AU2006201263B2 - 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 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:

ND

N<D

ci ci FIELD OF THE INVENTION The present invention is in the subject of extensfield of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositioaes 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'os 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 intracelllarsignal 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 csuch stimuli include environmental and chemical stress Ssignals osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H 2 0 2 cytokines (e.g.

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

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

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

Aurora-2 is a serine/threonine protein kinase that has been implicated in human cancer, such as colon, breast and.other solid tumors. This kinase is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-2 may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human.colon cancer tissue, the aurora- 2 protein has.been found to be overexpressed. See Bischoff et al., EMBO 1998, 17, 3052-3065; Schumacher 3 o et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.

Glycogen synthase kinase-3 (GSK-3) is a .serine/threonine protein kinase comprised of a and 3 C 5 isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry Biology, 7, 793-803 (2000); Kim and V0 Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)].

2- GSK-3 has been-implicated in various diseases including q diabetes, Alzheimer's disease, CNS disorders such as o 10 manic depressive disorder and neurodegenerative diseases, q 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 0-catenin, the translation initiation factor elF2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBa. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.

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

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

VD

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

However, in a diabetic patient where the insulin response e< 5 is impaired, glycogen -synthesis and glucose uptake fail to increase despite the presence of relatively high blood Slevels of insulin. This leads to abnormally high blood C levels of glucose with acute and long term effects that o may ultimately result in cardiovascular disease, renal ID 10 failure and blindness. In such patients, the normal O insulin-induced inhibition of GSK-3. fails to occur. It

C]

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 (1997)]. Therefore, it is believed that GSK-3 activity may promote generation of the neurtofibrillary 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

ID

D diseases related to increase in neuronal cell death [Zhong et al., Nature, 395, 698-702 (1998); Takashima et t al., PNAS, 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 IND effective GSK-3 inhbitors. Small molecules that inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) 0g and WO 00/38675 (SmithKline Beecham)].

0 10 For many of the aforementioned diseases Sassociated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating the same diseases. However, the various protein kinases often act through different biological pathways. For example, certain quinazoline derivatives have been reported recently as inhibitors of p38 kinase (WO 00/i2497 to Scios). The compounds are reported to be useful for treating conditions characterized by enhanced p38-a activity and/or enhanced TGF-A activity. While p38 activity has been implicated in a wide variety of diseases, including diabetes, p38'kinase is not reported to be a constituent of an insulin signaling pathway that regulates glycogen synthesis :or:glucose uptake.

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

There is a continued need to find new therapeutic agents to treat human diseases. The protein 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.

-ci, 6* 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: NdN d a b

C

NIN

eR e NtN i 9 g

VO

ID

0N1 and ci i cn G is Ring C or Ring D;

VO

C- 5 Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, 0 pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, OD wherein said' Ring C has one or two ortho substituents S.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 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

I is selected from -halo, -CN, -NO 2 T-V-R, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C 1 i- aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo,

VO

C oxo, or -R8, said CI-, aliphatic group optionally CN substituted with halo, cyano, nitro, or oxygen, or RI Sand an adjacent substituent taken together with their Sintervening 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 (S membered ring having 0-3 ring heteroatoms selected from o oxygen, sulfur, or nitrogen, wherein any substitutable \0 carbon on said fused ring formed by R x and R Y is Ssubstituted 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 C.-4 alkylidene chain;

R

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

R

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

-COR,

-COCOR, -COCH 2 COR, -NO 2 -CN,

-S(O)

2 R, -SR, -N(R 2, -CON(R 7

-SO

2

N(R

7 2 -OC R; -N(R 7

)COR,

-N(R

7 ).CO0 (optionally substituted

C-.

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

-C=NN(R

4 2 -C=N-OR, -N(R 7 )CON (R 7 2 -N(R SO 2 N (R 2 -N S2R, or -OC (=O)N(R 2; each R is independently selected from hydrogen or an optionally substituted group selected from C 1 6aliphatic, Cs-0o aryl, a heteroaryl ring having 5-10 ring atoms, or a beterocyclyl ring having 5-10 ring atoms;

VO

o each RI' is independently selicted from -CORi', -CO 2

(C

aliphatic), -CON(R) 2 or -SO 2 or two R' on the same C nitrogen are taken together to form a 5-8 membered heterocycly. or heteroaryl ring; (N 5 each R5 is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO 2 -CN, -S0 2 R, -SR, 2

-CON(R')

2

-SO

2

N(R')

2 -OC -N (R')COR, C0 2 (optionally substituted

C

1 aliphatic), 2

-CNN(R')

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

)CON(R'),

-N(R')SO

2

N(R)'

2 -N(R)SO0 2 R, or -OC(=O)N(R) 2 or R' and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -S02-, -N(R')SO 2

-SO

2

N(R

6 -N -C0 2 CO-, -N(R 6 )C

-N(R

6

)SO

2

-N(R

6

)N(R

6

-OC(O)N(R

6 2

-C(R

6 2

S-,

-C 2 2 s02-, -C (R 6

SO

2 N(R) 2 N (R 6 -c(R) 2 N(R)clo)-, -c(R 6 2 N(R)C(0)0o-,

-C(R

6

)=NN(R

6

-C(R

6

-C(R

6 2 N(R6)N(R 6

-C(R)

2

N(R')SO

2 or C aN (R 6 CON (R 6 W is 2 80-, -C(R 6 2 SO0 2

-C(R

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

N(R

6

-C

2 Oa-, OC

-C(R

6 2

N(R)CO-,

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

N-O-,

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

VO

0 nitrogen to form a 5-8 membered heterocyclyl or (C heteroaryl ring; Seach RB is independently selected from an optionally Ssubstituted Ci.4 aliphatic group, -OR 6

-SR

6

-COR

6 c 5 -SOaR 6

-N(R

6

)N(R

6 2 -CN, -NO 2 -CON(R6) 2 or

-CO

2

R

6 and M R 9 is selected from halo, -OR, -CO 2 R, -COCOR, C- -NO 2 -CN, -SOaR, -SR, -N(R 4 2

-CON(R

4 )a, O -SO 2

N(R

4 2

-N(R

4 COR, -N(R 4 CO2 (optionally D 10 substituted C1-6 aliphatic) -N(R)N(R 4 2 -C=NN(R4) 2, o -C=N-OR, -N(R 4

CON(R

4

-N(R

4

)SO

2

N(R

4 -N(R SO2R, or 2.

As used herein, the following definitions shall apply unless otherwise indicated. The phrase "optionally.

substituted" is used interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted." Unless otherwise indicated, an optionally substituted group may have a'substituent at each substitutable position of the group, and each substitution is independent of the other.

The term "aliphatic" as 'used herein means straight-chain, branched or cyclic CI-C12 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",-ai d "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 N straight and branched chains containing two to twelve carbon atoms. The term "cycloalkyl" used alone or as part of a 00 larger moiety shall include cyclic C 3

-C

12 hydrocarbons which are completely saturated, but which are not aromatic.

5 The terms "haloalkyl", "haloalkenyl" and ID "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case may S be, substituted with one or more halogen atoms. The term C "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, Cr phenethyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2t anthracyl. The term "aryl" also refers to rings that are optionally substituted. The term "aryl" may be used S interchangeably with the term "aryl ring". "Aryl" also includes fused polycyclic aromatic ring systems in which en an aromatic ring is fused to one or more rings. Examples Va Cr include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2o anthracyl. Also included within the scope of the term "aryl", as it is used herein, is a group in which an o aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.

The term "heterocycle, "heterocyclyl", or "heterocyclic" as used herein includes non-aromatic ring systems having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S. Examples of heterocyclic rings include 3-1Hbenzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2tetrahydropyranyl, 3-tetrahydropyranyl, 4tetrahydropyranyl,- -dioalanyl, 11,33-dithiolanyl, [1,31-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. Also included within the scope of the term

IND

S 'heterocyclylff or 'heterocyclicn, as'it is used herein, is a group in which a non-aromatic heteroatom-containing Ct ring is fused to one-or more aromatic or non-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinoliny., where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. The term 'heterocycleft, "he terocyclylff, or lxheterocyclicf whether saturated or 0 partially unsaturated, also refers to rings that ate NO 10 optionally substituted.

The tenm "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxym, refers to heteroaromatic ring groups having five to fourteen members. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyi, 2imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl', 2pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2thiazolyl, 4 -thiazolyl, 5 -thiazolyl, 5-tetrazolyl, 2triazolyl, 5-triazolyl, 2-thienyl, .3-thienyl, carbazolyl, benzimidazolyl, benzothienya, benzofuranyl, indolyl, gquinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benrimidazolyl, isoquinolinyl, idll isoindolyl, acridinyl, or benzoisoxazolyl. Also included.

within the scope of the term 'heteroaryl. as it is usedherein, is a group in which a heteroatomic ring is fused to one, or 'more aromatic or nonard'matic rings where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [3,4 -dipyrimidinyl.

The term uheteroazyinf also refers to rings that are optionally substituted. The tenm "heteroaryl" may be Va S used interchangeably with the term vheteroaryl ring" or -the term "heteroaromatic".

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

-CI

2 substituted

-CH

2

-CH

2

CH

2 substituted -a 2

CH

2

-NO

2 -CN, -N(R 2 -NRoC(O)RO, RO)C(0)N(Ro) 2

-NRCO

2 RO, -ONRRC -NR*NRc N (R) 2 -Nfl COc 2

R,

-C(O)Ca 2 c(o)R, -C0 2 R, -C RO, -C(0)N(RD),

-OC(O)N(RO)

2

-S(O)

2

R

0

-SO

2

N(R*)

2 -S(O)RO, -NRSOa 2

N(R

0 2 -NRso2R, -C(=S)N(Ro 2, -(CH2)YNH

R

(CRa2)yNHC(O)CH(V-RO) wherein

R

0 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 goup. Examples of substituents on the aliphatic group or the phenyl ring of. R include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkyl &minocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonylor, 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 heterocyclic Va ring include those listed -above for the unsaturated carbon of an aryl or heteroaryl group and the following: Ct=0, =NNHR', -NN 2 =NNHC(O)R,

NNHCO

2 (alkyl) =NNHSO (alkyl), or where each R' isi independently c 5. selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of cf D substituents on the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, 0 alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbbnyl, hydroxy, haloalkoxy, or haloalkyl.

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

-C(O)RP,

-COR, -C(O)C(O)RP,

-C()CH

2 -S0 2

-SO

2

N(R+)

2 2

-C(-NH)-N(R

4 2 and -NR'SO 2 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 -CH2-, -C(o)Na-, 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 t o a length of up to about six atoms. Examples of linkers C- include a saturated or unsaturated

C

1 -r alkylidene chain t which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by s -CONH-, -CONHNH-, -CO2-,

NHCO

2 -NHCONH-, OC(0)NH-, -NHNH-, -NHCO-, M -SO2-, -S0 2 NH-, or -NHS02-.

Oc The term 'alkylidene chain" refers to an D optionally substituted, straight or branched carbon. chain ND 10 that may be fully saturated or have one or more units of o unsaturation. The optional substituents are as described ab6ve 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 6f 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 1C- or 4C-enriched. carbon are within the scope of this invention.

VO

f Compounds of formula I or salts thereof may be formulated into compositione. 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 invention and pharmaceutical compositions thereof, which 0 comprise an amount of the protein kinase inhibitor Va 10 effective to treat or prevent a GSK-3-mediated condition Sand 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,

AIDS-

associated 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 Alzhelmer's disease. Another method relates to inhibiting the Sphosphorylation of p-catenin, which is useful for C treating schizophrenia.

t Another aspect of the invention relates to Sinhibiting GSK-3 activity in a biological sample, which CM 5 method comprises contacting the biological sample with a GSK-3 inhibitor of formula

I.

n Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, o which method comprises administering to the patient a 10 compound of formula I or a composition comprising said o 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 atreatment 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-medaated 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

IO

0 diseases with a CDK-2 inhibitor, which method comprises ^c 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 "CDK-2-mediated condition" or "disease", as used herein, means any disease or other Sdeleterious condition in which CDK-2 is known to play a

VO

C- role. The term "CDK-2-mediated conditionn or "disease" o also means those diseases or conditions that are C) 10 alleviated by treatment with a CDK-2 inhibitor. Such Sconditions 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

VO

gC condition in which ERK is known to play a role. The term Cq "ERK-2-mediated condition" or "disease" also means those t diseases or conditions that are alleviated by treatment Swith a ERK-2 inhibitor. Such conditions include, without C 5 limitation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, n Alzheimer's disease, cystic fibrosis, viral disease, Ci autoimmune diseases, atheroscleross, restenosis, O psoriasis, allergic disorders including asthma, ID 10 inflammation, neurological disorders and hormone-related o 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 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, 1 2 47; 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, .Sience 260, 1658; Frey Va D o and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, SAm. J. Resplr. Cell Mol. Blol. 16, 589]..

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

0 Another aspect of this invention relates to a 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 "AKT-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a AKT inhibitor. AKT-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders. The association of AKT, also known as protein kinase with.

various diseases has been described tKhwaja, 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

VO

CD 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.

5 The term "Src-mediated condition", as used herein means any disease state.or other deleterious cn condition in which Src is known to play a role. The term

VO

CI "Src-mediated condition" or "disease" also means those o diseases or conditions that are alleviated by treatment Ci q\ 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, Biochem. Biophys.

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

Staley, Cell Growth Diff., 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

VO

D 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 QD thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or 0 extracts thereof; and blood, saliva, urine, feces, semen, cO N 10 tears, or other body fluids or extracts thereof.

pC 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

VO

C spray, topically, rectally, nasally, buccally, vaginally C or via an implanted reservoir. The term "parenteral" as t used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, (g 5 intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

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

o Sterile injectable forms of the compositions of ND 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 o which are commonly used in the manufacture of ci pharmaceutically acceptable solid, liquid, or other dosage forms may also be-used for the purposes offormulation.

S The pharmaceutical compositions of this invention may be .orally administered in any orally IND acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In Ci the case of tablets for oral use, carriers commonly used o 10 include lactose and corn starch. Lubricating agents, q 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 orcoloring agents may also be added.

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

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

VO

CD (see above) or in a suitable enema formulation.

C Topically-transdermal patches may also be used.

SFor topical applications, the pharmaceutical Scompositions.may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical n administration of the compounds of this invention

VO

C-i include, but are not limited to, mineral oil, liquid O petrolatum, white petrolatum, propylene glycol, \D 1 0 polyoxyethylene, polyoxypropylene 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, 27

VO

0 fluorocarbons, and/or other conventional solubilizing or rC dispersing agents.

SIn addition to the compounds of this invention, -pharmaceutically 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 Sdiseases or disorders.

q A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ID 10 ester, salt of an ester or other derivative of a compound Sof 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, benzenesuifonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, Sfumarate, glucoheptanoate, glycerophosphate, glycolate, .C bemisulfate, heptanoate, hexanoate, hydrochloride, t hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- CI 5 naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, ^c succinate, sulfate, tartrate, thiocyanate, tosylate and o undecanoate. Other acids, such as oxalic, while not in ID 10 themselves pharmaceutically acceptable, may be employed o in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

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

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

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

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

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

O

o 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 compound in the composition.

I 5 Depending upon the particular protein kinasemediated condition to be treated.or prevented, additional Stherapeutic agents, which are normally administered to C treat or prevent that condition, may be administered 0 together with the inhibitors of this invention. For O 10 example, in the treatment of diabetes other anti-diabetic Sagents 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; anti-.

inflammatory 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, anti- convulsants, ion channel blockers, riluzole, and anti- Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents

IO

o for treating liver disease such as corticosteroids, CN cholestyramine, interferons, and anti-viral agents; t agents for treating blood disorders such'as corticosteroids, anti-leukemic agents, and growth C 5 factors; and agents for treating immunodeficiency disorders such.as gamma.globulin.

en Those additional agents may be administered (C separately from the protein kinase inhibitor-containing 0 composition, as part of a multiple dosage regimen.

IND 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.

NNH

HN N HN N

H

A A 1 2 RX and R (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 RE/R Y ring is optionally substituted.

Examples of Ring A systems are shown below by compounds I-A through I-DD, wherein Z 1 is nitrogen or C(R 9 and Z 2 is nitrogen or C(H).

R

T RN INDI- I-B I-c IND HN31 HN31 N o1 %z I-D I-E

I-F

HW HN37H 3 Me:- 0k5 I- Zl ilI

N

4 A

NI-

N-T HWt?

-N

4o Z, N "QU

J.-U

~N~z2 NS7 I-s2

.I-T

HN-31

I

I-N

1

I-U

Y

I-v 3-X

I-Y

1-t I -AA

I-BE

CC I-DD Preferred bicyclic Ring A systems. include. I-A, I-B, I-D, I-2, I-F, I-N, 1-I, I-s, I-L, and more preferably I-A, I-B, I-C, I-F, and I-N, and most preferably I-A, I-B, and I-9.

VO

o- In the monocyclic Ring A system, preferred R groups' when present, include hydrogen, alkyl- or Sdialkylamino, acetamido, or a C1.4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred

R

Y groups, when present, include

T-R

3 wherein

T

Sis a valence bond or a methylene, and R 3 is -N(R 4 2 ID or -OR. Examples of preferred R Y include 2-pyridyl, 4pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, Ci isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, o 10 optionally substituted phenyl such ap phenyl or halo- 0 substituted phenyl, and methoxymethyl.

In the bicyclic Ring A system, the ring formed when R x 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, -N (R 4 2

-CON(R

4 2 -S02N (R 4 -N(R COR, -N(R4)CO 2 (optionally substituted C1-s aliphatic),

-N(R

4 2

-C=NN(R

4 2 -C=N-OR,

-N(R

4

)CON(R

4 2 -N (R SO 2 N (R 4 2 -N (R 4 S0R, or N (R 4 2 wherein R and

R

4 are as defined above. Preferred

RX/R

y ring substituents include -halo,' -OR, -COR, -C0 2

R,

-CON(R)

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

R2 and R 2 may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring, wherein said fused ring is optionally substituted. These are exemplified in the following formula I compounds having a pyrazole-containing bicyclic ring system:

NN

A~K NH H> &HH and Preferred substituents on the R 2

/R

2 fused ring 0include one or more of the following: -halo, 2 3 IND 5 alkyl, -C3. haloalkyl, 41032, -O (C 1 3 alkylY, -C0 2

(C

1 3 o alkyl), -CN, -So 2 3 alkyl) -so 2

N*

2 OC'(0) NH 2

NH

2 S0 2

(C

1 3 ailkyl), -liIIC(o) (C1.3 alkyl), -C(O)1i1 2 and -CO(Cj..

3 alkyl) wherein the alkyl) is most preferablymethyl.

Then the pyrazole ring system is nonocyci .ic, preferred R 2 groups include hydrogen, C..4 aliphatic, alkoxycarbonyl, substituted phenyl., hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- ordialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dial1kylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl) carbonyl. ,.Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl,. 00 2

H,

0303, CH 2 OH, CIIZOCII, 013 C

H

2CM 2 OH, CCH 2

CHOCH

2 0 3

CH

2

OI

2

CH

2 00H 2 Ph, CH 2

CH

3

O!

2

NH

1 0(0 2 0(2C 2 NCOOC (013)3, CONHOB 2, CONHCH 2

CH=CH

2

CONHCH

2 01200(3, CONHO(4 2 Ph, CONH (cyclohexyl) CON (Et) 2 CON (CH 3

CH

2 Ph, CONH(n-C 3 H1), CON (Et) 0(420(20(3, CONIICH 2 CH (CHb) 21, CON (n-C 3

H

7 2 00 (3 methoxymethylpytolidin-I.yl), CONH(3.tolyl), CONH(4tolyl), CONIICH 3 CO(morpholin-1-myl), CO(4-methylpiperazinl-yl), CONIICH 2

CH

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

A

preferred A 2 group is hydrogen.

VO ID o An embodiment that is particularly useful for treating GSK3-mediated diseases relates to compounds of Sformula

II:

.HN N CcF

N

0 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 -R 6

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 -Re, said C 1 -6 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; CD R and R Y are independently selected from T-R, or R X and C

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 Soxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R x and RY is n substituted by oxo or T-R 3 and any substitutable C nitrogen on said ring formed by R x and R Y is o substituted by R'; M0 T is a valence bond or a C 1 -4 alkylidene chain;

SR

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

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or 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 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,

-CO

2

R,

-COCOR, -COCH 2 COR, -NO 2 -CM,

-S(O)

2 R, -SR,

-N(R

4

-CON(R)

2

-SO

2

N(R

7 R, -N(R')COR, -N CO 2 (optionally substituted

C

1 .6 aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R

4 2 -C=N-OR,

-N(R')CON

R7 2 -N (R )SO 2 N 2, N (R 4

)SO

2 R, or

N(R

7 each R is independently selected from hydrogen or an optionally substituted group selected from 6 aliphatic, C6-.o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -R 7

-COR',

-CO

2 (optionally substituted C-e 6 aliphatic),

-CON(R)

2 or -SO 2 or two R 4 on the same nitrogen are taken.

IND

o together to form a 5-8 memnbered he'terocyclyl or (N heteroarkyl ring; ct each R 5 is indendently selected from halo, -OR,

-CO

2 R, -COCOR,

-NTO

2 -ON, O)R, -SO 2 R, -SR, -N(Rt) 2 CON(Rf) 2

-SO

2

N(R')

2 -N(R 4 )cOR, 4 C02 (Optionally substituted aliphatic), n-N(Rt)N(R) 2 -C=lqN(R') 2 -C=N-OR,

-N(R

4 )CONq(R 4 2 -14 N(R 4 )S0 2 (R4) 2 -N (R4) so 2 R, or -OC NQW) 2 or Rs and o an adjacent substituent taken together with their IND 10 intervening atoms form said ring fused to Ring C; O. V is 80 2

-N(R

6 )0 2 -80 2

N(R

6

-N.(R

6 -C0 2 -1 -N(R 6

-N(R

6

-N(R

6

-N(R

6 )So 2 -N(R 6

)N(R

6 -C(0)N(R 6 -C2(R') 2 2 s-, -C(R6) 2 s0-, -C(R- 6 2 s0 2 -C(R 6 2 so 2 N(R)

-C!(R

6 3

-C(R

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

-C(R

6 2

N(R

6

)SO

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

-C!(R

6 -C(R'b2SO-. -C(a 6 )*so 2 -C(RG)2SO 2 N(1t6)-, -C(R6) 2 N(a 6 -CO2-,

-C(R

6 2

N(R

6 )co-, ;C C -C -C (R 6

-C(RG')

2 2

N(R

6

)SO

2 C (")2N(P6)CQ

-CON(RW)-

each .Rc is independently selected from hydrogen, an optionally substituted CI..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 7 iS independently selected from hydrogen or an optio'nal'ly substituted aliphatic group, or two R 7 on the-same nitrogen a re taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;, and Va Seach R 5 is independently selected from an optionally Ci substituted C 1 4 aliphatic group,

-COR,

t -S02R, 2 2 -CN, -NO 2

-CON(R')

2 or -C02R.

When the Re and RY groups of formula II are taken together to form a fused ring, preferred eRX/RY rings n include a or 8-membered unsaturated or Va c partially unsaturated ring having 0-2 heteroatoms, o wherein said R 2 /RY ring is optionally substituted. This IN 10 provides a bicyclic ring system containing a pyrimidine o ring. Examples of preferred pyrimidine ring systems of formula I are the mono- and bicyclic systems shown below.

F2

NH

HN HN/' HN3 II.-A I-B II-C HN1 HN' HN> IO NtN II-D II-E

II-F

HN> HN3? HN H

M

<Ky 11-0 I-I TT.T

LL-I

Va HNs? HN'-3

HN

ci i II-K

II-L

HNN

II-P

More preferred pyrimidine ring systems of ciHN HN31 formula II include IA, I-C, II- and II-, most preferably I-A, II-B, and I-N Morte mnocycicpreferred pyrimidine ring system of formula 11 include IX A, fl-n, il-c, IS-F, and 11-H3, most preferably I-A, lI-B, and 11,.

in the monocycJ.±c'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

7 groups include T-R' wherein T is a valence bond or a methylene, and R 3 is

-N(R

4 2 or -OR. When R is -R or -OR, a preferred R is an optionally substituted group selected from C 1 -6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred. Ry include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl Va such as phenyl or halo-substituted phenyl, and methoxymethyl.

In the bicyclic pyrimidine ring system of formula II, the ring formed when RX and ay are taken C- 5 together may be substituted or unsubstituted. Suitable substituents include, halo, -OR, -CO 2

R,

M -COCOR, -NO 2 -CN, S(O)R, -SOR, -SR, 2

-CON(R)

2 (N -so 2

N(R')

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

CO

2 (optionally o substituted C3.

6 aliphatic), -N(R 2

-C=NN(R

4 )2, IO 10 -C=N-OR, -N(Rf)CON(R') 2

-N(R!)SO

2

N(R

4 2 -N(R )SOR, or o -OC(=o)N(R) 2 wherein R and R 4 'are as defined above.

Preferred RI/R ring substituents include -halo, -OR, -COR, -CO 2 R, -CONJRt) 2 -CN, or- 2 wherein R is an optionally substituted Ct-6 aliphatic group.

The R 2 and R 2 groups Of formula II may be taken together to form a fused ring, thus providing a bicyclic.

ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula II compounds having a pyrazole-containing bicyclic ring system:

H

HHN N

N

tH H NH NH RY N N N

N

,.and Preferred substituents on the R 2

/R

2 fused ring of formula II include one or more of the following: 4 halo, -N(R 4 2 -C.4 alkyl, -C1, -4haloalkyl, -NO 2 -(CI1- 4 alkyl), -CO 2

(C

1 4 alkyl), -CN, -502 (CI-.

4 alkyl), -80 2

NH

2 -OC(Co)NH2, -NH 2 80 2

(C

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

VO

0 -C(0)NH 2 and -CO(C.4 alkyl), wherein the (C 1 4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, Sthe (Ci4 alkyl) group is methyl.

When the pyrazole ring system of formula II is c 5 monocyclic, preferred R 'groups include hydrogen, a substituted or unsubstituted group selected from aryl, 0 heteroaryl, or a C 1 6 aliphatic group. Examples of such preferred R' groups include methyl, t-butyl, -CO 2 0CH 3 Scyclopropyl, furanyl, thienyl, and phenyl., A preferred D 10 R 2 group is hydrogen.

c0 More preferred ring systems of formula II are the followihg, 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 1 and R Y are each methyl, or Rz and R Y are taken together with the pyrimidine ring to form a quinazoline or tetrahydroquinazoline ring: HH CH NH HN HN N HN N II-Aa Il-Ba Il-Ha -Particularly preferred are those compounds of formula SI-Aa, II-Ba, or II-Ha wherein ring C is a phenyl ring and R 1 is halo, methyl, or trifluoromethyl.

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

An important feature of the formula II compounds is the R' 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 R' groups include -halo, an optionally substituted Ci-s aliphatic group, phenyl, -COR 6

-OR

6 -S0 2

R

6 -SO0NH 2

-CO

2

R

6

-CONH

2

-NCOR

6 -OC(o)NH 2 or -NHso 2 When R 1 is o an optionally substituted Cl., aliphatic group, the most preferred optional substituents are halogen. Examples of preferred

R

1 groups include

-CF

3 -Cl, -CN, -COCH,

-OCH

3 -OR, -CH 2

CH

3

-OCH

2

CH

3 -CH3, -CFaCH, cyclohexyl, tbutyl, isopropyl, cyclopropyl, -0sM, -OsC-OH,, -s0 2 CH3, -So0 2

NH

2 N(CHR), -C0 2 CH, -CONH2, -NRCOCH 3 -0C(o)NH 2 -NHS0 2 CH3, and -OCF.

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

-N(R

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

-CO

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

-SO

2

N(R')

2 and

-N(R

4 S02R. More preferred

R

5 substituents include -C1, -CN,

-NH

2 -NH(C.-4 aliphatic),

-N(C

1 -4 aliphatic) 2 aliphatic), C1.4 aliphatic, and -COa(C.

4 aliphatic). Examples of such preferred

R

substituents include -Cl, CN,

-NH

2 -NHMe, -NMe, -bEt, 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 fonrm a bicyclic-ring VO ID D system, the bicyclic ring system is selected from.a naphthyl, quinolinyl or isoquinolinyl ring; Rx is hydrogen or CI-4 aliphatic and R is _T-R3, or Rx and R Y are taken together with their c( 5 intervening atoms to form an optionally substituted 5-7.

membered unsaturated or partially unsaturated ring having ID 0-2 ring nitrogens;

R

1 is -halo, an optionally substituted C-6 C0 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2

R

6 -S02NH 2 o 10 -N(R6) 2 -C0 2

R

6 -CONH2, -NHCOR 6

-OC(O)NH

2 or -NHSO2R 6 0D and

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 i- 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 IX have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R s wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl.ring; eR is hydrogen or methyl and R. is -R, N(R)2, or -OR, or R x and R Y are taken together with their intervening atoms to form a .5-7 membered unsaturated or partially unsaturated carbocyclo ring optionally substituted with halo, -OR, -CO 2 R, -COCOR,

-NO

2 -CN,

-SO

2 R, -SR, 2

-CON(R')

2

-SO

2 N(R)a, -N(R')COR, -N(R 4 )CO (optionally substituted CI-6 aliphatic)., -N (R)N (R 4 2

-C=NN(R

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

-N(R

4

)SO

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

VO

o

R

1 is -halo, a Ci-s haloaliphatic.group, a C-i C 1 -6 aliphatic group, phenyl, or -CN;

R

2 is hydrogen and R 2 is hydrogen or a C substituted or unsubstituted group selected from aryl, or C 5 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 unsubstituted benzo, pyrido, pyrimido'or partially

VO

Cq unsaturated 6-membered carbocyclo ring; and o each R 5 is independently selected from \D 10 -halo, -CN, -NO 2 optionally substituted o aliphatic group, -OR, -CO 2 R, -CONH(R 4

-N(R')COR,

-SO2N(R 4 2 or -N(R 4

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

X is hydrogen or methyl and R 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 C2-, aliphatic group optionally substituted with halogen, or -CN;

R

2 and R 52 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,-4baloalkyl,

-NO

2 -0(C 1 4 alkyl), -CO 2 (CI-4 alkyl), -CN,

-S

2

(CI-

4 alkyl), -S0 2

NH

2 -OC(0)NH 2

-NH

2 S0 4 alkyl) -NHC(O) (CI-4 alkyl), -C(O)NH 2 or -CO(C,1.4 alkyl), wherein the (C- 4 alkyl) is a straight, branched, or cyclic alkyl group; and each Rs is independently selected from -C1, -CN, '-CF 3

-NH

2 -NH(C-4 aliphatic), -N(CI-4 S aliphatic) 2 aliphatic), CI-4 aliphatic, and -C02 (Cl-4 aliphatic) Representative compounds of formula II are shown below in Table 1.

Table 1.

CH

3 HB4tN H I-C N HN H 11-2

F

HN

11-3 II-4 II-5S 11-6

F

H

N CF 8 11-7I1-89 11-7 II-9

F

HNH

NAY

11-12 11-10 Ii 11-13 HN

NCF

3 11-17 Il-is H

N(

N

11-8 c~-X 11-19' 11-201-2 11-21 11-22 11-23 11-24 HSCXIN

CI

11-26 11-25 11-27 11-28 11-29 11-30

F

H

HN

HS dN CI

H

3 0 N

C

11-32

OCH

3

HN

4 00H 3

OH

3 HNk 11-33

.CH

8 HN C 11-36 11-34 11-35

OH

3

OHS

Nk 11-37 OH 3

H

3 11-40

CH

3 11-43 HN9:

I

11-46

OH

3

HH

11-38 CR 3

HN

4

PH

CF

1I -41' HN3 11-39 OH 3 HN

H

t CH2OH3

N

11-42

OH

HN~P

11-45

H

11-4711A4

HNP

11-44

%H

-N CF 8 11-47 11-48

CH

3 ON CF3

N'L

11-49

HN

4

N

11-52 N-t 11-55 H2

NCFS

Il-so 11--53

HN

N"

OH

HN Jjp

N

11-54

HN

N

11-57

HN~

HN

N1-60

NOF

3

F

P, NCF 3 z 1

H

3

C

H2 P

N

F

3

C

HYN

HN

11-64

F

CI

11-62 F3C"?

H

Il-E

HN

11-63

I-S

NC

N

11-66

N

N

11-67 0 2

N

QfNCFa3

N

11-70 N CF 3

F

Hg

NCF

3 11-71 11-72 11-73 11-76

F

HN

NCI

11-74

F

3 0

NCI

11-77

HZ

CF

3 F

F

r, NCFa Z.

CF

3

NZ

Na 11-78

CF

3

F-F

HN

bIc

CF

Br, N CF

N

11-79 Br

HZ

QtNCFS

N

11-82 11-831-8 11-84 52 c~N Br k C 3

N

F I

NCF

3 F "6 IN

CF

8

IF

3 00H 3 11-92

F

r NNCl NO02 F

F

11-87 11-90 11-94 19 IS 11-96

HZ

11-97 H3

OH

H4 11-100

HN

2 11-103

N

HN-

2

H

11-98

HZ

11-99 11-101 11-102 1110 11-104

CH

HNiIJ* H3f"%F3 1I-los CH3- 11-106

H-

11-107 11-108 11-q09

HN

11-112 I 1-110 11-111 11-113 11-114

HNPH

'I-lieC 11-115 11-117 FrYF

HNN

"1N-118

HN

11-120 11-119 11-121

F

11-124

HN

F Q

F

11-122 MeOC

HNN

CF

3 II-12S 11-123 11-126 11-127 II -128 11-129 11-130 11-131 11-132

CO

HNg 11-;133 83C 11-136

F

11'-134 F Z 11-137.

11-135 11-138 HN*NH HNZ?:; N

H

3 0 HN F 3 C AcNH ;'F 3 11-139 11-140

H

HC

MeSO 2 NH C 11-141 il-'142 11-142 ~11-143 1-4 11-144 No

H

3 C Z HC N H

HN

N)

NSQ<

Cbz' CI. MSSO NQ

H

3 VN- F Va11-145 11-146 11-147 HN HN I 00 oo

N

~Me 11-148 11-149 11-150

F

RNJ NZF

HNO

QNLN C

NN

14N 11-5111-152 11-153 F e HNMBs'tr HN

HNH

H N 4 G H N J 6 3 H N Y P s *11-154 11-155 11-156 11-157

HN

N tNCF 3 If11-16

HNI

EtSAQ& Y. 0 11-161

CF

3 11-164 !N NCF 2 11-162 Me

NCF

3 11-165 11-160 11-163 Il-lEE11-167 11-168

MN

H

3 C%1 11-170 11-171 .11-172 11-173' 11-174 Cbz.asN CF 3 11-175

HN

2

H

2

N.%,CN

11-176

HN

9 J%1NN N CF 3 11-180 11-178 11-179 .St

HNZI

11-181

N

HN,.J OF,.H 3

C

3 11-183 c 11-184 11-186 11-187 11-188 11-189 AcNH 11-190 11-190 ~11-191 1-9 11-292 H HN MeNh(N CF, 11-194

HN

2

N-

N C195 11-193 11-196

F

HZ

AcHN <N CF 3 N t 11-197 11-198

F

HZ

Me.N, 1 11-200

HN

2 Met--N Cl

H

2

NO

2 S NS(561k 11-201 11-199

HN

11-202 F

ZF

H

.HN

LISC

N

IplwN 11-204 11-203

HN

OhN 1 11-205 11-206

OH

3 11-207 F

F

tN 11-210

F

*N)

11-213 11-208 11-209 OtN N.

N,

HNs 11-212

F

N A .11-215

HN_

CN CI

>NO

11-214 11-216 I1-217

HN

1 C.1 11-218 11-219 11-221 11-222 11-220 QNtfC(NH2 Me Me 11-223 11-224 Me me TI-225 N

*HNLI

N 91.4 NOMe 11-227 11-228 11-226 N' Me

N

11-229

KN$

Hno~ 11-231 11-232

N

3

C(O)NH

N

11-235 11-230

F

11-233 I-3 Hg Hg cN

NH

2 11-234 11-234 HN2V

NH

2 11-237

H

N

H H h.

11-238 :11-240 HN H C1 II-241

F

SN

II-244

F

F

II-247 2N S -250N(Me), 11-250

HZ

HN Z C I II-242

HZ

HCN CF 3 11-248

HN

HCN OF-251 11-251 HN H N 2 II-243

F

dH II-246

HZ

II

3 2NMe2 11-249 In another embodiment, this invention provides a composition comprising a compound of formula 11 and a pharmaceuitically acceptable carrier.

One.aspect of this invention relates to a method of inhibiting GSR-3 activity in a patient, O comprising administering to the patient a .therapeutically (C effective amount of a composition comprising a compound t of formula II.

Another aspect relates to a method of treating Ci 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 CN therapeutically'effective amount of a composition o comprising a compound of formula II.

ID 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.

0) 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 CI 5 therapeutically effective amount of a composition comprising a compound of formula II. This method is especially useful for treating cancer, such as colon, ^c ovarian, and breast cancer.

SOne aspect of this invention relates to a 10 method of inhibiting CDK-2 activity in a patient, ^C comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula II.

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

Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity in a biological sample, which method comprises contacting the biological sample with the GSK-3 or Aurora inhibitor of formula 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

VO

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

SAnother embodiment of this invention relates to Scompounds of formula IXI: R2' R N O

NIII

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

s and at any substitutable ring nitrogen by provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; R 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 Rx and R Y is substituted by oxo or T-R3; T is a-valence bond or a C 1 i- 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 A 2 is substituted by halo, oxo, -NO 2

_R

7 or ct

-V-R

6 and any substitutable nitrogen on said ring formed by R 2 and R" is substituted by R6;

R

3 is selected from -Rt, -halo, 0OR, -d(0O)R, C0 2

R,

-COCOR, -COCE 2 COR,. -NO 2 Mi, 2 t, SR, _N (R4') 2

-CON(R')

2

-SO

2

N(R

4 2 -N(Rt)COR, (N -N CO 2 (optionally substituted C 1 6 aliphatic) o 2

-C=NN(R')

2 *-C=N4-OR, -N(R)CON(R) 2 IND 10 -N(R')SO 2 N(a') 2 -N(R')S0 2 R, or -OC(nO)N(Rtz2; o each Rt is independently selected from hydrogen or an optionally substituted group selected f rom C 1 6 aliphatic, C 6 10 aryl, a h~teroaryl ring having ring atoms, or a heterocyclyl. ring having.5-10 ring atoms; each It' is independently selected from -CO2 (optionally substituted

C

1 6 Aliphatic),

-CON(R)

2

,F

or -S0 2

R

7 or two R' on the same'nitrogen are taken together to form a 5-S membered heterocyclyl or beteroaryl ring; each Rt 5 is independently se -lected from -It, halo, -OR,

CO

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

-CON(R')

2 -Bb 2 N(Rt) 2 -N(Rt)COR, C62Ioptionally substituted

C

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

-C=NN(R)

2 -C=N-OR, -N(R')CON(R) 2 -N(RflSd 2 NtR) 2 -N(R')S0 2 R, or 2 V is -S02-, -N(Rr)S0 2 -S0 2 -P0 2

-N(R

6 )CO0N(R)-, -N(R)SO 2

N(R

6

-C(O)N(R

6 -OC 20-r aS-,

-C(R

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

N(R

6 d(R 6 2

N(

6 -,C(Rh) 2 C(R 6 -C (R 6 )kNl-O-, (R6) 2K(R) N(R _C(R6)bN (R 6

SO

2 N or 2

N(R

6

COX(R

6 w is -C(R) 2 2

-C(R

6 2 SO-, C(R') 2

S

2 2

S

2

-C(R

6 2

N(R

6 -C0 2

-C(R

6

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

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

-C(R

6 2

-C(R

6

-C(R

6 2

N(R

6

-C(RE)

2 N(RG)SO2N or.-CON(R)-; each R6 is independently selected from hydrogen or an optionally substituted C.,4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R' is independentlV selected from hydrogen or an optionally substituted C.6 aliphatic group,- or two R' on the same nitrogen are taken together with the nitrogen to form a 5-B membered heterocyclyl or heteroaryl ring.

Preferred formula III 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 III 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 bicyclic Ring D systems include naphthyl and isoquinolinyl.

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

-N(R

4 2

-CO

2 R, -CONH(R 4

-N(R

4 )COR, -s0 2

(R

4 2, -N(R 4

)SO

2 R, -SR, -OR, or substituted or unsubstituted group.selected from 5-6 membered heterocyclyl, Cs-o aryl, or C1-6 aliphatic. More preferred Rs 5 substituents include -halo, -CN, -oxo, -SR, o -OR, 2 or a substitutedor unsubstituted group selected from 5-6 membered heterocyclyl, Cg- 1 o .aryl, or C 16 _r aliphatic. Examples of Ring D substituents include -OH, ph ,nyl, methyl; CH 2 OH, CH 2 Oi 2

OH,-

pyrrolidinyl, 0Th, CF 3 CinOH, Cl, NH 2 C(0)CH 3 I-propyl, tert-butyl, SEt., OMe, N(Me) 2 Methylene dioxy, IND and ethylene dioxy.

Pref erred rings f ormed when the Re and RY groups ci of formula III are taken together .to form a fused ring include a or ?-membered unsaturated or partially 0 unsaturat~ed carbocyclo ring, wherein any substitutable carbon on said fused ring is substituted by oxo or T-R 3 Examples of preferred bicyclic ring systems are shown below.

HNN.

Preferred suibstituents on the eRR fused ring off formula III include oxo, halo, -OR, -C(nO)R, -C0 2

R,

-COCOR, '-NO 2 -01, -S(0)iZ, -SO 2 R, -SR, -N(114) 2 -CON(Rt) 2 2 14(R' 2 -N(Rt)COR, -N (R4) C0 2 (optionall17 substituted C 1 aliphatic), 2

-C=NN(R')

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

-N(R

4

)SO

2 N(Rt 2

-N(R')SO

2 R, or

N(RW)

2 wherein R and R 4 are as defined above.

More preferred substituents on the RX/RY fused ring Ct include halo, CN,. oxo, C1...6 alkyl, C 1 6 alkoxy, (c 1 6 alkyl) carbonyl,

(C

1 6 alkyl) sulfonyl, mono- or s dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl.

en Examples of such preferred substituents include methoxy c-i methyl, isopropyl, methylsulfonyl, cyano, chioro, o pyrrolyl, methoxy, ethoxy, ethylamino, acetyl, and acetamido.

Preferred

R

2 sitstituents of formula III include hydrogen, C1..4 aliphatic, alkoxycarbonyl, (un)substzitnted phenyl, hydroxyalkyl, alkoxyalkyl, amninocarbonyl, monoor dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoaliyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyi. Examples of such preferred

R

2 substituents iaclihde methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopeneyl, phenyl, C0 2

H,

CO

2

CI{

3

CH

2 OH,' CH 2

OCH

3

CR

2

CH

2

CH

2 OH, CH 2

CH

2

CH

2 Oa 3

CM

2

CH

2 Ca 2 0CH 2 Ph, CH 2

VS

2

CH

2

NH

2 CH2CH 2

CH

2 NHCOOC (cn3) 3 comtci{(CH3 12, CONKCE 2 cn=cH 2 CQNHcS 2

CE

2 00H 3

CON'HCH

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

CON(CH

3

)CH

2 ph, CONH,(n-CR 7 CON (Et) Oi 2

CH

2 Ofl 3

CONHCR

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

H

7 h2, Co (3methoxymethylpyrrolidin.1.y.) CONH.(3 -tolyl), CONE (4tolyl), CONHCR 3 CO(mophlin-1-yl), CO(4-methylpiperazin..

1-yl), CONHCH 2 O2H, CONR 2 and CO(piperidin-1-yl).

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

R'/R

2 ring systems containing the pyrazole ring include beaxzo, pyrido, pyrimido, 3 -oxo-211-pyridazino, and a partially unsaturated E-membered* carbocyclo ring. Examples-of such *preferred-

R/

2 ring systems containing the pyrazole ring *include the following.: N0 0N

HHH

H H H H.

c Ca H and H IC S Preferred substituents on the R'/R 2 fused ring Sof formula III include one or'more of the following: -halo, 2

-C

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

-O(C-

4 alkyl), 02 (C1-4 alkyl), -CN, -SO 2 4 alkyl), -SO 2

NH

2

-OC(O)NN

2

-NH

2

SO

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

-C(O)NH

2 and -CO(C34 alkyl), wherein the (C14 alkyl) is a straight, branched, or cyclic alkyl group.. Preferably, the (C2-4 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-tetrahydtoisoquinolinyl, 1,2,3,4tatrahydroquinolinyl, 2,3-dihydro-iH-isoindolyl, 2,3dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; RX and Ry are taken together with their intervening atoms to form an optionally substituted benzo ring.or a 5-7 membered carbocyclo ring; and

R

2 is hydrogen or methyl and R 2 is T-W-R' or R, wherein W is -C(R 6

-C(R)

2

N(R

6 -002-,

-C(R

6 2

(R

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

5 More preferred compounds of formula III have one or mpre,.and more preferably all, of the features cn selected from'the group consisting of: Ring D is an optionally substituted ring 'selected from phenyl, pyridinyl, piperidinyl, MD 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; RX and RY are taken together with their intervening atoms to form a benzo ring or a 5-7 membered carbocyclo ring optionally substituted with oxo, halo, -OR,

-CO

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

-SO

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

-SO

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

-N(R

4 )COR, -N(R )CO(optionally substituted aliphatic), -N(Rf)N(R 4 -C=NN(Rt)a, -CrN-OR, -N(R )CON(R'),

-N(R

4 )So0 2 N (R 4 2

-N(R')SO

2 R, or N 2 and each R 5 is independently selected from halo, oxo, CN, NO 2

-N(R

4 2

-CO

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

COR,

-SO

2

N(R

4 2 -N(R4)SO 2 R, -SR, -OR, or a substituted .or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-io aryl, or aliphatic.

Even more preferred compounds of formula III have one or more, and more preferably all, of the features selected from the group consisting bf: R and R are taken together with their intervening atoms to form a benzo or 6-membered partially unsaturated carbocyclo ring optionally substituted with halo, CN, oxo, C1-_ alkyl, C1. alkoxy, (C 1 -s alkyl)carbonyl,

(C

1 -s 6 alkyl)sulfonyl, mono- or dialkylamino, mono- or Va o dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R' is independently selected from -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted group selected from 5-6 membered beterocyclyl, C6-io aryl, or C 1 aliphatic; and ID R' is hydrogen and R' is selected from R 3 is.hydrogen or methyl and R 2 is T-W-R6 or R, wherein W is 0 -C(R 6 2 o0-, -C(R 6 2 2 N(R)CO-, or and R is an optionally 0 substituted group selected from C 1 aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, or partially .unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -C1- alkyl, -CI-4haloalkyl, -NOa, -O(C1.4 alkyl), -CO2 (C-4 alkyl), -CN, -S0 2

(C

1 4 alkyl) -SO 2

NH

2

-OC(O)NH

2

-NH

2

SO

2

(C

1

I

4 alkyl), -NHC(O) (C alkyl), -C(o0)NH 2 or -CO(C-.

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

CH,

HN

2 H HNHAP 111.-1 III-2 111-3

CH

111-4

NMN

HNtt

(N

3

CH

3 *HNX4"

OH

3 ACN)io.NAQ

C

111-6 111-7 11I-9 %CH3 111-10 111-12 111-13 111-14 hI-IS CH9

%N

C113 N

*CY

N

Et

CH

3 3 111-16 111-17 111

OH

3 HNr-NH

NCJZ%

OH

3

OH

3 MN

J*}H

CH

3

NHN

CHs 111-22

OH

3 Hg

IH

3 Cj~l 111-25 111-20

CH

rW N

CH

3

SO

2 ,f 111-23 HA3 111-26 111-21

-N

111-24

H

HN

111-27

OH

3

HN~

111-28

OH

3

HN

111-31

OH

3

HN

111-29

OH

3

HN

111-32

OH

3

HN

W

NH

111-30

OH

3

NLH

111-33

OH

3

HN

t1 Br 111-34

OH

3 HN4* N H 111-37

CH

8 HNC 4 hN

H

111-35

OHS

HN4* *111-38

HH

N4

OH

3

HJI

t N H tANMO N1(1-44

K

OH

3 HN4 111-36

HN

SEt 111-39

HA

111-40 .111-42

OH

3

H

HN4 N4 0

H

N~

111-43 111-45 NN

H

HIA

111-46 CH3 N

H

01t 111-48 111-47 t

HN'*

'NH

H

3

HN<*

tN H 111-49 111-50 "I1-51

CH

3

HN*

OH

3 91 NH

CM

3

HN

N

H

N-

111-52.

111-53 111-54

CH

8

CH

3 HN4$ 111-56 111-55

H

3 tN

H

CF

3 HN4 N' H6

CH

3 HNAI4

NH'

OlrnoH 111-57

OH

3

N

111-59 Ill-GO HNH3

HN

HNQ

-131-62 116 111-63

CH

2 CH3

NH

24-6

GH

3 HNSd N NH 111-64 111-67 111-68 .11-69

HN

H

111-71

CH

2 0H HN4*

H,

111-70 111-72 111-73 111-74 111-75 111-76

-J-NH

2 HNr 111-79 111-77 111-78 111-80 Ill-81 111-82 111-83 111-84 09

HN$

0 rCH3 N

HB

NAI

.111-85 111-86 111-87 111-88 113 1.11-90

OH

3 HN4

'N;

Nl1 oHS 111-92 111-93 111-94 111-95 o ,CH 3

HN

4 111-96

OH

0 t

NH

rI-g 111-97 111-98 Br

HNI

111-N

H

111-100 111-102

NH

S.-d 111-203

OH

3 111-106

OH

3

HN

C

NH

111-104 gZH3 HN>iH

OH

3 'N

H

OH

3

HN*

0

'N

"II-los 111-110 II-ill

OH

3 1 .111-1131114 111-114

HNS

H

HA HN4 0 111-115 111-116 111-117 HN4 HN't KN

N

111-127 HN<f

NH

N&

t 11-2 HAr 111-120 11.1-123 .111-125

CONH

2

HN

OCH3 111-126

HN

NN

111-129 111-128

F

HN

N

H

Ns 111-130 111-133 111-131 111-134

CI

KNZ

cot'.N 111-137 111-132 111-135 tN 1-13N '111-135

HNA

111-136 PhO%%~

HN

2 -t

N

111-139- 111-140 ill-142

HN

2 HN. HN-r

HNN

N

H HN

H

J, N ,rM e

N

me Oe 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 I Anotheroaspect 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 provides comprising a compound of formula II.III and a Another aspect relates toa method of enhancing glycogen synthesis and/or lowering blood levels of glucosethod of in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula amount of a composition comprising a compound of formula Va o Il1. This method is especially useful for diabetic patients.

tAnother aspect relates to a method of inhibiting the production of hyperphosphorylated Tau SS protein ina patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising-a compound of formula IIX. 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 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 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.

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

CI 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 treatment of a disease alleviated thereby, is preferably (c carried out with a preferred compound of formula III, as Sdescribed above.

Compounds of formula III, wherein R 2 is 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 N AKT protein kinases.

o Accordingly, another method of this invention IN 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 Rx 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. is hydrogen and R x 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: IND o Ci

)HN-L-N

N H

D

VIV

Ci or a pharmaceutically acceptable derivative or prodrug o thereof, wherein: MO Ring D is a 5-7 membered monocyclic ring or 8-10 membered 0 bicyclic ring selected from aryl, beteroaryl, 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

5 and at any substitutable ring nitrogen by provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; Rx and R Y are independently selected from T-R 3 or RX and

R

Y

are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having i-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 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, o wherein said fused ring is optionally substituted by up to three groups independently selected from halo, oxo, ct

-NO

2 -at, Or

__R

3 is selected from -Rt, -halo 1 -OR, -CO 2

R,

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

-N(R

4 2 -CON(Rt 2 -S0 2

N(R')

2

-N(R

4

)COR,

IND -N (R0)C0 2 (optionally substituted Cj~ 6 aliphatic)

-N(R

4 )N(R'b2, -C=NN(Rt) 2 -C=N-OR, -N(R')CON(Rl 2 0 -N(R')SO 2

N(R

4 2

-N(RZ

4 )80 2 R.,.or -OC(=0)N(R 4 2 o each Rt is independently selected f row hydrogen or an ooptionally substitute .d group selected from'Claliphatic, CG..2 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each e' is independently selected from -it 7 -coat, S -CO 2 (optionally substituted C 1 6 aliphatic), -CON(R 7 2 or -S0 2 or two Rt 4 on the_ same nitrogen are taken together to form a 5-B merobered heterocyclyl or beteroaryl ring; each R' 5 is independently selected from -Rt, halo, -OR, -C0 2 R, -COCOR, -NO 2 -CNI -S0 2 R, -SRt, -N(W)t 2 CON(it 4 2 -80 2 N(Rt) 2 -OC(aO)R, -N(it 4

)COR,

4) C0 2 (option~ally substituted'C'- 6 aliphatic),

-N(R

4

)N(R

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

)CON(R')

2

-N'(R

4

)SO

2 (Rt) 2 -N1(R 4 )50 2 R, 'or -OC(=O)N(R 4) 2 is V is -SO 3

-N(R')SO

2

-SO

2 N(R6)-, -C0 2 -N(R6)CO-, '-N(it')C(O)0 7 -N Wt) -NtRi) SO 2 N -N (RZ) N -OC N(R) -C (i' 2 CWit) 2

S-,

2 2 N(R6)C(O}O-, -C(R')=bJN(R -C (R 6 2 -C (it' 2 N (it')SO2I4(it)-, or -C 2 N (R6) CON Va oN W is -C 20-, -C(R 6 2S-, -C(R 6 2 SO-, -C(R 6 2S0 2

SC(R)

2 80 2

N(R

6

C(R

6 N(R6) -CO, CO2-,

C(R

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

N(R

6

CO-,

-C(R

6 2 -C(R')=NN(R 5

-C(R

6

-C(R

6 2

N(R

6

-C(R

6 a 2

N(R

6 SON C(R) 2N CO. or. -CON(R 6 each R is independently selected from hydrogen or an IN 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; and each R' is independently selected from hydrogen or an optionally substituted C-6 aliphatic group, or two R7 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

-N(R)

2

-CO

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

N(R')

2

-N(R')SO

2 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-o aryl, or C 16 aliphatic. More preferred R5 substituents include -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 -C(O)R,.or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C-o aryl, or C. aliphatic. Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 oH, 2 CH320H, pyrrolidinyl, OPh, CF 3 C-CH, C1, Br, F, I, NH 2 C(O)CH3, I-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene dioxyj and ethylene dioxy.

When the- RX and R 1 groups of formula IV are taken together to form a fused ring, preferred RaX/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 IV are the mono- and bicyclic systems shown below.

.IV-D V-E IV-G

MN

IV-!

HN

HN Z

IV-J

HN

HN

IV-K

HN3 IV-L IV-I IV-N HN3! .Iv-o HN3' X:V- I 'v-P 'v-Q 'v-ti

HNN

'v-v S a- 'v-y

IV-EB

N A

<N

x:v-w i- z

HN

'V-cc IV-r 'v-x

HA

N

NVA

N HN 0

IV-DD

ID More preferred pyrimidine ring systems of formula IV include IV-E, IV-G, IV-H, IV-J, IV-K, IV-L, CN IV-M, IV-T, and IV-U.

\O

SIn the monocyclic pyrimidine ring system of 0* C formula IV, preferred R z groups include hydrogen, amino, nitro, alkyl- or 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 -R,

-N(R

4 2 or -OR. When R 3 is -R or -OR, a preferred R is an optionally substituted group selected from C 1 -6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred R Y groups include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, 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 R Y are taken together may be substituted or unsubstituted. Suitable substituents include halo, -OR, -COaR, -COCOR, -NO2, -CN, -SO 2 R, -SR, -N(R) 2

-CON(R

4 2 -S0 2

N(R')

2

-N(R

4 COR, -N(R 4 )C0 2 (optionally substituted C 1 6 aliphatic) 2

-C=NN(R')

2 -CtN-OR, -N(R')CON (R) 2 -N(R4)SO 2 N(R4) 2

-N(R')SO

2 R, or

-OC(=O)N(R

4 wherein R and R 4 are as defined above for compounds of formula IV. Preferred RX/RY ring

VO

D substituents include -halo, -OR, -COR, -CO0R, CN -CON(R4) 2 -CN, or -N(R4) 2 wherein R is a substituted or cunsubstituted C6 aliphatic group.

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

HH

RK N rf I ne) Ryt I Q$0NH H H NH S, and Preferred substituents on the R/R 2 fused ring of formula IV include one or more of the following: -halo, 2 -C-4 alkyl, -C1-4 haloalkyl, -NO 2 -O(Ci.

4 alkyl), -COa(C-4 alkyl) -CN, -S0 2

'(C

1 -4.alkyl) -SO2NHa.

-OC(O)NH

2

-NH

2

SO

2 (C3-4 alkyl), -NHC(O) (C1-4 alkyl),

-C(O)NH

2 and -CO (C.4 alkyl), wherein the (Ci-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (Ci-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 C-.6 aliphatic group. Examples of such preferred R 2 groups include methyl, t-butyl, -CH 2 0CH 3 cyclopropyl, furanyl, thienyl, and phenyl. A preferred

R

2 group is hydrogen.

S Preferred formula IV compounds have one or more, and more preferably all, of the features selected t from the group consisting of: S(a) Ring D is an optionally substituted ring CA 5 selected from a phenyl, pyridinyl, piperidinyl, .piperazinyl,. pyrrolidinyl,. thienyl, azepanyl, \M morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3- Sdihydro-1H-indolyl, isoguinolinyl, quinolinyl, or naphthyl ring;

R

x is hydrogen or CI-4 aliphatic and R 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 1-2 ring heteroatoms; and

R

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

-C(R

6 2

N(R

6 -C02-, 2 N(R6)CO-, -C(R 6 2

N(R

6 or

-CON(R

6 and R is an optionally substituted group selected from Cl-s aliphatic or phenyl, 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 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- H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, .or naphthyl;

R

X is hydrogen or methyl and R 7 is -R,

N(R')

2 or -OR, or R x and R

Y

are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, wherein said ring is optionally substituted with -R, halo, oxo, -OR, -COaR, -COCOR, -NO 2 -CN, -S(0)R,

-SO

2 R, -SR,

-CON(R)

2

-SO

2

N(R

4 2

-OC(=O)R,

-N COR, -N(R 4

C

2 (optionally substituted C.-6 aliphatic),

-N(R')N(R

4 2

-C=NN(R

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

)CON(R

4 2 -N(R)S0 2

N(R')

2 -N(R)S0 2 R, or -OC(=0)N(R 4 2 and each R 5 is independently selected from halo., oxo, CN NO, -N(R 4 2

-CO

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

-SO

2

N(R

4 2 -N(R')SOaR,. -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-o aryl, or C- 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:

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, CI-s alkyl, C 1 -6 alkoxy, (Ci- 6 alkyl) carbonyl, alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R is independently selected from -halo, -CN, -oxo, -SR, -OR, -N(R4) 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C-io aryl, or C 1 -6 aliphatic; and

R

2 is hydrogen and R 2 is T-W-R 6 or R, herein W is -C(R 0 -C (R 6 2

N(R

6 -C0 2

-C(R

6 -C(R6)2N(R 6 or -CON(R 6 and R is an optionally substituted group selected from C 1 6 aliphatic or phenyl, or R 2 and R 2 are. taken together with their Sintervening atoms to form a benzo, pyrido, or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, oxo, -NCR4) 2

-C

1 4 alkyl,

-C

1 4 cihaloalkyl,

-NO

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

L

4 alkyl)

-CN,

-SO

2

(C

1 4 alkyl), -50 2 2qH 2

-OC(O)NH

2

-NR

2 80 2

(C

1 4 alkyl), -NHC(D) 4 alkyl), -C(O)Nw 2 or -CO(C.- 4 alkyl), wherein the alkyl) is a straight, branched, or cyclic alkyl.

group.

CC)Representative compounds of formula IV are set

IND

ci forth in Table 3 below.

IND 10 Table 3.

CH Of-I

OH

3 HN*3 N* N N AoNH 0"Li MeG)P- N A Ome IV-l *IV-2 IV-3 Cl-I OH CH3 HNR H H 4

H

HNk NN&

HNN

02N tN HN 'Nr~ :14 IV- IV-6

OH

3 CO 2 Me

OH

3 HNr-t HN*4 *Nel H2N tN atN 0 rY

N

H3C NOH 3 IV- 7 IV-s IV-9 I"0

HNS

HC'Ntc IV-12 IV-11 g0

HN

IV-13

OH

3 IV- 16 IV- 14 CHs tN IV-17

OH

3 IV-18 2 A-1 HA3 H2 HsCX$'l IV-21 CHs HN J H IV-22

CH

3 HN H IV-23 IV- 23

CH

3

HNH

IV-24

CH

3 HN H uN dKC

H

HN MeOt IV-28

CH

3 IV-26

CH

3

HN*H

IV-29 IV-27

CH

HN

IV-31

NZHS

HN

N 3 IV-32

HH

N

IV CH3 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 1-0-2 o effective amount of a composition comprising a compound 0 of formula IV.

Another aspect relates to a method of treating a disease that is alleviated by, treatment with a GSIC-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 IND comprising a compound of formula IV.

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of *glucose in a patient in need thereof comprising Ci 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 proteini 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 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 IV. This method is especially useful for treatin§ 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.

ID

o Another aspect relates to a method of treating (N a disease that is alleviated by treatment with an Aurora 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 IV. This method is Sespecially useful'for treating cancer, such as colon, ovarian, and breast cancer.

0 One aspect of this invention relates to a

C-I

I 10 method of inhibiting CDK-2 activity in a patient, o comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula IV.

Another aspect relates to a method of treating a disease that is alleviated by treatment with a 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 144 CD carried out with a preferred compound of formula IV, as C described above.

3 Another embodiment of this invention relates to Scompounds of formula V:

R

2 R2'

N

H) H 0 -'HN

R

of Z2 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 -Rx, any substitutable nonortho carbon position on Ring C is independently substituted by -R s and two adjacent substituents on Ring C are optionally.taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having.0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, .0 -Roxo,Y or -Re Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocycly or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is (N substituted at any substitutable ring carbon by oxo or

S-R

5 s and at any substitutable ring nitrogen by -R 4 provided that when Ring D' is a six-membered aryl or (c 5 heteroaryl ring, -R s is hydrogen at each ortho carbon position of Ring D; SR is selected from -halo, -CN, -NOs, T-V-R 6 phenyl, 5-6 -N membered heteroaryl ring, 5-6 membered heterocyclyl o ring, or C 1 aliphatic group, said phenyl, heteroaryl, V0 10 and heterocyclyl rings each optionally substituted by Sup to three groups independently selected from halo, oxo, or -RO, said Ci- 6 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

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

R

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

R

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

R

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

R,

ci-COCOR,

'-COCH

2 COR, -NO 2 -aN, -SCO) 2 R, -SR,

-N(R

4 bf -CON(R 7 2

-SO

2

N(R)

2 -OC(cO)R, -N'(R 7

)COR,

-N (R7) CO 2 (Optionally substituted C 1 6 aliphatic), c-i -N N 2 -C=NN WRt 2 -C-N0R, -N CR) CON 2 -N (R )SO 2

N()SO

2 R, or rneach R is independently selected from hydrogen or an

IND

c-i optionally substituted group selected from C 1 6 o aliphatic, C 6 0 aryl, aheteroaryl ring having 5-3.0 IDring atoms, or a heterocyclyl ring having 5-10 ring 0 atoms; each a' is independently selected from -CoatR7 -CO2 (optionally substituted aliphatic), -CON 2 or -SO 2 R or two .R4 on the same nitrogen are taken.

together to form a 5-8 memibered heterocyclyl or heteroaryl ring; each R' is independently selected f rom halo, -OR, -co 2 a, -cocoa, -NO 2 -CN, -so 2 a, -SR,

-NCR')

2 -CON(R')1 2

*-SO

2 NC .R) 2

-N(R')COR,

-N (Re)C0 2 (optionally substituted C 1 6 ,saliphatic) -N (R4)N (R 4 2 -C=NN(Rfl 2 -Nq(R 4

)CON(R')

2 2 N(Wt 2

-NCR')SO

2 R, or -OC(uzO)N(R') 2 oraSz and an adjacent substituent taken together with their intervening toms form said ring fui ed to Ring C; V is -SO2-, -N(R')S0 2 S0 2 N(R6)-, -C0 2 -N(R6)CON(R') -N(R')SO 2 NUR6) -N(R6)N(R) -C(R6) 2 2

S-,

2 S0,, 2 So 2 -C(R'b2SO 2 2 N(Rat)-,

-C(R

6 2 -C(R6) 2W(R) C(0) -C (R6) nNN(R), -C(R6) 2 -CCR6) 2

NCR')SO

2 or 2 N(CR') CON CR 6 W is 2 S-,e '7g(R) 2 so-, 2 so 2 -c(R'h2SO 2 2 -002-, Va S-C

(R

6 OC OC -C (R) 2 N CO-, 2 N(R) -c =NN(R 6 -C N -C(R) 2 aN(R') SO 2 N or i S each R' is independently selected from hydrogen, an optionally substituted C.-4 aliphatic group, or two R' n groups on the same nitrogen atom are taken together S- with the nitrogen atom-to form a 5-6 membered heterocyclyl or heteroaryl ring; each R 7 is independently selected from hydrogen or an o~ 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; each Ra is independently selected from an optionally substituted

C

1 4 aliphatic group, -OR,

-COR',

-S0 2

R

6

-N(R

6 2

-N(R

6

)N(R)

2 -CN, -NO 2

-CON(R)

2 or -Co 2 R; and Ra is selected from halo, -OR, -C(tO)R, -CO 2 R, -COCOR,

-NO

2 -CN,

-SO

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

-CON(R

4 2

-SO

2

N(R')

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 )CON(R) 2

SO

2 SO 2

R,

or an optionally substituted group selected from C 1 -6 aliphatic, Cs-o 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 21 and Z 2 as shown below: 108 S, W HN HN R HN Fx N Rx 1 2

N

G G G S, and n Va Vb Vc

VO

ci O When the Rx and R Y groups of formula V are taken IO 5 together to form a fused ring, preferred Rf/RY rings Sinclude a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms., wherein said R/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Examples of preferred bicyclic ring systems of formula V are shown below.

F

2 t NH HNY HNN

N

HlN

NHN

N

Va-A Vb-A Vc-A HN- HN- HN- Vb-B -B Va-B Vb-B Va-B Va-C Va Cvt-c Va-c Va-D HN31 .Vt- D Va-D Va-E.

Vt-H Va-H Va-F Vt- F Va-F HN>3?

NN/

HN

Va-cr Va -3 :iLio HN' Z Va-L

HW?

Va-Nq Vb -K

~N

N24 Va-K VB- L Vc-L yb-K Va-H ,7 Th-N Va-N

N

Va -a Vb-o V- VC-0

VO

ID

HN/ HN/

HN

N

Va-P Vb-P Vc-P ID More preferred bicyclic ring systems of formula, V include Va-A, Vb-A, Vc-A, Va-B, Vb-B, Vc-B,,Va-D, Vb-D, Vc-D, Va-E, Vb-E, Vc-E, Va-J, Vb-J, Va-J, Va-K, Vb-Ki C Vc-K, Va-L, Vb-L., Vc-L, Va-M, Vb-M, and Vc-M, most C< preferably Va-A, Vc-A, Va-B, Vb-B, and Vc-B.

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

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

R

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

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

-CN,

-SO

2 -SR, -N(R 2, -CON (R 2, -SO 2 2 -N(R')COR, -N(R C02O(optionally substituted.C 6 aliphatic), -N(R 4

)N(R

4 2

-C=NN(R)

2

-C=N-OR,

-N CON(R 4 2 -N(R4)SO 2

N(R

4

-N(R

4

)SO

2 R, or -OC N (R 4 2 wherein R and R are as defined above.

142 D Preferred RX/RY ring substituents include -halo, -OR, 0 -COR, -CO 2 R, -CON(R 4 2 -CN, or 2 wherein R is an optionally substituted Ci, 6 aliphatic group.

SThe

R

2 and R 2 groups of formula V may be taken 5 together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused M rings include benzo, pyrido, pyrimido, and a partially IN unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula V compounds having a \0 10 pyrazole-containing bicyclic ring system:

IND

NH

HN N N Z L jN N NAN RyA,- Z NH L NH T^NH |r N and Preferred substituents on the R 2

/R

2 fused ring of formula V include one or more of the following: -halo, -N (R 4 2, -C-4 alkyl, -Cz-4 haloalkyl, -NO2, -0,(C3-4 alkyl) -CO2(C- 4 alkyl), -CN, -S0 2 (CI-4 alkyl) -SO 2

NH

2

OC(O)NH

2

-NH

2

SO

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

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

4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, Va Sisopropyl, propyl, t-butyl, cyclopentyl, phenyl, 00 2

H,

CO

2

CH

3 COH, CH 2 0CH 3

CH

2

CH

2 CR20H, CHC 2 Ca20CH 3 CH2CH2CH20CK2Ph, CKaCH 2

CH

2

NH

2 2

CHC

2 2NHCOOC (CH) 3 CONHCCH) 2, CONHCHCH2, COHaCEOCH 2 ocHa 3 CONHCHPh, C S CONH(cyclohexyl), CON (Et) 2

CON(CH

3

CH

2 Ph, CONH(n-C 3

H

7 CON(Et)CH 2 2

CH

3 CONRCHCaCH(CH3)2, CON(n-C3H,) 2 CO(3methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4- (N tolyl), CONHCH3, CO(morpholin--yl), CO(4-methylpiperazin- S1-yl),

CONHCHR

2 2C 2 0H, CONH 2 and CO(piperidin-l-yl).

A

preferred R 2 group is hydrogen.

More preferred'ring systems of formula V are the following, which may be substituted as described above, wherein R 2 and R' are taken together with the pyrazole.ring to form an optionally substituted indazole ring; and R" And RY are each methyl, or R' and RY are taken together with the pyridine ring to form an optionally substituted quinoline, isoquinolin, tetrahydroquinoline or tetrahydroisoquinoline ring: H NH NH HN HN 'NHN N V-Aa V-Ba V-Ha When G is Ring C, preferred formula V Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken togethe; 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 114 oN R groups include -halo, an optionally substituted CI-6 aliphatic group, phenyl, -COR, -CN, -S0 2 -S0 2

NH

2 2 -C0 2

R

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

R

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

Examples of preferred R' groups include -CF 3 -C1, -F, -CN, -COCH3, -OCHE, -OH, -CHCH 3

-OCH

2

CH

3 -C1, -CF 2

CH

3 /g cyclohexyl, t-butyl, isopropyl, cyclopropyl, -CaCH, o -CC-CH3, -S0 2 oCH 3

-SO

2 NHa 2

-N(CH

3 2 -C0 2 nCH 3 -CONa 2 IN 10 -NHCOCH 3

-OC(O)NH

2

-NHSO

2

CH

3 and -OCF 3 0 On Ring C preferred R 5 substituents, when present, include -halo, -CN, -NO 2 optionally substituted C- 6 aliphatic group, -OR, -CO 2

R,

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

N(R

4 2 and, -N(R 4 )SO0 2 R. More preferred R substituents include -C1, -CN, -CF 3 -NH2, -NH(C,.4 aliphatic), -N{(CI-4 aliphatic)2, -O(CI-4 aliphatic), CI-..

4 aliphatic, and -C02(CM.4 aliphatic).

Examples of such preferred R 5 substituents include -C1, -CN, -CF 3 -NHz, -NHMe, -NMe, -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -CO 2 Et.

When G is Ring D, preferred formula V Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl piperidinyl, 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-V Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

Preferred substituents on Ring D of formula V include one or more of the following: halo, oxo, CN, -NO2, 115 Va

S-N(R)

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

R,

-SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C-o10 aryl, or C1-s aliphatic. More preferred Ring D substituents include S -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6_20 aryl, or C 1 6 aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 OH, CH 2 CH20H, pyrrolidinyl, OPh, CP 3 CJH, C1,

CA

Br, F, I, NH 2

C(O)CH

3 i-propyl, tert-butyl, SEt, OMe, 0 N(Me) 2 methylene dioxy, and ethylene dioxy.

Preferred formula V compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R' is -halo, an optionally substituted CI-6 aliphatic group, phenyl, -COR', -OR 6 -CN, -S0 2

R

6 -S0 2

NH

2 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 pheryl, 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" is hydrogen or C.

4 aliphatic and RY' is T- R, 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 0-2 ring nitrogens; .and 116 Io R' is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C..

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 6rmembered carbocyclo ring.

More preferred compounds of formula V have one INDor 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 Ci adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R' is -halo, a CI- haloaliphatic group, a C:-s 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-IH-indolyl, isoquinolinyl, quinolinyl, or naphthyl; R is hydrogen or methyl and RY is -R, N(R)2, or -OR, or R and RY are taken together with their intervening atoms to form a benzo ring or.a 57 .membered partially unsaturated carbocyclo ring, said benzo-or carbocyclo ring optionally substituted with halo, -OR, -CO 2 R, -COCOR, -No 2 -CN, -S0 2 oR, -SR, -N(R) 2

-CON(R')

2

-SO

2

N(R

4 2

-N(R

4

)COR,

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

-N(R(R

4

(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(Rt)SO 2 R, or -OC(=O)N(R)2;

R

2 is hydrogen and R' is hydrogen or a substituted or unsubstituted group selected from aryl, or a C 16 aliphatic group, or R 2 and R 2 are taken together

IND

Swith their intervening atoms to form a substituted or (N unsubstituted benzo, pyrido, pyrimido or partially t unsaturated 6-membered carbocyclo ring; and Ring D is substituted'by oxo or R 5 wherein C 5 each R 5 is independently selected from -halo, -CN, -NO 2

-N(R

4 2 optionally substituted CI.6 aliphatic group, -OR, f

-CO

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

-N(R

4 S0 2

R.

o Even more preferred compounds of formula V have ND 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 3 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is.a naphthyl ring, and R1 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, isoguinolinyl, quinolinyl, or naphthyl; 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 x 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, 30 oxo, Ci-6 alkyl, Ci-6 alkoxy, (C-6 alkyl)carbonyl, (CL-6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; -A t rrr~ 1~7 r L18 D

R

2 and R" 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 S -C.4 haloalkyl, -NO2, -O(Cj.4 alkyl), -CO2(C..4 alkyl), -CN,

-SO

2 (C1-4 alkyl)., -SO 2

NH

2 OC NH, -NH 2 S0 2 (CI-4 alkyl) S-NHC(O)

(C

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

-NH

2

-NH(C

1 -4 aliphatic), -N(C-4 aliphatic) 2 -0(C..4 aliphatic), CI.4 aliphatic, and -CO2(C-4 aliphatic).

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

Table 4.

CHS Fg HHN H F V- V-2 V-CF3 V-1 V-2 V-3 V-4 V-5 V-6 F

ZF

H

H

OF

N' t3

N

HN?

LNI'dIL 3 V-7 V-8 V-9.- HN

H

cN&

F

3 0 v-i1o

HN

2

HN

3 0 -V-14 O83 HN<tpH V- 12 V- 13

HN

2

HN

2

NH

HC N

F

3

C

V-18

HN

F

3 0 V-iS V-17 120

H

3 0to- V-21 V-19 V-20 V-22 V-23 V-24 V-27 V-26

HN

F

8

C

V- cI' V-29 V-28 oH 3 C H 2

H

3 C NH

HN

H

3 C H 3 HCt enV-31 V-32 V-33 c~KI

OH

3

HH

H

3 0JS3H3C) 5V-34 V-35 V-36 F F F 04' H3Cfl34 V-37 V-384-3 ,1.22

F

9 HN NN O(a

F

3

C

V-43, V-44 Cll

F

8 C

C

V-46 V-47 -V-48'

F

3 V-'4 V-SO V-Sto HNJ1 V-49 V-50 V-51 V-ss SV-S6 V-57

HN

8 9

H

F

3 0 V-59 V-62 V-63

CH

3

.NIN.)

CH

3

HNA

F

3

C

V-66 V-64 V-65 124 Va ID

F

0 o 'HH SHN Hr H H N N SV-67 V-68

IN

In another embodiment, this invention .provides C- 5 a composition comprising a compound of formula V and a o pharmaceutically acceptable carrier C-i 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 Va 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 0-catenin in a patient (N 5 in need thereof, comprising administering to said patient a therapeutically effective amount of a composition Mn .comprising a compound of formula V. This method is especially useful. for treating schizophrenia.

One aspect of this invention relates to a C 10 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 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 ot 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, 126 I cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid Sarthritis.

SAnother method relates to inhibiting GSK-3, 5 Aurora, or CDK-2 activity in a biological sample, which method comprises contacting the biological sample with Sthe GSK-3 or Aurora inhibitor of formulaV, or a IN pharmaceutical composition thereof, in an amount Seffective to inhibit GSK-3, Aurora or CDK-2.

10 Each of the aforementioned methods directed to o the inhibition of GSK-3, Aurora or CDK-2, or the Ci 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: R2.

R2' aCNH

HN-N

NN

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 s and two adjacent substituents on Ring C are optionally taken together with their

VO

o intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 t heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, C 5 oxo, or -R; Ring D is a 5-7 membered monocyclic ring or 8-10 membered e bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl .or o heterocyclyl ring having 1-4 ring heteroatoms selected D 10 from nitrogen, oxygen'or sulfur, wherein Ring D is o 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;.

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

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C-.

6 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;

R

y is T-R3; 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 and R' are taken together with their intervening -atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -N 2

-R

7 or 148 o -V-R ,and any substitutable nitrogen on said ring 0 formed by R 2 and R 2 'i substituted by R; cRV ctR is an optionally substituted gtoup selected f rom C 1 -,s aliphatic, C 3 10 carbocyclyl, C 6 o aryl', a heteroaryl ring having S-10 ring atoms, or a beterocyclyl .ring having 5-10. ring atoms; each R is independently selected from hydrogen or an IND optionally .substituted grouip selected-from C1_ 6 oaliphatic,

C

6 10 aryl, a heteroaryl ring having 5-10 ci ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected f rom -R I-COR 7 C0 2 (optionally substituted. C3..

6 aliphatic), :-CON (R 7 2 S or -SO2R7, or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R' is independently selected from halo, -OR,

-CO

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

-NC(R)

2

-CON(R

4 2

-SO

2

N(R

4 2

-CO),-()CORI

-N(Rt)CO, (optionally substituted Ca-6*aliphatic)-, -N(R'4)N CR 4 2 -C=NN CR 4 2 CON CR 4 2 -NCRp 4

)SO

2

N(R

4 2

-N(R

4 )So 2 R, or 2 or R'and an adjacent substituent taken together with their intervening atoms form'said ring fused to Ring-C; V is -S02-, -N(R 6 ')S0 2

-SO

2

-NCR

6

-N(R

6

-N(R

6

-N(R

6

-N(R')SO

2

-NCR)N(R

6 -C(O)N(R 6

-OC(O)N(R

6

-C(R

6 2 C 2 s-,

-C(R

6 2 80-, -C(R6) 2 S0 2

-C(R

6 2 80 2

N(R

6 2

N(R

6 2 N(a 6

-C(R')=NN(R

6

-C(R

6 -C(R 6)gTN(a)bT(R 6

-C(R

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

-C(R

6

AN(R

6 CON CR 6 W is 2

-C(R

6 2

*-C(R

6 2 S90-, -C(R'h2SO 2 2

SO

2

NC(R

6

-CCR

6 2

VO

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

C(R)

2

N(R)CO-,

_C(R 2

N(R

6 -C (R R 6

-C(R)

2

N(R

6

SO

2 N

CON(R

6 or -CON(R C-I .5 each R 6 is independently selected from hydrogen, an optionally substituted aliphatic group, or two R 6 Sgroups on the same nitrogen atom are taken together C N with the nitrogen atom to form a 5-6 membered- 0 heterocyclyl or heteroaryl ring; ND 10 each R 7 is independently selected from hydrogen or an Soptionally substituted Ci-. aliphatic group, or two R 7 on the same nitrogen are taken together with-the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R is independently selected from an optionally substituted C1-4 aliphatic group, -OR 6

-COR

6

-SO

2

R

6

-N(R

6 2

-N(R

6

)N(R)

2 -CN, -NO 2

-CON(R

6 2 or

CO

2

R

6 Preferred R Y groups of formula VI include T-R 3 wherein T is a valence bond or a methylene, and R 3 is an optionally substituted group selected from C-6 aliphatic, carbocyclyl, C6s-o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms. A preferred.R 3 group is an optionally substituted group selected from C3-g 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 IND0 ounsaturated 6 -membered carbocyclo ring. These are c-i exemplified in the following formula V7 compounds having Ct a pyrazole-containing bicyclic ring system:

CNH

t4n HHH ci S H KQN and Preferred substituents on the R 2

/R

2 fused ring include one or more of the following: -halo, _N (R 4 2 -C..4 alkyl) -ON, -S0 2

(C

1 4 al~kyl) -SO 2 NH1 2 -0C (O)NH 2 -NHl 2 S0 2 (C3,4 alkyl) NHC (CL- alkyl) C N 2 and -CO(C-4 alkyl), wherein the (Cii- alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C2-.

4 alkyl) group is methyl.

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

H,

002 OR 3 011 2 0H, 01120C%,' CH 2

CH

2

CH

2 OH, CR 2

CH

2

C

2 0IH3, CH,2CH23CH3001H3Ph, 011 2 0H 2 C11 2

NH

2 CH3 2

C

2 N11000 (CH3) 3,

CONEHR(CR

3 2

CONRCR

2 CH=C%1,' CONEH 2

C

2 0CH%, CObIHC%2Ph, CONH(cyclohexyl), CON(Et) 2 CON(c11 3

)CH

2 Ph, CONH(n-0 3 110, CON (Et) 01130113, CONHCH 2 CR CON (n-C 3 11 7 2 CO (3methoxymetylpyrrolidin-l-yl), CON(3-tolyl), C0141(4- Va tolyl), CONECHQ 3 CO(morpholin-l-yl), CO(4-methylpiperazinc 1-yl), CONHCH 2 CH20H, CONE 2 and CO(piperidin-i-yl).

A

preferred

R

2 group is hydrogen.

When G is Ring C, preferred formula VI Ring C C 5 groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused n ring,.Ring C is contained in a bicyclic ring system.

c Preferred fused rings indlude a benzo or pyrido ring.

o Such rings preferably are fused at ortho and meta 10 positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinoliny1. Preferred groups include -halo, an optionally substituted

C

1 aliphatic group, phenyl, -COR', -CN, -80 2

-SO

2

NH

2 2

-CO

2

-CONH

2 -NHCOR',

-OC(O)NH

2 or -NHSO 2 R6.

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

Examples of preferred

R

1 groups include

-CF

3 -C1, -F, -CN, -COH3, -OCHI3, -oH, -CH2CH 3

-OCH

3

CH

3 -CH3, -CF 2

CH

3 cyclohexyl, t-butyl, isopropyl, cyclopropyl,

-OCH,

-OmC-CH 3

-SO

2

CH

3 -SO2NH2,

-N(CH

3 2 -C0 2 CH1 3

-CONH

2 -NHCOCHJ, -OC(0)NH,

-NHSO

2

CH

3 and -OCF 3 On Ring C preferred

R

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

-N(R

4 2 optionally substituted Ci.. aliphatic group, -OR, -C0 2

R,

-CONH(R

4 -N(R')COR,

-SO

2

N(R

4 2 and -N(R)SO 2 R. More preferred R5 substituents include -Cl, -CN, -CF,, -NH2, -NH(C1.4 aliphatic) aliphatic)2, (CI-4 aliphatic), C1-4 aliphatic, and -Co (C.4 aliphatic).

Examples of such preferred

R

5 substituents include -Cl, -CN, -CF 3

-NH

2 -NEMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, trbutyl, and -CO 2 Et.

When G is Ring D, preferred formula VI Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, 1.2 pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.

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

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

-N(R)

2

-CO

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

N(R

4 2

-N(R

4

)SO

2

R,

-SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl,

C

6 aryl, or C.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, C6-o0 aryl, or C2-_ aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 OH, 2CCH 2 OH, pyrrolidinyl, OPh, CF3,. CacH, Cl, Br, F, I, NH, C(0)CH3, 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 isoquinolinyl_ ring, and R 1 is -halo, an optionally substituted CI-6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO2R 6

-SO

2

NH

2

-N(R'

2

-CO

2

R

6

-CONH

2 -NHCOR', -OC(0)NH 2 or -NHSO 2

R

6 or Ring D is an optionally substituted ring selected from a Va 0 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; Ry is T-R, wherein T is a valence bond or a methylene; and C R2 is hydrogen and R' is hydrogen or a.

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

More preferred compounds of formula VI have oneor 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 C 1 6 haloaliphatic group, a 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

7 is T-Rr, wherein T is a valence bond or a methylene and R' is an optionally substituted'group selected from aliphatic, Cj.4 carbocyclyl, C6._o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; U4

VO

C R 2 is hydrogen and R 2 is hydrogen or a C- substituted or unsubstituted group selected from aryl, or Sa Ci-6 aliphatic group, or R 2 and R 2 are taken together Swith their intervening atoms to form a substituted or C 5 unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and c(d) Ring D is substituted by oxo or R 5 wherein

VO

C each R 5 is independently selected from -halo, -CN, -NO 2 optionally substituted CI-6 aliphatic group, -OR, 0 10 -COaR, -CONH(R'), -N(R4)COR, -SO 2 N(R4) 2 or o -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:

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 C1-4 aliphatic, C3-. 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 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 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, -N(R 4 2 -C1-4 alkyl, -C14 haloalkyl, -NO 2 -0(Ci-4 alkyl), -C0 2 (Ci- 4 alkyl), -CN, VO ID o -S0 2

(C

1 .4 alkyl), -SO 2 NHa, -OC(0)NH 2

-NH

2 SO2 (Ci4 alkyl) -NHC(0) (Ci-4 alkyl), -C(O)NHa, or -CO (Ci-4 alkyl) wherein the (CI-4 alkyl) is a straight, branched, or cyclic alkyl group; and Ci 5 Ring D is substituted by oxo or R s wherein each R 5 is independently selected from -Cl, -CN, -CF 3 Cc) -NH2, -NH(C1.4 aliphatic), aliphatic)2, -O(Cz-4 _.aliphatic), CI-4 aliphatic, and -C02(CI-4 aliphatic).

0 Another embodiment of this invention relates to IND 10 compounds of formula VIa:

R

2 Rr

NH

HNjN NkN 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 -R

Z

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 menibered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R; 136 I Ring D is a 5-7 membered monocyclic ring or 8-10 membered Sbicyclic ring selected from aryl, heteroaryl, Sheterocyclyl 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

s and at any substitutable ring nitrogen by ND provided that when Ring D is a six-membered aryl or heteroaryl ring, -R s is hydrogen at each ortho carbon 0 10 position of Ring D; C) R is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 0g membered heteroaryl ring, 5-6 membered heterocyclyl ring, or CI-. aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted, by up to three groups independently selected from halo, oxo, or -Ro, said C-e 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 C_.

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" and R 2 is substituted by halo, oxo, -CN, -NO 2

-R

7 or

-V-R

6 and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R'; each R is independently selected from hydrogen or an optionally substituted group selected from Ci-s aliphatic, C-6i0 aryl, a heteroaryl ring having ring atoms, or a heterocyclylir'hghaviing -10 ring atoms; IND each RI is independently selected from -a7, -Coat -CO2 (optionally sbstituted

C

1 6aliphatic) _CON (R7) 2 or S(2R, O t a'R on the same nitrogen "are taken Ct together to form a 5-8 memnbered heterocyolyl or hbeteroaryl ring;.

each a' is independently selected from halo, -oR, c~KI-C(=0)R,

-CO

2 R, -COCOa,. -N02, -CII, -SOR, -BR,' 2

-CON(R')

2 -80 2 N(R 4) 2 0C(cO)R, X--(R')COR, en -N (R4) Co% (optionally substituted CI-6 aliphatic), :L 0 -u 2 -C=NNWa) 2 -CmZI-0a,

-N(R

4 )CON(R 4) 2 o-N(e aN(R 2 Ng2') 2 R, ot: 2 or R' and cIN An adjacent substituent taken together with their inevnn0tmsfr adrn fsdt igC V is -802-, -N(R')50 2 -20 2 -C0 2 -N(R6)SO 2 -C (0-)M4a) -D 2 -C(aO) 2

S-,

-cCR') 80 -CCR') 2SO2-, -C 2 S0 2 wCR') N CR') 2 2 or -C 2 N CON{(R) N is 2 -C(R4) 3 s0-, -C 2 So 2 2 ao 2 -C(R'6) 3 j-CO-, -C0 2 -C Oc -cCR') 2 N 00-, -C 2 -C cNNR') CR6) c-N7-- -C(6)AR5C0](R6-,or

-CON(R)-;

each R' is independently selected from hydrogen, an optionally substituted

C

1 aliphatic group, or two Rt 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl o r heteroary. ring; each a' is independently selected from hydrogein or an optionally substituted

C

1 6 aliphatic group, or two a NO on the same nitrogen are taken together with the nitrogen. to form a 5-8 membered heterocyclyl or C' heteroaryl ring; and each R' is independently selected from an optionally substituted

C

1 4 aliphatic group, -COR6, 2 -N(R6) 2 -CN, -NO 2

-CON(R')

2 or -00R'.

-c0 3

R

6 Cr) Preferred rings formed by the R and R' groups NO of formula Via include benzo, pyrido, pyrimido, and a 10 partially unsaturated 6-membered carbocyclo ring. These 0 are exemplified in the following formula VIa compounds IDhaving a pyrazole-containing bicyclic ring system: HN)2dHN'k -k N -N N" NNH H H

H.

and Preferred substituents on the R 2 /Ra' fused ring include one or more of the following: -halo, 2

-CI-.

alkyl, -CL-4 haloalkyl, -No2, -0(CI- 'alkyl), -Co2(C1-4 alkyl), -CN, -S0 2

(C

1 alkyl), -SO 2

NH

2

-OC(D)NH

2 -NRSO (Cf4 alkyl), -NEC (C.

4 alkyl) -C NH 2 and -CO (C 1 4 alkyl), wherein the (C1- 4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C 1 1 alkyl) 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 ~f~c- Va positions of Ring. C. Examples of preferred bicyclic Rig C systems include naphthyl and isoquinolinyl. Preferred R1 groups include -halo, an optionally Substituted aliphatic group, phenyl, -COR', -ORO. -Cu, -50 2

-SO

2

NR

2 S 2

-CO

2 R6, -CONE%, -NECOR6,

-OC(O)N

2 ot -NHSO 2

R'.

When R t is an.optionaaly substituted

C.

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

Examples of preferred R 1 groups, include -Cl, -F, IND -CN, 7C0CH 3 -OCE, -OR, -CH 2 CH, '-OCHCH, -CH3, -cr 2 ai,, cyclohezyl, t-butyl, isopropyl, cyclopropyl, -baar, -CC-CH,, -SOi31 -SCEE2, -N(C71,) 2 -CO2CH,,

-CONE,

-miCOCu,, -OC(O)NE 2

-NHSO

2 CH3, and -OCF3.

On Ring C preferred R5h substituets, when *present, include -halo, -UN, -NO2, -N(R optionally substituted C2,_ aliphatic group, -OR,

-COR,

-CON(R),

-N(R

4 )COR, -So2N(R') 2 and -N(R')80 2 R. More preferred R 5 substituents include -Cl, -CN, -Cl 3 -NH2, -NH(C 1 2 4 aliphatic);

-N(C

1 4 aliphatic)2,

-O(C

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

Examples of such preferred R 5 substituents include -Cl,

-C?

3 -NE2, -NMe, -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -COEt.

When G is Ring D, preferred formula Via Ring D monocyclia rings include substituted and unhubstituted phenyl, pyridinyl, piperidtnyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.

When two adjacejit substituents on Ring D are taken together to form a fused ring,, the Ring- D system is bicyclic.' Preferred formula VXa Ring D bicyclic iings include l,2,3,4- tetrahydroisonanclil y 1,2,3,4tetrahydroqtinolinyl, 2,3 -dihydro-lH-isoindolyl, 2,3- dihydro-a'-indolyl, iaocjuinoflnyl, guinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoguinolinyl.

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

-CO

2 R, -CONHE(R'), -N(R')COR, -so 2

N(R)

2 S-N(R)So 2 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl,

.C

6 aryl, or C 1 aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR,

S-N(R')

2 or a substituted or unsubstituted group IND. selected from 5-6 membered heterocyclyl, Cs- 6 o aryl, or C 1 6 aliphatic. Examples of -Ring D aubstituents include -OH, 0 'phenyl, methyl, CH20OE, CR 2

CH

2 OR, pyrrolidinyl, OPh, CF,

\O

IN CMCH, C1, 1r, F, I, zN 2 C(O)cH,, 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'-Rs, 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..

6 aliphatic group, phenyl, -CORE, -CN, -so0 2

-SO

2

NE

2

-N(RC)

2 -CO2R', -CONE, -NHCOR, -OC(O)NH 2 or -NHSOR'; or Ring D is anoptionally substituted ring selected from.a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, i,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, .2,3-dihydro-1B-isoindolyl, 2,3-dihydro-1H-indolyl,.

isoquinolinyl, quinolinyl, or napbthyl ring; and

R

2 and R2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6membered carbocyclo ring.

141 IND More preferred compounds of formula Via have 0 one or more, and more.preferably all, of the features c 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 Rz is -halo, a haloaliphatic group, a C 1 _g aliphatic O group, phenyl, or -CM; or Ring D is an optionally 10 substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, o 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4o ~tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1z-indoly1, isoquinolinyl, quinolinyl, or naphthyl; R? and are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, 2 -C,4 alkyl, -C -4haloalkyl,

-NO

2 -O(C14 alkyl), -CO 2

(C

1 alkyl),

-CM,

-SO

2

(C

1 4 alkyl), -s0o 2

NE

2 -OC NM 2

-NI

2 S0 2 4 alkyl) -NHC() (C,-4-alkyl), -C(O)mj, and -CO(C.

4 alkyl), wherein *the alkyl) is.a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R, wherein each R3 is independently selected from -halo, -CN, -No2, 2 optionally substituted

C

1 aliphatic group, -OR,

-CO

2 R, -CONEH(R'), COR, -SO 2

N(R')

2 or -N 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 ringi optioally substituted by wherein when Ring-d and two IN adjacent substituents thereon form a bicyclic ring Ssystem, the bicyclic ring system is a naphthyl ring, and R' is -halo, a C..

4 aliphatic group optionally substituted C 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 INDnaphthyl;

R

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

-C

1 4 alkyl, -C1-4 baloalkyl, -NO 2 -6(C 1 -4 alkyl), -C0 2

O(C

1 4 alkyl), -CN, -80 (C 1 4 alkyl), -SONH 2 -OC(O)N1, -NE,80 2 s(C.-4 alkyl), -NEC(O) (C.

4 alkyl), -C(O)N 2 or -CO(Cz-4 alkyl), wherein the (C 1 alkyl) is a straight, branched, or cyclic alkyl.

group;. and Ring D is substituted byioxo or RS, wherein each RS 5 is independently selected from -C1, -Cr3, -NE2, -NHl(CI- aliphatic), -N(C1- aliphatic)2, -0(CI-4 aliphatic), C4 aliphatic, and -CO 2 (C-4 aliphatic).

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

Table CH 3 H NAH H -N -1N -N N NN N FN

N

VI-I VI-2 VT-3

HA

VI -4 N-6N v:1-5 84J N'4N VI -6 HNt HN4

N

4 JN N LN VI-7 fl-S Pr Pr NN

NA.*

E4 VI

N'N

VI -12 HzH

N

4

'N

VI -10

VI-".

OMS

N

4 CN N.

Nt~ VI-13 VI-14

'~H

VI-19 9H

NP

VI -22

IN

VI -17 0N1N

ONJ%

VI -23

FZ

IN

-VI -18 HiNP 0 INN VI -21

HNZ-

N

4 6N VI-24

O'N

VI -27 IAN) A I VI-26,

N

H Nxr>N VI-28

HNQ

AN

VI -31

HNZ

MAN

VI -37

HNZ

V7 VI -29

F

ANS

VI -32.

HNI-P

tN6

NN

VI -38

HN

tN VT- 33 N V:1-36

HN~

VI -39

NN

VI -40 HNI-t N ~N VI -43 VI -41

HN:

N N VI -44

*NN

NHg VI -42 H N

IN

Fsc VI H NS&H

N

VI a-S HNrP

HNQ

A -NO

F

IIAN

V~a-2 N'6N Me *N 4 kN CF 2 Vla- 6 Vla-4 Va-S.

H I[Z H H HN H HN HN H SN6 CN NAN Me N- N NHMe SVIa-7 VIa-8 VIa-9

S-NN

IC NAN NIN N-N 8a NHMe Via-10 VIa-11 VIa-12 S In another embodiment, this invention provideg a composition comprising a compound of formula VX 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 IN amount of a composition comprising a compound of formula SVI or VIa. This method is especially useful for diabetic C patients.

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

Ce Another aspect relates to a method of o inhibiting the phosphorylation of P-catenin in a patient 0 in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula VI or VIa. This method.

is .especially useful for treating schizophrenia.

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

Another aspect relates to a method'of treating a disease that-is alleviated by treatment with an Aurora inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a compositioncomprising 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.

OD Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 C inhibitor, said method comprising the step of Sadministering 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, Alzheimer's c disease, restenosis, angiogenesis, glomerulonephritis, D0 cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, 10 alopecia, and autoimmune diseases such as rheumatoid 0 arthritis.

O

D Another .method relates to inhibiting GSK-3, SAurora, 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:

HNN

R Y 1

VII

ND or a pharmaceutically acceptable derivative or prodrug O thereof, wherein: C G is Ring C or Ring D; SRing C is selected from a phenyl, pyridinyl-, pyrimidinyl, Spyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, C wherein said Ring C has one or two ortho substituents independently selected from any substitutable non- S .ortho. carbon position on Ring C is independently.

N0 substituted by -R 5 and two adjacent substituents on e- Ring C are optionally taken together with their eC intervening atoms to form a fused, unsaturated or IN 10 partially unsaturated, 5-6 membered ring having 0-3 Sheteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or 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, is hydrogen at each ortho carbon position of Ring D;

R

1 is selected from -halo, -CN, -NO 2 T-V-R6, phenyl, .5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or CQ. aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or said C.

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; IND R is hydrogen or T-R3'; o T is a valence bond, hydrogen, or a CI- 4 alkylidene chain; CN R and 2 are independently selected from or

R

2 and R2 are taken together with their intervening Satoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heterbatoms selected from nitrogen, oxygen, or sulfur, wherein each Ssubstitutable carbon on said fused ring formed by R2 I and R 2 is substituted by halo, oxo, -CN, -NO2, -R 7 or

-V-R

6 and any substitutable nitrogen on said ring 0 formed by R' and R' is substituted by R*, OD

R

3 is selected from an optionally substituted group o selected from- C3.

0 carbocyclyl, Cs-o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally substituted group selected from C.6 aliphatic, C6-,o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R 7

-COR

7 -CO (optionally substituted Ci- 6 aliphatic), -CON or SOR 7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -COR; COCOR, -NO, CN, -S2OaR -SR,

-N(R

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

-N(R

4

COR,

(optionally substituted CI-6 aliphatic), -C=NN(R -CN-OR, -N(R')CON(R)2, Na(R)SOsN(R') -N(R')SOaR, or or R and an adjacent. substituent taken together with their intervening atoms form said ring fused to Ring C; IND V is 0-5 -BC 2 '802N(R')-, -C2-1; -NCRI')C(0)0-, SC(O6)CNR)-,

-R)

2 0,

-CCR)

2 s- C')30 2 3 NCR)Co0)o-, -cCR) 2NC)XN -cCR')2N CR') BOshR 6 or C C(RO) 2 N (R')COq (Rr) IND W i. 2 -cC') 2

-CCR')

2 80-, -C(RG) 2 30 2

-CCR')

2 B0 2 -003-, -C -C (R0) Nu -C 6 N C-, o -C(R6) 2 5(R')tI(R6) -C(R'i) 2 NCR'SOshIR6)-, -C CR')2H CON or each R6 is independently selected frton hydrogen, an optionally substituted CX- 4 aliphatic group, or two R' *groups on the. same nitrogen. atom are taken toget-her with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R 7 'is' independently 'selected from bydrogen or an *optionally substituted C 1 L-6 aliphatic group, or two R 7 On the'same nitrogen are taken together with the nitrogen to form a'S-B membered heterocyclyl or heteroaryl ring; each Ro is independently selected from an optionally *substituted C 1 .4 aliphatic group, -BR6, -cos 1 -B0 3 2 '-aNI -NO 2 -CoN(R) 3 Or and R 9 is selected from halo, -OR, -CC-Cia, -CO 2 R, -COCOR, -NOn, -aN,

-SO

2 -SR, 2 -005(R4) 2 -SO2N(R') 2 -NCR')CCR, -N(R')CO2Coptionally *substituted C2-6~ aliphatic) NC(R')NCR') 2 2 -C-N-OR, CON R4, 303(R') 2

-N(R

4 50R, or *O -C0z)N W) 2 IN Preferred R Y groups of- formula .fII include T-R 3 o wherein T is a valence bond or a methylene. Preferred R 3 groups include an optionally substituted group selected t from C-.s carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred

R

Y

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

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

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

These are exemplified in the following formula VII compounds having a pyrazole-containing bicyclic. ring system: HiN S, and Preferred substituents on the R 2 fused ring include one or more of the following: -halo, 2 4 alkyl, -Ci-4 haloalkyl, -NOa, -O alkyl) CO (C2., alkyl), -CN, -SO (CI-4 alkyl), -SONH,, -OC(0)NH2, -NHaSO (Cz-4 alkyl), -NHC(O) 4 alkyl), -C(O)NH2, and -CO(Ci.- alkyl), wherein the alkyl) is a .straight, branched, or cyclic alkyl group. Preferably, the (C1-4 alkyl) group is methyl.

When the pyrazole ring system of formula VII. is monocyclic, preferred R' groups include hydrogen, C.-4 IND aliphatic, alkoxycarbonyl, (un) substituted phenyl, S hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, Ct dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl,.cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO 2

E,

C~CH,,S Ca 2 OE, CH 2

OCH

3 Ca 2 0[ 2 a 2 0E, CH 2 oi 2 aH 2 oa 3 IND

CH

2

CH

2

CH

2 Oca 2 PhL, CH 2

CE

2

CE

2

NE

3 CH2

H

2CHaNECOOC (cH 3 3 COIQECH (Ca,) 2 CONHa(CEC-1 2 Comicji 2 Moa 3 coMnCH2, CON(cycloeXYl), CON(at) 2 CON(CE,) CB 2 Ph, CONE(n-C,'H 7 IND CON(Et) CB 2 CH2CH 3

CONECECE{CH,)

2 CON (n-CE 7 2 CO (3o methoxymethylpyrrolidin-l-yl), CONE(3-tolylY, COII(4tolyl), CoNECa,, Co (morpholin-l-y1), CO (4-methylpiperazin- CONHCaCE 2 OE, coNK 2 and CO(piperidin-l-yl).

A

preferred R 2 group 'is hydrogen.

When G; is Ring C, preferred formula VIIZ Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C ar 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 ort~ho and meta positio ns of Ring C. Examples of.-preferred bicyclic Ring C systems include* naplithyl and isoquinolinyl. Preferred R' groups include -halo, an optionally substituted C 14 aliphatic group, phenyl, -CiOR', -OR 6

-SO

2 .4S%1H 2 2 -Co2R, -CONE 2 -I4HCOR', -OC(O)NH 2 or -NESO 2

R

6 When R2. is an optionally substituted C 1 6 aliphatic group, the most preferred optional subatituents are~halogen.

Examples of preferred e' groups include -CF3, -Cl, -F, -01, -COCE3, -0=13, -CE 2

-OCH

2 CMa, -CH 3

-CF

2 C3, cycloheoxyl, t-butyl, isopropyl, .rcyclopropyl, -CK, -CSC-CH,, -so 2 Cs,, -SO 2 NH,, -N(CE 3 2 '-CO2CH2, -CONE 2 -NECOCH,, -OC (O)NH 2

-NHSO

2 CH,, and -OCF 2 INDOn Ring C preferred a'substituents, wban 0present, include -halo, -CN, 4102, 41(R')2, Optionally substituted C 1 6 aliphatic group, -OR, -C%2R, Ct

-N(R

4 )coa, -80 2

N(R')

2 and -N(R')50 2 R More S preferred R' substituents -include -Cl, -01, -C? 3

NE

2

-NH(C

14 aliphatic), .aliphatic) 2

-O(C

1

L

4 aliphatic), C 1 4 aliphatic, and -C0 3 (c 14 aliphatic).

Examples of such preferred R5 aubstituents include -Cl, -aN, -CFar -N4H 2 -N24e, -liMe 2 -ait, methyl, ethyl, cyclopropyl, isopropyl, t-butyr:, and -CO 2 Et.

Whenr G is Ring D, preferred formula VII Ring D o monocyclic rinds 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 U-bicyclic rings include l,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroguinolinyl, 2, 3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, iaouinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

P referred substituents an Ring D include one or more of the following: halo, oxo, CN, -1102, -11(R) 2

-CO

2

R,

-COZQE(R'), -N(R 4 )COR, -802N(R 4 2 -N(R')Sc R, -SR, -OR, -C co) or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6- 0 aryl, or cl-i aliphatic. More preferred Ring D substituents include -halo, -CN, -ozo, -SR, -OR, -11(R') 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C: aryl, or C 1 6 aliphatic.

Examples-of Ring D substituents include phenyl, methyl, 01203, 01301303, pyrrolidinyl,'OPh, CKS, Cl, Br, F, I, NH 2 C(O)CHa, i-propyl, tert-butyl, SEt, OMe, o N(Me) 2 methylene dioxy, and ethylene dioxy.

Preferred formula VII compounds have one or tmore, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by wherein when Ring C and two Cr adjacent substituents thereon form a bicyclic ring 0O system, the bicyclic ring system is selected from a 10 naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is 0 -halo, an optionally substituted C 1 i. alipbatic group, N phenyl, -COR', -OR 6 -CN, -SOaR', -S0 2

NH

2

-N(R)

2 -COaR 6 -CONHa, -NHCOR 6 -OC(O)NHa, or -NHSOR'; 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-lr-isoindolyl, 2,3-dihydro-Z-indolyl, isoquinolinyl, quinolinyl, or naphtbyl.ring;

R

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

R

2 is hydrogen and R' is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1-6 aliphatic group, or R' and R2 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 s wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and INDRI is -halo, a C-s haloaliphatic group, a C 1 -s aliphatic group, phenyl, or -CN; or Ring-D is an optionally.

substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, S 1, 2 3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2, jdihydro-1a-indolyl, isoquinolinyl, quinolinyl, or naphthyl; IND RY is wherein T is a valence bond or 10 a methylene and R" is an optionally substituted group 0 selected from c3-s carbocyclyl, phenyl, or a 5-6 membered oN heteroaryl or heterocyclyl ring; o R' is hydrogen and R is hydrogen or a substituted or unsubstituted-group selected from aryl, or a CI. aliphatic group, 'or R2 and R2' are taken together with their intervening atoms to fotm a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and Ring D is substituted by, oxo or R5, wherein each R5 is independently selected from -halo, -CN, -NO 2 2 optionally substituted CI- aliphatic group, -OR,

-CO

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

N(R')

2 or

-N(R')SO

2

R.

Aven more preferred compounds of formula VII have one or more,.and more preferably all, of the features selected from.thegroup consisting of: RY is wherein T is a valence bond or a methylene and R1" 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 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R1 is -halo, a C3,_ aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally u substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisouinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; S R2 and R 2 are taken together with their IND intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring 0 optionally substituted with -halo, -N -Ca4 alkyl, IND

-C

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

(C

1 4alkyl), -C, O -sO2 (C.

4 alkyl), -SOaN 2

-OC(OJNH

2

-NH

2 80 (C.

4 alkyl), -NHC(O) alkyl), -C(O)NE 2 or -CO(C..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 R9 is independently selected from -Cl, -CN, -C? 3

-NE

2

-NH(C

1 aliphatic), aliphatic) 2 -O(C2.

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

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

Table 6.

FCZ

N- MI HN NN NN N6N o^ odo oio VII-1 VII-2 VII-3 HN jPX

N

VII -4

FG

HIZ

H

Fin

NIN

HN?

NI J- N

HN

N

4 N IN VIZ-I VIZ-S VIZ-fl in

F

N-LN

N

4 QN~%

HNJ>Z),

VlxIZ- VI-l2 F yyF

HN

N A- N UOA..A l FgC'Y*.

VII-14

HNZ

INN

VI Ii

N

4

HNZ

2

N

4 6N VII -19

HZ

VI 1-17

N

4

N

V3:1-20

HN*"

VII- 22

OHS

VII-19.

HZ

N

4

N

VI 2-21 9H O'N CF 8 VII -24

HZ

VII1-27 VI1-23

H

L N OFS N"I-N 0

)ON

-N

VII-26

HNJ

N

4

N

.iN z VII-28 HN H

HN

VII-31 CH,3

N

4

N

VII-34 VII-29

H

"HN

N0 N VII-32

C

HNtJ H

N'N

VII-35 VII-33

HN-P

N-N

VII-36 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 VIT.

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 IN therapeutically effective amount of a composition S comprising a compound of formula VII.

Another aspect relates to-a method of enhancing t 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 SVII. This method is especially useful for diabetic IN patients. ci 10 Another aspect relates to a method of C inhibiting the production of hyperphosphorylated Tau o protein in a patient in need thereof, comprising Sadministering to said patient a therapeutically effective amount of a composition comprising a compound of formula VII. This method is especially useful in halting or slowing the progression of Alzheimer's disease.

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

One aspect of this invention relates to a method of inhibiting Aurora activity in a patient, 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 IND especially useful for treating cancer, such as colon, ovarian, and breast cancer.

One aspect of this invention relates to a C method of inhibiting CDK-2 activity in a patient,.

comprising administering to the patient a therapeutically effective amount of.a composition .comprising a compound of formula VII.

q Another aspect relates to a method of. treating ID a disease that is alleviated by treatment with a CDK-2 10 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a IN therapeutically effective amount of a composition C 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 QSK-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:

OH

b HN z V1 m vzzz Ci INz or a pharmaceutically acceptable derivative or prodrug 0 thereof, wherein: ID

Z

1 is N or CR 9 z 2 is N orCH., and Z 3 is N or CR, provided Sthat one of Z 1 and Z' 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 0-3heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or Ring D is a S-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 halo, oxo, or -R s and at any substitutable ring nitrogen by

-R

4 provided that when Ring D is a six-membered aryl \O or heteroaryl ring, -Ra is hydrogen at each ortho o carbon position of Ring D; N

R

1 is selected from -halo, -CN, -NOa, T-V-R, phenyl, 5-6 Smembered heteroaryl ring, 5-6 membered heterocyclyl ring, or C 1 aliphatic group, said phenyl, heteroaryl, Sand heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R

B

said. C 1 5 aliphatic group optionally O substituted with halo, cyano, nitro, or oxygen, or R i and an adjacent substituent taken together with their C intervening atoms form said ring fused to Ring C;

SR

x is T-R3; o T is a valence bond or a C 1 4 alkylidene-chain; R' and R' are independently selected from -T-W-R 6 or R' and R' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R' and R 2 is substituted by halo, oxo, -CN, -NO2, or 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,

COR,

-COCOR, -COCH2COR, -NO, -CN,

-SR,

N(R'

4

-CON(R

7 -SOaN(R

-N(R

7

)COR,

-N CO (optionally substituted C 1 6 aliphatic),

-N(R

4

-C=NN(R

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

CON(R

7

-N(R

7

-N(R

4 SaR, or -OC (0-)N(R 7 each R is independently selected from hydrogen or an optionally substituted group selected from aliphatic, C-io aryl, a heteroaryl ring having 5-10 ring atoms, or a beterocyclyl ring having 5-10 ring atoms; IND each R4 is independently selected f ram -coit 7 0 -CC (optionally substituted C 1 -6 aliphatic) -CON (R 7 1 or -S2R 7 or two R 4 on the sams nitrogen are taken ct together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R' is independently selected f rom halo, -OR,

-CO

2 R, -COCOS, -1402, -014, -802R, -SR., en-N(W)' 2 -CON(W) 2 S0 2 N 2 -OC Nl(R )coa, IND -N(4 S) CO02(optionally substituted Ci,.aliphatic), -N(S')sogi2(A6) 2 -N(S')so 2 s, or -OC(nO)1I(R) 2 Or e' and oN an adj adent substituent taken together with their intervening atoms form said ring fused to Ring V is -202-, -N(R')S0' 2 -S0 3 14N(R)-, -C0 2 -Nq(R)C(O)O-, -C (0)1(R6) -OC -C -C (R'hS-, 2 so-, -CVR) 2 so 3 -c(Rt) 2 so 2 2 NC5'6)-, 'C 2 N(R)C(0)0r, -C(S'6)dNN(R6) 2 2 N(n6)so 2 or -C CC') 2H(R') CON(RW) W is -C(0t)20-, 2 2 S0-, -C(R) 2 S0 2 00-, -0 o 2 -C OC(0) -c OC 2N(2') CO-, -C 2 -C(R -C _C(R)2XRg)(E**u.

-CL(R')

2 jq(R')80 2 14(R)- -C(6)2(R)CO(R6-,or each R' is independently selected from'hydrogen, an.

optionally substituted C1..4 aliphatic group, or two A6 groups on the same nitrogen atom are taken together with. the nitrogen atom to form a 5-6 memnbered heterocyclyl or heteroaryl ring; each R7 is independently selected from hydrogen or an optionally substituted aliphatic group, or two R7 IDon the same nitrogen are taken together with the 0 o nitrogen to form a5s-S membered heterocyclyl or beteroaryl ring; each Ra is independently selected from an optionally substituted C..4 alipbatic group, -OR, -SR, -coao -SO2R6, -N(R6)2, -N(R6)N(R6)2, -CN. -N02, -CON(R6)2 or -CoR 6 and Cc R' is selected from halo, -OR, -CO 2 R, COCOR, -N0N, -CN, -S(O)R,-50s 2 R, -SR, 2 -CON(R')h,

-SON(R')

2 -N(R)COR, -N(R)C0 2 (optionally substituted CZ 1 -6 aliphatic), 2

-C=NN(R')

2 o -CaN-OR, -N(R')CON(R') 2

-N(R')SO

2

N(R)

2 -N(R')SOR, or

S-OC(=O)N(R)

2 Accordihgly, the present invention relates to compounds of formula VIa, V11Tb, VIZaIc and V111d as shown below:

RA

2 G n G G ""sAg rand VIlla V11b VIlla VfIId Preferred Rl groups of formula VITI include T-R 3 wherein T is a valence bond or a methylene and R 3 is CN, or -OR. When R 3 is preferred R' groups include an optionally substituted group selected from aliphatic, phenyl,. or a 5-6 membered heteroaryl or heterocyclyl ring. When R' is -OR, preferred R groups include an optionally substituted group C.-s aliphatic group such as alkyl- or dialkylaminoalkyl and aminoalkyl. Examples of INDpreferred r include acetamido, CN, piperidinyl, piperazinyl, phenyl, pyridinyl, imidazol-1-y, imidazol- 2-yl, cyclohexyl, cyclopropyl, methyl, ethyl, isopropyl, t-butyl,

N

2 aCM 2

CH

2 n, and NH 2 EH2cH20I.

Preferred R' groups of formula VIII, when .present, include R, OR, and N(R') 2 Examples Qf preferred R' include methyl, ethyl, NH 2 a, NH 2

MC

2 cNE, N(Ca)' 2 H2 3 cO 2

NH,

N. (CH) a 2 cao0, (piperidin-l-yl)

C

C

H 2 O, and N 2

CH

2

CH

2

O..

NO The R 2 and R 2 groups of formila 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, 0 and a partially unsaturated 6-membered carbocyclo ring.

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

H

HN

rl N t4\ N' IN 2o ,2 H $N and Preferred substituents on the formula VIII R2/R fused ring include one or more of the following: -halo, -N(R 4 2 -C.4 alkyl, -C halalkyl, -NO, -0(C,2alkyl), -co 2 (CI-4 alkyl), -802 (C 1 -4 alkyl), -SONaH 2 oc -Oc(o) NI, -NH 2 so 2 (c 1 alkyl), -NE alkyl), -C (0)N 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 groups include hydrogen, C-4,, INDaliphatic,- alkoxycaxbonyl, (us)substituted phenyl, 0hydroxyalkyl, alkoxyamkyl, amino .carbonyl, mono- or (N dialkylaminb~carbonyl, mminoalkyl, alkylaminoalkyli Ct dialkylaminoalkyx, phenylaminocarbonyl, -and (Nh eterocyclyl) carbonyl. Examples Of such preferred

A

2 substituents include methyl, cyclopropyl, ethyl, imopropyl, propyl, t-butyl, cyclopentyl, phenyl, C0 2

H,

CO

2 CH3, -CH 2 0E, CN 2 0CE 13 C2C 2 H0, cZ2H 2

C

2 0CHs,

INDCH

2 cH 2

CH

2 OcH 2 Ph, McH 2 cI 2 Nu 2 cH2 C2 VNCOOC (CH), CONECE (aH3 CoNH 01mar312 CONHCH 2 CESOCH,, CONECH 2

MP,

CONE(cyclohexyl), CON(Rt) 2 CON(01,)cEph, CONE(n-CE 7 INDCON(Ht) 01 2 C20 3

CONECH

3

CE(CH

3 2 CON (n-C 3

E

7 2 Co (3o methoxymeth lpyroli CONS (3-tolyl CONS (4tolyl), CONHCH, CO(morpholin-a-yl) CO (4 -methylpiperazin-.

1-yl), CONECE 2 CH2QB, CONE 2 and CO(piperidin-1-yl).

A

preferred

R

2 group is hydrogen.

When. C is Ring C, pref erred f ormula. V3III Ring C groups are phenyl and pyridinyl. When two adj acent 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 bens o or pyrido ring.

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

R

1 groups include -halo, an optionally substituted

C._

6 aliphatic group,- phenyl, -coati -CN, -sO 2 -&ogm 2 -N 2

-CO

3

-CONS

2 -iiacoa', -OC (O)NH 2 or -JAHSOR.

When R 1 is an optionally substituted C3.- aliphatic group, the most preferred optional substituents are halogen.: Examples of pref erred R' 'groups include -CF.

3 -r, -aX, -coca,, -00H1, -OH; -cH2a 3

-OCE

3 CH3,

-CF

2

OI,,

cyclohexyl, t-butyl, isopropyl, cyclopropyl, -~caC, -C&C-CHE,, -so 2 CH3, -so 2

N

2 -N(c% 3 2, -C0 2 -Comr6, -NECOCE3, -oc (0)12, -NHSO 2 CH3, anld' IND On Ring C preferred R 5 substituents, when S present, include -halo, -CN, -NO 2

-N(R)

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

R,

ct

-CONH(R

4 -N(R)COR, -BO 2

N(R

4 2 and -N(R')SO 2 R. More preferred R substituents include.-Cl, -CM, -C7 3 -bN2, -NH(C 1 4 aliphatic) -N(C 1 .aliphatic) 2 -o(C 1 4 aliphatic), C 1 4 'aliphatic, and -CO 2 (C3.- 4 aliphatic).

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

-N%

2 -fe, -NMe 2 -CEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -COEt.

When G is Ring D, preferred formula VIII Ring D monocyclic. rings "indlude. substituted and unsubstituted 0 pheny, 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 P bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, .2,3dihydro-1x-indolyl, isoquinolinyl, quinolinyl, and naphthyl'. Examples of more preferred bicyclic Ring D systems include napthyl and isoquinolinyl.

Preferred R 5 substituents on Ring D of formula VIII.include halo,. oxo, CS, -14(R) 2

-CO

2

R,

-501N(R 4 2

-N(R

4

)SO

2 R, -SR, -OR, -C(O or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C.;Ib aryl, or'C-O aliphatic. More preferred H' substibients include -halo, -oxo,- -SR, -OR, -C(O)R 1 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl,' C 0 aryl, or C 1 6 aliphatic. Examples of Ring D substituents include -OH, phenyl, 'methyl, C2 2 0E,

CSCH

2 OH, pyrrolidinyl, OPh, CF3, CeCIZ, Cl, Br, F, I, NEH, IN C(O)0C 3 I-propyl, tert-butl, SEt, OMe, N(Me)h, methylene o dioxy, and ethylene dioxy.

Preferred formula VIII compounds have one or more, and.more preferably all, of the features selected from the group consisting of: Ring C is a.phenyl or pyridinyl ring, optionally substituted by wherein when Ring C and two adjacent substituents thereon form a bicyclic ring IND system, the bicyclic ring system is selected from a naphthyl*, quinolinyl or isoquinolinyl ring, and R is -halo,.an optionally substituted C2- 6 aliphatic group, phenyl, O-COR', -CN, -80,R6, -SONH,

-COR,

-CONE2, -NECOR', -OC(0)NMh, or -NMSO2R; 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-dibydro-1H-isoindolyl, 2,3-diydro--indolyl, isoquinolinyl, quinolinyl, or naphthyl.ring; R 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..

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

R

1 is -halo, a C i -s haloaliphatic group; a C 1 6 'aliphati 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-l-isoindolyl, 2,3dihydro-tn-indolyl, isoquinolinyl, quinplinyl, or c naphthyl; IO R is T-R 3 wherein T is a valence bond or a methylene and R3 is CN, -R or -OR;

\O

0 Rt is hydrogen and R 2 is hydrogen or a N substituted or unsubstituted group selected from aryl, or a C 1 -6 aliphatic group, 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; and each Rt is independently selected from -halo, -CN, -N(R) 2 optionally substituted Ci.aliphatic group, -OR, -CO0R, -CONH(R'), -N(R')COR, -S42N(R') 2 or SOR.

Even more preferred compounds of.formula VIII have one or more, and more preferably all, of the' features selected from'the group consisting of: (a).Re 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.C 1 aliphatic, phenyl, or a 5-6 membered heteroaryl or beterocyclyl ring; Cb) Ring C is a phenyl or pyridinyl ring, optionally substituted by -R5, wherein when Ri g C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and

RI

1 is -halo, a C4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, IND piperidinyl, piperazinyl, pyrrolidinytl, morpholinyl, 1,2,3 4 -tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; S

R

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

-C

4 .alkyl, IND

-C.

4 haloalkyl,

-NO

2 -O(c 1 4 alkyl), -C02(C 1 4 alkyl), -CN,

(C.

4 alkyl), -0 2 N5 2

-OC(O)N

2 -M8OR2 CSMalkyl), -NEC(O) (C_4 alkyl); 2 or -C0C 1 4 alkyl); wherein the C 4 alkyl) is a straight, branched, or cyclic alkyl 0 roup;, cd) each R5 is independently selected from -Cl, -CN, -Cr 2

-NH(C-

4 aliphatic), -fl(CI.

4 aliphatic) 2 aliphatic), C- aliphatic, and aliphatic); and Ce) a' is R, OR, or N 2 Representative compounds of formula Vill are.

set forth in Table 7 below.

Table 7.

Me Me vtij-a VIII-2 -VIII-3 N4 VIII -4- Su WkAN VIII-7 me

HN'P

NCr- 2' VIII -6 iPr HNil- VIII -6

NH

NN2H

HN~

N

7-N VIII-3.3 VI-13VIII-14 Vill-is VII1-16

GN

*Ae VI 11-17 Nr NN

O

8 3 VII 1-21

HN)QNH

H

2 N rvZNO Me.H N N VI 11-is VIII -22 VI 11-20 N..QN *0i VIII -23

HN

N

VIII -24

ON

F

VIII -27 VIII-26 V11 1-28

HNH

VTII-29, VII11-32 9JH VII 1-30 HN2 V:111-33 V3:11-31

NH

MO-N

T

FAG

VIII -36 V1II1-34 VIII -35 H H~nNN 8

N

4 N C~s Fie viii -38..

9JH V711-39 VIII -37 o *HNN

HNQMFI

AUiA(N CF AL M (NF' ViII-4cI VIII-41. VII-42 O141 w&FS N CF8 N N CF 2 oVIII-43 VIII-44 ViUl-43 FINN NH N .LCIN<Z F

NCOF

3 -N OF,.

VIII-46 VIII-47 VIlI-48 HN1~(4 N CF3 N eF3 N CF 3 160 VIII-49 VI 1-9 II-SO VIII-Si

NO

o9lH' *H HH CFS N Q N CF3 c VIII-52 VIII-53 VIII-54 2 HN N N HN O 4 N CFs H 8

CF

8 O l C 5 VII-55 VIII-56 III-57 In another embodiment, this invention provides a composition comprising a compound of formula VIII and a pharmaceutically acceptable carrier.

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 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 VIIZ.

"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 IN0 VIII. This method is especially useful for diabetic o patients.

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

Another aspect relates to a method of (C inhibiting the phosphorylation of P-catenin in a patient 0 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.

NO Another aspect relates to a method of treating o a disease that is alleviated by treatment with a CDK-2 inhibitor, said method comprising the step of Sadministering to a patient in need of such a treatment a therapeutically effective amount of a-composition C- comprising.a compound of formula VIII. This method is especially useful for treating cancer, Alzheimer's (C disease, restenosis, angiogenesis, glomerulonephritis, C cytomegalovirus, EIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid C< .arthritis.

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

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

The above formula I compounds contain a pyrazole ring bearing the R 2 and R 2 substituents. In 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 IXt oN

N

Ci

HN

IN

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: z is nitrogen or CR' and Z 2 is nitrogen or CH, provided SG is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents S-independently selected from any substitutable noiortho 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 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 provided that when Ring D is a six-membered aryl or OD heteroaryl ring, -R 5 is hydrogen at each ortho carbon 0 position of Ring D; R is selected from -halo, -CN, -NO 2 T-V-R6, phenyl, 5-6 t membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci.s aliphatic group, said phenyl, heteroaryl, C and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or said C.-6 aliphatic group optionally IC substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their C intervening atoms form said ring fused to Ring C; o fR x and R-are independently selected from or R and q R Y are takeh together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8, membered ring having 0-3 ring beteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R* and Rk is substituted by oxo or and any substitutable nitrogen on said ring formed by R z and R is substituted by R4; T is a valence bond or a Ci 4 alkylidene chain; R2 is -R or

R

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

R,

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

N(R

7 2

-N(R

7

)COR,

-N (R 7

CO

2 (optionally substituted CI-. aliphatic),

-N(R

4

)N(R

4 -C=N-OR, -N(R 7 )CON (R 7 -N (R')SONf 7 -N O8 R or 2; each R.is independently selected from hydrogen or an optionally substituted group selected from C.aliphatic, C6-o aryl, a heteroaryl ring having 5-10.

ring atoms,. or a heterocyclyl ring having 5-10 ring atoms; IND each a' is independently selected from -a7, -Coat S C0z(optionaily substituted C 1 6 aliphatic), -CON(R') 2 ci or -S0 2 or -two R' on the same nitrogen are taken Ct.together to form a 5-8 membered heterocyclyl or Sheteroaryl ring; each..RB is independently selected from halo, -oR, -C(nO)R, CO 2 R, _-COCORI *N0 2 -CH, 8C0O)R, 80O 2 R, -SR, -NC(R) 2

-CON(R')

2 -So 2

N(R')

2 -N(Rt)coa, -N Wa) CO 2 (optionally substituted C 1 6 aliphatic), -N(R4'N(R') 3 -CnNNCR') 2 -CaN-OR,. -N(R')CON(R') 2 i-N

SO

2 N(RW) 2 -N (R)BS0 2 R, or -OC (-O)NRW) 2 or e 5 and o an adjacent subs tituent taken-together with their intervening atoms form said ring-fused to Ring c; V is -s8-i 503-, -N(R')50 2

-SO

3 N(R6)-, -NCR')50 2 -C(R6) 2 2 2 so-, 2 So 3 -C(R6)2S0 2 NT(R6), 62(6- -C CR6'N-C-, -C CR') 2 N{a)N CR 6 -cCR') 2 N CR6) 80 2 or -C WR) 2 N CON (R6) W is 2 2 -C(R6) 2 so-, -C(R')2S0 2 -C CR' 3 2 -C(Pr')AN(0) -C(R')gAjBY)CO-, -cCR6) 2 N CR') C(0)0-i -C CR') nlW(R) -C

-CCR')

2

-CCPY)

2 N(BY).so 2 -C CR') 2 CONCR') or -CON CR') each.a' 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 C3,.

6 aliphatic group, or two R 7 INDon the same nitrogen are taken tojether with the 0 o nitrogen. to form a 5-8 membered heterocyclyl or heteroaryl ring; each Re is independently selected from an optionally substituted C 1 4 aliphatic group, -COR6, -S0R6, -NIR') 2 -N(R6)N(R) 2

-NO

2

-CON(R')

2 or

-CO

2 and R9 is selected from halo, -OR, -C(eO)R, -COR, -COCOR, -N0, -CN, -S(O)Ra, -8 2 R, -SR, 2

-CON(R')

2

-O

2

N(R')

2 -OC(cO)R, -N(R')COR, -N(R')CO02 (optionally substituted

C

1 aliphatic), -CeNN(R')2, -C-N-OR -N(R')CON(R') 2 N(R)80 2

N(R

4 2 -N(R)SoR, or -OC 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.

N~R2 FJ2 Ft' N4~H N HN H HN

H

f' Y zRY Z1C 12 3 The R and RY groups of formula XX may be taken together to form a fused ring, providing a bicyclic ring system containing Ring A. Preferred R'/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said Ra/RY ring is optionally substituted. Examples of Ring A systems are shown below by compounds I-A through Zf-DD, wherein Z' is nitrogen or and Z 2 is nitrogen or C fl-A fl-B fl-c fl-D HNA3Z

HN'Z

N,

il-M Il-3 fl-F fl-if fl-3I

ZZ-L

fl:-K fl-N Ix-o IX-0 HN' Is-p fl-v

HNA

{4y fl-BD fl-a Is-a HN31 Iz.

II

fl-I fl-K,

Z.X-DD

Il-cc Preferred bicyclic Ring A sYstems-ot formula IX 135 include fl-A, IX-B, XX-C, IX-D, IX-3, fl-F, fl-U, fl-iB, fl-I, Il-6T, fl-K, fl-L, and XZR-K, more preferably Ix-A, IND n-B, nZ-C, Zl-I, and fl-H, and most preferably

ZX-

0 and zz-B.

In the monocyclic Ring A system of formula 3l, C preferred R groups include hydrogen, alkyl- or S dialkylamino, acetamido, or a C-4.aliphatic. group such as methyl, ethyl,.cyclopropyl, isopropyl or t-butyl.

Preferred RY groups, when present, inclide T-R' wherein T is a valence bond or a methylene, and R.is 2 IN or -OR. Examples of preferred

R

T include 2-pyridyl, 4pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, Alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl or halosubstituted phenyl, and methoxymethyl.

In the bicyclic Ring A system of formula-IX, the ring formed by R and RY taken together may be substituted or unsubstituted. Suitable substituents include halo, -OR,

-CO

2 R, -COCOR,

-NO

2

-CN,

-SOR, -SR, 2

-CON(R')

2

-SO

2 -OC(cO)R, -N(R')COR, C02 (optionally substituted aliphatic), 2 -CsNN(R') 2

-C=N-OR,

-N(R')CONl(R) 2 -NCR')s 2 N(Ra) 2 SOaR, or

-OC(O)N(RW)

2 wherein R and R' are as defined above.

Preferred

R

2 /Ry ring substituents include -halo,

-OR,

-COR, -CO 2 R, -CON(R), -CN, or 2 wherein R is an optionally substituted

C

1 6 aliphatic group.

Preferred

R

2 groups of formula IX include hydrogen, Cz4 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, CO 3

H,

CO

2 Ecs, CIOR, Ca2OCH 3 CHcR 2

CH

2 CE20H, CH 2

CCR

2 0C,

CH

2

CECOHC

2 Ph, CH 2 aCNCRN 2 CHa 2 a 2 CRuCOOC 3, O CONHC (CO!) 2 CONHCs 2 CE=HCa 2

CONMCHCROCH

3 CONICHsPh, CONE(cyclohexyl), CON(Et) 2 COl(CH)Ca 2 Ph, CONH(n-CH 7 CON(Et)CHCHa 2 C, COINHCa 2 CE(Cn 3 2 CON(n-C 3

H,)

2 CO(3methoxymethylpyrrolidin-1-yl), CONK(3-tolyl), CONE (4tolyl), cozqsac., CO(morpholin-2-yl), CO (4-methylpiperazin- 1-yl), CONCHZCHO0H,

CON

2 and CO(piperidin--yl).

A

more preferred R 2 group for formula =X compounds is D hydrogen.

.An embodiment that is particularly useful for treating 083-mediated diseases relates to compounds of formula X wherein ring A is a pyrimidine ring: R 2 0N

NH

0N06 isR

T

K 1 or a pharmaceutically acceptable derivative or pirodrug thereof, wherein; Ring C is.selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyli -pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two.ortho substituents independently selected from -R 1 any substitutable 'onortho 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 fromoxygen, sulfur or nitrogen, N said fused ring being optionally substituted by halo, 0 oXO, or -Re;

R

1 is selected from -halo, -CN, -NOq, T-V-R, phenyl, 5-6 Smembered heteroaryl ring, 5-6 membered heterocyclyl ring, or aliphatic group, said phenyl, heteroaryl, and.heterocyclyl rings.each optionally substituted by up to three groups independently selected from halo, Cr oxo, or -RB, said Ci-6 aliphatic group optionally ICN substituted with halo, cyano, nitro, or oxygen, or R S 1 0 and an adjacent'.substituent taken together with their C intervening atoms form said ring fused to Ring C; N R X and R Y are independently selected from T-R 3 or R and 0 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 beteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R x and R Y is substituted by oxo or and any substitutable nitrogen on said ring formed by R and R Y is substituted by R'; T is a valence bond or a C-.

4 alkylidene chain; R2 is -R or -T-W-R 6 R' is selected from -halo,

-CO

2

R,

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

-CON(R

7 -SOaN(R 7

-N(R')COR,

-N(R)CO (optionally substituted C.-s aliphatic), -C=N-OR, -N (R 7

)CON(R

7 -N(R')SONl(R' 7 -N(R')S02R, or .each R is independently selected from hydrogen or an optionally substituted group selected from Ci-.

aliphatic, C-i 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; IND each. R' is indeudently selected, f rm -It 7

-COR',

S-C% (optionally substituted C.

6 aliphatic), -CO)N(R 7 2 cior -BRa 7 or two R4' on the same nitrogen are taken together to form a 5-8 mambered heterocyclyl or heteroaryl ring; each R5' is independently selected from -Rt, halo, -OR, -C(cO)R, -C0 2 R, -000CR, -NO 2 -at, -SO 2R, -SR; *I N(R4) 2 -CONq(R') 2 -BO2N(R')2, -OC(nO)R,

-N(R')COR,

IND-NCR')002 (optionally substituted aliphatic), 22 10 2

-C-IN(R)

3 -IQ(R'yCoN(a') 2 0-N (R4) 80 2 N 2 -N(RflBSOaR, or-OC(O)(') 2 orRIt and oN an adjacent substituent taken together with their 0 intervening atoms -form aaid..ring fused to. Ring c; V is -soi-. -NT(R')so 2 -N(R6)CON(R6) -N (R')80C 2 N 2 cr-, -ctR') 2 s-, 2 so-, 2 2 S2N{R')- -C(,2(r 2 AN(R) C(o) C 2

N(R

6 -C(R'6)uI.Th(R), 2 6 2 N SN (26)-,o -C WI) 2N (Rt) CON V is 2 -C(1fl 2 2 s0-, -C (k 6 2

SO

2

_C(R

6 2 S0 2 3 -COr-, -C(R6') 3 N(a')co-, -C C(OYO-, -C cN (It) -cCR') -C C(R6) 2 N (R6)N(R6)- -C 2 so 2 zqRn)- C 2 CON Or CN(O each R6 is independdintly selected from hydrogen, an optionally substituted 4 aliphatic group, or two It' groups on the same nitrogen atom are taken together with-the. nitrogen atom to form a S-6 membered heterocyclyl or heteroaryl ring; each It7 is independently selected from hydrogen or an optionally substituted C 1 6 aliphatic group, or two R' Son the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and Seach RE is. independently selected from an optionally substituted

C.I

4 aliphatic group, -OR 6

-SR

6

-COR',

C O -2SOR 6

-N(R)

2

N(R')N(R

6 2 -CN, -NO 2

-CO(R

6 2 or -00 2

R

6 Cr 'Compounds of formula X are structurally similar k to compounds of formula II except for the replacement of the pyrazole ring moiety by the triazole ring moiety.

CA Preferred R 2 R, R Y and Ring C groups of formula X are as o described above for the formula II compounds. Preferred 0 formula X compounds have one or more, and more preferably all, of the featureB 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 selected from a naphthyl, quinolinyl or isoquinolinyl ring;

R

1 is hydrogen or C 1 4 aliphatic and R Y is T--

R

J

or R X and RY are taken.together with their intervening atoms to form an optionally substituted 5-7 membered uhsaturated or partially unsaturated ring having 0-2 ring nitrogens;

R

1 is -halo, an optionally substituted C 1 i- -allptatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2 -SONHRa, -N (R)r 2 -COaR', -CONHa, -NECOR', -OC(0)NH 2 or -NHSOaR 6 and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C.6. aliphatic group..

IO More preferred compounds of formula X have one o or more, and more preferably all,'of the features selected from the group consisting of: t Ring C is a phenyl or pyridinyl ring, optionally substituted by wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring; Cr R" is hydrogen or methyl and R Y .i -R, ION or -OR, or R x and R 7 are taken together with their intervening atoms to form a benzo ring or a 5-7 membered Ic carbocyclo ring, wherein said-ring formed by R' and R Y is 0 optionally substituted with halo, -OR, -COaR,.

S-COCOR, -SOaR, -SR, -Sq0 -N (R')COR, CO (optionally substituted Ci-6 aliphatic), -C=NN(R'4), -C=N-OR, -N(R' COH(R 4 -N 2N (R 4 2, or -oc R is -halo, a Ci- 6 haloaliphatic group, a C 1 Saliphatic group, phenyl, or -CN; R' is hydrogen or a substituted or unsubstituted group selected from.aryl or a Ci-. aliphatic group;.and each R 5 is independently selected from -halo, -CN, -NO2, optionally substituted C._6 aliphatic group, -OR, -CO2R, -CONH(R'), -N(R')COR, -SO2N(R') or -N(R')SO2R.

Even more preferred compounds or 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; ND R is hydrogen or methyl and. RY- is methyl,.

methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from S2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R" and R

Y

are taken together with their intervening atoms to form an optionally substituted benzo ring or a 6-membered carbocyclo ring; c Ra is -halo, a C 1 i aliphatic group Va optionally substituted with halogen, or -CN;

R

2 is hydrogen or a Ci- 6 aliphatic group; and each R 5 is independently selected from -Cl, S-F, -CN, -CPF, -NE2, -NH(CI- aliphatio), -N(C 1 -4 Saliphatic)2, -0(CI4 aliphatic),'C-4 aliphatic, and

-CO

2 (Ci-4 aliphatic).

Another embodiment of this invention relates to compounds of formula XI: N NH HN H

N

RYD

XI

or a pharmaceutically acceptable.-derivative, or prodrug t- hereof, wherein: Ring D is-a$-5-7 membered monocyclic ring or B-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms delectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or and at any substitutable ring nitrogen by -R, provided that when Ring D is a si-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; C r and R are taken together with their intervening atoms to form a fused benzo ring or 5-8 membered carbocyclo C- .ring, wherein any substitutable carbon on said fused ring formed by RX and RY is substituted by oxo or T-R'; T is a valence bond or a C 1 4 alkylidene chain; INDR' is -R or -T-W-Re; R' is selected from -halo, -OR, -CO 2

R,

-COCO, -COCH 2 COH, -No2, -cN -sR, \O -CON(R) 2 -00 2 N(0R) 2

-N(R

4

)COR,

Ca (optionally substituted C 1 -s 6 aliphatic),

-N(R

4 2

-C=NN(R')

2

-N(R)CON(R

4 2

-N(R

4

')SON(R)

2 -N(R)SO2R, or -OC(0O)N(R') 2 each R is independently selected from hydrogen or an optionally substituted group selected from C-.

6 aliphatic, C6-1o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -COR', -C0 2 (optionally substituted C1- 6 aliphatic), -CON(R') 2 or -SO 2 or two R' on the same nitrogen are takeh together to form a 5-8 inembered heterocyclyl or heteroaryl. rig; each Rs is independently selected from halo,' -OR, -C(nO)R, -cO 2 R, -CoCOR, -No, -8soR, -sR, 2

-CON(R

4 2 -S6N(R') 2 -OC R, -N (R')COR, -N CO, 2 (optionally substituted- Cj- aliphatic), 2

-C-NN(R')

2 -C-N-OR, -N(R')S0 2 2 -N(R')SOR, or -OC(cO)N(R') 2 V is -802-,

-CO

2

-N(R

6 -N -N(R')SoN(R 6 -C(Re)28S, 2 so-, -C(R')2so, -C(R 6 2 s80o 2 -C(R6)bN(RP)C(o)-, -C(R')2N(R 6 N(R')so 2 or (R)N W(R CON W is -C(R6).

2 -o -CCR6), 2 2 So 2

-C(R

6 2

N(R

6 -Co-, -c 2 N C -c =NN -c 2 -C(0)2N(R6)soN(R6)-, 2 or -CON(R 6 each R' is independently selected from hydrogen or an optionally -substituted C- 14 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R' is independently selected from hydrogen, or an optionally substituted C 1 j. aliphatic group, or two Rk' on the same nitrogen are taken together with the nitrogen to form a 5-B membered heterocyclyl or heteroaryl ring.

Compounds of formula fl are structurally similar to compounds of formula III except for the replacement of the pyrazole ring moiety by the triazole ring. moiety. Preferred R, R, RY, and Ring D groups of formula XI are as described above for the formula III compounds. .Prefei-red formula XI compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl,. thienyl, azepanyl, morpholinyl, 1, 2 3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydrouinolinyl, 2,3-dihydro-lE-isoindolyl, 2,3- IN dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or* naphthyl ring; R and R T are taken together with their intervening atoms to form an optionally substituted beanso ring or 5-7 membered carbocyclo ring; and R' is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a.

C:-

6 aliphatic group.

IN More preferred compounds of formula XI have one.

or more, and more preferably all, of the features selected from the group consisting of: Va Ring D is' an optionally substituted ring selected from phenyl,.pyridinyl,- pipertidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dibydro-1H-isoindolyl, 2,3-dihydro-i-indoly, .isoquinolinyl, quinolinyl, or naphthyl; R 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 RA and RY is optionally substituted with oxo,.halo, -OR, -Co 2 R, -COCOR, -No 2 -SO 2 R, -SR, -N(R) 2 -CON 2

-SO

2

N(R)

2 -OC(=o0)R, -N(R')COR, C02(optionally substituted CI-6'aliphatic), 2

-C=NN(R')

2 -C-N-OR, -N(R')CON(R') 2 -N(R')SO2N(R') 2

-N(R

4

)SO

2 R, or -OC(=0)N(R4); 2 .is hydrogen or a substituted orunsubstituted group selected from aryl or a C.l- 6 aliphatic group; and each R5 is independently selected from halo, oxo, CN, NO 2 2

-CO

2 R, -CONE(R'), -N(R')COR,

-SO

2

-N(R')SO

2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl,

C

6 1 0 aryl, or C 1 6 aliphatic.

IN Even more preferred compounds of formula XI o have one or more, and more preferably all, of the features selected from the group consisting of: R and RY are taken together with their

S

5 intervening atoms to form a benzo ring or 6-membered ^C carbocyclo ring,. wherein said ring formed by R X and R Y is optionally substituted with halo, CN, oxo, CI-. alkyl, Cl,- Salkoxy, (Ci. alkyl)carbonyl, 6 alkyl)sulfonyl, mono- or ID dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; C1 each R 5 is independently selected from -halo, -CN, -oxo, -SR, -OR, -N(R 4 or a 0 substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-io aryl, or C 1 aliphatic; and

R

2 is hydrogen or a CI-. aliphatic group.

Another embodiment of this invention relates to, compounds of formula XII:

NA

HN-

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, beterocyclyl 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 O

_-R

6 and at any substitutable ring nitrogen by Sprovided that when Ring D is a six-membered aryl or heteroaryl ring, -R s is hydrogen at each ortho .carbon position of Ring D; Rz and R Y are independently selected from T-R 3 or R" and C

R

Y are taken together with their intervening atoms 'to form a fused, unsaturated or partially unsaturated, 5-8 en membered ring having 1-3 ring heteroatoms selected from

VO

CI oxygen, sulfur, or nitrogen, wherein any substitutable Scarbon on said fused ring is optionally and (N independently substituted by T-R 3 and any o substitutable nitrogen on said ring is substituted by

SR

4 T-is a valence bond or a CI4 alkylidene chain;

R

2 is -R or -T-W-R6; R' is selected.from -halo, -OR, -CO 2

R,

-COCOR, -COCH 2 COR, NO2 -CN, R, -SR, -Sb2N(R')2, -N(R')COR, -N (R)C2 (optionally substituted C-s aliphatic),

-N(R')N(R

4 2

-C=TN(R

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

)CON(R

4 2

-N(R')SO

2

N(R')

2 -N (R)S0 2 R, or -OC(=0 N(R 2; each R is independently selected from hydrogen or an .optionally substituted group selected from C,-s aliphatic, C-i0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -R 7

-COR

7 -C0 2 (optionally substituted CI-s aliphatic), -CON(R') 2 or -SO 2

R

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

-N(R)

2

-CON(R

4 2

-N(R')COR,

IND -NCR) C02 (optionally substituted aliphatic), o 14(R')N(R') 3 -CnN(R) 2 -C-kN-OR, -N(R')CON(R') 2 -N(R4)so 2 14a) 3 -N(R)So 2 R, or -OC(-o)N(td) 21 V is

-BO

2 2 3 90-, 2 so2-, -C(RG) 2 S02N(R')- -C 62(g- IND -C(R 2 -C -C (a)23M(R')N 2N 80 3 or 0C

C(R')

2 N(R6) CON(R)...

IND W is 3 0O-, 3 -C(a6)hso-, 3 so 2 0 3 80 2 -C (R 6 2

-CO-

-C oc(o) -C (Ra oc N(R6) -CCRW)2N CO-, 1s -cCR6)s,1(R') -c -C CR)NGS%(6_ -C(Z')N(R)CO(R6-,or each is independently selected from hydrogen or an optionally substituted C2_.

4 aliphatic group, or two a' 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~i independently selected from hydrogen or an optionally substituted C 1 6 aliphatic group, or 'two k' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl ring or heteroaryl.

Compounds of formula XXX are structurally similar to, compounds of formula rV .ezccept ftor- the replacement of the pyrazole ring moiety by' the triazoleL ring moiety. Preferred'R 2 ae, and Ring D g;roups of formula XII are as described above for the formula XV Compounds. Preferred formula XXI compounds have one or O more, and more preferably all, of the features selected S from the group consisting of: Ring b is an optionally substituted ring Ct selected from a phenyl, pyridinyl, pperidizyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, Cq morpholinyl, 1,2,3,4-tetrabydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1- isoindolyl, 2,3r dihydro-1-indolyz, isoquinolinyl, quinolinyl, or

\O

naphthyl ring; R2 is hydrogen or C..4 aliphatic and RY is Tc- or R and RY are taken together with their intervening NO atoms to' form an optionally substituted 5-7 membered 0 unsaturated or partially unsaturated ring having 1-2 ring heteroatoms; and 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a

C,-

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-31-isoindolyl, 2,3-dihydro-is-indolyl, isoquinolinyl, quinolinyl, or naphthyl; R is hydrogen or methyl and RY is--R, or -OR, or R and RY are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, wherein said ring is optionally substituted with -R, halo, oxo, -OR, -coR, -cOCOR, -No2, -CN, -s(o)R, -SOR, -SR, -CON(R), -S0aN(R')2, -OC(=o)R, -N(R')COR, -N(R)CO2(optionally substituted aliphatic), N 2 -c.Nq(R') 2 -cN-OR,

-N(R

4 )cali(R 4 3 0 -N(R)so 2 N( R') 2 -N(R')so 2 or -OC(=O)N(R4), e is hydrogen or a substituted or unsubstituted group selected from aryl or a C- 6 aliphatic S group; and each R .is independently selected from halo, oxo, CN, N0 2

-N(R)

2

-CO

2 R, -CONH(R'),

-N(R')COR,

n -80 2

N(R')

2 -N(R')S0 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.

ci Even more preferred compounds of formula II o have one or more, and more preferably all, of the features selected from the group consisting of: R and R 7 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, 01, oXo, Ci- 6 alkyl, Cjf alkoxy,

(C

1 6 alkyl) carbonyl,

(C

1 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloy, or. 5-6 membered heteroaryl; each R 5 is independently selected from -halo, -CNa, -oxo, -BR, -OR, 2 or a substituted or unsubstituted group selected from 5-6 membered heterocycly, Cg.-o aryl, or C2_ 6 aliphatic; and

R

2 is hydrogen or a C 1 aliphatic group.

Another embodiment of this invention relates to compounds of formula XIII: oN

HNIL

C

M

RY

eni

IND

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: S' is nitrogen, CR a or CH, and Z 2 is nitrogen or CH; 0 provided that one of Z' and Z 2 is nitrogen; C 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 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, -oygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or and at any substitutable ring nitrogen by provided that when Ring D is a six-menibered aryl or bD heteroaryl ring, is hydrogen at each ortho carbon O position of Ring D;

SR

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

T-V-R

6 phenyl, 5-6 Smembered beteroaryl ring, 5-6 membered heterocyclyl ring, or Ce,. aliphatic group, said phenyl, heteroaryl, C1 and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, C oxo, or said C.i- aliphatic group optionally

VO

C< substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their \c intervening atoms form said ring- fused to Ring C; SR" and RY are independently selected from T-R 3 or R 2 and C 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 R" and- R Y is substituted by R'; T is a. valence bond or a C-.

4 alkylidene chain; R' is -R or -T-W-R 6 R' is selected from -halo, -OR, -COaR, -COCOR, -COCH2COR, -NO 2 -CN, -S(O) 2 R, -SR, 2; -CON(R), -SON (R' COR, CO0 (optionally substituted CI- 6 aliphatic), -N (R 2 -C=NN -C=N-OR, -N-(R CON 2 -N SOaN (R' SO 2 R, or -OC N (R7) 2 each R is independently selected from hydrogen or an optionally substituted group selected from C--6 alipbatic, C.s-o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; IND each R 4 is independently selected frbm -CoR7, o -Cc (optionally substituted C 1 5 aliphatic), -CON (R7) 2 or -90 2 R7, or two R' on the same nitrogen are taken Ct together to form a 5-8 membered-heterotyclyl or heteroaryl ring; each R5.is independently selected from halo, -OR, -co 2 a, -cocoa, -NO 2 -Cii, -SO 2 R, -SR, IND -NWC02C (optionally substituted Cl-.s aliphatic), N4(R')N(R') 2 1 2 _Cz.OR N('CNR) 2 00 -_OC_(O)NR,o 2

N(R')

2 -N(R)Soa, or K0(0N )2 rR and o'nadjacent eubstituent taken to~gether with their ointervening, atoms form said ring fused to Ring C; -so-#-SO 2 N(R)8o2,-SO 2 -N(RflC0I(a')-, -NI(R.')8o 2

-C(R)

2 2 3-# -C (R' 2 Bo-, -CWu.'2802-, -C 2 50A -cC(R') 2 NCR') 2 0 ;C -C(R'Y 3 2N{R')N 2 N CR') SO 2 N or -CRW)aNC0i6) CO(e') W1 is C(R)- 2 2 2 so7, 2 B0 2 -C(6)202XR6-, 2

N{

6 CO-, -CO.

2 2 N(R')cO-, 2 N(R')C -CCR') c=(R 5

N-O-,

-c(RYY 2 NCR')so 2 2 N9(R')CON(R)-, or -CONCW)each R6 is independently selected from hydrogen, an optionally substituted 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 beteroaryl ring; each. R' is independently selected-from hydrogen or an optionally substituted C 16 g aliphatic group, or two R".

IN on the same nitrogen are taken together with the o nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; C each RE is independently. selected from an optionally substituted

Q.

4 aliphatic group, OR', -BR 6

-COR',

-8OR', 2 2 -CN, -NO 2

-CON(R')

2 or

-CO

2

R

6 and tR is selected fromhalo, -OR,

-CO

2 R, -COCOR, N -NsO 2 -S(O)R -so 2 R, -SR, -N(R) 2

-CON(R)

2 -80s 2 N(R)2, -OC(wO)R, -N(R')COR, -N(R')C02 (optionally substituted cQs aliphatic), 2 -c-ut 4 2

O

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

N(R')

2 S -OC(=)N(R 4 2 or an optionally substituted group selected from CI-6 aliphatic, C6-,o aryl, a heteroaryl 1 ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

Compounds of formula XIII may be represented by Sspecifying Z' and Z 2 as shown below: *F RR2A N- N H

N-

HNJ HN HN H

IN

RY N A 7

RY

G G G and XIIIa IIIb

II

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 Ri, R R, and Ring s groups.

of formula zIII are as described above for the formula V compounds. Preferred formula XIII compounds have oe or IDmore, and more preferably all, of the features selected 0 from the group consisting of: Ring C is a phenyl or pyridinyl ring, Ctoptionally substituted by -Rs, wherein when Ring C and two adjacent substituents thereon form. a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R' is -halo, an optionally substituted

C--

6 aliphatic group, phenyl, -COR', -CN, -SO 2 -S0Na4,

-COR',

-CONb, -NECOR', -OC(O)IH 2 or -15SOaR'; or Ring D is an 0 optionally substituted ring selected from a phenyl, ci pyridinl, piperidinyl, piperazinyl( pyrroidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinoliny, 1,2,3, 4 -tetrahydroquinolinyl, 2,3-dihydro-1.-isoindolyl, 2,3-dihydro-S-indolyl, isoquinolinyl, quinolinyl, or naphthyl -ring; r is hydrogen or C 1 4 aliphatic and R' is Tor rz 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

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a

SC,-

6 aliphatic rroup.

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 pyridiyl ring, Soptionally 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' is -halo, a C 16 haloaliphatic group, a Cl,- aliphatic group, phenyl, or -cN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, S 1,2,3, 4 -tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinoiinyl, 2,3-dibydro-1H-isoindolyl, 2,3- C dihydro-lH-indolyl; isoquinolinyl, quinlinyl, or naphthyl; c 1(b) R is hydrogen or methyl and R' is -R,

N(R)

2 or -OR, or RW and RY are taken together with their r) ~intervening atoms to.form a benzo ring or a 5-7 membered IN carbocyclo ring, wherein said ring formed by Rx and RY is optionally substituted with halo, -OR, -COaR, -COCOR,

-NO

2 -SO 2 R, -SR,

-SO

2 N (R) 2 -OC -N(R')COR, -N(R')C0 2 (optionally substituted aliphatic), -N N (R) 2 -C=NN 2 -CnN-OR, N(R')CON 2

SO

2 N (R) 2 -N s0 2 R, or 2

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a C 1 6 aliphatic group; and each R 5 is independently selected from -halo, -CN, -NO 3

-N(R)

2 optionally substituted

C

1

.S

aliphatic group,. -OR,

-CO

2 R, -CONH(R'),

-N(R')COR,

-SO2N(R4), or -N(R')SO2R, and, when Ring a is Ring D,-Ring D is substituted by oxo or'R s; Even more preferred compounds of formula XIII have one or more, and more preferably all, of the features selected from the roup consisting of: R is hydrdgen or methyl and R 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 re.and RY is optionally substituted with halo, CN, oxo, C 1 6 alkyl, C 1 alkoxy, alkyl) carbonyl,

IND(C

1 alkyl) sulfonyl, mono- or dialkylamino, mono- or odialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; Ring C is a phenyl or pyridinyl ring, optionally substituted by -Rs, wherein when Ring C and two c~ adjacent substituents thereon form a bicyclic. ring system, the bicyclic ring system is a naphthyl ring, and RH is -halo, a CI.

4 aliphatic group optionally substituted

\O

with halogen, or -CN; or Ring D is an.optionally substituted ring selected frox phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; R2 is hydrogen or a aliphatic group; and each Rs is independently selected from -Cl, -CN, -NE 2

-NH(C.

4 aliphatic), aliphatic) 2 -o(C 1 4 aliphatic), Cz- 4 aliphatic, and

-CO

2 aliphatic), and when Ring G is Ring D, Ring D is substituted by oxo or Rs.

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

Table 8.

CHN

H-NC4N

CF

3 -kb HN c-i IX-2 IX-3.

11-4

C

HNSZ

N -sCF

~N

IX-,

C1 3

HNY$&W

N CFl

HN)&

N CFO

HN$

IX-12

PO

N4JH HN4 Ix- is IX-13 14 IX-24 IX-16 X-"IX-17 IX-is IX -19

OH

8 HNt IX-20

HS

HNS

N IX-26 0HS

NA

IX -21

HN&

Ha0 N OF3 11,0 N4 I IX-24 HN SV HA)C, N

C

IX-27 IX- 22 NsrO

HNMH

HSCtN OF,3 H-aC.N41 HN It-

N

IX-231

KN

o t rw

HN

IX- 31 *HNt X-3

N

HN- 7

ON

M,L

I-29

IS-SO

IX-32 HNk H3C 11X-35

OH,

HN

IX- 33 IX-36

NOH

11-38 HNt

OH,

N H 2 CH3

NO

IX -39.

N

OCH

2

CHI

IX-41 I1-42

H

IX-43

HN)(H

IX- 46 Ni TX- 49

HNLN

IX- 52

H

HNt ON CPs IX-47 N ~JCF 3

HN

H

NCPU

IX-48

NHA

Hn-si ix- *N C-3

NX-ON

OF

N aZ N- 'K-se

HN

4

PH

4 tF IX- 56 N 4 TX- 59 OHi 3

HA*

IX- 62 CH3

HN

IX- 57

NA--

NCF

8 IX-

OH

3 N A 06NH 2 IX-63 IX-61 N NG IX-64 IX;-65 IX1-66

OH

3

N

4 15-67 IX-66 IX-67 IX-69

HN&

IX-71.

IX- 70.

HNA2N IX-73 N Z 8 IX-72

HNS

IX-74

H

2 NI2Yt IX-76

NS

M t~ Nll 'XX- 77

PHS

H

HN-V

Ha

N

Ir A,

-S

H .Y aA, ,4

CH

8

HNNH

I4C 'Nxt~r Ra N 2

FO)JI

IX-si IX-79 Itx-GaO IX- 82flB3I-8 IX-83 IX-84 N

H

Nti 11-86

OH,

HN4 N xF f-B, 'i-Be fl-B 6 T-%-.a9

OH

3

A/H

HN&

~N CF, HNO ZX-93 2X-931 IX-92 N H~

N

4 HWA,-- OFH Hc N'tC S

J~

IX-94 11-94 11X-95 -9 IX- 96

OH

3 KN4H IX- 97 IX- 99

OH

3 IX-100 IX-1 01 HA3 I1-103

CHS

HN*t IX-102

NH

IX-104 IX-105

$HS

ON

11-106IX--07 IX-106 Ix-ios CHs g 1 4H N CF 2 iX-109 IX- 112 0KB

HA

OtC(O>NNI 11-11 Ic-i11 nt-110

OHS

HN4J I1-114 TX-113 In-117

NA

H'N)~

Os'

NH

11-119 11-120 11- 121

OH

3 HNk

HO~

IX- 122 CHs N A, HN 1__tpH IX- 125

HN

4

H

3 IX-123 HN

JI'

NH

2 IX- 126 IX-124 HN HN)4P (JLN SO 2 NQ(Ie) 2 OiN CN IX- 127 11-128 IX-129

CH

9 HN

H

IX- 130 11-131 IX-132 N i. I HN A HN~ EINH (X$ TX-134 IX-135 IX-133

HNST

UE- 13 6 IX-137 IX-138

OH,

HN4 IX-140 IX-139 C HS

HN

C0-NH IX1-143.

HN' 1

'N

IX-144

N?

HN AI

WNH

IX-142 IX-143 0-Ia3

N

4 HN AO cx4-.tN

N.

IX- 147 IX-145 11-145 -146 n

PH

2 0 r-P

HH

11-148 IX-149 Is-iso IX- 151

NIN

IX- 154 o r 0 Hs IX1-152

C

N -,(158 ,$Me IX-156

HNS

11-153

N?

HN AO" 6

-H

11-160 IX- 159 IX-161 n-lea IX-i62 IX- 163 IX- 163IX-164 11-165 Ix 168 IX1-166 IX- 167

CK

3

S

IX7170

OHS

pN Il-il IX-169 IX-172 IX1-173 M- 174 HN tP CnrSo 11-175' IX-176 I-177

VO

IND

0q In another embodiment, this invention provides a composition comprising a compound of formula IX and a pharmaceutically acceptable carrier.

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

o0 Another aspect relates to a method of treating ND 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 aX.

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. Thismethod 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 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 phosphorylati6n of P-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition ND comprising a compound of formula XX. This method is o especially useful for treating 'schizophrenia.

SOne aspect of this invention relates to a t 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 IX.

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

Another method relates to inhibiting GSK-3 or Aurora activity in a biological sample, which method comprises contacting the biological sample.with the GSK-3 or Aurora inhibitor of formula IX, or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3 or Aurora. Each of the aforementioned compositions and methods ditected to the inlibition of GSK-3 or Aurora, or the treatment of a disease illeviated 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 IN prepare compounds of this invention. Methods A-F below o are particularly useful for preparing formula I1 c compounds.. In most cases, Ring C is drawn as a phenyl t ring bearing an ortho R 1 substituent. However, it will be apparent to one skilled in the art that compounds having CI other Ring C groups may be obtained in a similar manner.

Methods analogous to methods A-F are also useful for Spreparing other compounds of this invention. Methods F-I CI below are particulary useful for preparing compounds of formula III or IV.

VO

D Method A 0 r O H2N H H (HOR 2

I

Method A is a general route for the preparation of compounds wherein ring C is an aryl or heteroaryl ring. Preparation of the starting dichloropyrmidine 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 1E-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POCl (60 mL, 644 nrmol) and N,N- .dimethylaniline (8mL, 63.1 mol) is heated under reflux IND for 2 h. Excess POC1 3 is evaporated under vacuum, the S residue is poured into ice, and the precipitate is.

collected by filtration. The crude solid 2,4dichloroquinazoline product may be used without further purification.

To a.solution of 2,4-dichloro-quinazoline (3.3 9, 16.6 mmol) in anhydrous ethanol (150 mL) is added Cr methyl-1H-pyrazol-3-yl amine (3.2 g, 32..9 mmol). The N.Dmixture is stirred at room temperature for 4 h, and the resulting. precipitate is collected by filtration, washed C- with ethanol, and dried under vacuum to afford (2-chloro-

\O

oN quinazolin-4-yl) (5-methyl- H-pyrazol-3-yl)- amine.

o To a solution of. (2-chloro-quinazolin-4-yl) methyl-1H-pyrazol-3-yl)-amine (50 mg, 0.19 mmol) in DMF (1.0 mL) is added the desired aryiboronic acid (0.38 amiol), 2M Na2CO3 (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). Under nitrogen, PdCl,(dppf) (0.011 mmol) is.

added in one portion. The reaction mixture is then heated at 80OC for 5 tol10-hours, cooled to rdom temperature, and poured into water (2 mL). The resulting precipitate is collected by filtration, washed with water, and purified by HPLC.

Method B O I FINH F1 1 .kLtN RI H2 *RY N~ p16 Y NS11) 3. 4 NH B 1 0 (ii) S 6 VO N<D 0 R 1 0 R' (iii) 7 Methods B through F describe routes where the S pyrazole ring system is introduced after Ring C and the

VO

Cq pyrimidine ring portion are first constructed. A versatile intermediate is the 4-chlorppyrimidine 4, which C is readily obtained from pyrimidinone 3 as shown in O Method This reaction sequence is generally 0 10 applicable for a variety of Ring C groups including aliphatic, aryl, heteroaryl, or heterocyclyl. See J.

Med. Chem., 38, .3547-3S57 (1995).

For quinazoline ring systems (where R and R 7 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 nmmol) in THF and CHC1l 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 CHa 2 C1 and water, and dried under vacuum. The crude 2-benzoylaminobenzamide may be used directly for the next step without further purification.

N

T

o a solution of the above crude product (13 Smmol) in ethanol (50 mL) is added NaOEt (26 mmol) at room temperature. The mixture is heated under reflux for 48 Sto 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 m without, further purification.

VO

CI .To a suspension of the above product (12 mmol) S 10 in POC1l (120 mmol) is added tri-n-propylamine (24 mmol).

C The mixture is heated under reflux for Ih. After removal Sof the excess POC13 by evaporation, the residue is C dissolved in ethyl acetate, and washed with IN NaOH (twice) and water (twice). The organic layer is dried over MgS04, the solvent is evaporated under vacuum, and the crude product is purified by flash chromatography (eluting with 10% of ethyl actetate in hexanes) to give 4-chloro-2-aryl quinazoline.

To a solution of 4-chloro-2-aryl quinazoline (0.16 mmol) in DMF (or 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°C for 16 h (or in ethanol at 130-160 0 C for 16 hours) and then poured into water (2 The precipitate is.

collected by filtration and purified by EPLC.

Method C NH R 1 RyOEt 8 9 N0 Method D(i) 0 CIHN C p 9 Methods C and D(i) above employ P-ketoesters 8 ID0 5 and 10, respectively, as pyrimidinone precursors. The 2- substitution pattern of the R' and R' groups on the C< pyrimidinone ring will be reversed if a chlorocrotonate 11 (Synth. Comm, (1986), 997-1002), instead of the S" 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. HC to pH 6, and then filtered tb obtain a solid product 2-aryl-3-pyrimidin-4-one (yield 75-87%), which may be purified by flash column chromatography if needed. To this pyrimidinone (3.7 mmol) is added POCI (4 mL) and n-PrN mL). The mixture is heated under reflux for 1 hour. After evaporation of the excess POC13, the residue is dissolved in ethyl acetate, washed'with IN NaOH solution (three times) and NaHCO, (once), and dried over MgS04. 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.

O

o Method D(ii) NH R' N-H o POC C1 0 to N R^ nPrN RN R O 38

-H

^0 RFIX FF

R

2 Smorpholle, CI N HN MeOH N R F ,N -R' 8~~3 relux ^N rN N 0 01reflux 0 Ci .39 Method D(ii) above shows a general route for the preparation of the present compounds, such as compound 40, wherein R' is N(R) 2 See l1 Farmaco, 52(1) 61-65 (1997). Displacement of the 6-chloro group is exemplified here using morpholine. This method is illustrated by the following procedure.

To a solution of 2-methylialonic acid diethyl ester (5 mmol) and sodium ethoxide (15 mmol) is added the appropriate amidine salt (5 Umol) in ethanol (10 mL) and the reaction heated at reflux for 2-24 hours. .The residue is dissolved in water and acidified with 2N HC1.

The resulting precipitate is filtered off and further purified by flash chromatography (yield to afford the pyrimidinedione 37.. To 37 (1.6 mmol) is added POCI 2 (32 mmol) and tri-n-propylamine (6.4 mmol) and the reaction refluxed is for lh. After evaporation of excess POC13, the residue is dissolved in ethyl acetate, basified with IN NaOH, separated and the aqueous phase twice more extracted with ethyl acetate. The combined organics are dried (sodium sulfate) and"evaporated. Purification by IN flash chromatography provides the dichloropyrimidine (38) Sas a yellow oil in 23% yield.

A solution of 38 (0.33 mmol) in methanol (5 mL) is treated with an amine, exemplified here using morpholine (0.64 mmol) and refluxed 1 hour. After C evaporation of solvent, the residue is purified by flash chromatography to provide the mono-chloropyrimidine 39 as ma colorless oil in 75% yield.

IN The mono-chloropyrimidine, 39, (0.19 mmol) may be treated with a 3-aminopyrazole or 3 -aminoindazole ri compound in a manner substantially similar those 0 described above. in Methods A and B.

Method E

AN'.R

R

1 0 o (A N==O R_ Hk NH RI NHOAc, RY NPO 12 AcOH, iLx 9(R H) 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 OOC under nitrogen is added dropwise over 5 min a solution of acyl isocyanate mmol) in tetrahydrofuran (5 mL). After stirring for h, acetic acid (30 mL) is added, followed by ammonium 231 I acetate (50 mol). The mixture is refluxed for 2 h with S. continuous removal of tetrahydrofuran. The reaction is cooled to room temperature and is poured into water (100 S mL). The precipitate is filtered, washed with water and ether and dried to provide the 2 -aryl-3H-pyrimidin-4-one.

Method F o oO 7 NHOH N Heat NNH 16 S13 14 Method F shows a general route for the preparation of the present compounds wherein R" and. R Y are taken together to form a 5-8 membered partially unsaturated saturated or unsaturated ring having 1-3 heteroatoms. The condensation of a 2 -amino-carboxylic acid, such as 2-amino-nicotinic acid 13, and an acid chloride 7 provides an oxazinone 14. Treatment of 14 with ammonium hydroxide will furnish the benzamide which may be cyclized to a 2-(substituted)-pyrido[2,3d] [1,3]pyrimidin-4-one 16. This method is illustrated by the following procedure.

2-(Trifluoromethyl)benzoyl chloride (4.2 ml, 29.2 mmol) is added dropwise to a solution of 2aminonicotinic acid (2.04g, 14.76 mmol) in 20 ml of pyridine. The reaction mixture is heated at i58 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 3] oxazin-4-one

IO

o (2.56 g, 60% yield) which may be used in the next step Swithout further purification.

2- (2-Trifluoromethyl-phenyl) -pyrido [2,3d] 11,3]oxazin-4-one (2.51g) is stirred in 30% ammonium 5 hydroxide (25 ml) at room temperature overnight. The Cresulting precipitate is filtered and rinsed with water and.diethyl ether. The precipitate is dried under vacuum w at 50'C overnight to give 2- (2-trifluoromethyl- C]1 benzoylamino)-nicotinamide (850 mg, 33% yield) 10 2-(2-Trifluoromethyl-benzoylamino)-nicotinamide \0 (800mg, 2.6mmol) is dissolved in loml of ethanol.

o Potassium ethoxide (435mg, 5.2mmol) is added to the C- .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 (1g, 3.43 mmol) is suspended in phosphorus oxychloride (4 mL) and the reaction mixture was stirred at 110°C for 3 hours. The solvents are then evaporated and the residue is treated carefully with an ice cold aqueous saturated solution of NaHCO 3 The solid is collected by filtration and washed with ether-to give 4-chloro-2-(3,5-dichlorophenyl)-guinazoline as a white solid (993 mg, 93%).

To 4-chloro-2-(3,5-dichloro-phenyl)-quinazoline (400mg, 1.29 mmol) in TEF (30 mL) is added

IO

methyl pyrazole (396 mg, 2.58 mmol) and the reaction o mixture is heated at 65°C overnight. The solvents are Sthen evaporated and the residue triturated with ethyl acetate, filtered and washed with a minimum amount of ethanol to give [2-(3,4-dichlorophenyl) -quinazolin-4-yl]- C (5-methyl-2H-pyrazol-3-yl)-amine as a white solid (311 mg mp 274*C;.

1 H NMR (DMSO) 5 2.34 (3H, 6.69 (IH, sl 7.60 7.84 (1i, 7.96 (2H, 8.39 (1H, C- dd), 8.60 (1H, 8.65 (1H, 10.51 (1I, 12.30 (1H, IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, \0 1376, 1352, 797, 764, 738; MS 370.5 The THF solvent used in the previous step may C be replaced by other organic solvents such as ethanol, N,N-dimethylformamide, or dioxane.

Method H 'r 2 '(HO)2B.

R

-17 18 N dCH3)sSI HN (ii) 17 19 Method H shows routes in which a Ring D aryl group bearing a halogen (X is Br or I) may be converted to other formula.III compounds. Method H(i) shows a phenylboronic acid coupling to Ring D to provide compound 18 and Method H(ii) shows an acetylene coupling to provide compound 19. Substituent X 'in compound 17 may be 234 o bromine or iodine. These methods are illustrated by the 0 following procedures.

Method To a mixture of [2-(4-bromophenyl) -quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl) -amine (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol) in THF/water 4 mL) is added Na 2 CO3 (219 mg, 2.06 mmol), triphenylphosphine (9mg, 1/15 molt) and Cf palladium acetate (1 mg, 1/135 mol%). The mixture. is Ci heated at 80 0 C overnight, the solvents are evaporated and the residue is purified by flash chromatography (gradient Cl of CH 2 Cl 2 /MeOH) to give -(2-biphenyl-4-yl-quinazolin-4-yl) S(5-methyl-2H-pyrazol-3-yl) -amine as a yellow solid (99 C ag, H NMR (DMSO) 8 2.37 (3H, 6.82 (IH, 7.39- 7.57 (4H, 7,73-7.87 (6H, 8.57 (2H, 8.67 (IS, 10.42 (ll, 12.27 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 CuI (1,1 mg, 1/50 mol%), Pd(PPh) C1 (4.2 mg, 1/50 molt) and triethylamine (121 mg, 0.36 mmol). The mixture is heated at 120 0 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 (IM 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 CHCl 2 /MeOH) to give [2-(4-ethynylphenyl)-quinazolin-4yll-(5-methyl-2H-pyrazol-3-yl)-amine as a white solid. (68 img, 1 H NMR (DMS0) 8 2.34 (3H, 4.36 (IH, 6.74 (1H, 7.55 (IH, 7.65 (2H, 7.84 (2H, 8.47 S(2N, 8.65 10.43. 12.24 (15, MS S326.1 Method I Fe R 2 R12 e¢ Ry R NI, RYN0 2 C0 Method I above shows a general route for the O preparation of the present compounds wherein ring D is a CI 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)- (1l-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 1000C for 6 h and then purified by reverse-phase EPLC.

Method J 21 22 236 o

H

CIe:_ HN HN S23 24 Cr Method J above shows the preparation of S compounds of formula V via the displacement of a chloro group from an appropriately substituted pyridyl ring.

C-i Method J(i) is a route for preparing compounds of formula 0 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 chloropyridinea 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 (S-Methyl-2H-pyrazol-3-yl)-(2-.

phenyl-quinolin-4-yl)-amine. To 4-chloro-2phenylquinoline (J.Het. Chem., 20, 193, 121-1 2 8)(0.53g, 2.21 mmol) in diphenylether (5 mL) was added methylpyrazole (0.43g, 4.42 mmol) and the mixture.was 'heated at 200C 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 (Si0,. gradient DCM-MeOH) to give the title compound as a white solid: mp 242-244OC; IH NMR (DMSO) 8 2.27(3H, 6.02(1I, 7.47(2H, 7.53- 7.40(2H, br 7.67(1H, 7.92(1H, 8.09(2H, d), D 8.48(2H, 9.20(1H, 12.17(1I, br .I (solid) 8 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301,2 (M+H)4 Method J(ii). (5-Methyl-2H-pyrazol-3-yl)-(3t phenyl-isoquinolin-l-yl)-amine. To l-chloro-3phenylisoquinoline Het. Chem., 20, 1983, 121- C1 12) (0.33g, 1.37 mrol) in dry DMF (5 mL) was added 3- (0.27g, 2.74 mmol) and potassium Cc carbonate (0.57g, 4.13 mmol)and the mixture was heated

\O

IC under reflux for 6 hours. The mixture was cooled and the 10 bulk of DMF was evaporated. The residue was extracted C- twice with ethyl acetate and the combined organic layers o were washed with brine, dried (MgSO), filtered and O concentrated. The crude was purified by flash chromatography gradient DCM-MeOH) to give the title.

compound as a colourless oil; 1H NMR (MeOD) 8 2.23 (3H, 5.61 (1I, 7.41 (1H, 7.52(2H, 7.62(1H, m), 7.81(1H, 8.07(1H, 8.19(2H, 8.29(1H, 8.54' MS 301.2 Method K

R

2 C1 CI CI H N N N N. N~N HNvi CiN"CI ,N R N" 26 27 Method K shows.a route for the preparation of compounds of formula VI. -A versatile starting material is 2 ,4, 6 -trichloro-[1,3,5]triazine 25 in which the chlorine substituents may be sequentially displaced. The displacement of one of the chlorines by an aryl Grignard reagent or an aryl boronic acid is described in PCT patent application WO 01/25220 and Helv. Chm. Acta, 33, 1365 (1950). The displacement of one of the chlorines by a heteroaryl ring is described in WO 01/25220; J. Het.

NO Chem., 11, 417 (1974); and Tetrahedron 31, 1879 (1975).

0 These reactions provide a 2,4-dichloro-(6substituted) [1,3,5]triazine 26 that is a useful intermediate for the preparation of compounds of formula VI. Alternatively, intermediate 26 may be obtained by C- constructing the triazine ring by known methods. See US patent 2,832,779; and US patent 2,691020 together with J.

m Am. Chem. Soc. 60, 1656 (1938). In turn, one of the

LO

IC chlorines of 26 may be displaded as described above to provide 2-chloro-(4,6-disubstituted) [1,3,5]triazine 27.

The treatment of 27 with an appropriate aminopyrazole 0 provides the desired compound of formula VI.

Method L urea FPOC1 28 29 H H N HN 31 Method L shows a route for preparing compounds of formula VIZ. For illustration purposes the trifluoromethylcbalcone 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 O trifluoromethylphenyl and phenyl rings of compound 28.

S Substituted chalcones may be prepared by known methods, for example as described in the Indian J. Chemistry, 32B, t 449 (1993). Condensation of a chalcone with urea provides the pyrimidinone 29, which may be treated with C POCl, to give the chloropyrimidine 30. See J. Chem. Eng.

Data, 30(4) 512 (1985) and Egypt. J. Chem., 37(3), 283 Cc) (1994). In an alternative approach to compound 30, one

VO

C-i of the aryl rings attached to the pyrimidine. is introduced by displacement of of the 4-chloro group of 2,4-dichloro- (6-aryl) -pyrimidine by'an aryl boronic acid

NO

Susing a palladium catalyst such as (PhbP) 4 Pd in the presence of a base'such as sodium carbonate as described in Bloorg. 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-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 nL).

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, ap 193-195°C; 1H NMR (DMSO) 5 0.91 (3H, 1.04 (2H, 1.67 (3H, m), 2.16 (3H, 2.83 (2H, 4.31 (2H, m),.6.19 (2H, m), IND 7.87 (iN, 8.80 hr 11.71 (iN, IR (solid) 1627, 1579, 1541, 1498, 1417, 1388, 1322, .1246; MS 273.3

(M+EN).

Method

M

C1 en N

H

2

N

N

ci 32 00 N V111b 33 N VllaC 34 Method!4 provides routes for obtaining compounds -of formula VII. A general' proceduite for displacing the chlorine of a 4 -chloro-6-substituted pyridazine, 32, with an appropriateiy substituted I0D pyrazole to provide VIfla is described in et. Chem., O 20, 1473.(1983). Analogous reactions may be carried out as follows: with 3-chloro--substituted-pyridazine, S33, to provide VIIIb is described in J. Med. Chem., S 311 (1998); with 5-chloro-3-substituted- C 11,2,4]triazine, 34, to provide VIIIc is described in Heterocycles, 26(12), 3259 (1987); and with 3-chloro- 5-substituted-[1,2,4]triazine, 35, to provide VIIId is \O IND C( described in Pol. J. Chem., .57, 7, (1983); Indian J.

Chem. Sect. B, 26, 496 (1987); and Agric. Biol. Chem., C 154(12), 3367 (1990). An alternative procedure to Scompounds of. formula VIIIc is. described in Indian J.

C

C

hem. 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 of this invention-relates to a 3-aminoindazole compound of formula A:

H

NHj

A

where R 10 is one to three substituents that are each independently selected from fluoro, bromo, Ci- 6 haloalkyl, nitro, or 1-pyrrolyl. Examples of such compounds the following: include F

H

H,,

H F H F

N

F H A4 A2 F F H Hg Br H H Br H8 17 ANH A7 As

AS

H

OA9

H

N

U

Another aspect of this invention relates to a 4-chloropyrimidine compound of formifla. 8:

CI

wherein R7 and RY are as defined above; R 1 is selected from C1, F, CF 3 CN, or NO 2 and is .one to three substituents that are each independently selected from H, Cl, F, CF 3

NO

2 or CN; provided that R' and RS are not simultaneously C1. Examples of compounds of formula B are shown below: CI 0 M 81 2 Me 31 32 243

C'

MtN C4 36 B4 B5 Cl Cl iT N. CF

'N

B 7 ~a~""d;CI NF CF 9 8B9 Cl ci N i N CF 3 I N CFS

F

B1 Bit 312 dN C 313 VSa

CF

314 NCl S1

CI

NON

320 B19 Another aspect of this invention relates to compounds of formula C:

HNH

HN

RixN

C

wherein W, R2y, R, and R" are as defined above.

of compounds of formula C are shown below: Examples

F

N

HC

C1 C4 HN tH C2

HN

C3 HN QM F H HN NH C7 H N CS Ns .C9

H

HN 3 N)

RN

NNCI

HN

C13 C11

H'N

C12 Me

HN

4

P

cis HN2H NC1 C14 Yet another aspect of this invention relates to.

compounds of formula b:

O

NH CF Ry

-N

D

where R5, R and Ry are as defined above. Examples of formula D compounds and other useful pyrimidinone intermediates are shown below: 0 0 HsC NH CF 3

H

3

C

HaC N H31 Cf D1 D2 00 D4

DS

D4 DS

O

NH

CF

3 HaC

N

0

C

3 D6 246 0 C1 ,j^NH CFa D7 0 D9NH CF 3 D9 0 WftNHCI N N D13 DlI 0 )Y NH CF 3 D14 D12 0 D8NH CF D18 D16 D17 0 w-"INH CFa 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.

O

C SYNTHETIC EXAMPLES .The following HPLC methods were used in the Sanalysis of the compounds as specified in the Synthetic 5 Examples set forth below. As used herein, the term "Ru" refers to the retention time.observed for the compound using the.HPLC method specified.

\O

C- HPLC-Method As 0 10 Column: C18, 3 um, 2.1 X 50 mm, "Lighting" by Jones O Chromatography..

SGradient: 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 Cz Column: Cyano, 5 um, 4.6 X 150 mm "Microsorb".by Varian.

Gradient: 99% water TFA), 1% acetonitrile (containing 0.1% TFA) to 50% water TFA), acetonitrile (containing 0.1% TFA) over 20 min, hold for .8.0 min and return to initial conditions. Total run time 30 min. Flow rate: 1.0 mL/min.

HPLC-Method

D:

o Column: Waters (YMC) ODS-AQ 2.0x5onm, 85, 120A.

Gradient: 90% water Formic acid), lot ctacetonitrile (containing 0.1% Formic acid) to water formic acid), 90% acetonitrile (containing 0.1V formic acid) over 5.0 tin, hold for 0.8 min and return to initial conditions. Total run time 7.0 min.

Va Flow rate: 1.0 ni/min.

HPLC-Method

E:

Va o Column: 50x2.Omm Hypersil CIS BDS;5 un *.Gradient: elution 100% water TPA), to.% water TFA), 95% acetonitrile (containing 0.1% TFA) over 2.1 rin, returning to initial conditions after 2.3 min.

Flow rate: 1 t/mmin.

Eample 1 (2-(2-Clorophienyl)

,S

6 -dimethylpyrizidn-4-y l (5-Methyl-2H-pyrazol-3.yl).amine 1 HNM (500 MHz, DMSO-d) 510.4 br, 7.74 7.68 1H), 7.60 12), 6.39 Cs, 1H), 2.52 C, 3H), 2.30 Cm, 3H), 2.22 3H); MS 314.4L Example 2 2 2 -Chloro-phenyi)- 6,7,,9-tetrahydroL-S.

cycloheptapyimidin4..yl3 -(1H-indazcl-a-yl) -amine (11-2): Prepared in 30% yield. '3NM (50MHz, DMSO-d) 6 1.72 (M, 4H), 1.91.Cm, 22), 3.02 42), 7.05 12), 7.33 Ct, 7.39 12), 7.47 7.55(m,' 3H), 7.59 (d, 12), 10.4 Cm, 12),'13.11 (br. a, 12); El-MS 390.2 HPLC-Method.A, Rt 2.99 min.

Exmple 3 (5-Fluoro-a-ndaol.3.y (2- 6 7 ,S-tetrahydro-pyridoEs,4 d]Yrimidn-4yl 3ami..j Compound 11-18 (90 mg 1 0.17 mmol) was treated with an equal weight of Pd/c in 44% foric acid in MeOW at room temperature for 14 h.

The mixture was filtered through celite, the filtrate was evaporated, and crude product was purified by PLO to Cl provide 18 mg of the desired product as pale yellow solid. 1 HMR (500 MHz, DMSO-d) 812.9 13), 9.51 (s, 31H), 9.26 2H1), 7.72 Cd, 1W), 7.63 t, 1H), 7.58 (t, CAL), 7.49 m, 2H), 7.21 (td, 131, 7.15 (dd, 13), 4.24 (a, 231), 3.56 2H), 2.95 2H) ppm- 'MS m/en IN 42922 M+H) HPLC-Method A, Rt 2.88 min.

0Ex,: le 4 2 -(Z-Chlaro-phenyl) 6,7,8,g.tetra,,i,..ss..

cycloheptapyrimdin-4-yll -(7-fluoro-1E-indazol-3-yl) amine Prepared in 52% yield to afford a white solid. 1 mMR (500MHz,. DMSO-d) 5 1.72 4H), 1.92 (m, 2H), 3.00 4H), 7.02 (td, 13), 7.20 (da, 13), 7.40 (N, 1H), 7.42 (dl3), 7.52 3H1), 10.5 1H), 13.50 (br.

a, 13); Rl-MS 408.2 HPL -Method'A, Rt 3.00 min.

Example 5 2 -Chloro-phenyl)-6,7,es-tetrahydro-SH, cycloheptapyrimidin- 4.pl3 (5-fluoro-1-indazol.3..yl) amine Prepared in 51* yi~1d. HNM (501Hz, DMSOdE) 8 1.71 Cm, 4H), 1.91 2H), 3.01 4H), 7.24 (td, 1H), 7.41 Cm, 2H), .7.54 4H), 10.5 m, 131), 13.1 Cbr.

8, 13); El-MS 408.2 HPLC-Method Rt 3.05 min.

Example 6 2 -(2-Chloro-peny)-67,,9-tetr cycloheiptapyiidin..4.y 7-difluoro.lH-idaol-3 syl)amine (11-6Y: Prepared according to Method C in 72V yield. 1 HNMR (5004Hz, DMSO-dG) 8 1.72 (in, 4H), 1.91 (m, 2H), 3.01' Cm, 4H), 7.31 2R), 7.41- m, 131), 7.54 (m, 3H), 19.5 (in, lW), 13.6 (br. 1H); El-MS 426.2 HPLC-Method A, R,,3.21 rin.

Va Example 7 (7-Fluoro-1s-indazol-3-yl)-2- (2trifluoromthyl-pheyl)-5,6,7,8-tetrahydroqutnazolin-4- G yl]-amine Prepared in 62% yield.' IHNMR (500 mHz, DMSO-d6) 513.5 hr, 10.1 Cs, br, 11), 7.75 (m, 41H), 7.33 1H), 7.17 (dd, 1H), 7.00 (td, 11), 2.80 (m, 2H) .2.71 .2H) 1.89 (br, 4H) ppm; LaO-MS (ESi) 428.44 e) 426.43 HPLC-Method A, Rt 3.02 min.

Example 8 (5-Fluoro-1-indazol-3-yl)-[2-(2ci trifluoromethyl-phenyl) -5,6,7,8-tetrahydroquinazolin-4o ylj -amine Prepared in 53% yield. IHNMR (500 MHz, Ci DMSO-d6) 613.1 11), 10.2 br, 113), 7.75' 4H), 7.50 (dd, 1R), 7.27 (dd, 7.21. (td, 11), 2.80.Cm, IS 21), 2.72 2H), 1.88 4H) ppm; MS 428.43 426.43 CM-H); HPLC-Method A, Rt 3.01 min.

Example 9 (5,7-Difluoro-H-indasol-3-yl)-[2- (2trifluoromethyl-phenyl)-5,6,7,8-tetrahydraquinazglin-4yl]-amtne Prepared in 37% yield. 'HNMR (500 MHz, DMSO-d6) 813.7.(s, 1K), 10.2 br, 11),7.80 IH), 7.76 1H), 7.E9 2H)i 7.31 Ct, 11), 7.18 1IH), 2.81 Ct, br, 2H), 2.72 br, 1.90 4H3) ppm; MS 446.42 444.37 CM-B); HPLC-Method A, Rt 3.09 min.

Example 10 (5-Trifluoromethyl-1E-indazol-3-yl)-[2- (2trifluoromethyl-phenyl) -5,6,7,8-tetrahydroquiinazolin-4ylJ -amine (11-10): Prepated by Method C in ethanol in 35% yield. "HNMR (500 MHz, DMSO-d) 6813.2 10.1 br. 13H), 8.01 IE, 7.76 7.66 4R), 7.57 11), 2.79 2H),.2.73 2H), 1.99 4H) ppm. MS 478.45 476.42 HPLC- Method A, Rt 3.21 min.

Cl ~~Eample11 (S,7-.diflucro..1H.indazo..3.yi) 2 (2tri fluorom thy.-phenyl) 6, 7, 8, 9 -te trabydro Sz.

OYclOheOPtaPYrimidin.4..yI3]ami (11-11): Prepared in yield. White solid.7:H~ (500MHz, DMSO-dE) 8 1.72 (m, Cl4H1), 1.91L Cj, 211), 3.01- 4H1), 7.1s (dd, 111), 7.30 (td, 1H1), 7.66 2H1), C.2 t, IH, .78ad H,1. m Cfl 111), 13.5 (br. a, 111); El-MS 460;'2 HPIC-Method

A,

Cl Rt 3.13 mint o Cl Example 12 (6-Eenzyl-2-.( 2 -trifluoromethyl.ph~ay1) o Sf EsIStetrahydro-pyrido£4,s- alpyr.midn 4 yl) -S fluoro-1H-ndazo..3yi)..am±n 0 (11-12): Prepared in 49% yield. "MM~ (500o MHz, DMSD-d6) 612.8 111), 9.11 Ca, 111), 7.68 11) 7. 58 C t, 7. 53 11) 7. 44 (m, 411), 7.37 2H1), 7.29 111), 7.19 (mn, 2H1), 3.78 (s, 61 2H1), 2. 81 br, 411) ppm; LC-MS (ES+) 519.24 HPLC-Methoa A, Rt 3. 11 mini.

Examle 13. (t&U-Indaza-3.y1) 2 -trifluorometyl.

phenyi) .6789tetra]ydro..Sacyaheptapimd 4 l atine. (11-13) :_Prepared in 40% yield. '11144 (50014Hz, flMSO-de) 8 1. 70 Cm, 4H), 1. 90 2H1), 3. 00 Cm, 4H1), 7. 01 Ct, 11) 30 (t d, 11), 7. 44 1H1), 7. 49 1-H) 7.68a (mn, 7.77 111), 10.01 1H1), 12.83 111); El- MS 424.2 HPLC-Method A, Et 3.17 mini.

Exai~j 4 C?-FlUoro-1H-ndazo..i.y1) (2trifluorometby1..phny1) -6,758,9 -tetrahydro-Sg- Y0cicohePtaPYrimtdin-4-y1]..min. (11- 14): Prepared in 78% yield:' lflt4 CSOOMHz, DMSO-d6) 81.71 4H) 1.91 (in, 2H), 3.00 (mn, 411), 6.98 (td, 111), 7.16 Cdd, 111), 7.31 (d, 111), 7.68 3H) 7.77 11) 10.25 Cm, 111), 13.40 Cbr. s, 110); El-MS 442.2 RIPW-Methoa A, Rt 3.12 IO min.

Example 15 (5-tluoro-1z-indazol-3-yl)- trifluorcothyl-phenyl)-6,7,8,9-tetrahydro-5zcycloheptapyriidin-4-yl]-amine (II-15): Prepared in 63% Ci yield. EMR (500SMHz, DMSO-d)-8 1.71 4H), 1.91 (m, 2H), 3.00 (mn, 4H), 7.20 (td, 1K), 7.25 (dd, 7.49 (dd, iN), 7.69 (br. t, 2H), 7.74 IN), 7.79 1H), IND10.35 1H), 13.00 (br. a, 1H); El-MS 442.2 HPLC-Method A, R 3.21 min.

\O

)O Example 16 (5-Fluoro-1E-indazol-3-yl)- 011 trifluoramethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3dpyrinidin-4-yl]-amine (11-16): A solution of compound 11 -12 (45mg, 0.087 mmol) in methanol ECOOH) 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. EEM (500 MHz, DMSO-d6) 612.9 IN), 9.52 1N), 9.32 2H, TFA- OH), 7.72 7.59 2H), 7.149 2K), 7.21 (m, 1H), 7:15 4.31 2H), 3.55 28), 3.00 (m, 2HY ppm; LC-MS 429.20 HPLC-Method.A,vR 2.79 min.

Example 17 (ZH-indazol-3-yl)-[2-(2-trifluoroiethylphenyl)-5,6,7,8-tetrahydroquinazolin-4-y1] -amine (11-17): Prepared in 58% yield. 1 1 MUiR (500 MHz, DMSO-d6) 813.0 LH), 10.3 br, 7.74 4H), 7.51 1H), 7.47 1H), 7.32 7.03 1H), 2.82 2H), 2.73 2H), 1.90 4H).ppm; LC-MS- -410.21 HPLC-Method A, Rt 2.99 min.

253 Va Exaple 18 7 -enzyl-2- 2 -trifluoromethyl.phenyl) 5,6,7, 8-tetrahydro-pyrid [4,3-d3 pyrimidin-4-yl) fluoro-1-indazobl. -yl) -amine (11-18): Ptepared from CompOund B11 in 92% yield. HNMR (500 MHz, DMSO-dS) 8l 12.9 (aBIN), 10.5 br, 1H), 9.58 I1H, TFA-OH), 7.71 7.52 im, 9H), 7.19 2H), 4.57 2H), Cf 4.20 (in, 2H), 3.70 2H), 3.00 2H)' ppm; LC-MS (ES+) C519.23 HPLC-Metbod A, Rt 3.23 min.

Example 19 (tE-Indazol-3-yl)- 6-methyl-2-(2trifuoromeby1-phenyl) -pyrimidin- 4-yl] -amine (11-19): Cl Prepared in 42% yield. Melting point 235-237 0 C; 'HHMR (500 MHz, DMSO) 8 2.44 (3H, 7.09. (IN, J=7.5 Hz, t), 7.40 (lB, J-7.1 Hz, 7.49 (1N, J-8.3 Hz, 7.70 (3H, 7.79 (1K, J=7.3 Hz, 7.87 (iH, J=8.3 Hz, 8.03 (11, J-7.7 Hz, 10.3 (1N, 12.6 (i1, B) ppm; HPLC- Method A, Rt2.95 min; MS (PTA) 370.2 Example 20 (1E-Indazol-s-yl) -[6-phenyl-2-(2trifluorcmethyl-phenyl) -pyrimidin-4-yll -amine (11-20): Prepared in 32% yield. 1 HNMR (500 MHz, DMSO) 8 6.94 (1, L=7.4 Hz, 7.24 (IH, J-7.4 Hz, t),.7.33 (1H1, =8.4 Hz, 7.42 (31, 7.57 (IN, J=7.3 Hz, 7.68 (2H, m), 7.75 (1R, J=7.9 Hz, 7.93 8.18 (11, hr a), 10.45 (11, hr 12.5 (11, -br.s) ppm; HPLC-Method A, Rt min; MS (FIA) 432.2 Examle 21 (2H-lndazal-3-yl)-[6-(pyridin-4-yl)-2-(2trifluorcmekthyl-phayl) -pyrimidin-4-yi -amine (11-21): Prepared in 12k yield. 'HNMR (500 MHz, DMSO) 8 7.16 (11, J=7.4 Hz, t),7.46 (1K, J7.6 Hz, -7.56 (11, J=8.3. Hz, 7.80 (11, J=7.2 Hz, 7.90 (2H, 7.97 (11; J=7.8 IDHz, 8.09 (11, br), 8.22 (2H, J-4..9 Hz, 8.45 (11, or 8.93 (2H, J-4.8 Hz, 10.9 (11, hr 12.8 (1H, br s) ppm; HPLC-Method A, Et 3.307 min; MS (FIA) 433.2 t

(M+H)

bxample 22 (1EH-Indazol-3 -yl) 6- (pyridin-22-yl) (2 trifluromethyl-phenyl) -pyrimidin-4-yl] -amine (11-22): enf~f Prepared in 42% yield. 'm5h2 (500 MHz, DMSO) 8 7.07 (1I, J=7.4 Hz, 7.36 (1H, J-7.4 Hz, 7.46 (11, J=7.4 Hz, 10 7.53 (IM, J=5.0 iiz, 7.70 (1H, J-7.4 Rz, 7.79 ci* J-=7.1 Hz, 7.83 111, J-7.4 Hz, 7BS (1H, o J=7.8 Hz, 7.97 J=7.7 Hz, 8.02 (11, J=5.5 Hz, Ci br 8.36 (1H, J7=7.8 Hz, 8.75 (2H, J=4.1 Hz, d), 10.5 hr 12.7.(ap, brs)ppm; RPLC-Method A, at 3.677 min;MS (PTA) 433.2 (M+H) 4 Example 23 16- (2-Chiorophenyl) -2-(2-trifluormethylphenyl) -pyrimidin-4-yl] -(1R-indazol-3-yl) -amine (X1-23): Prepared' in 44% yield; 'IHNMR (500 MRz, DMSO) 8 7.08 (111, T=7.5 Hz, 7.37 (11, J=7_25 Hz, 7.45 (11, 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, d)i 8.04 J-6.2 Hz, br .10.7 hr 12.6 (11, br a) ppm; HPLC-Method A, Rt 3.552 min; MS (PTA) 466 .2 Example 24 CS,6-Dimethy-2 2 -trifluoromethyl-pieny1) pyrimidin-4-yl)- (1H-ixdazol-3-yl) -amine (11-24): Prepared in 35% yield; mp iB3-186*C; 1 9MM4p (500 MHz, DMSO) 8 2.14 (3R, 2.27 6.85 J-7.5Hz, 7.15 CiH, J76 Hz, 7.32'(3H, 7.38 3=7.5-Hz, 7.42 J=7.4 Hz, 7.53 (1H, J7.6 Hz, 8.88 (LH, a), 12.5 (1H, ppm; HPLC-Method A, Rt 2.889 min.; MS (PIA) 384.2 (14+11).

Va Example 25 [5,6-Dimothyl-2- (2-trifluoromethyl-phenyl) pyrimidin-4-yll- (5-fiuoro-ll-indazol--yl) -amine (11-25): Prepared in 440 yield. Melting point 160-163OC; NMR (500 MHz, DMSO) 8 2.27 (3H, 2.40 (3M, 7.16 (2H, C~l 7.44 (2H, 7,52 (INI, J-7..4 HZ, 7..57 URI, J-7.4 Hz, 7.67 (1H, J7.8 Hz, d 9.03 UH, 12.75 !IN, \O~f8) ppm; HPLC-Method'A, Rt 2.790 min; MS (FIA) -402.2 Example 26 [2-(2-Chiorophenyl) -5,6-dimethyl -pyrimidin-4o yl]-(z-idazol-3.yl-amne (11-26): Prepared in C-i yield. 'HNMR (SOO MHz,"DMSO) 8 2.14 (3M, 2.33 (3H 6.84 (in, J77.4 Hz, 7.13 J=7.4 Hz, 7.19 (1H, 7=6.9 Hz,- br 7.27 J77.4 Hz, 7.32 (3H, br 7.37 (iH, J-7.1 Hz, 10.0 (IH, br), 12.8 (1LH, br SI ppm; 8 2.919 min; MS (FIA) 350.1 Example 27 t5,6-Dimethyl-2- (2-trifluoromethyl-phenyl) pyrimidiun-4 -yl l- (7-fluoro- 1-indazol-3-yl) -amine (11-27): Prepared in 92% yield. 'HNMR (500 MHz, DMSO) 8 2.33 (3M, 2.50 (34, 6.97 (1H, in), 7.15 (IN, 7.30 (iN, J8.1 Hz, 7.65 (3M, 7.76 (LM, Jc7.5 Hz, d), 10,0 (IN, 13.4 (IN, a) ppm; HPLC-Method A, t 3.053 min; MS (PEA) 402.2 Example 28 (5,-7-Difiuorc-1H-indazol-3-yl)- 6-Dimethyl- 2- 2 -trifl uoromethyl-phnyl) -pyrimiidnn-4-yl -amine (11- 28): Prepared iaf 50% yield. 1 32NMR (500 MHz, DMSO) 8 2.42 (3M, 2.63 (3H, 7.22 (IN, J-=7.6 Hz, 7.3B (IH, J-9.3, 1.7 Hz, dt), 7.71 (11, 7.75 (Ii, .7=7.0 Hz, dl, 7.79 (11, J=6.7 Hz, dl, 7.86 (iN, J=8.O0Mz, 10.0 _(IN, .256 .s13.2 (1K, a) PPM; HPLC-Mthod A,n't 3.111min;

MS

0 (FA) 420.2 (M+H)t.

ctExamle 29 (2-Chlorophenyl) 6 -dimethyl-yimidin.4 y2.J- (S7-difluoro-E-±nabo..3yl) -amine (311-.29): Prepared in 58% yield, 1 Jfl4 (50.0 1Hz, DMSO) t 2.47 .2.66 (3H, 7.44 (2H, 7.53 (12, m)O, 7.64 (3H, en in), 10.4 13.8 (12, br s) ppm; HPLC-Method A, Rt 2.921 main; MS (FIlL) 386.1 o Ci Example 30 (2-Chiloropheanyl) -Si6-dimethyl-pyrmadn..4 0 -7furoI-nao-3y)aii (Xl-So0): Prepared in yield. 1 jflqR (500 MHz, DMSO) 8-2.35 (3H, 2.51 (32, 7.03 (11N, J-7.8, 4.4 Hz, dt) 7.22 (12, in), 7.33 (12, Jc7.4 Hz, 7.42 (1H1, mn), 9.19 (1H, 13.3 (1ff, s) ppm; HPLC-Method A, Rt 2.a59 rain; MS (FIlL) 368.2 Example. 31 (2-Chiorophenyl) 6-diLmabyl-pyragdn.4 *ylJ-(S-flucro-lr-izdazol.3-.y1)-.ane (11-31): Prepared in 86&% yield. 1 HZ4MR (500 M4Hz, DMSO) 52.49 (32, 2.,68 (3H, 7.38 (1H, J-19.0 Hz, 7.54 (2H, Mn), 7.67 (4H, nm), 10.5 (12, br), 13.2 (12,-bta-) ppm; HPLC-Nethod A, Rt 2.850 min; MS (FIL) 368.1 Example 32 2 -(2,4-Dichl.orophenyl) -5,6-dimetbylpyrimidin-4-ylj (1-indazol-3.-yl) -amine (11-32): Prepared in 52% yield. 1 HN'4 (500 M4Hz, DM50) 52.46 2.64 (32, 7.16 (12, J=7.5 Hz, 7.46 (1H, Jm7.6 Hz, t), 7.61 (2H, mn), 7.68 (2H, J.=8.2 Hz, 7.82 (12, mn), 10.2 (LH, br), 13.0 (iM, br a) ppm; HPLC-Method A, Et 2.983 main; MS (FIlL) 384.1 257 Va Example 33 (S-etkyl 2pyraol.3.-y) (2- Methylhenyl) quinaz'Oliu-4-Yl] nemile (11-33): 1HNMIR (DMSo) $1.21 2.25 (3H, 6.53 (15, 7.38 (4H, 7.62 (1H, d, 7.73 (IN, 7.81 (as, 7.89 (as, t), 8.70 (iH, 12.20 MS 316.3 Cf Exmle 4 (2,4-Difuorophyl) -quinazolin4.yl methyl-2-pyrazol-3-y) -amine (11-34): 'Hmm (500 1Hz, DMSO-de) 512.4 fbr a, 1H), 10.8 (r a, 1H), 8.58 IND 7.97 8.36 7.85 15), 7.60

XH),

6.62 1H), 2.30 MS 338.07'(M+H).

Example 35 2,5-Dimetbocyphenya) methyl-2R-pyrazol-3-yl) -al (11-35): 'HNMR (500 MHz, DMSO-dG) 512.5 (br a, iH), 8.69 (hr, 15), 7.92 t, J Rz, 15), 7.86 J 8.2 Hz, in), 7.65 J a Hz, 15), 7.45 12), 7.14 Cm, 2H), 6.51 15), 3.79 3H), 3.67 s, 3H), 2.14 3H); MS 362.2 Example 36 (2-(2-Chlorophenyl) -quinazolin-4-yl]- ietyl-2Hpyrazcl-3-yyl-auine (11-36): 1 Iiflft (500 MHz, DMsd-ds) Sii.e (br, 15), 8.80 J 8.3 Hz, 15), 9.00 J m 7.6 Hz, 7.92 Cd, J 8.3 Hz, IH), 7.78 (m, 25), 7.67 J 7.9B Hz, 7.61 J 7.0 Hz, 15) 7.55 J 7.4 Hz, 15), 6.56 1H), 2.18 3H);fIs 336.1 ExaMple 37 (2-Methoxyphenyl) -quinaaolin-4-yl] methyi-2H-pyrazol-3-yl) -mie (11-37): 14NMR (500 MHz, DMSO-d6)S 8.78 Cs, br, in), 8.00 t, 7.4 Hz, iR), 7.90 2H), 7.74 J' 7.5 Hz, 15), 7.63 J 7.3 z, 15), 7.30 L 7 8.4 Hz, 15), 7.18. J 7.5 Hz, IND 6.58 br, 1R), 3.90 3H), '2.21 3H); MS o 332.1 C Example 38 6-Dinethylphenyl) -qninazclin-d-y]- S methy1-2R-pyrazol-3-y) .ami (11-38): 1 HNMR (Soo MHz, DMSO-d.) 812.2 a, br, 2H), 8.88 J 7.7 1z, 1H), .8.05 J 7.7 Hz, 1H), 7.80 (in, 2H), 7.37 J 7.6 Hz, iH, 7.21 J 7.7 HZ, 2H), 6.36 1H), 2.16 (s, N 3H), 2.15 6H1); MS 330.1 Example 39 (2-(2-Aetylphenyi) -quinazolin-4-ylJ metbyl-2apyrazo1-3 -yl) -amine 1 HNMR (500 MHz, DMSO-d6) 512.35 br, 11), 8.93 J a 8.4 Hz, 1H),' 8.37 Cd, J 8.6 Hz, 1H), 8.20 Cd, J 7.6 Hz, 1H1), 8.11 Jr 8.0 Hz, 21), 7.89 2H), 7.77 2H), 6.93 (a, 11), 2.33 3H), 2.04 3H) MS 344.1 Exmple 40 2-(2,3-Dimethyphenyl) methyl-2z-pyrazol-.yl-a)jine (11-40): 1 1*M (500 MHz, DMSO-dE) 812.6 br, 13), 12.-1 br, 11), 8.91 T 7.7 Hz, IH), 8.14 J 7.2 Hz, 7.95 J 8.4 Hz, 13), 7.89 Jr- 7.7 Hz, 1K), 7.58 J 7.6 Hz, 1H), 7.53 J 7.0 Hz, 11), 7.42 J 7.6 Hz, 11), 6.60 11), 2.43 3H), 2.35 3H), 2.32 Cs, 3H); MS 330.1 ExaM2e 41 (S-Methyl-au-pyraj.-3-yl)- trifuormethylpbenyx) -quinazolin-4-yl] -amine (11-41)s '1f'1 oR o MHz, fMS0-d6) 512.3 11, 8.77 J 8:2 lz;" 1H) 7.92 2H), 7.85 3H), 7.56 Ct, j 8.1 Hz, 1H), 7.67 Ct, J 7.4 Hz, 6.63 2.27 Csi 3H); MS 370.1 CM+H-).

Va Examle 42 -(2-EthylPhnyl) uifao1n-4-y1J- 2 E-pyrazol-3-yl) -amino (11-42): 3 NMM (500 MHz, DMS0-d6) IN), 8.02 br, 1H), 7.82 J 8.4 Hz, 1H), 7.77 12), 7.62 Cd, J 7.6 Hz, IN), 7.54 (i, 11, 7.41 m, 6.40 S, I) 2.75 J 7.1 2H), 2.17 32), 0.99 J 7.5 Hz, 3H); MS 330.1 c \O (M+EI) Exmle 43 2 -BiPhenyl-2-lr1Jinazo±n-4.yi).-(s.methyl- 2 E-p$razol-3-y1).-amine (11-43); 'nrM (500 MHz, DMSO-d6) 8.76 Cd, J 7.6 Hz, 12), 8.04 12), 7.75 6H), 7.30 SE), 5.34 11)72.14 Cs, 310 3 MS 378.2 (14+H).

is Example 44 (2-Nydroxyphenyl) -quinazolin-4-yll-( Methyl-2-pyrazol- 3-yl1) -amixe (X 1 4 4 3 'mo (500 MHz, DMSO-dG) 8Io.s s, br, 1N), 8.62 Cd, J 8.2 Hz, 3-)H 8.28 J 7.9 Hz, 12), 7.87 22), 7.60 J 7.9 Hz, 7.37 t, J s 7.8 Hz, iR), 6.92 2H), 6.45 Cs, 1H), 2.27 3H); MS 318.1 Example 45 2 2 -Ethcxyphenyl) quinazoa.n-4.yi Kethy1-2N-pyrazo1-3..yl) -mine (11-45.) 'HNMR (500 MHz, DMSO-d6) 812.1 Ca, br, iN), 8.75 J Hz, 1), 7.97 J 7.8 Hz, 1H), 7.82 J B.3 Hz, 7.78 J 7.5 Hz, 12), 7.70 Ct, J 7.8 Hz,, 1H), 7.56 Ct, J 7.8 Hz, 110, 7.22 J 8.4 Hz, 12), 7.12 7.6 Hz, is), 6.55 iN), 4.11 J 6.9 Hz,. 2H), 2.16 (s, 3H), 1.22 Ct, J 6.9 Hz, 32); MS 346.1 Example '46 [5-(Thiophen-2-yI) -2-pyrazl-3-yl trifluoromethylphenya)..uinazolin..4 -yl -amine (1Z-46) 'HM (500 MHz, DMSO-dE) 88.04 Cd, S 8.3 Hz, 12), 8.05 (dd, 3. 7.3, 8.2 Hz, i1), 7.93 J 6.5 Hz, 12H), 7.81 o 52), 7.34 J 5.0 Hz, 12), 7.25 12), 7.00 (m, 1H), 6.87 11); MS 438.1 Example 47 14-CThiophen-2-yl)-2aH-pyrazol-3-y23- Irif luoranmethylphnyl) -quiasolin-4r-yyl -ne (II-47) Prepared acbordung to Metbod'B. lHNM (500MHz, DMSO-d) 6.97 12), 7.08 12), 7.27 1H), 7.36 12), 7.66 2H), 7.77 3H), 7.83 8.00 Cm, 1H), 8.18 Cs, 1H), 8.62 Jr= 8.2 Hz, 12), 10.7 (br. a, 1H); EI-MS 438.1. HPLC-Nethod A, Rt 2.97 min.

Example 48 (4-Phenyl-2H-pyrazol-3-yl) triiluoromethylphenyl)-quinazolin-4-yi] -amine (11-48): Prepared according, to Method B. 1 RNMR (500MHz, DMSO-d6) S 7.05 Cbr. a, 12), 7.14 J 7.8 Hz, 12), 7.25 32), 7.43 2H), 7.60 22), 7.73 22), 7.80 IH), 7.95 12), 2.12 (br. a, 11), 8.60 12), 10.6 (br.

S, 12); El-MS 432.2 HPLC-Method A, Rt 3.04 min.

Exaiple.49 (5-tert-Bntyl-23-pyrazol-3-yl)-[2- (2trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (11-49): IHNM (500 MHz, DMSO-d6) 8 8.76 C(d, J 8.3 Hz, 12), 7.94 21), 7.79,(m, 4H), 7.70 Ct, Jr 7..6 Hz, 12), 6.51 Cs, 12), 1.16 9H; MS 412.2 (14+H).

Example 50 (5-Phenyl-2B-pyrazol-3-yl)-12-(2trifluoromethylphenyl)-guinazolin-4-yll-nine (11-50): lflMW (50OMHz, DMSO-dE) 8 7.09 Cs, lI), 7.36 Ctd, J =7.8, 1.1 Hz, 12), 7.46 Jr 7.8 Hz, 22), 7.65 (br. d, 3 8.1 Hz, 22), 7.78 7.90 Cm, 4H), 7.95 J 7.7 fz, IH), 8.00 J 7.8 Hz, 12), 8.81 3 8.6 Hz, 12), 11.29 (br. a, 11); EIZMS 432.1 2PLC-Nethod A, Rt 3.24 min.

Example s1 4 i 5 -Dipheny-2-pyrazol.a.y:L)- trifluoromethylphny1) -quinazolin-4-yl] -amine (tZ-Si).

'MM~d (500*4Hz, D14SO-dE) 8 7.13 (mn, 1K), 7.18 (in, SlM), 7.36 5H), 7.62 3M), 7.73 2H), 7.ss'(in, in), 9.48 d, J 8.7 Hz 1 iN), 10.02 13.19 1H); El-MS 508.2 (14+1) HPLC-IMetbod A, R, 3.39 muin.

Exaple 5..2( 4 Carbamoy1..2E.pyrazol..3.yl) 2- (2o 10 trifluoramethylphenya,-quinazolin-4-ylj -amine (11-52): o Prepared in 40* yield. 1 'EqiM4 (500MM:, DMSO-d6). 8 12.85 o(a, IH), 12.77 15), 11.80.(a, 15), 10.80 c 8.5-7.42 9H); MS 399.13 (14+5) HPLC-Method A, Rt 2.782 mini.

Example 53 2 3-Pyrazl-3-yl).(2.(2 Prepared in 38% yield. 'HNMR7 (5oo MHz, DM80-ds) 8.12.S2 1K), 10.65 15), 8.75 15), 7.91-7-68 Cm, 82), 6.87 15). (14+5) 356.17. HPLC-Method A, Rt 2.798 min.' Example 54 (S-Nydrozy-2H-pyrazo1..3.yl).. 2- (2trifluomethylphny1) -quinazolin-4-y1J-ine (11-54): Prepared in 36% yield; HNMra (5oo MWz, DMs0-d6) 8 10.61.

15), 8.75 1M), 8.03-7.75 (in, 9H), 5.97 iR); MS 372.18 HPLC-Method Rt.2.766 min.

Exainile 55 (S-Cyclopropy-2z.pyrazo1..s.yl) (2triflnoromethy1-pheny1) -quinazolin-4-y1] -amine (11-55): Przepared in 30* yield. Nmm (5oo M~z, DMSo-ds) 812.21 15), 10.45 1E), 8.68 7.89-7.45 Cm, SM), 6.48 Cs, 1H), 0.89 Cm, 2H), 0.62 Cs, 2H). MS 396.28 o (MeH); PLC-Method A, Rt 3.069 min.

Example 56(5-Methozymethy-2-pyrazl..s-3'yl trif uoromethy1-phnyl) -quinazolin-4-yl -amine (11-56): Prepared in 33% yield; 'IWMR (500 MHz, DMSO-dS) 8 12.51 (syi1H), 10.48 Cs, 1H), 8.60 C8, 1H), 7.81-7.55 7H), 6.71 Cs, 1H), 4.28 2H), 3.18 3H). MS 400.19 HPLC-Method A, R, 2.881 min.

C Exaple 57 (1H-indazol-3-yl) (2-trifluormethylphenyi) -quinazolin-4-yl] .amine (11-57): Prepared to afford 51 ug (18% yield) as pale yellow solid. lHNMR (500 'lz, DMSO-d6) 612.7 Cs, 10.4 12), 8.55 12), 7.81 12), 7.71 12), 7.61 1H), 7.58 Ct, in), 7.46 42), 7.36 7.22 Ct, 6.91 Ct, 1H) ppm; LC-MS 406.16- 404.19 BPLC- Method A, Rt 3.00 min.

Example 58 (4-Chioro-31E-indazal-a-y1) (2trifluoromathyl-phenyl) -quinazolin-4-yl] -amine Prepared in DM7 (70% yield) as pale yellow solid. 'HNMi (500 MHz, DMSO-d6) 813.3 br, 1H), 10.9 hr, 1H), 8.60- d, 1H), 7.97 12), 7.81 1H), 7.75 Ct, 12), 7.67 7.63 (dd, 12), 7.57 Cm, 2H), 7.43 1H), 7.28 (dd, 7.08 12) ppm; .LC-MS 440.10 438.12 CM-H); HPLC-Method A, Rt 3.08 min.

Example 59 (5-Fluoro-1z-indazol-37yl)- (2trifluoromethyl-pheny) -quinazolin-4-yl]-amine (11-59): Prepared in DMF (34% yield) as pale yellow solid. 1 HlMM (500 Ma~z, DMSO-dG) 813.0 e, 12), 10.6 1H), 8.72 (d, 12), 7.99.Ct, 12), 7.89 12), 7.79 12), 7.75 (t, 1H), 7.68.(m, 32), 7.56 (dd, 12), 7.39 12), 7.28 (t, Va 1H) ppm; LC-MS 424.12 r/es 422.13

(M-

HPLC-Method A, Rt 3.05 min.

ct Example 6O (7-Fluoro-1B-indazol...yl)-(2- (2trifluoromethy1 pbhenyl) -quinazolin-4-y1 -amine (1-60): Ci Prepared in DMF 511 yield) as yellow solid. 'HNMR (500 MHz, DMSO-dE) 863.4 lH), 10.6 Cs, 1H), 8.68 11), 7.95 1H), 7.85 1H), 7.72 21),.7.63 Cm, 2H), C 7.58 1H), 7.43 IH), 7.18 (dd, 1H),.7.00 1H) ppm; LC-MS 424.11 422.15

IPLC-

Method A, Rt 3.06 min.

Example 61 (5-Kethyl-1a-indazol.3..yl) trifluorcmethyl.pheyl) .quinasolin4.ylj -amine (11-61): IS Prepared in DIG (81% yield) as yellow solid. 1 HNMR (500 MHz, DMSO-dE) 813.0 br, 8.79 Cbr, 11), 9.11 (br, 1K), 7.96 11), 7.82 7.46 Cs, 1H1), 7.41 (d, 1H), 7.20 Cd, 1H), 2.33 Cs, 3H) ppm; MS 420.15 CM+H), 419.17 CM-H) EPLC-Method'A, Rt 3:07 min.

Example 62 6-Dichloro-phenyl) -qaunazolin-4.yl fluoro-lB-indazol 3-yl)-amin, (11-62): Prepared in DMP (37t yield) as yellow solid. 'ENMR(500 1Hz, DMSO-de) 813.0 11), 10.8. s, 11), 8.72 1H), 7.97 t, 11), 7.90 1H1), 7.75 11), 7.53 3H), 7.43 t, 7.35 1H), 7.23 111) ppm; LC4S 424.08.(M+H)) 422.10 HPLC-zethod A, 1t 3.06 min.

Example 63' t 2 -(2-Chloro-phenyl)-quinaolin-4-.ll.

.H-

indazol-3-yl)-amine (11-63): Prepared in 911. yield. 'mgNMR (5001MHz DMSO-dE) 8 7.06 11), 7.36 Ct, 11), 7.39 t, 11), 7.52 311), 7.62 1H), 7.72 1H), 7.82 Cm, 1H), 7.90 Cd, 111),.8.05 1H), 8.76 11), 11.5.(m, 1H), 13.02 Cs, 111); EI-MS 372.1 EPLC-Method A, Rt' IND 2.93 min.

Example 64 (E-Trif uoromthyl- ndazo1..yl) trifluaraethyl..phenyx) -quinazolin-4-lJ Zamine (11-64): Prepared in DM7 (57% yield) as yellow solid. 1 RNMR (500 Ci 1 MHz, DMSO-d6)813..4 br, lI), 11.4 (br, IN), 8.172 (d, 19), 8.12 Cs, IN), 7.98 lI), 7.83 IN), 7.76 (d, 1iN), 7.73 (dd, IN), 7.60 Cm, 4H), 7.52 I) ppm; LC-MS 474.12 472.17-CM-H) RPLC-Metbod A, Rt 3.25 min.

0l cExample 65 (4-Trifluoromethyl-s-inazol.s-3 (2trifluoromethy1 phenyl) -quinazolin-4-yi -amine (11-65): Prepared in DMF (t yield) as yellow solid. 1NMR (500 MHz, DMSO-d) 813.9 br, IN), 11.2 (br, IN), 8.70 (d, 8.05 Cs, 1H), 7.85 3H), 7.65 Cm, 4H), 7.51 (mi 2H) ppm; LC-MS 474.13 472.17 HPLC-Method A, Rt 3.15 min.

Example 66 [2-.(2,6-DIicfloro-phenyi) -qulnazolin-4-yl]- indaol-3-yl)-aine (11-66): Prepared in DMP (30% yield) as yellow solid. 1 jMR (500 MHz, DSO-d6) 812.9 Cs, I), 11.1 8.69 IN), 7.95 Ct, IN), 7.92 Cd, IN), 7.73 Ct, IN), 7.56 Cd, IN), 7.47 IR), 7.45 Cs, 1W), 7.39 Cm, 2H), 7.26 Ct, 6.92 11W) ppm; LC-MS CES+) 406.11 404.12 CM-H); HPLC-Method A; at 3.00 min.

Example 67 (1E-indazol-3-yl (2-methyi-phenyl) quinazolin-4-yl] amIne. (11-67): Prepared-in 55% yield.

'HNM14 (500MHz, DMSO-dE) 8 2.15 Cs, 3H), 7.09 Ct, 19) 7.26 Cd, IN), 7.31 Ct, 1W), 7.'39 7.42 Cm, IH), 7.55 (d IN), 7.64 lI), 7.74 Cd, 1H), 7-.89 7.96

IN

0 1H), 8.10 Cm, 11), 8.81 1H), 12.0 11), 13.18 iH); 11-14 352.'2 HPLC-Method A, Rt 2.93 min.

ct SExaple 6 (7-T rifloretxyl-IZ-indazol-3-yl triluorcretbyl -henyl) -uinaolin-4yl -amine (11-6 Prepared in VMF (75t yield) as yellow solid. 'HNM (500 MHz, DMSO-d6) 613.5 br, 1H), 11.2 br, 11), 8.69 IND 13), 7.97 1H1), 7.92 13), 7.82 cd, 1H), 7.74 1R), 7,70 cd, 13), 7.68 1H), 7.64 2H), 7.57 13), 7.14 1R) ppm; LC-MS 474.11 IN 472.14 CM-H); EPLC-ethod A,Rt 3.24 min.

Example 69 (6-Trifluoromethyl-IH.4 ndaol-3.yl)- (2trifluoromethyl-phenyl) -quinazolin-4-ylJ -amine (11-'69): Prepared by Method B in DMF (78% yield) as yellow solid.

HNMt (500 MHz, DMSO-d6) a 13.4 br, IH), 11.1 br, 13), 8.67 7.95 7.82 3H), 7.72 (m, 23), 7.63 Cm, 2H), 7.57 Ct, 7.23.(d, iN) ppm; LiC-MS 474.12 472.15 CM-H); HPLC-Method A, Rt 3.28 min.

Example 70 C5-Nitro-1H-indazol-s-yl) (2trifluoromethyl-phenyl) -quinazolin-4-ylJ -amine (11-70): Prepared in DMF (82t yield) as yellow solid. 'Mm (500 MHz, DMSO-d) 613.6 Cs, br, lH), 11.4 Cs, br, iN), 8.75 Cs, 13), 9.72 1H), 8.09 Cdd, 21), 7.98 13), 7.83 7.75 Ct, 11), 7.70 Cm, 21), 7.61 3H) ppm; LC-MS 451.14 449.12 CM-H); 3PLC-Method A, Rt 3.02 min.

Example 71 (5,7-Difluoro-1B-indazol-3-yl)- 2- (2triflnoroinethyl-phenyl) -quinazolin-4-yll -amine (11-71): Prepared in Di (60% yield) as yellow solid. 1 HNMR (500 M.Hz, DMSO-d6)t13.7(, br, 11.2 br, is), 8.73

\O

12), 8.03 11),.7.88 11), 7.80 2H), 7.70 o- 3H), 7.32 2H) ppm; LC-MS 442.14 (ES- 440.14 HPLC-Method A, R 3.11 min.

Ct Example 72 4 -Pyrrol-1-yl-1-indazol-3-yl)-[2-(2- C-i trifluoramethyl-phenyl) -quinaolin-4-yll -amine (11-72): Prepared in DMF (33% yield) as yellow solid. lHNt (500 n MHz, DMSO-d6) 813.4 br, 11.0 br, 1H), 8.53 Cr 1H), 7.98. 12), 7.75 4H), 7.62 2H),.7.52 1H), 7.43 12), 7.05 12), 6.80 2H), 5.61 C) 2H) ppm; LC-MS 471.18 (ES-).469.18.(Mo HPLC-Method A, Rt 3.12 min.

Example 73 (5-Amino-t&-indazol-3-yl)-[2-(2trifluormethyl-phenyl)-quinasolin-4-yll-amine (II-73): A solution of compound II-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 mit, the mixture was filtered through celite, the resulting celite was washed with MeOH (5 times), and the solvent was evaporated in vacuo to provide a crude product that was then purified by HPLC to give the title compound as a yellow solid mg, 15%Y. m.p. 221-223cC; 1ENMR (500 MHz, DMSO-d6) 813.2 br, 1H), 10.7 br, 1H), 9.80 (br, 2H), 8.68 1H), 7.97 1H), 7.87 1H), 7.75 2H), 7.65 52), 7.30 12) ppm; MS 421.16 (ES-) 419.17 HPLC-Method A, RP 2.41 min.

Example 74 2 -(2-Chloro-pheny1)-quinazolin-4.-yl]-(7fluoro-1E-indazol-3-yl)-amine (i11-74): Prepared in DMF yield) as yellow solid. 10NMR (500 MHz, DMSO-d6) 813.7 IH), 11.7 br, 1H), 8.80 1H), 8.15 (t, 12), 7.99 12), 7.88 12), 7.68 1H), 7.60 (m, 2K), 7.53 1H), 7.46 1H), 7.25 (dd, 18), 7.04 (M, 01) ppm; LC-MS 390.16 UPLC-Method A, Rt 3.00 min.

Exple 75 12-(2-Chlorophenyl)--quinazoli-4-yl]-(S.

cil fluoro-1a-indazol-3-yl)-amine. (11-75): Prepared in DMP.

1 88HMR (500 MHz, DMSO-d6) 813.2 11.7 Cs, br, 1), Cf 8.80 18), 8.10 Ct, 18), 7.91 28), 7.70 1H), 7.58, 48), 7.50 It, 7.29 Ct, 1H) ppm; LC-MS (ES+) o 10 390.17 CM+8); HPLC-Metbod A, Rt 3.00 min.

Va 0 ]*I92le 7 6 (2-chloro-phenyl) -quinazolin-4-ya3 (5,7- Ci difluoro-1E-idazol.3..yl) -auine Prepared in DMF yteld) as yellow solid. 1 JHNMR (500 M4Hz, DMSO-d6) 8r3.e 18), 11.5 br, 1H), 8.76, 1H), 8.08 (t, 1H), 7.93 Cd, 1H), 7.84 7.64 18), 7.55 (d, 1H), 7.50 1H), 7.44 Cm, 2H), 7.36 iN) ppm; LC-MS 408.15 406.17 CM-H); HPLC-Method A, Rt 3.08 min.

Exale 77 (2-Cbloro-phenyl) -quinazolin-4-y1l- trifluoromethyl-a-indazol-3-yl)-amine (11-77): Prepared in DMF (66% yield) as yellow solid. 'HNMR (500 MHz, DMSOd6) 513.5 Cs, 1H), 11.4'(s, br, 1H), 8.79 IR), 8.29 1' 8 .07 18), 7.93 1H), 7.84 Ct, 18), 7.72 Cd, 18), 7.63 2H), 7.53 Cd, 7.48 7.36 18) ppm; LC-MS rn/en 440.16 m/en 438-.18 HPLC-Method A, Et 3.22 min.

Example 78 [2-(2-cyano-phenyl) -quiazolia-4-yl] -(1Hindaizol-3-yl)-ammne'(11-78). Prepared in 13% yield. 1H- NMR (500 MHz, DMSO) 5 12.9 (br, LH), 10.8 (br, 18), 8.73 Cbr a, 18), 7.97 Cm, 7.74 IH), 7.5 Cm, 48), 7.42 ID(M, 1H), 7.08. C m, XI) ppm; MS (VIA) 363.2 HPLC- Method A, at 2.971 min.

C Example 79 (5-Bromo-1E-indazol-3-yl)..2-'(2 S trifluoromethyl-pbhnyl) -quinazolin-4-yll -nine (11-79),: Prepared in DMF (64% yield) as yellow solid. 1UNMR (500 MHz, DMSO-d6)' 513.4 1H), 11.6 br, 1H), 8.93 (d, (fl HIH), 8.21 Ct, 1H), 8.14 11), 8.05 1H), 7.95 Cm, 4H), 7.86 7.65 7.59 1H) ppm; MS (ESt) 486.10 484.09 CM-H); HPLC-Method A, Rt 3.22 min.

Example 80 (6-Chtoro-rw-mndazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-ylJ -amine (11-80): Prepared in DMF (94% yield) as yellow solid. 1 MOMf (Soo MHz, DMSO-d) 813.1 1H), 11.2. br, 1H), 8.73 (d, 1R), 8.03 1H), 7.87 IH), 7.79 2H), 7.73 Cm, 2H), 7.67 2H), 7.58 IH), 7.04 (dd, 1R) ppm. LC-MS 440.14 436.16 HPLC-Nethod A, Rt 3.25 min.

Example 81 (l-Fluoro-6-trifluor ethyl -indazcl.3-yl) (2-trifluo3ometiyl-phenyl) -qa inazolin-4-yll -amine (XI- 81): Prepared in DMF (30% yield) as yellow solid. 'HNMR (500 MHz, DMSO-d) 513.9 Cs, IH), 11.0 br, 111), 8.64 11), 7.94 7.81 11), 7.71. 2H), 7.60 4H), 7.20 (dd, 11) ppm. LC-14S 492.18 490.1B (N-H) 7 HPLC-Method A, Rt 3.44 min.

Example 82 (6-Eromo-l-ninazol.s.yl)-[2- (2trifluorom thyl-phenyl) -quinazolin-4-ylj -amine (11-82): Prepared in DHF (40% yield) as yellow-solid. LHNMR (500 MHz, DMSO-d) 813.1 IX), l.2 Cs, br,1IH), 8.73 (d, 1H), 8.03 11), 7.87 1H), 7.80 2H), 7.73 (m, S 3H)U, 7.6.7 (mn, IE), 7.61. 1H3), 7.15' (dd, Ili) ppm; MS Cl 486.07' HPLC-Method A, Rt 3.28 min.

Examle 83 C2- (2,4-Bif-trifluoromethayl-pheiyL) Cl (Il-93): Prepared in DMF in 28* yield. 1 1NMR3 (500MHz, MeOH-d4) 8 8.81 J=8.4Hz, 113), 8.35-8.20 313), .8.19-7.96 Cm, 313), 7.40-7.34 113), 7.29-7.14 (mn, 113); Cl LC-MS {ES+i) 510.14 (Mi-H) HPLC-Method C, Rt 8.29 'min.

o Exal1e 84 (5,7-Difluoro-iaf-mndazol-s-yl)- (2-C4-fluoro-2- 0trifluoraethy-pheny)-qina zoin4yj..am±n. (11-84'): Cl Prepared in 48%' yield. 1 HNMR (800MHz, MeOH-d4) 68.74- 8.63 1H3), 8.23-8.10 113), .7.99-7.90 (mn, 213), 7.89- 7.60 (in, 7.71-7.61 (mn, 113), 7.61-7.50 Cm, 1H3), 7.24- 7.15 113), 7.14-7.02 113); LC-MS 460.14 (14+1) HPLC-Method C, Rt 7.59 min.

Examle 85 (2-Broio-phenyl) -quinazolin-4-ylJ difluora-1H-indazcl-3-y1)-amine (r1-85): Prepared in TftF (21% yield) 1 "Dq'M (500MHz, MeOH-d4) 6 8.83. J-8. 4Hz, 113),, 8.35-8.20 3H3), 8.19-7.96 3H3), 7.40-7.34 (mn, 2.1) 7.29-7.14, 13) LC-4S (ES8+) .510.14 HPLC- Method C, 8.29 min.

Example 86 (5,7-Difluoro-2.H-indazol-3-yl)- (5-fluoro-2triflucromethyl--phenyl) -quinazolin-4-yl] -nine (11-86): Prepared in THE' (26t. yield). 'lNR (500MHz, MeOH-d4) 68.62 Cd, J-8.4iz, 113), 8.16-6.02 m1H,7.96-7.73 Cm, 31H)', 7.S9-7-.48 (in; 113), 7.48-7.35 1H3), 7.21-7.09 (mt, 3M), 7.09-6.89 113); LC-)48 460.16 CN.H); HPLC- Method C, R, 7.28 win.

IND Exmple 87 E2- (2 ,4-Dichloro-phenyl) -qujinszolinj-4-yl] o (5,7-Ditluoro-ll-indaol-3.yl) -amine (11-87): Prepared in THP (16% yield) 'HNNR (500M~z, MeOH-d4) 8 8. 81 C-d, Jn8.4Hz, 29), 8.35-8.20 (in, 3H), 8.19-7.96 3H), 7.40- ;L~ehd, 7.3, (m 9,72-.4(I LC-MS 510.14 Example 88 C2- (2-Chloro-5-trifluorcnethyl-phenyl) ci quinazolin-4-Yl C5,7-Difluoro-1H-±ndazol-3-yl) -amine (11-88) Prepared in TSP (33% yield).. 1 'HNM~ (500MHz, DMSO-dE) 8 10.76 8. 66 Cd, JcB.3Hz, 12), 8.06o 7.84 (in, 3H), 7.81-7.63 Cm, 3H), 7.48-7.16 22) LC-MS Cl(ES+) 476.16 HPfLC-Method C, At 19.28 mini.

Example 89 (4-Fluoro-1R-inxdazol-3-yl)-2-(2.

trifluoromethyl-phenyl) -quinazolin-4-yll -amine (11-89): Prepared'in I4MP (79% yield) as yellow solid. 'IMM ('500 M4z, DMSO-d6) 513.2 1H), 10.8 br, 13), 8.63 (d, 1H),'7.97 13), 7.85 1H), 7.74 2H), 7.64 Ct, 12), 7.57 Cm, 12H), 7.32 Cm, 2H) 6.52 13). ppm; LC-MS (ESt) 424.17 HPLC-Method A, Rt 3.14 min.

Example 90 (1H-Indazol-3-yl) 8-methoxy-2- trifluoroinethyl-phenyl) -qninazolun-4-ylJ -nmine (11-90): Prepared usfig TSP as solvent to afford the title compound as a TPA, salt (23% yield). HPLC-Method A, Rt 2.97 min 'HNMR (DMSO-d6, 500 M4Hz) 12.9 (13, 11.0 -10.7(12, be), 8.25 (12f, mn), 7.75-7.50 (8H, 7.30.

(12, mn), 6.90 rn) 1 4.0 MS 436.2 Example .91 (5-Fluoro-3-indazol-3-yl)-CE.-meuwoxy-z-(2'trifluoroinethyl-phenyl) -quiunazolin-4-ylJ -amine (11-91): Prepared using TPA as solvent to afford the title compound as a TPA salt (23% yield) H PLC-Method A, Rt o3. 10 'uin. (99W) 1 HNMR (DMSO-d6, 500- M'z) 13.0 (111, be), 11.0 10.7(111, be), 8.25- (11, in), 7.75-7.50 (7M, Mn), 7.35 (111, in), 7.25 (111, 4.0 (3H1, MS 454.2 Example 92 (7-Fluoro-1E-indazol-a-yl) C8metlzoxy-2- (2trfurmty-hnl-qiaoi--l-mn Prepared using THF as. solvent oafr'h il (N compound as a TFh salt (98 mg, 58% yield). 1{PLC-Method A, ERt 3.20 min 'THNR (DMwo-d6, 500 MHz) 8 13.45 (11, bs), 11.0 10.7CmH, be), 8.25 7.75-7.60 o 7.50) (111, mi), 7.40 (12, 7.15 6.95 CO) 4.0 (3H, MS 454.2 Examle 93 (5 3 7-Difluoro-l-nazo..3yl) -[S-inetboxy-2- (2 -trifluormethyl -phenyl) -quinazolin-4 -ylJ -amine (I I- 93): Prepared using-mrP as solvent to afford the title compound as a TFA salt (36 yield) HPLC-Method A, Rt 3.27 min. 'MM14 (DM4SO-dG, 3500 MHz): 13.65 (lIN, be) 11.0 10.7(11!, ha), 8.22 (1H1, un), 7.75-7.60 (SE, 7.4 0 (Iii, mn), 17.35 in), 7.19 (1H1, M),1 4. 0 (OH, s);14 472.2, M-iH) Example (2-Chloro-pyridin-a-y1) -quinazolin-4-ylJ

(S,

7 -Difluoro-1sinazo-a-y)-amine (11-94)- Prepared in DMF. 'HNhR (50014Hz, DM0-dc) 5 13.62. (bras, 13, 11. 06- 10.71 (li) 1H, 8.16-7.70 (mn, 4H), 7.60-7.09 (mu, 3H); LC- MS 409.14 HPLC-Method A, Rt 2.8.9 win.

Example. 95 (2-Chloi'a-4-nitro-.phenyl) -quinazolin-4-ylJ lua.4 -l4a iamolJ-y)-aian5 (11r95): Prepared-in nIP. 'HmmR (50014Hz,,DMSO-d 6) 8 13.35 IN) 10.74 (s, IN1), 8.67 J-8.4Hz, 1H), 8.29 J=2.OS~z, 8.18- IND8.08 (mn, 12), 8.07-7.60 42), 7.53-7.10 2H). LCo MS 453.15 RPLC-Method D, Rt 3.63min.

Ct Example 96 [2-(4-Amino-2-chloro-phenyl)-quinauolin-4-yl (5,7-Difluoro-ln-indazol-3-yl)-amine (11-96):.

SA solution of compound 11-95 (8mg, 0.018mmol) and tin chloride dihydrate (22mg, 0.lmmol) in ethanol (2mL) was Cc heated at 100 0 C for 24h. The reaction was diluted with Va IN EtOAc (lOmL), washed with 1N NaOH solution (2xlOmL), brine, and dried over anhydrous sodium sulfate to afford C the crude product. Purification was achieved by flash \O chromatography on silica gel (eluting with 1-3% NeOM in HCl 2 12.) 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-1H-indazol-3-yl) 12-(2-trifluoromethyl-phenyl)-quinazolin-4-yl] -amine (11-97): Prepared in 34% yield. 1HNMR (500MHz, D1SO-d6) 6 1.58 21), 1.66 2H), 2.24 2H), 2.54 (m-29), 7.63 32), 7.71 1H), 7.75 7.78 1H), 7.85 1H), 8.53 1H), 9.99 1H), 12.09 121; EI-MS 410.2 HPLC-Method A, REt 3.05 min.

Example 98 (1B-Pyrazolo[4,3-b]pyridin-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yll -amine (11-98): Prepared in DMF (37% yield) as yellow solid. IHNMR (500 MHz, DMSO-d6) 613.1 br, 1H), 11.2 br, 1H), 8.73 12), 8.54 (dd, 8.12 IH), 8.06 1iH), 7.90 18), 7:84 12), 7.75 1H), 7.69 2H), 7.65.

7.47 (dd, 12) ppm; LC-MS 407.18 HPLC-Method A, Rt 2.77 min.

273

IND

o Example 99 (1R-Pyrazolo[3,4-blpyridin'-3-yl)- 0 trifluaromethyl-phenyl) -quinazolin-4-ylj -amino Prepared in DMF (45% yield) 1 HMq' (500 M4Hz, DMSO-dE) *813.S br, 12), 11.3 br, 1H), 8.7'8 12), 8.49 IS), 8.17 12), 8.03 IS), 7.89 12), 7.80.

C~1 22), 7.74 22), 7.68 1S), 7.06 (dd, 12) ppm.

14S X(ES+) '407.16' 405.16 CM-H); HPLC-Method A, Rt' 2. 80 min.

Exapje 100 (6-Mothyl-trH-pyrazolccs,4-blpyridan.3.yl). 2- IND (2-trifluoromethyl-phenyl) -quinazclin-4-yl) -amine (11- 0 100) Prepared in Dd? (11% yield). 1 HNI4R (500 MHz, Cl d6) 613.2 br, 12), 10.8 is, br, 1S), 8.57 lH), 7..95 12), 7.82 12f), 7.72 Ct, 12), 7.65 2H), 7.56 2H), 2.44 3H, buried by DMSO), 2.20 Ca, 3H) ppm. LC-MS 435.22 433.25 HPLC- Method A, Rt 2.94 min.

Example 101 (6-0xo-5-phenyl-5,6-dihydr6-1x-pyrazolo[4,..

ojpyridazin-3-yl) C2-trifluoromethyl-phenyl) qninazolin-4-yl] -amine 3:X-101: Prepared in Did? (691 yield). 'HNMR (500 MHz, DMSO-de) 8 12.6 IS) 11. 0 (s, br, 1S) 8. 60 12), 7.95 12) 7. 88 12),1 7.8 0 Cd, IS), 7.68 Cm, 4H), 7.40 Cs, 3H), 7.22 C8, 2H), 6.61 12) ppm. LC-MS 500.21.(4+), 498.16 (14- IPLC-Method A, at 3. 00 mini.

Examplej13 [6-Kethyl-2- (2-trifluorcmethoxy-phenyl) pyrimidin-4-yl (5-phenyl-21-pyrazol-3-yl) -amine (11- 103): MS 412.13 HPLC-Method 2 Rt 1. 248 win.

Example 104 (5-Furan-2-yl-23-pyrazol-s-y1) 6-methyl-2trifluoromethozy-phenyl) -pyrimidin-4 -yl] -nine (11- 104); MS 402.12 2PLC-Method.H, Rt 1.168 mini.

o Example 105 C6 -Ethyl -2 (2 trif luoromethoxy-phenmyl) pyrintidin-4-yll -0(-metbyl- 25-pyrazcl-3-yl) -amine (II- 105): MS 364.14 HPLC-Method E, at'1.112 min.

Exaple 1o6 (2-chioro-phenyl) -pyrido[2,3-dlpyrimidin- 4-yl] -(S-methyl-2s-pyrazol-s-yly-a-4ne (11-106): HNNMR en(500 MHz, DM90) 812.23 12), 10.78 Cs, 12), 7.73-7.47 m, 72), 6.72 12), 2.21 Cs, 3H). MS: (14+H) 337.02.

HPLC-Method A, at 2.783 min.

o Example 107 (5-Fluoro-2z-indazol-3-yl)-2-2.

trifluorometyl-pheny.) -6 oyclopentapyrimidin.4ylj..amine (11-107):- Prepared in 68%' yield. 'HgsR (500Mz, DMSO-dE) 8 2.16 2.88 (m, 22), 2.98 Ct, 2H), 7.21 (td, 12), 7.29 (dd, 1H), 7.50 (dd, I2), 7.65 Ct, 12), 7.67 Ct, 12), 7.73 Ct, IN), 7.79 10.22 (br. B, 12), 12.99 (br. s, 12); El-MS 414. 2 HPLC-Method A, Rt 2.S92 min'.

Exajmple 108 (iBf-Indatzol-3-yl)-[2-(2-trifluromethyl.

phenyl) -pyrido[2,3-djlpyrimidin-4-y] -amine (11-108): HPLC-Method A, Rt 2.78 min. ?IUIMR (DM4SO-ds, 500 MHz): 12.95 (12, ba), 11.45 8 11.15(12, be), 9.20 (2H, mn), 7.85-7.70 (2H, mn), 7.70-7.55 (4H, mn), 7.50 (12, mn), 7.35 (12, mn), 7.05 (12, mn); MS 407.03 (14+2).

ExamTple 109 (5.7-Difluoro-1E-indazol-3-yl)- (2trifluoromethyi-phenyL) -pyrido [2,3-djpyrimidin-4-yl] amine (IS-109): Yellow, di.-TPA salt (251% yield). HPLC (Method A) 3.10 mint. 'HNMR (DM80-d6, 500 MHz): 13.8-13.6 (1H, bs), 11.4 11.2(12, be), 9.15 (2H, in), 7,85-7.75 7.75-7.62 (3H, mn),'7.32 (2H, m)l 442.98 (14+2).

Example 110 (12- (2-Chioro-phenyl) -pyido (2,3-dlpyimidizz- 4 -Y]-(lH-indamol-3-yl)-amine (11-110), Prepared from 2aminonicotinic acid and 2-chlorobenzoyl chloride afforded the title compound as a di-TFA salt (28* yield). .HPLC- Cl Method A, Rt 2.985 muin. 1 NNMR (DMSO-dG, 500 MHz): 12.90 (1H, 11.10 10.90 (12, be), 9.05 (2N, in), Cfl 7.75-7.60 (2H,rn), 7.51 (IN, in), 7.45-7.25 (SH, mn), 6.95- Cl (IN. MS (m/z).372.99(M+H).

o Enjle111 (5-Fluoro-1a-±ndazol-3-yl) (2trifluormethl*-phenyl) lO-hexahyiro..

oyclooctapyriinidin4-yll-azine Prepared in 43% yield. 'aNRm (50014Hz, DMSO-dE) 81.46 (mn, 2H), 1.53- (m, 2H), 1.77 Cm, 4H1), 2.95 (in, 2H), 3.04 (tu, ZR), 7.22 (m, 2H), 7.50 (dO, 1ff), 7.72.(m, 3H), 7.80 1If), 10.5 (mn, 1N), 13.05 (br a, 210; El-RS 456;2 (M+10; UP LC-IMethod C, 11.93 mini.

Example 112 (2-chi.oro-phenyl)-6,7-dihydro-SEcye lopentapyrimidin-4 -yll fluoro -If- indazol -3 -yl) aie(11-112): Prepared in 67% yield. 'HNMR (500MHz,.

DMSO-dS) 52.18 2ff), 2.89 Cm, 2H), 3.02 2R1), 7.24 (td, 3. 7.42 (in, 2H), 7.49 (td, iN), 7.52 Cdd, iNf), 7.54 1H), 7.57 (dd, 1ff), 10.50 Cbr. B, IE0, 13.06 Cbr. s, 1H); El-MS 380.1 NPLC-Method C, Rt 9.68 mini.

Examgple 113 (R1-Indazor.-3-yl) (2-trifluromethylphenyl) -6,7-dihydro-5E-oyclopentapyrinidin-4..yl) -aimine (11-.113): Prepared in 37% yield. HM (50014z, DMSO-dE) 8 2.65 2H), 2.85-.Cm, 2.99 2H), 7.02 IN), 7.32 IH), 7.47 IN), 7.55 12), 7.68 Ct, iN), NO 7.74 irn, 7.80 IN), 10.37 (hr. a, iN), 12.91 (hr.

0 5, 1H) El-MS 396.1 HPLC-Metbod B, R, 9.88 min.

ct Ex~pjlej14 (7-Fluoro-1E-indazol-s-yl) 2- (2- *S trifluorasthyl-phenyl) -6,7 -dihydro-Saci Cyclopentapyriidi-4.ylI..amn (11-114): Prepared in yi eld. 1 (SOOMHmz, DMSO-dE.) 8 2. 15 2H) 2. 87 (m, Cr) 2H), 2.97 211) 6.99 (td, iN) 7.17' (dd, 15), 7.38Cd

IND

ci 15), 7.65 Cm, 2H), 7.71 IM), 7.78 15), 10.21 (hr.

s, 15), 13.40 (br. s, 1S); Rl-MS 414.1 HPLC-Metbod C, Rt 9.99 min.

Cl Excample- 11S (5,7-Difluoro..±H-idazo..sy)r2.(2.

trifluoromethy1-phny1) -6,7 -dihydro-SEcyciopentapyrimidn.4.yll..nine(- Prepared ac'cording to Method c in 52* yield. 1 HNMR (50014Hz. dE) 5 2.16 2H1), 2.89 2H1), 2.97 25), 7.19 (dd, 7.29 {td, IX), 7.63 Ct, 1H1), 7.66 15), 7.1 C(t, 1K), 7.78 ID,,10.16 (hr. a, 1111, 13-.55 (br. B, 1K); El-MS 432.1 HPIc-Metho~d C, Rt 10.09 min.

Exa-mle 116 (2-Chiloro-phenyl) -6,7-dihydro-Szeyolopentapr;Lzdin-4.ylz (1E-±zdazol-3-yl) -amine (11- 116): Prepared in S6% yield. 1 IDAJR (50014Hz, DMSO-dE) 8 2.16 (in, 2.85 2H1), j.01 2K), 7.06 111), 7.34 1K), 7.40 Ct 1 1K), 7.48. 2H),-7.53 C(d, 1n)., 7.56 15) 7.63: 1H), 10.39 (hr. s, 15), 12.91 (a, 1H); El-MS 362.1 HPLC-Method A, Rt 3.09 min.

Example 117 2 -(2-Chloro-pheyl)-,7.ehydro.5H c yclopentapyrtxidiu-4-yl] luoro-1H-indazol-3-yl) amine (11-117): Prepared in 63% yield; 1 HN'MR (50014Hz, DNSO-dG) 82.15 C(m, 25), 2.87 2H), 3.00 Ct, 2H),'7.01 Ctd,1IH), 7.19 Cdd, 7.39 Ct, 111), 7.45 Cm, 2H), 7.'51

IND

o 1H), 7.55 13), 10.35 (br. s, 13H), .13.45 (br. s, c-i 1H); El-MS 380.1 HPLC-Method A, Rt Rt 3.15 udin.

Examle 118 (2-Chlo'ro-phenyl) -6,7-dihydro-SaZoyclopentapy-rimidin-4-yl (5,7-difluoro-1E-indazal-3-y1) aine(11-118) Prepared in 60t yield. 1'w.43 (500M4~z, DMSO-d6) 62 .18 2H) 2. 91 2H) 3. 01 2H) 7.3 2 Va Ct, 110, 7.33 (td, 1H), 7.41 1H), 7.48 Ct, 110, .7.53 1H), 7.55 (dd, 1H), 10.35 (br. s, 1H), 13.45 (br. s, 1H); El -MS 3 98.1 HPLC-Method'A, Rt &t 3 .24 min.

o Example 119 (1E-Indazol-3-yl) (2-trifluoromethiylphenyl) -5,6,7,S.9,1-hcaiydro-cycooctapyrijdi..4y amine (11-119): Prepared in 36% yield. 1 E M (500!O~z, D1480-d6) 6 1.47 (mn, 23H), 1.53 (mn, 2H), 1.78 43), 2.96 m, 2H), 3.06 2H), 7.03 Ct, 1H), 7.47 1H), .7.72 iH), 7.73 110, 7.72 3H), 7.81 1H), 10.52 Im,11, 12.97 (br. 0, 110; El-MS 438.2 (Mf1); ItPLC- Method A, Rt 3.37 min.

S Examle 120 (7-Fluoro-1E-indazol-3-yl)-[2-(2trifluoromethayl-phenyl) -5,6,7,8,9,1O-hexahydrocyclooctapyrimidin-4-yl] -amine (11-120): Prepared'in yield. 1 nNMR CSOOMHz, DM50-d6) 8 1.46 2H), 1.52 (m, 2H1), 1.77 Cm, 4H), 2.94 23), 3.04 2H), 7.00 (td, 13), 7.17 (dd, 1H), 7.30 7. 70 (in, 3H), 7.79 (d, 1K), 10.5 Cm, 1H), 13.49 (br a, 13); El-MS 456.1 CM+I0; HPLC-Method A, at 3.43 min.

Excample 121 (5,7-Difluoro-1a-±ndazol-'3-yl) (2trifluorcinethyl-phenyl) -5,6,7,8,9,1O-beukydrooyolooctapyrimidin-4-ylj-amin, (11-121): Prepared in 49% yield. l'flNM (500M~z, DM50.4d6) 8 1.46 (mn, 2H), 1.52 Cm, 2K), 1.77 (mn, 43), 2.95 (tm, 2H), 3.03 21K), 7.14 (d, \o H, 7.30 iH), 7.73 3H), 7.80 1H), 10.5 (m, o 1iN), 13.62 (br. a, iH); EI-MS 475.1 HPLC-Method A, R 3.52 min.

Example 122 [6-Cyclohexyl-2-(2-trifluoroaethy-pheny1)- Cl pyriidin-4-yl (X-indazol-3-yl) -amine (IZ-122):S Prepared in 45V yield. 'flIMR (500 MHz, CDCl3) 8 1.30 (2H, 1.46 (2H, 1.65 (2H, 1.76 (2H, 1.91 (2H, cl 2.61 (IH,.br 7.08 (iN, t, J=7.4 Hz), 7.27 (lE, d, J8.0 Hz), 7.35 (iN, t, J- 7.1 Hz), 7.50 (1Hi, t, Hz), 7.58 C1H, t, J7.4 Hz), 7.66 (3H, 7.72 (1H, d, o=7.8 Hz), 8.0 9.87 (iN, br) ppm; HPLC-Method D, Rt 3.57 min; LC-MS 438.17 (M+H) t Example 123 (2-lluoro-phenyl) (2-trifluoromethylphenyl)-pyrimdin-4-yll-(In-indazol-3-yi)-amine (11-123): Prepared in 8% yield. 'HNMR (500 MHz, CDCl 3 7.18 (3H, 7.37 (iN, 7.43 (IN, t, J=7.9 Hz), 7.51 (1K, d, J=7.9 Hz), 7.55 (1H, t, J-7.6 7.65 (iN, t, J-7.4 Hz), 7.79 (iN, d, J.7.9 Hz), .7.85 (IN, d, L= 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 (M H)* Example 124 (6-Pluoro-tl-indazol-3-yl)-[2-(2trifluoromethyl-phenyl) -quinazolin-4-yl amine II1-124).

Prepared in DMF (87% yield) as yellow solid. 'HNMR (500 MHz, DMSO-dE) p13.0 IN, 11.1 IN), 8.66 (d, 1K), 7.95.Ct, 1K), 7.80 7.72 2H), 7.62 (m, 4H), 7.21 (dd, 1K), 6.84 (td, iN) ppm. LC-KS 424.15 KPLC-Method A, Rt 3.05 min.

Example 125 3-(2-(2-Trifluormethyl-phenyl )-quinuzolLn-4ylaminol-LEf-indazole-S-oarbozylia acid methyl ester (11- 125): To a solution of compound 11-79 (100 mg 0.21 mmol).

O

o in DMF (2 mL) was added MeoH (1 mL), DIREA (54-uL, 0.31 0 mmol) and PdCl 2 (dppf) (4 mg, 0.005 mmol). The.flask was flushed with CO three times and then charged with a CO balloon. The reaction mixture was heated at 809C 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 cI afford II-125 as yellow solid. 1 HNMR (500 MHz, o 10 DMSO-d6) 813.3 11.3 br, 1K), 8.70 12), \C 8.36 12), 7.97 1H), 7.82 7.71 3H), S7.58 2H), 7.51 12), 3.75 32) ppm;,LC-MS (ES+) 464.13 KPLC-Method A, Rt 3.12 min.

Example 208 (5-Methyl-2E-prazol-3-yl)-[2-(2 naphthyl-lyl)-quinazolin-4-yl]-amine (II-208)t 1 NMR (500 MHz, DMSO- 66) 88.92 1H), 8.73 1H), 8.39 8.09 (m, 2H), 7.95 3H), 7.62 3H), 6.78 2.32 (of 3H); MS 352.2 Example 209 (2-Chloro-phenyl) -pyrido[2,3-djpyrimidin- 4-yl]-(7-flucro-1R-indazol-3-yl)-amine (II-214)r Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido 2,3-d pyrimidine (100 mg, 0.36nimol) and 7-Fluoro-lH-indazol-3-ylamine (1b8mg, 0.72mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (93 ig, 46% yield). HPLC-Method A, Rt 3.04 min; *H NMR (DMSO, 500 MHz): 6 13.67 (1N, 11.40-11.25 bs), 9.35- 9.25 (22, 7.95 7.80-7.47 (Sn, 7.35(18, 7.15 (12, MS M2 391.1.

Example 210 [2-(2-Chloro-phenyl)-pyrido[2,3-d] pyrimidin- 4-yl]-(5-fluoro-1B-indazol-3-yl)-amine (11-215): Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-dI pyriniidine (100 mg, 0.36mmol) and 5-Fluoro-lH-indazol-3- 0 ylaMine (108M9, 0.72mmol). Purification by preparative* 3{PLC afforded the title compound as a yellow, di-TFA sal~t tug, .22% yield). HPLC-Method A, Rt 3.00 min; H NMP.

(DMS0, 500 MHz)-. 8 13.0 (IN, a) l0.90(lH, be), 9.15-9.05 Cl 7.70 (13, in), 7.60-7.3O0 (6H, mn),'7.20 mY-; MS bM* 39 1.1.

Cl ~E Mje 11 (2-chioro-phenyl) -pyrido 3-dlpyrimitditio 10 4-yl (5,7-difluoro-1Hf-indazo1-3-y1) -amine. (11-216): Cl Prepared from 4-Chloro-2- (2-chioro-phenyl) -pyrido (2,3dlpyriinidine (100 mng, 0.3 Gmmol) and -7-Difluoro-lapreparative.HPLC afforded the title compound as a yellow, dii-TFA salt (130 mg, 62% yield) HPLC-Method A, Rt 3.12 mini; 13H NR (DM50, 500 M~z) 13.80-13.60 (IN, be) 11l.30- 11.10 (1HI be), 9.20-9.10 mn), 7.80 in), 7.60- 7.30O m) ;MS MH* 409. 1.

Examle 212 (2-Chloro-phenyl) -pyrido[3,4-dlpyrimidin- 4-yl]-(1R-indazol-3-yl)-anine (11-217): Prepared from 4- Chloro-2- (2-chioro-phenyl) -pyrido[3,4-dlpyrimidine (100 mng, O.3Emmol) and Ili-undazol- 3-ylamine (88mg, '0.E6mmol) Purification by preparative HPLC aff-orded the title compound as a yellow., di-TPA salt (72- mng, 33% yiel HPLC-Method A, Rt 3.21 mini; 'LH 1MR (DM50O, 500 Mez): 8 12.95 (lH, 10.90 be), 9.25113!, 8.75 (13!, in), 6.55 in), 7.65 mn), 7.55 7.50-7.30 (SN, 00) 7. 0 0 MS z M 3 373. 1.

Example 21-3 (2-Cliloro-phenxyl) -pyrido[3,4-djpyrinidin- 4-yl]'-(7-fluoro-lH-indazol-3-yl) -attn. (XXt-ne): Prepared from 4-Chloro-2- (2-chioro-phenyl) -pyrido[3,4-d~pyrirnidine (100 mng, 0.3Einmol) and 7-Fluoro-lH-undazol-3-ylamine

IN

(108mg, 0.72miol). Purification by preparative HPLC Cl afforded the title compound as a yellow, di-TFA salt (48.7 mg, 22% yield). HPLC-Method A, Rt 3.35 min; f NMR (Mo, 500 MHz): 8 12.95 (iN, 10.90 (1N be), 9.25.

(iN, 8.75 (iN, 8.55 (1H, 7.70-7.35 (SN, n), 7.25(lH, 6.95 MS Nar 391.08.

Example 214 [2-(2-Chloro-phenyi) -pyrido(3,4-d]yrimidn..

Cl 4-yll- (S-fluoro-2-indaosl-3-yl) -amine (11-219): Prepared from 4-chloro-2-(2-chloro-5-fluoro-1H-indazol-3.ylaine *(108mg, 0.72inmol). Purification by preparative

HPLC

afforded the title compound as a yellow, di-TFA salt Cl (57.2 mg, 26% yield). HPLCIethod A, Rt 3.27 min; 1H NMR (DMSO, 00O MHz): 5 13.05 (iN, 10.95 (iN, 9.25 (lB, 8.75 iN, 8.55 (iH, 7.60 (iN, tn), 7.55 7.50-7.30 (SH, 7.25(1IH, MS M4W 391.1.

Example 215 (2-Chloro-phenyl) -pyridoE3.4-dlpyrimidnd- 4-yiI-(5, 7-difiuoro-ll-ndaol-3.yl)-amine (11-220): Prepared from 4-chloro-2- (2-chloro-7-difluorolH-indazoa..

3-ylaine (112mg, 0.66mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (57.2 mg, 26% yield). HPLC-Nethod A, Rt 3.45 min; 1 H NMR (DMSO, 500 MHz): 813.65 11.0 (IU, 9.25 (H, 8.80 (1H, 8.50 (IN, 7.60 (1f, 7.55 (1H, 7.50-7.30 (SE, MS MH* 409.1.

Example 216 G-Fluaro-1a'-±ndazo.3..ylamine 1

HNMR

(500 MHz, DMSO-d6) .811.4 lab. 7.68 (dd, 1f), 6'.95 (dd, 1N), 6.75 (td, 1ff), 5.45 2H) ppm; IC-MS (ES+) 152.03 HPLC-Method A, Rt 2.00 tin.

IND Example 2'17 S-Fluoro-IHzindaza-3y1a~mi~

'HMRP

0 (500 M4Hz, DMSO-d6) 611.3 7.43 iN), 7.22 (mn, 2118 7.08 (mn, iN), 5.29 ppm; Ic-ms (S)120 HPLC-Method A, Rt 1.93 mitn.

MHZ, CD 3 oD) 87.22 -Jc2.0,. 8.45Hz, 1H), 7.04-6-87 Cfl(m, 1H); [aC-MS 169.95 HPLC-Method C, Rt 2.94 CA mini o Example 219 7 -Wluoro~-±lf:ndazo3y1amg- (AL4)- 1 1Df 0 14MHz, DMSO-d6) 811.8. 111), 7.42 111), 6.97 111), 6.78 iN), 5.40 2.H) ppm; ILCMS 152.01 (14+1); HPLC-zdetho~d A, R, 2.00 mini.

Example 220 7-loo6tiloomty-Hidzl3 ylanune 1 H-N~mR (500 IMlz, iDmSO) 8 12.5 111), 7.75 IX), 7.25 mIN), .5.85 1H1) ppm; MS (FIA) 220-.0 HPLC-MethOd'A, Rt 2.899 mini.

Example 221 6-Bromo-Ia-±ndazo1.s.y1amne IN-1AmR (soc 14HZ, DM80) 8 11.5 111), 7.65 Cd, 1H), 7.40 iN), 7.090 IN), 5.4.5 (br a, IS) ppm; MS (FIA) 213.8 (14+H); HPLC-Method.A, at. 2.441. mlin.

0 M4Hz, DM50) -8 11.7 111), 7.17 (mn, lH), 7.0'5 (d, 1H), 6.7 11) .6.6 0 Cdd, 15), 5.2 0 Cbr S, 2H) ppm; MS (FIA) 152.0 Method A, at 2.256 mii.

Example 223 S-Sromo-az-indazo1..3.y1am±ne 1 H-WIR (500 MHz, DM80) 11.55 (br s, 15), 7.95 lH), 7.30 (d, Va o 111), 7.20 1H), 5.45 (br a, 2H) ppm; MS (FIA) 213.8 C-i (MiH); Method A, Rt 2.451 min.

Example 224 S-Nitro-LE-indazol-3-yleaine 'H-1Th (500 MHz, DMS0-d6) 8 9.00 1K), 8.20 1H), 7.45 lE), 6.15 C(br IR) ppw; Method A, Rt 2.1B4 min E ample 225 4 -Pyrrol-1-yl-1H-±ndaol-3-ylInamne (A10): 'H- Nb (500 14Hz, DMSO) 8 7.20 2H), 7.00 2H), 6.75 IR), 6.25 2H), 4.30 I2) ppm; Method A, Rt IN 2.625 min.

Example 226 4-Chloro-5, 6-dimethyl-2- (2-trifluoromethylphenyl)-pyrimidine Prepared to afford a colorless oil in 75% yield. 'H-NHR (500 MHz, CDC13) 5 7.70 (d, J=7.8 Hz,'lH), 7.64 .U7.6 Hz, iH), 7.55 Ct, J=7.6 Hz, IM), 7.48 Ct, J=7.5 Hz, 1H), 2.54 3H), 2.36 3H) ppm; MS (PEA) 267.0 PLC-Method A, Rt 3.891 mmn.

Example 227 4-Chlaro-2-(2-chloro-phenyl)-5,6-dimethylpyrimidine Prepared to afford a yellow-orange oil in 71% yield. 'H-NMR (500 M4Hz, CDCl3) 5 7.73 1K), 7.52 Cm,.1K),.7.39 Cm, 2H), 2.66 Cs,-3H), 2.45 3H) ppm; MS (FIA) 253.0.(M+H); EHPLC-Metbod A, Rt Rt 4.156 min.

Example 228 4-Chloro-6-methyl-2-C2-trifluoromethylphenyl)-pyrimidine Prepared to afford a pale yellov oil in 68% yield. 'H-NMR (500 MHz, CDC13) &-7.72 (d, J-7.8 Hz, LH), 7.65 J=7.9 Hz, 7-57 Ct, J=7.5 Hz, iN), 7.52 Ct, J0=7.8 Hz, 1H), 7.16 1H), 2.54 3H) ppm; MS (FIA) 273.0 KPLC-Method A. Rt 3.746-min.

IN jM z2 4-Chloro-6-ayclohexyl-2-((2-trifluormetbylo phnyl)-pyrimidine Prepared to afford a yellow oil in 22% yield. t H-NMR (500 MHz, CDCl3) 8 7.70 2R), E 7.57 J-7.5 z, BH) 7.50 J-7.5 Hz, 1H), 7.19 (s, S 2.65 1K), 1.9 2H), 1.8 2H), 1.5 2H), 1.3 (FIA) 341.0 Example 230 4-Chloro-6-phenyl-2- (2-trifluoromethylphnyl)-pyrimidine Prepared to afford a yellow oil in 53% yield. 'H-NMR (500 MHz, CDC13) 8 8.08 (dd, J-7.9, ci 1.6 Hz, 2H), 7.80 Cd, Jm7.6 Hz, iH), 7.77 Jc7.8 Hz, o 1H), 7.67 1H), 7.61 t, J=7.5 Hz, 7.54 J=7.6 Hz, 1H), 7.47 3H) ppm; MS (FIA) 335.0 HPLC- Method A, Rt 4.393 min.

xample 231 4-Chloro-2-(2,4-dichioro-phenyl) -5,6ditethyl-pyrimidine Prepared to afford a white solid in 91% yield. 'H-NMR (500 MHz, CDCl3) 8 7.62 (d, J=8.3 Hz, 11), 7.43 J=7.0 Hz, 1H), 7.27 (dd, J=8.3, 2.0 Hz, 14), 2.55 Cs,'3H), 2.35 3M) ppm; MS (FIA) 2875 289 CM+H); HPLC-Method A, Rt 4140 min.

2xample 232 4-Chloro-6 -(2-ohiord-phenyl)-2-(2trifluoromethyl-phnyl) -pyrimidtne Prepared to affod a yellow oil in 52% yield. 'H-NMR (500 MHz, CDCL3) 8 7.75 3H), 7.65 2H), 7.53 Cm, 1H), 7.44 lI), 7.36.(m, 2H) ppm; MS (FIA) 369.1 HPLC-Method A, Rt 4.426 min.

Example 233 4-chloro-6-(2-fluoro-phenyl)..2q2trif iuoromethyl-pbenyl) -pyrimidne (38) Prepared to afford a yellow oil in 95t yield. .'H-NMR (500 MHz, CDC13) 6 8.24 Ct, J-7.9 Hz, 7.84 lB), 7.78 3-7.7 285 Va Hz, 7.76 J.8.O Hz, IH), 7.60 J-7.5 Hz, 1H), 0 7.53 Ct, J-7.6 Hz, iN), 7.43- 1H), 7.23 Ct, J-7.6 Hz, 1K), 7.13 Cm, IN) ppm; Ms (FIA) 353.0 Example 234 4-Chloro-6-pyridin-2-yl-2- (2-trif luormethyLcI phenyl) -pyrimdine Prepared to afford a pale yellow solid in 501 yield. 'H 7 NMR (500 Mfz, cDCl3) 8 8.68 (m, Ia, 8.48 dd, J-7.9, 0.9 Hz, 8.38 J-2.3 Hz, 1H) 7.84 Cm, 3H), 7.62 J=7.6 Hz, iN), 7.55 J-7.6 o 10 Hz, 1H), 7.38 Cm, 1H) ppm; MS (FIA) 336.0 HPLC- Va Method A, Rt 4.575 min.

Cl Example 235 6-enzyl-4-chioro-2- (2-trifluoromethylphenyi)-5,6,7,8-tetrahydro-pyrdo[4,3.dpyrimidine (310): 1 HNMR 500 MHz, CDC1 3 87.70 iN), 7.62 Cd, 1H); 7.55 iH), 7.48 lH), 7.32 Cm, 4H), 7.25 1H), 3.74 2H), 3.66 Cs, 2H), 2.99 t, 2H), 2.90 2H) ppm; LCMS 404.17 HPLC-Method A, Rt 3.18 min.

Example 236 7-Denzyi-4-cboro-2- (2-trifluoromethyl-, phenyl) 8 -tetrabydro-pyrido [3,-4-d]pyrimidine (l1): 1 HNMR (500 MHz, aDC1 3 87.69 ik), 7.60 Cd, iNH), 7.54 7.47 Ct, 7.28 Cm, 4H), 7.20 IH), 3.68 Cs, 2H), 3.67" 2H), 2.86 214), 2.79 2K) ppm. MS 404.18 HPLC-Method A, Rt 3.12 min.

Exatdple 237 4-Chloro-2-(4-fluoro-2-trifluoromethylphenyl)-qinazoline LRNM (50OMHz, CD 3 oD) 8 8.43 JB.Hz, IN), 8.20-8.05 Cm, 2H), 8.05-7.82 Cm, 2K), 7.71-7.51 21). LC-MS 327.09 HPLC-Method D, Rt 4.56 min.

IND Example 238 4-Chloro-2- phenyl)-quinazolne LC-MS '342.97 UPLC-Method D, Rt 4.91 min.

Example 239 4-chloro-2- (2-chloro-4-nitro-pheyl),.

guinazoline (914) JC-MS 319.98 (KtE) HPLC-Method D, Rt 4.45 min.

IND Example 240 4-Chloro-2- (2-trifluoromethyl-phetyl) quinazoline (915): Prepared in 57% yield. White solid.

S1ENMA (500MHz, DMSO-d6) 8 7.79 1H), 7.86 1K), 7.94 IND 3H), 8.15 (dd, 8.20 (td, 11), 8.37 Elo MS 309.9 Example 241 4-Chloro-2- (2-trif luaromethyl-phenyl) -6,1- -dihydro- 5R-cyclopentapyrimidine (916): Prepared in 22% yield. 1 NMR (500MHz, DMSO-d) S 2.19 3.01 (t, 211), 3.08 2H), 7.49 1H), 7.55 M1), 7.62 (d, 1K), 7.71 11). El-MS 299.0 242 4-Chloro-2-C2-chloro-phenyl)-6,7,8,9t e trahydro 5H- cyclohep tapyrmi dine (B17): Prepared according to Method.C in 82% yield to afford a white solid.. 1 HNMR (0014Hz, CDC 3 8 1.67 (m 4H), 1.87 (m 3.02 (m 4H), 7.28 7.40 1K), 7.65 11); EI-MS 293-.0 .Example 243 4-Chloro-2 (2-trifluoromethyl-phenyl) 6,7,8,9,10-hexthydro-cylooctapyriaidine (918): Prepared in 38% yield to afford a brown oil. 1

HNMR

(501OMHz, CD 3 8 1.35 (m 2H), 1.41 (m 2E), 1.76 (m 4H), 2.96 4H), 7.48 1K), 7.56 11), 7.66 Cd, 11), .7.70 1H); El-MS 341.0 IND xamle344 4 -Chioro- 8-Zmethoacy-2 trifluoromethyl- 0 pyhenyl) -quinamoline (319): Prepared from.8-methoxy-z- (2trifluoromethyl-phenyl) -3H-quinazolin-4-one 3.l2mmol), triethylamine hydrochloride (472mg, 3.43mmol),' ah O1-Priiainb flash chroma 'tography afforded acht sld(9yed mctoA. R .0mi, MS 258.08 (14+H).

ciExample 245 2- (4-Chloro-quinazolin-2-yl) -benzonitrile o310 CRS20): Prepared to'afford a yellow solid in 1.5% yield.

1-NNR (S00 MHz,-CDC1S) 8 8.47 12), 8.24 1H), 8.16 0 8.07 (impurity), 7.94 12), 7.92 (impurity), c-i7.86 12), 7.68 2H), 7.65 (impurity), 7.54 (impurity), 7.49 iHI, 4.2 (impurity), 1.05 (impurity) PPM; MS CLC/MS) 266.05 EPLO-M4ethod A, Rt 3.88 min.

4Ecample 246 6-Methyl-2 -trifluoroimethyl-phenyl) -3Mpyrimidin-4-one Prepared to afford a yellow solid in 50% yield. 'H-NMR (500 M. z, DMS0-dC) 8 12.7 (br s, 1H), 7. 9 12), 7.8 aCm, 2H) 7. 7 (in, 110), 6.3 Cs, 12) 2.21 Cs, 3H) ppm; MS (FIA) 255.0 HPLC-Metbod A, Rt 2.578 main.

Example 247 6-Cyolohexyl-2- (2-trifluoromethyl-_phenyl) -3Dpyrtm~idin-4 -one Prepared. to af ford an off -white solid in 54% yield. 1 2-NMR (500 MHz, DMSO-dE) 8 '12.9 (br s, 7.9 42), 6.3 12), 2.5 (Mi 1E),.1.9 CM, 52), 1.4 (in, SE) ppm; MS (FIA). 323.1 CM+Hb,.HPLC-Method A, Rt 3.842 min.

Examiple 248 2-(2-Chloro-5-trifluoronethyl-pheny1)-3zquinazoli-4-one '2q'1f (50014Hz, 'CD 2 OD) 89.32-8.25 12), 8.01 Cs, 12), 7.91-7.72 Cm, 12), 7.66-7.55 (m, 3M.LC-145 325.01 HPLC-Method D, Rt 3.29 0 min.

Ct Exale32' 2- 4 -Fluoro-2-trifluoroetzy..pzenyl) -3M- S quinazolin-4-one (D14): 1 pNMR (soomz, r-D30D) 8 8.28 (d, 8.0Hz, 111). 7.94-7.84 (m, 1 11), 7.84-7.77 (mt, 1H0, 7.76- 7.67 Cm, 2H1), 7.65-7.53 2H1). LC-14S (ES+t) 309.06 CM-tN). HPLC-Method'D, Rt 2.88 min.

Exainple 250 2 4 -Nitro-2-hloro-peny)-3..qunazoln.4.

(neiW1): LC-148 CES+i) 302.03 HPLC-Method D, Rt O 2.81 min.

Example 251 2- (S-Fluoro-2-trifluoromethyl-.phenyl) -3Mis qainazol~in-4 -one (D17): 1 jHNMj, (500MHz, CD 2 OD) 5,8.28 (d, Rt J=8.0511 2 1H), .7.96 Cdd, J=5.05, 8.55Hz, 111), 7.89 (t, Je7.SHz, 1H), 7.78-7.69 Ci,1H), 7.66-7.46 3H1). LC-MS 30 9.14 (H-iH) NPLC-Method Rt 2.90 win.

Example 252 (1E-Zndazol-3-yl) -(2-phenyl-quinazoltn-4-yl) amie (iz-):Prepared by Method A in DM7 to afford mg (56W yield) as pale yellow solid. -1H NMt (500 MHz, 81'3.1 Cs, br, 1K), 8.48 iN), 7.91. Wd 2H1), 7.76 (hr, 7.45 Cm, 2H), 7.36 13), 7.20 Cm, 4H1), 6.86 Ct, 1K) ppm. MS (ES+I) 338.07 336.11 (N- H) HPLC-MethodA, Rt 2.68 Tmi.

Example 253 (S-Methyl-2r-pyrazol-3-yl)-2-p2enyl.s,6,7,8.

tetrahydraquminazofl n-4-yi) -amine (111-7): Prepared according to Method A. 'H1 NM24 (500 MHz, DMSO-d6) 612.1 br, 8.70 br, iN), 8.37 J 6.711z, 23), 7.54 (mn, 33), 6.67 Cs, lH)I, 2.82 2H1), 2.68 Cm, 2H)', 2.37 3H), 1.90 Cs, br, 43); MS 306.1 CM-iH).

IND Example 254 (5-Methyl-28-pyrazol-3-yl')- (2-phenyl-6,7,8,9- 0 tetrahydro-5z-oylheptapyrmdn-4-yl) -amine (izI-a) z HS 320.48 (14+1) HPLC-Method E, R& 1. 124 min.

Examle 255 (5-Methyl-22-pyrazol-3-yl) -(2-pyridin-4-yl- Cl qinasolin-4ryl) -amine. (111-9): Yellowv solid, nip 286- 289 0 C, "R NMR (DM30) 8 2.35 (31H, 6.76 iN, s),'7.61 (111, in), 7.89 (2H1, 8.32 (2H, 8.70 (111, 8.78 Cl (2H1, d) 10. 56 (111, br 12.30 (111, br s) IR (solid) 1620, 1598, 1571, 1554, 1483, 1413, 1370, 1328; MS 303.2 ClExample 256 (7-Chloro-2-pyridini-4--yl-quina zoIin -4 -yl) m ethyl-23-pyrazol-3-yl) -amine (111-28) 1 H Nba (DM0-d6) 6' 2.3 5 (3R, 6. 75 (11, '7.155 d) 7.93 (111, a) 8.30 8.73 (1H1, 8.79 (211, 10.69 (11, B1, 12.33 (111, 8);,MS m/z 337.2 Example 257 (6-Chloro-2-pyridin-4-yl-quinazolin-4-y) rnethyl-2H-pyrazol-3-yl)-amine .(111-29): 'S YhIMR (DMSO-dE)B 2.31 (311, 6.74 (1H,s),-7.89 8'.30 (211, d), 8.80 (2H1, 8.9i (12, 10.63 (11, '12-29 s); MS 337.2 (M+lfl t ExpMle258 (2-Cyolohezyl-qainazolin-4-yl) (-methyl-23pyazol-3-yl)-anine (111-30): 'K1 UMR (DMSO) 2.35 (311, 1.70 (DR, 1.87 (2H1, 1.99 (2H1, id), 2.95 (11, t0, 6.72 (is, 7.75 (11, 7.88 (11H, s) 7. 96 (111, 8.83' (11, 11.95 (1H1, s) 12.70 (1H1, MS 308.4

(MHHP

Example 259 (S-Hethyl-2H-pyrazol-3-yl (2-phenylquinxazolin-4-yl) -amine (111-31): nip 246 0 C, 1H NN R (40014HZ)- IN 2.35 (38, 6.70 br 7.51-7.57 (48, 7.83- 0 7.84 (2H3, 8.47-8.50 (2H, 8.65 (13, dl, 10.4 .(1H, 12.2 (1H, bs); IR (solid) 3696, 3680, 2972, 2922, G 2865; MS 302.1 1 Example 260.. [12- (4-odophenyl)-quina-olin-4-yl-(5ymethyl- 2H- pyrazol-3-yrl)-amine (III-32): H NMR (DMSO-d6) 6 2.34 6.72 (1H, 7.56 (1H, 7.84 (2H, 7.93 N~ 8.23 (2H, 8.65 (1H, 10.44 (18, 12.24 (1H, MS 428.5

\O

Example 261 [2-(3,4-Dichlorophenyl)- methyl-2H-pyrazol-3-yl)-amine (1II-33): A suspension of.

2-(3,4-dichloro-phenyl)-3H-quinazolin-4-one (1g, 3.43 mmol) in phosphorus oxychloride (4-mL) was stirred at 110C for 3 hours. The solvent was removed by-evap~oration and the residue is treated carefully with cold aqueous, saturated NaHC0 3 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-s-methyl-pyrazole (396 mg, 2.58 mmol) and the resulting mixtur heated at 65 0

C

overnight. The solvents were evaporated and the residue triturated with ethyl acetate, filtered, and washed with the minimum amount of ethanol to afford compound 111-33 as a white solid (311 mg mp 274 0 C; 1H NMR (DMSO) 8 2.34 (3H, 6.69 (1H, 7.60 (13, 7.84 (1H, d), 7.96 (2H, 8.39 dd), 8.60 (1H, 8.65 (11, d), 10.51 (1H, 12.30 (13, IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797,.,764, 738; MS 370.5 aWm)*.

IND Example 262 (4-Brmwophenyl) -quinazolin-4-ylJ methy-2-prazol-3-yj) -amino (111-34): ap 262-265 0 C; '2 NMR (DM80) 8 2.34 (3S, 6.73 (IN, 7.55 (12, m), 7.74 (2H, 7.83 (2H, 8.40 (2H, 8.65 (1H,d) 10.44 12.25 IR (solid) 1603, 1579, 1546, 1484, 1408,.1365; MS 380.1/382.1 CC)~f Example 263 (4-Chiorophenyl) -qiinazolin-4-yl]- methyl-2Hfpyrazol-3.-yl)-amine (11-35): np >3OOc; 'K NMR (DMSO) 8-2.34 (3H, 6.74 (12, 7.53-7.62 (3H, m), ci 7.84 (22, 8.47 (2H, 8.65 (Il, 10.44 (12, a), o 12.26 R (solid) 1628, 168, 1584, 1546, 1489, 1408, 1369, 1169; MS 336.2 Example 264 3 ,S-Dichlorphenyl)-qtuinaoln-g-ylj methyl-2-pyrazo.-3-yl) amine (I-36)h mp228 0 c; 'H NMR (DM36) 82.34 (3H, 6.69 (12, 7.96 (1N, 8.21' (32, 8.56 (12, 8.60 (2H, 10.51 (11, 12.30 (12, IR (solid) 1546, 1331, 802,.763, 729, 658, 652;.

MS 370.5 Example 265 4 -Cyanophenyl) -quinazolin-4-yl3-(5methyl-2H-prat6.-3-yl).-amine (111-37): np 263OC; H NMR (DMSO) 6 2.34 (3H, 6.72 7.61 (12, 7.88 (2H, 8.04 (2H, 8. 63 (2H, 8.67 (12, 10.52 (12, 12.27 (lI, ZR (solid) 1739, 1436, 1366, 1229, 1217; MS 327.2 Example 266 .[2-(3-odophenyl) -quinazolin-4-ylJ 20-pyrazol-1-yl) -amine (11-38): np 234-235 0 C; 'H NMP.

(DMSO) 82.35 (3H, 6.73 (111, 7.35 (12, 7.56 (12, 7.85 (3H, 8.47, 8.65 (1H, 8.86 ID(12, 10.49 (1H, 12.28 (21, br IR (solid) 1560, 1541, 1469, 1360; MS 428.1 ct Example 267 (4-Ethylaulfanylphenyl) -quinazsolin-4-yll (5-methyl-2-pyrazol-3-yl)-amine (11-39): mp 229-231 0

C;

1R NMR (DMSO) 8 1.29 (32, 2.35 3.07 (2H, q) 6.76 (12, 7.43 (2H, 7.51 mi), 7.81 (2H, m), 8.41 8.64 (1H, 10.38 (1H, 12.24 (1H, br INDa); IR (solid) 1587, 1574, 1555, 1531, 1484, 1412, 1369; MS 362.1 Example 268 (5-Cyclopropyl-2-pyrazol-3-yl)-(2-phenyl- 0 quinazolin-4-y1)-amine (111-40).: p 218-219*C; '2 NMR (DMSO-d6) 8 0.70-0.80(21, 0.90-1.00 (28, 6.70 (1H, 7.45-7.55.(4H, 7.80-7.85 (2H, 8.45-8.55 (2H, 8.65 (1a, 10.40 (11, 12.27 (1H, a) 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-Butylphenyl) methyl-20-pyrazol-3-yl)-amine (111-41): mp >300OC; H11 NMR (DMSO-d6) 8 1.35 (9H, 2.34 6.79 (12, a), 7.55 (3H, 7.85 (2H, 8.39 (2H, 8.62 d), 10.35 (111, 12.22 (12, IR (solid) 1603, 1599, 1577, 1561, 1535, 1481, 1409, 1371, 1359, 998, 841, 825, 766, 757; MS 358.3 Example 27 0 [(2-(4-Chlorophenyl)-quinazolin-4-yll-(5cyclopropyl-2-pyrazol-3-yl) -amine (111-42): 1H NMR (DMSOd6) 6 0.77 (4H, br.m) ,2.05 (12, 6.59 (1H, 7.60 (12, 7.85 (22, 7.91 (2H, 8.22 (2H, 8.65 (11, 10.51 12.33 MS 362.1 IND Example 271 (2-Benhol,31d1zol-S-yl.quinaoflin.4.yl).-(S.

o~ methyl-2H-pyrauol-3-yl) -amine (111-43): 1H NMR (DMSO) S 2.33 (3H, 6.13. (2H, 6.76 7.11 (1N, 7.80 (1H, 7.94 (11, 8.09 (3H, 8:25 d), 10.34 (1H, 12.21 (11, MS 346.5 Example 272 [2 (4-Dimethyiaminophenyl) -quinazolin-4-yl en, (S-metbyl-ZE-pyrazol-3-yi)-amine (111-44): 1'HM* (DMSO- 66) 5 2.02 (6H, 2.39 (3H, 6.83 (1H, 7.71 (1H, O 10 7.98 (2H, 6.04.(2H, 8.33 (2H, 8.67 (1H, a) 11.82 12.72 (11, MS 345.3 Example 273 (3-Metboxyphenyl) -quinasolin-4-yl] methyl-2E-pyrazol-3-yl)-amino (111-45): mp 226OC; 1H NMR (DMSO) S 2.34 3.92 (3 H, 6.72 (12, 7.21 (12, 7.57 (12, 7.7s 8.02 (3H, 8.14 (12, 8.79 (12, 10.39 12.22 (12, ZR (solid) 1599, 1572, 1538,.1472, 1427, 1359, 833, 761, .661; MS 332.2 Example 275 (5-Cyclopropyl-20-pyrazol-3-yi)-r2-(3,4dichlorophenyl) -quinazalin-4-ylJ -ailne (111-46): "H NMR (DMS0-d6) 5 0.86 (21, 1.02 (22, 1.69 (in, i), 6.56 7.57 (12, 7.84 (4H, .8.40 (11, d), 8.58 (1H, 8.64 (1H, 10.53 (12, 12.36 (12, a); MS 396.0 (M+H) Example 276 (2-Eiphenyl-4-yl-quinazolin-4-yl)- 2H-pyrazol-3-yl)-azmine (111-47): To a-mixture of -bromo-phenyl) -quinazolin-4-yl]- (5-methyl-2-pyrazol-ayl)-amine (111-34) (196 mg,. 0.51 mmol) and phenylboronic acid (75 mgt 0.62 mmol) in TEF:water 4 zL) was added NaCO, (219 ig, 2.06 mmol), triphenyiphoaphine (9mg, 1/15 molt) and palladium acetate 1 mg, 1:135 mol%). The resulting mixture was heated at 80 0 C overnight, the solvents were evaporated and the residue purified by flash chromatography (gradient of dichloromethane:MeOH) G to afford III-21 as a yellow solid (99 mg, 51t): NMR (DMSO) S 2.37 (3H, 6.82 (1K, 7.39-7.57 (4H, m), -7.73-7.87 (6H, 8.57 8.67 (1H, 10.42 (1H, 12.27 (1K, MS 378.2

\O

INDExample 277 (2-(4-Ethynylphenyl)-quinazolin-4-yl]-(5methyl-25-pyrazol-3-yl) -amine (IXI-48): To a mixture of 12-(4-bromo-phenyl) -quinazolin-4-yl] (5-methyl-2Hpyrazol-3-yl)-amine (111-34) (114 mg, 0.3 mml), and 0 trimethylsailylacetylene (147 mg, 1.5 mmol)in DMF (2 mL) was added Cul (1.1 mg, 1:50 mol%), Pd(PPh,) 2 Cll (4.2 mg, 1:50 molt) and trietylamine (121 mg, 0.36 mmol). The resulting mixture was heated at. 120'C overnight and the solvent evaporated. The residue was triturated i ethyl acetate and the resulting precipitate collected by filtration. The collected solid was suspended in THF (3 mt) and TBAF (1M in THIP, 1.eq). 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) 8 2.34 (3H, 4.36 (1H, 6.74 (1R, 7.55 (1K, 7.65 (2H, 7.84 (2H, 8.47 (2H, 8.65 dj, 10.43 (1K, 12.24 (1K, MS 326.1 Example 278 12- (3-Ethynylphenyl) -quinazolin-4-yllj methyl-2E-pyrazol-3-yl)-amine (IIZ-49): mp 204-207 0 C; 'E NMR (DMSO) 8 2.34 (3H, 4.28 6.74 (1l, s), 7.55-7.63 (3H, 7.83-7.87 (2H, m),-8.49 (18, 8.57 8.65 (1K, 10.46 (1H, 12.27 IR

NO

2O (solid) 1598, 1574, 1541, 1489, 1474, 1422, 1365; MS 326.1 SExample 279 [2-(3-Methylphenyl)-quinazolin-4-yl] 5 methyl-2a-pyrasol-3-yl)-amine (III-50): A suspension of Cl lH-quinazoline-2.,4-dione (10.0.g, 61.7 mmol) in POCI 3 mL, 644 mmol) and N,N-dimethylaniline. (8mL, 63.1 mmol) \0 was heated under reflux for 2 h. The excess POC13 was Cl removed in vacuo, the residue poured into ice, and the o 10 resulting precipitate collected by filtration. The crude \l solid product 2,4-dichloro-quinazoline (6.5 g, 53% yield) o was washed with water and dried under vacuum for next C 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 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-guinazolin-4-yl)-(5-methyl-IHpyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of the (2chloro-quinaolin-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 Na2C0 3 (0.96 mmol), and trit-butylphosphine (0.19 mmol). The flask was flushed with nitrogen and the catalyst PdC12(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 III-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 IH), 8.25 1H), Va o 7.78 2H), 7.55 Cm, 7.45 11, 7.35 Cm, 12), 6.80 11, 2.47 3H), 2.30 3H); (.316.1 (Me).

Eapl 280 12- 5-Difluorophenyl) -quinazolin-4-yl- methyl-2aH-pyrazol-3.yl) -azine (111-51) 'H NMR (500 MHz, Cl DMSO-d6) 612.3 (br s, 10.8 (br s, 8.63 12), 7.95 22), 7.85 2H), 7.58 Ct, 12), 7.41 Ct, 12), Cfl 6.59 Cs, 1H)Y 2.27 Cs, MS 338.1.(M+H).

Example 281 2 -(3-Chloro-4-fluorophnyl-qmuinaolin-.4.

1'l]-(S-methyl-2-pyrazo1-yl)-amj.e 6 (11P52): 2H NMR (500: MHz, DMSO-d) 812.4 (br s, 1H) 10.8 br a, 8.65 (d, C1 1H), 8.50 d, 1H), 8.36 7.85 7.60 1H), 6.62 1H), 2.30 3H); MS 354.1 Example 282 (5-Methy1-2B-pyrazo1-3-y1)-[2-(3trifluoromethyphenyl) -quinazolin-4-yl] -amine (111-53): 'H UMR (500 MHz, DMSO-dE) 812.2 (br, 10.45Cbr, 1H), 7.53 Cs, 1H), 7.43 J =7.2 Hz, 12, 7.06 J 8.2 Hz, 1H), 6.65 J 8.3 Hz, IH), 6.57 J 7.6 Hz, 1H), 6.51 Cd, J 7.8 Hz, 12), 6.43 Ct, J 7.6 Hz, 12), 6.32 Ct, J3- 7.6 Hz, 12), 5.51 IH), 2.-03 Cs, 3H); MS 370.2 Example 283 £2-(3-Cyanophenyl)-quia"o±-4-yll-(2S.

methyl-2-pyrazol-3-yl)-ainne (111-54): 'H.NMR (500 EHz, DMSO-d6) 89.0. 110 8.96(m, 22), 8.28 Cd, J 7.3 Hz, 12), 8.16 s, br, 6.06. J 7.8 Hz, 1R), 7.88 (m,1sH), 6.96 12), 2.58 Ca, 32); MS 327.1 CM+H).

Example 284 (3aIsopropylphsnyl) -qauinaoln-4-ylJ methyl-'2E-pyraso1-3-yl)..-amin (111-55):* 1H NMR (500 MHz, DMSO-d6) 58.89 Cd,- 7.5 Hz, 12), 8.37 1H) 8.26 I(sO 1H), 8.09 2H), 7.81 br, 15), 7.67 0~ 6.88 1H), 3.12 2.40 3H), 1.36 J= 6.9 Hz, 6H); 8 344.2 Example 285 (S-Methy1-2K-pyrmol3-yl) (2yridin3-yl quinazolin-4-yl) -nine (111-56): 1 NMR (500 MHz, DMSO-d6) 89.50 15), 8.84 J 7.3 Hz, 15), 8.60 J 4.4 en~ Hz, 1K), 8.66 J 8.2 Hz, 1N), 7.87 2H), 7.77 (m, 7.60 3 7.2 Hz, 15), 6.67 15), 2.28 (s, 3H); MS 303.1

INO

0l Example 286 (3-Acetylphenyl) -quinazolin-4-yl]- methyl-2s-yrazoa-3-yl)-amie (III-57):1' NMR (500 MHz, DMSO-d6) 88.80 IR), 8.55 Cd, J 7.7 Hz, 1H), 8.42 J 7.6 Hz, 15), 8.00 J 7.0 Hz, 15), 7.76 (m, 2H), 7.58 J 7.7 Hz, 1E),.7.48 Cs, br, 15), 6.0 (s, 2.49 3H), 2.03 3H); MS 344.1 Example 287 [2-(3,5-Ditrifluoramethylpienyl) -quinazolin- 4 (S-metbyl-2-pyrazol--yl)..amne (X11-B8): 2H INS.

(500 MHz, DMSO-dE) S10.7 br, 15), 8.95 2H), 8.63 J 8.2 Hz, 1H), 8.25 15), 7.86 Cm, 2H), 7.58 Ct, J 6.9 Hz, 15), 6.62 15), 2.26 35); MS 438.1 Example 288 [2-(3-Bydroxymethylphenyl) -quinazolin-4-yl]- -methyl-20-pyazol.- 3 amne 1H NM (500 MHz, DMSO-d6) 8 8.74 7.9 Hz, 15), 8.33 Cs, 1H), 8.17 hr, 15), 7.95 br, 7.99 br, 7.62 35), 6.72 Ca,1H), 5.53 15), 4.60 2H), .2.28 3H); MS 332.1 Example 289 (S-Methyl-2R-pyrazol-3-yl)-12-(3phenoxyphemyl) quinazoln--ylj,-amine (111-60): mp 231- 232OC; 1-NMR (D1S0-dE) 8 2.21 (3H, 6.59 (1N, a), 7.10-7.22 (4H, 7.41-7.45 (2H, 7.54-7.59 (21, m), 7.81 (2R, 8.09 (1N, 8.27 (1H, 8.64 (11, m), 10.40 (1N, 12.20 (11, IR (solid); IR (solid) 1589, 1560, 1541, 1536, 1484, 1360, 1227; MS 394.7 Example 290 (S-Cyoloproyl-20-pyrazol-3-yl)-[2-(3phenoxyhenyl) -g:nazolin-4-yl -amine (111-61): Mp 193- 195 0 C; 'H NMR (DMSO-dE) 5 0.67 (2H, 0.93 (2H, m),1.87 (1HI,m), 6.56 (I1, 7.06-7.20 (4H, 7.40-7.43 (2H, Cl 7.55-7.59 (2H, 7.81 (2H, 8.11 8.27 o (111, 8.63 (11, m) 10.43 (111, 12.26 (11, ZR (solid); ZR (solid) 1589, 1574, 1527, 1483, 1369, 1226; MS 420.7 (Mu)+t Example 291 (5-Netbyl-25-pyrazol-3 -yl)-(2-thiophen-s-ylquil&Zolin-4-yl) -amine (131-62) s12H NMR (500 lI-z, DMSO-d6) 811.78 br, 1H), 8.75 J 8.1 Hz, 11), 8.68 (a, 11), 7.98 (dd, J 7.9, 7.5 Hz, 1H), 7.89 2H), 7.81 1H), 7.68 J 7.5 Hz, 6.69 2.30 (s, 3W); MS 308.1 Example 292 (2-Phenyl-quinazoli-4-yi) (2E-pyrazol-3-yl) amine (111-63): ip 247-249 0 C; 'H NR (DMSO) 8 6.99 br 7.49-7.58 (5H, 7.81 (11, br 7.83 (2H, 8.47-8.49 (2H, 8.66 (1H1, 10.54 12.59 (12, ZR (solid) 3145, 2922, 1622, 1597; MS 288.2 Example 293 (2H-Pyrazol-3-yl)- 2 pyridin-4-yl-quinazolin- 4-yl)-amine (111-64): mp 285-286 0 C; 'H NNR (DMSO) 8 6.99 (1H, br 7.65 7.81-7.94 (3H, 8.3-8.35 (2H, 8.73 (iN, 8.84-8.90 (2H, 10.76 (iN, a), O 12.6 (1N, IR (solid) 3180, 2972, 1600, 1574; MS 289.2 Example 294 5-Ethyl-23-pyrasol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-65): mp 221-222 C; 'N NMR 8 1.31 2.68 (2R, 6.80 (1I, 7.50- 7.60. (4H, 8.45-8.55 (2H, 8.65-8.75 (N1H, 10.44 en 12.27 IR (solid) 3190, 1622, 1595, 1575, 1533, 1482, 1441, 1420, 1403, 1361, 758, 711; MS 316.2

\O

SExample 295 (2-Phenyl-quinazolin-4-y1)-(5-praopyl-2Epyrazol-3-yl)-anine.(111-66): mp 204-2050C; H NMR (DMSOd6) 8 1.02 (3H, 1.66-1.75 (2H, 2.69 (2H, 6.80 (iN, 7.45-7.60 7.80-7.88 (25, 8.45-8.50 (2n, 8.65 (iN, 10.39 (1i; 12.25 (1iN, IR (solid) 1621, 1560, 1572, 1533, 1479, 1441, 1421, 1363, 1328, 999, 827, 80.8, 763, 709, 697; MS 330.2 Example 296 (5-Isopropyl-20-pyrazol-3-yl)-(-phenylquinazolin-4-y)-amine (III-67): mp 218-219OC; 1

NMR

(DMSO-dG) 6 1.36 3.05 (1i, 6-.86 a), 7.48-7.59 (4H, 7.80-7.88 (2H, 8.49-8.58 (2H, m), 8.66 (1N, 10.47 (N1H, 12.30 (iN, 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-23-pyrazol-3 -yl) )-(2-phenylquinazolin-4-yl) -amine (111-68): mp 136-137-C; 'H NMIR (DMSO-d6) 8 1.38 (98, 6.87 (1i, br s3, 7.51-7.57 (4H, 7.84-7.85 (2H, 8.49-8.51 (2H, 8.65 (lE, d), 10.43 12.21 (1K, br IR (solid) 3162, 2963, 1621,1590, 1572; MS 344.2(M+H)+.

VO

o2 Example 298 (5-tsrt-Butyl-20-pyrazol-3-yl)-(2-pyridin-4yl-quinasolin-4-yl)-amine (111-69): mp >300 0 C; 1H NMR (DMSO) 6 1.38 (9H, 6.82 (18, br 7.63 (1K, m), 7.86-7.91 (2H, 8.32-8.33 (2H, 8.69 d), 8.75-8.76 (2H, 10.60 (1N, 12.31 br IR (solid) 3683, 3149, 2963, 1621; MS 345.2(M+H) 4 INDExample 299 (5-Cyclopentyl-2a-pyrazol-3-yl)-(2-phenylquinazolin-4-yl) -amine (111-70): mp 240-241-C; H NMR ClI (DMSO-d6) 6 1.68-1.89 (68, 2.03-2.17 (2H, 3.14- S3.22 (32, 6.80 (iN, 7.50-7.60 (4H, 7.80-7.89 (2H, 8.45-8.52 (2H, 8.67 (1H, 10.52 (1K, a), 12.26 (iH, 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-Pheny1-2-pyrasol-3-yl)-( 2-phenylquinazolin-4-yl)-anine (111-71): mp 207-209 0 C; 1 j NMR (DMSO) 8 7.38-7.40 (1H, 7.50-7.58 (R6H, 7.82-7.88 (4H, 8.51 (2H, 8.67 (1K, 10.58 13.11 (1H, br IR (solid) 3345, 3108, 1627, 1612; MS 364.2 Example 301 (5-Carboxy-2E-pyrazol-3-yl)-(2-phenylquinazolin-4-.yl)-amine (111-72).: (5-Methoxycarbonyl-2Hpyrazol-3-yl)-(2-phenyi-quinazolin-4-yl)-amine (111-73) (345mg, 1 mmole in THN, 6 mL) was treated with NaOH: (iM, mL), stirred at 50 0 C for 5 hours, cooled to room temperature, and neutralised with IM HC. The mixture was concentrated in vacuo to remove THF then diluted with waterand the resulting precipitate filtered. The residual solid was dried at 80 0 C under vacuum to afford 111-72 as an off-white solid (312 mg, mp 289-291 0

C

\O

'H NMR.(DMSO) 8 7.45 br 7.50-7.60 (52, 7.80-7.88 (2H, 7.40-7.50 (2K, 8.60-8.70 (1, 10.70 (1R, 13.00-13.80 (2H, br IR (solid) 1699, 1624, 1607, 1570,1539, 1506, 1486, 1398, 1333, 1256, 1177, 1004, 827, 764, 705; MS 332.3(M+H)*.

Example 302 (5-Methoxycarbonyl-2 -pyrazol-3-yl)-(2cc) phenyl-quinazolin-4-yi)-amine (I11-73): mp 271-273OC; H NMiP (DMSO) 8 3.95 (35, 7.50-7.65 (SH, 7.80-7.98 (2H, 8.40-8.50 8.65-8.73 (12, 10.80 (1H, Ssa), 13.80 (1H, IR (solid) 3359, 1720, 1624, 1597, 0 .1561, 1538, 1500i 1475, 1435, 1410, 1358, 1329, 1283, C 1261, 1146, 1125, 1018, 1010, 944, 827, 806, 780, 763, 703, 690, 670; MS 346.3(M+H)*.

Example 303 (S-Eydroxymethyl-2-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-74): A solution of Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4yl)-amine (III-73) (345mg, 1mmol) in anhydrous TUF (LOmL) 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 oyer magnesium sulphate and concentrated. Purification by.flash chromatography (Sio, methanol-dichloromethane gradient) afforded 111-74 mg, 30%) as an off-white solid: mp 238-2390C; 1H NMR S (DMSO) 3 4.58 (22, d, CH2), 5.35 (1H, s, OH), 6.94 (IH, 7.50-7.60 (4H, 7.85-7.90 (2H, 8.48-8.54 8.69- 12), 10.40 (1H, 12.48 (12, IR (solid) 1652, 1621, 1603, 1575, 1558,1539, 1532, 1480, -1373, 1320, 1276,1175, 1057, 1037, o1007, 95i, 865, 843, 793, 780, 7124; MS 318.2(M+H).

VO

o Example 304 (5-Methoxymethyl-2-pyrauol-3-yl)- (2-phenylquinazolin-4-yl)-amine (III-75): mp 190-191; 1 H NMR (DM0SO) 8 3.34 (3H, 4.45 (2H, 7.00 (1I, 7.50- 7.62 (4H, 7.82-7.90 (2H, 8.45-8.52 (2H, 8.65 c- (1H1, br 10.50 (1H, 12.30 (1H, IR (solid) 3177, 1606, 1589, 1530, 1479, 1441, 1406, 1374, 1363, Cf) 1329, 1152, 1099, 999, 954, 834, 813, 766, 707, 691; MS Va 332.3(M+H).

IExample 305 [5-(3-Rydroxyprop-1-yl)-20-pyrazol-3-yll-(2o phenyl-quinazolin-4-yl)-amine (111-76)t A solution.of Sbenzyloxypropyl-2H-pyrazol-3-yl)- (2-phenyl-quinazolin-4yl)-amine (111-78) (200mg, 0.46mmol) in toluene (4mL) and acetonitrile (8mL) was stirred with trimethylsilyl iodide (0.64ml, 4.6mmol) at 55 0 C for 3 hours to afford an amber coloured solution. This mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate. The resulting layers were-separated, the organic layer was dried over magnesium sulphate and concentrated In vacuo.

Purification by flash chromatography (Sic 2 methanoldichloromethane gradient) affords a yellow oil (115mg).

Trituration with dichloromethane affords III-76 as an off-white solid dried at 75 0 C under vacuum (83mg, mp 164-165c; 1H NIP. (DMSO) 8 .1.80-1.90 2.70-2.80 (2H, 3.50-3.60 (2K, 4.59 (1H, 6.80 (IR, s), 7.50-7.60 (4H, 7.82-7.90 (2H, 8.48-8;53 (2H, m), 8.63 (13, 10.40 12.25 (1H, s);.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 346.0O(M+H).

Example 306 (3-Methoxyprop-1-y1)-2-pyrasol-3-yll]- (2phenyl-quinazolin-4-yl)-amine (13i-77) i mp 169-170OC; 1H

VO

o NMR (DMSO-dS) 8 1.86-1.97 (2E, 2.75 (2H, 3.30 (31H, 3.45 (2H, 6.80 7.50-7.60 (4H, 7.80- 7.90 (2H, 8.45-8.55 (2H, 8.67 (1H, 10.30 (1H, 12.25 (1H, IR (solid) 21620, 1591, 1572, 1532, 5 1476, 1425, 1408, 1373, 1326, 1117, 1003, 831, 764, 714, 695; MS 360.3(M+H)4.

e Example 307 3 -Beszyloxyprop-1-yl)-20-pyrazol-3-yl- 2 -phenyl-quinazolin-4-yl)-amine (III-78): mp 177-1i78soC; 1 j NMR (DMSO) 6 1.92-2.03 (2H, 3.76-3.85 (2H, m), 3.52-3.62 (2H, 4.51 (2H, 6.82 (1H, 7.28-7.40 02 (58, 7.46-7.58 (4H, 7.80-7.85 (2Hm), 8.47-8.52 (2H, 8.66 (11, 10.45 (1H, IR (solid) 1621, 1591, 1562, 1532, 1479, 1454, 1426, 1408, 1374, 1101, 1006, 835, 766, 738, 712, 696; MS 436.3(M+H).

Example 308 15-(3-Aminoprop-1-yl)-2E-pyrazol-3-yll-(2phenyl-quinazolin-4-yl)-amine (111-79): A solution of (3-tert-butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-yl]- (2-phenyl-quinazolin-4-yl)-amine (111-80) (250mg, 0.56mmol), in dichloromethane (3mL) at OC was treated with TFA (2mL). The mixture was warmed to room temperature then concentrated in vacuo. The residue was triturated and concentrated from dichloromethane and ether, then triturated with dichloromethane to crystallize the TFA salt. The resulting solid was collected by filtration and dissolved in a mixture of ethanol (3mL) and water (3mL). Potassium carbonate was added in portions to achieve pH 8 then the mixture allowed to crystallize. The product was collected by filtration and dried at 80 0 C under vacuum to afford 111-79 as an off-white powder (122mg, mp 205-207 0 C; 'H NMR (DMSO) 8 1.68-1.83 (2H, 2.65-2.80( 4H, 6.80 (1N, 7.50-7.60 (4H, 7.80-7.90 (2H, 8.45-8.53 (2H, IND 8.65 (1H, 10.45 (1H, bra9); ZR (solid) 1621, 8 1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 951, .830, 776, 764, 705, .677; MS 345.3(M+H)+.

Example 309 ES (3-tort-Butxyoarbonylamipr opr l) prazol-73-yll- (2 -phnyl-quinazo l) emime(111-80)mp 199-200 0 c; HNMR (DMSO) 8 1.37 (9H, 1.71-1.82 en) 2.67 (2H, 3.00-3.11 (2H, 7.81 (1H, a), 7.99 (1H, 7.50-7.60 (41, 7.80-7.85 (2H, 8.48- 8.52 (2H, 2.63 (11, 10:40 (IH, 12.26 (11, m); ci ZR (solid) 2953, 1667, 1622, 1594, 1573, 1535, 1481, o 1441, 1419, 1364, 1327, 1281, 1252, 1166, 1070, 1028, 998, 951, 848, 807, 768, 740, 728, 710,693; MS 445.3 Exa!!le2 1 0 S -Ifoprcpylaarbamoyl-2-pyrazol-3..yl)-,(2phenyl-quinaziin-4-yl)-amine (111-81): 1H NMR (500MHz, DMBO-d6) 5 1.20 7 6.6 Hz, 6H), 4.13 11), 7.42 (br. a, 1H), 7.61 (dd, J 7.0, 7.7 Hz, 210), 7.66 J 7.1 Hz, 1H), 7.71 (mn, 11) '7.99 21H), 8.39 1H), 8.42 J 7.1 Hz, ZR), 8.74 3 8.2 Hz, IH), 11.41 (br. 1H); EI-MS 373.2 HfLC-Method C, Rt 14.09 rin.

Example 311 (5-Allylcarbamoyi-23-pyrazol-3-yl) (2-phenylqainazolin-4-yl) -mine (111-82): 1H NR (500MHz, DMSO-d6) 54.02 2H), 5.15 1H), 5.23 11), 5.94 1H), 7.45 (br. a, 11), 7.60 JT 6.9 Hz, 2H) .7.64 1H), 7.72 1H), 7.98 2H), 8.43 (m 21), 8.72 J 8.2 Hz, 1H1), 8.84 1H) .11.34 (br. a, El-MS 371.2 HPLC-Method C, Rt 13.67 min.

Example 312 C (2 -MethoxysthylCarbeamoyl) 2-pyrazol -3yll- (2-pbenyl-qunabolin.4.y1) -amine (111-83): 3'H MR Va o (500MHz, DMBO-d6) 8'3.32 3H), 3.48 4H), 7.36 (br.

a, 7.62 2K), 7.63 1H), 7.71 19), 7.98 Im, 2H), 8.41 (dd,J a 1.4, 7.0, 2H), 8.70 2H), 11.30 (br. s, 1N); El-MS 389.2 HPLC-Method C, Rt 12.37 min.

ExEple 313 (5-Benzylcarbaoy-2-pyrazol.-3-yl)-(2en phenyl-quinazolin-4-yl)-amine (111-84): -IK NMR (5001Hz, DMSO-d6) 8 4.52 J 6.0 z, 2H), 7.29 iN), 7.38 O 10 J 4.2 Hz, 4H), 7.58 J a 7.5 Hz, 2H), 7.63 (m, 1H1), 7.72 11), 7.98 Cm, 2H), 8.43 J 7.7 Hz, 2H), 8.72 J 75 Hz, 1H), 9.23 (br. a, 2H), 11.34 (br. a, El-MS 421.2 HPLC-Method C, Rt 16.76 min Example 314 (S-Cyclohexylcarbamoyl-2pyazol-3-yl)- (2phenyl-quinazclin-4-yl) -amine (111-85): H NMR (500MHz, DMSO-dE) 51.16 1.34 4H), 1.62 J 2.6 Hz, 1H), 1.76 2H), 1.5 2H), 3.79 1H), 7.43 iN), 7.60 Ct, J 7.2 Hz, 2H), 7.65 It, J a 7.1 Hz, 11), 7.71 (dd J 2.2, 5.4, 8.2 Hz, 1K), 7.98 2H), 8.35 1H), 8243 Cdd, L a Hz, 2H), 8.72 J t-8.2 Hz, 1H), 11.34 Cbr. a, 1K); El-MS 413.5 (M+1; HPLC-Method C, Et 17.18 min.

Example 315 (S-Diethylcarbanyl-2r-pyrazol-3. y1)-(2phenyl-quinazolin-4yl)..amane (111-86): 'H NMR (500MHz, DMSO-d) 1.18 (br. a, 3H), 1.25 Cbr. 3H), 3.49 (br.

a, 2H), 3.69 2H), 7.21 7.59 J a 6.9 Hz, 2H), 7.62 m, 11), 7.70 Cm, 21), 7.96 21), 8.39 J 7.1 Hz, 2H), 8.74 J a 8.4 Hz, 11.37 (br.

a, IN); El-MS 387.2 HPLC-Method C, Rt 14.50 min.

IN Example 316 (Benwyl-methyl-carbamoyl) -2H-pyrazol-3 yll- (2-phenyl-quinazolin-4-yl) -azine (111-87): 'H NM (500MHz, DMSO-d6) 8 3.33 4.75 2H), 7.26 (m, IH), 7.31 (in, lx), 7.38 4H), 7.58 2H), 7.70 (m, 11), 7.95 31), 8.26 1H), 8.40 J 7.8 Hz, 8.75 1H), 11.2 (br. 8, 11); EL-MS 435.2 HPLC-Metbod C, Rj 16.77 min.

Example 317 (2-Phenyl-quinazolin-4-yl)-(5propylcarbamoyl-2a-pyrazol-a-yl)-amine (111-88): 'K NM Cl (5001Hz, DMSO-d6) 8 0.94 J 7.3 HZ, 3H), 1.57 (i, 2H), 3.24 J 6.5 Hz, 2K), 7.39 (br. a, UI), 7.60 Ct, J 7.3 Hz, 2H), 7.64 IH), 7.71 (br. t, J 6.5 Hz, 7.98 2H), 8.42 J 7.2 Hz, 2H), 8.61 (br. s, 11), 8.72 3 8.5 Hz, 11.34 (br. a, El-MS 373.3 IPLC-Method C, Rt 13.51 min.

Example 318 CEthyl-iaopropyl-carbamoyl) -2H-pyrazol-3yl1-(2-phenyl-quinazolin-4-yl)-amine (111-89): '1 IMR (SOOMHz, DMSO-d) 8 0.92 J Hz, 6H), 1.52 (m, 2H), 1.59 IR), 3.79 2H), 7.53 (br. a, 11), 7-.57 J 7.5 Hz, 2H), 7.65 J 7.2 Hz, 7.71 (m, 11), 7.99 21), 8.23 (br. d, J Hz, 1K), 8.46 (d, J 7.5-Hz, 2H), 8.74 J 8.4 Hz, 1K), 11.34 (br. a, 1K); El-MS 401.2 (M+H0 HPLC-Method C, Rt 15.51 min.

Example 319 (S-Cylopropylcarbamoyl-2H-pyrazoal-3-yl)- (2phenyl-quinazolin-4-yl)-amine (111-90): 'H IOMR (SOOMHz, DMSO-d6) 50.60 2H), 0.74 2.86 1H), 7.34 (br. 7.62 7..70 1H), 7.97 2H), 8.41 J 7.9 Hz, 2H), 8.63 (br. a, is), 8.72 J 7.8 Hz, 1R), 11.35 (br. a, 1K); EL-MS 371.2 (M+H)fHPLC- Method C, at 12.64 min.

Example 320 'sobutyoarbaacyl-2s.yrazo..3.y1) Phenyl-quinazoln-4-yl) -aminao (111-91): IH fMR DMSO-d) 8 0.94 J. 6.7 Hz, 6H), 1.89 8m, 1K), 3.12 J 6.4 Hz, 21), 7.45 (hr. B, 1H), 7.S8 J 7.2 Hz, 3E), 7.64 Ct, J 7.1 Hz, IH), 7.71 1N), 7.98 (m, 2H)1 8.44 (dd, J. 1.3, 7.9 Hz, 2H), 8.62 s, i), 9.72 J 8.3 Hz, 1H), 11.33 (hr. a, El-MS 387.2 EPLO-Method C, Pt 14.70 min.

10 Example 321 {S-[(3S)-3,-Xethoymethy1.pyrr±idine-lcarbonyl) -2H-pyrazol-3-yl)- 2 -pbenyl-quinazolin-4yljamine (111-93): lH NMP (500MHz, DMSO-dG) S 2.00 (im, 2H), 2.12 1K), 3.29 3H), 3.45 J 8.7 Hz, 1K), 3.57 Cdd, J 3.2, 9.3 Hz, 1K), 3.86 3.92 (m, 1H), 4.36 Cm, 2R), 7.45 (hr. a, 7.59 J 7.2 Hz, 2H), 7.63 1K), 7.69 11), 7.97 Cm, 2H), 8.40 J Hz, 2H), 8.74 Cd, J 7.6 Hz 1 1K), 11.38 (hr. a; iN); EIMS 429.2 HPLC-Method C, Rt 13.84 min.

'-Example 322 (2-Phenylquinazoin-4.Lyl).(S.-mtolylaarbemoyl-2a-pyrazol-3-yl)-amine (11-94): 1

HNMR

DMO-d6) 8 2.33 3H), 6.97 J 7.'5 Hz, iN), 7.27.Ct, 3 7.8Hz, 1K), 7.62 7H), 7.72 Cm, 1H), 7.98 2H), 8.46 fdd, J 2.0, 7.9 Hz, 2K), 9.71 10.29 1H),.11.31 a, 1K); El-MS 421.2 HPLC-Methbd C, Pt 17.11 min.

Exjmple 323 (2-Phenyl-quinazolin-4-y1) tolylarbamoyl-2Hpyrazol-3-yl) -amine (111-95): 1 H iNMR (500MHz,* DMSO-dE) 5 2.30 3H), 7.20 J 8.3 Hz, 2H), 7.62 SH), 7.68 3 J 8.3 Hz, 2H),.7.72 (m, 7.98 2H),'8.46 (dd, J= 1.8, 7.0 Hz, 2H), 8.72 10.31 Ca, 1H), 11.36 (hr. a, iN); EI-MS 421.2 HPLC-Method C, Rt 16.95 min.

o Exa Mle 324 (5-Nothylcarbamoy-2f-pyrao3-y.) phenryl-qua'zolin..4.yl) -amine (111-96): 31H NI4R C5001#ijz, ct ~DMSO-d6) 6 2.82 J 4.6 Hz, 3H1), 7.3'1 Cbr. 8, 11) 7.62 311), 7.69 111), 7.97 Cm, 2H), 8.42 Cd, J ci7.1 Hz, 211), 8. 59 -1H) 8.71 J .oHz, is) 11.30 (br. a, 11) E1-M4S 345.1 C?4+H) HPIC-Method C, Rt 11. 02 win.

Example 325 ES-(Morpholine-4-oarbony)zH..pao.3yll.

(Z-pbenyl-quinazolin-4-yl).amine (111-97): 'H NMR (50014Hz 4 o DMSO-d6) 6 3.33 4H1), 3.83 (m 411), 7.34 (br. a, 1H1), 0 ~7.53 4H1), 7.86 Cm, 2H1),.8.43 Cm,,211), 8.67 Cd, J a 8.6 HZ, 10.70 111), 13.56 111); El-MS 401.2 CM+1) HPLzC-Method A, Rt 2..68 mini.

Exml 326 (l-kethylpiperazin.-4-aarbonyl) pyrazol-3-yl (2-phenyl-quinazolk-4.y1) -amine (111-98.): 1H NMP. (500MHz, DMSO-dS) 8 2.25 3H1), 2.43 4H1), 3.987 (tn 4H), 7. 33 (br. a, 11), 7. 53 411) 7.987 (m, 2H1), 9.45 21H), 8.67 J 7.6 Hz, 111), 10.70 Cs, 111), 13.30 111]; EI-MS 414.2 HPLC-Method A, Rt 2.38 min.

Exle pj3Z7 (2-Hydroxiyethyiaarboy..2.pyrazo..a-yl] 2 -phenyl-guinazoln-4.yl)..amine (111-99): 'H NMR (500MHZ, DMSO-dG) 6 3.36 211), 3.52 Cm, 2H1), 4.79 IH, 7.50 511), .7.83 211), 8.50 4H1), 10.52 (br. s, 11H), 13.25 11); El -MS 3 75. 1 CM+H);AIPLC-Method A, Rt 2. 51 min.

Examle 328 C5-C~rbamoy.-2H-pyrazo..3 y)(2.phiyl quinazolin-4-yi).a-n 0 (111-OO0): To a solution of 5-C2phenyl-quinazofln-4-ylamjno) -lH-pyrizole-3-carboxyicI

O

oN acid 2 ,5-dioxo-pyroliin-a.-y ester (270 us, 0.63 mmolj.

in DMF (20 ml) was added a solution of ammonia in 1,4dioxane (0.5 M, 10 ml). The resulting mixture was stirred at room temperature for 24 h. After concentration of t he solvents, the residue was added to water (20-ml). The resulting precipitate was collected to afford 111-10Q (168 mg, 80%)as a yellow solid. 1H NMR en (500MHz, DMSO-dS) 5 7.77-7.51 6H), 7.86 (br s, 2H), 811 1H), 9.50 2H), 8.63 10.52 1I), 11.25 EI-MS 331.1 HPLC-Method A, Rt 2.52 min.

c Example 329 (4-Bromo-2a-pyrazol-3-yl)- (2-phenylquinasolin-4-yl)-amine (111-101): Prepared according to Method A to afford'a yellow solid, mp 189 0 C; 'H NMR (DMS0d) 8 7.44-7.46(3H, 7.58 (1H, 7.87 (2H, 8.15 (1H, 8.31-8.34 (2H, 8.49 (1K, 10.08 s), 13.13 (1K, IR (solid) 3286, 2969, 1738, 1632; MS 366.2/368.2(M+iH)'.

Example 330 4 -Bromo-5-methyl-2B-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (III-102): mp 183-185WO; 'H NMR (DMSO) 8 2.33 (3H, br 7.44-7.46 (3H, 7.57 (1H, 7.84-7.87 (2H, 8.31-8.34 (2H, 8.48 (1K, d), 10.05 (1iN, 12.91 (1N, br IR (solid) 3362, 3065, 2831, 1619, 1578; MS 380.2/382.2(M+H).

Example 331 (4-Cyano-2-pyrazol-3-yl)-(2-phenylquinazolin-4-yl) -amine (III-103): mp 2500C; H NMR (DMSO) 8 7.47-7.49 (3H, 7.64 (1K; 7.91 (2H, 8.40- 8.43 (2H, 8.53 (1K, 8.71 (1H, 10.61 (1in, a), 13.60 IR (solid) 3277, 3069,'2855, 2231, 1625; MS 313.2(M+H)*.

IND Exmple 332 (5-Methyl-2B-pyrazol-s-y1) -(2-morpholin-4-yl- S quinazolin-4-yl) -amine (1IZ-104). tap 223-224-C; 1 E NMR- 8 2.260H3, 3.65(4H, 3.75(4K, 6.44(lK, ct 7.12(1K, 7.33(1K, 7.56(1K, 8.37(1K,- d), 10.01(1, 12.13(1K, br 1K (solid) 1621, 1579, c-I 1537, 1475, 1434, 1385; MS .311.0 en Example 333 (5-Methyl-Z2H-pyrazol.3-y1) -(2-piperazin-1-yl- IND qtdinaxolin-4-yl) -nmine (111-105) nip 179-181CC; 11 I1hff o 10 (DM80) 8 2.26(3H, 2.74 (4H1, br 3.71(4K, br s), c-I ~6.43(12K, 7.08(1K, t0, 7.30(11, 7.53(111, t), o 8.34(111, dY', 9.50(11, 12.08(1K, br 1K (solid) 2853, 1619, 1603, 1566, 1549, 1539; MS 310.0 Examle 334 !2-(4-Methylpiperidin-1-y)uinazo~i..4.Y1J.

(S-methyl-2n-pyrazol-3.yl) -amine (111-106): nip 1L48-150 0

C;

In Zmm (P14.5) 8 1. 06 (3E1, d) 1. 03 ml 1.5S1 70(3H, 2.26(3H1, 2.86(2H, 4.73(2H1, 6..44(111, s), 7.06(111, 7.29(11, 7.52(111, 8.32(111, d), .9.92(111, rsI, 12.09(11, br IR (solid) 2917, 2840, 1629, 1593, 1562, 1546, 1486; MS 323.0 (I+H1+.

Example 335 (4-Netbylpiperazin-1.yz) -qninazolin-4-y1] (5-methyl-2a-pyrazol-a-y)..amine (111-107):- mp-10S-107 0

C;

111 NNR (IDM801 B-2.21(3H, 2.26(3K, 2.34(4H1, m), 3.75 (411, m, 6.45(1K, 7.09(111, 1.31(1K, d), 7.54(111, 8.34(11, 9.96(111, 12.12(11T, br IR (solid) 2934, 2844,' 2804, 1620, 1593, 1572, 1536, 1476; MS 324.0 -(M+Kl t Example 336 (5-Methyl-25f-pyrasol-3-y1) -(2-piperidin-1l-ylquinasolin-4-yl) -azine (111-108) nip 294 0 C; 111 NMR 6 1.45-1.58 (4kS En), 1.63 (2K, 2.26 (3K, 3.79

\O

(41, 6.45 br 7.06 (1H, 7.29 (12, d), S7.52 (1H, 8.33 (12, 9.92 (12, 12.11 (12, br IR (solid) 2929, 2847, 1632, 1591, 1500, 1482, 1437, C 1382; MS 309.3 ClExample 337 (2-Azepan-1-yl)-quinasolin-4-yll- 2-pyrazol-3-yl)-amine (111-109): mp 269 0 C; H NMR (DMSO) 8 1.50 (4H, br 1.76 (4H, br 2.25 (3H, 3.78 (4H, 6.55 (1H, br 7.03 7.28 d), 7.50 (1H, 8.33 (12, 9.92 (1H, 12.09 (12, br C) IR (solid) 3427, 2963, 2927, 2909, 2872, 2850, 1623, S1595, 1586, 1568, 1504, 1486, 1468, 1386, 1427; MS 323.3

(M+H)

4 Example 338 2 4 -(2-sydrozyethylpiperidin-1-y1)quinazolin-4-yll (5-methyl-20-pyrazol-3-yl) -amine (III- 110): mp 175 0 C; 1H NMR (DMSO) 8 1.08 (2H, 1.38 (2H, 1.57-1.83 (3H, 2.26 (3H, 2.85 (21, tQ., 3.47 (2H, 4.38 (12, 4.75 (21, 6.45 (12, br a), 7.06 (1H, 7.29 (1H, 7.52 (1H, 8.32 (1H, d), 9.93 (12, 12.12 (1H, br IR (solid) 3365, 3073, 2972, 2868, 1622, 1604, 1586, 1568, 1486, 1463, 1440, 1394; MS 353.2 Example 339 (5-Cyclopropy1-2H-pyrazol-3-yl)-12-(4methylpiperidin-1-yl)-quinazolin-4-yl -amine (III-111): To a solution of (5-cyclopropyl-nq-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 mmolY 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 rn). Potassium carbonate (57mg, 0.41 mmol) was added and the mixture stirred at-room temperature for 2 IN hours. The resulting suspension was filtered, washed o with water and rinsed with Et 2 0 (x2) to afford III- 111 as a white solid (123mg, mp 190C; 'I NMR C 8 0.66 (2H, 0.93 (SH, br 1.07 (2H, 1.66 (3H, s) 1.91 (1H, 2.85 (2H, 4.72 (28, 6.33 (1, 7.06 (1R, 7.29 (1H, 7.52 (1H, 8.31 (12, 9.95 (1H, 12.18 (13, br IR (solid) 2925, en 2852, 1622, 1590, 1581, 1558, 1494, 1481, 1453, 1435,

\O

1394; MS 349.2 Cl Example 340 [2-(1,4-Dioxa-8-asa-spiro4,5dec--yl)o qunazolin-4-yll-(5-methyl-23-pyrazol-3-yl)-amine

(III-

112): mp 191*C; 'H NMR (DMSO) 1.65 (4H, 2.26 (3H, 3.90 (4H1, 3.93 (4H, 6.43 (1H, br 7.09 (1H, 7.32 (11, 7.54 (11, 8.35 (1H, 9.99 (1H, br 12.13 (11, br IR (solid) 3069, 2964, 2927, 2868, 1618, 1581, 1568, 1540, 1495, 1481, 1435, 1390; MS 367.3 Example 341 4 -Cyclopentylamino-piperidin-1-yl).quinazolin-4-yll (5-methyl-25-pyrazol-3-yl)-amine

(III-

113): mp 191CC; 1H NMR (DMSO) 8 1.33 (2H, 1.65 (4H, 1.87 (2H, 2.20 (11, 2.26 (3H, 2.49 (2H, 3.00 (2H, 3.36 (2H, 4.6i (2H, 6.45 (Is, br 7.07 (1H, 7.31 (1H, 7.52 8.33 (1H, 9.94 -br 12.12 (10, br IR (solid) 3371, 2943, 1622, 1600, 1581, 1545, 1509, 1463, 1440, 1390;' MS 378.2 Example 342 2 4 -Hydroxypiperidin-1-yl)-quinazolin-4yl] (5-methyl-23-pyrazol-3-yl)-anine (111-114): mp 1230C; 'H NMR (DMSO) 8 1.34 (2H, 1.90 (2H, 2.26 (3K, a), 3.24 (2H, 3.72 (11, br 4.39 4.70 (1H, 6.44 (1H, br 7.07 (1I, 7.30 (11, 7.53

IO

o 8.33 (1H, 9.94 (11, br 12.11 (10, 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-Cycrlopropyl-20-pyraol-3-yl)-[2-(4hydroxy-4-phenylpiperidin-1-yl)-quinasolin-4-yl-amine (111-115): mp 131C; 1H NMR (DMSO) 8 0.64 (2H, 0.93 (2H, 1.68 (21, 1.83-1.97 3.20-3.45 (2H, 4.69 (2H, 5.11 6.37 (1H, br 7.08 \C 7.20 (1H, 7.31 (318, 7.49 (2H, 7.53 02 8.33 (11, 9.98 (1K, br 12.18 br a); cl IR (solid) 3362, 2952, 2934, 2911, 2870, 2825, 1618, 1584, 1570, 1559, 1536, 1481, 1459, 1431, 1372, 1336, 1213, 994; MS 427.6 Example 344 (5-Cyclopropyl-2H-pyrazol-3-yl)- 2-(1,3dihydro-isoindol-2-yl) -quinazolin-4-yll -amine (111-116) Prepared according to Method E-I to afford an off-white solid, mp 2370C; 3H NMR (DMSO-dG) 8 0.79 (2H, 1.00 (2H, 1.99 4.92 (4H, 6.72 br a), 7.13 (11, 7.33 (211, 7.30-7.48 (3H, nm), 7.58 (1N, 8.40 (1N, 10.12 (11, 12.17 (IH, 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-y1)-q uinazolin-4-yll cyclopropyl-2-pyrazol-3-yl)-amine (111-117):-mp 199- 2000C; 1H NMR (DMSO-d6) 8 0.60-0.70 (2H, mY, 0.90-1.00 (2H, 1.45-1.57 (42, 1.70-1.85 (41, i.88-1.97 3.75-3.87 (41, 6.42 (11, 7.02 (IN, t), 7.27 (1I, 7.49 8.29 (1H, 9.91 (12, a), 12.19 (1H, br IR (solid) 2929, 1624, 1595, 1581, IND 1563, 1542, 1496, 1462, 1440, 1426, 1397, 1356, 1305, 1000, 625, 754; MS 349.2 Example 346 (S-Cyclopropyl-2E-pyrazol..a.yl) dihydro-1B-isoquinolin-2-ya) -quinazolin-4-yl-amine (111- 118): mp 1B2-184 0 C; 'H !NR (DMSO) 8 0.75 (21, 1.02 1.96 (1W, 2.89 (2H, 4.05 (2H, 4.94 (2H, 6.46 (111/a, 7.10 (11, 7.21 (49, 7.37 (LW, 7.55 8.36 (IH, 10.05 (1H, 12.23 br IR (solid) 1621, 1581, 1560, 1537, 1479, 1456, 1426, 1396, 1374, 1341, 1222; MS 383.3 Va Example 347 (S-Cyclopropyl-2H-pyrauol-s-yl)-[2- (2,3dihydro- indol-1-yl) -quinatolin-4-yll -anine (111-119)z.vip 150-153C; 'H NMR (DMSO) 8 0.74 (2N, 0.98 (2N, d), 1.96 (1W, 3.15 (2H, 4.25 (2H, -6.45 (11, br 6.88 (LW, 7.09 7.20 7.53 (1W, 7.65 (1H, 8.43 (ZR, br 10.09 (1H, 12.28 (1W, br IR (solid) 1621, 1588, 1577, 1564, 1537, 1467, 145, 1425, 1386,.1259; MS 369.3 Example 348 (S-Cyclopropyl-2H-pyrazol-3-yl)-[2- (4hydroxymethylpiperiin -y1) -quinazolin- 4-ylJ-amine (III- 120): up 142OC; 'H NMR (DMSO) 8 0.67 (21, 0.96 (2, 1.10 (2H, 1.55-1.70 1.91 (11, 2.BS (2H, t),'3.28 (2H, 4.48 (1H, 4.76 6.34 (1R, 7.06 (iN, 7.30 (iR, 7.52 (IH, 8.31 9.9 6. (1W, 12.19 (IH, ZR (solid) 3363, 3000, 2927, 2854, 1618, 1604, 1573, 1536, 1509, 1477, 1436, 1395, 1354, 1314, 1241, 1196, 1091, 995, 941, 823; MS 365.8 (M+H) t Example 349 (5-Cyclopropyl-2H-pyrasol-3-yl)- (3,4dihydro-2E1-quinolin--y1)- -quinazolin-4-yll -mine (III-

\O

121): mp 137-145*C; 'H NMR (DMSO-d6) 8 0.55 (2E, 0.88 C (2H, 1.78 (12, 1.92 (2H, 2.75 (2H, 4.04 (2H, 6.20 br 6.97 (1H, 7.14 (12, m), 7.19 (1H, 7.42 (1H, 7.61 7.67 (1H, d), 8.43 10.04 12.21 br IR (solid) 1622,..1572, .1539.,.1493, 1454, 14'20, 1373, 1249; MS 383.3 Exmaple 350 (5-Methoxyoarbony1-2-pyrazol-3-yl)-[2- (piperidine-1-yl)-quinaolin-4-y1]-amine (III-122): 1H NMR (500rMHi2, CDC1 3 81.7-1.8 5 3.8 (4H, 8 3.9 (3H, a 5 5.5 (1H, 6 7.15 (11, 8 7.4 (1H, 8 7.6 (1H, 8 8.0 HPLC-Method B, (starting with Rt 7.4 min; MS 353.24 Example 351 [5-(Piperidine-1-carbonyl)-20-pyrazol-3-yll- (2-(piperidine-1-yl)-quinazolin-4-yl]-amine (II1-123):- MPLC-Method B, (starting with 95% H20:0.1% TFA) Rt min; MS 406.30, 404.30.

Example 352 (5-Eydroxymethyl-2g-pyrazol-3-yl)- [2- (piperidin-1-yl)-quinazolin-4-yl] -amine (111-124): To a solution of III-122 (10.0 mg, 0.028 mmol) in THF (6 mL) at ambient temperature was slowly added a lM solution of LiAlH4 in THF (o.c5 mL,. 0.05 mmol). After 15 minutes the solution' was quenched with water and N HC01. The product was extracted from the aqueous layer with EtOAc. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by preparatory RPLC to afford 111-124 (4.0 mg, HPLC- Method B, (starting with 95% H 2 0:0.l% TFA), lt 6.1 min; MS 325.13 323.13 EXimple 353 (5-Carbamoyl-20-pyrazol-3-yl) -(2-(piperidino 1-yl) -quinazolin-4-yll -amine (111-125): A solution of 111-122 (1.5 g, 4.3 mol) in 2.0 M NH 2 /MeOH (100 tnt) was heated at*110 0 C for 2 days. The dark brown reaction mixture was concentrated In vacua to afford a viscous oil which was purified by column chromatography to yield 0.7 g of 111-125. 'H NMR (500MHz, CD30D-d 3 51.6 en (4H,in), 51.7 (2H,in), 8 3.3 (IH, 8 3.8 (4H, 855.5 CIR, 5 7.15 (1H, 5 7.45 (lH, 6 7.55 (1H, S o 10 8.0 (12, HPLC-Method B, (starting with 95% H 2 0:0.it Va TFA) Rt 5.9.mii; MS 338.13, 336.15.

Ci Example 354 (5-Carbamoy'-2-pyrazol-3-yl)-c2-(4methylpiperidin-1-y) -qninazolin-4-ylJ -amine (111-126): HPLC-Metbod B, (starting with 95% HtO:0.1% TFA) Rt 6.4 min; MS 352.19, 350.20.

Example 355 (5,7-Difluoro-2.-indazol-3-yl)-(2-phenyl- 7 ,8-tetrahydroquinazolin-4-y)-amine (111-127): 'H DWR (500 MHz, DMSO-d) 813.7 1H), 10.3 Ca, br, 1H), 7.90 2H); 7.52 1H), 7.45 Cm, 3H), 7.26 IH), 2.99 Cm, 2.75 2H), 1.95 (br, 41) ppm; MS 376.24 376.23 CM-H); HPLC-Nethod A, Rt 3.04 min.

Example 356 (2-Phenyl- 5,,7,-tetrahydrauinazolin-4-yl) ff-i±nazol-3.yl).amne (III-128):' 12 N1*4 (500 MHz, DMSO-d6) 513.4 1H), 10.2 br, 1H), 8.13 Cs, 12), 7.86 Cd, 2H), 7.78 1H), 7.69 11, 7.50 t, 12), 7.35 2.69 2H), 2.72 2H), 1.99 br, 42) ppm; MS 410.24 CEs-) 408.23 CM-H); HPLC-Metbod A, Rt 3.19 min.

Example 357 (7-Fluoro-3-±aiaol.3-y) (2-phenylquinazolin-4 -yl) -amine -XIx-29). :H NMR (500 MHz, DMSO- 66) 813.6 1H), 11.1 br, flU, 8.65 Cd, IN), 8.03 2H), 7.95 2R), 7.67 Cm,.1K), 7.45 7.33 2H), 7.22 (dd, IN), 6.99 (td, 1H) ppm. MS r/e.

3S6L20 PLC-Method A Rt 3.00 min.

Example 358 (S-Pluoro-H-±ndaol-3-yl)-(2-phenylquinazolin-4-yl) -amine (111-130): 2H NMR (500 MHz, dE) 813.2 IN), 11.3 br, lE), 8.67 flU, 8.04 2H), 7.96 2H), 7.70 Cm, lE,. 7.58 Cdd, 1K), 7.43 Cm, 4H), 7.28 (td, IR) ppm. MS 356.20

HPLC-

Method A, Rt 3.00 min.

Example 359 (5 1 7-Difluoro-nLindazol-3yl)- (2-phenylqainazolin-4-yl) -amine (111-131): 11 NMR (500 M4Hz, DMSOd6) 813.-7 1H), B.65 8.04 Cd, 2K), 7.95 (s, 2H), 7.68 3M), 7.45 Cm, 32),.7.35 Cm, 4H) ppm. MS r/e- 374.17 NPLC-Method A, lI 3.07 min.

Example 360 (1Hf-Indazcl-3-yl)-[2-(3-trifluormettyi-.

Phenyl')-quinazoin-4-yJ -amin (111-132)-: 1 NMR (SOOMHz, DMsO-66) 6 7.06 Ct, 1H), 7.42 Ct, li), 7.59 3S), 7.63 iN), 7.66 1K), 7.71 Cm, 1H), 7.80 IR), 7.98 2H), 8.33' iN), 8246 3H), 8.71 1K), 11.04 Cbr. s, 3M), 12.97 Cs, iN); fl-MS 406.1

HPLC-

Method A, Nt 3.15 win.

Example 361 (2-Phenyl-quinazolin-4-yl) (H-pyrazooLo[4,3blpyridin-3-yi)-amine (11-133) 1 E NR (So0 MHz, DMSO-d) 513.3 br, 1H), 11.4 br, 15), 8.78 1K), 8.38 Cdd; 8.24 8.10 210, 7.95 2H), 7.86 (to 1H1), 7.56 214), 7.44 214) ppm. M4S (ES+e) 339.11 o flPILC-ethod A, Rt 2.63 min.

ct ~Example 362 ebx-hny)6oo56-iyr-n pyrazolc(4,3-cpyriazns..ya] (2-phenyl-quinazotin4.

yl)-amzine (111-134): '14.MR (500 M4Hz, MeOH-d4) 86.65 (d, 114), 8.17 M3), 8.10 14) 7.90 Ct, 14) 7.75 (t, en 110), 7.58 214), 7.25 111), 6.95 2H4), 6.85 (d, INO I1i), 6. 80 14) 3.64 Cs, 3H) ppm. MS rn/em o 10 462.2(4+1).

O Example 363 (G-Oso-5Svheny..sfG.d:Lhydro.1z.pyrazolo4,3.

clpyriazin- -)(2-ph~enyl-.qaintazoljn-4-y)aie(M 135): 1H NMR (500 MHz, MeOH-d4) 88.61 1H4), .8.13 (m, 3R), 8.05 IH), 7.85 Ct, 110, 7.70 Ct, 1H), 7.58 (M, 2H); 7.32 54) 6.79 Ca, 114) ppm. MS rn/em 4322(4+).

Example 364 I5- (4-Methozy-pheny.) -6-oxo-5, 6-dihydxo-n2pyrazolo [4,3 -clpyridazin-3-ylJ 2 -phenyl-quinazolin-4.

yl)-mmine (X11-136): M4S (ES+e) 462.2(4+).

Example 365. 5(,-ihoo.pey)6'xo56dhdo 1B-pyrazolo[4, 3-clpyridazin-3-ylJ C2-phenyl-qtinazolin.4 yl)-aaine (111-137):. 3H NM (500 M4Hz, MeOH-d4) 58.63 C(d, 110, 8.17 4H4), 7.89 Ct, 311), 7.73 Ct, 1N) 1 61. Ct, 7.57 13), 7.32 1IX), 7.21 Cd, 130, 6.84 (s, 114) ppm. MIS CES+): mien 500.1CN+H).

xaple 366 [6-Oxo-5- (3-.trifluoromethyl-phenyl) 6dihydxo-1H-pyraz~o[4,..cpyrdazn-3.yj.. (2-phenylquinazolin-4-yl) -amine (111-138): 'R4 NMR (500 MHz, MeORd4) 58.55 1H), 8.19 2H4), 7.92 21), 7.65 (m, VaO 35), 7.45 2H), 7.25 IN), 7.13 1H), 7.05 (t, o 15), 6.75 I.5) ppm. MS rn/en 500.2 (14+R).

ct ainle 367 (6-Oxo-S- (4-Phenoxy-phenyl) 6-dihydro-ix- S. pyrazoloL4,3-cpyridahin3y1 (2-phenyl-quinagol~in.4.

c-iyl)-amin., (111-139):, HS S24,3(M+H).

en ~Eample368 (4 -Chioro-phenyl) -6 -ao-S 6 -dihydro-3lxpyrasolo 3 -clpyridazin-3-y3-(2-phenyl-quinasoln-4..

yl)-amine (111-140): MS 466.2(M+4).

o ~E!522te3 6 9 2 -±midazo1-1-y1-quinazolin.4..y) c-i ifdazol-3-yl) -amine (111-141) "H MNR (500MHz, DMSO-dE) 8 7.10 1H), 7.44 t, IH), 7.50 (br. a, 15), 7.60 (d, 15), 7.72 CM, 2H),'7.77 110, 7.88 15), 7.98 Ct, 8.73 Cd, 1H), 8.96 Cs, 15), 11.23 15), 13.06 (e, El-MS 328.1 (Mii) HPLC-Metbod A, R: 2.93 -mini.

Example 370 (lH-hndazoi-3-yl) -12-(2-methyl-imidazol-a..ylqttinatolin-4-yl] -amine (111-142) 2H INhm (500MHz, DM4SO-dE) 3 2.48 7;nLo 1H), 7.43 Ct, 15), 7.57 iH), 7.60 Cd, IN), 7.67 15), 7.76 (td, 15), 7.86 iH), 7.51 1H), 8.01. (td, 15), 8.72 231), 11.15 Cs, 1N), 13.10 iH); El-MS 342.1 HPLC-Method A, Rt 3.06 mini.

Example 371 (lBH-Zndazol-3-yl)-(2.piperidixn1.yi qulnazolin-4..yl) -amine (111-143) 1H NM CSOOMHz, DMSO-d6) 51.48 6H), 3.60 Cm, 4H), 7. 11 Ct,. 15) 7. 52 7.55 Cd, 1H), 7.64 15), 7.69 1H), 7.75 1N), 7.90 Ct, IH), 8.58 Cd, iS), 11.82 (br. a, 15), 13.25 Cs, RI-M$ 345.1 RPLC-Mathod A, Rt 3.03 mini.

IN Example 372 (LZ-Indazol-3-yl) 2-(octahydro.qu iholn-lyl) -quiazolin-4-ylI -aJne (111-144): 1H NMR (500MHz, DMSO-d6) 8 0.6-1.9 Cin 13.H), 3.15 1H), 3.25 1), C 4.0 1H), 7.10, t, 0.51), 7. 12 Ct, 0.5H), 7.55 (m, 21), 7.66 0.5 7.69 Cd, 0.5 7.77 Cd, 11), 7.91 *8.S5..d,o.5 .8.59 0.5 11.46 11.54 0.5 11.78 0.5 11.84 0.5 H), .13.10 0.5 H),.13.12 0.5 El-MS 399.3 IDHPLC-Method A, at 3.37 'min.

C-i Example 373 (1-Indazol-3-yl)-[2-1(2i6-diinethl-morpholin- I 4-yl) -quinazolin-4-yl] -aiine (23:-145): 'H NMR CSOOMHz, DMSO-d6) 8 1.0 Cm, 6H), 4.0 6H), 7.12 l1t), 7.41 (td, 1H), 7.56 1M), 7.58 1H), 7.68 (dd, 1H), 7.77 1E1), 7.93 8.60 1H), 11.69 Cs, 1H), 13.16 1H) El-MS 375.3 HPLC-zethod A, at 2.93 min.

Example 374 (5-Methrl-2H-pyrasol-3-yl)- (2-phenylpyrimidin-4-yl) aine mp 245-246 0 C; 1H IhR (DMSO) 8 2.26 (3H, 6;32 (11, hr 7.07 Ia, hr 7.48- 7.54 8.33-8.39 (3H, 9.87 (1H, 12.03 (1H, ZR (solid) 1628, 1589, 1579, 1522, 1479, 1441, 1393, 1336;MS 252.2, Example 375 (4-Acetamidophenylsulfanyl) -2-phenylpyrimidin 4-yll S-methyl 2-pyrazol-3 -yl -amirke (IV-3): A suspension of Fenclorim (4,6-dichloro-2phenylpyrimidine) CO.g, 0.44 mmol), rqethylpyrazoie (0.045 g, 0.47 mmol), Ndiiaopropylethylaiex (0.08 ml, 0.47 mmol) and sodium iodide (0.067 g, 0.44 mmol) in n-butanol.(5 ml) were heated at 117 OC-for 18 hours. The solvent was removed in vacua and the crude product purified by flash chromatography (silica gel, 3:2 PetroirEtOAc) to afford N 0.037 g (29 yield) of (6-Chloro-2-phenyl-pyrimidin-4o~ yl)-(5-methyl-2s-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 nmnol) in tert-butanol was heated at 85 OC under nitrogen ci for 2 days. The reaction mixture was cooled -to room temperature and the solvent removed in vacuo. The n concentrate was dissolved in EtOAc, and washed with NaHCO 3 (sat, The organic layer is concentrated in vacuo, and the crude product by preperative HPLC. The residual c disulfide that still remained in the mixture after HPLC o may be removed by precipitation from EtOAc and filtration. The mother liquor was concentrated to afford rV-3 (7mg, 13 t yield) as an off-white solid: mp 235- 236 0 C; 'H NMR (DMSO) 5 2.10 (3OH, 2.21 (3H, 6.33 br 7.50 (3H, 7.7-7.59 (2H, 7.76-7.78 (28, 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 [2-(4-Methylpiperidin-1-yl)-pyrimidin-4-ylJ- (5-methyl-20-pyratol-3-yl) -mine mp 215-216 0 C; 'H NMR (CDO 3 0D) 8 0.96 (311, 1.16 (2H, 1.66 (3H, m), 2.27 2.86 (2H, 4.58 (2H, 4.78 (2H, exch.protons), 6.13 (2H, 7.83 .R (solid) 1593, 1550, 1489, 1436, 1331, 1246, 1231; MS 273.1 Example 377 [2-(4-Methylpiperidin-1-yl)-5-nitropyrimidin- 4 -yll-(5-methyl-2R-pyrazol-3-y) -anine np 185- 187 0 C; 11 NMR (DM80) 8 0.93 (3H, 1.06-1.18 (2H, m), 1.68-2.90 (3H, 2.26 3.01-3.12 (21, 4.63 (18, 4.80 (1n, 6.39 (1E, 9.00 (11, 10.41 IND 12.36 IR (solid) 1589, 1517, 1479, 8 1446, 1346, 1317, 1246, 1222, 1055; MS 318.2 Example 378 [5-Amino-2- (4-Methylpiperidin-1 pyrimidin-4-yll (5-ethyl-20-pyrazol -3-yl) -amine (IV-6): To a solution of. IV-. (48 mg, 0.151. mmol) in.ethanol mL) was added tin dichloride dihydrate (171 mg, 0.756 mmol) and the resulting mixture heated at reflux for 3 IND hours. The reaction was cooled to room temperature and poured onto a mixture of 1M NaOH:dichloromethane:propanol (18:84mL) and stirred for 15 minutes. The layers were

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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:Me0H) to afford 1V-6 as a grey solid (27mg, 1 H NMR (DMSO) S 0.88-1.04 (SH, 1.55-1.62 (3H, 2.21 (3H, 2.70 (2H, 3.36 (2H, 4.40 (2H, 6.37 (1R, 7.49 (1I, 8.40 (1H, 11.92 br MS 288.2 (M+H) 4 Example 379 (5-Amino-6-methyl-2-(4-methylpiperidin-i-yl)pyrinidin-4-yll-(5-methyl-2-pyrasol-3-yl)-amine (IV-7): mp 172-175C 1H NMR (DMSO) 8 0.90 (3H, 1.03 (29, m), 1.52-1.62 (3H, 2.13 (3H, 2.20 2.69.(2H, 3.92 (2H, br B),.4.44 (21, 6.35 (1H, 8.41 (12, 11.85.(1K, br IR (solid) 1612, 1589, 1489, 1446, 1317; MS 302.5 Example 380 [6-Methyl-2-(4-methyl-phenyl)-pyrimidia-4yl]-(5-phenyl-2-pyrazol-3-yl)-amine (XV-lO): MS 342.34 HPLC-Method E, R 1.334 min.

SExa~mple 381 E2-(4-Chioro-phenyl) -6-methyl-pyrimidia-4..

Cl ~ylj fuxan-2-y1-2a-pyrauo1-s-yl) -amine (IV-fl)s s 3 52. 11. (1iH) HPLC Method B, Et 1. 194 mint 5 Example 382 5-Furan-2-yl-2-pyazol.s.yl) -(6-methyl-2- Cl phenyl-pyrimidin-4-yl).a-4ne (IV-12): MS 318.21 (14+1); HPLC-Method E, 1.192 mint.

Cl Example 383 [6-Methyl-2- (4-trifluoromethyl-phenyl) o 10 pyrimidiLn-4-yl] (5-phenyl-2-y1-2H-pyrazo1-3-yl) -aie Cl (IV-13): MS 396.24 EPLC-Method E,.Rt 1.419 mint.

Exampl 384 (S-luran-2-yl-2-pyraol.3yl) 6-methyl-2- (4-trifluromethyl-phenyl) -pyrimidin-4-yl] -amine (IV-14): MS 386.08 HPLC-Method 2 1.347 mint.

Example 385 (2,3-Dihydro-benmo[1,4]a±ofr..2.y)..s methyl -pyrimidin-4-yl (5-furan-2-yl-2E-pyrazol-3-yl) amine (XV-iS): MS 376.18 (14tH); IWLC-Method E, Rt 1.161 min- Example 386 (2 5 3-Dihydro-hezollx,4doxdn.2yl) -6ethyl -pyriiidin- 4 .ylJ (5-methyl-20-pyrazol-3-yl) -amine MS 339.17 HPLC-Method E, Rt 1.082 mint.

Example 387 (6 -Ethyl-2-phenyl-pyrimk~n4-yl)_-(5-methkyl- 2E-pyrazo1-3-y1)-amine (IV-17)z MS 280.18

HPLC-

Method E, at 1. 024 mitt..

Example 388 6 -Mthyl-2-pbenyl-pyrimidin..4.yl) (S-phenyl- 2 0-pyrazol-3-y)-amine'(V..9): MS 328.51 HPLC- Method E, Rt.1.192 mint.

V.0 Examle 38 C6-Ethyl-2- (4-trif luoromethy1-phimy1)o pyrtuddin-4-y1 5 -methyl-25-pyrazol-3.yl) -amine MS 348.5 EPLO-Met hod E, Rt 1.224 mini.

Example 390 5 -Furaa-2-yl-2-pyrazol.3yl)- [6-methyl-a- 4 -methyl-phenyl)j-pyrimidin..4..Yl]-amfine (ZV-21); MS 332.23 (Mi-H) HPLC-Method E, Et 1.139 min.

IDExample 391 (E-Kethoxymethyl2phenylpyrimidn4yl)..(5mnathll25;pyrazl..3.yl) -amine (iV-22)zi MS 296.31 0~xml 3p 92 6 -Dimethr1-2-pheny-pyridn.4.y1) methyl-2-pyrazol..3.yl).-amine (IV-23):s MS 260.2 HPLC-Method E, Rt 0.927 min.

Example 393 (6-Methy1-2-pheny1-pyrimidi.4.y1) 2B7-pyrazol-3-yl)-jne (XV-24): MS 266.18

HPLC-

Method E, Rt 0.925 mini.

Example 39-4 [6 -Ethyl 2- (4 -methyl -phenyl) -pyrimidAin- 4-y13 (S-methyl-20-pyrazol-3-yl)..amm.n (IV-25). MS 294".4.6 HPLC-Method E, Rt 1.174 miii.

Example 395 C2 (4 -Chioro-jphIenyl) 6-ethyl -pyrixmdan-4.yl] (S-metbhyl-2H-pyrazo-3.y1)..imine (IV-26): MS 314.42 RPLC-Method R Rt 1.213 miun.

Example 396 (5-Methyl-ZH-pyrazol-3.yl) -(6-methyl-2-ptOlyl-pyrimidin-4-'yl)..emjne (117-27). MS 280.45 HPLC-Me~thod 9, Rt 1.135 mini.

Example 397 (1H-Indazo1-3- y1) -(6-methozymethyl-2-phenylpyrimidin-4-yl) -amine (TV-2 8) 1 H NMR (500 44HZ, o 3.57 (3R, 4.65 7.23 (15, J=7.5 Ez, 7.52 (19, J-7.6 Hz, 7.63 (4H, .7.75 (15, br), 8.13 Hz, br 8.44 (1H, Jn5.7 Hz, br 10.6 (1K, br), 12.8 (iS, br s) ppm; HPLC-Method A, R. 2.944 min; MS S 332.1 Example 398 (5-Methyl-2H-pyrasol-3-yl)-(2-pridin-4-yl e thienoC[3,2-djpyrimidin-4-yl)-amine (IV-29): 15 NMR (DMSO) cN 2.34 (3H, 6.66 (iH; 7.53 (15, 7.84 (1I, d), O 10 8.32 8.70 (2K, MS 309.6

O

Example 399 (5-Methyl-2-pyraxol-3-yl) (2-phenyl- C pyrido[3,4-d]pyrimidin -4-yl)-amine (rV-30): mp 225 0 C; 1 NMR (DMSO) 8 2.35 (3H, 6.81 (15, 7.50-7.63 8.45-8.52 12H, 8.54 (18, 8.62 (l5, 9.20 (1H, 10.79 (1H, 12.38 (15, br IR (solid) 2958, 2917, 2852, 1593, 1565, 1524, 1467, 1450; MS 303.2 Example 400 (5-Methyl-2E-pyrazo1-3-y1)- (2-phenylpyridot2,3-dlpyrimidin-4-yl)-amine (IV-31): To a solution of 4-chloro-2-phenyl-pyrido2,3d]pyrimidine Pharm. Belg., 29, 1974, 145-148) (109mg, 0.45 mmol) in THF (15 mL) was added pyrazole (48 mg, 0.5 imol) 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 4 filtered, and concentrated.in vacuo. The residue was purified by flash chromatography (Si0 3 DCM-MeOH gradient) to afford IV-31 as an off-white solid (69 mg, mp 234C; 12 NMR I (DMSO) 8 2.14 (3H, 5.99 (1H, 7.20-7.40 (3H, 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 C<1 Example 401 (5-Cyclopropyl-2H-pyrazol-3-yl)- (2-phenylpyrido[3,4-dlpyrimidin-4-yl)-amine (IV-32) off-white rn solid,'mp 232-233C; 'H NMR (DMSO) S 0.70-0.85 (2H, m), 1C 0.90-1.05 (2H, 1.05-2.Q7 (1H, 6.75 (1H, 7.50- 7.75 (3H, 8.40-8.70 (4H, 9.20 (1H, 10.80 (1H, O) 12.41 IR (solid) 3178, 1601, 1573, 1532, 1484, S1452, 1409, 1367,.1328, 802, 781, 667; MS 329.2 Example 402 [2-(4-Methylpiperidin-l-yl)-purin-4-yl]- methyl-2R-pyrazol-3-yl)-amine (IV-33) To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-lf-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-1H-pyrazol-3-yl)-amine which was used in the next step without further purification.

To a solution of (2-chloro-purin-4-yl)-(5-methyl-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 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 (x2) and rinsed with EtaO (x2) to afford IV-33 as a white solid (225mg, mp >300*C; H NMR (DMSO) 8 0.91 (3H, 1.10 (2H, 1.65 (3H, m),

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2.24 2.84 (2H, 4.60 (2H, 6.40 (1H, a), 0 7.87 (1H, 9.37-9.59 12.03-12.39 (2H, IR (solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3 (M+H)*t Cl Example 403 (5-Cyclopropyl-2-pyrazol-3-yl)r L2-(4methylpiperidn-1-yl1)-pyrrolo 3,2-d pyriidin-4-yl -amine S(IV-34): white solid; t 8 NMR (DMSO) 8 0.65 (2H, 0.91- 0.96 (5H, 1.08 (2H, 1.58-1.64 (3H, 1.89 (1H, 2.77.(2H, 4.57 (28, 6.09 (1H, 6.59 (1, ID 7.33 (12, 9.42 (1H, 10.65 (1H, 12.02 (12, 0 br MS 338.3 Example 404 [6-Benzyl-2-phenyl-5,6,7,8-tetrahydropyridoc4,3-dpyrinidin-4-yll-(5-fluoro-1E-indazol-3-yl)-.

amine (ZV-35): IsR NMR (500 MHz, DMSO-d6) 813.0 1H), 10.4 br, 12), 9.73 111, TFA-OH), 8.00 2H), 7.64 2H), 7.59 (dd, 1H), 7.52 3H), 7.41 1R), 7.31 3H), 7.14 (dd, 12), 4.58 2H), 4.35 (br, 2H), 3.74 2H), 3.17 2H) ppm. MS m/e= 451.30 HPLC-Method A, Trt 2.96 min.

Example 405 (5-Fluoro-1B-indazol-3-yl)-(2-phenyl-5,6, 7 ,8tetrahydro-pyrido[4,3-d]pyrinidin-4-yl)-anmine (ZV-36): Prepared from IV-35 (0.13 mmol) by treatment with an equal weight of Pd/C in 4.40 HCOOH in MeOH at room temperature for 12 h. The mixture was filtered through celite, the filtrate was evaporated, and crude product was purified by UPLC to afford IV-36 as yellow solid in 35% yield. "a NMR (500 MHz, DMSO-d6) 812.9 12), 9.06 7.99 22), 7.57 (dd, 12), 7.34 I(m, 12), 7.28 3H), 7.22 12), 3.83 2H), 3.05 2R), 2.72 2H) ppm. MS m/e= 361.20 HPLC-Method A, Tt'2.68 min.

O ID 0 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- 128) (0.33g, 1.37 mmol) in DMF (anhydrous, 5 mL) was added Ci 3-amino-5-methylpyrazole (0.27g, 2.74 mmol) and potassium carbonate (0.57g, 4.13 mmol)and the resulting mixture was r heated at reflux for 6 hours. The reaction mixture was

VO

C then cooled and solvent removed in vacuo. The residue was extracted twice with ethyl acetate and the combined.

C organic layers washed with brine, dried (MgSO 4 filtered o and concentrated in vacuo. The crude product was (0 purified by flash chromatography (SiO 2 gradient DCM-MeOH) to afford V-I as a colourless oil; 'H NMR (MeOD) 8 2.23 (3H, 5.61 (1H, 7.41 (1H, 7.52(2H, m), 7.62(1H, 7.81(1H, 8.07(1H, 8.19(2H,. m), 8.29(1H, 8.54 (1H, MS 301.2 Example 407 (LH-Indazol-3-yl) [3-(2-trifluoromethylphenyl)-isoquinoline-1-yll-amine A solution of 1chloro-3- (2-trifluoromethyl-phenyl)-isoquinoline (100 mg, 0.326 mmol) and 1H-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:dichlorometbane (50 mi 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 solid (35 mg, 1H NMR (500 MHz, d- -DMSO) 8 9.78 (br s, 1l), 8.62 1H), 7.9-7.85 1H), 7.78-7.72 1H), 7.70-7.68 1H), 7.65-7.62

IH),

7.60-7.55 1H), 7.52-7.45 3H), 7.41-7.38 1H),

VO

oN 7.28-7.25 1H), 7.18 1H), 6.95-6.92 1H), 5;76 0 IN); LC-MS B(ES+) m/e= 405.18 HPLC-Method D Rt 2.74 min.

Ct Example 408 (5,7-Difluro-1-indaol-3-yl)-[3-(2-.

Cl trifluoromethyl-phenyl) -ioquinolin-i-yl -amine Prepared from 5,7-difluoro-1H-indazol-3-ylaminato afford S compound V-3 as a yellow solid (90 mg, 1H NMR (500 MHz, d 6 -DMSO) 5 13.25 1H), 9.92 (hr a, 1H), 8.61 (d, 19), 7.9 7.81-7.49 6G), 7.26-7.2 21), 7.12-7.10 1H); LC-MS m/e= 441.16

HPLC-

Method D, Rt 3.58 din.

Example 409 (5-Methyl-2E-pyrazol-3-yl)-(2-phenylqBainolin-4-yl)-amine To a mixture of 4-chloro-2phenylquinoline Net. Chem., 20, 1983, 12 1- 1 2 8)(0.53g, 2.21 mmol) in diphenylether (5 mL) was added methylpyrazole (0.43g, 4.42 mmol) and the resulting mixture heated at 200 0 C overnight with stirring. The reaction mixture was cooled to ambient temperature then petroleum ether (20 mL) was added and the resultingprecipitate as isolated by filttation. The crude solid was purified by flash chromatography (SiQo, gradient DCM- MeOH) to afford V-4 as a white solid: mp 242-244OC; 11 NMR (DMSO) 8 2.27(3H, 6.02(1H, 7.47(2H, 7.53- 7.40(2H, br 7.67(1H, 7.92(11, 8.09(2H, d), 8.48(2H, 9.20(1H, 12.17(1H, br IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 Example 410 (1Z-Indazol-3-yl)-(2-phenyl-quinolin-4-yl)amine 1 R NMR (500 MHz, d6-DMSO) 5 12..78 1H), 9.50 11), 8.65 1H), 8.15 il), 8.04-7.98 (m, 3H), 7.94 1H), 7.78-7.75 1H), 7.60-7.40 61), ID7.15-7.10 1g1). LC-MS (ESt) r/a- 337.11

HPLC-

Method D, Rt 2.10 min.

C Example 411 (2-Phenyl-quinoli (h-pyrazolo[4,3blpyridin-3-yl)-amine 'H NMR (500 MHz, PMSO-d6) 613.6 1H), 11.4 8.94 11), 8.61 (dd, 11), 8.23 IH), 8.16 (dd, 1H), 8.12 t, 1H), 7.99 1H), 7;86 1H), 7.65 4H), 7.54 1M), 7.52 (dd, 11) IN .ppm. MS n/e= 338.11 (14+11); HPLC-Nethod A, HPLC- Method D, Rt 2.91 min.

o Exkmple 412 (1-Indazol-3-yl)- E2- (2-trifluoromethyl 0 phenyl) -qainolin-4-ylJ -amine 'H NMR (500 MHz, dc- DMSO) 8 12.68 1H), 9.51 1H), 8.7 1H), 7.95- 789 2H), 7.83-7.70 (ni, 3H), 7.68-7.62 2H), 7.60 1s, Hi), 7.55-7.52 is), 7.49-7.4S 1H), 7.40-7.37 7.12-7.09 11); LC-MS r/e= 405.15 (MuJ); PLC-Method D Rt 2.25 win.

Example 413 (5,7-Difluoro-x-ndazol.3-yL) (2trifluoromethy1-phenyl) -quinclin-4-yl -amine 'H NNR (500 MHz, 46-DMSO) 6 13.31 1H), 9.49 11), 8.70- 8.67 1H), 7.96-7.92 1E), 7.85-7.66 7H), 7.63- 7.60 1S), 7.42-7.40 11). LC-MS (ESi) r/en 441.18 HPLC-Method D Rt 2.39 min.

Example 414 (2-trifluoromethyl-phenyl)-quinolin-4-yl- (lE-wrazoloU,3-blpyridfl.3..y)-amine 2H MR (SOO MHz, DtSo-ds) 813,6 11), 11.6 br, 1H), 8.98 (d, 11), 8.57 (dd, IS), 8.12 3H1), 7.97 2A), 7.96 (m, 3H), 7.49 (dd, 11), 7.23 1H1) ppm. MS m/en 406.20 HPLC-Method A Rt 2.91 min.

Va o Example 415 (2-Phenyl-q4inaolin-4-yl) li 2 ,4]triazol-3-yl)-ammne (72-154): off-white solid, np c 266-267 0 C; NNR (DM80) 6.7.50-7.70 (4H, 7.85-8.00 (2H, 8.15-8.25 (2H, 8.37-8.45 (2H, 8.58 13.90 (12, br ZR (solid) 3344, 3059,-1630, 1609, 1570, 1557, 1543,.1501, 1495, 1445, 1411, 1355, 1326, 1267, 1282, 1053; 1038, 760, 676, 667, 654; MS 289.2.

ci \O Examle 416 (5-aethyl-2H- [l, 2 1 4Jtriazol-3-yl) -(2-phenyl- O uianzolin-4-yl) -amin (11-155): 'H NMR (500 MHz, DMSO- 'dE) 68.59 8.42 J 6.7 Hz, 2H), 7.79 (m, 4H), 8.03 2H), 7.74 4H), 2.51 s, 3M) ppm. MS r/em 303.08 SPLO-Method Rt 2.6 4 min.

is Example 417 -Triazal-3-yl) -22-(2.

trifluoromethylphenyl)-quinaxolin-4-yl]-amine (1-47): Pale yellow solid (52% yield). 'H NMR (500 MHz, DMSO-d6) 58.54 Cs, 15), 8.15 Cs, br, IH), 7.91 Ct, iH), 7'.85 Cm, 2H), 7.76 3H), 7.66 15) ppm. MS r/ew 357.13 r/en 355.15 CM-H); HPLC-Methbd A, Rt 2.81 min.

Example 418 (5-Nethyl-25- (1,2,4]triazcl-3-yl)- C2-(2trf luoromethylphenyl) -quinazolin-4 -yiJ, -amine (XX-38): Pale yellow solid (54% yield). 'H NMR 5*00 MIz, DMSO-d6) 68.44 br, IH), 7.92 3H), 7.84 1H), 7.77 (m, 2H), 7.68 C(t, 12), 2.28 Cs, 3H) ppm. MS (ES+):.r/es 371.14 m/es 369.18'(M-H).; HPLC-Method A, Rt 2.89 min.

Example 419 (5-Methylsulfanyl-2s- [1,2,43 tziazol-3-yl)- 2- :-trifluoromethylphenyl) -uinazolin--y -min (SM- 156): Pale yellow solid (65% yield).. 'H NMR (500 )Sz,

\O

IDDMSO-dE) 88.56 (br, IN), 7.90 1I), 7.84 2H), 7.78 2H), 7.67 2H), 2.51 3H, buried by DMSO) ppm.

MS m/e- 403.12 m/e= 401.16 C HPLC-Method A, Rt 3.20 min.

Ci Example 4201- (12,2,41Triazol-3-yl) trifluoromethyl-phenyl)-isoquipolin-1-yll-amine (1X-175): ~A solution of 1-chloro-3-(2-trifluoromeftyl-phenyl)isoquinoline (0.326 mmol) and 1H-[1,2,4triazol-3-ylamine 10 (0.651 mmol) in ethanol (3 mL) was heated at 160 0 C and C the solvent evaporated with a stream of nitrgen. The o remaining oil was then heated at 1600C for 18 hours under nitrogen. The resulting melt was dissolved in methanol/dichloromethane (50 taL), washed with saturated aqueous sodium bicarbonate (1 x 25 i) then dried over magnesium sulfate. Purification by silica gel chromatography afforded 11-175 as a colorless oil (4% yield). NMR (500 MHz, CDC1s) 8 9.18 1H), 8.82 (s, 1H), 7.90 7.85-7.75 3H), 7.71-7.62 3H), 7.60-7.55 21), 4.42-4.35 1i). LC-MS 356.16 HPLC-Method D, Rt 3.55 min.

Example 421 (2TPheny1-quinolin-4-yl)-(1B-[1,2,4] triasol- 3-yl)-anine (11-176): Pale yellow solid (30% yield). 'H NMR (500 MHz, de-DMSO) 8 13.82 1H), 9.91 i), 8.80 IN), 8.70-8.65 1H), 8.55 8.15-8.12 2H), 8.03-7.98 1H), 7.75-7.72 1H), 7.57-7.49 3H). LC-MS m/ec 288.11 HPLC-Method D, Rt 1.55 min.

Example 422 (LE-11,2,4]triazol-3-yl)-[2-(2trifluoronmethyl-phenyl)-quinolin-4-yl] -amine (IX-177) t Pale yellow solid (46% yield). 1H MR (500 MEz, d 4

-DMSO)

8 13.70 1H), 9.98 1K), 8.70 1H), 8.49 (s, 333 o 1H), 8.30 1H), 7.94-7.88 2H), 7.80-7.68 3H), 07.64-7.56 2H). LC-MS m/e= 356.18 HPLC- Method D, Rt 1.68 min.

S. 5 Example 4 2 3 (l-H-Indaol-3-yl) 5-methyl-6-morpholin-4yl-2- (2-trlfluoromethy phylhenyl) -pyrimidin-4-yl] -amine

(II-

2 51)i Colorless film; 2 yield; IH-NMR (500 MHz,

CD

3 OD) 8 7.84 2H), 7.71 3H), 7.41 2H), 7.14 1H), 3.74 4H), 3.69 4H), 1.24 3H) ppm; HPLC-Method A Rt 3.26 min; MS (FIA) 455.1

\O

o BIOLOGICAL TESTING The activity of the compounds as prbtein 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 MgCl 2 25 mM NaCl, NO 300 uM NADH, 1 mM DTT and 1.5% DMSO. Final substrate o concentrations in the assay were 20 pM ATP (Sigma Chemicals, St Louis, MO) and 300 pM peptide G (HSSPHQS (P 3

H

2 EDEEE, American Peptide, Sunnyvale, CA).

Reactions were carried out at 30 °C and 20 nM GSK-3p.

C Final concentrations of the -components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 pM N MADH, 30 pg/ml pyruvate kinase and 10 pg/ml lactate Va Ci dehydrogenase.

An assay stock buffer solution was prepared r C containing all of the reagents listed above with the o exception of ATP and the test compound of interest. The C- assay stock buffer solution (175 pl) was incubated in a 96 well plate with 5 pi of the test compound of interest at final concentrations spanning 0.002 pM to 30 pM 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 pi of ATP (final concentration 20 1M).

Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 min at oC. The Kivalues were determined from the rate'data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 pM for GSK-3: compounds II-l, II- 105, 11-33, 11-34, 1-36, 11-39, 11-38, 11-39, 11-40, II- 41, 11-42, 1I-46, 11-57, 11-59, 11-60, 11-61, 11-62, II- 63, 1-64, 11-66, 11-67, 11-69, II-70; 11-53, 11-71, II- 99, 11-73, 11-74, 11-75, 11-76, 11-77, 11-7, 11-8, 11-9, 11-10, 11-24, 11-19, 11-78, 11-54, II-79, 11-80, 11-81, 11-82, 11-83, II-84, 11-56, 11-86, 11-20, II-25, 11-26, 11-85, II-21, 11-27, 11-28, 11-87, 11-88, 11-29, Ii-11, 11-12, 11-30, 11-31, II-13, 11-14, II-15, 11-16, 11-17,

VO

S11-18, II-79, II-23, 11-2, II-90, 1-91, II-92, 11-93, 11-3, 11-4, 11-5, II-6, 11-94, 11-95, 11-96, 11-107, II- 108, II-109, 11-110, II-124, 11-125, Ii-ill, 11-112, II- 113, II-114, 11-115, I-116, 11-117, 11-118, 11-119, II- 120, 11-121, 11-208, 111-8, 111-7, 111-9, 111-37, 111-38, 111-39, 111-40,.111-42, 111-45, III-46, 111-47, 111-48, 111-49, 111-51, 111-52, 111-53, III-54, 111-55, III-56, 111-57, 111-58, 111-59, 111-60, III-61, 111-62, 111-63, 111-30, 111-65, 111-66, II-67, 111-70, 111-73, 111-31, O 10 III-75, III-76, III-77, 111-33, III-34, I-106, III-108, IN 111-109, III-111, III-351 111-116, 111-117, 111-118, III- 119, 111-120, 111-121, 111-127, 111-128, 111-141, 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.OpM for GSK-3: compounds II- 103, II-104, 11-35, 11-44, 11-45, 11-49, 11-50, 11-97, 11-101, II-22, 11-32, 111-41, 111-43, 111-44, 111-28, 111-50, 111-29, 111-64, 111-71, III-74; 111-78, 111-82, III-88, 111-90, 111-102, 111-105, 111-107, 11-110, III- 112, 111-114, 111-115, 111-122, 111-124, 111-124, fIV-1, III-1, 111-138, 111-140, 111-142, 111-129, 111-132, III- 134, III-135, 11I-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 WM for GSK-3: compounds 11-43, 11-65, 11-48, 11-47, 11-51, 11-68, 11-52, 11-72, II-100, 11-98, Il-89, 111-68, 111-81, 111-83, IIl-91, 111-94, 111-95, 111-96, III-97, 111-98, 111-99, III-100, III-101, 111-103, III-123, 111-137, 111-139, 111-143, 111-145, 111-146, V-4, V-8, IX-156, and IX-176.

ND BIOLOGICAL TESTING EXAMPLE 2 0 KI DETERMINATION FOR THE INHIBITION OF AURORA-2 Ci Compounds were screened in the following manner Sffor their ability to inhibit Aurora-2 using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7, (C 2249).

To an assay stock buffer solution containing C 0.1M HEPES 7.5, 10 mM MgCl 2 1 mM DTT, 25 mM NaC1, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate o 10 kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and i 800 .pM peptide (LRRASLG, American Peptide, Sunnyvale, CA) Swas 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. The reaction was initiated by the addition of 10 4L of Aurora-2.stock solution to give a final concentration of nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over a 5 minute read time at.30 OC using a BioRad Ultramark plate reader (Hercules, CA). The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 pM for Aurora-2: compounds 11-33, II-34, 11-36, 11-37, .11-40, 11-41, 1-55, III-7, III-9, III-37, III-38, III-39, III-40, III-41, III-42, III-44, III-46, III-47, III-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, 11I-30, III-65, III-66, III-67, 1-31, III-76, III-77, III-78, 111-80, III-32, III-33, III-34, III-106, III-108, III-109, III-110, III- 111, III-112, 111-114, III-35, III-115, III-116, III-117, III-118, III-119, III-120, III-121, IV-7, IV-30, IV-32, and IV-34.

IO

O The following compounds were shown to have Ki C 1values between 0.1 and 1.0 pM for Aurora-2: compounds II- 1, 11-105, II-35, 11-38, 11-39, 11-42, II-64, 11-70, II- S53, 11-99, 11-77, 11-79, 11-86, 11-20, 11-93, 11-94, III- 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, IV-1, IV-3, IV-4, IV-6, IV-29, IV-33, and V-4.

kO The following compounds were shown to have Ki values between 1.0 and 20 JM for Aurora-2: compounds II- 103, II-104, II-57, 11-59, 1-61, 11-63, 11-67, II-69, IN 11-75, 11-76, II-10, 11-19, II-78,11-54, II-80, 11-82, S11-21, 11-90, 11-91, 11-96, 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 (199D) Protein Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgCl 2 1 mM DTT, 25 mM NaC1, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and 100 pM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 pM.

The resulting mixture was incubated at 30 OC for 10 min.

The reaction was initiated by the addition ofpL 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 IO Ultramark plate reader (Hercules, CA). The Ki values were o determined from the rate data as a function of inhibitor c concentration.

BIOLOGICAL TESTING EXAMPLE 4 ERK INHIBITION ASSAY Compounds were assayed for the inhibition of.

SERK2 by a spectrophotometric coupled-enzyme assay (Fox et I al (1998) Protein Sci 7, 2249). In this assay, a fixed concentration of activated ERK2 (10 nM) was incubated 0 with various concentrations of the compound in DMSO f for 10 min. at 30 0 C in 0.1 M -EPES buffer, pH Scontaining 10 mM MgC1 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 pM ATP. The rate of decrease of absorbance at 340 nM was monitored. The ICs was evaluated from the rate data as a function of inhibitor concentration.

The following compounds were shown to have a K value of <lpM for ERK-2: III-109, III-1ll, III-115, III- 117, III-118, 1-120, and IV-4.

The following compounds were shown to have a Ki value of between IpM and 12pM for ERK-2: III-63, 111-40, and III-108.

BIOLOGICAL TESTING EXAMPLE AT INHIBITION ASSAY Compounds were screened for their ability to inhibit ART using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mM MgC12, 25 mM NaC1 I mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 170 pM ATP (Sigma 2 Chemicals) and 200 pM peptide (RPRAATF, American Peptide, C Sunnyvale, CA). Assays were carried out at 30 'C and nM AKT. Final concentrations of the components of the Scoupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 VM NADH, 30 pg/ML pyruvate kinase and 10 Ug/ml lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of the reagents listed above, with the C( exception of AKT, DTT, and the test compound of interest.

o 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 Scontaining the test'compound (final compound C1 concentration 30 The plate was preincubated for about 10 minutes at 30'C and the reaction initiated by addition of 10 p1 of enzyme (final concentration 45 nM) and 1 mM DTT. Rates of reaction were obtained using a BioRad Ultramark plate reader (Hercules, CA) over a minute read time at 30"C. Compounds showing greater than inhibition versus standard wells containing the assay mixture and DMSO without test compound were titrated to determine ICso values.

BIOLOGICAL TESTING EXAMPLE 6 SRC INHIBITION ASSAY The compounds were evaluated as inhibitors of human Src kinade using either a radioactivity-based assay or spectrophotometric assay.

Src Inhibition Assay A: Radioactivity-based Assay The compounds were assayed as inhibitors.of full length recombinant human Src kinase (from Upstate Biotechnology, cat. no. 14-117) expressed and purified from baculo viral cells. Src kinase activity was monitored by following the incorporation of "P from ATP into the tyrosine of a random poly Glu-Tyr polymer substrate of composition, Glu:Tyr a 4:1 (Sigma, cat. no.

IND P-0275). The following were the final concentrations of O the assay components: 0.05 M HEPES, pH 7.6, 10 TM MgCI 2 2 mM DTT, 0.25 mg/ml BSA, 10 pM ATP (1-2 UCi "P-ATP per Sreaction), 5 mg/ml poly Glu-Tyr, and 1-2 units of recombinant human Src kinase. In a typical assay, all the reaction components with the exception of ATP were pre-mixed and aliquoted into assay plate wells.

Inhibitors dissolved in DMSO were added to the wells to D give a final DMSO concentration of The assay plate was incubated at 30 *C for 10 min before initiating the reaction with 33 "P-ATP. After 20 min of reaction, the o reactions were quenched with 150 1l of trichloroacetic acid (TCA) containing 20 mM Na 3

PO

4 The quenched samples were then transferred to a 96-well filter plate (Whatman, UNI-Filter GF/F Glass Fiber Filter; cat no. 7700-3310) installed on a filter plate vacuum manifold. Filter plates were washed four times with 10% TCA containing 20 mM Na 3

PO

4 and then 4 times with methanol. 200l 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 K 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 Scl 7, 2249). In this assay one molecule of NADH is oxidised to NAD for every molecule of ADP produced in the kinase reaction. The

VO

D disappearance of NADH can be conveniently followed at 340 nm.

The following were the final concentrations of t the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgC12, 5 2 mM DTT, 0.25 mg/ml poly Glu-Tyr, and 25 nM of Cl recombinant human Src kinase. Final concentrations of the components of the coupled enzyme system were 2.5 mM en phosphoenolpyruvate, 200 pM NADH, 30 pg/ml pyruvate kinase and 10 pg/ml lactate dehydrogenase.

o 10 In a typical assay, all the reaction components C with the exception of ATP were pre-mixed-and aliquoted O 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 for the compound.

The following compounds were shown to have a K 4 value of <100nM on SRC: 111-31, III-32, 11-33, III-34, III-47, III-65, III-66, III-37, III-38, III-39, III-42, III-44, 111-48, III-49, III-70, III-78, III-76, and IV- 32.

The following compounds.were shown to have a Ki value of between 100nM and 1pM for SRC: III-63, III-71, III-73, III-72, III-74, III-80, III-50, The following compounds were shown to.have a K 1 value of between 1pM and 6pM for SRC: III-79, IV-1, and IV-31.

While we have hereinbefore presented a number of embodiments of this invention, it is apparent that our basic construction can be altered to provide other 00 342 CI embodiments which utilize the compounds and methods of this invention. Therefore, it will be appreciated that 00 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.

The term "comprise"- and variants of the term such as S"comprises" or "comprising" are used herein to denote the IN inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, unless in the context or usage an exclusive 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 (21)

1. A compound of formula IV: rNH HN N C, Rx c- or a pharmaceutically acceptable derivative or prodrug as hereinbefore defined, 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 independently 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 Rx 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 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 344 00 atoms to form a fused, 5-8 mnembered, unsaturated or partially unsaturated, ring containing 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein said fused ring is optionally substituted by up 00 to three groups independently selected from halo, oxo, -CN, -NO 2 -R 7 or R 3is selected from -halo, -OR, -CO 2 R, -COCOR, -COCH- 2 COR, -NO 2 -CN, -S(O) 2 R, -SR, -N(R 4 2 -CON(R 4 2 -SO 2 N(R 4 2 -N(R 4 COR, IND -N(R 4 C0 2 (optionally substituted C 1 -6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 -C=N-OR, -N(R 4 CON(R 4 2 -N(R 4 SO 2 N(R 4 2 -N(R 4 SO 2 R, or each R is independently selected from hydrogen or an optionally substituted group selected from C1- 6 aliphatic, C6-jo aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R -COR, -CO 2 (optionally substituted CI- aliphatic) -CON (R 7 2 or -S0 2 R 7 or two R4on 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 4 2 -SO 2 N(R 4 2 -N(R 4 COR, -N(R 4 C0 2 (optionally substituted C1- aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 4 CON(R 4 2 -N(R 4 SO 2 N(R 4 2 -N(R')SO 2 R, or V is -SO 2 -N(R 6 S0 2 -SO 2 N(R 6 -N(R 6 -C0 2 -N(R 6 CO_, -N(R 6 )C -N(R 6 CON(R 6 -N(R 6 S0 2 N (R 6 -N(R 6 )N(R 6 -C(O)N(R 6 -OC(O)N(R 6 -C(R 6 2 -C(R 6 2 S-, -C(R 6 2 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 -C(R 6 =NN(R 6 345 00 -C(R 6 -C(R 6 2 N(R)N(R 6 -C(R) 2 N(R 6 )SO 2 N(R 6 or 0 -C(R 6 2 N(R 6 )CON(R 6 W is -C(R 6 20 -C(R 6 2 -C(R 6 2 SO-, -C(R 6 2 S0 2 c- -C(R 6 2 S0 2 N(R 6 -C(R 6 2 N(R 6 -CO 2 00 S-C (R 6 -C (R 6 )OC(O)N(R) -C(R 6 2 N(R 6 )CO-, -C(R 6 2 N(R) C (0) O -C(R 6 )=NN(R 6 -C(R 6 -C (R 6 2 N(R 6 )N(R 6 -C 2 N (R 6 SO 2 N(R 6 C -C(R 6 2 N(R 6 )CON(R 6 or -CON(R 6 each R 6 is independently selected from hydrogen or an IND 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; and each R 7 is independently selected from hydrogen or an optionally substituted C1- 6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl ring or heteroaryl; provided that when Rx is H or C 2 Hs, and R Y is methyl, then Ring D is not pyrazol-l-yl optionally substituted with CH 3 C 2 Hs, C 3 H 7 or C 6 H 13 and when R 2 R 2 and Rx are H, and R Y is CF3, then Ring D is not 3-pyridinyl.

2. The compound according to claim 1, wherein said compound has one or more 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, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- 346 00 dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or 0 naphthyl ring; R x is hydrogen or C1- 4 aliphatic and R y is T- R or R x and R Y are taken together with their intervening 00 atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring Sheteroatoms; and R 2 is hydrogen or methyl and R 2 is T-W-R 6 or R, wherein W is -C(R 6 2 -C(R 6 )N(R 6 -C02-, N -C (R 6 OC -C(R 6 2 N(R 6 -C(R) 2 N(R 6 C or -CON(R 6 and R is an optionally substituted group selected from C 1 -6 aliphatic or phenyl, 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.

3. The compound according to claim 2, wherein: 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; Rx is hydrogen or C1- 4 aliphatic and R y is T- R 3 or Rx and R Y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring heteroatoms; and R 2 is hydrogen or methyl and R 2 is T-W-R 6 or R, wherein W is -C(R 6 2 -C(R 6 2 N(R 6 -C0 2 -C(R 6 )OC 0 -C(R 6 2 N R 6 -C(R 6 2 N(R 6 C or -CON(R 6 and R is an optionally substituted group selected from Ci-6 aliphatic or phenyl, or R 2 and R 2 are 347 00 taken together with their intervening atoms to form a 0 substituted or unsubstituted benzo, pyrido, pyrimido, or (N partially unsaturated 6-membered carbocyclo ring. 00

4. The compound according to claim 2, wherein said compound has one or more features selected from the group Sconsisting of: Ring D is an optionally substituted ring Sselected from phenyl, pyridinyl, piperidinyl, Spiperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4- Ci tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3-dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl; Rx is hydrogen or methyl and R y is -R, N(R 4 2 or -OR, or Rx and R Y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, wherein said ring is optionally substituted with -R, halo, oxo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -S(O)R, -SO 2 R, -SR, -N(R 4 2 -CON(R 4 2 -SO 2 N(R 4 2 -OC(=O)R, -N(R 4 )COR, -N(R 4 )C0 2 (optionally substituted C 1 -6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 4 )CON(R 4 2 -N(R 4 SO 2 N(R 4 2, -N(R 4 )SO 2 R, or -OC(=O)N(R 4 2; and each R 5 is independently selected from halo, oxo, CN, NO 2 -N(R 4 2 -C0 2 R, -CONH(R 4 -N(R 4 )COR, -SO 2 N(R 4 2 -N(R 4 )SO 2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6- 10 aryl, or C 1 -6 aliphatic. The compound according to claim 4, wherein: 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, 348 0 00 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, 0 isoquinolinyl, quinolinyl, or naphthyl; R x is hydrogen or methyl and R y is -R, n N(R 4 2 or -OR, or R x and R y are taken together with their 00 intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, n wherein said ring is optionally substituted with -R, halo, oxo, -OR, -C02R, -COCOR, -NO 2 -CN, -S(O)R, -S0 2 R, -SR, -N(R 4 2 -CON(R 4 2 -S0 2 N(R 4 2 -OC(=O)R, IN -N(R 4 )COR, -N(R 4 )C02 (optionally substituted C1-6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 4 CON (R 4 2, -N(R 4 SO 2 N(R 4 2 -N(R 4 )SO 2 R, or -OC(=O)N(R 4 2 and each R 5 is independently selected from halo, oxo, CN, NO 2 -N(R 4 2 -CO 2 R, -CONH(R 4 -N(R 4 )COR, -SO 2 N(R 4 2 -N(R 4 )SO 2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cg- 10 aryl, or Ci-6 aliphatic.

6. The compound according to claim 4, wherein said compound has one or more features selected from the group consisting of: Rx and R Y are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, optionally substituted with halo, CN, oxo, C 1 -6 alkyl, C 1 -6 alkoxy, (Ci-6 alkyl)carbonyl, (Ci-6 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 4 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C 6 10 aryl, and C 1 -6 aliphatic; and R 2 is hydrogen and R 2 is T-W-R 6 or R, wherein W is -C(R 6 2 -C(R 6 2 N(R 6 -C0 2 349 00 -C(R 6 -C(R 6 2 N(R 6 or -CON(R 6 and R is an 0 optionally substituted group selected from C 1 -s aliphatic or phenyl, or R 2 and R 2 are taken together with their 'n intervening atoms to form a substituted or unsubstituted 00 benzo, pyrido, or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, oxo, -N(R 4 2 -Ci-4 alkyl, -C1-4 haloalkyl, -NO 2 -O(C 1 -4 alkyl), -C0 2 (C4 alkyl) -CN, -S02 (C-4 alkyl), -SO 2 NH 2 -OC(O)NH 2 -NH 2 S0 2 (C1- 4 alkyl), -NHC(O) (C1- 4 alkyl), -C(O)NH 2 or I -CO(C 1 -4 alkyl), wherein the (C1- 4 alkyl) is a straight, Cq branched, or cyclic alkyl group.

7. The compound according to claim 6, wherein: Rx and RY are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, optionally substituted with halo, CN, oxo, Ci-6 alkyl, C 1 -6 alkoxy, (Ci- 6 alkyl)carbonyl, (CI- 6 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 4 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-10 aryl, and C1-6 aliphatic; and R 2 is hydrogen and R 2 is T-W-R 6 or R, wherein W is -C(R 6 -C(R 6 2 N(R 6 -CO 2 -C(R 6 )OC(0) -C(R 6 2 N(R 6 or -CON(R 6 and R is an optionally substituted group selected from C 1 -6 aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, oxo, -N(R 4 2 -CI- 4 alkyl, -C1- 4 haloalkyl, -NO 2 -0(C 1 -4 alkyl), -C02 (C- 4 alkyl) -CN, -SO (C 1 -4 alkyl), -SO 2 NH 2 -OC(O)NH 2 350 -NH 2 SO2 (C- 4 alkyl), -NHC (C1- 4 alkyl), -C(O)NH 2 or -CO(CI-4 alkyl), wherein the (C1- 4 alkyl) is a straight, branched, or cyclic alkyl group.

8. The compound according to claim 7, wherein said compound is selected from the following compounds: O ID IN 0q CH 3 HN NH N Nl~i CH 3 HN H MeO N' MeO C OMe IV-2 CH 3 CH 3 HN N AcNH N IV-3 CH 3 H N H HN N IV-1 0 2 N IV-4 IV-5 IV-6 CO 2 Me H HN SN N No N N IV-7 IV-8 IV-9 351 H 3 C"N- 'v-il HN H3C4 CF 3 IV- 14 CH 3 HN N-ol IV-17 IV- 12 HN H 3 C' IV-13 CH H N Nt H 3 C, Ir IV- 16 OH 3 H N N~d IV-l18 CH 3 NN H 3 C" loCF 3 IV- 19 IV-20IV2 IV-21 352 OH 3 HN4P H H N MeC N N IV-22 OH 3 H 3H N N H 3 CH HN MeO jN IV-28 OH 3 HN f-JtPH H3C(N I N H 3 C IV-23 OH 3 H N Nl C N- IV-26 IV-24 IV-27 OH 3 H N ffJ H H N N -N IV-29 OH 3 H N N~t N CH 3 H N H N N NS IV-31 IV-32 IV-33 H N.N NH NH HNN VNH I I3 IV-35 IV-34 IV-36. 353 00 9. A composition comprising a compound according to any one of claims 1-8 and a pharmaceutically acceptable carrier. 00 The composition according to claim 9 further comprising a second therapeutic agent. \O S11. A method of inhibiting GSK-3 or Aurora activity in a patient in need thereof, comprising the step of \O Iadministering to said patient a therapeutically effective C amount of the 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 the compound according to any one of claims 1-8.

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 in need of such a treatment a therapeutically effective amount of the compound according to any one of claims 1-8 or the composition according to claim 9 or claim The method according to claim 14 further comprising the step of administering to said patient a second therapeutic agent.

16. The method according to claim 14, wherein said disease is diabetes. 354 00

17. The method according to claim 14, wherein said disease is Alzheimer's disease. 00

18. The method according to claim 14, wherein said disease is schizophrenia. \O

19. A method of enhancing glycogen synthesis in a patient in need thereof, which method comprises the step \O Iof administering to said patient a therapeutically C effective amount of the 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 the compound according to any one of claims 1-8 or the composition according to claim 9 or claim

21. A method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of the compound according to any one of claims 1-8 or the composition according to claim 9 or claim

22. A method of inhibiting the phosphorylation of 1-catenin in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of the compound according to any one of claims 1-8 or the composition according to claim 9 or claim 355 00 C 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 00 in need of such a treatment a therapeutically effective amount of the compound according to any one of claims 1-8 M or the composition according to claim 9 or claim IND

24. The method according to claim 23, further Icomprising the step of administering to said patient a p second therapeutic agent. The method according to claim 23 wherein said disease is cancer.

26. 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 or the composition according to claim 9 or claim

27. A method of treating schizophrenia in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to any one of claims 1-8 or the composition according to claim 9 or claim

28. 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 356 00 29. 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 c, compound according to any one of claims 1-8 or the 00 composition according to claim 9 or claim

30. A compound of formula IV as defined in claim 1 NO and substantially as described in at least one of the Saccompanying examples. (O C- 31. A pharmaceutical composition comprising the compound of claim 30 and a pharmaceutically acceptable carrier. 32 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 30 or the composition according to claim 31. Dated this 18 th day of July 2008 Vertex Pharmaceuticals Incorporated By their Patent Attorneys CULLEN CO