H), 6.72 1H), 5.53 1H), 4.60 Cs, 2K), 2.28 3H); MS 332.1 Example 289 (5-Metyl-2H -pyrazol-3-yl)-(2-(3phenoxyphenyl) -quinazolin-4-yl] n+ine (111-60): mp 231- -297- Va 232 0 C; 1H NMRP. (DMSO-d6) 8 2.21 (3H, 6.59 a), 7.10-7.22 (4H, 7.41-7.45 (2H, 7.54-7.59 (2H, m), 7.81 (2H, 8.09 (1H, 8.27 8.64 (1H, m), 10.40 (1H, 12.20 (1H, IR (solid); IR (solid) C- 5 1589, 1560, 1541, 1536, 1484, 1360, 1227; MS 394.7 Example 290 (5-Cyclopropyl-2H-pyrazol-3-yl) C phenoyphenyl)-quinazolin-4-yll-amine (11-61): mp 193- S1950c; H NMR (DMSO-dG) 8 0.67 (2H, 0.93 (21, m),1.87 6.56 (1H, 7.06-7.20 (4H, 7.40-7.43 (2H, 0 7.55-7.59 (2H, 7.81 (2H, 8.11 (1H, 8.27 (1H, 8.63 (1H, 10.43 (1H, 12.26 (1H, IR (solid); IR (solid) 1589, 1574, 1527, 1483, 1369, 1226; MS 420.7 (M+H) t Example 291 (5-Methyl-2H-pyrazol-3-yl) (2-thiophen-3-ylquinazolin-4-yl)-amine (III-62): '1H NMR (500 MHz, DMSO-d6) 811.78 br, 1H), 8.75 J 8.1 Hz, 1H), 8.68 (s, 11), 7.98 (dd, J 7.5 Hz, 7.89 2H), 7.81 1H), 7.68 J 7.5 Hz, 1H), 6.69 1H), 2.30 (s, 3H); MS 308.1 Example 292 (2-Phenyl-qtinazolin-4-yl) (2H-pyrazol-3-yl) amine (III-63): m 247-249oC; 11 NMR (DMSO) 6.99 (1H, br 7.49-7.58 (5Hi 7.81 br 7.83 (2H, m), 8.47-8.49 8.66 10.54 (1H, 12.59 (11, IR (solid) 3145, 2922, 1622, 1597; MS 288.2 Example 293 (25-Pyrazol-3-yl) (2-pyridin-4-yl-quinaolin- 4-yl)-amine (111-64): mtp 285-2860C; 'H NMR (DMSO) 8 6.99 br 7.65 7.81-7.94 (3H, 8.3-8.35 (2H, 8.73 (1H, 8.84-8.90' 10.76 a), -298-

VO

12.6 (1H, s);.IR (solid) 3180, 2972, 1600, 1574; MS 289.2 c Example 294 5-Ethyl-2H-pyrazol-3-yl))-(2-phenyl- C- 5 quinazolin-4-yl)-amine (111-65): mp 221-222C; 'H NMR (DMSO) 8 1.31 (3H, 2.68 (2H, 6.80 (IH, 7.50- \o 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 IND 10 (M+H) 4 Example 295 (2-Phenyl-quinazolin-4-yl)-(5-propyl-2pyrazol-3-yl)-amine (III-66): mp 204-205SC; '1 NMR (DMSOd6) 8 1.02 (3H, 1.66-1.75 (2H, 2.69 (2H, 6.80 (1H, 7.45-7.60 7.80-7.88 (2H, 8.45-8.50 (2H, 8.65 (1H, 10.39 (1H, 12.25 (1H, IR (solid) 1621, 1560, 1572, 1533, 1479, 1441, 1421, 1363, 1328, 999, 827, 808, 763, 709, 697; MS 330.2 Example 296 (5-Isopropyl-2E-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine mp 218-2190C. 'H NMR (DMSO-d6) 8 1.36 (6H, 3.05 (IH, 6..86 (1H, s), 7.48-7.59 (4H, 7.80-7.88 (2H, 8.49-8.58 (2H, m), 8.66 (1H, 10.47 (1H, 12.30 (1H, IR (solid) 3173, 2968, 1619, 1593, 1573, 1533, 1478, 1438, 1413, 1398, 1363, 1329, 995, 822, 798, 761, 707, 666, 659; MS 330.2 Example 297 (5-tert-Butyl-2H-pyrazol-3-yl)- (2-phenylquinazolin-4-yl)-amine (III-68) :mp 136-137C; 'H NMR (DMSO-d6) 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 (1H, d), 10.43 (1H, 12.21 (1H, br IR (solid) 3162, 2963, 1621, 1590, 1572; MS 344.2(M+H) -299- Va Cl Example 298 (5-tert-Butyl-20-pyiazol-3-yl)-(2-pyridin-4yl-quinazolin-4-yl)-anmine (III-69): mp >300 0 C; 'H NMR (DMSO) 1.38 (9R, 6.82 (1H, br 7.63 (1H, m), Cl 5 7.86-7.91 (2H, 8.32-8.33 (2H, 8.69 d), 8.75-8.76 (2H, 10,60 12.31 br IR (solid) 3683, 3149, 2963, 1621; MS 345.2(M+H)'.

o Example 299 (5-Cyclopentyl-2H-pyrazol-3-yl)-(2-phenylquinasolin-4-yl)-atine (111-70): mp 240-241C; 1H NMR o (DMSO-d6) 8 1.68-1.89 (61H, 2.03-2.17 (2H, 3.14- 3.22 (1H, 6.80 (lH, 7.50-7.60 (4H, 7.80-7.89 (2H, 8.45-8.52,(2!, 8.67 10.52 (XH, e), 12.26 IR -(solid) 2957, 1621, 1591, 1571, 1531, 1476, 1438, 1405, 1370, 1325, 999, 951, 801, 775, 761, 747, 710695, 668, 654; MS 356.2(M+H)+.

Example 300 (5-Phenyl-20-pyrasol-3-yl).-(2-phenylquinazolin-4-yl)-amine (111-71): mp 207-209 0 C; 'H NMR (DMSO) 8 7.38-7.40 (1H, 7.50-7.58 (6H, 7.82-7.88 (4H, ml, 8.51 8.67 (1H, 10.58 (1H, 13.11 (1H, br IR (solid) 3345, 3108,. 1627,.1612; MS 364.2 Example .301 (5-Carboxy-20-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (III-72): (5-Methoxycarbonyl-2Hpyrazol-3-yl) (2-phenyl-quinazolin-4-yl)-amine (111-73) (345mg, 1 mmole in THF, 6 mL) was treated with NaCH (M, mL), stirred at 50 0 C for S hours, cooled to room temperature, and neutralised with IM HC1. The mixture was concentrated in vacuo to remove THF then diluted with water and the resulting precipitate filtered. The residual solid was dried at 80 0 C under vacuum to afford III-72 as an off-white solid (312 mg, mp 289-291C -300-

VO

o 1H NMR (DMSO) 8 7.45 (1H, br 7.50-7.60 (SH, 7.80-7.88 (2H, 7.40-7.50 (2H, 8.60-8.70 (IH, Sd), 10.70 (1H, 13.00-13.80 (2H, br IR (solid) 1699, 1624, 1607, 1570,1539, 1506, 1486, 1398, 1333, C 5 1256, 1177, 1004, 827, 764, 705; MS 332.3(M+H) \D Example 302 (5-Methoxycarbonyl-2H-pyrazol-3-yl) C phenyl-quinazolin-4-yl)-anine (III-73): mp 271-273oC; H C] NMR (DMSO) 8 3.95 (3H, 7.50-7.65 (5H, 7.80-7.98 o 10 (2H, 8.40-8.50 (2H, 8.65-8.73 (1H, 10.80 (1H, C 13.80 (1H, IR .(solid) 3359, 1720, 1624, 1597, 1561, 1538, 1500, 1475, 1435, 1410, 1358, 1329, 1283, 1261, 1146, 1125, 1018, 1010, 944, 827, 806, 780, 763, 703, 690, 670; MS 346.3(M+H) Example 303 (5-Hydroxymethyl-2H-pyrazol-3-yl) (2-phenylquinazdlin-4-yl)-amine (III-74): A solution of Methoxycarbonyl-25-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 (Si0 2 methanol-dichloromethane gradient) afforded III-74 mg, 30%) as an off-white solid: mp 238-2390C; IH NMR (DMSO) 6 4;58 (2H, d, CH2), 5.35 (1H, s, OH), 6.94 (1H, 7.50-7.60 (4H, 7.85-7.90 (2H, 8.48-8.54 (2H, 8.69 (1H, 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) -301- Va Cl Example 304 (5-Methoxymethyl-2.H-pyraol-3-yl) (2-phenylquinazolin-4-yl) -amine (111-75): mp 190-191 0 C; 2H NMR (DMSO) 5 3.34 (3H, 4.45 (2H, 7.00 (1H, 7.50- Cl 5 7.62 (4H, 7.82-7.90 (2H, 8.45-8.52 (2H, 8.65 br-s), 10.50 (1H, 12.30 IR .(solid) 3177, 1606, 1589, 1530, 1479, 1441, 1406, 1374, 1363, -1329, 1152, 1099, 999, 954, 834, 813, 766, 707, 691; MS C 332.3(M+H)*.

NO o Example 305 [5-(3-Eydroxyprop-1-yl)-2B-pyrazol-3-yll-(2phenyl-quinazolin-4-yl)-amine (II-76): A solution of benzyloxypropyl-2H-pyrazol-3-yl) (2-phenyl-quinazolin-4yl)-amine (11-78) (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 chromatography (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 164-165OC; 'H NMR (DMSO) 8 1.80-1.90 (2H, Tn), 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 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) t Example 306 [5-(3-Methoxyprop-1-yl)-2E-pyrazol-3-yl] phenyl-quinazolin-4-yl)-mine (III-77): nmp 169-170 0 C; 21 -302-

VO

o NMR (DMSO-d6) 1.86-1.97 (2H, 2.75 (2H, 3.30 (3H, 3.45 (2H, 6.80 (1H, 7.50-7.60 (4H, 7.80- S7.90 (2H, 8.45-8.55 (2H, 8.67 (1H, 10.30 (1H, 12.25 (1H, IR (solid) 1620, 1591, 1572, 1532, Ci 5 1476, 1425, 1408, 1373, 1326, 1117, 1003, 831, 764, 714, 695; MS 360.3(M+H)*.

\o Example 307 [5-(3-Benzyloxyprop-l-yl)-2H-pyrazol-3-yl 0 2 -phenyl-quinazolin-4-yl)-amine (111-78): mp 177-178 0

C;

H NMR (DMSO) 8 1.92-2.03 (2H, 3.76-3.85 (2H, m), (C 3.52-3.62 (2H, 4.51 (2H, 6.82 (1H, 7.28-7.40 7.46-7.58 (4H, 7.80-7.85 (2H, 8.47-8.52 (2H, 8.66 (1H, 10.4.5 (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 (3-Aminoprop-i-yl) -2H-pyrazol-3-yll- (2phenyl-quinazolin-4-yl)-amine (III-79): A solution of (3-tert-butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-yl] (2-phenyl-quinazolin-4-yl)-amine (XII-80) (250mg, 0.56mmol)., in dichloromethahe (3mL) at OOC 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 III-79 as an off-white powder (122mg, mp 205-207OC; 1H NMR (DMSO) 8 1.68-1.83 (2H, 2.65-2.80( 4H, 6.80 (1H, 7.50-7.60 7.80-7.90 (2H, 8.45-8.53 (2H, -303- 8.65 (1W, 10.45 (1W, br IR (solid) 1621, 1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, .1030, 951, 830, 776, 764, 705, 677; MS 345.3(M+H)t.

S ExaMpjj 309 (3 -tert-Eutoxycarbonylamnprop..1.y1) -2K- PYrazol-3-yll-(2-phenyl-quinazolin-4-yl)-amine (111-80): znp 199-200 0 C; 1H NMR (DMSQ) 61.37 (9H, 1.71-1.82 2.67 (2H, 3.00-3.11 (2H, 7.81 (1H, s), o 7.99 (11, 7.50-7.60 (4H, 7.80-7.85 (2H, 8.48- 8.52 (2H, 8.63 (1W, 10140 (11, s),-12.26 (11, m); O ZR (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 (M+eH) Exam-le 310 S-Isopropycarbamoyl2a.-pyrazol-3yl) phenyl-quinazoli.4-yl) -amine (111-83.): 'H NMR (SOOMHz, DMSO-d6) 8 1.20 J 6.6 Hz, GE), 4.13 lW), 7.42 (br. s, 1W), 7.61 (dd, J 7.0, 7.7,Hz, 2K), 7.66 J 7.1 Hz, 1H), 7.71 1E), 7.99 8.39 14), 8.42 J 7.1 Hiz, 2H), 8.74 J 8.2 Hz, 1H), 11.41 (br. s, 11); EI-MS 373.2 HPLC-Method C, Rt 14.09 min.

Example 311 (S-A1ylcarbamoy1-2z-pypazo1.3-yl)- (2-phenylqifazolin-4yl) amjne (111-82): 'H NR (5OOMHz, DMSO-d6) 8 4.02 2H), 5.15 1H),.5.23 1H), 5.94 1H), 7.45 (br. a, 7.60 LT 6.9 Hz, 2H),.7.64 1W), 7.72 IH), 7.98 2H), 8.43 (m 2H), 8.72 J 8.2 Hz, 1H), 8.84 (br. a, 1H), 11.34 (br. a, 1W); El-MS 371.2 'HPLC-Method C, Rt 13.67 min.

Example 312 (2-Methoxyethyloarbamoyl) -2H-pyrazol-3- Y13 (2-pheny-quiazolin-4-yl) -amine (11-B3) 'H NMR -304- Va S(500MHz, DMSO-d) 63.32 3H), 3.48 (ml 4H), 7.36 (br.

s, 1H), 7.62 2H), 7.63 1H), 7.71 1H), 7.98 4m, 21), 8.41 (dd, J 1.4, 7.0, 2H), 8.70 2H), 11.30 (br. s, 1H); EI-MS 389.2 HPLC-Method C, Rt 12.37 min.

Example 313 (5-Benzylcarbamoyl-2H-pyrazol-3-yl)-(2phenyl-quinazolin-4-yl)-amine (111-84): 'H NNR (500MHz, Ci DMSO-d6) 8.4.52 J 6.0 Hz, 2H), 7.29 1H), 7.38

O

J 4.2 Hz, 4H), 7.58 J 7.5 Hz, 2H), 7.63 (M, 0 11), 7.72 1H), 7.98 2H), 8.43 J 7.7 Hz, 2H), 8.72 J -7.5 Hz, 11), 9.23 (br. a, 2H), 11.34 (br. s, 11); EI-MS 421.2 HPLC-Method C, Rt 16.76 min.

Example 314 (5-Cyclohexylcarbamoyl-2E-pyrazol-3-yl)- (2phenyl-quinazolin-4-yl) -amine (111-85) 1H NMR (500MHz, DMSO-d6) 6 1.16 1H), 1.34 4H), 1.62 J 2.6 HfIz, 1H), 1.76 2H), 1.85 2H), 3.79 1H), 7.43 7.60 J 7.2 Hz, 2H), 7.65 J .7.1 Hz, j 1H), 7.71 (ddd, J 2.2, 5.4, 8.2 Hz, IH), 7.98 i(m, 21); 8.35 11), 8.43 (dd, J 1.4, 7.2 Hz, 2H), 8.72 J S8.2 Hz, 1H), 11.34 (br. s, 1R); EI-MS 413.5 HPLC-Method C, Rt 17.18 min.

Example 315 (5-Diethylcarbamoyl-2H-pyrazoi-3-yl)-(2phenyl-quinazolin-4-yl)-amine (111-86): 1H NMR (SOOMHz, DMSO-d6) 1.18 (br. a, 3H), 1.25 (br. a, 3H), 3.49 (br.

S, 2H), 3.69 a, 2H), 7.21 1H), 7.59 J 6.9 Hz, 2H), 7.62 1H), 7.70 11), 7.96 2H), 8.39 J =7.1 Hz, 8.74 J 8.4 Hz, 11.37 (br.

8, 1H); EI-MS 387.2 HPLC-Method C, Rt 14.50 min.

-305- I:*4 I~CIP~C. Va o Example 316 £5-(Benzyl-methyl-carbamoyl) -2H-pyrazol-3- C-i yll-(2-phenyl-quinazolin-4-y)-amne (111-87): 'H NMR (500MHz, DMSO-dE) 8 3.33 3H), 4.75 2H), 7.26 (m, 1H), 7.31 1H), 7.38 4H), 7.58 21), 7.70 (m, 1H), 7.95 3H), 8.26 1H), 8.40 J 7.8 Hz, 2H), 8.75 Cm, 1H), 11.2 (br. a, 11); El-MS 435.2 In HPLC-Method C, Rt 16.77 min.

Va O Example 317 C2-Phenyl-quinazolin-4-yl)-.-(s IN 10 propylcarbamoy-2-pyrazol-3-yl) -amine (111-88): 1H NMR o (SOOMHz, DMSO-d6)l 8 0.94 J 7.3 Hz, 3H), 1.57 (m, 2H), 3.24 J 6.5 Hz, 2H), 7.39 (br. a, 1H), 7.60 (t, J 7.3 Hz, 21), 7.64 Cm, IH), 7.71 (br. t, J 6-5 Hz, 11), 7.-98 2H), 8.42 J 7.2 Hz, 2H) 8.61 (br. a, 11), 8.72 J 8.5 Hz, 11.34 (br. a, 11); EI-MS 373.3 HPLC-Method C, Rt 13.51 min.

Example 318 (Ethyl-sopropyl -carbamoyl) .20-pyrazol-3ylJ (2-phenyl-quinazolin-4-yl) -amine (111-89): 1H NMR (500MHz, DMSO-dE) 6 0.92 J 7.4 Hz, 6H), 1.52 (m, 2H), 1.59 Cm, 11); 3.79 2H), 7.53 (br. 11), 7.57 J 7.5 Hz, 7.65 C.t',f J 7.2 Hz, 1H), 7.71 (m, 1H), 7.99 Cm, 8.23 Cbr. d, L 8.8 Hz, 8.46 (d, J 7.5 Hz, 2H), 8.74 J 8.4 Hz, 1H), 1;.34 (br. a, 11); El-MS 401.2 HPLC-Method C, Rt 15.51 min..

Example 319 (5-Cydlopropylcaxbamoyl-2H-pyrazcl-3-yl) (2phenyl-quinazolin-4-yl)-amine (111-90): 'H NNR (500MHz, DMSO-d) 80.60 Cm, 2H), 0.74 Cm, 2H),-2.86 Ct' 11), 7.34 (br. a, 1H), 7.62 3H), 7.70 1H), 7.97 2H), 8.41 J 7.9 Hz, 2H), 8.63 Cbr. a, 1H), 8.72 Cd, j 7.8 Hz, 1H), 11.35 Cbr. a, 11); El-MS 371-.2 CM+H), HPLC- Method c, Rt 12.64 min.

-306- Va o Example 320 (5-Isobutylcarbamoyl-2H-pyrazol-3-yl)-(2- Cl phenyl-quinazolin-4-yl)-amine 'H NMR (500MHz, DMSO-d) 8 0.94 J 6.7 Hz, 6H), 1.88' m, 3.12 J 6.4 Hz, 2H), 7.45 Cbr. s, IH), 7.58 J 7.2 C~l 5 Hz, 311), 7.64 J 7.1 Hz, 1H), 7.71 1K), 7.98' (m, 2H), 8.44 Cdd, J 1.3, 7.9 Hz, 2K),.8.62 (b r. s, 1H), 8.72 J 8.3 Hz, 111), 11.33 (br. s, 11); El-MS 387.2 CM+H); KPLC-Method C, Rt 14.70 min.

INO 10 Example 321 {S-r.(3)-3-Methoymethyl-pyrrolidine-1o carbonyl] -2H-pyrazol-3-yl)- (2-phenyl-quinasolin-4-yl) amine (111-93): 1 NMR (500MHz, DMSO-dC) 8 2.00 m, 2H), 2.12 1H), 3.29 Cs, 311), 3.45 J n'8.7 Hz, lE), 3.57 (dd, J 3.2, 9.3 Hz, 1H), 3.86 11), 3.92 Cm, lU), 4.36 2H), 7.45 (br. s, 1H), 7.59 J 7.2 Hz, 2H), 7.63 1H), 7.69 IH), 7.97 21), 8.40 J 7.5 Hz, 21), 8.74 J 7.6 Hz; iH), 11.38 (br. s, 1H); El-MS 429.2 HPLC-Method C, Rt 13.84 min.

Exape 322 (2-Phenyl-quinazolin-4-yl)-(5.mtolylcarbamoyl-25-pyrazol-3-yl)-antne (111-94): 'H NMR DNSO-d6) 8 2.33 3H), 6.97 J 7.5 Hz, 1H), 7.27 J 7.8 Hz, 11), 7.62 C(m, 7H), 7.72 (m, 1R), 7.98 21), 8.46 Cdd, J 2.0, 7.9 Hz, 21), 8.71 10.29 Cs, 11), 11.31 (br. a, 1H1); El-MS 421.2 HPLC-Method C, Rt 17.11 min.

Exampl-e 323 (2-Phenyl-qainazolin-4-yl)-(S-ptolylcarbamoyl-ZH-pyrazol-3-yl)-amine (111-95): 1H NMR.

CSOOMHz, DMSO-dC) 8 2.30 Cs, 3H), 7.20 j 8.3 Hz, 2H), 7.62 5H), 7.68 J 8.3 Hz, 2K), 7.72 (m, 7.98 2H), 8.46 Cdd, J 1.8, 7.0 Hz, 2H), 8.72 IH), 10.31 11), 11.36 Cbr. s, IH); El-MS 421.2 (MiH); HPLC-Method C, Rt 16.95 min.

-307- Va 0Exaple 324_ (5-M~thycarbamoy1-2z-pyrazo1-3-yl)- (2phsnyl-quinazoli-4-yl)amine (111-96): 'H NNR (500MHz, DMSO-dE) 8 2.82 Cd, J 4.6 Hz, 7.31 (br. s, 1H), 7.62 3H), 7.69 1H), 7.97 Cm, 2H), 8.42 Cd, J= 7.1 Hz, 21), 8.59 (br. s,1H), 8.71 J 8.0 Hz, 1H), 11.30 (br. s, 1H); El-MS 345.1 HPLC-Method C, Rt Va Cl 11.02 min.

Example 325 (Morpholine-4-carbonyl)-2H-pyrazol..yl.

(2 -phnyl-quinazolinn4 -yl)-amine (111-97): '1 NMR (500MHz, DMSO-dE) 8 3.33 4H), 3.83 Cm 4H), 7.34 (br. s, 1H), 7.53 4H), 7.86 Cm, 2H), 8.43 2H), 8.67 JX 8.6 Hz, 1H), 10.70 Cs, 1H), 13.56 Cs, 1R); El-MS 401.2 HPLC-Method A, Rt 2.68 min.

Example 326 (1-Methylpiperazine-4-erbonyl) -2Hpyrazol-3-yl] (2-phenyl-quinazolin-4-yl) -amine 'HNM (500MHz, DMSQ-d) 8 2.25 Cs, 3111, 2.43 4H), 3.87 (m 4H), 7.33 (br. s, 1H), 7.53 4H), 7.87 (m, 2H), 8.45 2H), 8.67 J 7.6 Hz, 1H), 10.70 (s, 1H), 13.30 lH); El-MS 414.2 HPLC-Method A, Rt 2.38 min.

Example 327 [5-(2-Eydroxyethylcarbaxoyl-20-pyrazol-3-yl (2 -pheny1v-qu~azcn-4 -yl) amine (111-99): '1H NMR (500MHz, DMSO-d6) 6 3.36 2H), 3'.52 2H), 4.79 1H), 7.50 51), 7.83 2H), 8.50 10.52 (br. a, 1H), 13.25 Cs, 1H); El-MS 375.1 CM+H); HPLC-Method A, Rp 2.51 min.

Example 328 (5-Carbanoyl-23-pyrazol-3-yl)-(2-phenylquinazolin-4-y1)-aamine (111-100): To a solution of 5-(2phenyl-quinazoli&-4-ylamino) -1H-pyrazole-3 -carboxylic -308-- Va F: acid 2 ,'5-dioxo-pyrrolidin-1-yl ester (270 mg, 0.63 mmol).

in DMP (20 ml) was added a solution of amonia in 1,4t dioxane (0.5 M, 10 ml). The resulting mixture was stirred at room temperature for 24 h. After Cl 5 concentration of the solvents, the residue was added to water (20 ml). The resulting precipitate was collected to afford II-100 (168 mg, 80%)as a yellow solid. 1H NMR C (SOOMHz; DMSO-d6) 8 7.77-7.51 6H), 7.86 (br s, 21), 8.11 1H), 8.50 8.63 1H), 10.52 1H), IN 10 11.25 1H); EI-MS 331.1 HPLC-Method A, Rt 2.52 Smin.

Example 329 (4-Bromo-2E-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-101): Prepared according to Method A to afford'a yellow solid, mp 189 0 C; H MAR (DMSOd6) 6 7.44-7.46 (3H; 7.58 (1H, 7..87 (2H, 8.15 8.31-8.34 (2H, 8.49 10.08 a), 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 (III-102): mp 183-185 0 C; .1H NM (DMSO) 8 2.33 (3H, br 7.44-7.46 7.57 (1H, 7.84-7.87 (2H, 8.31-8.34 (2H, 8.48 (15, d), 10.05 (1H, 12.91 (1H, br IR (solid) 3362, 3065, 2831, 1619, 1578; MS 380.2/382.2(M+H)+.

Example 331 4 -Cyano-2H-pyrazol-3-yl)-(2-phenylquinasolin-4-yl)-amine (11-103): tp >250 0 C; NMR (DMSO).

8 7.47-7.49 (31, in), 7.64 (11, 7.91 (2H, 8.40- 8.43 (2H, 8.53 (1H, 8.71 (15, 10.61 (11, s), 13.60 IR. (solid) 3277, 3069, 2855, 2231, 1625; MS 313.2(M+H)+.

-309- Va oEample 332 (5-Methyl-20H-pyrazol-3-yl) (2-morpholin-4-yl- Ci quinazolin-4-yl)-amine (111-104): utp 223-224 0 C; 'H NMR (DMSO) 8 2.26(3W, 3.65(4H, 3.75(4, 6.44(1W, s) 7.12(1H, 7.33(1, 56(1H, 8.37(1W, d), 10.01(1W, 12.13(1, br 1k (solid) 1621, 1578, 1537, 1475, 1434, 1385; MS 311.0 (MsH).

Va N Example 333 (S-Methyl-2H-pyrazol- 3-yl)-(2-piperazin-1-ylo quinazolin-4-yl) -amine (111-105): mp 179-181 0 C; 1H NMR ci' (DMSO) S 2.26(3H, 2.74 (4W, br 3.71(4H, br a), O 6.43 7.08 (1H, -7.30 (1H d) T.-53 (19i t), 8.34(111; 9.50(11, 12.08(1W, br ZR (solid) 2853, 1619, 1603,' 1566, 1549, 1539; MS 310.0 (M+H) t Example 334 (4-Methylpiperid.n-1-yl) -quinazolin-4-yll 7 2K-pyrazol-3-yl)-amine (111-106): mp 148-1500C; HWNMR (DMSO) S 1.06(3H, 1.03(2H, 1.51-1.70(3, 2.26(3, 2.86(2H, 4.73(2, 6.44(!H, S), 7.06(1W, 7.29(11, 7.52(1H,-t), 8.32(1, d), 9.92(1W, 12.09(1W, br IR (solid) 2917, 2840, 1629, 1593, 1562;. 1546, 1486; MS 323.0 Example 335- [2..(4-ethylpiperazin-1-yl) -quinazolin-4-yl] (5-iethyl-2H-pyrazol-3-yl)-anine (111-107): ip-105-107 0

C;

H NMR (DMSO) 8 2.21(3W, 2.26(3H, 2.34(4W, 3.75(4H, 6.45(11, 7.09(1, 7.31(1W, d), 7.54(1, 8.34(111, 9.96(1W, 12.12(1W, br a); IR (solid) 2934, 2844, 2804, 1620, 1593, 1572, 1536, 1476; MS 324.0 (M+H) 4 ExalM2e '336 (5-Methy1-2R-pyrazol-3-y) (2-piperidin-1-ylquinazolin-4-yL)-amine (111-108) np 294C; 1H NMR (DMSO) 8 1.45-1.58 (4H, 1.63 (2H, 2.26 (3W, 3.79 -310- Va (4H, 6.45 br 7.06 t),.7.29 d), C 7.52 (11, 8.33 9.92 (1H, 12.11 (1W, br ZR (solid) 2929, 2847, 1632, 1591, 1500, 1482, 1437, 1382; MS 309.3 C S Example 337 (2-Azepan-t-yl)-quinazolin-4-yl]-(5-methyl- 2H-pyrazol-3-yl)-amine (II1-109): mp 269 0 C; 'H NMR (DMSO) C 6 1.50 (4H, br 1.76 (4H, br 2.25 3.78 (4H, 6.55 (1H, br 7.03 (11, 7.28 (11, d), 7.50 (1H, 8.33 (in, 9.92 (1H, 12.09 (1H, br IR (solid) 3427, 2963, 2927, 2909, 2872, 2850, 1623, 1595, 1596, 1568, 1504, 1486, 1468, 1386, 1427; MS 323.3

(M+H)

t Example 338 (2-(4-(2-Bydroxyethylpiperidin-1-yl) quinazolin-4-yl] (5-methyl-23-pyrazol-3-yl) -amine (III- 110): mp 175CC; 'H NMR (DMSO) 8 1.08 (2H, 1.38 (2H, 1.57-1.83 (3H, 2.26 (3H, 2.85 (2H, 3.47 (2H, 4.38 (1H, 4.75 (2W, 6.45 (1H, br 7.06 (1H, 7.29 (15, 7.52 (1H, 8.32 (111, d), 9.93 (11; 12.12 (15, br IR (solid) 3365, 3073, 2972, 2868, 1622, 1604, 1586, 1568', 1486,..1463, 1440, 1394; MS 353.2 Example 339 (5-Cyclopropyl-2a-pyraaol-3-yl)-12-(4-' methylpiperidin-1-yl)-quinazolin-4-yl -amine (III-111): To a solution of (5-cyclopropyl-1H-pyrazol-3-yl)-(2chloro-quinazolin-4-yl)-amine (118 mg, 0.41 mmol) in tert-butanol (3.0 mL) was added 4-methylpiperidine (0.49 mL, 4.1 mmol) and.the reaction mixture heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in a mixture EtOH:water 4 mL). Potassium carbonate (57mg, 0.41 mmol) was added and the mixture stirred at room temperature for 2 -311-

IN

o hours. The resulting suspension was filtered, washed C- with water and rinsed with Et 3 0 (x2) to afford IIIt 111 as a white solid (123mg, 85*) 2 mp 190C; 'H NMR (DMSO) 8 0.66 (2H, 0.93 (5M, br 1.07 (2H 1.66 (3H, c- 5 1.91 (1H, 2.85 (2H, 4.72 (2H, 6.33 (1H, 7.06 (11, 7.29 (1H, 7.52 (1H, 8.31 (1H, 9.95 (1H, 12.18 br IR (solid) 2925, Cl 2852, 1622, 1590, 1581, 1558, 1494, 1481, 1453, 1435, o 1394; MS 349.2 IND o Example 340 [2-(1,4-Dioxa-8-aza-spiro[4,5]dee-8B-yl)quinazolin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (III- 112):; mp 191C; 'H NMR (DMSO) 8 1.65 (4H, 2.26 (3H, 3.90 (4H, 3.93 (411, 6.43 br 7.09 (1H, 7.32 (1H, 7.54 8.35 (1H, 9.99 (11, br 12.13 br IR (solid) 3069, 2964, 2927, 2868, 1618, 1581, 1568, 1540, 1495, 1481, 1435, 1390; MS 367.3 (M+H) 4 Example 341 [2-(4-Cyclopertylamino-piperidin-1-1y)quinazolin-4-yl (5-methyl-2-pyrazol-3-yl)-amine (III- 113): mp 191C; 1'H NMR (DMSO) 8 1.33 (2H11, d) 1.65 (4H, 1.87 (2H, d),.2.20 (1H, 2.26 (3H, 2.49 (2H, 3.00 (2H, 3.36 (2H, 4.61 (2H, 6.45 (1H, br 7.07 (11, 7.31 (11, 7.52 (1H, 8.33 (11, 9.94 br 1-2.12 br IR (solid) 3371, 2943,. 1622, 1600, 1581, 1545, 1509, 1463, 1440, 1390; MS 378.2 Example 342 (2-(4-Hydroxypiperidin-1-yl)-quinasolin-4yl]-(S-methyl-2-pyrazol-3-yl)-asine (111-114): mp 123 0

C;

'H NMR (DMSO) 8 1.34 (211, 1.80 2.26 (3H11, s), 3.24 (28, 3.72 (1H, br 4.39 (2H, 4.70 (1H, 6.44 (11, br 7.07 7.30 (1R, 7.53 -312-

NO

o 8.33 (15, 9.94 br 12.11 br a); IR (solid) 3265, 3151, 2927, 2863, 1622, 1600, 1572, 1540, 1504, 1476, 1440, 1390, 1349, 1066, 1098; MS 325.3 Example 343 (5-Cyclopropyl-2a-pyrazol-3-yl)-12-(4hydroxy-4-phenylpiperidin-1-yl)-quinazolin-4-yl] -mine A (li-115): mp 131.C; H NMR (DM0SO) 8 0.64 (2H, 0.93 (2H, 1.68 (2H, 1.83-1.97 (3H, 3.20-3.45 (2H, 4.69 (28, 5.11 (1a, sa), 6.37 (15, br 7.08 o(1H, 7.20 (1H, 7.31 (311, 7;49 (2H, 7.53 (1H, 8.33 9.98 (1H, br 12.18 (15, 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-2-pyrazol-3-yl)-[2-(1,3dihydro-isoindol-2-yl)-quinazsolin-4-yl -amine -116): Prepared according to Method E-I to afford an off-white solid, mp 237-C; 3H NMR (DMSO-d6) 8 0.79 (2H, 1.00 (2H, 1.99 (1H, 4.92-(4H, 6.72 (1H, br a), 7.13 (111, 7.33 (2H, 7.30-7.48 (3H, 7.58 (1H, 8.40 (11, 10.12 (1H, 12.17 (1H, IR (solid) 3449, 3318, 2850, 1623, 1595, 1577, 1541, 1509, 1482, 1432, 1391, 1359, 1141, 1027, 877, 814; MS 369.4 Example 345 (2-Azepan-1-yl)-quinazolin-4-yl3-(5cyclopropy1-2H-pyrazol-3-yl)-amine (111-117): mp 199- 200CC; 1H NMR (DMSO-d) 8 0.60-0.70 (25, 0.90-1.00 (2H, 1.45-1.57' (4H, 1.70-1.85 (45, i.88-1.97 3.75-3.87 (4H, 6.42 (1H, 7.02 t), 7.27 (11, 7.49 (15, 8.29 (1R, 9.91 S), 12.19 (1H, br IR (solid) 2929, 1624, 1595, 1581, -313- Va o 1563, 1542, 1498, 1482, 1440, 1426, 1397, 1356, 1305, C] 1000, 825, 754; MS'349.2 (M+H) 4 Example 346 (5-CycloPropyl-2-prazol-3-yl dihydro-1E-isoquinolin-2-yl)-quinaoli n-4-yll-amine (III- 118): mp 182-184cC; 1H NMR (DMSO) 8 0.75 (2H, 1.02 1.96 2.89 (2H, 4.05 (2H, 4.94 Cl (2H, 6.46 (1H, 7.10 (1i, 7.21 (4H, 7.37 o (1K, 7.55 (in, 8.36. (1H, 10.05 (1K, 12.23 ID 10 (1H, br IR (solid) 1621, 1581, 1560, 1537, -1479,. o 1456, 1426, 1396, 1374, 1341, 1222; MS 383.3 Example 347 (5-Cyelopropyl-2B-pyrazol-3-yl)-[2-(2,3dihydro-indol-1-yl)-quinazolin-4-yl] -amine (111-119): mp 150-153 0 C; 1H NMR (DMSO) 8 0.74 (2H, 0.98 (2H, d), 1.96 (1H, 3.15 (2H, 4.25 (2H, -6.45 (11, br 6.88 (iH, 7.09 7.20 7.53 (1iHI 7.65 (1M, t),'8.43 (2H, br 10.09 (1H, 12.28 (1i, br IR (solid) 1621, 1588, 1577, 1564,.1537, 1487, 1455, 1425,'1386, 1259; MS 369.3 (M+H) 4 Example 348 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-.

hydroxymethylpiperidin-1 -yl)-quinazolin-4-yl]-amine (III- 120): mp 142 0 C; 1H NMR (DMSO) 8 0.67 (2H, 0.96 (2H, 1.10 (21H, 1.55-1.70 (3H, 1.91 (1K, 2.85 (2H, 3.28 (2H, 4.48 (1H, 4.76. (2H, 6.34 (1i, 7.06 7.30 (iN, 7.52 (1H, 8.31 (1n, 9.96 (1K, 12.19 (in, IR (solid) 3363, 3000, 2927, 2854, 1618, 1604, 1573, 1536, 1509, 1477, 1436, 1395, 1354, 1314, 1241, 1186, 1091, 995, 941, 823; MS 365.8 Examplee349 (5-Cydlopropyl-2H-pyrazol-3-yl)-[2-(3,4dihydro-2-quinolin-1-yl)-quinazolin-4-yll-amine

(III-

-314- Va o 121): mp 137-145 0 C; 3l NMR (DMSO-d6) 8.0.55 (2H, 0.88 (2H, 1.78 (111, 1.92 (2H, 2.75 (2H, t)0, 4.04 (2H, 6.20 (1H, br 6.97 7.14 (1H, m), 7.19 (1H, 7.42 7.61 (11, 7.67 d), 8.43 (1H, 10.04 (1H, 12.21 (1H, br IR (solid) 1622,..1572, -1539, 1493,.1454, 1420, 1373, 1249; MS 383.3 IN 0 Example 350 (5-Methoxycarbonyl-2H-pyrazol-3-yl)- 12- Ci (piperidine-1-yl) -quinazolin-4-yl -amine (III-122):-.H 1NMR 0 (500MHz, CDC1 3 81.7-1.8(6H, 8 3.8 8 3.9 (3H, 8 5.5 (1H, 8 7.15 (1H, 8 7.4 (1H, 6 7.6 (1H, 6 8.0 (111, HPLC-Method B, (starting with Ha0) Rt 7.4 min; MS 353.24 Example 351 [5-(Piperidine-1-carbonyl)-2H-pyrazol-3-yllt2- (piperidine-1-yl) -quinazolin-4-yll-amine (III-123)z HPLC-Method B, (starting with 95% 120:0.1% ThA) Rt min; MS 406.30, 404.30.

Example 352 (5-Hydroymethyl-2-pyrazol-3-yl) (piperidin--yl)-quinazolin-4-yl-amine (111-124): To a solution of III-122 (10.0 mg, 0.028-minol) in THF (6 ut) at ambient temperature was slowly added a IM solution of LiAIH 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 organic layer was dried over MgsO0 4 filtered, and concentrated in vacuo. The residue was purified by preparatory HPLC to afford II1-124 (4.0 mg, HPLC- Method B, (starting with 95% H20:0.1% TFA) Rt 6.1 min; MS 325.13 323.13 -315- Va Exdmple 353 (5-Carbamoyl-2s -pyrazol-3-yl)-[2-(piperidin- 1-fL) -quinazolin-4-yl] -amine (111-125): A solution of 111-122 (1.5 g, 4.3 mmol) in 2.0 M NHJMeOH (100 mL) was heated at 1100C for 2 days. The dark brown reaction mixture was concentrated in vacuo to afford a viscous oil which was.purified by column chromatography to yield 0.7 -g of 111-125. 'H NMR (500MHz, CD3OD-d 3 81.6 (4H, 81.7 (2H, 8 3.3 (IH, 8 3.8 (4H, m) 1 0 (1H, 6 7.15 (1H, 8 7.45 (1H, 8 7.55 (1H, t) S 8.0 (lB, HPLC-Method B, (starting with 95% H20;:0.1% 0 TFA) Rt 5.9.min; MS .338.13, 336.15.

Example 354 (5-Carbamoyl-2E-pyrazol-3-yl) methylpiperidin-i-yl)-qunazolin-4..yll-amne (111-126): HPLC-Method (starting with 95% H20:0.1% TFA) Rt 6.4 min; MS 352.19, 350.20.

Example 355 (5,7-Difluoro-1E-indazol-3- yl) (2-phenyl- Si 6 ,8-tetrahydroqutnazolin-4-yl)-emine (111-1217): 'H NMR (500 MHz, DMSO-dE) 513.7 11), 10.3 br, 1H), 7.90.

2K), 7.52 1H), 7.45 3H), 7.26 1H), 2.99 2H), 2.75 2H), 1.95. (br, 4H) ppm; MS (ES) -378.24 376.23 HPLC-Method A, Rt 3.04 min.

Example 356 (2-Phenyl-5,6,7,8-tetrabydroquinazolin-4-yl) (S-trifluoroaethyl-l1-indazol-s-yl) -amine (111-128): 'H NMR (500 MHz, DMSO-d) 813.4 IH), 10.2 br, 11), 8.13 7.86 210H, 7.78 7.69 1II), 7.50 1H), 7.35 (dd, 2H), 2.89 2H), 2.72 (m,2H), 1.90 br, 41) ppm; MS 410.24 408.23 HPLC-Method A, Rt 3.19 min.

-316- Va Example 357 (7-Fluoro-.H-indazo'l-3-yI)-(2-phenylquinazolin-4-yl) -amine .(111-129): 'H NMR (500 MHz, DMSOd6) 813.6 11.1 br, 8.65 IN), 8.03 2H), 7.95 2H), 7.67 I1), 7.45 Cm, 2H), 7.33 2H), 7.22 (dd, 1K), 6.99 (td, 1) ppm. Ms r/en 356;20 HPLC-Method A Rt 3.00 min.

Example 35B (5-Fluoro-1H-indazol-3-yl)- (2-phenyl- 0 quinazolin-4-yl) -amine (111-130): 32 NMR (500 MHz, DMSOci d6) 813.2 Cs, 11.3 br, 1K), 8.67 1H), 8.04 Ci C(d, 2H), 7.96 Cs, 2H), 7.70 Cm, 1H), 7.58 (dd, 7.43 4H), 1.28 1K) ppm. MS 356.20 HPLC- Method A, Rt 3.00 min.

Example 359 (5,7-Difluoro-1H-indazo-3 Tyl) (2-phenylquinazolin-4-yl) -amine (111-131): 'K NMR (500 MHz, DMSOd6-) 813.7 1H), 8.'65 8.04 2H), 7.95 Cs, 2H), 7.68 1H), 7.45 Cm, I1), 7.35 4H) ppm. MS m/e= 374.1.7 KPLC-Method A, Rt 3.07 min.

Example 360 (1H-Indazol-3-yl)-[2- (3-trifluoromethjl phenyl) -quinazolin-4-yl3 -amine (111-132): 'H NMR (500MHz, DMSO-dE) S 7.06 1W) 7.42 7.59 1W) 7.63 t, 1H)1 7.66 1H), 7.71 Cm, 1H), 7.80 7.98 2H), 8.33 Cs, 1, 8.46 10, 8.71 11.04 (br. a, 1H), 12.97 1H); El-MS 406.1 EPLC- Method A, Rt 3.15 min.

Example 361 (2-Phenyl-quinazolin-4-yll-(lE-pyrazolo[4,3blpyridin-3-yl) -amine (nZi-133): "H NIR (500 MHz, DMSO-d6) 813.3 Cs, br, 1K), 11.4 hr, 1K), 8.78 8.58 (dd, 1W) 8.24 '1H) 8.10 2H), 7.95 2H) 7.86 -317- C,1H), 7.56 (mn, 2H), 7.44 ppm. Ms CEs+) 339.11 Example 362. (3-Methoxy-phenyl) -6-oxo-5,6-dihydro-1Hpyrazolo[4,3-clpyridazin-3-ylI (2-phenyl-quinazolin-4yl)-amine (111-134): '3 1%MR (500 MHz, MeQH-d4) 88.es (d, 8.'17 3H) 8.10 111), 7.90 Ct, 1 Hli), 7.75 (t, 1!),7.58 2H), *7.25 13), 6.95 2H1), 6.85 (d, o 13H), 6.80 1H), 3.64 311) ppm. MS in/e= 462.2(M+H).I Example 363 (6-Oxo-5-pbenyl-S,6-dihydro-lx-pyrazolo [4,3clpyridazin-3-yl) .(2-phenyl-qluinazolin-4-yl) -amine (III- 135): '3 NMR (500 MHz, Meo3I-d4) 88.61 111), 8.13 (m, 3H), 8.OS 110, 7.85 Ct, 13), 7.70 1H), 7.58 (m, 2H), 7.32 Cm, 5H), 6.79 110. ppm. MS (ESi): m/e= 432.2(M,-).

Exaple 364 15-( (4-Methoxy-phenyl) -6-oxo-5, 6-dihydro-lEpyrazolo[4,3-cjpyridazin-3-yl (2-phenyl-quinazolin-4yl)-amine (111-136): MS 462.2(MiH).

Example 365. (2,4-Dichioro-phenyl) -6-oso-5,6-dihydro- 3.H-pyrazoo4,3-'clpyridazin-3-yl].- (2-phenyl-quinazolin-4yl)-mmins (111-117) 13 NMR (500 MHz, MeO3-d4) 88.63. (d, 13), 8.17 4H), 7.89 110, 7.73 Ct, 1H1), 7.61 Ct, 21), 7.57 1H), 7.32 13), 7.21.Cd, 1H), 6.84 Cs, 13) ppm. MS m/e= 500.1CM+H)..

Example 366 [6-Oxo-5- (3-trifluoromethy-pheny1) -5,6dihydro-1BR-pyrazolo pyridazin-3 -y3- (2-phenylquinazolin-4-yl)-amine (111E-138): "H I1MR (500 M'~Uz, MeOHd4) 88.55 Jd, 8.19 2H), 7.92 2H1), 7..65 (m, -318o 3H) 7.45 2H1), 7.25 111), 7.13' Ct, 11) 7.05 (t, CA 1H1), 6.75 Cs, 111) ppm. MS m/e= 500.2 (14+1).

CExample367 [5-O(4-Chlor-phsnxhnyl) x-'56-dhydro-no pyrazolo[4,3-cjpyridazin-3-yl) (2-phenyl-quinazolin-4- V.0 10 yl)-anmtne, (111-139),: 14S 546.(M+H) Example 369, (2-iaidazol-1-yl-quinazolin-4-yl) -(1E- ±ndazol-3-yl)-am~ine (111-141): '11 NNR (500MHz, DMSO-dG)S 7.10 Ct, 111), 7.4.4 111), 7.50 (br. s, 111), 7.60 (d, is1 1H1), 7.72 Cm, 2H), 7.77 Cm, 1H1), 7.88 1H1), 7.98 (t, 1IM), 8.73 Cd, 1H), 8.96. 11), 11.23 Cs, 111), 13.06 (s, El-MS 328. ;HPLC-Method A, Rt 2.93 mm~.

Exjale 370 C1H-Indazcl-3-yl) (2-methyl-imidazol-1-ylqutnazolini-4-yl]-aine (111-142): 'H NMR (50014Hz, DMSO-dE) S2. 48. 3H1), 7 ;10' 11) 7. 43 C(t, 1H1), 7. 57 11) 7.60 111), 7.A7 111), 7.76 Ctd, 1H1), 7.86 Cd, 111), 7.91. 111), 8.01' (td, 1H1), 8.72 1H1), 11.15 111), 13.10 11); El-MS 342.1 CM+1); HPLC-Method A, Rt 3.06 min.

Example 371 (1H-lndazol-3-yl) (2-piperidin-1-ylquinazolin-4-yl)-'amine (X11-143): '3 NM (500MHz, DMSQ-dE) S1;48 Cm, 6H), 3.60 Cm, 7.11 t, 111), 7.52 Ct, 111), 7.55. 111),' 7.64 111), 7.69 111), 7.75 1H1), 7.90 Ct, 111), 8.58 IH), 11.82 (br. s, 111), 13.25 (s, 1H); HI-MS 345. 1 CM*1) HPLC-Method A, Rt 3.03 mini.

-319- Va o Example 372 (1l-Indazol-3-yl) (octahydro-quinolin-1yl)-quinazolin-4-yl-amine (111-144): 1 NMR (500Mz, DMSO-d6) 8 0.6-1.9 13 3.15 3.25 1H), 1K), 7.10 0.5H), 7..12 0.5H), 7.55 (m, Cl 5 2H), 7.66 0.5 7.69 0.5 7.77 XE), 7.91 1I), 8.55H-d,0.5 8.59 0.5 11.46'(s, 11.54 0.5 11.78 0.5 11.84 0.5 H), Cl 13.10 0.5 13.12 0.5 H);.EI-MS 399.3 S HPLC-Method A, Rt 3.37 min.

0O o Example 373 (1H-Indazol-3-yl)-[2-(2,6-dimethyl-morpholin- 4-yl)-quinazolin-4-yl] -amine (111-145): 1H NMR (500MHz, DMSO-d6) 8 GE), 4.0 6H), 7.12 7.41 (td, 1H), 7.56 1H), 7.58 1H), 7.68 (dd, 1H), 7.77 1H), 7.93 1K), 8.60 1H), 11.69 IH), 13.16 1H); EI-MS 375.3 HPLC-Method A, Rt 2.93 min.

Example 374 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylpyrimidin-4-yl)-amine mp 245-246 0 C; 1 H NMR (DMSO) 6 2.26 (3H, 6.32 (1H, br 7.07 (1H, br 7.48- 7.54 8.33-8.39 (3H, 9.87 (1H, 12.03 (I, IR (solid) 1628, 1589, 1579, 1522, 1479, 1441, 1393, 1336;MS 252.2 Example 375 [6-(4-Acetamidophenylsulfany)'-2-phenylpyrimidin-4-yll (5-methyl-2-pyrazol-3-yl) -amine (IV-3): A suspension of Fenclorim (4,6-dichloro-2phenylpyrimidine) (0.lg, 0.44 mmol), ethylpyrazole (0.045 g, 0.47 mmol), N, Ndiisopropylethylamine (0.08 ml, 0.47 mmol) and sodium iodide (0.067 g, 0.44 mmnol) in n-butanol. (5 mi) were heated 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 -320-

VO

0.037 g (29 yield) of (6-Chloro-2-phenyl-pyrimidin-4c yl)-(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

C

l S 'mmol) in tert-butanol was heated at 85 *C under nitrogen for 2 days. The reaction mixture was cooled to room S' temperature and the solvent removed in vacuo. The concentrate was dissolved in EtOAc, and washed with NaHC03 C (sat, The organic layer is concentrated in vacuo, cO and the crude product by preperative HPLC. The residual 0 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; 1H NMR (DMSO) 6 2.10 (3H, 2.21 (3H, 6.33 (1H, br 7.50 (3H, 7.7-7.59 (2H, 7.76-7.78 (2H, 8.25 (2H, 9.72, 10.26 and 11.93 (3 H, 3 x br IR (solid) 1669, 1585, 1551, 1492, 1392, 1372, 1312, 1289, 1259, 1174, 1102, 1089, 1027, 1015, 984; MS 417.3 Example 376 (4-Methylpiperidin-l-yl) -pyrimidin-4-yl] (5-methyl-2b-pyrazol-3-yl)-amine mp 215-216 0 C; 'H NMR (CD 3 0D) 8 0.96 (3H, 1.16 (2H, 1.66 (3H, m), 2.27 (3H, 2.86 (2H, 4.58 (2H, 4.78 (2H, exch.protons), 6.13 (2H, 7.83 (1H, .IR (solid) 1593, 1550, 1489, 1436, 1331, 1246, 1231; MS 273.1 Example 377 (4-Methylpiperidin-1-yl) 4 -yll-(5-methyl-2H-pyrazol-3-yl)-amine mp 185- 187°C; 'H NMR (DMSO) 8 0.93 (3H, 1.06-1.18 (2H, 1.68-1.80 (3H, 2.26 (3H, 3.01-3.12 (2H, 4.63 (1H, 4.80 (1H, 6.39 (1H, 9.00 (1H, 10.41 -321- Va (11, 12.36 IR (solid) 1589, 1517, 1479, Cl 1446, 1346, 1317, 1246, 1222, 1055; MS 318.2 Example 378 E5-Amino-2-(4-Methylpiperidin-1-yl)pyrimidin-4-yll (5-methyl-25-pyrazol-3-yl) -amine (TV-6) To a solution of IV-5. (48 mg, 0.151 mmol) ii ethanol D mtL) was added tin dichloride dihydrate (171 mg; 0.756 Cl mmol) and the resulting mixture heated at reflux for 3 o hours. The reaction was cooled to room temperature and ID 10 poured onto a mixture of IM NabH:dichloromethane:propanol o (18:8:4mL) and stirred for 15 .minutes. The layers were separated and the aqueous layer extracted twice with dichloromethane. The combined organic-layers were concentrated in Vacuo and the residue purified by flash chromatography (silica gel, gradient dichloromethane:MeOH) to afford V17-6 as a grey solid (27mg, 1H NMR (DMSO) 6 0:88-1.04 (5W, 1.55-1.62 (3H, 2.21 2.70 (2H, 3.36 (2H, 4.40 (2H, 6.37 (1H, 7.49 (1W, 8.40 (11, 11.92 br MS 288.2 Example 379 [5-Amino-6-methyl-2- (4-methylpiperidin-1-yl)pyrimidin-4-yl] (5-methyl-2E-pyrazol-3-yl) -amine (IV-7): mp 172-175 0 C; 'H NMR (DMSO) 6 0.90 (3H, 1.03 (2H, m), 1.52-1.62 (3H, 2.13 (3H, 2.20 (3H, 2.69 (2H, 3.92 (2H, br 4.44 (2H, 6.35 (1H, 8.41 (1H, 11.85 (iH, br IR (solid) 1612, 1589, 1489, 1446, 1317; MS 302.5 Example 380 [6-Methyl-2-(4-methyl-phenyl)-pyrimidin-4yl]-(5-phenyl-2BH-pyrazol-3-yl)-amine (IV-10): MS 342.34 UPLC-Method E, Rt.1.334 min.

-322o Example 381 2 4 -Chlorb-phenyl)-6-methyl-pyrmdn.4 ylJ- 5 -furan-2-y1-2-pyrazo-3-yl).amine (IV-1l): MS 352.11 IWLC Method E, Rt 1.194 mini.

(N S5 Example 382 'S-F ran-2-yl-2H-pyrazo-3-yl.(6methy..2 phenyl-pyri3.din-4-yl)-azine (17-12): MS 318.21 HPLC-Metbod E, 1.192 min.

0 Ekample 383 6 -MethyI-2-(4-trifluormethyl.phenyl).

PYrimidin-4-y11-( 5-pheny1 -2 -y1 2apyrazo1-3 -y1) amine o (IV-13): MS 396.24 HPLC-Method E,.Rt 1.419 mini.

Example 384- (5-Furan-2-y1-2E-pyrazo1-3-yx) 6-methyl-2- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl] -amine (IV-14): MS 386.08 HPLC-Method E 1.347 mini.- Example 385 [2-(2,3-Dihydro-bnzotl,4]dioxn2yl).6.

methyl-pyrimmidin-4-yl] furan-2 -yl- 2H-pyrazol-3 -yl) amine (IV-15) MS .376.18S RPLC-Method E. -Rt 1. 181 mani.

ExaImple 386 E2-(2 1 3-Dihydro-bezo[1,4dioxn2yl).6ethyl -pyriuidin.4.,Y1] (5 -methyl 2-pyrazol-3 -yl) amine (tV-1G) 2 MS 338.17 HPLC-Method E, Rt 1.082 mini.

Examle 387 (6-Ethyl-2-phenyl-pyrimidin-4-yl)- 2 E-pyrazol-3-yl)-amjne (IV-17): MS 280.18

HPLC-

Method E, Rt 1. 024 mini.

Example 388 (6-Methyl-2-phenyl-pyrimidiin-4-yl) 2 H-pyrazol-3-yl)-Akmine (IV-19): MS 328.51

HPLC-

Method Rt 1A192 1mini.

-323- Example'389 [6 -Ethyl -2 (4 -tri fluoromethyl-phenyl) CA pyrimidin-4-yl (S-methy1--2B-pyr.azo1-3-yl)eaaine MS 348.5 HPLC-Method E, Rt 1.224 min.

Exa-mt1e 390 (S-Furan-2-yl-2-pyrazol.3ylp)rs..mthy..2 4 -methyl-phenyl)-pyrmidin-4.yl] -amine (1v-21j: MS ~332.23 HPLC-Method E, Rt 1. 139 min.

oxample391 (6 -Mithoxye thy1 -2 -phenyl -pyrimi di1n -4 -yl) =ethyl -2-pyrazol-3..yl) -ami~ne (IV-22): MS 296'31 (M+rn; i o HPLC-Method. E, Rt 0. 971 min.

Exa mple 392 (5,6-Dimethyl-2-phenyl-pyrmdin4.yl) methyl-2a-pyrazol-3-yl)-amine MS 280.2 HPLC-Method E, Rt 0.927 min.

Examle 393 (6-Meithyl-2-phenyl-pyrimidin-4-yl) 2 H-pyrazol-3-yl)-an4ine (Iy-24): MS 266.16 EPLO- Method E, Rt 0.925 mini.

Exml 9 16 -Ethyl -2 (4 -methyl -phenyl) -pyrimidun- 4 -yl] (S-methyl-2.&-pyrazol-3-yl) -amine'(IV..25): MS 294'.46 HPLC-Metbod E, Rt I1.174 mini.

Example 39S (2-(4-Chloro-phnyl)-6-ethyl-pyrm±dn.4ylp.

(S -=ethyl 2-pyrazol-3 -yl) 6mine (IV-26): MS 314.42.

HPLC-Method H Rt 1.213 mini.

Example 396 (5-Methyl-tH-pyrazol-3-yl) -*(6-methyl-2-ptolyl-pyrim~tdin-4-'yl)-amine (IV-27): MS 280.45 HPLC-Metbod E, Rt 1.135 mini.

Exaiiple 397 (lE-Indazol-3-yl) -(6-me thoxymethyl-2 -phenyl- Pyrimidin-4-yl)-amlne (IV-28): 'LH NMvR (S00 MHz, DM50)8 -324- Va o 3.57 (3H, 4.65 (211, 7.23 (1H, J=7.5 Hz, 7.52 (1H, J=7.6 Hz, 7.63 (4H, 7.75 br), 8.13 (1H, Hz, br 8.44 (1H, J=5.7 Hz, br 10.6 (IH, br), 12.8 (1H, br a) ppm; HPLC-Method A, Rt 2.944 min; MS C S5 (FIA) 332.1 o Example 398 (5-Methyl-2-pyrazol-3-yl)-(2-pyridin-4-yll thieno[3,2-dl]pyrmidin-4-yl)-amine (IV-29): 1H NMR (DMSO) 0 8 2.34 (3H, 6.66 (1iH, 7.53 (1H, 7.84 (1H, d), Cl oN 10 8.32 (2H, 8.70 MS 309.6 Example 399 (5-Methyl-2H-pyrazol-3-yl) (2-phenylpyrido[3,4-d]pyriidin -4-yl)-amine (IV-30): mp 2250C; 'H NMR (DMSO) 8 2.35.(3H, 6.81 7.50-7.63 (3H, 8.45-8.52 (2H, 8.54 (1H, 8.62 (1H, 9.20 10.79 (11, 12.38 (1H, br IR (solid) 2958, 2917, 2852, 1593, 1565, 1524, 1467, 1450; MS 303.2

(M+H)

t Example 400 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylpyrido[2,3-d]pyriinidin-4-yl)-amine (IV-31): To a solution of 4-chloro-2-pheyl-pyrido[2,3dpyrimidine Pharm. Belg.-, 29, 1974, 145-148) (109mg, 0.45 mmcl).in-THF (15 mL) was added pyrazole (48 mg, 0.5 mmol) and the resulting mixture -heated at 65 OC overnight. The mixture was cooled to room temperature and the resulting suspension was filtered and washed with Et 2 O. The solid was dissolved in a mixture EtOH:water and the pH adjusted to pH 7. The aqueous- was extracted twice with ethyl acetate and the combined organic layers were dried (MgSO), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Sio 2 DCM-MeOH gradient) to afford IV-31 as an off-white solid (69 mg, mp 2340C; 11 NMR -325- Va (DMSO) 5 2.14 (3H, 5.99 (1H, s),.7.20-7.40 m), 7.40-7.50 (3H, 8.60 (1H, 8.79 (1H, 12.82 (1H, br IR (solid) 2957, 2921, 2857, 1644, 1560, 1459, 1427; MS 303.2 (M+H) 4 C- Example 401 (5-Cyclopropyl-2B-pyrazol-3-yl)-(2-phenylpyrido[3,4-d]pyrimidin-4-'yl)-amine (IV-32): off-white solid,*mp 232-233OC; 'H NMR (DMSO) 8 0.70-0.85 (21H, m), 0.90-1.05 (2H, 1.05-2.07 (1H, 6.75 (1H, 7.50- 7.75 (3tH, 8.40-8.70 (4H, 9.20 (1H, 10.80 (1H, 12.41 IR (solid) 3178, 1901, 1573, 1532, 1484, 1452, 1409, 1367, 1328, 802, 781, 667; MS 329.2 (M+H) 4 Example 402 [2-(4-Xethylpiperidin-a-yl)-purin-4-yl]-(5methyl-25-pyrazol-3-yl)-amine (P1-33): To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-1H-pyrazol-3-yl amine (2.05 g, 21.2 mmol). The resulting mixture was stirred at room temperature for 48 h. The. resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 1.524 g (58% yield) of (2chloro-purin-4-yl)-(5-methyl-H-pftazol-3-yl)-amine which was used in the next step without further purification.

To a solution of (2-chloro-purin-4-yl)-(5-methyl-1Hpyrazol-3-yl)-amine (200 mg, 0.80 mmol) was added 4methylpiperidine (4 mL, 8.01 mmol) and the reaction mixture heated at reflux overnight. The solvent was evaporated and the residue dissolved in a mixture EtOH:water (1:3,,44 Potassium carbonate (57mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 .hours. The resulting suspension was filtered, washed with water (x2) and rinsed with Eto0 (x2) to afford IV-33 as a white solid (225mg, mp >3000C; 'H NMR (DMSO) 5 0.91 (3H, 1.10 (2H, 1.65 (3H, m), -326- Va o 2.24 2.84 (2H, 4.60 (2H, 6.40 (1n, S), 7.87 9.37-9.59 (10, 12.03-12.39 (2H, IR (solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3 Cl Example 403 (5-Cyclopropyl-2E-pyrazol-3-yl)-[2-(4- ND methylpiperidin-1-yl) -pyrrolo [3,2-djpyrimidin-4-yl -amine.

S (IV-34): white solid; 1H NMR (DMSO) 8 0.65 (2H, 0.91- Cl 0.96 (50, 1.08 (2H, 1.58-1.64 (3H, 1.89 (1H, 2.77.(2H, 4.57 (2H1, 6.09 (1H, 6.38 (1H, S 7.33 (1H, 9.42 (10, 10.65 (1H, 12.02 (1H, br MS 338.3 (M+H) 4 Example 404 [6-Benzyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-dpyrimidin-4-yl (5-fluoro-1H-indazol-3-yl) amine (IV-35): 1H NMR (500 MKz, DMSO-d6) 813.0 1), 10.4 br, 1H), 9.73 1H, TFA-OH), 8.00 2H), 7.64 2H), 7.59 (dd, 1H), 7.52 31), 7.41 1H), 7.31 31), 7.14. (dd, 4.58 2H), 4.35 (br, 2H), 3.74 2H), 3.17 2H) ppm. m/e= 451.30 HPLC-Method A, T. 2.96 min.

Example 405 (5-Fluoro-1H-indazol-3-yl)-(2-phenyl-5,6,7,8tetrahydro-pyrido[4,3-dlpyriiidin-4-yl)-amine (IV-36): Prepared from IV-35 (0.13 mmol) by treatment with an equal weight of Pd/C in 4.4% HCOOH in MeQH at room temperature for 12 h. The mixture was filtered through celite, the filtrate was evaporated, and crude product was purified by HPLC to afford PV-36 as yellow solid in 35% yield. '1 NMR (500 MHz, DMSO-d6) 812.9 9.06 1H), 7.99 2H), 7.57 (dd, 1H), 7.34 10), 7.28 3H), 7.22 11H), 3.83 2H), 3.05 21), 2.72 21) ppm. MS m/e= 361.20 HPLC-Method A, Trot 2.68 min.

-327- VO ID c Example 406 (5-Methyl-2H-pyrazol-3-yl)- (3-phenylisoquinolin-1-yl) amine To a solution of 1-chloro- 3-phenylisoquinoline Het. Chem., 20, 1983, 121- Cl 5 128)(0.33g, 1.37 mmol) in DMF (anhydrous, 5 mL) was added (0.27g, 2.74 mmol) and potassium carbonate (0.57g, 4.13 mmol)and the resulting mixture was heated at- reflux for 6 hours. The reaction mixture was then cooled and solvent removed in vacuo. The residue O. 10 was extracted twice with ethyl acetate and the combined o organic layers washed with brine, dried (MgS0 4 filtered and concentrated in vacuo. The crude product was purified by flash, chromatography (SiO 2 gradient DCM-MeOH) to afford V-1 as a colourless oil; 1H NMR (MeOD) 8 2.23 (3H, 5.61 (1H, 7.41 (IH, 7.52(2H, m), 7.62(1H, 7.81i(1H, 8.07(1H, 8.19(2H, m), 8.29(1H, 8.54 (1H, MS 301.2 Example 407 (1i-Indazol-3-yl)-[3-(2-trifluoromethylphenyl)-isoquinoline-1-yl]-amine A solution of 1chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (100 mg, 0.326 mmol) and lI-indazol-3-ylamine (86 mg, 0.651 mmol) in ethanol (3 mL) was heated at 160 C and the solvent evaporated with a' stream of nitrogen. The remaining oil was then heated at 160 C for 18 hours.under nitrogen.

The resulting melt was dissolved in methanol:dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1 x 25 mL) then dried over magnesium sulfate. Purification by-silica gel chromatography (25% to 50% hexane:ethyl acetate) afforded V-2 as a yellow sblid (35 mg, 1 H NMR (500 MHz, de- DMSO) 8 9.78 (br s, 1H), 8.62 1H), 7.9-7.85 1H), 7.78-7.72 1H), 7.70-7.68 1H), 7.65-7.62 1H), 7.60-7.55 1H), 7.52-7.45 3H), 7.41-7.38 1H), -328- Va 7.28-7.25 1H), 7.18 IS), 6.95-6.92 (mi, IH), 5.76 1I); LC-MS m/e= 405.18 HPLC-Method D Re 2.74 min.

Cl 5 Example 408 (5,7Difluoro-1H-indazol-3-yl)-3-(2-.

trifluoromethyl-phenyl)-isoquinolin-1-yl]-amine Prepared from 5,7-difluoro-1H-indazol-3-ylamineto afford compound V-3 as a yellow solid (90 mg, 1 H NMR (500 SMHz, d 6 s-DMSO) 8 13.25 9.92 (br s, 1H), 8.61 (d, oN 10 1H), 7.9 1H), 7.81-7.49 7.26-7.2 2H), 0g 7.12-7.10 1iH); LC-MS m/e= 441.16 HPLC- Method D, Rt 3.58 min.

Example 409 (5-Methyl-22-pyrazol-3-yl)-(2-phenylquinolin-4-yl)-am4ne t To a mixture of 4-chloro-2phenylguinoline Het. Chem., 20, 1983, 121-128)(0.53g, 2.21 mmol) in diphenylether (5 mL) was added methylpyrazole (0.439, 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 precipitate was isolated by filtration. The crude solid was purified by flash chromatography (SiO 2 gradient DCM- MeOH) to afford V-4 as a white solid: mp 242-244C; 'H NMR (DMSO) 8 2.27(3H, 6.02(1H, 7.47(2H, 7.53- .740(2H, br 7.67(1W, 7.92(1%i 8.09(2H, d), 8.48(2H, 9.20(1H,-s), 12.17(1H, br IR (solid) 1584, 1559, 1554,;1483, 1447, 1430, 1389; MS 301.2 Example 410 (1-Indazol-3-yl) (2-phenyl-quinolin-4-yl)amine H NMR (500 MHz, d 6 -DMSO) 8 12.78 1), 9.50 lH), 8.65 8.15 1H), 8.04-7.98 (mn, 3H), 7.94 1H), 7.78-7.75 iH), 7.60-7.40 6H), -329- Va 7.15-7.10 LC-MS (ESt) m/e= 337.11 HPLC- Method D, Rt 2.106 in.

Example 411 (2-Phenyl-qninolin-4-yl) -(1H-pyrazoloE4,3b]pyridin-3-yl) -amine 'H NMR (500 MHz, DMSO-dS) 813.6 11.4 1EV), 8.94 1N), 8.61 Cdd, 11), 8.23 in), 8.316 (dd, 11), 8.12 IN), 7.89 Ct, 1H)), 7.86 1H) 7.65 4H), 7.54 11), 7.52 (dd, IH) ppm. MS r/e= 338.11 EPLC-Metbod A, HPLC- Method D, Rt 2.91 min.

Example 412 (1-XIndazol-3-yl)- C2- (2-trifluorrnethylphenyl) -quinolin-4-ylI -amine 'H NMR (500 MHz, d 6 DMSO) 8 12.6 Cs, l) 9.51 11), .8.7 Cd, 7.95- 7.89 2H), 7-.83-7.70 3H), 7.68-7.62 Cm, 2H), 7.60 Cs, 11), 7.55-7.52 Cm, I1), 7.49-7.45 1N), 7.40-7.37 Cm, 1H), 7.12-7.09 11); LC-MS m/e= 405.15 HPLC-Method D Rt 2.25 min.

Example 413 (5,7-Difluoro-1H-indiazol-3-yl)-[2-(2trifluormethyl -phenyl) -quinalin-4-yl] -amine 3H NMR .(500 MHz, d 6 -DMSO) 8 13.31 Cs, 11), 9.49 in), 8.70- 8.67 7.96-7.92 111), 7.85-7.66 71), 7.63- 7.60 11), 7.42-7.40 1H). LC-MS rnen 441.18 HPLC-Method D Rt 2.39 min.

Example 414 (2-trifluoromethyl-phenyl) -quinolin-4-yll (1E-pyrazolo[4,3-bjpyridin-3-yl)-amine 3H NNR (500 MHz, DMSO-dE) 813.6 11.6 11), 8.98 Cd, 1N), 8.57 (dd, IN), 8.12 3H),L7.97 2H), 7.86 (im, 3H), 7.49 (dd, 7.23 Cs, IN) ppm. MS r/en 405.20 HPLC-Method A Rt 2.91 min.

-330- Example 415 (2-Phenyl-quinazolin-4-yl)-(20- Cl Eli2,4Jtriazol-3-yl)-amine (11-154): off-white solid, mp 266-267-C; "R I*IR'(DM80) 8 7.570-7.7O (4H, rn), 7.85-8.00 (2H, mn), 8.15-8.25 (2H, in), 8.37-8.45 (2WH, 8.58 (111, lS. 13.90 (1W, 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 Cl (MnH)4 IND 10 XQ eA416 (5-Methyl-2E-[1,2,4]triazol-3-yl)-(-phenyl.

o quinasolin-4-yl)-anine (11-155):. 'H NMR (500 MHz, DMSOd6) 858. 59 111) 8 .4 2 J 6. 7 Hz, 2H1), 7. 79 (n 4H1), 8.03 (mn, 2H1), 7.74 4H1), -2.5.1 3H1) ppm. M4S m/ee 303.08 HPLC'-Method A,-.Rt 2.64 min.

Example 417 (23- -Triazol-3-yl) (2trifluoromethylphenyl) -quinazolin-4-ylJ -nine (11-47): Pale yellow-solid, (52* yield) 1'H )MR 1500 MHz, DM4SO-dE) 8 8. 54 1H1), 8. 15 br, 1H1), 7. 91 7. 85 (m, 211), 7.76 (mn, 3H1), 7.66 Ct, 111) ppm. MS m/e= 357.13 (M-iH) rn/e=.355.15 HPLC-Method A, Rt 2.81 mitn.

trifluoromethylphenyl) -quinazolin-4- yl]-amine (11-38): Pale yellow solid (54% yield). 'IH NMR (5*00 MHz, DMSO-dG) 58.44 br, 1H1), 7.92 (in, 3H), 7.84 (mn, 1W), 7.77 (mn, 2H1), T.6E;8(t, 11) 2.2 8 3H1) ppm. MS rn/er= 371.14 rn/en 369.18C(M-H).; HPLC-Method A, Rt 2.89 min.

Example 419 (5-Methylhulfanyl-2f- triazol-3-yl) (2 -trfluoromethylphenyl) -quinazolin-4 -yl] -amine (IX- 156): Pale yellow solid yield) IS NMR (500 MHz," -331- Va DMSO-d6) 8B.56 (br, 1U), 7.90 1K), 7.84 2H), 7.78 CI(m, 21H), 7.67 2H), 2.51 3H, buried by DMSO) ppm.

MS m/e= 403.12 m/e= 401.16 HPLC-Method A, Rt 3.20 min.

C~ Example 420.-(1H-[1,2,4]Triazol-3-yl)-E3-(2trifluoromethyl-phanyl) -isoquinolin-1-yll-amine (IX-175): A solution of l-dhloro-3-(2-trifluorometyl-phenyl)o isoquinoline (0.326 mmol) and 1H-t1,2,4]triazol-3-ylamine IN 10 (0.651 mmol) in ethanol (3 mL) was heated at 160 0 C and o the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160 0 C for 18 hours under nitrogen. The resulting melt was dissolved in methanol/dichloromethane (50 nt), washed with saturated.

aqueous sodium bicarbonate (1 x 25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography affotdedIXzz-175 as a colorless oil (4% yield). H NMR (500 Hz, .CDCI 3 6 9.18 1H), 8.82 (s, 1H), 7.90 1H), 7.85-7.75 3H), 7.71-7.62 3H), 7.60-7.55 2H), 4.42-4.35 1H). LC-MS 356.16 HPLC-Method D, Rt 3.55 min Example 421 (2-Phenyl-quinoldin-4-yl)- (11- 1l,.2,4] triazol- 3 -yl)-amine (X1-176): Pale yellow solid (30% yield). 1H NMR (500 .MHz,.d 6 -DMSO) 5 13.82 1H), 9.91 1H), 8.80 11), 8.70-8.65 1K), 8.55 1K), 8.15-8.12 2H), 8.03-7.98 1K), 7.75-7.72 1M), 7.57-7.49 3H). LC-MS m/em 288.11 HPLC-Method D, Rt 1.55 min.

Example 422 (1EH-[1,2,4]triazol-3-yl)- trifluoromethyl-phenyl) -qunolin-4-ylJ -amine (11-177): Pale yellow solid (46% yield). 3HN MR (500 MHz, d-DMSO) 8 13.70 1H), 9.98 1H), 8.70 1H), 8.49 (s, -332-

VO

o 1 H 8.30 1H), 7.94-7.88 2H), 7.80-7.68 3H), 7.64-7.56 2H). LC-MS m/e= 356.18 HPLC- SMethod D, Rt 1.68 min.

C( 5 Example 423 (1-H-Indazol-3-yl)- [5-methyl-6-morpholin-4yl-2- (2 -trifluoromethyl-phenyl) -pyrimidin-4-yl] -amine S(11-251): Colorless film; 2 yield; H-NMR (500 MHz, CDOD) 8 7.84 2H), 7.71 7.41 2H), 7.14- C 1H), 3.74 4H), 3.69 4H), 1.24 3H) ppm; \0 HPLC-Method A Rt 3.26 min; MS (FIA) 455.1 ci BIOLOGICAL TESTING The activity of the compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of the activated protein kinase.

Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding,': isolating the inhibitor/protein kinase complex and determining the amount of radiolabel bound; Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with the protein kinase bound to known radioligands.

BIOLOGICAL TESTING EXAMPLE 1 Ki DETERMINATION FOR THE INHIBITION OF GSK-3 Compounds were screened for their ability to inhibit GSK-30 (AA 1-420) activity using a standard coupled enzyme system (Fox et al. (1998) protein Sci. 7, 2249). Reactions were carried out in a solution containing 100 mM HEPES (pH 10 mM MgC12, 25 mM NaC1, -333- Va O 300 pM NADH, 1.mM DTT and 1.5% DMSO. Final substrate C( concentrations in the assay were 20 pM ATP (Sigma t Chemicals, St Louis, MO) and 300 pM peptide S(HSSPHQS

(PO

3

H

2 )EDEEE, American Peptide, Sunnyvale, CA).

Ci 5 Reactions were carried out at 30 °C and 20 nM Final concentrations of the components of the coupled Senzyme system were 2.5 mM phosphoenolpyruvate, 300 M NADH, 30 pg/ml pyruvate kinase and 10 pg/ml lactate o dehydrogenase.

I 10 An assay stock buffer solution was prepared o containing all of the reagents listed above with the exception of ATP and the test compound of interest. The assay stock buffer solution (175 ul) was incubated in a 96 well plate with 5 pl of the test compound of interest at final concentrations spanning 0.002 uM to 30 uM at OC for 10 min. Typically, a 12 point titration was conducted by preparing serial dilutions (from 10 mM compound stocks) with DMSO of the test compounds in daughter plates. The reaction was initiated by the addition of 20 pl.of ATP (final concentration 20 pM).

Rates of reaction'were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 min at The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 M for GSK-3: compounds II-1, II- 105, 11-33, II-34 11-36, 11-39, 11-38, 11-39, 1-40, II- 41, 11-42, II-46, II-57, 11-59, II-60, II-61,.11-62, II- 63, II-64, II-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, 11-24, 11-19, 11-78, 11-54, 11-79, II-80, 11-81, 11-82, 11-83, 1-84, II-S6, II-86, 11-20, II-25, II-26; 11-85, 11-21, 11-27, 11-28, 11-87, II-88, 11-29, 11-11, 11-12, 11-30, 11-31, 11-13, 11-14, 11-15, 11-16, 11-17, -334- Va S11-18, 11-79, 11-23, 11-2, 11-90, 11-91, II-92, 11-93, 11-3, II-4, 11-5, 11-6, 11-94, 11-95, II-96, 11-107, II- 108, 11-109, II-110, II-124, II-125, II-ill, II-112, II- 113, II-11,-II-115, 11-116, II-117, 11-118, II-119, 1I- 120, 11-121, 11-208, III-8, 111-7, III-9, 111-37, 111-38, 111-39, 111-40,.111-42, 111-45, 111-46, 111-47,. 111-48, IND111-49, 111-51, 111-52, III-53, 111-54, III-55; III-56, III-57, 111-58, III-59, 111-60, 111-61, III-62, III-63, Cg 111-30, III-65, 111-66, 111-67, 111-70, III- 7 3 ,11I-31, 111-75, 111-76, 111-77, 111-33, 111-34, 111-106, 111-108, 4 III-109, III-111, 111-35, 111-116,111-117, 111-118, III- 119, 111-120, III-121, 111-127, II.1-128, III-141, III- 130, 111-131, IV-15, IV-16, IV-17, IV-20, IV-25, IV-26, IV-34, V-3, and IX-47.

The following compounds were.shown to have Ki values between 0.1 and 1.0 gM for GSK-3: compounds II- 103,-11-104, 11-35, II-44, 11-45, 11-49, 11-50, 11-97, II-101, 11-22, II-32, 111-41, 111-43, III-44, III-281 111-50, 111-29, 111-64, 11I-71, 111-74, 111-78, 111-82, 111-88, 111-90, 111-102, 11I-10oS, III-107, III-110, III- 112, 111-114, 111-115, 111-122, 111-124, II1-124, IV-1, III-1, III-138, 111-140, III-142, 111-129, 111-132, III- 134, 111-135, 111-136, IV-1, IV-10, IV-11, IV-12, IV-13, IV-14, IV-19, IV-21, IV-22, IV-23, IV-24, IV-3, IV-4, IV- 6, IV-7, IV-8, IV-29, IV-31, IV-32, IV-33, IV-36, V-2, V- 7, IX-38, IX-154, and IX-177.

The following compounds were shown to have Ki values between 1.0 and 20 JIM for GSK-3: compounds 11-43, 11-65, 11-48, II-47, 11-51, 11-68, II-52, 11-72, 11-100, 11-98, 11-89, 111-68, 111-81, 111-83, 111-91, III-94, 111-95, 111-96, II-97, 111-98, 111-99, III-100, III-101, III-103, III-123, 111-137, 111-139, 111-143, 111-145, III-146, V-4, V-8, IX-156, and IX-176.

-335-

VO

o BIOLOGICAL TESTING EXAMPLE 2 C( Kz DETERMINATION FOR THE INHIBITION OF AURORA-2 Compounds were screened in the following manner Sfor their ability to inhibit Aurora-2 using a standard C( 5 coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249).

V

n To an assay stock buffer solution containing

VO

C .0.1M HEPES 7.5, 10 mM MgC12, 1 mM DTT, 25 mM NaCI,.2.5 mM o phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate \D 10 kinase, 10 mg/ml lactate .dehydrogenase, 40 mM ATP, and o 800 pM peptide (LRRASLG, American Peptide, Sunnyvale, CA) was added a DMSO solution-of a compound of the present invention to a final concentration of 30 pM. The resulting mixture was incubated at 30 "C for 10 min. Thereaction was initiated by the addition of 10 uL of.

Aurora-2 stock solution to give a final concentration of nM in the assay. The rates .of reaction were obtained by monitoring absorbance at 340 nm over a 5 minute read time at 30 °C using a BioRad Ultramark plate reader (Hercules,. CA). The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 pM for Aurora-2: compounds 11-33, II-34, 11-36, 11-37, 11-40, 11-41, 11-55, II-.7, III-9, III-37, III-38, III-39, III-40, 1-41, III-42, III-44, III-46, III-47, 11I-48, III-49, III-50, III-51, III-52, III-53, III-54, III-55, III-56, III-57, III-59, III-61, III-63, III-30, III-65, III-66, III-67, 111-70, III-31, III-76, III-77, III-78, III-80, 111-32, III-33, III-34, III-106, III-108, 111-109, III-110, IIIill, III-112, III-114, III-35, III-115, III-116, III-117, III-118, 111-119, III-120, III-121, IV-7, IV-30, IV-32, and IV-34.

-336-

VO

0 The following compounds were shown to have Ki values between 0.1 and 1.0 pM for Aurora-2: compounds II- 1, II-105, 11-35, II-38, 11-39, 11-42, 11-64, 11-70, II- 53, 11-99, 11-77, 11-79, 11-86, 11-20, 11-93, 11-94, III- C 5 28, III-58, III-64, III-71, III-73, III-74, III-75, III- 102, III-105, III-107, III-113, III-124, III-1, III-130, ID IV-1, IV-3, IV-4, IV-6, IV-29, IV-33, and V-4.

The following compounds were shown to have Ki C values between 1.0 and 20 gM for Aurora-2: compounds II-

VO

o 10 103, 11-104, 11-57, 11-59, 11-61, 11-63, 11-67, 11-69, C II-75, -11-76, 11-10, 11-19, 11-78, II-54, 1-80, II-82, 11-21, 11-90, 11-91, II-96, 11-107, III-68, III-79, III- 82, III-101, III-103, III-127, III-141, III-129, III-132, IV-31, V-2, IX-47, IX-154, and IX-177.

BIOLOGICAL TESTING EXAMPLE 3 CDK-2 INHIBITION ASSAY Compounds were screened in the following manner for their ability to inhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998) Protein Sal 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgC1 2 1 mM DTT, 25 mM NaCi, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and 100 uM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 pM.

The resulting mixture was incubated at 30 OC for 10 min.

The reaction was initiated by the addition of pL of CDK-2/Cyclin A stock solution to give a final concentration of 25 nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over a 5-minute read time at 30 *C using.a BioRad -337-

VO

C Ultramark plate reader (Hercules, CA) The Ki values were C .determined from the rate data as a function of inhibitor t concentration.

C 5 BIOLOGICAL TESTING EXAMPLE 4 ERK INHIBITION ASSAY n Compounds were assayed for the inhibition of (C ERK2 by a spectrophotometric coupled-enzyme' assay (Fox et o al (1998) Protein Sci 7, 2249). In this assay, a fixed ID 10 concentration of activated ERK2 (10 nM) was incubated O with various concentrations of the compound in DMSO for 10 min. at 30C in 0.1 M HEPES buffer, pH containing 10 mM MgCI 2 2.5 mM phosphoenolpyruvate, 200 PM NADH, 150 pg/mL pyruvate kinase, 50 pg/mL lactate dehydrogenase, and 200 pM erktide peptide. The reaction was initiated by the addition of 65 1M ATP. The rate of decrease of absorbance at 340 nM was monitored. The ICso was evaluated from the rate data as a'function of inhibitor concentration.

The following compounds were shown-to have a Ki value of <IpM for ERK-2: III-109, III-ll1, III-115, III- 117, III-118, III-120, and IV-4.

The following compounds were shown to have a Ki value of between 1pM and 12pM for ERK-2: III-63, and 111-108.

BIOLOGICAL TESTING EXAMPLE AKT INHIBITION ASSAY Compounds were screened for- their ability to inhibit AKT using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mM MgC12, 25 mM NaCI 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 170 pM ATP (Sigma -338-

VO

S Chemicals) and 200 1M peptide (RPRAATF, American Peptide, Sunnyvale, CA). Assays were carried out at 30 "C and t nM AKT. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, CN 5 300 pM NADH, 30 pg/ML pyruvate kinase and 10 pg/ml lactate dehydrogenase.

In An assay stock buffer solution was prepared containing all of the reagents listed above, with the 0 exception of AKT, DTT, and the test compound of interest.

IND 10 56 pl of the stock solution was placed in a 384 well o plate followed by addition of 1 pl of 2 mM DMSO'stock containing the test:compound (final compound concentration 30 The plate was preincubated for about 10 minutes at 30'C and the reaction initiated by addition of 10 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 ICs0 values.

BIOLOGICAL TESTING EXAMPLE 6 SRC INHIBITION ASSAY The compounds were evaluated as inhibitors of human Src kinase using either a radioactivity-based assay or spectrophotometric assay.

Src Inhibition Assay A: Radioactivity-based Assay The compounds were assayed as inhibitors of full length recombinant human Src kinase (from Upstate Biotechnology, cat. no. 14-117) expressed and purified from baculo viral cells. Src kinase activity was monitored by following the incorporation of 33 from ATP into the tyrosine of a random poly Glu-Tyr polymer substrate of composition, Glu:Tyr 4:1 (Sigma, cat. no.

-339-

VO

o P-0275). The following were the final concentrations of C- the assay components: 0.05 M HEPES, pH 7.6, 10 mM MgC12, 2 S-mM DTT, 0.25 mg/ml BSA, 10 1M ATP (1-2 pCi "P-ATP per reaction), 5 mg/mi poly Glu-Tyr, and 1-2 units of recombinant human Src kinase. In a typical assay, all .the reaction components with the exception of ATP were ln pre-mixed and aliquoted into assay plate wells.

VO

C- Inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of The assay plate ID 10 was incubated at 30 OC for 10 min before initiating the o reaction with "P-ATP. After 20 min of reaction, the reactions were quenched with 150 pl.of trichloroacetic acid (TCA) containing 20 mM Na 3 P04. The quenched samples .were then transferred to a 96-well filter plate (Whatman, UNI-Filter GF/F Glass Fiber Filteri cat no. 7700-3310) installed on a filter plate vacuum manifold. Filter plates were washed four times with 10% TCA containing 20 mM Na 3

PO

4 and then 4 times with methanol. 200pl of scintillation fluid was then added to each well. The plates were sealed and the amount of radioactivity associated with the filters was quantified on a TopCount scintillation counter.. The radioactivity incorporated was plotted as a function of the inhibitor concentration. The data was fitted to a competitive inhibition kinetics model to get the Ki for the compound.

Src Inhibition Assay B: Spectrophotometric Assay The ADP produced from ATP by the human recombinant Src kinase-catalyzed phosphorylation of poly Glu-Tyr substrate was quanitified using a coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay one molecule of NADH is oxidised to NAD for every molecule of ADP produced in the kinase reaction. The -340disappearance of NADH can be conveniently followed at 340 nm.

The following were the final concentrations of the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgC12, 2 mM DTT, 0.25 mg/ml poly Glu-Tyr, and 25 nM of recombinant human Src kinase. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 200 pM NADH, 30 pg/ml pyruvate kinase and 10 p.g/ml lactate dehydrogenase.

In a typical assay, all the reaction components with the exception of ATP were pre-mixed and aliquoted into assay plate wells. Inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of The assay plate was incubated at 30'C for 10 min before initiating the reaction with 100 pM ATP. The absorbance change at 340 nm with time, the rate of the reaction, was monitored on a molecular devices plate reader. The data of rate as a function of the inhibitor concentration was fitted to compettive inhibition kinetics model to get the Ki for the compound.

The following compounds were shown to value of <100nM on SRC: III-31, III-32, III-33;, III-47, III-65, III-66, III-37, III-38, III-42, III-44, III-48, III-49, III-70, III-78, III-76, and IV- 32.

The following compounds were shown to value of between 100nM and 1IM for SRC: III-63, III-73, III-72, III-74, III-80,.III-50, The following compounds were shown to have a Ki III-34, 11-39, have a Ki III-71, have a Ki value of between 1pM and 6pM for SRC: II1-79, IV-1, and IV-31.

-While we'have hereinbefore presented a number of embodiments -of this invention, it is apparent that our basic construction can be altered to provide other -341- 00 342 embodiments which utilize the compounds and methods of Sthis invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments which have been represented by way of example.

NO

The term "comprise"- and variants of the term such as "comprises" or "comprising" are used herein to denote the Sinclusion 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 interpretation of the term is required.

Any reference to publications cited in this specification is not an admission that the disclosures constitute common general knowledge in Australia.

Claims (27)

1. A compound of formula VII: R- R 2 (Nq' R2' RY NH HN N N N R SO IVII or a pharmaceutically acceptable derivative or prodrug as hereinbefore defined, wherein: G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R 1 any non-ortho carbon position on Ring C is optionally and independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, Oxo, or -R 8 Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R 5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or -343- 00 heteroaryl ring, -R 5 is hydrogen at each ortho carbon 0 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 (N Ci ring, or Ci- 6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, c oxo, or -R 8 said C 1 -6 aliphatic group optionally. i substituted with halo, cyano, nitro, or oxygen, or R Sand an adjacent substituent taken together with their >s intervening atoms form said ring fused to Ring C; R Y is hydrogen or T-R 3 T is a valence bond or a C1- 4 alkylidene chain; R and R 2 are independently selected from -T-W-R 6 or R 2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO 2 -R 7 or -V-R 6 and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R 4 R 3 is selected from an optionally substituted group selected from C3- 10 carbocyclyl, C-i 10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C 6 10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R 7 -COR 7 -CO (optionally substituted C1- 6 aliphatic), -CON(R 7 2 or -SO2R 7 or two R 4 on the same nitrogen are taken -344- 00 together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R is independently selected from halo, -OR, -CC=O)R, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, c-i -NCR 4 2 -CON(R 4 2 -SO 2 N(R') 2 -OCC=O)R, -N(R 4 )COR, -NCR 4 C0 2 (optionally substituted C 1 -6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 4 CON(R 4 2 4 SO 2 N(R 4 2 -N(R 4 SO 2 R, or -OC(=O)N(R 4 2 or R 5 and an adjacent substituent taken together with their IND intervening atoms form said ring fused to Ring C; V is -SO- -S02-, -N S0 2 -SO 2 N -NCR 6 -C0 2 -N(R 6 -N(R 6 C -N(R 6 )SON(R5)-, -N(R 6 N(R 6 -CCO)N(R 6 6 -C(R5) 2 -C(R 6 -CCR 6 2 S0-, -C(R 6 2 S0 2 -C(R 6 2 S0 2 N(R 6 -C(R 6 2 N(R 6 C(R 6 2 N(R 6 C -C(R 6 2 N(R 6 -C(R 6 =NNCR 6 -C CR 6 -C (R 6 2 N(R 6 )N(R 6 -C (R 6 2 N SON (R 6 -,or C(R'S) 2 N (R 6 )CON(R 6 W is -C(R 6 2 -C(R 6 2 -C(R 6 2 S0-, -C(R 6 2 S0 2 -C(R 6 2 S0 2 N(R 6 -C(R 6 2 N(R 6 -CO- -C0 2 -C (R 6 OC() -C (R 6 OC(O)N(R) -C (R 6 2 N(R 6 CO-, C 6 2 N(R 6 C -C(R 6 =NN(R 6 C 6 -CCR 6 2 N(R 6 )N(R 6 -C(R 6 2 N(R 6 SO 2 N(R 6 2 CON (R 6 or -CON each R 6is independently selected from hydrogen, an optionally substituted C 1 4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R 7is independently selected from hydrogen or an optionally substituted CI- 6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; -345- 00 each R 8 is independently selected from an optionally 0 substituted C1- 4 aliphatic group, -OR 6 -SR 6 -COR 6 -S0 2 R 6 -N(R 6 2 -N (R 6 N (R 6 2 -CN, -NO 2 -CON(R 6 2 or S-CO 2 R 6 and R 9 is selected from halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2 -CON(R 4 2 -SO 2 N(R 4 2 -N(R 4 )COR, -N(R 4 )CO2 (optionally substituted C 1 -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 )SO 2 N(R 4 2 -N(R 4 )SO 2 R, or IN -OC(=0)N(R 4 2

2. The compound 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 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, -SO 2 R 6 -S0 2 NH 2 -N(R 6 2 -C0 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, pyrrolidinyl, thienyl, azepanyl, 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 ring; R y is T-R wherein T is a valence bond or a methylene; and R 2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 -6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a -346- 00 substituted or unsubstituted benzo, pyrido, pyrimido or Spartially unsaturated 6-membered carbocyclo ring. c- 3. The compound according to claim 2, wherein: C-i Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C l and two adjacent substituents thereon form a bicyclic c ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is IN -halo, an optionally substituted C 1 -6 aliphatic group, phenyl, -COR 6 -OR 6 -CN, -SO 2 R 6 -S02NH 2 -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, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; R Y is T-R wherein T is a valence bond or a methylene; and R 2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 -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.

4. The compound 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, -347- 00 and R 1 is -halo, a C 1 -6 haloaliphatic group, a C1-6 C aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, C- morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3- V dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl; 3 R Y is T-R wherein T is a valence bond or O a methylene and R 3 is an optionally substituted group selected from C3-6 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 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 2 optionally substituted C1-6 aliphatic group, -OR, -C0 2 R, -CONH(R 4 -N(R 4 )COR, -S 2 N(R 4 2 or -N(R 4 SO 2 R. The compound 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 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, 1,2,3,4- -348- 00 tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3- 0 dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl; R Y is T-R 3 wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from C 3 -6 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 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 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 2 optionally substituted C 1 -6 aliphatic group, -OR, -CO 2 R, -CONH(R 4 -N(R 4 )COR, -SO 2 N(R 4 2 or -N(R 4 S02R.

6. The compound according to claim 4, wherein said compound has one or more of the features selected from the group consisting of: R Y is T-R wherein T is a valence bond or a methylene and R' is an optionally substituted group selected from phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; 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 -4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, -349- 0 OO morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- 0 tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; c- R 2 and R 2 are taken together with their C-i intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring O optionally substituted with -halo, -N(R 4 2 -Ci-4alkyl, -C- 4 haloalkyl, -NO 2 -0 (Ci 4 alkyl), -C0 2 1 4 alkyl), -CN, 0 -SO 2 (C 1 4 alkyl) -S0 2 NH 2 -OC(O)NH 2 -NH 2 S02 (C 1 4 alkyl), S-NHC(O) (Ci- 4 alkyl), -C(O)NH 2 or -CO(C 1 4 alkyl), wherein C- the (C1- 4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R S wherein each R 5 is independently selected from -Cl, -CN, -CF3, -NH 2 -NH(C 1 -4 aliphatic), -N(C 1 4 aliphatic) 2 -O(C 1 4 aliphatic), C1- 4 aliphatic, and -C02(C1- 4 aliphatic).

7. The compound according to claim 6, wherein: R w is T-R wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; Ring C is 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 -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; -350- R 2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R 4 2 -C 14 alkyl, -C 1 -4 haloalkyl, -NO 2 -O(C 1 4 alkyl), -C0 2 (C 1 4 alkyl), -CN, -SO 2 (C1- 4 alkyl), -SO 2 NH 2 -OC(O)NH 2 -NH 2 SO2 (C 14 alkyl), -NHC(O) (C 14 alkyl), -C(O)NH 2 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 R 5 wherein each R 5 is independently selected from -Cl, -CN, -CF 3 -NH 2 -NH(C 1 4 aliphatic), -N(C 1 4 aliphatic) 2 -O(C 1 4 aliphatic), C1- 4 aliphatic, and -C0 2 (C 14 aliphatic).

8. The compound according to claim 7, wherein said compound is selected from the following compounds: F HN F I 'NN F C VII-4 HN r VII-4 dI' HNH N N F 3 C VII-2 F _dH HN N'-N F 3 C VII-5 VII-3 VII-6 -351- H N 0N' VII-7 F H~N vil-lo 2NH N )N VII -8 HN NA, HN N -lN N A4:k HN")F 3 C'L VII-14 HN2 N AL F 3 C VII-9 F NN N A~ HN jl>cI VII-12 FC VII-13 NA ViILE H~N NA FN F 3 VII-17 NA 3FA-i -352- N VII-19 N kt, NC~ VII-20 N N F 3 C CI VII -21 HN2Np N' N CF 3 CH 3 VII -24 VII-22 VII-23 HN N'-N CF 3 CH 3 HN Jtp H N' N VII-28 H~ HN N' N CI VII-26 CH 3 H N N~r VII-29 N2PH CI HNJ NN -353- CH3 HN eNNH N'"N VII-34 F r 9NN VII-32 CH 3 HN N H N'J N CI CH 3 HN J N 0N)t N VII-33 Et HN J N H N'"N VII-36.

9. A composition comprising a compound according to any one of claims 1-8 and a pharmaceutically acceptable carrier. The composition according to claim 9 further comprising a second therapeutic agent.

11. 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 a compound according to any one of claims 1-8 or the composition according to claim 9 or claim

12. The method according to claim 11, wherein said method inhibits GSK-3 activity in said patient.

13. A method of inhibiting GSK-3 or Aurora activity in a biological sample comprising contacting said biological sample with a compound according to any one of claims 1-8. -354- 00

14. A method of treating a disease that is alleviated by treatment with an GSK-3 inhibitor, said method comprising the step of administering to a patient C-i in need of such a treatment a therapeutically effective amount of a compound according to any one of claims 1-8 V) or the composition according to claim 9 or claim \O IND

15. The method according to claim 14 further \O ND comprising the step of administering to said patient a Ssecond therapeutic agent.

16. The method according to claim 14, wherein said disease is diabetes.

17. The method according to claim 14, wherein said disease is Alzheimer's disease.

18. The method according to claim 14, wherein said disease is schizophrenia.

19. 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 a compound according to any one of claims 1-8 or the composition according to claim 9 or claim 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 a compound according to any one of claims 1-8 or the composition according to claim 9 or claim -355- 00

21. A method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, which method comprises the step of administering C-i to said patient a therapeutically effective amount of a compound according to any one of claims 1-8 or the n composition according to claim 9 or claim IND \O

22. A method of inhibiting the phosphorylation of ON -catenin in a patient in need thereof, which method Ci comprises the step of administering to said patient a therapeutically effective amount of a compound according to any one of claims 1-8 or the composition according to claim 9 or claim

23. A method of treating a disease that is alleviated by treatment with an aurora inhibitor, which method comprises the step of administering to a patient in need of such a treatment a therapeutically effective amount of a compound according to any one of claims 1-8 or the composition according to claim 9 or claim

24. The method according to claim 23, further comprising the step of administering to said patient a second therapeutic agent. The method according to claim 23 wherein said disease is cancer.

26. The composition according to claim 9, in combination with an anti-proliferative agent or a chemotherapeutic agent. -356- 00 27. A method of treating Alzheimer's disease in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to any one of claims 1-8 C- or the composition according to claim 9 or claim

28. A method of treating schizophrenia in a patient \O in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a \O ND compound according to any one of claims 1-8 or the Scomposition according to claim 9 or claim

29. 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 1-8 or the composition according to claim 9 or claim 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 1-8 or the composition according to claim 9 or claim

31. The method of claim 30, wherein said cancer is melanoma or is selected from colon, lung, stomach, or breast cancer.

32. The method of claim 30, comprising the additional step of administering to said patient an anti- proliferative agent or a chemotherapeutic agent, wherein said additional therapeutic agent is administered together with said composition as a single dosage form or -357- 00 separately from said composition as part of a multiple dosage form.

33. A compound of formula VII as defined in claim 1 C- and substantially as described in at least one of the accompanying examples. NO

34. A pharmaceutical composition comprising the C compound of claim 33 and a pharmaceutically acceptable \O 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 33 or the composition according to claim 34. Dated this 2 2 nd day of July 2008 Vertex Pharmaceuticals Incorporated By their Patent Attorneys CULLEN Co. -358-