AU2006201230B8 - Triazole 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 Qld 4000 Australia Triazole 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: -1-

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0 Ci protein kinase inhibitors, compositions containing such compounds and methods of use. More particularly, this invention relates to compounds that are inhibitors of GSK-3 and Aurora-2 protein kinases. The invention also relates to methods of treating diseases associated with these protein kinases, such as diabetes, cancer and Alzheimer's disease.

BACKGROUD 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 enzymesthat has been the subject of .extensive study is the protein kinases.

Protein kinases mediate intracellular signal tranduction. They do this by effecting a phsphoryl The present invention ie in the field of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositions containing such compounds and methods of use. More particularly, this invention relates to compounds that are inhibitors of GSK-3 and Aurora-2 protein kinases. The invention also these protein kinases, such as diabetes, cancer and greatly aided in recent years by better understanding of transduction. They do this by effecting a phosphoryl IN extracellular and other stimuli cause a variety of o cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress C signals osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H202),-cytokines (e.g.

interleukin-1 (IL-1) and tumor necrosis factor a (TNFo and growth factors granulocyte macrophage- C colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF). An extracellular stimulus may effect one 4c 10 or more cellular responses related to cell growth, Smigration, 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 -2-

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

SGlycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of a and B Ci 5 isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry Biology, 7, 793-803 (2000); Kim and 0 Kimmel,, Curr. Opinion Genetics Dev., 10, 508-514 (2000)].

GSK-3 has been implicated in various diseases including o diabetes, Alzheimer's disease, CNS disorders such as Va 10 manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; and-Haq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor A-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, S8455-9 (1996); Cross et al., Biochem. 303, 21-26 o (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J. 299, 123-128 (1994)].

However, in a diabetic patient where the insulin response is impaired, glycogen synthesis and glucose uptake fail Sto increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood Slevels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal Sinsulin-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 potentiallyuseful for treating diabetic patients suffering from an impaired response to insulin.

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

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

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

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o -diseases related to increase in neuronal cell death CI [Zhong et al., Nature, 395, 698-702 (1998); Takashima et t al., PNAS, 90, 7789-93 (1993); Pei et al., J.

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

C 5 As a result of the biological importance of GSK-3, there is current interest in therapeutically O effective GSK-3 inhbitors. Small molecules that inhibit C-i GSK-3 have recently been reported [WO 99/65897 (Chiron) 0 and WO 00/38675 (SmithKline Beecham)].

ID 10 For many of the aforementioned diseases o associated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating the same diseases. However, the various protein kinases often act through different biological pathways. For example, certain quinazoline derivatives have been reported recently as inhibitors of p38 kinase (WO 00/12497 to Scios). The compounds are reported to be useful for treating conditions characterized by enhanced p38-a activity and/or enhanced TGF-P activity. While p38 activity has been implicated in a wide variety of diseases, including diabetes, p38 kinase is not reported.

to be a constituent of an insulin signaling pathway that regulates glycogen synthesis or glucose uptake.

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

There is a continued need to find new therapeutic agents to treat human diseases. The protein kinases aurora-2 and GSK-3 are especially attractive targets for the discovery of new therapeutics due to their important role in cancer, diabetes, Alzheimer's disease and other diseases.

DESCRIPTION OF THE INVENTION It has now been found that compounds of this invention and pharmaceutical compositions thereof are effective as protein kinase inhibitors, particularly as inhibitors of aurora-2 and GSK-3. These compounds have the general formula I: v0 or a pharmaceutically acceptable thereof, wherein:

Z

1 to Z4 are as described below; Ring A is selected from the group RYa b a b derivative or-prodrug consisting of: N R dRy W c d RY-1 e f

NO<N

A

-6-

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N

ci 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 o independently selected from any substitutable non- Ci ortho carbon position on Ring C is independently substituted by -R s and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R e 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 -R4., provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D;

R

1 is selected from -halo,

-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, -7-

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oxo, or -R 8 said Ci-s aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R' and 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 o form a fused, unsaturated or partially unsaturated, 5-8 C membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable S- carbon on said fused ring formed by R X and R Y is Ssubstituted by oxo or T-R 3 and any substitutable Ci 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 beteroatoms.

selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R 2 and R' is substituted by halo, oxo, -CN, -NO 2

-R

7 or

-V-R

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

R

3 is selected from -halo, -OR, -CO2R, -COCOR, -COCH 2 COR, -NOa, -CN, -S(O) 2 R, -SR, -N -CON (R 2 -SO2N(R 7 2 R, -N COR, -N (R 7 C0 2 (optionally substituted C 1 6 aliphatic), -N(R)N(R4)2, -C=NN(R 4 -C=N-OR, -N(R 7

)CON(R

7 -N(R 0 2

N(R)

2

-N(R')SO

2 R, or -OC (O)N(R 2; each R is independently selected from hydrogen or an optionally substituted group selected from Ci-s.

aliphatic, Cs-lo aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; Va o each R 4 is independently selected from -R 7 -COR7, -C0 2

O(C-

6 c aliphatic), -CON(R 7 2 or -SOaR7, or two R4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; c 5 each R 5 is independently selected from halo, -OR, -CO2R, -COCOR, -NO 2 -CN,

-SO

2 R, '-SR, FO 2

-CON(R')

2

-SO

2

N(R')

2 -OC(r0)R, -N(R')COR, c CO2 (optionally substituted CI-6 aliphatic), o 2 -C=N-OR, -N(R')CON(R') 2 N 10 SO 2

N(R

2

SO

2 R, or 2 or R5 and 0 o 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(R

6

-CO

2 CO-, C

-N(R

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

-C(R

6 2

S-,

2 -C(R6) 2 so 2 2

SO

2 N(R6-, -C(R) 2 NN(R) C (RS) 2N C C(R6 )2N(RS)C(0)0-, -C(R6)-NNR6)-,

-C(R

6 2 N(R6')N(R or 2N CON (R 6 W is 2 2

-C(R)

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

-C(R)

2 so 2 -C(R6') 2 -C0 2 2N(R) CO-,

-C(R)

2 -C(R 6 2 2 N(R')SaN -C (R6) 2N(R)CON or each R6 is independently selected from hydrogen or an optionally substituted CI 4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each k' 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 -9-

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CD nitrogen to form a 5-8 membered heterocyclyl or C .heteroaryl ring; each R 8 is independently selected from an optionally substituted C1-4 aliphatic group, -OR 6

-SR

6

-COR

6

-SO

2

R

6

-N(R

6 2

-N(R

6 2 -CN, -N0 2

-CON(R)

2 or -CO2R 6 and O R 9 is selected from halo, -OR, -C0 2 R, -COCOR,

-NO

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

-CON(R

4 2 o -SO 2

N(R

4 2 -N(R')COR, -N(R)C0 2 (optionally 10 substituted Ci- 6 aliphatic)., -N(R4)N(R 4 2 -C=NN(R) -C=N-OR, -N (R CON(R 2, -N(R 4 S0 2

N(R

2

-N(R

4

)SO

2 R, or

C

N 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 .C-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", and "alkoxycarbonyl", used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety shall include both

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0l straight and branched chains containing two to twelve C carbon atoms. The term "cycloalkyl" used alone or as t part of a larger moiety shall include cyclic C 3

-C,

Shydrocarbons.which are completely saturated or which (C 5 contain one or more units of unsaturation, but which are not aromatic.

o The terms "haloalkyl", "haloalkenyl" and Ci "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case o may be, substituted with one or more halogen atoms. The .D 10 term "halogen" means F, Cl, Br, or I.

O 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 -11- IND five to fourteen members, such as phenyl, benz'yl, phenethyl, 1-naphthyl, 2-naplithyl, 1-anthracy. and 2anthracyl. The term 'aryl, also refers to rings that are optionally substituted. The term 'OarylO may be used interchangeably with the term 'aryl ring'f. "AMyl also includes fused polycyclic aromatic-ring systems in which an aromatic ring is fused to one ot more rings. Examples en include 1-naphthyl 2-naphthyl, 1-anthracyl and 2- Also included within the scope of the term 'Iaryl"f, as it is used herein, is a group in which an o aromatic ring is fused to one -or more non- aromatic, -rings, Ci such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.

The term Oheterocycl1", uoheterocyclyla, or 'heterocyclicf ais 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 fo-ur, are each replaced by a heteroatom such as N, 0, or S. Examples of heterocyclic rings include 3-111benzimidazol-2-one, (1-subs -tituted) -2-oxo-,benzimidazol-3yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2tetrahydropyranyl, 3- tetrahydropyranyl, 4-.

tetrahydropyranyl, -dioxalanyl, -dithiolanyl, -dioxanyl, 2-tetrahydrothiophenyl, 3tetrahydrothiophenyl, 2 -morpholinyl, 3 -morpholinyl, 4morpholinyl, 2 -thiomorpholinyl, 3 -thiomorpholinyl, 4- *thiotnorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3pyrrolidinyl, 1-piperazinyl,. 2-piperazinyl, 17 piperidinyl, 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 -12- "lheterocyclylf or u'heterocyclica, 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 0 heteroatom- containing ring. The term Oheterocycle"f, (N "heterocyclyl", or "heterocyclic' whether saturated or 0 partially unsaturated, also refers to rings that are IND 10 optionallyr substituted.

oThe term "heteroaryx', used alone or as part of a larger moiety as in "heteroaralkyl" or v'heteroaryllkoxrO refers to heteroaromatic ring groups having five to fourteen members. Examples of heteroaryl rings include 2-f uranyl, 3-furanyl, *N-imidazolyl, 2imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2pyrrolyl, 3-pyrrolyl, 2-pyridyl, 34pyridyl, 4-pyridyl, 2pyrimidyl, 4-pyrirxhidyl, 5-pyrimidyl, 3-pyridazinyl, 2-.

thiazolyl, 4'-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2triazolyl, 5-triazolyl, 2-tbhienyl,. 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl,.isoguinolinyl, indolyl, isoindolyl, acridinyl, or benzoisoxazolyl. Also included within the scope 'of the term "heteroaryl"', *as it is used herein, is'a group in which a. heteroatomic ring is fused to one or more aromatic or nonaromatic rings where the radical or point of attachment is on the heteroaromatic *ring. -Examples include tet-rahydroquinolinyl, tetrahydroisoquinoiinyi, and pyrido (3,4 -d]pyriraidinyl.

The -term "heteroaryl', also refers to rings' that are optionally substituted. The term 'Ibeteroaryl" may be IDused interchangeably with the term "heteroaryl ring". or o the term "heteroaromatic".

An aryl (including aralkyl, aralkoxy, S- aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Examples of o suitable substituents on the unsaturated carbon atom of Mn an aryl, heteroaryl, aralkyl, or heteroaralkyl group include a halogen, -R 0 -OR, -SRO, 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acylxy), phenyl substituted Ph, substituted -0(Ph),

-CH

2 substituted.-cw 2

-CH

2

CH

2 substituted

-CH

2

CH

2 (Ph) -NO 2 -CN, 2

-NR

0 C(o)R 0 -NROC N(R) 2 -NRCoC 2 -NRONROC R, -NR 0 NROC N -NR 0

NR

0

CO

2

R

0 -c(o)c(o)Ro, -C(0)H 2 c(o)Ro, -C0 2 Ro, -C(O)RO, 2 -OC(o)N(R) 2

-S(O)

2

R

0

-SO

2

N(R

0 2 -S(O)RO, -NR 0

SO

2

N(R)

2 -NRoSO 2 R, 2 2 -(CH2)yNHC(o)R 0

(C

2 yNHc.(o) CH(V-Ro) (Ra) wherein R" is. hydrogen, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl substituted Ph, substituted -O(Ph),

-CH

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

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

Examples of suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic -14.- Va ring include those listed above for the unsaturated carbon of an aryl 'or heteroaryl group and the following: t =NNHR, =NN(R) 2 NNHC(R =NNHC)R, NCO 2 (alkyl),

=NNHSO

2 (alkyl), or =NR where each R' is independently g 5 selected from hydrogen, an unsubstituted aliphatic group or a subbtituted aliphatic group. Examples of 0 substituents on the aliphatic group include amino, (N alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, o alkylaminocarbonyl, dialkylaminocarbonyl, IN 10 alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, o nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

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

-CO

2 R -C(O)CH2C()a, -SO2R+, -SO 2

N(R)

2 2 2 ,1 and -NRSO 2 wherein R' is hydrogen, an aliphatic group, a substituted aliphatic group, phenyl substituted Ph, substituted -0O(Ph), C%2(Ph), substituted

CH

2 (Ph), or an unsubstituted heteroaryl or heterocyclic ring.

Examples of substituents on the aliphatic group or-the pheny2 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 -C 2 -C(0)NH-, or a chain of atoms, such as an alkylidene chain. The molecular mass of a linker is typically in the range of about 14 to 200, preferably in .the range of 14 to 96 with N a length of up to about six atoms. Examples of linkers include a saturated or unsaturated Ci-s alkylidene chain Swhich is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by -CONH-, -CONHMN-, -CO 2

-NHCO

2 -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -S0 2

-SO

2 NH-, or -NHS0 2 C-M .The term "alkylidene chain" refers to an optionally substituted, straight or branched carbon chain that may be fully saturated or have one or more units of. unsaturation. The optional substituents are as described

C

above for an aliphatic group.

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

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms L of the structure; the R and S configurations 'for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 2C- or C-enriched carbon are within the scope of this invention.

-16-

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0 Compounds of formula I or salts thereof may be C( formulated into compositions. In a preferred embodiment, t the composition is a pharmaceutical composition. In one Sembodiment, 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 O a patient. In another embodiment,. compounds of this invention and pharmaceutical compositions thereof, which Scomprise an amount of the protein kinase inhibitor V0 ro-. bff^tW -Tht -o prevent" a GSK-3Wiimedited conditfon 0 o and a pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient.

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

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

method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the -17-

ND

o phosphorylation of 0-catenin, which is useful for 0q treating schizophrenia.

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

o Another aspect of this invention relates to a C method of inhibiting Aurora-2 activity in a patient, 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 a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. The term "Aurora-2-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which Aurora is known to play a role. The term "Aurora-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with an Aurora-2 inhibitor.

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

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

Another aspect of this invention relates to a method of treating or preventing a CDK-2-mediated -18-

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Sdiseases 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.

cS 5 The term "CDK-2-mediated condition" or "disease", as used herein, means any disease or other 0 deleterious condition in which CDK-2 is known to play a ^C role. The term "CDK-2-mediated condition" or "disease" o also means those diseases or conditions that are IO 10 alleviated by treatment with a CDK-2 inhibitor. Such o conditions include, without limitation, cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis. See Fischer, P.M.

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

Another aspect of the invention relates to.

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

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

The term "ERK-mediated condition", as used herein means any disease state or other deleterious -19condition in which ERK is known to play a role. The term 0 "ERK-2-mediated condition" or "disease" also means those cdiseases or conditions that are alleviated by treatment Swith a ERK-2 inhibitor. Such conditions include, without 5. limitation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, O Alzheimer's disease, cystic fibrosis, viral disease, c, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, S0 10 inflammation, neurological disorders and hormone-related diseases. The term "cancer" includes, but is not limited C 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), i lip, tongue, mouth, pharynx, small intestine, colonrectum, large intestine, rectum, brain and central nervous system, and leukemia. ERK-2 protein kinase and its implication in various diseases has been described [Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478; Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al.

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

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

Another aspect of the invention relates to C 5 inhibiting ERK-2 activity in a biological sample or a patient, which method comprises administering.to the patient a compound of formula I or a composition CA comprising said compound.

Another aspect of this invention relates to a

CA

IN 10 method of treating or preventing an AKT-mediated diseases Swith 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 t 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 B, with various diseases has been described [Khwaja, Nature, pp. 33-34, 1990; Zang, Q. et al, Oncogene, 19 2000; Kazuhiko, et al, The Journal of Neuroscience, 2000].

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

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

IN

o with a Src 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 "Src-mediated condition", as used herein means any disease state or other deleterious Scondition in which Src is known to play a role. The term q "Src-mediated condition" or "disease" also means those Sdiseases or conditions that are alleviated by treatment k0 10 with a Src inhibitor. Such conditions include, without limitation, hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and Paget's disease. Src protein kinase and its implication in various diseases has been described [Soriano, Cell, 69, 551 (1992); Soriano et.al., Cell, 64, 693 (1991); Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli, Drugs of the Future 2000, 25(7), 717, (2000); Talamonti, J. Clin. Invest., 91, 53 (1993); Lutz, Blochem. Blophys.

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 0_ (1993); Wiener, Clin. Cancer Res., 5, 2164 (1999); Staley, Cell Growth Diff., 269 (1997)].

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

The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and -22- Swhich does not destroy the pharmacological activity C thereof.

The term "patient" includes human and veterinary subjects.

C 5 The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts 0 thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or 1. extracts thereof; and blood, saliva, urine, feces, semen, ID 10 tears, or other body fluids or extracts thereof.

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

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

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

The compositions of the present invention may be administered orally, parenterally, by inhalation -23- D spray, topically, rectally, nasally, buccally, vaginally C or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial,

S

5 intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

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

Sterile injectable forms of the compositions of S110 this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to C 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 mono- _i or 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 pqlyoxyethylated 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 -24which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other Ct dosage forms may also be used for the purposes of.

formulation.

ci SThe pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. in o the. case of tablets for oral use, carriers commonly used oN 10 include lactose-and corn starch. Lubricating agents, o such as magnesium stearate, are also typically added.

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

Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable nonirritating ercipient 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 lover intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

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

Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical o administration of the compounds of this invention C-q include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, IND 10 polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical Scompositions 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, -26-

VO

fluorocarbons, and/or other conventional solubilizing or C dispersing.agents.

t -In 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 o diseases or disorders.

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

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

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

Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, -27-

VO

0* fumarate, glucoheptanoate, glycerophosphate, glycolate, Cq hemisulfate, heptanoate, hexanoate, hydrochloride, Shydrobromide, hydroiodide, 2-hydroxyethanesulfonate, Slactate, maleate, malonate, methanesulfonate, 2- C 5 naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, o phosphate, picrate, pivalate, propionate, salicylate, Cq. succinate, sulfate, tartrate, thiocyanate, tosylate and o undecanoate. Other acids, such as oxalic, while not in D 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*(C 1 -4 alkyl).

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

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

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

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

O

Sthe judgment of the treating physician and the severity -of the particular disease being treated. The amount of Sthe inhibitor will also depend upon the particular compound in the composition.

C( 5 Depending upon the particular protein kinasemediated condition to be treated or prevented, additional 0 therapeutic agents, which are normally administered to C treat or prevent that condition, may be administered Stogether with the inhibitors of this invention. For N 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, giitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonyl ureas.

Other examples of agents the inhibitors of this invention may also be combined with-include, withoutlimitation, chemotherapeutic agents or other antiproliferative agents such as adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives; antiinflammatory agents such as corticosteroids,

TNF

blockers, IL-I RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti- Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors., diuretics, nitrates, calcium channel blockers, and statins; agents.

-29- D for treating liver disease such as corticosteroids, C-q cholestyramine, interferons, and anti-viral agents; c agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth 5 factors; and agents for treating immunodeficiency disorders such.as .gamma globulin.

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

ND 10 Alternatively, those agents may be part of a single C) 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.

H N H HNA HN-N 1 2 Rx and R y (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 Rx/R y ring is optionally substituted.

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

Va 0 0 ci ci 0 en ci 0 ~ci Va 0 0 ci

NH

HN N

I-D

I-B

X-C

3 I-B.

Z-G

I-H 1-1 HNe

HWNZ

Nl VtZ2 1-4 I-L 1-14 IN I-0 -31-

I-

*H'

itk

I-H

H'1 ci 1-T I-uy I-v I -W I-s I-y :r-z I -Ak I B I- cc

I-DD

P referred bicyclic Ring A systems include I-A, 31-C, T-D, 1-E, 11F, 1-G,I-,l!13 ItIr and I-x, more preferably I-A, I-B, I-C, I-F, and and most preferably I-A, I-B, and I-E.

-32-

VO

o In the monocyclic Ring A system, preferred R x groups, when present, include hydrogen, alkyl- or C dialkylamino, acetamido, or a C 1 -4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

c-i 5 Preferred R Y groups, when present, include T-R 3 wherein T is a valence bond. or a methylene, and R 3 is 2 0 or -OR. Examples of preferred R Y include 2-pyridyl, 4- Spyridyl, piperidinyl, methyl, ethyl, cyclopropyl, o isopropyl, t-butyl,. alkyl- or dialkylamino, acetamido, IN 10 optionally substituted phenyl such as phenyl or haloo substituted phenyl, and methoxymethyl.

In the bicyclic Ring A system, the ring formed when R x and R Y are taken together may be substituted. or unsubstituted. Suitable substituents include halo, -OR, -COaR, -COCOR, -NO 2 -CN, -SO 2

R,

-SR, -N(R 4 2

-CON(R

4 2 -S0 2

N(R

4 2

-N(R

4

)COR,.

-N(R

4

)CO

2 (optionally substituted Ci-s.aliphatic), 2 -C=N-OR, -N(R 4

)CON(R

4 2 -N (R 4

)SO

2

N(R

4 2 -N(R')SOaR, or 2 wherein R and

R

4 are as defined above. Preferred RX/RY ring substituents include -halo, -OR, -COR, -CO2R,

-CON(R

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

R

2 and R 2 may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring, wherein said fused ring is optionally substituted. These are exemplified in the following formula I compounds having a pyrazole-containing bicyclic ring system: -33- 9>J HN

N

and Preferred substituents on the R 2

/R

2 fused ring include-one or more of the following: -halo, 2 3 alcyl,. haloalkyl,

-NO

2 O (C 1 alicyl) -0O3 o alkyl),-J -SO 2 (CI. alkyl)., -SO 2

N.H

2 -OC NR 2

NX

2

SO

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

When the pyrazole ring system is monocyclic, preferred R 2 groups include hydrogen, CI..4 aliphatic, alkoxycarbonyl, (tin) substituted phenyl., hydroxyalkyl, alkoxyalcyl, aminocarbonyl, mono- or dialkcylaminocarbonyl, aminoalkyl, alkylaminoalkyi, dialkylaminoalkyl, phenylaminocarbonyl., and (Nhieterocyclyl)carbonyl. Examples of such preferred R12 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO 2

R,

CO

2 CH3, CE 2 OH, aiHocii,, CH 2

CH

2 aIH 2 OH, Ci 2 cu 2 a! 2 oa3,

CH

2

CH

2

CR

2

OCR

2 Ph, CH 2

CR

2

CR

2

NR

1

CR

2 a1 2 c1{ 2 NHCoOC CONHCI (CH3) 2

CONECH

2

CH-CE

2

CONECH

2

CE

2 OCE,, CONHR 2 Ph, CON~cyclohexyl), CON(Et 2

CON(CN,)CH

2 Ph, CONH(n-CE 7 CON (It) CH 2

CH

2 CH,, CONflCr 2 ca(CH,) 2 CON(n-CH,) 2 CO (3maethoxymethyJlpyrrolidin-a..yjj, Cobm(3- tolyl), CONH(4tolyl), CONHCE,, Co (morpholin-l-yl), co (4-methylpiperazinl-ylj, 'CONHCH 2

CR

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

A

preferred 112 group is hydrogen.

-34-

VO

o An embodiment that is particularly useful for treating GSK3-mediated diseases relates to compounds of t formula II: SR

RA

2

H

V.0 s0 N 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 S substituted by and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a .fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, OXO, or -RO;

R

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

T-V-R

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

SR

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

R

Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 Smembered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable.

carbon on said fused ring formed by R x and R Y is o substituted by oxo or T-R 3 and any substitutable C nitrogen on said ring formed by RX and R Y is substituted by R'; D T is a valence bond or a C1-4 alkylidene chain; O R 2 and R 2 are independently selected from -T-W-R 6 or C

R

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

-V-R

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

R

3 is selected from -halo, -OR,

-CO

2

R,

-COCOR, -COCH 2 COR, -NO2, N,

-S(O)

2 R, -SR,

-N(R

4 2

-CON(R

7 2

-SO

2

N(R

7

-N(R

7 )COR,

CO

2 (optionally substituted CI-4 aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R

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

)CON(R

7 2 -N SO 2 N -(R 4 )SOR, or (R 2; each R is independently selected from hydrogen or an optionally substituted group selected from C 1 -6 aliphatic, Cs-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring.

atoms; each R' is independently selected from.-R 7

-COR

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

-CON(R

7 2 or -SO 2 R or two R 4 on the same nitrogen are taken -36-

L

o together to form a 5-8 mnembered heterocyclyl or, h eteroary). ring; each Rs is independently selected from halo, -OR,

-CO

2 R, -COCOR, -NO0 2 -cn, -SO 2

-SR,

Ci -N(ft) 2 -CON(Rl 2 -SON4(R 4 2 -OCC-o)a, -N(Rt)COR, -N.(R)CMa(optionally 'substituted C2_.

6 aliphatic), -N (R 4 2

-C=NN(R)

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

(R

4 )80 2 N(R)t 2 -N (R 4 )80 2 R, or -OC N(R) 2 or PO and an adja&cent substituent taken together with their IND 10 inter-vening atoms form said.'ring fused to Ring C; oV is -0 -S02-, -N(R 6 )S0 2 -S0 2

)T(R

6

-NCR

6 -C0 2

-N(R

6

-N(R

6

)CON(R

6 -N(R')so 2

-N(R

6

-C(O)N(R

6 2 2 8-,

-C(R)

2 so-, 2

SO

2 -C (R6) 2 S0 2 N _(R 6 2N RG 2

-C(R

6 2

N(R

6

-C(R

6

-C(R

6

-C(R.

6 2

N(R

6

-C(R

6 ),N(R6)SO2N(R 6 or C(RW) 2 N (R 6 )CON W is 2 -C(R)hSO-, 2 S0 2 2 sO 2

-C(R

6 2 N(R 6 -C0 2 -C CC -C(R 6 )oc(o)N(R 6

-C(R

6 2 N(R CO-, 2 -c(R6)=NNq(R 6

-C(R

6 2 N(R'Ybr(R 6 2 N(R')t0 2 -C or each R 6 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; 3 0 each Ra7 is independently selected from hydrogen or an optionally substituted C,1- 6 aliphatic group, or two R 7 on the-same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and -37- Va o each R' is. independently selected from an optionally substituted C1-4 aliphatic group, -oR 6 -sR6, -COR 6

-SO

2 R6 -b(R) 2

-N(R

6 )N(R6j 2 -C -N0 2

-CON(R

6 2 or -C0 2

R

6 When the RX and RY groups of formula II are taken together to form a fused ring, preferred RX/Ry rings o include a or 8-membered unsaturated or N partially unsaturated ring having 0-2 heteroatoms, o wherein said'RX/R ring is optionally substituted. This IN 10 provides a bicyclic ring system containing a pyrimidine 0 o ring. Examples of preferred pyrimidine ring systems 6f formula II are the mono- and bicyclic systems shown below.

Fe fNH HN N

HN'

O~t~b.

rI-A .11-B II-C HNA? HNI I HN\ II-D II-E II-P HN HN0 HN M H -M8e II-G II-N Il-I -38-

VO

c KHNC HN HN

O

HN HN N N II-J II-K

II-L

HN *nn H A (N NN (N 5 I- I-N 110-

HN'"

N

II-P

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

In the monocyclic pyrimidine ring system of formula II, preferred R X groups include hydrogen, alkylor dialkylamino, acetamido, or a C- 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' is -N(R 4 2 or -OR. When

R

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

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

-CO

2

R,

O -COCOR, -NO 2 -ZN, S(O)R, -SOR, -SR, -N(R 4 2

-CON(R

4 2 c- -SO 2

N(R)

2

-N(R

4 )COR, -N(R')C0 2 (optionally Ssubstituted C3 6 aliphatic), -N(Rt)N(R') 2

-C=NN(R')

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

)CON(R')

2 -N(R)SON( R 2

-N(R

4

)SO

2 R, or i o 2 wherein R and R4 are as defined above.

Preferred R"/RY ring substituents include -halo, -OR, -COR, -CO 2 R, -CON(R') 2 -CN, or 2 wherein R is an optionally substituted C1_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

HN

N

a NNH H H H Y -qN' ,and Preferred substituents on the R 2

/R

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

-C

1 -4 alkyl, 4 haloalkyl, -NO 2 -O(C-t alkyl), -COZ(C1-4alkyl), -CN, -so 2

(C-

4 alkyl), -S02NH 2

-OC(O)NH

2

-N

2

SO

2

(C

1 4 alkyl), -NHc(o) alkyl),

VO

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

When the pyrazole ring system of formula II is Cl 5 monocyclic, preferred R 2 groups include hydrogen, a substituted or unsubstituted group selected from aryl, heteroaryl, or a CI- aliphatic group. Examples of such preferred R 2 groups include methyl, t-butyl, -CH 2 0CH 3 0 cyclopropyl, furanyl, thienyl, and phenyl. A preferred ID 10 R 2 group is hydrogen.

More preferred ring systems of formula II are the following, which may be substituted as described above, wherein R 2 and R 2 are taken together with the pyrazole ring to form an indazole ring; and Rx and R Y are each methyl, or Rx and R7 are taken together with,the pyrimidine ring to form a quinazoline or tetrahydroquinazoline ring: NH NH NH HN N HN HN N II-Aa II-Ba II-Ea Particularly preferred are those compounds of formula II-Aa, II-Ba, or II-Ha wherein ring C is a phenyl ring and R 1 is halo, methyl, or trifluoromethyl.

Preferred formula II Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring c are taken together to form a fused ring, Ring C is contained in a bicyclic ring system. Preferred fused rings include a benzo or pyrido ring. Such rings -41- Va preferably 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 1 ortho substituent on Ring C. An ortho position on Ring C or Ring D is defined relative to the Sposition where Ring A is attached. Preferred RI groups include -halo, an optionally substituted C-,s aliphatic o group, phenyl, -COR, -OR, -CN, -OR 2, -so 2

NH

2 2 10 -CO 2

R

6

-CONH

2 NHCOR', -QC(O)NH 2 or -NHSO 2 R6. When R* is o an optionally substituted C1-6 aliphatic group, the most preferred optional substituents are halogen. Examples of preferred RX groups include -CF 3 -Cl, -CN, -COC%,

-OCH

3 -CH2C 3

-OCH

2

CH

3

-CH

3

-CF

2

CH

3 cyclohexyl, tbutyl, isopropyl, cyclopropyl, -CH, -CeC-CH 3

-SO

2 aH 3

-SO

2

NH

2

-N(CH)

2

-CO

2

CH

3 -CONH2, -NHCOCH 3 -OC(o)NH 2 -NHS02CH 3 and -OCF,.

On Ring C of formula II, preferred R substituents, when present, include -halo, -CN, -NO, 2 optionally substituted aliphatic group, -OR,

-CO

2 R, -CONH(R 4

-N(R

4 )COR, -S0 2

N(R

4 2, and

-N(R')SO

2 R. More preferred R 5 substituents include -C1, -CN, -CF3, -NH 2 f -NH.(C 1 -4 aliphatic), 4 aliphatic) 2

-O(C

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

(C

1 4 aliphatic). Examples of such preferred

R

substituents include -Cl, -CN, -CF3, -NH 2 -NEMe, -NMe 2 -OEt, methyl,-ethyl, cyclopropyl, isopropyli 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 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring -42- 0D system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring; t R" is hydrogen or C.-4 aliphatic and R y is or R x 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 0 0-2 ring nitrogens; (c).R 1 is -halo, an optionally substituted Ci-6 Saliphatic group, phenyl, -COR 6 -OR6, -CN, -SO 2

R

6 -SO2NH 2 O 10 -N(R6) 2

-CO

2

R

6

-CONH

2

-NHCOR

6

-OC(O)NH

2 or -NHSOaR 6 and

R

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

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

R

x is hydrogen or methyl and R Y is -R, N (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, -CO 2 R, -COCOR, -NO2, -CN, -SO 2 R, -SR, -N(R 4 2

-CON(R

4 )a,

-SO

2

N(R*)

2 COR, -N(R 4 C2 a(optionally substituted C 1 aliphatic), 2 -C=NN (R 2 -C=N-OR, -N(R 4

)CON(R

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

-N(R

4

)SO

2 R, or- -OC(=0)N(R 4 )2; -43- O R I is -halo, a Ci- 6 haloaliphatic group, a q aliphatic group, phenyl, or -CN;

R

2 is hydrogen and R 2 is hydrogen or a Ssubstituted or unsubstituted group selected from aryl, or a C 1 -6 aliphatic group, or R 2 and R 2 are taken together with.their intervening atoms to form a substituted or o unsubstituted benzo, pyrido, pyrimido or partially c unsaturated 6-membered carbocyclo ring; and 0(e) each R 5 is independently selected from \0 10 -halo, -CN, -NO 2 2 optionally substituted CI-s 6 aliphatic group, -OR,

-CO

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

N(R

4 2 or -N (R 4

)SOR.

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 RX is hydrogen or methyl and R Y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R 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' is -halo, a C-.4 aliphatic group optionally substituted with halogen, or -CN;

R

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

4 alkyl), -CO2(Ci-4 alkyl), -CN,

-SO

2 (C-4 alkyl), -SO 2

NH

2 -OC(0)NH 2

-NH

2 SO2(Ci-4 alkyl), -NHC(O) alkyl), -C(O)NH2, or -CO(CI-4 alkyl), wherein -44the (C 1 4 alkyl) is a straight, branched, or cyclic alkyl group; and each R 5 is independently selected from -Cl, -CTN, -CF 3

-NH

2

-NH(C

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

-O(C

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

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

Table 1.

CH

3

HN

4

P

SSC tN CI

N'

h-i

,H

HN

SII

N

LI

II-4

F

H

HN

N CF II-3 II-2

F-

H

HN

MN

CI

N4"- II-5

F

3 HN1 CN CF3 II-8 -N CI

N

11-6 II-7 II-9 Va 0 0 ci .cN' 11-10 0 en ci 0 ci Va 0 0 ci c IlN CF 3 11-14 .11-12 H HJ9 HN- N

CF

3 11-13 2NH )N ,N CF 3 11-16 Q(NOCFs .0 11-17 11-18 11-21 11-20 -46- HNr-P H NZt N CFS Cl N CF 3 (N

N

H

3

C,

11-22 11-23 11-24 0 en ci 0 Cr] 0 0 ci H3CtI N Cl

H

3 0 NWt CrF HCtN CFs

H

3 C 'NtO 11-25 11-26 11-27 HSCX&. N CF 3

H

3 C Nt~ 11-28 ci H13 H3CXI 4 N 01

H

3

C

11-29 .11-30 11-32 CHt -HNf*P 11-33

CH

3 11-36

CH

3 rVNKIoH 3 11-35 -47-

CHS

HN

4

P

Nh 11-37

OH

3 .11-38 HN4PdH

N*

N r CF 3 Z N l: C 3 :"b

H

3 11-39

OH

3

HN<P

N tH2CH3 11-42 4 5 HCHa N 1I-45

C)

11-40 11-41

OH

3 H-Nk Cl-I

HA

11-44 11-43

N

11-46

HN

NCF8 11-47 N NF *11-48 Va 0 0 ci ci 0 en ci 0 -ci cc 0 0 ci

HN

11-49 0

HN'

MN F

N

11-52 cc4

N'

11-58 91 Q NCF 3 11-50

HNQ

11-53 HNr

NCF

8

N'-S

HN

H

HN

c- 11-5

OH

HN gpJH 4N CF3 11-54 HN!

H

11-57

OWNCF

3 11-60 1-49-

IN

CA

HN

N

11-64 11-62,

HNN

NCFS

z C)S in-6 Nr 11-63 HN2

CF

2 CMF3

NIH

NN

11-72 Ci) HN2?

N'

11-67 QNCFs

N"

11-70"

NCF

3 11 -6 11-71 1

H

2

N

11-73 N 9 11-76 Br

HNZH

0% F

N

11-82

H!I

11-74

F

3 0

HN

NCI

H

N

11-75

HN

11-77 11-78

C

HN

NCF

3

CF

3 11-83

CF

3

HN

HN

11-81

F

HN

N1-84 -51-

HN

Br 11-85

CF

3 11-88

H

11-91

HN

11-94

F

HZ

N CF 3 1-86

HN

N CF 3 11-89 C F 8 N CFS

OCHX;L

11-92 F

F

H

HN

N C I 11-87 phN 11-93.

r If-95 It-SE -52-

IN

CA

N F 711-97

OH

3

'N

C3H HN

I

N

NCF3 11-98

N

HN?

CFS

11-101

CF

3 11-104

F

NCFS

.11-99 rN 11-102

N

HgC

NNA

11-106 11-107 'I1-108 53- 11-109

HN

11-112 HN2PQI

NCF

3 11-113 11-116

F

'Iil L. 11-114 11-118 11-117 HN

JP

11-119 11-120 -54ci 0"C~ 0O 0

HN

11-121

F

11-124

HN

I CF 11- 122 N CF 3 HN? H F. eN CFs 11-123

HN

2 C'-lN 11-126

F

C N 11-129 11-127 11-128 11-130 11-131 11-132

IN

0 cA 0O Ht-; FCba 11-133

OH

3 11-136

HN

1-134

HN

F 11-137 11-135 11-138

HN

2

NH

H

3 11-139 HNQiI

H

3 C ~N ACNH[ Fs

C)

MeSOgNH- CI 11-140 11-141 11-142 11-143.

11-144 -56-

IN

CA

HN*

C~qN HN2*" C N ~s 11-146 11-147

H-

HN

NCF

3 Me F Ih

H*NZ.

11-148 11-149 11-150 N N

H

2

N

N

U -151L 11-152 XI-J-ss 11-154 11-1561 -57-

H

N -N,.CF 3 *II-158W l 11-157 11-159 0 ci Va 0 0 ci Nyhj-N CF 3 ha-isoN~ H aI N- N F EtS--'N i-61 11-162

HN

No *N CF 3 11-164 .Me HN -t 1 N CF 3 N116 i 11-163

HN

2 P 0 H N 2

P

HCF JN CF 3 11-166 11-167 11-168 -58- 2,.

11-169 11-170

NNN

HsLt% 1 11-171.

11-172 11-173 11-174 Cbz.

H

11-175 11-176 11-17 HNq-NN AC.NJ[ CF 3 11-178 117179 Il1-180 -59- Va 0 0 ci ci HN Jd4H MeO2SNr% 4

N

11-181 1. 11-182 11-183 0 en ci 0 ci Va 0 0 ci

C)

11-184 'I-l85 11-186 C' "N Nfl 11*N-187CF

HN

3 It C'-N N>f

CH

3 rN2, CF 3 11-289 11-188 MN

XHHTH

Ac 3

MSO

2 jNCF Il-190 11-191 11-192

IND

IN

CA

.11-193 11-194 cr Nb 11-196 11-195 HN 2 t4JH H 1-9 11-197 11-199 HN2-XpH COtN 11-202

F

HZ

MeN- C 11-200

F

HNZ

11-203

HN

2 Me

CI

H

2 N0 2 5

'I

11-201 11-204 -61-

ON

11-205

OH

3

HN

4 11-208 11-206 11-207

C)

11-209 11-210

CH

3

HNH

1-211

.NJ*

HN

N,

N C 11-214

HN

N1N,

F'

HPN

11-213

NI

11-213 11-215 -62-

IN

0

IN

CA

Cg

N

11-217 Cl 12 11-220

N,~

11-218 11-219 11-221 11-222 N11-22

NH

11-223 11-224 Me Me 11-225

N'

11-228 11-226 11-227 -63- OMe

QN

11-229 11-232 -I23

F,

NONH2

L%

11-235

F

N'

11-230

NH

11-233 Hg

NH

11-236 11-231

HN,

t-Bu 11-234 11-237

HN

11-240 11-238 -64c 0

HN

CI

11-241

HN

0HN

O

II-242 11-243

NI_

N02 II-244

HN

'HN

JN

ct CN

CH

11-245 HN

H

SSO

2

NH

2 11-248

F

H

IN

11-246 F

NH

QI NSO2NH2 11-247.

F

N O2NM)2 11-250 H2 N(0 2 N e) 2 II-249 11-251 In another embodiment, this invention provides a composition comprising a compound of formula II and a pharmaceutically acceptable carrier.

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

Another aspect telates to a method of treating a disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of oadministering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula 11.

Another aspect relates to a method of enhancing I 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 I. 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 A-catenin in a patient in need thereof, comprising administering to said patient a therapeuticaliy effective amount of a composition comprising a compound of formula 11. 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.

-66o Another aspect relates to a method of treating (N a disease that is alleviated- by treatment with an Aurora tinhibitor, said method comprising the step of administering to a patient in need of such a treatment a 5 therapeutically effective amount of a composition comprising a compound of formula IX. This method is 0especially useful for treating cancer, such as colon, (N ovarian, and breast cancer.

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

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

Another method relates to inhibiting GSK-2, 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 th&reby, is preferably -67-

VO

0 carried out with a preferred compound of formula II, as Cq described above.

cAnother embodiment of this invention relates to Scompounds of formula III:

NH

Rx 0N IND 5 0

III

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

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or.

heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D;

R

X and R y are taken together with their intervening atoms to form a fused, benzo ring or a 5-8 membered carbocyclo ring, wherein -any substitutable carbon on said fused ring formed by R z and R Y is substituted by oxo or T-R3; 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 -68substitutable carbon on said fused ring formed by 112 and R2' is substituted by halo, oXo, -ONI -NO 2 -RU or ct and any substitutable nit .rogen on said ring formed by R12 and R' is substituted by 11'4; R' is selected f rom -halo, -C R, -02R1, -COCOa, -COOH 2 COR, -NO 2 CN, -S(0)11, -S(O) 2 1, -SR, 0 -N(Rt) 2

-CON(R')

2

-SO

2

N(R

4 2 -N(R')COR,

(N-N(R

4 )C0 2 (optionally substituted C,-saliphatic), o -N(Rt(R 4 2 2 -0=14-OR, -N(R 4

)CON(R')

2 IND 1.0 -N(Rt)S 2

N(R)

2

-N(R

4 )80 2 1, -or -OC(=O)N(R 4 2 o each R is independently selected from hydrogen or an optionally substituted group selected from 0a4' aliphatic, 0613o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyc lyl ring having 5-10 ring atoms; each R4 is independently selected from -al, -0011', -C02a(optionally substituted C:_6 aliphatic),I -CON(IR') 2 or. -SO2R7, or two R ori the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from -11, halo, -OR,

-CO

2 R, -000011, -NO 2 -ON, -$0211, -SRI -N(Rt3,1 -SO3N(RM), -N(R4)COR, -NRW)0C02 (optionally 'Substituted Ca-c6aciiphatic), -N(R')N(Rt) 2

-C=NN(R

4 2 -C=N-OR, -N(R')CON(Rt) 2 -N (R)S0 2 1( 4 W) 2 -()S0 2 R, or O=)NR2 *V is -SO2-, -N(R 6 )SOrI -80 2 N(R6)-, -N 0C(R')2S02-, 0C(R') 3 S0 2 2 -o(R6' 2 3 2 N(R')S0 2 or 2N (R')CON Va o W is -C(R 6

-C(R

6 2

-C(R

6 2 SO-, -C(R6)hSO 2 2 S0 2 -C(R C 2 -C02-, -C(R')OC N(R 6 2

N(R

6

CO-,

-c (R 6 2

(R

6

-C(

6 -C N-O-,

N(R

6 2 N(R) N 2 N SO 2

N(R

6 -C 2 N CON (R6) or. -CON (R 6 each R 6 is independently selected from hydrogen or an optionally substituted 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 Ci each R is independently selected from hydrogen or an optionally substituted C1- 6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred 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-1-isoindolyl1, 2,3-dihydro-lH-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

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

-N(R

4 2

-CO

2 R, -CONH(R 4 -N(R')COR, -S02N(R') 2

-N(R

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

C

6 1 0 aryl, or 6 aliphatic. More preferred R 5 substituents include -halo, -CN, -oxo, -SR, Va -OR, 2 or a substituted or unsubstituted C group selected from 5-6 membered heterocyclyl,

C

6 10 aryl, t .or C- 6 aliphatic. Examples of Ring D substituents include -OII, phenyl, methyl, CH20H,

CH

2 2

H,

C- 5 pyrrolidinyl, OPh, CF 3 CsCH, C1, Br, F, I, NH 2

C(O)CH

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

Preferred rings formed when the R" and RY groups 0 of formula III are taken together to form a fused ring include a or 7-membered unsaturated or partially unsaturated carbocyclo ring, wherein any substitutable carbon on said'fused ring is substituted by oxo or T-R'.

Examples of preferred bicyclic ring systems are shown below..

AZ

H

HN317 HN3??

N

I I cXi: IIz-A lzz-s III-C HN>?

HN>?

IIl-F

II-I

Preferred substituents on the R 2 /RY fused ring of formula III include oxo, halo, -OR,

-CO

2

R,

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

-CON(R)

2

-SO

2

N(R

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

-N(R

4

)N(R

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

)CON(R)

2 -N(Rt)SO 2

N(R')

2 -N(Rt)SO 2 R, or -71-

IND

S -OC 2 wherein R and It' are as def ined above.

More pref erred substituents on the R 1 /ky f used ring include halo, aN, oxo, C:L, alkyl, C 1 -c alkoxy, (C 1 6 alkyl) carbonyl,' (C 1 6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyxy, or 5-6 membered heteroazyl-.

o Excamples of such preferred substituents include methoxy, methyl,..isopropyl, methylsulfonyl, cyano, chioro, o pyrrolyl, methoxy, ethoxy, etbylamino, acetyl, and acetamido.

oPreferred At 2 substituents of'formula Ill'include hydrogen, C.14 aliphatic,' alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, monoor dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkyl aminoalkyj.phenylaminocarbonyl, and heterocyclyl )carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl,' propyl, t-butyl, cyclopentyl, ph~enyl, C0 2

R,

co 2 Cg 3 Ca 2 os, GE1 2 0G 3

GH

2 t$ 2 a1 2 0'H, GH 2 OiHaOO20H 3

,U

CH

2

CH

2

C~HOCH

2 Ph, CI{ 2

CH

2

CE

2

NH

2 a! 2 a! 2 2 NHCOOC GONECH (CH 3 2 CONHaI 2 CH=cH 2

CONHCH

2

CH

2

OCH

3

CONHCH

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

CON(CH

3

)CI

2 Ph, CONH(n-C 3

B

7 CON (Et) CH 2

CHCH

3

CONRCH

2 CH (cxU 2 CON (n-C 3

H

7 2 00(3methoxymethylpyrroliin-a-yl), CONE (3-tolyl), CONH (4tolyl1), CONHCH 3 CO (morpholin-i-yl), CO (4-methylpiperazin- 1-yl), CONHCH 2

CH

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

Then the Rt 2 and Rt 2 groups of f ormula III are -taken tog'ether to form a ring, pref erred R 2

/R

2 -ring systems containing the pyrazole ring include benzo, pyrido, pyrimido, 3-oxo-2H-pyridazino, and a partially unsaturated 6-membered carbocyclo ring. Examples of such pref erred R 2 /It 2 ring systems containing the pyrazole ring.

include the following: -72- Va X 0 k~H H, H, H, H, H H nand 0O 5 Preferred substituents on the R 2

/R

2 fused ring of formula III include one or more of the following: -halo, -C1-4alkyl, -Ci-4haloalkyl, -No21 -O(CI-4 alkyl), -CO 2

(C-

4 alkyl), -CN, -SO 2

(C

1 4 alkyl), -S02NH 2

-OC(O)NH

2

-NH

2

S

2

(C

1 4 alkyl) -NHC(0) (C1-4 alkyl),

-C(O)NH

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

Preferred formula III compounds have one or more, and more preferably all, of the features selected from the group. consisting of: Ring D is an-optionally substituted ring selected from 'a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2, 3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dibydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; eX and RY are taken together with their intervening atoms to form an optionally substituted benzo ring or a 5-7 membered carbocyclo ring; and R2' is hydrogen or methyl and R' is T-W-Rr or R, wherein W is -C(R 6 2 -COn-,

-C(R

6

-C(R

6 2 or

-CON(R

6 and R is an optionally substituted group -73-

VO

D selected from aliphatic or phenyl, or R 2 and R 2 are C taken together with their intervening atoms to form a c substituted or unsubstitutedbenzo, pyrido, pyrimido, or Spartially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula III have one or more, and more preferably all, of the features o selected from the group consisting of: Cq Ring D is an optionally substituted ring o selected from phenyl, pyridinyl, piperidinyl, \0 10 piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4- S tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl;

R

x and R Y 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, -C(O0)R, -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')

2

-OC(=O)R,

-N(R

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

-N(R

4

)N(R

4

-C=NN(R

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

-N(R

4

)SO

2N

(R

4

-N(R

4

)SO

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

-N(R

4 2 -Ca0R, -CONH(R 4

-N(R')COR,

-S0 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, C 6 -io aryl, or C 1 -s aliphatic.

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

R

x .and R y are taken together with their intervening atoms to form a benzo or 6-membered partially unsaturated carbocyclo ring optionally substituted with halo, CN, oxo, alkyl, C.- 6 alkoxy, (Ci- 6 alkyl)carbonyl, 6 alkyl)sulfonyl, mono- or dialkylamino, mono- or -74o 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, aryl, or C,-s aliphatic; and 0 R 2 is hydrogen and R 2 is selected fromR" 2 is hydrogen or methyl and R 2 is T-W-R 6 or R, wherein W is o -C(R) 2 C(R6)2N(R6)-, -C0 2

-C(R

6 IND .10 -C(R 6 2 N(R)CO-, or and R is an optionally o. substituted group selected from C1-6 aliphatic or phenyl, or R and R are taken together with their intervening atoms to form a benzo, pyrido, or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, 2 -C.-4alkyl, 4 haloalkyl,

-NO

2

-O(C-

alkyl), -CO 2

(C.

4 alkyl), -CN, -SO2 (C.

4 alkyl), -SONH 2 -OC NH 2

-NH

2 S0 2

(C.

4 alkyl) -NHC(0) alkyl), -C(0)NH2, or 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

3 s H sH HN! HN HN N25 I-i 1I1-2 II-3 111I1 I-2 111-3 Va

CA

111-4

HN

3 C)

N

-11-8 11I-6 111-7 Ill-9 CH3 111-10

CH

3 HN4$H

N

111-14 CH3 HN

_(N

EtNHQZGCfl~ 111-12 4i i 111-13 #4- 0N N O* NH Hs III-is 111-16 111-17 -76-

CH

3 OAXs H 1 0 en ci 0 -Cl -Va 0 0 ci 111-;19 111-20 111-21

OH

8

CH

3 NHj:(N

OH

8 111-22

CH

8 HN4NP 111-25

OH

2 IkN

NH

111-23

OH

8

OH

3 HN 111-24

OH

8 HN4 0 111-27 111-26

OH

8

H

111-28

OH

8

HN

111-29

OH

8 ctH *111-32

OH

3 111-30 111-31 111-33 -77-

OH

3 111-34 111-35

ON

3 HN4 tN 111-37

HNS

H

N4 0 111-40 8N4 111-43 111-46

CH

3 b H 111-36

CH

3 HN4* 111-39 111-38

OH

3 HN4* CH3H3 .111-41 111-42 6H 3 HN4JI~

OH

3 HN4

H.

CJl y0 M e 111-45 1.

111-44 111-47 111-48 -78- 7 S 0N

CA

OH

3 HN e 111-49

OH

3 HN4NJE

NH

.4F 111-52

CM

3

OH

3

HN

NH

111-53

OH

3

NF

111-51

OH

3 HN4O 111-54

OH

3

HNJ$

NH0

N$'%OCH

3 111-57

OH

3 HN4*

WNH

111-56 111-55 tNH H

CPU

111-SB 111-59

H

111-60 111-63 111-61 111-62 -79-

H..

111-64

CH

2

CH

HN4 N

H

NE

11~-65 H H O 3 HN ,ctCp

'H

111-68 111-66 f 111-67 111-69 111-70

HNX?,

H

N.

111-71

CH

2

OH

HN4

NH

111-74 CO 2

H

HN<*I

H

111-72 1±1-73 111-75 111-76 111-79 111-77 00H 3 0r'

HNC

111-83 111-78

H

3 0C a )-0H 9 OtHMIN Nt 1 1-8 111-82 111-84 HN 4;N .111-85 o r1CHs 111-86 111-87.

-81- 0or-'

HNX-

r -e .QN 0 en ci

OH

3

HNC

111-89

OH

3 111-92 111-90 III-~9i 111-93

HN

111-94 0 N4 111-97 111-95 111-96 111-98 111-99 -82- Br INt 0 en ci 0 ci 'Va 0 0 ci 111-100

NC

HN r 111-103 111-101

OH

3 111-104 Br

OH

3

HN*

OH

3 HN *1.

OH

0CH3 Nr *111-106

CH

3

HN<N*

Po-NaH 111-108

CH-I

HN<

H

111-110 HN4

OH

3 HN4

H

111-124.

OH

3 HN<Cl H2 N1-1

H

111-113

HNS

OH

111-115

HN?

III-liB HN4 111-121

CH

2 0H NV

H

111-124 HN4 N

H

111-116 111-119

HN'

e0 111-117

HZ

CoN

H.

111-120 C0 2

CH

3 111-122

CONH

2

HN<*I

III-12S II-123

CONH

2 H4 &cHs 111-126

-F

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

F

HN

N

H

NlV

~F

HN

N

H

111-130 111-131 111-132 c 0O MeOC FIN oNn nI o

HNZ

'111-133 111-134 111-135 0

HNL

111-136 111-137 111-136 PhOx 0 HN NH 0 KNA HN5-

OK

WNJ

111-139 111-140 111-141 Va HN HN HNQ NJ C N III-142 III-143 III-144 0 o

HNN

2

H^^

C N 'me, MaioJ III-145 III-146 In another embodiment, this invention provides a composition comprising a compound of formula III and a pharmaceutically acceptable carrier.

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

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

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula -86o III. This method is especially useful for diabetic CN patients.

t Another aspect relates to a method of _inhibiting the production of hyperphosphorylated Tau Ci 5 protein in a patient in need thereof, comprising administering to said patient a therapeutically effective 0 amount of a composition comprising a compound of formula II. This method is especially useful in halting or Sslowing the progression of Alzheimer's disease.

IN 10 Another aspect relates to a method of o inhibiting the phosphorylation of P-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula 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 II.

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 toa patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula III. This method is especially useful for treating cancer, such as colon, ovarian, and breast cancer.

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

-87- 0C Another aspect relates to a method of treating Cq 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 5 therapeutically effective amount of a composition comprising a compound of formula III. This method is o especially useful for treating cancer, Alzheimer's C disease, restenosis, angiogenesis, glomerulonephritis, o cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, Ic 10 alopecia, and autoimmune diseases such as rheumatoid arthritis.

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 -88treatment of a disease alleviated thereby, is preferably CN carried out with a preferred compound of formula III, as Sdescribed above.

Compounds of formula III, wherein R" is Ci 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 c AKT protein kinases.

SAccordingly, another method of this invention IN 10 relates to a method of inhibiting ERK-2 or AKT activity 0 in a patient, comprising.administering to the patient a therapeutically effective amount of a composition comprising a compound of formula III, wherein R 2 is hydrogen and R x and R Y are taken together with the pyrimidine ring to form an optionally substituted quinazoline ring system.

Another aspect relates to a method of treating a disease that is alleviated by treatment with a ERK-2 or AKT inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula III, wherein R 2 is hydrogen and 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: -89- Rxt SR' NH 3HN,,N

N

RN..

IV

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

-R

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

R

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

R

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

R

4 T is a valence bond or a C.4 alkylidene chain; R' and R 2 are independently -selected from -T-W-R 6 or

R

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

-NO

2 or -V-R6;

R

3 is selected frouv-R, -halo, -OR, -C(c0)R, -C0 2

R,

-COCOR, -COCR 2 COR, -NO 2 -CN, -S(o) 2 a, -SR,

-NR')

2 -CON(R) 2

-SO

2

N(R

4 2

-N(R

4

)COR,

o -N (R)CO 2 (optionally substituted C1_6 aliphatic), -N (R 4 -Cr)NN(R) 2 -C=N-OR, -N(Rt)cON(Rt 2 o

-N(R')SO

2 N(R)i, -N(R 4 )s0 2 R, or -OC(=O)N(R4)2; each R is independently selected from hydrogen or an o optionally substituted group selected from Cl-.

6 aliphatic, C..

10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -A7, -COW, -C02(optionally substituted

C

1 s aliphatic), -CON (R 7 2 or -SO 2 R7, or two R' on'th6 -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, -SR, -SR,

-N(R

4

CON(R')

2

-SO

2 N(Rt) 2 -OC(zO)R, -N(R 4

)COR,

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

-N(R

4

)(R

4 2

-C=NN(R')

2 -C=N-OR, -N(R')CON(R') 3

-N(R

4

SO

2

N(R')

2

-N(R

4

)SO

2 R, or -OC'=O)N(R 4 2 V is -SO2, -N(R6)S0 2

-SO

2

N(R

6 -C0 2 -N(R6)SO 2 -C(R6) 2

S-,

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

-C(RY)

2

SO

2 2 N(R')-l

C(R

6 2 -C(R6) 2 wa.R)CO)O-, '-C(R6) 2 -C(R 6 2 N(R6)so 2 or -c (R6) 2 N CON (R6) -91- O W is 2 0o-, 2 SO-, 2 a0 2 0 2 So 2 -C(R -co2-,

-C(R

6

-C(R

6

-C(R

6 2

N(R

6

)CO-,

-C(R)2N(R 6

-C(R

6 )rN-O-,

-C(R

6 2

N(R')SON(R

6

C(R)

2 or..-CON(R 6 Seach R' is independently selected from hydrogen or an Ci optionally substituted C1.. aliphatic group, or two R 6 o groups on the same nitrogen atom are taken together ND 10 with the nitrogen atdm-to form a 5-6 membered o heterocycly. or.heteroaryl ring; and each R 7 is independently selected from hydrogen or an optiohally 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 ring or heteroaryl.

Preferred formula TV Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyrl, 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-lH-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyi. 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(R4)t, -CO 2 R, -CONH(R 4 -N(R')COR, -SO 2

N(R)

2

-N(R

4

)SO

2 R, -SR, -OR, -C()R,or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-3o aryl, or C16- aliphatic. More preferred R 5 substituents include -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-10 aryl, -92- Va Sor C1-6 aliphatic. Examples of Ring D substituents include -OH, phenyl, methyl,

CH

2 0H, pyrrolidinyl, OPh, CF 3 COnCH, C1,- Br, F, I, NE 2

C(O)CH

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

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

S HN HN' Z R XN'- N Me IV-D IV-E

IV-G

HN HN

HN

Me N Me)Nl, N Nj' fIV-H IV-J

IV-K

HN3 HN

HN-

N

IV-L flV-M

IV-N

-93- .HN

Z

N rpl 'k-N NM N-s Iv-P I- 0 0 en ci 0 ci Va 0 0 ci

KNA

3V- R 'v-u Irv.-

S

HN31

HN

Iv-r HN37 Ot fl-ES IV-7 HN3? k.

Nly iv-w

HN

I-

NN

N:

'N

N4

R

3V-IA HN Z N2Ik fl-CC -94- Va o

N,

IV-DD

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

o In the monocyclic pyrimidine ring system of Ci formula IV, preferred RX 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 RY-groups include T-R 3 wherein T is a valence bond or a methylene, and R' is -R,

-N(R

4 2 or -OR. When R3 is -R or -OR, a preferred R is an optionally substituted group selected from C-6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred RY groups include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl, methoxyphenyl, trimethoxyphenyl, or halo-substituted phenyl, and methoxymethyl.

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

-CO

2

R

-COCOR, -NO 2 -ON,

-SO

2 R, -SR, 2

-CON(R

4 2 -S02N(R 4 2

-N(R

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

-C=NN(R

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

-N(R')SO

2

N(R

4 2 -N S0 2 R, or 2 wherein R and R' are as defined above for compounds of formula IV. Preferred R/RY ring o substituents include -halo, -OR, -COR, -CO2R, C -CON(R 4 2 -CN, or -N(R 4 2 wherein R is a substituted or t unsubstituted Ci-6 aliphatic group.

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

NH-

HN N Rx N .i NN Ry,,N NH NNH

H

of formula IV include one or more of the following: -halo, -N(R 4 2, -C3-4 alkyl, -Cz-4 haloalkyl, -NO2, -O(Ci-4 alkyl), -C02(C-4 alkyl), -CN, -SO 2 alkyl), -SO 2

NH

2 -QC(0) NH 2

-NH

2 SO2 (C- 4 alkyl), -NHC(O) (CI-4 alkyl), -C(0)NH 2 and -CO(C1-4 alkyl) wherein the (C1-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C2-4 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 C1i- aliphatic group. Examples of such preferred R 2 groups include methyl, t-butyl, -CH 2

OCH

3 cyclopropyl, furanyl, thienyl, and phenyl. A preferred

R

2 group is hydrogen.

-96-

VO

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

R

3 or R X and R Y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring' heteroatoms; and

R

2 is hydrogen or methyl and R 2 is T-W-R 6 or R, wherein W is 2 -C(R6) 2

NCR

6 -C0 2

-C(R

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

-CON(R

6 and R is an optionally substituted group selected from C2- 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.

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-1R-isoindolyl, 2,3-dihydro-lH-indolyl, isoquinolinyl, quinolinyl,.or naphthyl; Rx is hydrogen or methyl and R Y is -R, or -OR, or R x and RY are taken together with their -97- Va Sintervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, t wherein said ring is optionally substituted with -R, halo, oxo, -OR, -C(iO)R, -COaR, -COCOR, -NO 2 -CN, -S(O)R,

-SO

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

-CON(R)

2

-SO

2

N(R)

2

-OC(=O)R,

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

-C=NN(R

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

-N(R

4

)SO

2 N (R 2 -N(R')S0 2 R, or -OC(-O)N(R) 2 .and O each R 5 is independently selected from halo., ID 10 oxo, CN, NO 2 -N(R4) 2

-CO

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

N(R')

2

-N(R')SO

2 -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, CG- 10 aryl, or C 1 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: Re and RY are taken together with their intervening atoms t6 form a 6-membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, optionally substituted with halo, CN, oxo, C2-4 alkyl, C 16 alkoxy, (C 1 6 alkyl) carbonyl, (C 1 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, 2 or a substituted or unsubstituted group selected from 5-6 membered beterocyclyl,. Cs-o 10 aryl, or C.I-6 aliphatic; and

R

2 is hydrogen and R' is T-W-R6 or R, wherein W is 2 -C(R6) 2

-CO

2

-C(R

6 2

N(R

6 or -CON(R6)-, and R is an optionally substituted group selected from C 1 6 aliphatic or phenyl, or R' and RI 2 are. taken together with their intervening atoms to form a.benzo, pyrido, or.partially unsaturated 6-membered carbocyclo ring optionally 98substituted with -halo, oxo, 2 alkyl, -C 1 4 haloalkyl, -N02, -O(C-4 alkyl), -C02(C1-4 alkyl), -CN,

-SO

2

(C

1 4 alkyl), -so 2

NH

2 -OC(O)NH, -NH 2

SO

2

(C.

4 alkl), -NHC(O) 4 alkyl), -C(O)NH2, or alkyl), wherein the (C1.4 alkyl) is a straight, branched, or cyclic alkyl group.

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

Table 3.

c 0O

OH

3 HN'4$

A'-N

HA

MoO Meov OMe IV-2

OH

3

HN~.~

AcNH QaSe"' IV-3 HN )*H

H

2

N

IV-4 IV-5 IV-6

H

2

N.

CMe 4H IV- 8

OHS

HN"P

Nv-s IV_9 IV-7 -99- Iv-11 INSQ H 8 CNk y IV-13. IV- 14 H8C040 HSC %o N IV-12 HNSt

H

3

CN

HN$

IV- 18 IV- 16 IV-17 IV-20 IV-19 I3V-23.

-100-

(N

ci ci

.CHS

HNOH

Me Ot IV-22

.HC

HO J, CH

HNH

IN

MeO IV-28 IV-23 CHg HIV-2 IV-24

CJ

3

H

HN

H

IV-26

CH

3 HN N IV-29 IV-27

HNH

IV-32 IV-31 IV-33 In another embodiment, this .invention provides a composition comprising a compound of formula IV and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, comprising administering to the patient a therapeutically -101- O effective amount of a composition comprising a compound C- of formula IV.

cAnother aspect relates to a method of treating C 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 o therapeutically effective amount of a composition CA .comprising a compound of formula IV.

Another aspect relates to a method of enhancing DO 10 glycogen synthesis and/or lowering blood levels of o glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful for diabetic patients.

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

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

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

-102-

ID

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

O C ne aspect of this invention relates to a IND 10 method of inhibiting CDK-2 activity in a patient, Scomprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula 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 -103- O carried out with a preferred compound of formula IV, as Ci described above.

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

S

SR

2 m -HN

N

S- HN IN o tz2

(N

V

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

1 is N, CRa or CH and Z 2 is N or CH, provided that one of Z 1 and Z 2 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pytimidinyl, 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 -RS; 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 -:104z. from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

S-R

s and at any substitutable ring nitrogen by -R 4 provided that when Ring D' is a six-membered aryl or Ci 5 heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; o R' is selected from -halo,, -CN, -NO2, T-V-R 6 phenyl, 5-6 ^c membered heteroaryl ring, 5-6 membered heterocyclyl o ring, or CI.

6 aliphatic group, said phenyl, heteroaryl, IND 10 and heterocyclyl rings each optionally substituted by 0 up to three groups independently selected from halo, oxo, or -R e 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' and R Y are independently selected from T-R 3 or R x and

R

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

R

2 and R 2 are independently selected from or

R

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

-R

7 or and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R4; -105-

IND

S R3 is selected from -halo,

-CO

2

R,

-COCOR, -COCH 2 0OR, -N0 2 -CN, -S(O) 2 R, -SR, 2 -CON(R 2

-SO

2

N(R)

2 -OC (nO)R, -N (R 7

CR

-N (R 7

CO

2 (optionally substituted C1_6 aliphatic),

-N(R

4

).N(R

4 2

-C=NN(R)

2 -N (g7)CON(RW) 2 -N (R 7 )8S0 2 N 2

(R

4 so 2 R, or O(-)NR) o each R is independently selected from hydrogen or an c-i optionally substituted group selected from C1_.6 o. alip'hatic, 0 610 ioary1, aheteroaryl ring having IDring atoms, or a heterocyclyl ring having 5-10 ring 0 atoms; *each.R 4 is independently selected from -R 7

-COR',

-002 (optionally substi tuted CIG aliphatic)', -CON or -S0 2

R

7 Or two RI on the same -nitrogen are taken together to form a-5-8 membered heterocyclyl or heteroary. ring; each R 5 is independently selected f rom halo, -OR, -CU=o)R, -00 2 R, -COCOaI, -NO2, -atI -SO 2 R, -SR,

-N(R

4 -CON(R')2, -So 2 N(Rt,,

-N(R')COR,

-N (R')C0 2 (optionally substituted C:a-s aliphatic), -NRW)nIV(R 4 )2 -C=NN(R 4 -N (R 4 )CONRW) 2 -N (R 4 ).SON(R) 2, -N (R 4 SOR, or or*R 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is so-, -N(R6)SO2-, -SO 2 -N(RW) CON -1N(RG)S02N

-C(R

4 5)2s-, -C(R 6)2SON(R')-, -C(R6)2N(R6)Co0)C-,

-C(R

8 41-0-, -C CR 6

CR

6 N(R6) -C 2N S02?(R0) -,or -C 2 N (R6) CON4 (R 6) W is 2 2 S02-, -C(R6')2SO2N(R)-, -002-, -106-

VO

-C C(0) -CROC N -C

R

6 )o(R' 2 N (R CO-, c N C -C(R 6 NN (R 6 -C (R 6

N-O-,

C

-C(R

6 2N(R 6

N(R

6

-C(R

6 2N(R6 S02N(R 6 R -C(R) 2

N(R')CON(R

6 or -CON(R 6 CN 5 each R' is independently selected from hydrogen, an optionally substituted C.-4 aliphatic group, or two R 6 c groups on the same nitrogen atom are taken together with .the nitrogen atom to form a 5-6 membered o heterocyclyl or heteroaryl ring; SND 10 each R 7 is independently selected from hydrogen or an Soptionally substituted C 1 6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 8 is independently selected from an optionally substituted

C

1 -4 aliphatic group, -OR 6

-COR

6

-SO

2

R

6

-N(R

6 2

-N(R

6 2 -CN, -NO 2

-CON(R

6 2 or

-CO

2

R

6 and

R

a is selected from halo, -OR,

-CO

2 R, -COCOR,

-NO

2 -CN, -SOaR, -SR, 2

-CON(R

4 2

-SO

2

N(R')

2 -N(R 4 COR, -(R 4 CO2 (optionally substituted Ci-e aliphatic), -N(R)N(R 2, -C-NN(R 4 )2, -C=N-OR, -N(R 4

)CON(R

2

SO

2

N(R

4 2

-N(R

4 S02R -OC(=0)N(R 4 or an optionally substituted group selected from Ci-6 aliphatic, Cs-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

Compounds of formula V may be represented by specifying Z 1 and Z 2 as shown below: -107- RFr Va Vb When the R and R Y groups of formula V are taken together to form a fused ring, preferred RX/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said 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.

Rt 2

_,NH

N' N G- Va-A

HN-A

vb-A

HNA

VC-A

Va-B Vb-B Va-B -108- HN-H N7 H N A N C~IVa-C Vl-C Va-C N HN IND

N

R 42i N4A4t.N Va-D Vb-D Vc-D HNA?- HNN3? HN'3L Va-KVb-E Vc-E

HN)~?N

Va-F lVb-F. Va-F HN31HNN Z HN Z S? a Va-J Vb-J Va-cT -109-

~NI

Va-K HN-3N VN HN31 fl-K Va-K f Vb -L Va- L

HW?

Va-N fl-K

H

rN*1N flM-N Ye -K VaN Va-N Va-0 fi -0 Vc-0 -110- Va HN HN HNk Va-P Vb-P Va-P n More preferred bicyclic ring systems of formula V include Va-A, Vb-A, Vc-A, Va-B, fb-B, Va-B, Va-D, fb-D, VC-D, Va-E, Vb-E, Vc-B, Va-J, V-J, Vc-J, Va-K, Vb-K, o Va-K, Va-L, Vb-L, Va-L, Va-M, Vb-N, and Va-M, most Cx preferably Va-A,-Vb-A, Va-A, Va-B, Vb-B, and Vc-B.

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

Preferred RY groups include T-R 3 wherein T is a valence bond or a methylene, and R is -N 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 RY include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cy6lopropyl, 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 RZ and R3 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) 3

-CON(R)

2

-SO

2

N(R')

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

)N(R)

2

-C=NN(R

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

-N(R')SO

2

N()

2

SO

2 R, or

-OC(.)N(R

4 2 wherein R and R' are as defined above.

-111- S Preferred Px/RY ring substituents include -halo, -OR, C- -COR, -CO 2 R, -ON(R 4 2 -CN, or -N(R)2 wherein R is an optionally substituted CI-6 aliphatic group.

The R 2 and R 2 groups of formula V may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused Srings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are Sexemplified in the following formula V compounds having a ci 10 pyrazole-containing bicyclic ringasystem: 9'H HN N

NW

ci~c YIKQ g H NNH H dNH RY Z'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 1 4 alkyl, -C_4 haloalkyl, -NO 2 -O(Cj.4 alkyl),

-CO

2

(CI-

4 alkyl), -CN, -S0 2

.(C

1 4 alkyi), -SOa 2

NH

2

-OC(O)NH

2

-N

2 S0 2

(C-

4 alkyl)., -NHC(0) (C 1 4 alkyl)), -C(O)NH 2 and -CO(C.-4 alkyl), wherein the (C-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (Calkyl) 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, -112- Va oisopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO 2

H,

CO2CH3, CH20H, C10CH, CH 2

C

2 CHM20H, CR 2

CH

2 CR20CH 3 CH2C 2

CH

2 0CH 2 Ph, CH2C 2

CH

2

HH

2 2

M

2

CH

2

NHMCOOC(CH

3 3 CONRHC(CH3) 2

COMNHCH

2

C=CH

2

CONHCH

2 CH20CH 3

CONHCH

2 Ph, CA 5 CONH(cyclohexyl), CON(Et)2, CON(CH 3

)CH

2 Ph, CONH(n-C3H 7 CON(Et)C 2

CH

2

CH

3

CONIHCHI

2 cIC 3 2 CON(n-CIH 7 2 CO(3- 0 methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4tolyl), CONHCH 3 CO(morpholin-1-yl), CO(4-methylpiperazino CONECH 2

CHR

2 0, CONH 2 and CO(piperidin-1-yl). A ID 10 preferred R 2 group is hydrogen.

0More preferred ring systems of formula V arethe following, which may be substituted as described above, wherein R' and R 2 are taken together with the pyrazole ring to form an optionally substituted indazole ring; and R and RY are each methyl, or RX and RY are taken together with the pyridine ring to form an optionally substituted quinoline, isoquinoline, tetrahydroquinolineor tetrahydroisoquinoline ring: INH NH HN HN HN

HNQ

oc

H

3 0 V-Aa V-Ba V-Ba When G is Ring C, preferred formulav Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system.

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at ortho and meta positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred -113- SRI 3groups include -halo, an optionally substituted C 1 6 0 aliphatic group, phenyl, -COR', -OR -CN, -SO 2

-SO

2

NH

2 -N(R 2

-CO

2 -CONiH2, -NHCOR 6 -OC(O)NH, or -NHS0 2

R'.

WhenR' is an optionally substituted C1. aliphatic group, the most preferred optional substituents are halogen.

Examples of preferred RI groups include -CF, -C1, -F, o -CN, -COCH 3 -0CHa, -OH, -CH 2 CH,, -OCI 2

CH

3 -CH3, -CF 2

CH

3 ci cyclohexyl, trbutyl, isopropyl, cyclopropyl, -CCH, o -MC-CH3, -S0 2 CH3, -SO 2

NH

2 -N(CH3) 2

-CO

2 CH3, -CONE 2 IO 10 -NHCOCH3, -OC(0) NHa, -NHSo 2 CH,, and -OCF,.

o On Ring C preferred R 5 substituents, when present, include -halo, -CN, -NO 2

-N(R

4 2 optionally substituted CI-6 aliphatic group, oR, -CO 2

R,

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

N(R

4 2 and -N(R 4

)SO

2 R. More preferred R5 substituents include -Cl, -CN, -CF, -NH2, -NH(C1-4 aliphatic), -N(C1- aliphatic)2, -O(CI-4 aliphatic), C..4 aliphatic, and -C02 (C-4 aliphatic).

Examples of such preferred R' Bubstituents include -C1, -CN, -CF, -NH 2 -NEMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -CO 2 Et.

When G is Ring D, preferred formula V Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, 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, 2,3dibydro-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, -NO 2 -114- Va o 2

-CO

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

-N(R')SO

2

R,

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

C

6 1 o aryl, or C3.

aliphatic. More preferred Ring D substituents include C 5 -halo, -CN, -oxo, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 en membered heterocyclyl, C 6 1 o aryl, or C 16 aliphatic.

Examples of Ring D substituents include -OR, phenyl, C- methyl, CH20H, CH 2 CH20H, pyrrolidinyl, OPh, CF3, CCH, C1, O 10 Br, F, I, NH 2 C(O)CH3, i-propyl, tert-butyl, SEt, OMe, 0g 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 -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-r 6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2 R6, -SO 2

NH

2

-N(R

6 2 -C0 2

R

6

-CONH

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

R

6 or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl., morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,;4-tetrahydroquinolinyl, 2,3-dihydro-R1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; R' is hydrogen or C.

4 aliphatic and RY is T-

R

3 or Rx and RY are taken together with their intervening atoms to.form an optionally substituted 5-7 memberedunsaturated or partially unsaturated ring having 0-2 ring nitrogens; and -115o

R

2 is hydrogen and R' is hydrogen or a Ci •substituted or unsubstituted group selected from aryl, t heteroaryl, or a Ci-6 aliphatic group, or R 2 and R 2 are Staken together with their intervening atoms to form a Cp 5 substituted or unsubstituted benzo, pyrido, pyrimido'or partially unsaturated 6-membered carbocyclo ring.

O More preferred compounds of formula V have one C- or more, and more preferably all, of the features o selected from the group consisting of: \D 10 Ring C is a phenyl or pyridinyl 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

l is -halo, a C 1 -6 haloaliphatic group, a Ci-6 aliphatic group, phenyl, or -CN; or Ring D is an optionally.

substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyL, 1,2,3, 4 -tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; R" is hydrogen or methyl and R Y is -R, N(R4)2, or -OR, or R" and R y are taken together with their intervening atoms to form a benzo ring or a 5-7 membered partially unsaturated carbocyclo ring, said benzo or carbocyclo ring-optionally substituted with halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SOaR, -SR, -N(R) 2

-CON(R

4 2

-SO

2

N(R

4 2

-N(R'COR,

-N(R

4 )C02 (optionally substituted C 1 -6 aliphatic), 2

-C=N(R

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

-N(R

4

)SO

2

N(R

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

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a C.1- aliphatic group, or R 2 and R 2 are taken together -116- 0 with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially i unsaturated 6-membered carbocyclo ring; and Ring D is substituted by oxo or R 3 wherein C 5 each R 5 is independently selected from -halo, -CN, -NO 2

-N(R)

2 optionally substituted Ci.

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

N(R

4 2 or 2 -N (R 4

SO

2

R.

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

R

3 is -halo, a C 1 -4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,.

1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-.

tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; 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, oxo, Ci-' alkyl, Ci-6 alkoxy, (Ci-6 alkyl)carbonyl, (C-1 alkyl)sulfonyl, mono- or dialkylamino, mono-'or dialkyl-aminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; -117- Va R' and R 2 are taken together with their N intervening atoms to form a benzo, pyrido, pyrimido or t partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, 2 -C.4 alkyl,

-C

1 -4 haloalkyl, -NO 2 -0o(CI- 4 alkyl), -C02 (Q.

4 alkyl), -CN, -S0 2

(C-

4 alkyl), -SO 2

NH

2 OC NH2, -NH 2 SO2 (C 1 .4 alkyl) O -NHC(O) (C 1 4 alkyl), -C()NHA 2 or -CO(C 14 alkjl), wherein C the (C 1 -4 alkyl) is a straight, branched, or cyclic alkyl o group; and .10 Ring D is substituted by oxo or R, wherein I 0 o each Rs is independently selected from -C1, -CN, -CF,

-NH

2

-NH(C

1 4 aliphatic), -N(C 1 4 aliphatic) 2 -0O(C.-4 aliphatic)-, C1-4 aliphatic, and -CO2(C 1 -4 aliphatic).

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

Table 4.

F

H H NS -t d F N CF 3 V-1 V-2 V-3 HN< N )H V-4 V-S V-6 -118-

NR

CF

3 V-9.

HNS3 V-7 V- 8 0 en ci 0 *-ci 0 0 ci

OH

3 HNkP V-13

F

H

3 V-16 V-11

H

3

CA.

H

3 C INj V-14 V-12 HNqdbJH

H

3

C

V-1s V-18 V-17 119-

NH

I

N%

O~uN v-

F

HZ

F

3

C

V-20 V-i9 HZ

O

H

3

C"N

V-21

FS

V-24 V-22 V-23 V-26 V- 27 V-28 V-29 -120- V-

HN

2

C

V-31 V-32 V-33 OH3 V- 35

HN;

H

3 C

N

H

80t S V-34 V-36 V-37 V-38 V- 39

MNZ

H3Cf VA 0 V-41 V-42 -12l- V-43 V-3 ~V-44V-4 a' V-47 V~-46 V-48 V-49 V-50 V-51 V-52 51-B3 V-54 -122- HNPd-OH

HN

NH

V-58 V-56

HN

2 0~

NH

2 V-S 9 V-57 V- V-El.

p 3

C

V- 62

CM

3

F

3

C*.

V-65

OH

V-63

HN

2

H

NN

4 eF V- 64

CH

3

HN

4

P

N-

N

FaC V-66 123c.ct ,v.Jj..

Va oD F ci HN H H OH

N

9 cFKI

F

3 0 o V-67 V-68 ci In another embodiment, this invention .provides qCi 5 a composition comprising a compound of formula V and a pharmaceutically acceptable carrier.

ci 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 aidor 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 hyperphosphory-lated 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 -124two* ,a Va

D

o V. This method is especially useful in halting or slowing the progression of Alzheimer's disease.

Another aspect relates to a method of inhibiting the phosphorylationof P-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition ncomprising a compound of formula V. This method is 2-2 especially useful for treating schizophrenia.

CA One aspect of this invention relates to a Va o 10 method of inhibiting Aurora activity in a patient, 0q 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 of this invention relates to a method of inhibiting CDK-2 activity in a patient, comprising administering to the patient.a therapeutically effective amount of a composition comprising a compound of formula V.

Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula V. This method is especiaily useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, -125- C cytomegalovirus, KIV, herpes, psoriasis, atherosclerosis, C< alopecia, and autoimmune diseases. such as rheumatoid Ct arthritis.

Another method relates to inhibiting GSK-3, 5 Aurora, or CDK-2 activity in a biological sample, which method comprises contacting the biological sample with 0 the GSK-3 or Aurora inhibitor of formula V, or a ci pharmaceutical composition thereof, in an amount o effective to inhibit GSK-3, Aurora or CDK-2.

ID 1 0 Each of the aforementioned methods directed to o the inhibition of GSK-3, Aurora or CDK-2, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula V, as described above.

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

Rr

NH

HN

NLN

RY

VI

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 s and two adjacent substituents on Ring C are optionally taken together with their -126- 4 j* c

VO

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, oxo, or -R

B

Ring D is a 5-7 membered monocyclic ring or 8-10 membered C bicyclic ring selected from aryl, heteroaryl, Sc heterocyclyl or carbocyclyl, said heteroaryl .or Sheterocyclyl ring having 1-4 ring heteroatoms selected ND 10 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 provided that when Ring D is a six-membered aryl or heteroaryl ring, -R s is hydrogen at each ortho carbon position of Ring D;

R

1 is selected from -halo, -C-NO2, T-V-R 6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C 1 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or said C 1 -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;

R

y is T-R 31 T is a valence bond or a Cz-4 alkylidene chain;

.R

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

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO2, -R 7 or -127- IND o -V-Pt, and any substitutable nitrogen on said ring ci formed by R2 and Rt 2 is'substituted by Rt; R 3 is an optionally substituted group selected from C 1 6 aliphatic, C 3 10 carbocyclyl, C 6 10 aryl, a heteroaryl c-i ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10. ring atoms; each Rt is independently selected from hydrogen or an c-i optionally substituted 4roup selected from C 1 6 oaliphatic, Cc,.

10 aryl, 'a heteroaryl ring having 5-10 IN ring atoms, or a heterocyclyl ring having 5-10 ring o atoms; c-ieach R4' is independently selected from -R 7

-COR',

-C02(optionally substituted C3.- 6 asliphati6) )CNR 2 S Or -SO 2 or'two Pt' on the samne nitrogen. are taken together to form a 5-8 membered heterocyclyl. or heteroaryl ring; each Rt 5 is independently selected from -Rt, halo, -OR,

-CO

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

-CON(R

4 2 -80 2 N4(R') 2 -N(Pt')COR,

CO

2 (optiOn'ally substituted C 1 4 'aliphatic), *-N(R'4)Nj(Rt) 2 2 -N(R')CON(Pt') 2 -N(Rt)SO 2

N(R)

2 j, -N(R')SO 2 R, or -OC(eO)N(Rt) 2 Or Rt 3 and an adjacent. substituent taken together with their intervening atoms form said ring fused to Ring C; V is -S- 1 -S02-, -N(R6)S0 2

-SO

2 N(Pt 6 -N (R 6 C-,-C0 2 CO-, -N (R 6 C 0-, -N (R 6 CON (R 6 -&(Pt')So 2 -OC(0)N(R 6 2 2

S-,

-C(R 2 so-, 2 S0 2 2 So 2 N(a 6 6 2 N4(R 6

-C(R

6 2 lq( 6

-C(R

6 2 N(sff)C(o)o-, 2 N -C (Pt) 2 N 80 2 N(R6'- Vor 2 N (k6) CON W is -C(R'5) 2 2 2 50-, 2 S0 2 -CCR') 2 S0 2 N -C 2 N8R') -CO 2

VO

o -C(R 6

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

6

-C(R

6 2

N(R

6

)CO-,

_C(R6) 2N(RC)C(0)0-, SC 2 N(R 6 N (R6) -C (R S 2 N (RSOR 6 2 2

N(R

6

CON(R

6 or -CON(R 6 Cl 5 each R 6 is independently selected from hydrogen, an optionally substituted Ci-4.aliphatic group, or two R 6 n groups on the same nitrogen atom are taken together with the nitrogen atom.to form a 5-6 membered h beterocyclyl or heteroaryl ring; ND. 10 each R' is independently selected from hydrogen or an o optionally substituted C-.

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

-SR

6

-COR

6 -S0 2

R

6

-N(R

6 2

-N(R

6

N(R

6 2

-CN,.-NO

2

-CON(R

6 2 or

-CO

2

R'.

Preferred RY 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 1 -6 aliphatic,

C

3 s- 1 carbocyclyl, C 6 -Io 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 C 3 -s carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred R Y include 2-pyridyl, 4-pyridyl, piperidinyl, Smorpholinyl, cyclopropyl, cyclohexyl, and optionally substituted phenyl such as phenyl or halo-substituted phenyl.

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

NO

S unsaturated.6-meinbered carbocyclo ring. These are ri exemplified in the following formula VI comqpounds having Ct a pyrazole-containing bicyclic ring system: 9NH M HN Q O N -"N NH NHN H- N.~H I ,and Preferred substituents on the R 2 fused ring include one or more of the following: -halo, -NCR 4 2

-C-

alkyl, 4 haloalkyl, -NO 2 -O (CI-4 alkyl) C0 2 4 alkyl) -Cii, -S0 2 4 alkyl) -80 3

W!

2 -OC N1 2

-NH

2 80 2

(C

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

when the pyrazole ring-system is monocyclic, preferred R 2 groups of formula VI include hydrogen, Ca.

4 aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl,. aminocarbonyl, mono- or dialkylamitnocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, C0 2 C0 2 0H 3

CH

2 OH, CI{ 2

OCH

3 Cs 2

CH

2 ai 2 oH, Ol 2 C.HaCH 2 OCIHs,

CH

2

CH

2

CM

2

OCH

2 Ph, CH 2

CE

2

CH

2

XH

2 a! 2 dn 2 Cn 2 NuCOb5C (CHO) 3 comiar (a! 3 2 CONH H 2

CH=CH

2

CONHCH

2

CE

2 OCH,, CONRCH 2 Ph, CONH(cyclohexyl), CON(Et), 2

CON(CH

3

)CH

2 Ph, CONH(n-C 3

H

1 cow T(Etj CR 2 0H 2

CH

3 ;F CONHCH 2 CH (CE 3 2 CON (n-C 3 7 2 CO (3methoxcymethyJlpyrrolidin-l-yl), CON!(3 -tolyl), CON!!(4- -130o tolyl), CONHCH 3 CO(morpholin-l-yl), CO(4-methylpiperazin- 1-yl), CONHCH 2 CH20H, CONH 2 and CO(piperidin-1-yl).

A

preferred R 2 group is hydrogen.

When G is Ring C, preferred formula VI Ring C A 5 groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused 0 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 Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred R1 groups include -halo, an optionally substituted CI.

6 aliphatic group, phenyl, -COR, -CN, -SO 2

-SO

2

NH

2 2

-CO

2 R6, -CONH 2 -NHCOR, -OC(o)NH 2 or -NHSO 2

R'.

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

Examples of.preferred R 1 groups include -CF 3 -C1, -F, -CN, -COCH 3 -OCH3, -OH, -CK2CH 3

-OCH

2

CH

3 -CH3, -CF 2

CH

3 cyclohexyl, t-butyl, isopropyl, cyclopropyl, -CCH, -CC-C, -0 3 S0 2

C

3

-SO

2 NH, -N(CH 3 2

-CO

2

CH

3 -CONHb, -NHCOCgs, -OC(0)NH 2

-NHSO

2

CH

3 and -OCF 3 On Ring C preferred Rs 5 substituents, when present, include -halo, -CN, -NO 2

-N(R)

2 optionally substituted C3- aliphatic group, -OR, -C0 2

R,

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

N(R')

2 and -N(R SO 2 R. More preferred Rs 5 substituents include -C1, -CN, -CF 3

-NH

2

-MH(C.-

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

-O(C

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

Examples of such-preferred

R

5 substituents include '-C1, -CN, -CF 3

-NH

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

When G is Ring preferred formula VI Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, -131-

VO

0 C pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.

C When two adjacent substituents on Ring D are taken t together to form a fused ring, the Ring D system is Sbicyclic. Preferred formula VI Ring D bicyclic rings 5 include 1, 2 3 4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- 0 dihydro-IH-indolyl, isoquinolinyl, quinolinyl, and Ci naphthyl. Examples of more preferred bicyclic Ring D O systems include naphthyl and isoquinolinyl.

1D 1 0 Preferred substituents on formula VI Ring D O include one or more of the following: halo, oxo, CN, -NO2,

-N(R

4 -CO2R, -CONH(R 4 -N (R COR, -SO 2

N(R

4 2, -N(R'SO2R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl,

C

6 1 o aryl, or C 1 ialiphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, -N(R 4 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-io aryl, or C2- 6 aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CHOH, CH2CH2OH, pyrrolidinyl, OPh, CFa, C CH, Cl, Br, F, I, NH2, C(O)CH 3 i-propyl, tert-butyl, SEt, OMe, N(Me)2, methylene dioxy, and ethylehe 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

C

1 -6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SOaR 6 -SONH2, -CO2R 6 -CONHa, -NHCOR 6 -OC(O)NH2, or -NHSO 2

R

6 or Ring D is an optionally substituted ring selected from a -132- Va phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, .1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1u-isoindolyl, 2,3-dihydro-1-indolyl, C 5 isoquinolinyl, quinolinyl, or naphthyl ring;

R

T is T-R3' 1 wherein T is a valence bond or 0 a methylene; and

R

2 is hydrogen and-R 2 is hydrogen or a substituted-or unsubstituted group selected from aryl, o- 10 heteroaryl, or a eC 1 aliphatic group, or R 2 and R 2 are o taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula VI have one.

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

R

1 is -halo, a C- 6 haloaliphatic group, a C 1 6 alikhatic 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-1Ff-indolyl, isoquinolinyl, quinolinyl, or naphthyl; RY is T-R3', wherein T is a valence bond or a methylene and R is an optionally substituted group selected from CI-.

6 aliphatic, C 3 6 carbocyclyl, Cs-1o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -133- O R 2 is hydrogen and R 2 is hydrogen or a C- substituted or unsubstituted group selected from aryl, or t a C, 1 aliphatic group, or R 2 and R 2 are taken together C with their intervening atoms to form a substituted or 5 unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo.ring; and O Ring D is substituted by oxo or R 5 wherein C- each R 5 is independently selected fr6m -halo, -CN, -NO 2

-N(R

4 2 optionally substituted C1.i aliphatic group, -OR, 0 -CO 2 R, -CONH(R4), -N(R)COR, -SO 2 N(R4) 2 or -N (R SO2R'.

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 wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from C,-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 R1 is -halo, a C-.4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4 -tetrahydroisoquinolinyl, 1 2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl;

R

2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, 2 -CI-4 alkyl, 4 haloalkyl, -NO2, -O(CI- 4 alkyl), -COa(C:.4 alkyl), -CN, -134-

VO

o -S0 2 (Ci-4 alkyl), -SO 2

NH

2 -OC (O)NH 2

-NH

2 SO (C1- 4 alkyl) S-NHC(O) (CI-4 alkyl), -C(O)NH 2 or -CO(C..

4 alkyl), wherein the (C 1 4 alkyl) is a straight, branched, or cyclic alkyl Sgroup; and CN 5 Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -Cl, -CN, -CF 3 S-NH2, -NH(C1-4 aliphatic), -N(Ci-4 aliphatic) 2 -0(Cz-4 aliphatic), Ci-4 aliphatic, and -C0 2 (C-4 aliphatic).

Another embodiment of this invention relates to ND 10 compounds of formula Via:

NH

HN N 'N 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 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 8 -135-

VO

D Ring D is a 5-7 membered monocyclic ring or 8-10 membered C bicyclic 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 o -R 5 and at any substitutable ring nitrogen by -R 4 ci provided that when Ring D is a six-membered aryl or 0 heteroaryl ring, -R s is hydrogen at each ortho carbon \D 10 position of Ring D; o R 1 is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or CI- 6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R 8 said C-s 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 1 i- alkylidene chain;

R

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

-R

7 or and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R 4 each R' is independently selected.from hydrogen or an optionally substituted group selected from Ci-_ aliphatic, C6-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -136-

I_

each R 4 is independently selected from -a 7 -co 7 C- -COa(optionally substituted C 1 6 aliphatic), -CON(Rb 2 or -SO 2 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or S heteroaryl ring; each R 5 is independently selected from halo, -OR, o

-CO

2 R, -COCOR, NO 2 -SN, -80 2 R, -Si, C- -N(Rt) 2

-CON(R')

2 -S0 2

N(R

4 2 -N(R4)COR, C0 2 (optionally substituted Cl~5 aliphatic), IN 10 -N(RN(R 2 -CeNN(R 4 2 -CnN-OR, -N(R)CON()) 2 oN(Rt)SO2N(Rta,

-N(R')SO

2 R, or -OC(=O)N( 4 2 or R 5 and an. adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -503-, -N(R)SO 2

-SO

2 _C02-1 -N(R 6)Co_, -N (R6 d 0) 0-, -t(R)CON(R 6

-N(R')S

2

N(R

6

-C(O)N(R

6

-OC(O)N(R

6

-C(R

6

-C(R

6 2 S,1

-C(R)

2 SO-, -c(a 6 2

SO

2 -C(R6) 2 S0 2 -C(R6) 2

(R

6

-C(R

6 2

N(R

6

-C(R

6 2

N(R

6

-C(R

6

)=NN(R

6 -C(R6)cN-O-, -C(R 6 2

N(R

6

)N(R

6

-C(R

6 2 N(R So 2 N(a 6 or

-C(R

6 2

N(R

6 )CCON(R6) W is -C(R) 2 -C(R6) 2

-C(R

6 2 S0-, -C(R 6 5)SO 2

-C(R

6 2 -O 2 c( 6 -c(R6OC(O)N(R_ 6 -C(R6'hN(R 6

)CO-,

-C(R'h2N(Rt)C()o-,

-C(R

6 Ce (R6) 2N -c(R0) 2 N(R) SO 2

N(R

6

-C(R

6 3 N(R6)CON(a'6)-, or -CON(R)-; each R' 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 C 1 aliphatic group, or two a 7 -137-

NO

0 on the same nitrogen are taken together with the q nitrogen to form a 5-8 membered heterocyclyl or Sheteroaryl ring; and each RB is independently selected from an optionally substituted CI-4 aliphatic group, -OR 6

-SR

6

-COR

6 -S0 2

R

6 2

-N(R)N(R)

2 -CN, -NO 2

-CON(R

6 2 or o0 -COaR 6 Cr Preferred rings formed by the R 2 and R 2 groups o of formula Via include benzo, pyrido, pyrimido, and a \D 10 partially unsaturated 6-membered carbocyclo ring. These o are exemplified in the following formula VIa compounds having a pyrazole-containing bicyclic ring system: HN

N

NNN

NH INH Q

H

Qd N G 'N and Preferred substituents on the R 2 fused ring include one or more of the following: -halo, -NC(R) 2

-CI-

4 alkyl, -CI.

4 haloalkyl, -NO 2

-O(C-

4 alkyl), -CO 2 (CI-4 alkyl), -CN, -SO 2

(C

1 -4 alkyl), -SO0NH 2

-OC(O)NH

2 -NH2SO 2

(C

1 -4 alkyl), -NHC(O) (C-4 alkyl), -C(O)NH 2 and -CO(Ci-4 alkyl), wherein the (C2i- alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the. (Ci- 4 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 -138-

O

positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred

R

1 groups include -halo, an optionally substituted C-6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2

-SO

2

NH

2 N 5 -N(R 6 2

-CO

2

R

6 -CONH2, -NHCOR 6

-OC(O)NH

2 -or -NHS0 2

R

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

Examples of preferred R1 groups include -CF 3 -Cl, -F, o -CN, -COCH 3

-OCH

3 a, -OH, -CHCH 3

-OCH

2

CH

2

-CH

3

-CF

2 CHa1, NO 10 cyclohexyl, t-butyl, isopropyl, cyclopropyl, -COiM, o -CSC-CH 3

-SO

2

CH

3 -SO2NH 2

-N(CH

3 2

-CO

2

CH

3 -CONHa,

-NHCOCH

3 -OC(0)NH 2

-NHSO

2

CH

3 and -OCF 3 On Ring C preferred R 5 substituents, when present, include -halo, -CN, -N0 2

-N(R

4 2 optionally substituted

C

1 6 aliphatic group, -OR,

-CO

2

R,

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

N(R')

2 and -N(R')SO 2 R. More preferred Rs 5 substituents include -C1, CN, -CF 3

-NH

2

-NH(C

1 4 aliphatic), -N(C2-4 aliphatic) 2 -O(C.-4 aliphatic), C..

4 aliphatic, and -C0 2

(C

1 4 aliphatic).

Examples of such preferred R 5 substituents include -Cl,

-CF

3

-NH

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

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

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

-139- C Preferred substituents on the formula Via Ring 0 D include one or more of the following: halo, oxo, CN,

-NO

2 -N 2

-CO

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

N(R

4 2

-N(R

4 )S02R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, .Cs-10 aryl., or C1-. aliphatic. More preferred o Ring D substituents include -halo, CN, -oxo, -SR, -OR, -N(Rt)2, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-.o aryl, or C1-6 aliphatic. Examples of-Ring D.substituents include -OH, phenyl, methyl, C 2 0H, CH 2

CH

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

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

-OR

6 -CN, -SOaR', -S0 2 NH, 2

-CO

a

R',

-CONH

2

-NHCOR

6

-OC(O)NH

2 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-1-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; and

R

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

-140- Va o More preferred compounds .of formula VIa have one or more, and more.preferably all, of the features selected from the group consisting.of: Ring C is a phenyl or pyridinyl ring, .optionally substituted by wherein when Ring C and two adjacent substituents thereon form a bicyclic ring 0 system, the bicyclic ring system is a naphthyl ring, and R' is -halo, a C3 1 haloaliphatic group, a C 1 aliphatic group, phenyl, ot -CN; or Ring D is an optionally IND 10 substituted ring selected from phenyl, pyridinyl, o) piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyi, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1-indolyl, isoquinolinyl, quinolinyl, or naphthyl;

R

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

-C

1 4 alkyl, 4 haloalkyl, -NO 2

-O(C

1 alkyl), -CO2(C 1 4 alkyl), -CN,

-SO

2

(C

1 4 alkyl), -SO NH2, -OC NH 2 -NH2SO2 (c2-4 alkyl) -NEC(0) (c.

4 alkyl), -C(O)NH 2 and -CO(C 1 -4 alkyl), wherein the 4 alkyl) is a straight, branched, .or cyclic alkyl group;* and (c)-Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -halo, -CN, -NO 2

-N(R

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

-CO

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

optionally substituted by -R 5 wherein when Ring C and two -141adjacent substituents thereon form a bicyclic ring C( system, the bicyclic ring system is a naphthyl ring, and t R 1 is -halo, a C..

4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, .morpholinyl, o 1,2,3,4-tetrahydrbisoquinolinyl, 1,2,3,4c tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or o naphthyl; ID 10 R 2 and R 2 are taken together with their o intervening atoms to form a benzo, pyrido, orpartially unsaturated 6-memberede carbocyclo ring optionally substituted with -halo, -N(R 4 2 4 alkyl, -C 1 4 haloalkyl, -NO 2

-O(C

1 4 alkyl), -COa 2

(C

1 4 alkyl>, -CN, -S0 2

(C

1 -4 alkyl) -S021H 2

-OC(O)NH

2

-N}

2 SO2 (C 1 4 alkyl) -NHC(0) (C 1 4 alkyl), -C()NH 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 R5, wherein each R 5 is independently selected from -Cl, -CN, -CF 3 -NR2, -NH(C..

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

-O(C

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

(C

1 4 aliphatic).

Representative compounds of formula VI.and Iva are set forth In Table 5 below.

Table

CH

3

HHH

HN HN 2

HNZ

IN -N NN NJ% 0N NA N o ^o o VI-1 VI-2 VX-3 -142- FN <PN VI -4

H

4 VI -7 IPr

HN

4 IANf CN Jw N VI -13

CH

3 HN

_H

VI -5

HNZH

N VI -8 Pr VI -11

HN

N J-N VI -14

OH

3 VI -6 Et

N'

N t VI -9 Bu HNgPH VI -12

HN~

NA--

01Act -143- 9H

I-N

NAN

PN

VI -9 VI -17 F3 VI VI -18.

F n

F.

*PN

VI 21 VI -24 VI -22 VI -23

PN

VI -25

F

N

4 6N ci VI -26 VI -27 -144- VI-28 -VI-29 V 3 VI-30 N N VI-31.

NN

MI-34 VI -32 HN2P N VI-35

HNI-X

N CN VI -38

WN

N F 3 0) VI -33 2 N SN VI -36 HN Z

NN

VI-39 VI -37 -145-

N

VI -40 HN Z N VI -41 N~rANNf

F,

3

C

vi -44

HN

N

NH

2 VI -42 VI VI.-43

HN

N J-N Vla-i Hg NJ-N CN VI a- 4 Vla-2' Via-S

F

KNZ

.Vla-5

N

IL

VIa-6 -146- H H H HN; HN HN SN'N ON N'N Me NN N CF

N

NHMe o Va-7 VIa-8 VIa-9 ci 0

N

HN HN C N'N N'N N'N ONHg2 NHMe VIa-10 VIa-11 VIa-12 In another embodiment, this invention provides a composition comprising a compound of formula VI or Via and a pharmaceutically acceptable carrier.

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

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

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

NO

O amount of a composition comprising a compound of formula C< VI or VIa. This method is especially useful for diabetic patients.

SAnother aspect relates to a method of 5 inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising o administering to said patient a therapeutically effective C< amount of a composition comprising a compound of formula SVI or VIa. This method is especially useful in halting \D 10 or slowing the progression of Alzheimer's disease. SAnother aspect relates to a method of inhibiting the phosphorylation of 0-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula VI or Via. This methodis .especially useful for treating schizophrenia.

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

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

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

-148- C Another aspect relates to a method of treating C a disease that is alleviated by treatment with a CDK-2 t inhibitor, said method comprising the step of administering to a patient in need of such a treatment a (S 5 therapeutically effective amount of a composition comprising a compound of formula VI or Via. This method o is especially useful for treating cancer, Alzheimer's Ci disease, restenosis, angiogenesis, glomerulonephritis, o cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, ID 10 alopecia, and autoimmune diseases such as rheumatoid S- arthritis.

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

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

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

'RA

2 Rz

NH

HN N

NNN

VII

-149-

VO

D or a pharmaceutically acceptable derivative or prodrug 0 thereof, wherein: G is Ring C or Ring D; SRing C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one. or two ortho substituents independently selected from -R 1 any substitutable non- C\ ortho carbon position on Ring C is independently Ssubstituted by -R s and two adjacent substituents on \c Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or 1 0 partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -Re; 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 i provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D;

R

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

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C 1 -s aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo,. or -R 8 said C 1 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;.

-150-

VO

o R' is hydrogen or T-R3"; CN T is a valence bond, hydrogen, 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 Cq atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms o 5 selected from nitrogen, oxygen, or sulfur, wherein each Ci substitutable carbon on said fused ring formed by R 2 o and R 2 is substituted by halo, oxo, -CN, -NO 2 or ND -V-R 6 and. any substitutable nitrogen on said ring 0 formed by R 3 and is substituted by R 4 R is selected from an optionally substituted group selected from .C3-0 carbocyclyl,

C

6 -io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, Cs-o 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R 7

-COR,

-CO2(optionally substituted C-I 6 aliphatic), -CON(R) 2 or -SO 2

R

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

-CO

2 R, -COCOR, -NO6, -CN, -SO 2 R, -SR, -N(R -CON(R 2 -SOaN(R) 2

-N(R

4

COR,

-N(R

4

CO

2 (optionally substituted C.i- aliphatic), -N

-C=NN(R')

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

N(R

4 -N(R4)SO 2 R, or -OC(=O)N(R) 2 or R 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; -151o V is -SOs-, -N(R')S0 2 80O 2 0 -lN(R)C(O)o-, -N(R6)SO 2 -C(R6) 2 -C(R'b2S-, -C SO- -cCR') 2S02-, -C WR) 2 80 3 N WR) C -WCR) 2N (R6) -C (RE) 2 N(R6) C -cCR') 2 N CR')C -C (a 6 o-CR') 2 -C(R'hN21(R)S90 2 N'(a6) -,or -C (R6) 2 NRW)CON oW is 2 2 2 S0-, 2 S0 2 -CiRj) 2

SO

2 -C- (6 N(6C -CR')2N -CR 6) C (R -CCW) 2 N (R 2 NCR)so 2 -C 2 6CONR6_,or -CON(R')- 1 15 each R6 is. independently selected from hydrogen, an optionally substituted C-.

4 aliphatic group, or two R6 groups on the. same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroary. ring; each R 7 is independently selected from hydrogen or an optionally substituted CI- aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 memibered heterocyclyl or heteroaryl ring; each Ra is independently selected from an optionally substituted CI- aliphatic group,

OCR',

2 NCR6) 2 -N(R')N(R6) 2

-NO

2 -CON(R6) 2 or

-CO

2 R'6;-and R9 is selected from halo,. -OR, -C0 2 R, -000CR,

-NO

2 -ON, -80 3 R, -SR, 2 1 -CONR4),

-SO

2 2 -N(a 4 )coR, -N(R')C0 2 (optionally substituted C.-6 aliphatic),*-Ch~';

CN('

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

-NWCR

4

SO

2

N(R')

2

C

4 S0 2 R, or -OC N WR) 2

VO

0 Preferred RY groups of formula VII include T-R 3 CN wherein T is a valence bond or a methylene. Preferred R 3 t groups include an optionally substituted group selected from C3- 6 carbocyclyl, phenyl, or a 5-6 membered C 5 heteroaryl or heterocyclyl ring. Examples of preferred R

Y

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

SThe

R

2 and R 2 groups of formula VII may be IND 10 taken together to form a fused-ring, thus providing a Sbicyclic ring system containing a pyrazole ring.

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

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

H

HN N N I -3

NAN

NY N RH an d Preferred substituents on the R'/R 2 fused ring include one or-more of the following: -halo, -N(R) 2

-C

1 zalkyl, -Cz- 4 haloalkyl, -NO 2

-O(C

1 -4 alkyl), -CO 2

(C-

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

NH

2

-OC(O)NH

2 -NH2SO2 (C1-4 alkyl), -NHC (C 1 .4 alkyl) -C(0)NH 2 and -CO (CI- 4 alkyl), wherein the (C1-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (Ci- 4 alkyl) group is methyl.

When the pyrazole ring system of formula VII is monocyclic, preferred R 2 groups include hydrogen, Cz.

4 -153-

IND

S aliphatic, alkoxycarbonyl, (unisubst'ituted phenyl, c-i hyd-roxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminiocarbonyl,' and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, o isopropyl, propyl,, t-butyi, cyclopentyl, phenyl, C0 2

H,

co 2

CH

3 Cii 2 ow, CH 2 OCE,, cw 2 cii 2 ai 2 on, CH 2 Cli 2

CH

2 0i, o

CE

2

CE

2

CE

2

OCH

2 Ph, CH 2 CH2CH 2

VH

2 I CH 2

CH

2

CH

2 NHCOOC (CE,) 3 cIN 10 CONECH (CE,) 2

CONHCH

2

CH=CH

2

CONHCH

2

CH

2

DOE

3

CONHCH

2 Ph, oCONH (cyclohexyl), CON (Et) 2 CON (Oi,)cH 2 Ph, CONH-(n- C3H,), CA CON(Et) CE 2

CH

2 CH3, CONHCH 2 C{(C%3) 2 CON(n-C3 7 2 CO (3methoxynethylpyrroldin-i..yl), CONE (3 -tolyl),, CONE (4tolyl), CONECH3, Co (morpholin-1-yl), CO (4-methylpiperazin-: l-yl),'CONECH 2

CH

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

A

preferred RV' group is hydrogen.

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

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at. ortho and meta positions of Ring C. Examples of preferred bicyclic Ring.

C systems include naphthyl and isoquinolinyl. Preferred R'.groups include -halo, an optionally substituted CaL- 6 aliphatic group, phenyl, -COR', -01, -S0 2 R6, -80 2

NH,,

21

-CO

2 -CONE%, -NRCOR 6

-OC(O)NE

2 or -NESO 2 R6.

When R3 1 is an optionally substituted C 1 6 aliphatic group, the most preferred optional substituents are halogen.

Examples of preferred R' groups include -CF3, -Cl, -F, -Cli, -COCH 3 -OCH3, -OHi, -CH 2

CH

3

-OCH

2 CH,,

-CF

2

CH,

cyclohexyl, t-butyl, isopropyl, cyclopropyl, -CCH,

-SO

2 CH3, -SO 2

NH

2

-N(CH,)

2

-CO

2 CH3, -CONE 2 -NHCOCH3, -00(0) NH 2

-NHSO

2 CE3, and -OCF3.

-154 Va o On Ring C preferred R 5 substituents, when c present, include -halo, -CN, -NO 2

-N(R)

2 optionally ct substituted

C

1 6 aliphatic group, -OR,

-C

2

R,

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

N(R')

2 and -N(R 4

)SO

2 R. More e 5 preferred R 5 substituents include -C1, -CN, -CF 3 -NH2, -NH(C1_4 aliphatic), -N(C.4 .aliphatic)2, CD aliphatic), Ci- 4 aliphatic, and 4 aliphatic).

c- Examples of suich preferred R5 substituents include -Cl, o-F, -CN, -CFa,--NH 2 -NHMe, -NMe 2 -OEt, methyl, ethyl, IN 10 cyclopropyl, isopropyl, t-butyl, and -COEt.

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

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

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

-N(R

4 2 -cO 2

R,

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

N(R

4 2 -N(R')S0 2 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-io aryl, or C.-6 aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or-unsubstituted group selected from 5-6 membered heterocyclyl,

C

6 o aryl, or C3..

6 aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 O0H, CH 2

CH

2 O, pyrrolidinyl, OPh, CF3, iCH, C1, -155o Br, F, I, NH 2 C(0)CH 3 i-propyl, tert-butyl, SEt, OMe, 0 N(Me) 2 methylene dioxy, and ethylene dioxy.

Preferred formula VII compounds have one or Smore, and more preferably all, of the features selected from the group consisting of: Ring C.is a phenyl or pyridinyl ring, Soptionally substituted by -R s wherein when Ring C and two C adjacent substituents thereon form a bicyclic ring Ssystem, the bicyclic ring system is selected from a 10 naphthyl, quinolinyl or isoquinolinyl ring, and R' is S-halo, an optionally substituted CI-6 aliphatic group,

C

N phenyl, -COR', -OR 6 -CN, -SO 2

R

6 -SO2NH, -N(R6) 2

-COR

6 -CONH2, -NHCOR', -OC(O)NH, or -NHSO 2 R6; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-IH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

R

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

R

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

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

system, the bicyclic ring system is a naphthyl ring, and -156-

VO

g R 1 is -halo, a C3.

6 haloaliphatic group, a CI- 6 aliphatic CA group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, Ce 5 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- Sdihydro-iH-indolyl, isoquinolinyl, quinolinyl, or CA naphthyl; O

R

y is T-R 3 wherein T is a valence bond or

CA

I N 10 a methylene and R 3 is an optionally substituted group o selected from C 3 carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring;

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a C1-6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and Ring D is substituted by.oxo or R 5 wherein each R 5 is independently selected from -halo, -CN, -NO 2

-N(R

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

-CO

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

N(R

4 or -N SO 2

R.

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

R

Y is T-R 3 wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and -157- 1-r^ Va o R 1 is -halo, a C-.

4 aliphatic group optionally substituted 0 .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; C R2 and Ri 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring o optionally substituted with -halo, 2

-C

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

4 alkyl), -CN,

-SO

2

(C

1 -4 alkyl), -SO 2

NH

2

-OC(O)NH

3

-NH

2

SO

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

-NH

2 -NH(C3 4 aliphatic), aliphatic) 2 -0(Ca 4 aliphatic), C14 aliphatic, and -C0 2

(C.

4 aliphatic).

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

Table 6.

F' F H H HN .HN6. HN

I.

N

4 N N N VIE-1 VII-2 VII-3 -158-

N

4

"N

VI 1-4

F

N N VII-5 VI 1-6 1111-7 vii- S

ON

4

F

8 C-k -VII -9 VII1-12

HN

N

NIIi vil-11 VII1-13 VII1-14 -3.59-

HNQP

A)"

NOlN

OH

HA

N

4

N

0 3

C

VII-16

N

4

N

VII -19

HN

N AN

NH)C

VII -22 VII -1.7 N -N VII -20 .VII-18 VII .21 t-CH VI 1-24 VII1-23 HN2V N'zN CF3 n) HN 11H

N

4 N CI tOkk HN44 OAN Cl VII -27 VII -26 -260- CH3 HN NN VII-28 HN N VII-31 CHs

HNN

H

t NV -34N VII-34

HNZ

NN

NZ

0 0 VII-29

F

NHN

VII-32 CHs

HN-

NH

N' N VII-35

CH

3

HNP"

VII-33 El

NN.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 VII.

Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a -161oD therapeutically effective amount of a composition o comprising a compound of formula VII.

Another aspect relates to a method of enhancing Sglycogen 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 patients.

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

Another aspect relates to a method of inhibiting the phosphorylation of 0-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula VII. This method is especially useful for treating schizophrenia.

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

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

.^T

ID

0 especially useful for treating cancer, such as colon, C- ovarian, andbreast cancer.

bJ t One aspect of this invention relates to a method of inhibiting CDK-2 activity in a patient, 5 comprising administering to the patient a therapeutically effective amount of.a composition comprising a compound o of formula VII.

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

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

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

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

VO

C R R2 HN H 0 (c or a pharmaceutically acceptable derivative or prodrug o thereof, wherein: C Z is N or CR 9 2 is N or CH, and Z 3 is Nor CRx, provided that one of Z 1 and Z 3 is nitrogen; G iS Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from 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 -R8; 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 halo, oxo, or -R 5 and at any substitutable ring nitrogen by

-R

4 provided that when Ring D is a six-membered aryl -164o or heteroaryl ring, -R s is hydrogen at each ortho C carbon position of Ring D; t

R

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

T-V-R

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

R

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

R

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

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or 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, or

-V-R

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

R

3 is selected from -halo, -OR,

CO

2

R,

-COCOR, -COcsCOR,

-NO

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

-CON(R')

2

-SO

2

N(R

7 2 -N(R 7

)COR,

C2 (optionally substituted

C

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

-C=NN(R

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

-N(R

4

)SO

2 R, or N(R 2; each R is independently selected from hydrogen or an optionally substituted group selected from C-.

6 aliphatic, Cs-o 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -165-

IN

0 each R is independently selected from -t7, -COR 7

-CO

2 (optionally substituted Cl- 6 aliphatic) -CON (R 7 2 or -SO 2 R7, or two H' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryi ring; each R 5 is independently selected from halo, -OR, -C(nO)R, -CO 2 R, -COCOR, 7 N0 2 -CIN, -SO 2 R, -SR, -N(R4 2 -CON(R4) 3 -S0 2

N(R')

2

-N(R')COR,

o C0 2 (optionally substituted C 1 6 aliphatic),

-N(R

4 2

-C=NN(R

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

N(R)

2

-N(R

4

)SO

2 R, -or 2 or Rs and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -S02-, -N(R')S0 3 -S0 2

N(R

6 -Co 2 1

-N(R

6 -N (R 6 CON (R 6 -N S0N (R 6 -N (R 6

-C(O)N(R

6 -OC(o)N(RJ-,

-C(R

6 2 -C(R6) 2

S-,

(R'

2 S0-, C(R') 2 S0-, -C(R 6 V3SON(R 6

-C(R)N(R,

-C(R6) 2

N(R

6

-C(R)

2

N(R

0

-C(R

6 2 N(a')N(a 6

-C(R

6 2

N(R

6 )so 2

N(R

6 or -C (R 6 2

N(R

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

-C(R

6 2

-C(R'

2 SO-, 2 SO0-, -C(R6) 2 so 2 N(a 6

-C(R

6 2

N(R

6 -CO-,I COi

-C(R

6

-C(R

6 2

N(R)CO-,

-C(R

6 )N(Rnc(o)o-,

-C(R

6 =NN(R 6

-C(R

6

-C(R)

2 N(R6)N(R 6 2

N(R')SO

2 N(R)

-C(R

6 2 N(R)cON(R6) or -CONH')-; each H 6 is independently selected from -hydrogen, an optionally substituted CI 4 aliphatic group, or two H' groups on the same nitrogen atom are taken together with the nittogen atom to form a 5-6 membered heterocycly or heteroaryl ring;.

each k' is independently selected from hydrogen or an optionally substituted c 1 6 aliphatic group, or two R' -166- Va S on the same nitrogen are taken together with the CN nitrogen to form a 5-8 membered heterocyclyl or heteroaryl .ring; each R' is independently selected from an optionally substituted C..4 aliphatic group, -SR6, -COR',

-SO

2 -14(R') 2

-N(R

6

)N(R

6

-NO

2 -CON(R')2, or -C0 2

R

6 and Rs is selected from halo, -OR,

-CO

2 R, -COCOR, -N02, -CN, -SO 2 R, -SR, 2

-CON(R')

2

-SO

2

N(R')

2

-N(R

4 )COR, -N(R)CO02 (optionally 0 substituted

C

1 aliphatic), -N(Rt)N(R 4 2

-C=NN(R')

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

)CON(R')

2

-N(R

4 )S0 2

N(R')

2 -N(R SO 2 R, or Accordingly, the present invention relates to compounds of formula VIIa, VIIIb, VIIIc and VIIId as shown below: NH H N tNH tN NH SN N N N

NN

N GR G ,and VIlla VIIIb VIIIa VIId Preferred RX groups of formula VIII 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 Cz-G aliphatic, phenyl, or a 5-6 membered beteroaryl or heterocyclyl ring. When R is -OR, preferred R groups include an optionally substituted group C1-6 aliphatic group such as alkyl- or dialkylaminoalkyl and aminoalkyl. Examples of -167-4 preferred RX include acetamido, CN, piperidinyl, o piperazinyl, phenyl, pyridinyl, imidazol-1-yl, imidazol- 2-yl, cyclohexyl, cyclopropyl, methyl, ethyl, isopropyl, t-butyl, NHaCH2CH 2 NH, and NH2CCHH 2 0.

Preferred R' groups of formula VIII, when .present, include R, OR, and N(R) 2 Examples of preferred R9 include methyl, ethyl, NH 2

NH

2

CH

2

CH

2 NH, N(C 3 )2CHa 2

CH

2

NH,

en N(CH 3 2

CH

2

CH

2 0, tpiperidin-1-yl) CH 2 aC 2 0, and NH2CH220.

The R2 and R 2 groups of formula viII may be c- 10 taken together to form a fused ring, thus providing a o bicyclic ring system containing a pyrazole ring.

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

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

NH

HN

N N \N qf NN /NH NH>[H and Preferred substituents on the formula VIII R2/R' fused ring include one or more of the following: -halo, -N(R4)2, -CI-4 alkyl, -CI.4 haloalkyl, -NO2, -0(C3alkyl), -CO2 (C.4 alkyl), -CN, -SO2 alkyl), -SO 2

NH

2 -OC(O)NH2,

-NH

2 SO0 2 alkyl), -NHC (Cj_4 alkyl),

-C(O)NH

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

When the pyrazole ring system of formula VIII is monocyclic, preferred

R

2 groups include hydrogen, C.4 -168aliphatic, alkoxycarbonyl,' (un)sabstituted phenyl., CA hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nsheterocyclyl~carbonyl. Examples of such preferred R2.

substituents include methyl, cyclopropyl, ethyl, 0 isopropyl, propyl, t-butyl,- cyclopentyl, phenyl, CO 2

H,

CA C02CR 3 01 2 0H, O{ 2

OCH

3

CH

2

OH

2

CH

3 OH, CH 2

CZH

2

CH

2

OCH

3 o OCH 2 CH2C 2 00I 2 Ph, 0U 2 a1 2 0! 2 Nm 2

CH

2 aT 2 a{ 2 NHCoOC (CH 3 3 IND 10 CONHCH(c5 3 2 coisC 2 cs=oi 2 CONHCs~H 2 oCa2C 3

CONHOH

2 Ph, oCONEH(cyclohexyl), CON( CO(H 3

)CU

2 Ph,CO1 1-37 CON (Et) CH 2

OH

2 Ci 3

CONHCH

2 CH (CH 3 2, CON (n-C 3 7 2 CO (3methoxymethylpyrroliain-1...yl), CONH(3-tolyl), CONH(4tolyl), CONROH 3 CO (morpholin-l-yl), CO (4-methylpiperazinl-yl), CONHCH 2

CR

2 OH, CONUI 2 and CO(piperidin-l-yl).

A

preferred R 2 group is hydrogen.

When G3 is Ring C, preferred formula VIII Ring C groups are phenyl and pyridinyl When two adjacent substituents on Ring d are taken together to fonn 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 naphtbyl and isoquinolinyl. Preferred R' groups include -halo, an optionally substituted CIaliphatic group, phenyl, -OR6, -OR6, -CN, -SO 2 -S0 2

N

2

I

-14(R 6 3 -C0 2

R

6 -CONI!, -NEICOR6, -OC(O)14H2, or -NRSO 2 When R' is an optionally substituted aliphatic group, the most preferred optional substituents are halogen.

Examples of pre ferred R' groups include -OF 3 -Cl, -F, -ON, -OCH3, -OH, -CR3013, -OOCz2CaI -CH 3 -CP2ai 3 cyclohexyl, t-butyli isopropyl, cyclopropyl, -cCl, -cSC-CH 3 -so.Icw,, -SO 2

NH

2 -14(013)2, -CO2CH~, -CONS 2 NHC0C%1 -00(0) NH2, -NHSO 2

CII

3 and -OCP 3 e-j On Ring C preferred Rs substituents, when 0 present, include -halo, -CN, -N0 2

-N(R)

2 optionally substituted aliphatic group, -OR,

-CO

2

R,

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

N(R)

2 and -N(R)SO 2 R. More preferred Rs substituents include -Cl, -CN, -CF 3 -NH2, -NH (CI-4 .aliphatic)., N(CL.4 .aliphatic)2, -0(CI-4 o aliphatic), C14 aliphatic, and -CO2(C.-4 aliphatic).

C Examples of such preferred R 5 substituents include -C1, -CN, -CF3, -NH 2 -NUMe, -NMe 2 -GEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -CO 2 Et. 0 tWhen G is Ring D, preferred formula VIII Ring D monocyclic rings include substituted and.unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl,.

pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.

When two adjacent substituents on Ring D are taken' together-to form a fused ring, the Ring D system is bicyclic. Preferred formula VIII Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3.-dihydro-1I-isoindolyl, 2,3- 29 dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

Preferred a 5 substituents on Ring D of formula VIII. include halo., oxo, CN, -NO 2 2 -C0 2

PR

-CONEH(R

4 -SO2N(R') 2

-N(R)SO

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

C

6 s-o aryl, or C3-s aliphatic. More preferred Rs 5 substitdents include -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Os..o aryl, or CI-6 aliphatic. Examples of Ring D substituents include -OH, phenyl, :methyl, CHZOH, CH2CH 2 OH, pyrrolidiny, OPh, CF 3 OSOH, C1, Br, F, I, NH 2 -170- 4w

VO

C(O)CH

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

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

-OR

6 -CN, -S0 2

R

6 -SOaNH2, -N(R 6 2

-CO

2

R

6

-CONH

2

-NHCOR

6

-OC(O)NH

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

R

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

R

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

More preferred compounds of formula VIII have one-or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or.pyridinyl ring, optionally substituted by -R s wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and -171- QD R' is -halo, a C1- haloaliphatic group, a CI.- aliphatic 0q group, phenyl, or -CN; or Ring D is'an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-.

Stetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3o dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or C naphthyl;

R

x is T-R 3 wherein T is a valence bond or a 10 methylene and R 3 is CN, -R or -OR; f S(c) R' is hydrogen and R 2 is hydrogen or a CI .substituted or unsubstituted group selected from aryl, or a Ci-6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and each R 5 is independently selected from -halo, -NO, -N(R 4 optionally substituted Ci-.

aliphatic group, -OR, -CO 2 R, -CONH(R 4

-N(R')COR,

-SO

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

)SO

2

R.

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

R

x 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 C1-s aliphatic,.phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R s wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system,. the bicyclic ring system is a naphthyl ring, and R' is -halo, a aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, -172f. 1

I

Va piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1 2 3 ,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; S(c) R' and R" are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or O partially unsaturated 6-memrbered carbocyclo ring optionally substituted with -halo, -C.1-a alkyl, o ~-Cl4 haloalkyl, -NO 2

-O(C

1 4 alkyl), -C0 2 4 alkyl), -CN, -SO2(C-1-4alkyl),

-SONH

2

-OC(O)NH

2

-NH

2 SO2 (C 1 4 alkyl), O -NHC(0) alkyl), -C(0)NH 2 or -CO(C 1 -4 alkyl), wherein the (c 1 4 alkyl) is a straight, branched, or cyclic alkyl group; each R 5 is independently selected from -C1, -CN, -CF 3

-NH

2 -NH(C1- 4 aliphatic), 4 aliphatic) 2

-O(C

1 -4 aliphatic),

C

1 o.

4 aliphatic, and -C02(C 1 4 aliphatic); and R9 is R, OR, or N(R 4 2 Representative compounds of formula VIII are set forth in Table 7 below.

Table 7.

Me 1 Me HN HNAHN VIII-1 VIII-2 VIII-3 -173- Et J44H VIII-4 1.7111-5 B fu

HN*P

N

4

"N

VI1I1-7' Me HN J*?1H VIII -6 INr

HN<

VIII -9

N

4

N

VIII -12 VIII-8

HN?

NNo VI Il-li

HN

NH

2 0 VIII-13 VIII -14 VI 11-15 -174- 2-,fi Vill-1s VIII-17 I-I 1 Vill 18

N

4 1-N CF 8 HN 4XsfN b VIII-19 N'-N CF 3 VIII1-22 N'-N CF 3 Me VIII -20 HNt N C4 VIII-23 N'N CF 3

H

2 N JO' VIII-21

NV

VIII -24

HN

N N C N VIII -25

-NH

VIII -26 F HN Z

N

4 A,.N CI VIII -27 -175- VIII-28 VIII-29 HN VIII -32 a HN2PH N- F VIII VIII -33 VIII-31 VIII1-34 VIII -35 VIII -36 HNl-N

N

4 N CF 3 Me.N%jXO VI11-38

HN

N'N CI Me.N 0 VII11-39 VII11-37 -176oND HN

H

CF

3

CI

VIII-41 -V111-42 Cl

F

yqWN H9JH -l>HN <HN NN o F CF-

CF

3 oNNAb; H AWX6i 5VIII-43 VIII-44 IN CF 3 C1yN CF 3 'N CF,, VIII-46 VIII-47 VIII-48

F]

HNN N>H c H1NO 3 CIN"4N CF.

CF

3 F VIII-49 VIII-50 VIII-Si -177- N QyN CF 3 N C N CF 3 VIII-52 VIII-53 VIII-54 0 ci Me ,H H H HN N f H

HN

2 SN CFs H 2 NNN C 0 N-t 5VIII-55 VIII-s VI-56 VIII-57 In another embodiment, this invention provides a composition comprising a compound of formula VIII and a pharmaceutically acceptable carrier.

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

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

Another aspect relates to a method of enhancing.

glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula -178- .o 4 j,.y y

NO

S VIII. This method is especially useful for diabetic.

c-i 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 o amount of a -composition comprising a compound of formula VIII. This method is especially useful in halting or o slowing the progression of Alzheimer's disease.

Another aspect relates to a method of

NO

o inhibiting the phosphorylation of f-catenin in a patient *in need thereof, comprising 'administering to said patient a therapeutically effective amount of a composition .comprising a compound of formula 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 ihhibitor, 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 CJDK-2 -activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising -a compound of formula. VIII.

-179- ND 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 Sadministering to a patient in need of such a treatment a J 5 therapeutically effective amount of a composition comprising.a compound of formula VIII. This method is Sespecially useful for treating cancer, Alzheimer's M disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid 0 arthritis.

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

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

The above formula I compounds contain a pyrazole ring bearing the R 2 and R 2 substituents. In their search for further inhibitors of the protein kinases GSK and Aurora, applicants sought to replace the pyrazole moiety of formula I with other heteroaromatic rings. one of the more effective pyrazole ring replacements was found to be a triazole ring. Inhibitors having this triazole ring are otherwise structurally similar to the formula I compounds and are represented by the general formula IX: -1 80

I

ID R RR2

S-HN)N

e3 ix C- or a pharmaceutically acceptable derivative or prodrug thereof, wherein: C Z' is nitrogen or CR 9 and Z 2 is nitrogen or CH, provided that at least one of Z' and Z 2 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents Sindependently selected from.-R, 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 -Ra; 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 -181-

VO

CD heteroaryl ring, -R 5 is hydrogen at each ortho carbon Cq position of Ring D;

R

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

T-V-R

6 phenyl, 5-6 Smembered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by o up to three groups independently selected from halo, eC oxo, or -R 8 said C 1 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 0 10 and an adjacent substituent taken together with their Sintervening atoms form said ring fused to Ring C; c Rx and RY are independently selected from T-R 3 or R x and

R

y are taken.together with their.intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8' membered ring having 0-3 .ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R x and R Y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by R" and R is substituted by R 4 T is a valence bond or a CI-. alkylidene chain;

R

2 is -R or -T-W-R 6 1

R

3 is selected from -halo, -OR,

-CO

2

R,

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

-CON(R

7 2

-SO

2

N(R

7

-N(R')COR,

-N (R 7 C0 (optionally substituted Ci-6 aliphatic),

-N(R

4 N

R

4 2

-C=NN(R

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

)CON(R

7 2 -N(R S0 2 N (R 7 2 -N (R 4 S0R, or -OC(=0)N 2; each' R is independently selected from hydrogen or an optionally substituted group selected from C.ialiphatic, Cs-o0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -182- *a. ^f *ts .S sa each R 4 is independently selected f rom -R_ 7

COR

7 (N-C02a(optionally substituted d1_6aliphatic), -CON (R 7 )2, Or -SO 2 or two Rt 4 on the same nitrogen are 'taken together to form a 5-8 membered heterocayclyl or heteroaryl ring; each. R 5 is independently selected from halo, -OR, 0

-CO

2 R, -COCOR, -NO 2 -UN, -SO 2 R, -SR, ci-NRW) 2, -CONCW) 2 S0 2 N(Rt 2 -OCC=O)R, -NA(RtCOR, o-NC(R 4 C02 (optionally <'substituted

C-

6 aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R)

2 -C=N-OR, -N(RtCONR') 2 o

SO

2 N(R4) 2 -N (R 4 )OR or -OC(-O)N(R) 2 or R 5 and an madjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -S- 1 -S02-, -N(R 6 )S0 2 -S0 2

N(R

6

-N(R

6 -C02-, -N CR 6 CONCR') -NCR') SO 2 N CR') -NCR') NCR') -cC0O)N(R') 2 2 s-, -cCn') 2 2 so 2

-C(R

6 2 S0 2 N(R6)_ 2 2 2 -C -0(R 6 2 -CR 6) 2 N SO 2 .N (R6) -,or -C (Rr' 2 N (R6) CON W is 2 2 -C(R6) 2 2 S0 2 2 S0 2 2 I4Ut')-, -003-, -C -C(R)OC

-C(RW)

2 N (R 6)Co-,

C(R')

2 -C(R)2NR6)(R6-, 2 N(R')so 2 -C((')1qR6)0IqR6-, or -CON(R') each It' is independently selected from hydrogen, an 6 optionally substituted Cj..4 aliphatic group, or two It groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5- 6 miembexed heterocyclyl or heteroaryl ring; each It' is independently selected from hydrogen or an optionally substituted Ci..s aliphatic group, or two Rt'

I

O on the same nitrogen are taken together with the C nitrogen to form a 5-8 membered heterocyclyl or Sheteroaryl ring; each R' is independently selected from an optionally substituted C 1 -4 aliphatic group, -OR 6

-SR

6

-COR

6 -S02R 6

-N(R

6 2

-N(R

6

)N(R

2 -CN, -NO 2

-CON(R')

2 or O -CO 2

R

6 and C- R' is selected from halo, -OR, -C02R, -COCOR,

-NO

2 -CN, -SO 2 R, -SR, 2

CON(R

4 2 \O 10 -SO 2

N(R

4 2 -N(Rf)COR, -N(R4)CO 2 (optionally o substituted Ci-6 aliphatic), -N(R')N(R 4 2

-C=NN(R

4 2 -C-N-OR,

-N(R')CON(R

2, -N(R 4

S

2

N(R

4 2

-N(R

4 )S02R, or -C N (R 4 2 Compounds of formula IX may exist in alternative tautomeric forms, as in tautomers 1-3 shown below. Unless otherwise indicated, the representation of any of these tautomers is meant to include the other two.

S

R2 2 N4, N< -HN HN H HN -NH HN I H Z2 RY RY ZI' R y

Z

1 2 3 The R* and R Y groups of formula IX may be taken together to form a fused ring, providing a bicyclic ring system containing Ring A. Preferred RX/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said Rx/y ring is optionally substituted. Examples of Ring A systems are shown below by compounds IX-A through IX-DD, wherein Z 1 is nitrogen or C(R 9 and Z 2 is nitrogen or C -184-

IND

IN

CA

NH

H73'- f OJ2X NQ l- .IX -B 'K-c.

32-3H Il-F., Il-0 Il-H II- I Ix a nx- IX- L N Y z flK IX-N Is-o ~i aA- I-3%

N'

HNN

IS-P

IS-Q

IX-R

HN

Z

HN'3't' 0 Z1, 'K-s IX-T

IS-U

HN37

HNA'

I

A

4 IS-v 3IS-s nx-S

IS-Y

Ix- Z

XX-AA

12-BE tx-cc

IX-DD

Preferred bicyclic Ring A systems ~of formula IX include TX-A, IX-B, IX-C, IS-fl, IS-H, IS-Fr IS-S. IS-E, IS-I, IX-J, IS-K, IS-LI and 1K-M, more preferably Il-A, -186- IX-B, IX-C, IX-F, and IS-H, and most preferably Is-A, IX- B, and IS-H.

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

Preferred RY groups, when present, include T-R 3 wherein T is a valence bond or a methylene,.and

R

3 is -N(R 4 2 or -OR. Examples of preferred RY include 2-pyridyl, 4pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl or halosubstituted phenyl, and methoxymethyl.

In the bicyclic Ring A system of formula-IX, the ring formed by RX and RY taken together may be substituted or unsubstituted. Suitable substituents include halo, -OR, -COo 2 R, -COCOR, -NO 2

-CN,

-SO

2 R, -SR, 2

-CON(R

4 2 -so0 2

N(R')

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

CO

2 (optionally substituted C 1 6 aliphatic),

-C=NN(R')

2

-C=N-OR,

-N CON(R 4 2

-N(R')SO

2 N (R4) 2

-N(R

4

SO

2 R, or

-OC(=O)N(RW)

2 wherein R and R' are as defined above.

Preferred R 1 /Ry ring substituents include -halo, -OR, -COR, -CO 2 R, -CON(R')2, -CN, or 2 wherein R is an optionally substituted C 1 6 aliphatic group.

Preferred R 2 groups of formula IX include hydrogen, C.

4 aliphatic,. alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, monoor dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl; propyl, t-butyl, cyclopentyl, phenyl, C0 2

H,

CO

2 CH3, CI 2 OH, CH20CH 3 CH2CH 2 CH30H, CH 2

CH

2

CH

2 0CH, Va o CCH 2 CH20CH 2 Ph, C H2

CH

2

CH

2

NH

2

CH

2

CH

2

CR

2 NRCOOC (CH 3 3 SCONHCH (Na 3 2, CONHcIHaCHCH 2

CONCH

2

CH

2

OCH

3

CONHCH

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

CON(CH

3

)CH

2 Ph, .CONRI(n-C 3 H7) CON(Et)aCH2C 2

CH

3

CONHCH

2

CH(CH

3 2 CON(n-CH,) 2 CO(3methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4tolyl), CONHCH 3 CO(morpholin-i-yl), CO(4-methylpiperazin- Sl1-yl), CONHCH 2

CR

2 0H, CONH 2 and CO(piperidin-l1-yl). A Cg more preferred R2 group for formula IX compounds is hydrogen.

An embodiment that is particularly useful for treating GSK3-mediated diseases relates to compounds of c. formula X wherein ring A is a pyrimidine ring: R2 N -ANH

HN/LN

RY N x~x 1 or a pharmaceutically acceptable derivative or prodrug thereof, wherein; Ring C is selected from-a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from any substitutable nonortho carbon position on Ring C is independently substituted by -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, -188- 24

VO

0 said fused ring being optionally substituted by halo, C-i Oxo, or -R 8 SR3 is selected from -halo, -CN, -N0 2

T-V-R

6 phenyl, 5-6 C membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C.- 6 al'iphatic group, said phenyl, heteroaryl, and.heterocyclyl rings.each optionally substituted by o up to three groups independently selected from halo, Cq oxo, or said C1-6 aliphatic group optionally Ssubstituted with halo, cyano, nitro, or oxygen, or R 1 IND 10 and an adjacent substituent taken together with their 0 intervening atoms form said ring fused to Ring C;

R

x and R Y are independently selected from T-R 3 or Rx and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R X and R y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by R and R Y is substituted by R'; T is a valence bond or a Ci-4 alkylidene chain;

R

2 is -R or -T-W-Re;

R

3 is selected from -halo, -OR, -CO2R, -COCOR, -COCH 2 COR, -NO 2 -CN, -S 2 R, -SR,

S-N(R

4 2

-CON(R

7 2

-SO

2 -N(R')COR, -N (R 7 C02(optionally substituted Ci- 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 SON (R 2

-N(R)SO

2 R, or -OC(=O)N(R 2; each R is independently selected from hydrogen or an optionally substituted group selected from C2-s aliphatic, CS-_o aryl, a heteroaryl ring having 5-10 ring-atoms, or a heterocyclyl ring having 5-10 ring atoms; -189-

I

Seach R' is independently selected. from -CoR7, -CO2(optionally substituted C-6s aliphatic),

-CON(R)

2 or -SO 2 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocycly1 or heteroaryl ring; each R 5 is independently selected from halo, -OR, O

-CO

2 R, -COCOR, -NO 2 -CN, so0 2 R, -SR; -N(R 2

-CON(R)

2

-SO

2 N(Rt) 2 -N(R)COR, o -N(R C2O(optionally substituted CI-6 aliphatic), .0 10 -N(R4)N(R 4 2

-CNN(R

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

SO

2 N a) 2 -N (R')SO2R, or -OC N 2 or Rs and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is

-SO

2 -N(R')S0 2

-SO

2

-N(R

6 -C02-,

-N(R

6

)CON(R

6

-N(R')SO

2 2

-C{R

4 )2S-, 2 so-, -c(RY) 2 s0 2 -c(R6)2so 2

-C(R)

2 N

-C(R

6 2 2

-C(R

6 2 N(R6)N(R 6

-C(R

6 2

N(

6

)SO

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

-C(R

6 )ns0-, -C (R 6 2S02-,

-C(R

6 )S0 2

N(R

6

-C(R

6 2 -C2-,

-C(R

6 2

N(R

6

)CO-,

-C(R

6 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 2 N (R 6 CON(R) or -CON (R 6 each R' 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; eachR' is independently selected from hydrogen or an optionally substituted CI-6 aliphatic group, or two R 7 -190- .24< ~i~ :'lii~ ~e

VO

o on the same nitrogen are taken together with the C( nitrogen to form a 5-8 membered heterocyclyl or c heteroaryl ring; and each R e is independently selected from an optionally (Ce 5 substituted CI- 4 aliphatic group, -OR 6

-SR

6

-COR

6

-SO

2

R

6

-N(R

6 2 -N(R N(R 6 2 -CN, -NO 2

-CON(R')

2 or C0 -CO a

R

6 CA Compounds of formula X are structurally similar S-to compounds of formula II except for the replacement of I ND 10 the pyrazole ring moiety by the triazole ring moiety.

SPreferred R, R y and Ring C groups of formula X are as described above for the formula II compounds. Preferred formula X compounds have one or more, and more preferably all, of the features selected from'the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 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" is hydrogen or C-.

4 aliphatic and R Y is T-

R

3 or R x and R Y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens;

R

I is -halo, an optionally substituted

C

1 ialiphatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2

R

6

-SO

2 NH2, -N (R 2

-CO

2

R

6

-CONH

2

-NHCOR

6 -OC(0)NH 2 or -NHSO a

R

6 and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci- aliphatic group.

-191-

I

VO

.D More preferred compounds of formula X'have one CA or more, and more preferably all, of the features c selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, C 5 optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring 0 system, the bicyclic ring system is a naphthyl ring; C R x is hydrogen or methyl and R Y is -R, SN(R')R or -OR, or Rx and R Y are taken together with their \D 10 intervening atoms to form a benzo ring or a 5-7 membered 1 o carbocyclo ring, wherein said ring formed by R* and R Y is optionally substituted with halo, -OR, -CO 2

R,

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

-CON(R

4 2

-SO

2

N(R')

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

CO

2 (optionally substituted Ci-s aliphatic), -C=NN(R)2, -C=N-OR, -N(R')CON(R)2a, -N(R 4 )SO2N(Rt, -NtRo)SO0R, or -OC 2 R' is -halo, a CI-6 haloaliphatic group, a C3 1 6 aliphatic group, phenyl, or -CN;

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl or a Ci-6 aliphatic group;.and each R 5 is independently selected from -halo, -CN, -NO2, -N(R) 2 .optionally substituted C-g aliphatic group, -OR, -CO2R, -CONH(R'), -N(R')COR, -S02N(R4'), or -N(R)SOR.

Even more preferred compounds of formula X have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring; -192-

VO

RX is hydrogen or methyl and R Y 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 2 and R

Y

C 5 are taken together with their intervening atoms to form an optionally substituted benzo ring or a 6-membered 0 carbocyclo ring; S.

R

1 is -halo, a C2-4 aliphatic group Soptionally substituted with halogen, or -CN; Va 10

R

2 is hydrogen or a CI-6 aliphatic group; and o each R 5 is independently selected from -Cl, -CN, -CF 3

-NH

2

-NH(C-.

4 aliphatio),

-N(C

1 -4 aliphatic) 2 -O(CI.4 aliphatic), CI-4 aliphatic, and -C02 (Ci-4 aliphatic).

.Another embodiment of this invention relates to compounds of formula XI: HND %y N

XI

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

-R

s and at any substitutable ring nitrogen by -R 4 -193- Va Fl provided that when Ring D is a six-membered aryl or c- heteroaryl ring, -R5 is hydrogen at each ortho carbon t position of Ring D; ax and RY are taken together with their intervening atoms to form a fused benzo ring or 5-8 membered carbacyclo ring, wherein any substitutable carbon on said fused Sring formed by RX and RY is substituted by oxo or T-R; T is a valence bond or a C 1 4 alkylidene chain;

SR

2 is -R or -T-W-RG; N 5 R 3 is selected from -halo, -OR, -CO 2 R, -COCOR, -COca 2 COR, -NO 2 -s(0)2R, -SR, 2

-CON(R)

2

-SO

2

N(R

4 2 -N(R')COR,

-N(R')CO

2 (optionally substituted Cls. aliphatic), 2

-C=NN(R')

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

-N(R

4

)SO

2 N(a) 2

-N(R

4

)SO

2 R, or -OC(=O)N(R4)2; each R is independently selected from hydrogen or an optionally substituted group selected from C 16 aliphatic, 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',

-CO2(optionally substituted

C

1 -s.aliphatid),

-CON(R

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

-SO

2 R, -SR,

-N(R)

2

-CON(R')

2

-SO

2

N(R')

2 R, -N COR,

CO

2 (optionally substituted

C

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

-C=NN(R

4 2 -CnN-OR, -N(Rt)CON(R) 2 -N(R4)SO2N(R4)2,

-N(R')SO

2 R, Or -OC(O)N(R)2; V is -so02-,

-SO

2 -Co 2 -N (R')CON -N SON -N -194- Va 0 -C(0)N 2

-C(R

6 )2S-,

-C(R)

2 N()so) 2 N, C (0R) 2'N (R6) C rC(R"),N(R6) -CC(Rq) 2

N(R

6

)N(R

6 2 N(R')s 2

N(R

6 or

-C(R

6 2N CON W is -C(R 6 2 2 S0 2 n. -C(R) 2 S0 2

-C(R

6 2

-CO-,

22 -C(R 6

-C(R

6 )OC CO-,

-C(R)

2

N(R

6 -C(R6)N-O-, NO 10 -C (R 6 2 N )N(R 6 -0 2 N o -c(R) 2 N(Rt)CON(R)-, or -CON(R 6 each R 6 is independently selected from hydrogen or an optionally substituted C1.4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together.

with the nitrogen atom to- form a 5-6 membered heterocyclyl or heteroaryl ring; and each R' is independently selected from hydrogen or an optionally substituted C 16 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.

Compounds of formula XI are structurally similar to compounds of formula III except for the replacement of the pyrazole ring moiety by the triazole ring moiety. -Preferred R 2 RX, RY, and Ring D groups of formula XI are as described above for the formula III compounds. Preferred formula XI compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an'optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,.2,3,4tetrahydroquinolinyl, 2,3-dihydro-l-isoindolyl, 2,3- -195- L~w. qa o dihydro-1H-indolyl, isoquinolinyl, qiinolinyl, or o naphthyl ring; Rx and RY are taken together with their intervening atoms to form an optionally substituted benzo ring or 5-7 membered carbocyclo ring; and

R

2 is hydrogen or a substituted or C unsubstituted group selected from aryl, heteroaryl, or a C1-. aliphatic group.

More preferred compounds of formula ME have one or more, and more preferably all, of the features selected from the group consisting of; Ci Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; Cb) RX and RY are taken together with their intervening atoms to form a benzo ring, or 5-7 membered carbocyclo ring, wherein said ring formed by R M and RY is optionally substituted with oxo, halo, -OR, -C(nO)R,

-CO

2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R' 4 2

-CON(R

4 2

-SO

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

-N(R

4

)CO

2 (optionally substituted C1- aliphatic), N (R 4 2

-C=NN(R

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

SO

2 N 2

-N(R

4

SO

2 R, or -OC N R) 2;

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl or a Ct-s aliphatic group; and each R' 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(Rt)SO 2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-o aryl, or C3._ aliphatic.

-196-

VO

o Even more preferred compounds of formula XI C have one or more, and more preferably all, of the c features selected from the group consisting of: S(a) Rx and- R are taken together with their eC 5 intervening atoms to form a benzo ring or 6-membered carbocyclo ring,.wherein said ring formed by R x and R Y is 0 optionally substituted with halo, CN, oxo, Ci-6 alkyl, Cz-6 C alkoxy, (CI-6 alkyl) carbonyl, alkyl) sulfonyl, mono- or o dialkylamino, mono- or dialkylaminocarbonyl, mono- or IND 10 dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; o each R 5 is independently selected from -halo, -CN, -oxo,. -SR, 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl,. Cg-o aryl, or CI-6 aliphatic; and

R

2 is hydrogen or a C 1 aliphatic group.

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

R

2

NH

N"

XII

or a-pharmaceutically acceptable derivative or prodrug thereof, wherein: Ring D is a 5-7 membered.monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -197-

VO

CD and at any substitutable ring nitrogen by -R4; C 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 3 are independently -selected from T-R 3 or RX and

R

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

R

4 T is a valence bond or a C3-4 alkylidene chain;

R

2 is -R or -T-W-R6;

R

3 is selected from -halo, -OR, -C(0O)R, -CO 2

R,

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

-N(R

4 2

-CON(R),

2

-S

2

N(R

4 2

-N(R

4

)COR,

-N CO (optionally substituted C-6s aliphatic), -N(R4)N(R) 2

-C=NN(R')

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

)CON(R')

2

-N(R

4

)SO

2

N(R

2

-N(R

4 )S0 2 R, or -OC(O) N(R 4 2 each R is independently selected from hydrogen or an optionally substituted group selected from Ci-6 aliphatic, CE-_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 -C02(optionally substituted C1_- aliphatic), -CON or -SOAR, 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, -C0 2 R, -COCOR, -NO 2 -CN, -SOaR, -SR, 2

-CON(R

4 2

-SO

2

N(R

4 2

-N(R

4

)COR,

-19.8-

I

VO

S-N(R)

CO

2 (optionally substituted

C

1 aliphatic),

-C=NN(R)

2 -CN-OR, -N(R')CON(R 4 -N S0 2 N 2 s02R, or -OC N V is

-N(R

6

-SO

2

N(R

6 -C02-, -N(R6)CO-,

N(R

6 )S0 2 O

-C(R

6 2

-C(R

6 2 s-, N. 2 so-, 2 s0 2

-C(R

6 2

SO

2

-C(R)

2

S-C(R')

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

)=NN(R

6 2

N(R

6 aN(R) -so 2 N( or 2N(R") CON(R6) W is -C(R 6 2 2 SO-, -C(R6) 2

SO

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

-C(R

6 )OC(0)N(R 6

-C(R

6 2N CO-, is -C (R 6 2 N C -C(R 6 -C(R6) 2N (R6 N 2N(R6) SO2N R6) 2 or -CON(R 6 each R' is independently selected from hydrogen or an optionally substituted Cj_ aliphatic group, or two R'' groups .on the same nitrogen atom are taken togetherwith the nitrogen atom to form a 5-6 membered heterocyclya or heteroaryl ring;. and each R' is independently selected from hydrogen or an optionally substituted C 1 -6 aliphatic group, or two R' on the same nitrogen.are taken together with the nitrogen to form a 5-8 membered heterocyclyl ring or heteroaryl.

Compounds of formula X11 are structurally similar to compounds of formula IV except for the replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred Ra 2 RX, RY, and Ring D groups of formula XII are as described above for the formula IV compounds. Preferred formula XII compounds have one or -199-

I

Va o more, and more preferably all, of the features selected 0 from the group consisting of: Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4o tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3- Cg dihydro-1l-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; i *10 Rz is hydrogen or C 1 4 aliphatic and RY is T-

R

3 or R and RY are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring heteroatoms; and

R

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-tetrahydroqtinolinyl, 2,3-dihydro-1a-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl;

R

2 is hydrogen or methyl and RY is -R, N W) 2, or -OR, or R 2 and 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, -No0, -CN, -S(o)R,

-SO

2 R, -SR, 2

-CON(R

4 2 -S0 2

N(R')

2

-OC(=O)R,

-N(R

4 COR, C02 (optionally substituted C-.

6 aliphatic) -200- '-s o -N(R)N(R 4 2

-C=NN(R

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

)CON(R

4 2 C

-N(R')SO

2

N(R

4 2

-N(R

4

)SO

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

R

2 is hydrogen or a substituted or i unsubstituted group selected from aryl or a Ci-s aliphatic group; and each R 5 .is independently selected from halo, o oxo, CN, NO 2

-N(R

4 2 -CO2R, -CONH(R 4

-N(R

4

)COR,

Cq -S0 2

-N(R

4 )S0 2 R, -SR, -OR, or a substituted Sor unsubstituted group selected from 5-6 membered k0 10 heterocyclyl, C6-.o aryl, or C 1 -6 aliphatic.

SEven more preferred compounds of formula XII have one or more, and more preferably all, of the features selected from the group consisting of:

R

X and R Y are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, optionally substituted with halo, CN, oxo, Ci~. alkyl, C 1 6 alkoxy, (C-6 alkyl)carbonyl,

(C

1 -s alkyl)sulfonyi, 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, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C1-i 0 aryl, or C-e 6 .aliphatic; and

R

2 is hydrogen or a Ci-6 aliphatic group.

Another embodiment of this invention relates to compounds of formula XIII: -201c~i;a~

\O

IAN

o ^N HN N

H

SXIII

ci or a pharmaceutically acceptable derivative or prodrug ^C thereof, wherein: S21 is nitrogen, CR', or CH, and Z 2 is nitrogen or CH; CI provided that one of Z' and Z 2 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R

I

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; 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 -202- -I .4 -y

VO

D heteroaryl ring, -R 5 is hydrogen at each ortho carbon C position of Ring D;

R

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

T-V-R

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

R

X and R Y are independently selected from T-R 3 or R x and

R

y are taken together with their intervening atoms to.

form a fused, unsaturated or partially unsaturated, 5-8membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R and' R is substituted by oxo or T-R 3 and any substitutable .nitrogen on said ring formed by R z and R Y is substituted by R 4 T is a valence bond or a Ci-4 alkylidene chain;

R

2 is -R or -T-W-R6;

R

3 is selected from -halo, -OR,

-CO

2

R,

-COCOR, -COCH 2 COR, -NO 2 -CN, -S 2 R, -SR, 2

-CON(R')

2 -SOaN(R -OC -N(R COR,

-N(R

7 C02(optionally substituted CI_, aliphatic), -N (R N(R)

-C=NN(R

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

-N(R

7 S0 2 N (R -N(R 4 S0R, or -OC N (R' each R is independently selected from hydrogen or an optionally substituted group selected from CI-6 aliphatic, CG-6o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -203-

IND

o each R' is independently selected from -COR 7 07 _C0 C~(optionally substituted C 1 6 aliphatic) -CON (R 7 2 Or -SO 2 or two R 4 on the same -nitrogen are taken together to form a 5-8 meuibered-heterocyclyl or heteroaryl ring; each R 5 .16 independently selected from halo, -OR, o -C0 2 R, -COCOR, NO 2 -04, -50 2 R, -SR, -Nq(R4) 2

-CON(R')

2

-SO

2 N(R 4 -0C6=c8R,

-N(R')COR,

4ci2opi o ~pinally substituted C3.- 6 aliphatic),

N(RW)

2

-C=NN(R

4 2 -0=14-OR, -N(R 4 )CON(R'4) 2 o-N(R4)

SO

2 N (el) 2 -N(R4)'so 2 R, or -OC 2 'or R5 and an adjacent substituent taken td~gether with their intervening atoms form said ring fused to Ring C; V is

-SO

2 -NWR)S0 2

-SO

2 N(R 6

-N(R

6

-N(R

6

-N(R

6

)SO

2 -N(R 6

N(R

6 2

-C(R

6 2

S-,

-C (R6) 2 20-; -C(R6) 2 s0 2 2 S0 2

-C(R

5 6) 2

C(R')

2 -C(R 6 2 14(R 6

-C(R

6 )=14w.(a 6 2

N(R

6

-C(R

6 2 ±i(R')so 2 zq(a 6 or -C (R 6 N (R 6 CONq(R) Wis 2 -C(R6) 2

-C(R

6 2 2 SO2-, 2 S0 2 N(R -C(R 6 -COr, -C OC -C (R 6 OC N(R 6 -i(6 N R)C- -C (R 6 2 N(a 6 -C (PR)

-C(R

6 2

N(RZ

6

)N(R

6

-C(R

6 2

N(R

6 )so 2 N(a 6 (p 2 CN orI CON (R 6 each k 6 is independently selected f rom hydrogen, an optionally. substituted C1..4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with. the nitrogen'atom to form. a S-6.membered heterocycy. or heteroaryl ring; each R 7 is independently 'selected from hydrogen or an optionally substituted Ci-e aliphatic group, or two R 7 -204- Va on the same nitrogen are taken together with the CA nitrogen to form a 5-8 membered heterocyclyl or t heteroaryl ring; each R3 is independently selected from an optionally substituted C._ 4 aliphatic group, -SR6, -COR6, -S0 2

R

6 2 2 -CN -NO 2

-CON(R')

2 or o -C0 2

R

6 and Ra is selected from halo, -OR,

-CO

2 R, -COCOR, O

-NO

2 -CN, -S0 2 R, -SR, -N(R 4 2 -CON(R 2, I 10 -SO 2

N(R)

2 -N(R')COR, -N(R)C0 2 (optionally O substituted C 1 aliphatic), 2 -C-NN(R4)2, -C=N-OR,

-N(R

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

N(R)

2

-N(R

4 ).so 2

R,

or an optionally substituted group selected from C 1 -s aliphatic, Cs-.o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

Compounds of formula SIII may be represented by specifying Z 1 and Z 2 as shown below: FeR2 2 N NH N NH

NNH

HNHNL

HNN

N Fix

N-N

RY'N RY RY G G G and A XIZha XIIIb XIII Compounds of formula XIII are structurally similar td'compounds of formula V except for the replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred R, RX, RY, R, and Ring G groups of formula fIII are as described above for the formula V compounds. Preferred formula XIII compounds have one or -205- I

ID

o more, and more preferably all, of the features selected C- from the group consisting of: c Ring C is a phenyl or pyridinyl ring, Soptionally substituted by -R 5 wherein when Ring C and two F3 5 adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from.a o naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is C- -halo, an optionally substituted C 1 -6 aliphatic group, Sphenyl,

-COR

6

-OR

6 -CN, -SO 2 R, -SO 2

NH

2

-N(R

6 2 -COaR 2 \0 10 -CONH2, -NHCOR 6 -OC(O)NH2, 6r -NISO 2 R6; or Ring D is an 0 optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro -H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; Rz is hydrogen or C-.4 aliphatic and R 7 is T-

R

3 or R x and R Y are taken together with their intervening atoms to form an optionally .substituted 5-7 membered.

unsaturated or partially unsaturated ring having 0-2 ring nitrogens; and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a

C

1 -6 aliphatic group.

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

R

1 is -halo, a Ci-a haloaliphatic group, a Ci-6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, -206g piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, (C 1, 2 ,3,4-tetrahydroisoquinolinyl, 1,2,3,4- Stetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or C 5 naphthyl; R is hydrogen or methyl and RY is -R, 0 N(R4)2, or -OR, or R x and R are taken together with their C( intervening atoms to form a benzo ring or a 5-7 membered o carbocyclo ring, wherein said ring formed by R X and RY is I C 10 optionally substituted with halo, -OR, -C02R, O -COCOR, -N0 2 -CN, -SO 2 R, -SR, -N(R 4

-CON(R

4 2

-SO

2

N(R

4 2

-N(R

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

-CNN(R')

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

)CON(R')

2

-N(R

4

SO

2

N(R)

2

SO

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

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a C.aliphatic group; and each R s is independently .selected from -halo, -CN, -NO 2

-N(R

4 2 optionally substituted C1- 6 aliphatic group, -OR, -CO 2 R, -CONH(R'), -N(R 4

)COR,

-SO2N(R*4), or -N(R 4

)SO

2 R, and, when Ring G is Ring D, Ring D is substituted by oxo or Ra.

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

R

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

Y

are taken together with their intervening atoms to form a benzo ring or a 6-membered carbocyclo ring wherein said ring formed by R x and Ry is optionally substituted with halo, CN, oxo, Ci-6 alkyl, C3.6 alkoxy, (Ci- 6 alkyl)carbonyl, -207- Va o (C- 6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; Ring C is a phenyl or pyridinyl ring, S optionally substituted by -Rs, wherein when Ring C and two adjacent substituents thereon form a bicyclic.ring o system, the bicyclic ring system is a naphthyl ring, and

R

1 is -halo, a Cz- aliphatic group optionally substituted o with halogen, or -CN; or Ring D is an optionally \O 10 substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1, 2 3 ,4-tetrahydroisoquinoliny, 1,2,3,4tetrahydroquinolinyl, isoquin'olinyl, quinolinyl, or naphthyl;

R

2 is hydrogen or a C 16 aliphatic group; and Id) each R 5 is independently selected from -C1, -CN, -CF 3

-NH

2

-NH(C

1 4 aliphatic),

-N(C

1 4 aliphatic) 2 -0(C 1 4 aliphatic), C..

4 aliphatic, and -C0 2

(C

1 4 aliphatic), and when Ring G is Ring D, Ring D is substituted by oxo or Rs.

Representative compounds of formula IX are shown below in Table 8.

Table 8.

CHs HN H HN H HN H HsCtN C1 N CI

CF

H IG N' N-6 N IX-2. IX-2 IX-3 -208-

CM

3

HNV'

NU

IX-4

HN.

6 IX -6 IX -5 IX-7 Ix-B8 IX-9

NF

IX-12 fl-li C H3 IX- 13 IX-14 is -209- 4~ 'K-1s

NOH

HN

4

P-

H3C N IX -19

OH

3 N A

N;CF

UN"-fl IX-17

OH

3 N CF 3 IX -20

CH

3 N

HNCF

H3C

CHS

HNI H HaCjjN

CI

IX -26 IX-18 1X -21 IX-24

H

3

CC

N

IX- 25 XX-27 21-0-

IND

IN

CA IX-28

OH

8

NA

HN

NF

IX -31

NH

IX-34

OH

3 HNNt

HS

IX-37 2IH H NcI

H

3 0 N IX-29

OH

3

NA

HNAN('H

NOCHS

IX-32

OH

3

NH

HN r4 O H 3

N

N

H'

NOF

3 IX-38

OH

3 N A HN' 4

H

N.OH

IX-41

NH

N

IX

OH

3

HN

4

HN

IX-33

CH

NH

li-36

OH

3 HN t tN.C 5 2CH3

NI

IX-39 OH1 3

NH

NOH2CHS IX -42 CH3 -211- N 2 IX-43

N

N C HN 1 br IX-46 N CF 3 IX -44

HN

IX-47

N

HN 1

N

HNZ

N.

OH

HN"J'm IX- 48

OH

8

HN'

4

P

N C

CI

IX- 51 HN

H

HN

IX-52

*CHS

HN4P IX-54 Xl-.3 -212-

OH

8 HNt

N

IX -55

CH

8

NA

KNAIP-

QNNCFS

1K-s S

H

3

HN

tN CF 3

CM

8

HN

P, N CF 3

OH

3

NH

NO

2 IX-62

NNH'

0F 8 C-a

N

IX-57

OH

3

NA

N

Q-N CF3

NA

N NH 2 IX- 63 N HN4

HN*

I" 1

SF

OH

3 N A

HNX$

X-1 IX- 64 OHs HN*t Ni0 IX- 67

H

8

NA-H

HN4P EN

CF

8

IVE

IX-68 -2 13'- IX -70 IX-71

CH

3

HN-

F SO IX- 72 IX-73 IX-74 IX-

OH

3

HNNJ.H'

H

3 C 1'N H2N IX.--76

OH

3

HN

ACNH-I: 3

HN

6

*H

H

8 C

'N

MeSO 2 NHJrco IX-77 IX-78

OH

3

HN$

HSCX

N

OH

8 HC tN IX-79 IX -80 ix-Bi1 -214-

OH

9

N

NH

HN*

NCF

3 Me

CHS

0~

HN

4

H

N'

0 en ci 0 'Va 0 0 ci IIX-82 IX-83 IX- 84

GM

3 N

HM

HN

N:-),-NCF

3 IX-86

CH

3 IX -87 Gil 3

N

Il.-s9o 11-88 IX-89 HN4V bZL .W N CF 3

H

2 N, ,41 IX- 91 IX- 92. IX-93

GH

3

N

4 HNVL% 1NH

NCF

3 CH3

N-

HN j,

IN

CbZ.Nj IX- 94 11-95 IX-96 -215- MeO2S.N^ 'ANtS IX-97

CH

3 IX- 100

OH

3

HN

IX-98

H

3

N

4

HNV

IX-101 IX -99 IX- 102

OH

3 HN

PX

ON

IX-103

OH

3 N

HN~

IX- 106

OH

3 IX-104 HaC< H3 HN~rPV IX-lOS

HN$

"C,-o IX- 107 -216-

OH

3 ISN CF 3 IX-109

N?

NN

IX- 112

OH

3

HN

NCF

3 IX-110

OH

3 IX- 113

OH

3 HN 4

OH

3

'N

IX-114 HNt Me N Me O H 3

HNZ

vQ NOMe IX -120

OH

3 N A P7% 5 N ()H2 Nx 1

N

me IX- 116

CH

3 N JH IX- 118 IX-119.

217ci

CHS

HAH

N"

IX-121

OH

3

HN

IX -122

NA

ZcroQN

NH

2 IX- 125

OH

3 NAk

N

IX -124

CH

3 HN4P

H

3 O H IX-123

OH

8

HNZP

NH

2 IX- 126

OH

3

HN

NI

IX-129

OH

3

NA

HN 'a:X r~N SO 2 N(Me) 2 IX-128 IX-127 IXr 130 IX- 131 IX -132

OH

3

N-

HNAIP"

H y I i N H IX-133

H

IX -134 IX-135 -218- Va c~ICH 3 OH 8 CH 8 HN)'.N HNXN,' HN HN

H

OCH

3 SIX-13 6 X-137 IX-138 c 5 Cl-Is

CH-

3 ClN-"( N1$( VaHN Ao HNp Ao o

H

S OrSgN H ~N N N 00 IX-139 IX-140 IX-141 CH3 HN vS

HN

4 11, IX-142 IX-143 IX-144

OH

3 HN S HN

HN'Z

VH to NNH I

N

IX-145 IX-146 IX-147 -219-

IND

IN

CA

IX-148 0Q

HNAXIP

NtH IX-149 Ix-iso o r-CHs HNr IX-152 o rCA HN Ado

%NH

IX-153 sme HNANNo

N'

IX-156 Nt HN

A

IX -159 11- 154

W?

HNk AleJ IX-157 11-155 N

NH

IX- 158, 2

NY

MN ,4l IX-161 -220- IX- 160 IX-162

NH

IX-163 IX-164 IX- 165

NH

IX-166 IX-167 HN %I IX-169 I-168

CH

3

NA

IX-171 IX-170

CH

3

CM

3 OH

NA

IX-174 11-172 IX-173

MN--

HN'Y;P

HN

N-

15 IX- 175 IX-176 -221- IX- 177 Va c-i In another embodiment, this invention provides a composition comprising a compound of formula Ix and a pharmaceutically acceptable carrier.

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

Another aspect relates to a method of treating

U

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

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

Another aspect relates to a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a. composition comprising a compound of formula IX. This method is especially useful in halting or slowing the progression of Al'zheimer'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 -222comprising a compound of formula This method is (N especially useful for treating schizophrenia.

Ct -One aspect of this invention relates to a method of inhibiting Aurora ac tivity mna patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound o of formula IX.

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

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

Each of the aforementioned compositions and methods directed to the inhibition of GSK-3 or Aurora, or the treatment of a disease alleviated thereby, 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.

GenralSythetic Methods The general synthetic methods below provide a series of general reaction routes that were used to -223o prepare compounds of this invention. Methods A-F below C are particularly useful for preparing formula II compounds. In most cases, Ring C is drawn as a phenyl ring bearing an ortho R 1 substituent. However, it will be apparent to one skilled in the art that compounds having other Ring C groups may be obtained in a similar manner.

SMethods analogous to methods A-F are also useful for C preparing other compounds of this invention. Methods F-I below are particulary useful for preparing compounds of formula III or IV.

Ci Method A 2' R 21 I RPHc N RN 6 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 dichloropyrimidine 1 may be achieved in a manner similar to that described in :Chem. Pharm. Bull., 30, 9, 1982, 3121-3124. The chlorine in position 4 of intermediate 1 may be replaced by an aminopyrazole or aminoindazole to provide intermediate 2 in a manner similar to that described in J. Med. Chem., 38, 3547-3557 (1995). Ring C is then introduced using a boronic ester under palladium catalysis (see Tetrahedron, 48, 37, 1992, 8117-8126). This method is illustrated by the following procedure.

A suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POC1 3 (60 mL, 644 mmol) and N,Ndimethylaniline (8mL, 63.1 mmol) is heated under reflux -224-

I

ID

for 2 h. Excess POC1 3 is evaporated under vacuum, the CN residue is poured into ice, and the precipitate is Scollected by filtration. The crude solid 2,4dichloroquinazoline product may be used without further C- 5 purification.

To a.solution of 2,4-dichloro-quinazoline (3.3 0 g, 16.6 mmol) in anhydrous ethanol (150 mL) is added methyl-1H-pyrazol-3-yl amine (3.2 g, 32..9 mmol). The Smixture is stirred at room temperature for 4 h, and the O 10 resulting precipitate is collected by filtration, washed o with ethanol, and dried under vacuum to afford (2-chloroquinazolin-4-yl) (5-methyl-1H-pyrazol-3-yl) -amine.

To a solution of (2-chloro-quinazolin-4-yl)- methyl-IH-pyrazol-3-yl)-amine (50 ag, 0.19 mmol) in DMF (1.0 mL) is added the desired arylboronic acid (0.38 mmol), 2M Na2C03 (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). Under nitrogen, PdC12(dppf) (0.011 mmol) is added in one portion. The reaction mixture is then heated at 80 0 C for 5 to 10 hours, cooled to room temperature, and poured into water (2 nL). The resulting precipitate is collected by filtration, washed with water, and purified by HPLC.

Method B e 0 Cl. R H RjxNH.R 1 POC N R 1 H2 N 3 4 NH R' C H 0 H2N

NH

(ii) 5 6 -225-

VO

0 COR CONH r o R& 0 NH 2 CM (iii) 7 O Methods B through P describe routes where the S. 5 pyrazole ring system is introduced after Ring C and the o pyrimidine ring portion are first constructed. A V0 versatile intermediate is the 4-chloropyrimidine 4, which o is readily obtained from pyrimidinone 3 as shown in Method This reaction sequence is generally applicable for a -variety of Ring C groups including aliphatic, aryl, heteroaryl, or heterocyclyl. See J.

Med. Chem., 38, 3547-3557 (1995).

For quinazoline ring systems (where R and R

Y

are taken together to form a benzo ring), the useful intermediate 6 may be obtained by condensing an anthranilic acid or its derivative with a benzamidine as shown in Method B(ii) or by condensing a benzoylchloride with an anthranilamide as shown in Method B(iii). Many substituted anthranilic acid, anthranilamide, benzamidine and benzoylchloride starting materials may be obtained by known methods. See Aust. J. Chem., 38, 467-474 and J.

Med. Chem., 38, 3547-3557 (1995). Method B(iii) is -illustrated by the following procedure.

To a solution of anthranilamide (33 mmol) in THF and CH2C12 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 CHC2 and water, and dried under vacuum. The crude 2-benzoylaminobenzamide may be used directly for the next step without further purification.

-226-

ID

C To a solution of the above crude product (13 Ci mmol) in ethanol (50 mL) is added NaOEt (26 mmol) at room c temperature. The mixture is heated under reflux for 48 to 96 h. The solvent is evaporated and the residue is ci 5 neutralized using concentrated HCI to pH 7. The product is then collected by filtration and dried under vacuum to o provide 2 -phenyl-3H-quinazolin-4-one that may be used Cq without further purification.

o To a suspension of the above product (12 mmol) SD 10 in POCI 3 (120 mmol) is added tri-n-propylamine (24 mmol).

o The mixture is heated under reflux for lh. After removal of the excess POC1 by evaporation, the residue' is dissolved in ethyl acetate, and washed with IN NaOH (twice) and water (twice). The organic layer is dried over MgSO 4 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 1100C for 16 h (or in ethanol at 130-160°C for 16 hours) and then poured into water (2 mL) The precipitate is collected by filtration and purified by HPLC.

Method C NH R 1 HaN

O

Ry 2CO2Et 8 9 -227-

I

VO

0 Method D(i) SNH R' 0 01 26N RLCOREt PO

C

O

3

W.CO

2 Et ciY 11 Methods C and D(i) above employ 0-ketoesters 8 and 10, respectively, as pyrimidinone precursors. The q ssubstitution pattern of the R x and R Y groups on the Spyrimidinone ring will be reversed if a chlorocrotonate Ci 11 (Synth. Comm, (1986), 997-1002), instead of the corresponding A-ketoester 10, is condensed with the desired benzamidine. These methods are illustrated by the following general procedure.

To a solution of a A-ketoester (5.2 mmol) and amidinium chloride (5.7 mmol) in ethanol (5 mL) is added sodium ethoxide (7.8 mmol). The mixture is heated under reflux for 7-14 hours. After evaporation the resulting residue is dissolved in water, acidified with concentrated HC1 to pH 6, and then filtered tb obtain a solid product 2-aryl-3H-pyrimidin-4-one (yield 75-87%), which may be purified by flash column chromatography if needed. To this pyrimidinone (3.7 mmol) is added POCa1 (4 mL) and n-Pr 3 N (1.4 mL). The mixture is heated under reflux for i hour. After evaporation of the excess POC 1 3, the residue is dissolved in ethyl acetate, washed with IN NaOH solution (three times) and NaHC03 (once), and dried over MgS0 4 The solvent is removed under vacuum and- the residue is purified by flash column chromatography eluting with 10% of ethyl acetate in hexanes to give 2aryl-4-chloro-pyrimidine as a pale yellow syrup. This crude product may be treated with a 3-aminopyrazole or 3aminoindazole as described above.

-228- Va 0 C- Method D(ii) NH R 1 HaN'l 0 POC13,

CI

SCO23 R NH R nPrN R N R 1 RN reflux CIN' 2 36 37 38

RR

morpholine, HN S MeOH .N R' 'N R a38 W) RF .NN refOux 1 reflux 39 Method D(ii) above shows a general route for the preparation of the present compounds, such as compound 40, wherein R Y is N(R 4 2 See 1 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-methylmalonic acid diethyl ester (5 mmol) and sodium ethoxide (15 mmnol) is added the appropriate amidine salt (5 mmol) in ethanol (10 mL) and the reaction heated at reflux for 2-24 hours. The residue is dissolved in water and acidified with 2N HCl.

The resulting precipitate is filtered off and further purified by flash chromatography (yield 5-35%) to afford the pyrimidinedione 37. To 37 (1.6 mmol) is added POC1 3 (32 mmol) and tri-n-propylamine (6.4 mmol) and the reaction refluxed is for Ih. 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 -229-

VO

D flash chromatography provides the dichloropyrimidine (38) C as a yellow oil in 23% yield.

A solution of 38 (0.33 mmol) in methanol (5 mL) Sis treated with an amine, exemplified here using morpholine (0.64 mmol) and refluxed 1 hour. After evaporation of solvent, the residue is purified by flash o chromatography to provide the mono-chloropyrimidine 39 as eC a.colorless oil in 75% yield.

The mono-chloropyrimidine, 39, (0.19 mmol) may \0 10 be treated with a 3-aminopyrazole or 3-aminoindazole 0 compound in a manner substantially similar those

C

N described above in Methods A and B..

Method E

R'NE

Ri O LC 0 5N=C-0 Ry H' H NH R

NH

4 OAc R' N 12 AcOH, ref l ux 9 (R H) As shown by Method E, an acyl isocyanate 12 may be condensed with an enamine to provide-pyrimidindne 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 mmoi) in tetrahydrofuran (30 mL) at DoC 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 -230- O acetate (50 mmol). The mixture is refluxed for 2 h with C- continuous removal of tetrahydrofuran. The reaction is cooled to room temperature and is poured into water (100 SmL). The precipitate is filtered, washed with water and ether and dried to provide the 2-aryl-31-pyrimidin-4-one.

o Method F c 0 0

O.

7 NH r NH 2 Heat 0 13 14 15 R Method P shows a general route for the preparation of the present compounds wherein R x and R Y are taken.together to form a 5-8 membered partially urisaturated 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)benzoyi chloride (4.2 ml, 29.2 mmol) is added dropwise to a solution of 2aminonicotinic acid (2.04g, 14.76 mmol-) in 20 ml of pyridine. The reaction mixture is heated at 158 C for min then cooled to room temperature. The reaction is poured into 200 ml of water and an oil forms which solidifies upon stirring. The solid is collected by vacuum filtration and washed with water and diethyl ether. The product is dried to give 2-(2tri fluoromethyl-phenyl)-pyrido[2,3 d] [1,3]oxazin-4-one -231-

I

VO

o (2.56 g, 60% yield) which may be used in the next step C without further purification.

2-(2-Trifluoromethyl-phenyl)-pyrido[2,3- Sd] [1,3]oxazin-4-one (2.51g) is stirred in 30% ammonium 5 hydroxide (25 ml) at room temperature overnight. The resulting precipitate is filtered and rinsed with water o and diethyl ether. The precipitate is dried under vacuum (C at 50 C overnight to give 2-(2-trifluoromethyl- 0 benzoylamino)-nicotinamide (850 mg, 33% yield) 10 2 2 -Trifluoromethyl-benzoylamino)-nicotinamide o (800mg, 2.6mmol) is dissolved in 10ml of ethanol.

C Potassium ethoxide (435mg, 5.2mmol) is added to the solution which is heated to reflux for 16 h. The reaction mixture is evaporated in vacuo to afford a gummy, residue that is dissolved in water and acidified with sodium hydrogen sulfate to pH 7. The resulting precipitate is filtered and dried under vacuum at 50 C to.

give 2-(2-trifluoromethyl-phenyl)-3H-pyrido[2,3d] pyrimidin-4-one.

Method G Method G is analogous to Method B(i) above.

This method is illustrated by the following general procedure.

2-(3,4-Dichloro-phenyl)-3H-quinazolin-4-one.

(ig, 3.43 mmol) is suspended in phosphorus oxychloride (4 mL) and the reaction mixture was stirred at 110 0 C for 3 hours. The solvents are then evaporated and the residue is treated carefully with an ice cold aqueous saturated solution of NaHC03. The solid is collected by filtration and washed with ether to give 4-chloro-2-(3,5-dichlorophenyl)-quinazoline as a white solid (993 mg, 93%).

To 4-chloro-2-(3,5-dichloro-phenyl)-quinazoline (400mg, 1.29 mmol) in THF (30 mL) is added -232- Siitsaab^^-tt,/:.:.

l

VO

o methyl pyrazole (396 mg, 2.58 mmol) and the reaction CO mixture is heated at 650C overnight. The solvents are t then evaporated and the residue triturated with ethyl Sacetate, filtered and washed with a minimum amount of Cq 5 ethanol to give [2-(3,4-dichlorophenyl)-quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl)-amine as a white solid (311 mg o mp 2740C; 1H NMR (DMSO) 8 2.34 (3H, 6.69 (IH, C 7.60 (1H, 7.84 (1H, 7.96 (2H; 8.39 (1H, Sdd), 8.60 (1H, 8.65 (1H, 10.51 (1H, 12.30 (1H, IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, o 1376, 1352, 797, 764, 738; MS 370.5 Cl The THF solvent used in the previous step may be replaced by other organic solvents such as ethanol, N,N-dimethylformamide, or dioxane.

Method H R 5 (HOB R

R

2

HNUN

N

HN

I PdO RY N I RY N 17 18 r R 2 R2 R 2 SHN (CH3).-S -H HN N C ul

N

(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 -233- Va D bromine or iodine. These methods are illustrated by the following procedures.

Method To a mixture of [2-(4-bromophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (196 mg, 0.51 nmol) and phenylboronic acid (75 mg, 0.62 mmol) in THF/water 4 mL) is added Na 2

CO

3 (219 mg, S2.06 mmol), triphenylphosphine (9mg, 1/15 mol%) and en palladium acetate (1 mg, 1/135 mol%). The mixture is heated at 80 0 C overnight, the solvents are evaporated and the residue is purified by flash chromatography (gradient of CH2C12/MeOH) to give (2-biphenyl-4-yl-quinazolin-4-yl)c- (5-methyl-2H-pyrazol-3-yl)-amine as a yellow solid (99 mg, 51%):1H NMR (DMSO) 8 2.37 (3H, 6.82 (lB, 7.39- 7.57 (4H, 7.73-7.87 (6H, 8.57 (2H, 8.67 (lB, 10.42 (1H, 12.27 (1H, MS 378.2 Method H(ii). To a mixture of [2-(4-bromophenyl)-quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl) -amine (114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, mmol)in DM (2 mL) is added CuI (1,1 mg, 1/50 molt), Pd(PPh)C1 2 (4.2 mg, 1/50 molt) and triethylamine (121 mg, 0.36 mmnol). The mixture is heated at 120"C overnight and the solvent is evaporated. The reidue -is triturated in ethyl acetate and the precipitate is collected by filtration.

To the above precipitate suspended in THP (3 mL-is added tetrabutylammonium fluoride (1M in TER, 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 C22C1 2 /MeOH) to give [2-(4-ethynylphenyl)-quinazolin-4yl]-(5-methyl-2H-pyrazol-3-yl)-amine as a white solid (68 mg, NMR (DMSo) 5 2.34 (3H, 4.36 (1H, 6.74 7.55 (1iH, 7.65 (2B, 7.84 (2H, 8.47 -234j1

O

S(2H, 8.65 (1H, d) 10.43 (1H, 12.24 (1H, MS N 326.1 SMethod

I

PFt Fe R R 2 oNNQH HN N H

RYNN

,5 2 o Method I above shows a general route for the preparation of the present compounds wherein ring D is a heteroaryl or heterocyclyl ring directly attached to the pyrimidine 2-position via a nitrogen atom. Displacement of the 2-chloro group, exemplified here using piperidine, may be carried out in a manner similar to that described in J. Med. Chem., 38, 2763-2773 (1995) and J. Chem. Soc., 1766-1771 (1948). This method is illustrated by the following procedure.

To a solution of (2-chloro-quinazolin-4-yl)- (1H-indazol-3-yl)-amine (1 equivalent, 0.1-0.2 mmol) in N, N-dimethylacetamide (1 ml) is added the desired amine (3 equivalents). The resulting, mixture is maintained at 100OC for 6 h and then purified by reverse-phase HPLC.

Method J

NH

(i)R H2N R

N

21 22 -235- F 1

IND

VO

o R R (ii) ^0ly 23 24 C Method J above shows the preparation of o 5 compounds of formula V via the displacement of a chloro \D group from an appropriately substituted pyridyl ring.

o Method J(i) is a route for preparing compounds of formula C Va (see Indian J. Chem. Sect.B, 35, 8, 1996, 871-873).

Method J(ii) is a route for preparing compounds of formula Vb (see Bioorg. Med. Chem.,6, 12, 1998, 2449- 2458).. For convenience, the chloropyridines 21 and 23 are shown with a phenyl substituent corresponding to Ring D of formula V. It would be apparent to one skilled in the art that Method J is also useful for preparing compounds of formula V wherein Ring D is heteroaryl, heterocyclyl, carbocyclyl or other aryl rings. Method J is illustrated by the following procedures.

Method (5-Methyl-2H-pyrazol-3-yl)-(2phenyl-quinolin-4-yl)-amine. To 4-chloro-2phenylquinoline Het. Chem., 20, 1983, 121-128) 0.53g, 2.21 mmol) in diphenylether (5 mL) was added methylpyrazole (0.43g, 4.42 mmol) and the mixture was heated at 200 0 C overnight with stirring. To the cooled mixture was added petroleum ether (20 mL) and the resulting crude precipitate was filteredand further washed with petroleum ether. The crude solid was purified by flash chromatography (Si02, gradient DCM-MeOH) to give the title compound as a white solid: mp 242-244OC; 1H NMR (DMSO) 8 2.27(3H, 6.02(1H, 7.47(2H, 7.53- 7.40(2H, br 7.67(1H, 7.92(1H, 8.09(2H, d), -236-

VO

o 8.48(2H, 9.20(1H, 12.1.7(1H, br IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 (M+H) C Method J(ii). (5-Methyl-2H-pyrazol-3-yl)-(3phenyl-isoquinolin-1-yl)-amine. To l-chloro-3- CN 5 phenylisoquinoline Het. Chem., 20, 1983, 121- 128)(0.33g, 1.37 mmol) in dry DMF. (5 mL) was added 3- (0.27g, 2.74 mmol) and potassium carbonate (0.57g, 4.13 anol)and the mixture was heated o under reflux for 6 hours. The mixture was cooled and the bulk of DMP was evaporated. The residue was extracted o twice with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO 4 filtered and concentrated. The crude was purified by flash chromatography (SiO2, gradient DCM-MeOH) to give the title compound as a colourless oil; 'H NMR (MeOD) 8 2.23 (3H, 5.61 (1H, 7.41 (1H, 7.52(2H, 7.62(1H, m), 7.81(1H, 8.07(1H, 8.19(2H, 8.29(1H, 8.54 (1H, MS 301.2 Method K R2,

A

2 CI CI CI R2 H N N N -N NN HN aCI NI Cl 01N' RY N

W

A

26 27 Method K shows a route for the preparation of compounds of formula VI. A versatile starting material is 2 ,4,6-trichloro-[1,3,5]triazine 25 in which the chlorine substituents may be sequentially displaced. The displacement of one of the chlorines by an aryl Grignard reagent or an aryl boronic acid is described in PCT patent application WO 01/25220 and Helv. Chim. Acta, 33, 1365 (1950). The displacement of one of the chlorines by a heteroaryl ring is described in WQ 01/25220; J. Ret.

-237- IN Chem., 11, 417 (1974); and Tetrahedron 31, 1879 (1975).

C These reactions provide a 2,4-dichloro-(6substituted) [1,3,5]triazine 26 that is a useful Sintermediate for the preparation of compounds of formula 5 VI. Alternatively, intermediate 26 may be obtained by constructing the triazine ring by known methods. See US o patent 2,832,779; and US patent 2,691020 together with J.

(q Am. Chem. Soc. 60, 1656 (1938). In turn, one of the Schlorines of 26 may be displaded as described above to \O 10 provide 2-chloro-(4,6-disubstituted) [1,3,5]triazine 27.

SThe treatment of 27 with an appropriate aminopyrazole provides the desired compound of formula VI.

Method L urea rY 3POrC 0 N NH

IN

0 28 29 R2

R

2 ,NH H H2N. N HN .N 31 N 31 Method L shows a route for preparing.compounds of formula VII. For illustration purposes the trifluoromethylchalcone 28 is used as a starting material; however, it would be apparent to one skilled in the art that other rings may be used in place of the -238trifluoromethylphenyl and phenyl rings of compound 28.

CI Substituted chalcones may be prepared by known methods, Sfor example as described in the Indian J. Chemistry, 32B, S449 (1993). Condensation of a chalcone with urea 5 provides the pyrimidinone 29, which may be treated with POC13 to give the chloropyrimidine 30. .See J. Chem. Eng.

0 Data, 30(4) 512 (1985) and Egypt. J. Chem., 37(3), 283 Ci (1994). In-an alternative approach to compound 30, one o of the aryl rings attached to the pyrimidine is O 10 introduced by displacement of of the 4-chloro group of S2, 4 -dichloro-(6-aryl)-pyrimidine by an aryl boronic acid using a palladium catalyst such as (Ph 3

P)

4 Pd in the presence of a base such as sodium carbonate as described in Bioorg. Med. Lett., 1057 (1999). Displacement of the chlorine of compound 30 by an appropriate aminopyrazole provides compounds of this invention, such as 31. The last step of this method is illustrated by the following procedure.

[4-(4-Methylpiperidin-1-yl)-pyrimidin-2-yll .methyl-2H-pyrazol-3-yl)-amine. To a solution of 2chloro-4- (4-methylpiperidin-1-yl) -pyrimidine (prepared using a procedure similar to the one. reported in 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 mixturewas then heated under reflux overnight. The solvent was evaporated and the residue dissolved in a mixture ethanol/water 4 mL).

Potassium carbonate (57mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water twice and rinsed with ether twice to give the title compound as a white solid (143mg, mp 193-195 0 C; 1H NMR (DMSO) 8 0.91 (3H, 1.04 (2H, 1.67 (3H, m), 2.16 (3H, 2.83 (2H, 4.31 (2H, 6.19 (2H, -239-

VO

O 7.87 (1H, 8.80 (IH, br 11.71 (1H, IR (solid) Cl 1627, 1579, 1541, 1498, 1417, 1388, 1322, .1246; MS 273.3(M+H).

C. 5 Method M SCI

H

H

2 N "a c 32 Cl SVIIIb 33

CI

34

CI

N "N Method M provides routes for obtaining compounds of formula VIII. A general procedure for displacing the chlorine of a 4-chloro-6-substitutedpyridazine, 32, with an appropriately substituted -240o pyrazole to provide VilIa is described in J. Het. Chem., Cq 20, 1473 (1983). Analogous reactions may be carried out as follows: with S33, to provide VIIIb is described in J. Med. Chem., 5 311 (1998); with 5-chloro-3-substituted- [1,2,4]triazine, 34, to provide VIIla is described in o Heterocycles, 26(12), 3259 (1987); and with 3-chloroeC 5-substituted-[l,2,4]triazine, 35, to provide VIIId is described in Pol. J. Chem., 57, 7, (1983); Indian J.

Chem. Sect. B, 26, 496 (1987); and Agric. Biol. Chem., 54(12), 3367 (1990). An alternative procedure to C( compounds of formula VIlIe is.described in Indian. Chem. Sect. B, 29(5), 435 (1990).

Compounds of formula IX are prepared by methods substantially similar to those described above for the pyrazole-containing compounds of formula I. Methods A-J may be used to prepare the triazole-containing compounds of formula IX by replacing the amino-pyrazole compound with an amino-triazole compound. Such.methods are specifically exemplified by Synthetic Examples 415-422 set forth below. The amino-triazole intermediate may be obtained by methods described in J. Org. Chem. USSR, 27, 952-957 (1991).

Certain synthetic intermediates that are useful for preparing the protein kinase inhibitors of this invention are new. Accordingly, another aspect of this invention relates to a 3-aminoindazole compound of formula A:

H

NH

2

A

"where R"o is one to three substituents that are each independently selected from fluoro, bromo, Cz- 6 haloalkyl, -241- Va nitro, or 1-pyrrolyl. Examples of such compounds include the following: H H. F H F H F F FY ~N r~r c INH 2

NH

2

NH

2

NH

2 Al A2 A3 A4 c F F H H H CF B Br

NH

2 NH2 H 2

NH

2 AS AG A7 AB H H 02N

NH

2 N NH 2 AS Another aspect of this invention relates to a 4-chloropyrimidine compound of formula 8:

CI

NR

RY

B

wherein RX and RY are as defined above; R' is selected from Cl, F, CF 3 CN, or NO 2 and is one to three substituents that are each indepebdently selected from H, Cl, F, CF, NO, or CN; provided that R' and R 3 are not .simultaneously C1. Examples of compounds of formula B are shown below: CI C1 CI Me N CF 3 Me N C

N

Me N Me NSMe CN B1 B2 B3 -242cI B4.

CI

B7 It- B8 Nty Er

NC-

310 Eli 312

CF

8 313 B14 cl N CF3

N

tdl sis B16 C4 B19 Cl O tN Cl 317 320 319 -s Another aspect of this invention relates to compounds of formula C R2

HN

HN):

C

wherein R, Ry, Ra, and R' are as defined above. Examples of compounds of formula C are shown below:

F

H H C1 nl HN2N C2

I

HN

CS

cit HNt C3

HN

HC

F

H

N

N

CS

C4

HN

C7 -244-

N

IcN 5 HN6

HN

e1 Y$'3GI

CIO

F

C11 Cli

HNIH

N N C14 N C12 Me H eH HN1 cis Yet another aspect of this invention relates to compounds of formula D:

O

RX NH

CF

3 Ry N FY$s

D

where R 5 R and RY are as defined above. Examples of formula D compounds and other useful pyrimidinone intermediates are shown below: D2 D3' NH C DS D)4 D5 -245-

VO

0 0 o 0 1 N E

N

D7 DS D9

OO

O 0 0 D10 D14 D12 0 -yNHCI N H:Cr NH C1 NH F3 N% NH C

CF

3 o 1

NO

2 D13 D14.

DIS

0 00

NCF

3 Nl'H CF 3 N H CF' 3 D16 D17 DiS 0 KkNH GF 3 In order that the invention described herein may be .more fully understood, the following examples are set forth. It should be understood that.these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

-246 1y ~t 14 :Z4 Y. -:9 o C SYNTHETIC EXAMPLES SThe following HPLC methods were used in the Sanalysis of the compounds as. specified in the Synthetic (c 5 Examples set forth below. As used herein, the term "Rt" refers to the retention time observed for the compound C using the HPLC method specified.

ci o HPLC-Method A: 1 0 Column: C18, 3 um, 2.1 X 50 mm, "Lighting" by Jones Chromatography.

C

N Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) over 4.0 min, hold at 100% acetonitrile for 1.4 min and return to initial conditions. Total run time min. Flow rate: 0.8 mL/min.

HPLC-Method

B:

Column: C18, 5 um, 4.6 X 150 mm "Dynamax" by Rainin Gradient: 100% water (containing 1% acetonitrile, 0.1%.TFA) to 100% acetonitrile (containing 0.1% TFA) over 20 min, hold at 100% acetonitrile for 7.0 min and return to initial conditions. Total run time 31.5 min. Flow rate: 1.0 mL/min.

HPLC-Method

C:

Column: Cyano, 5 um, 4.6 X 150 mm "Microsorb" by Varian.

Gradient: 99% water TFA), 1% acetonitrile (containing 0.1% TFA) to 50% water TFA), acetonitrile (containing 0.1% TFA) over 20 min, hold for 8.0 min and return to initial conditions. Total run time 30 min. Flow rate: 1.0 mL/min.

-247- Va RPLC-Method

D:

Column: Waters (YMC) ODS-AQ 2.OxS0mm, SS, 120A.

Gradient: sot water Formic acid), acetonitrixe (containing Formic acid) to water formic acid), 90% acetonitrile (containing 0.1% formic acid) over 5.0 min, hold for o 0.8 min and return to initial conditions. Total run time 7.0 min.

Flow rate: 1.0 mL/min.

KPLC-Method.

E:

Column: 50x2.Omm Rypersil CIS BDS;S Um Gradient: elution 100 water TPA), to 5% water TFA), 95W acetonitrile (containing oai* TFA) over 2.1 min, returnihg to initial conditions after 2.3 min.

Flow rate: 1 mL/min.

Example I 12- (2-Cloropheyl)-5, 6-dimethylpyrmidin.4-yll- (S-Kethyl-2a-pyrazol-3-yl)-amine KMR (500 M4z, DMO-d6) 810.4 (s,br, 1K), 7.74 ZR), 7.68 1H), 7.60 1H), 6.39 It), 2.52 3H), 2.30 31), .2.22 3H); MS 314.1 Example 2 12- (2-Chioro-phenyl)-6G,7 1 8,9-tetrahydro-

SH

cycloheptapyrmidin4yl (1H-indazol-3-yl) -amine (11-2): Prepared in 30% yield. 'IWMR (500Mz, DMS0-d) 81.72 (m, 4H), 1.91 3.02 4H), 7.05 t, 1K), 7.33 (t, 1H), 7.39 1H), 7.47 11), 7.55 3K), 7.59 (d, 10.4 Cm, 1K), 13.11 {br. s, iN); I-MS 390.2 (MHfl); HPLC-Method A, Rt 2.99' min.

Example 3 (5-Fluoro-ia-±ndazol.s..yl) (2trifluoromethyl-phenyl) -5,6,7,8-tetrabydro-pyrido3,4 -248-

I

Va o]Wrimidin-4-yl]-amilne Compound 11-18 (90 tg, (Nl 0.17 mmol) was treated with an equal weight of Pd/c in 4.4W formic acid in MeOR at room temperature for 14 h.

The mixture was filtered through celite, the filtrate was S evaporated, and crude product was purified by HPIC to provide 18 mg of the desired piroduct as pale yellow solid. 'HNMR (500 MHz, PMSO-dE) 812.9 Cs, 31H),S9.51 (s, 1H), 9.26 2R), 7.72 Cd, 1H), 7.63 7.58 (t, o 7.49 7.21 (td, 1H), 7.15 (dd, 1H), 4.24 (s, IND 10 211), 3.56 Cm, 2H), 2.95 2H) ppm. MS m/et o 429.22 HPLC-Method A, Rt 2.88 min.

Example 4 (2-Chloro-phenyl)- 6 ,7,8,9-tetrahydro-SH- Cycloheptapyriidn4 -ylJ fluoro-la-indazol-3-yl) amine Prepared in 52% yield to afford a white solid. 1 HNImR (500MHz, DMSO-d6) 8 1.72 4H), 1.92 (m, 2H), 3.00 4H), 7.02 (td, 1H), 7.20 (dd, 1H), 7.40 (im, 1H), '7.42 iN), 7.52 3H), 10.5 (in, IH), 13.50 (br.

3, El-MS 408.2 CM+H); HPLC-Method'A, Rt 3.00 min.

Example 5 (2-(2-Chioro-phenyl)-6,7,8,9-tetrahydro-Sacycloheptayriinidin4.y1J (5-fluoro-1S-idao-3 y1)amine Prepared in 51% yield. 1NMR (500MHz, DMSOd6) 6 1.71 414), 1.91 2H), 3.0i 4H), 7.24 (td, 1H), 7.41 2H), 7.54'(m, 10.5 13.1 (br.

El-MS 4b8.2 CM+H);HPLC-Method Rt 3.05 min.

Example 6 12-(2-Chloro-phenyl) -'6,7,8,9-tetrhy4ro,-5Hcycloheptapyridin4 -yl (5,7-difluoro-E-indazol.3..yl) amine Prepared according to Method C in 72% yield.. H 1 ImM (500MHz, DXSO-dE) S 1.'72 4H), 1.91 Cm, 2H), 3.01 4H), 7.31 7.41 (in, 7.54 Cm, 3H), 10.5 Iw), 13.6 (br. s, El-MS 426.2. (MH); HPLC-Method A, Rt 3.21 min.

249- Va c-i Examle 7 7 -Fluoro-ll-indazol-a-yl) (2trifluoromethyl-phenyl) B-tetrahydroquinaolin-4ylJ-amine (11e7): Prepared in 62% yield. lfHNMRf(500 MHz, C- 5 DMSO-dE) 813.5 br, lW), 10. hr, 1H), 7.75 (m, 4H), 7.33 IW), 7.17 (dd, 1W), -7.00 (td, 1H), i.80 (m, 0 2H), 2.71 2H), 1.89 (br, 4H) ppm; LC-MS 428.44 (N 426.43 CM-H); WPLC-Method A, Rt 3.02 min.

IND 10 Example 8 (5-luro-3-indaol trifluoromethyj.-pienyl) -5,6,7,8-tetrabydtoouina2Clin- yllJ-amine Prepared in 53% yield. 1 HMNe(soo00 MHz, DMSO-d6) 813.1 Cs, 1H), 10.2L br, 1W), 7.75 4H), 7.50 (ad, lB), 7.27 (dd, 1H), 7.21 (td, iN), 2.80 i, 2H), 2.72 2H), 1.88 4H) ppm; MS 428.43 426.43 HPLC-Method A, Rt 3.01 min.

Example 9 (5,7-Difluoro-1H-idazal-3-yl)- 12-(2 trifluorcmethyl-phenyl) 5, 6, 7, 8 tetraiydroquinazolin-4 ylJ-amine Prepared in 37% yield. 1HNMR (500 MHz, DMSO-d6) 813.7 1H), 10.2 br, 1H), 7.80.(d, 1W), 7.76 iH), 7.69 2H), 7."31 1H, 7.18 iN), 2.81 br, 2H), 2.72 br, 2H), .1.90 4H). ppm; MS (ESt) 446.42 444.37 HPLC-Method A, Rt 3.09 min.

Example 10 (5-Trifluaromthyl-1H-indazol-3-yl) (2trifluoromethyl-phenyl) 6,7' 8-tetrahydroquinazolin-4yl] -amine (11-10): Prepared by Method C in ethanol in 35% yield. 1 mMR '(500 MEz, DMSO-d) 813.2 1H), 10.1 br, 11), 8.01 iN). 7.76 1) 7.66 4H), 7.57 Cd, lW), 2.79 2H), 2.73 2W), 1.89 4) ppm. MS 478.45 476.42 HPLC- Method A, Rt 3.21 min.

.1 7, -7 -250- Va Example 11 (5,7-difluoro-22-niaaol3-yl)- E2-(2trifluoromethyl-phyl).... 7,8,9-tetrabydro-SHcyclohePtapyrimidin-4-yyj -amine (II-11)' Prepared in yield. White solid. lHNMR l(500MHz, DMSO-dE) 8 1.72 42), 1.91 Cm, 2H), 3.01 7.15 (dd, 1H), 7.30 (td, oI 7.66 2H), 7.72 11), 7.78 1R), 10.2 (m, N1), 13.5 Cbr. a, 12); El-MS 460.2 CM+H); HPLC-Method

A,

Rt 3.13 min.

Example 12 (G-Benzyl-2- (Z-trifluoromethy.pienyl 5,6,7,8- tetrahydro-pyrido [4,3-dlpyrimid~n-4-yl)-(SfluoroezR-indaol- 3 .yl) -amne (11-12): Prepared in 49% yield. 'HNMR (500 MHz, DMSO-d6) 812.8 Cs, 12), 9.11 (s, Lf), 7.68 11), 7.58 Ct, 7.53 Ct, 1N), 7.44 m, 4H), 7.37 Ct, 2H), 7.29 Ct, 12), 7.19 Cm, 2H), 3.78 Cs, 21), 3.61 Cs, 22)I 2.81 Cs, br, 42) ppm; LC-MS (ES+) 519.24 HPLC-Method A, Rt 3.11 min.

Example 13 (B-Indazol3.yl)-2- 2 -trifluoromthyl pheyl) S-tetrahydro-5-cycloheptapyrmdin- 4 -y amine (11-13):-Prepared in 40t yield. 1 aNMf (SOOMHz, DMSO-dE) 6 1.70 4H), 1.90 23), 3.00 4H), 7.01 7.30 (td, 12), 7.44 12), 7.49 12), 7.68 3H), 7.77 10.01 Cm,' 1N), 12.83 I, El- MS 424.2 (K4H); HPLC-Method A, Rt 3.17 min.

Example 14 .(V-FPluoro-1E.indazol-3-yl) [2-m(2trifuoromethyl-phany)-6,7,8,B-tetrahydro-5cycloheptapyrmidin-4-yl] -amine (11-14); Prepared in 78% yield. m'HiMR (50014Hz, DMSO-d6) 8 1.71 4H), 1.91 Cmi, 2H), 3.00C(m, 6.98 (td, 12), 7.16 dd, 7.31 (d, 12), 7.68 3H), 7.77 11), 10.25. 1N), 13.40 (br. s, 1N); El-MS 442.2 (MtH); HPLC-Method A, Rt 3.12 -251-

VO

Co min.

Example 15 (5-Fluoro-1r-indazol-3-yl)- (2trif luoromethyl-phenyl) cycloheptapyrimidin-4-yl] -amine (11-1S): Prepared in 63% yield. HNMR (500MHz, DMSO-d6).8 1.71 4H), 1.91 (m, 2H), 3.00 4H), 7.20 (td, IH), 7.25 (dd, 7.49 Ci (dd, 1H), 7.69 (br. t, 2H), 7.74 1H), 7.79 1H), o 10.35 1H), 13.00 (br. s, IH); EI-MS 442.2 ND 10 HPLC-Method A, Rt. 3.21 min.

Example 16 (5-Fluoro-1H-indazol-3-yl) trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3d]pyrimidin-4-yll-amine (11-16): A solution of compound 11-12 (45mg, 0.087 mmol) in methanol HCOOH) was treated with an equal weight of Pd/C at room temperature for 14 h. The mixture was filtered through celite, the filtrate evaporated, and the crude product was purified by preparative HPLC.to provide 15 mg (41%) of the desired product as yellow solid. 'HNMR (500 MHz, DMSO-d6) 812.9 1H), 9.52 11H), 9.32 2H, TFA- OH), 7.72 1H), 7.59 2H), 7.49 21), 7.21 (m, 1H), 7.15 1H), 4.31 2H), 3.55 2H), 3.00 (m, 2H) ppm; LC-MS 429.20 HPLC-MethodA, Rt 2.79 min.

Example 17 (1B-indazol-3-yl)- [2-(2-tri£1uoromethylphenyl) 6,7,8-tetrahydroquinazolin-4-yll -amine (II-17): Prepared in 58% yield. EHMR (500 MHz, DMSO-d6) 813.0 IH), 10.3 br, 1H), 7.74 4H), 7.51 1H), 7.47 1H), 7.32 1H), 7.03 1H), 2.82 2H), 2.73 (in, 2H), 1.90 4H) ppm; LC-MS 410.21 HPLC-Method A, Rt 2.99 mini.

-252r Va Example 18 (7-Denzyl-2-(2-trifluorom etll-phenyl)- 5sG,7,8tetrahydropyido[4,3.dpyrimidin-4-yl)-(5fluoro-I-indazol-3-yl)-amine (11-18): Prepared from Ci 5 compound B11 in 92% yield. 1HNM (500 MHz, DMSO-dE) 812.9. 1H), 10.5. br, 1H), 9.58 1H,. TFA-OH), 0 7.71 7.52 19H), 7.19-Am, 2H), 4.57 2H), 4.20 (mn, 2H), 3.70 2H), 3.00 2H1) ppm; LC-MS (ES+) 519. 23 HPLC-Method A, It 3.23 min.

o oxample 19 (1H-Indazol-3-yl)-C6-methyl-2-(2trifluoromethyl-phenyl)-pyrimidin-4-ylJ-nmine (11-19): Prepared in 42% yield. Melting point 235-237 0 C; 1 fHNM (500 MHz, DMSO) 8 2.44 (3H, 7.09 (11, J=-7.5 Hz, t), 7.40 (11, J-7.1 Hz, 7.49. (11, J-8.3 Hz, 7.70 (3H, 7.79 (11, J-7.3 Hz, 7.87 (11, J=8.3 Hz, 8.03 (11, J=7.7 Hz, 10.3 (11, 12.6 (1H, a) ppm; HPLC- Method A, Rt 2.958 min; MS (FIA) 370.2 (M+HP+.

EK2Mpe 20 (1H-Indazol-3-yl)-t6-phenyl-2-(2trifluoroiethyl-phenyl) -pyrimidin-4-ylJ-amine (11-20): Prepared in 32% yield. 'HNMR (500 MHz, DMSO) S 6.94 (IH, J=7.4 Hz, 7.24 (l1. J=7.4 Hz, t),.7.33 (1H, J=8.4 Hz, 7.42 (3H, 7.57 (1H, 3=7.3 Hz, 7.68 (2H, i), 7.75 (1H, J=7.9 Hz, 7.93 (3H, 8.16 (18 br a), 10.45 (H,-br 12.5 (11, br a) ppm; IPLC-Metbod A, Rt min;.MS (FIA) 432.2 Example 21 (1R-Indazol-3-yl) (pyridin-4-yl) (2trifluoromethyl-phenyl) -pyrimidin-4-yll amine (11-21): Prepared in 12% yield. 1 ENMR (500 MHz, DMSO) 87.16 (1 J-7.4 Hz, 7.46 (11, 7=7.6 Hz, 7.56-(11, 3=-8.3 Hz, 7.80 J=7.2 Hz, 7.90 (2H, 7.97 (11, J=7.8 sr t t -253- Va Hz, 8.09 (IU, br), 8.22 (2H, J=4.9 Hz, 8.45 (1H, br 8.93 (2H, J=4.8 Hz, 10.9 br (H, br s) ppm; HPLC-Method A, Rt 3.307 min; MS (FIA) 433.2

C

Example 22 (1Z-Indazol-3-yl)-[6-(pyridin-2-yl) 2.(2 0 trifluoromethyl.phenyl) -pyrimidin-4-ylJ -amine (11-22): Cl Prepared in 421 yield. 'HNMR (500 MHz, DMSO) 7.07 (1H, J=7.4 Hz, 7.36 (1H, J=7.4 Hz, 7.46 (11, Jt7.4 Hz, Cl 7.53 (1H, Js5.0 Hz, 7.70 (1H, J=7.4 Hz, 7.79 o~ (11, J=7.1 Hz, 7.83 (11, J=7.4 Hz, 7.88 (1H, J=7.8 Hz, 7.97 (IH, J=7.7 Hz, 8.02 (1H, J5.5 Hz, br 8.36 (23, J=7.8 Hz, 8.75 (2H, J=4.1 Hz, d), 10.5 (LH, br 12.7 (iN, br a) ppm; HPLC-Method A, Rt 3.677 min; MS (FIA) 433.2 (M+H) 4 Example 23 (6-(2-Chiorophenyl) (2-trifluoromethylphenyl)-pyrimidin-4-yi]-(1K-indazol-3-yl)-amine (11-23): Prepared in 44% yield; 1 fHNMR (500 MHz, DMSO) 8 7.08 (1H, J7=7.5 Hz, 7.37 (1H, J=7..5 Hz, Q, 7.45 (1R, 7=8.4 Hz, 7.51 (2H, 7.61 (11, J=7.4, 1.9 Hz, ad), 7.69 (2H, 7.79 (21H, 7=4..O Rz, 7.86 (3H, J=7.8 Hz, di, 8:04 (2H, J=6.2 Hz, br'd), 10.7 (11, br 12.6 (1H, br a) ppm; HPLC-Method A, Rt 3.552 rin; MS (FIA) 466.2 Example 24 [S,6-Dimethyl-2- (2-trifluoromethyl-phenyl) pyrimidin-4-yl]-(LH-indazol-3-yl)-amine (11-24): Prepared in 35% yield; ap 183-186 0 C; NM (500 MHz, DMSO) 8 2.14 (Hs, 2.27 (3H, 6.85 (15, J=7.5-Hz, 7.15 (In1, J717.6 Hz, 7.32 (3H, in), 7.38 (1R, J=7.5 Hz, 7.42 (1H, Hz, 7.53 Hz, 8.88 (lH,a), 12.5 (111, a) ppm; HPLC-Method A, Rt 2.889 min.; MS (FIA) 384.2 (M+HY'.

-254- Va Example 25 t5,6-Dimnethyl-2- (2-trifluoramethyl-phanyl)pyrimdi.-4-yl] -(5-fluoro-1E-indazol-3-yl)-amine (11-25): Prepared in 44 yield. Melting point h1-1636C; 'HMR cl s (SOO MHz, DMSO) 8 2.27 (3H, 2.40 (3H, 7.16 (2H, 7.44 (2H, 7.52 (1H, J77.4Hz, 7.57 LT=7.4 0 Hz, 7.67 (1H, J=7.8 Hz, 9.03 (1H, 12.75 hN, a) ppm; HPLC-Method A, Rt 2.790 min; MS (FIA) 402.2 O 2 C 01 o tExample 26 (2-(2-Chiorophenyl) 6 -diothy-pyrimidUn- .4 Yll-D.8-indazol-3-yl)-amine (11-26): Prepared in yield. 1 HNMR (too MHz, DM80) 2.14 (3H, 2.33 (3H, 6.64 (1R, J-7.4 Hz, 7.1311!, J-7.4,Hz, 7.19 (in, J-6.9 Hz, br 7.27 (21, J=7.4 Hz, 7.32 (3H, br 7.37 J7=7.3 Hz, 20.0 (IN, br), 12.8 (11, br ppm; 6 2.919 min; MS (FIA) 350.1 (l4+H).

Example 27 [5,6-Dimethyl-2- (2-trifluorciethy1 phenyl) pyrfridin-4-yl] (7-fluoro-LH-indazol-3-y) -amine (11-27): Prepared in 92% yield. l1fMMR (500 MHz, DMSO) 8 2.33 (3M, 2.50 (3H, 6.97 (11, 7.15 (1N, 7.30 (Ii, J-8.1 Hz, 7.65 (3H, 7.76 (I11, Hz, d), 1010 (1N, 13'4 s) ppm; HPLC-Method A, Rt 3.053 min; MS (FIA) '402.2 Examle 28 ('5,7-Difluoro-1-indazol.3.y) -(5,6-Driiethyl- 2- 2 trifluoromethyl-phenyl) -pyriaidin-4-yl -amine (I- 28): Prepared in 50% yield. 'HNMR (500 MHz, DMSO) 6 2.42 (311, 2.63 (3H, s),-7.22 (1H, J-7.6 Hz, 7.38 (1H, J-9.3, 1.7 Hz, dt), 7.7. 7.75 (1N, J=7.0 Hz, d), 7.79 J-6.7 Hz, 7.86 (1N, L7=8.0 Hz, 10.0 (1H, -255- O 13.2 (iN, a) ppm; HPLC-Method A, Rt 3.111m m; mi s (PMA) 420.2 (MiH).

Example .29 C 2 -(2-clorophenyl) 6-dimethy1-pyrimidin-4 Yl]-(5, 7 -difluora-1Hmindazo1-3-y1)-amne (11-29): Prepared in 58% yield. 'HNMIR (50,0 MHz, DMSO) .8 2.47 (31, 0c,~1 2.66 (3R, 7.44 (2H, 7.53 (1H, 7.64 (3H, 10.4 (iN, brl, 13.8 (iH, br a) ppm; HPLC-Method A, Rt o 2.921 min; MS (FIA) 386.1 IND Example 30 2- (2-Chlorophenyl) -5,6-dimethyl-pyrimidun-4yl- (7-fluoro-1B-indazol-3-yl) -amine Prepared in yield. 1 q'HN (500 MHz, DMSO) 8 2.35 2.51 (3H, 7.03 (1H, J=7.8, 4.4 Hz, dt), 7.22 (1H, 7.33 (iM, Ja7.4 Hz, 7.42 (1H, 9.19 (31, 13.3 (iH, a) ppm; HPLC-Method A, Rt 2.859 min; MS (PIA) 368.2 (M+n) Example 31 [2-(2-Chiorophenyl) -S,6-dinethyl-pyrimidin-4 yll (S-fluoro-l-±ndazol-3yl) -amine, (11-31): Prepared in 86% yield. 1HNN (500 MHz, DMSO) (3H, 2.68 (3H, 7.38 JL9.0 7.54 m),.7.67 (4R, 10.5 (1R, br), 13.2 (iH, bra ppm; HPLC-Method A, Rt 2.850 min; MS (FIA) 368.1 Example 32 12- (2,4-Diohloropheanyl) -5,6-ditmethyl- .Pyrimtdn-4-yl]- (R-indazol-3-yl) -amine (11-32): Prepared in 52% yield. 'HNMR (500 MHz, DMSO) S 2.46. (3H, 2.64 (3H, 7.16 (11, J=7.5 Hz, 7.46- (11, J=7.6 Hz, t), 7.61 (2H, 7.68 (2H, J=8.2 Hz, 7.82 (1R, m, 10.2 (11, br), 13.0 (IR, br a) ppm; HPLC-Method A, Rt 2.983 miin; MS (FIA) 384.1 -256- Va Ex Mle 33' (5-Methyl-22-pyrazol-3-yl) t2- (2methyiphenyl) -quinazolin-4-yll -amine (11-33): 'HMt4 (DMSO) 81.21 2.25 (3H, 6.53 (1W, 7.38 (4H, m), 7.62 (1W, 7.73 (aM, 7.81 (iN, 7.89 (1S, t), 8.70 12.20 (15, MS 316.3 Example 34 (2-(2,4-Difluorophenyl) 0~ methyl-2-pyrazol.3-yl)-amine (11-34): 'lMm (500 MHz, DMSO-d6) 812.4 (br a, 1H), 10.8 (br a, 1H), 8.58 lay, C- 7.97 1H), 8.36 1H), 7.85 1H), 7.60 1W), 6.62 1H), 2.30 3M); MS 338.07 Example 35 (2,5-Dimethozyphenyl) -quinazolin-4-yl methykl-2H-pyrazol-3-yl) -amine (11-35): l5NMR (500 MHz, DMSO-d6) 812.5 (br a, IS), 8.68 (br, IH), 7.92 J Hz, 1W), 7.86 J 8.2 Hz, 1H), 7.65 J Hz, 1W), 7.45 15), 7.14 2H), 6.51 IH), 3.79 3H), 3.67 3M), 2.14 3H) MS 362.2 Example 36 [2-(2-Chloropenyl) -quinazoln-4-ylJ methyl-20-pyrazol-3-yl)-amine (11-36): 1 HNNR (500 MHz, DMSO-dG) 611.8 (br, 1M),,8.80 Cd, J 8.3 Hz, 15), 8.00 J 7.6 Hz, 111), 7.82 J Hz, 11), 7.78 (m, 2H), 7.67 J- 7.8 Hz, 1H), 7.61 J 7.0 Hz, '7.55 J 7.4 Hz, IH), 6.56 lH), 2.18 3H); MS 336.1 Example 37 (2-(2-Methosyphenyl)-quinazolin-4-yl]-(5methyl-2H-pyrazol-3-yl) 'amine (11-37): 1 jNM (500 MHz, DMSO-d6)' 88.78 br,. 1W), 8.00 7.4 Hz, i), 7.90 2H), 7.274 C(t, J- 7.5 Hz, 1H), 7.63 J 7.3 Hz, 1H), 7.30 L 8.4 Hz, 11), 7.18 J 7.5 Hz, -257- Va 1K), 6.58 br, 1l), 3.90 3H), 2.21 3K); MS 332.1 Example 38 C2-(2,6-Dimethyiphenyl) methyl-2a-pyrazol..3..yl) -amine (11-38): 1 NrM (500 M4Hz, DMSO-dE) 812.2 br, 2H), 6.88 J 7.7 Hz, 1K), 8.05 J 7.7 Hz, 1K), 7.80 2H), 7.37 J 7.6 Hz, 1H), 7.21 J 7.7 Hz, 2H), 6.36 1H),'2.16 (a, o 3H), 2.15 6K); MS 330.1 O o Example 39 [2-(2-Acetyiphenyl) -quinazolin-4-yll- (Smethyl-2-fpyrazol-3-yl) -amine (11-39): 'TH-R (500 MRz, DMSO-dE) 612.35 br, iH), 8.93 J 8.4 Hz, IN), 8.37 J 8.6 Hz, 1K), 8.20 J 7.6 Hz, 8.11 C 8.0 Hz, 2H), 7.89'(m, 2H), 7.77 2H), 6.93 (s, 2.33 3H), 2.04 3H) MS.344.1 Example 40 [2-(2,3-Dimethylphenyl) -qi:nazolin-4-yl'- .methyl-2H-pyrazol-3-yl-anie (I-40)''LHNMR (500 Mfz, DMSO-dE) 612.6 br, 1K), 12.1 br, IN), 8.91 J 7.7 Hz, iN), 8.14 J 7.2 Hz, 1K), 7.95 J 8.4 Hz, IN), 7.89 J n 7.7 Hz, iN), 7.58 J 7.6 Hz, 1V,) 7.53 Cd, L 7.0 Hz, 7.42 J 7.6 Hz, 1), 6.60 1H), 2.43 3H), 2.35 3H), 2.32 3H); MS 330.1 Example 41 (5-Hethyl-2H-pyrazol-3-yl)-[2-(2trifluoromethylphenyl) -quinazolin-4-ylJ3-amine (11-41): 'HNMR (500 1Hz, DMSO-d) 812.3 1K), 10.5'(s, 13), 8.7.7 J 8.2 Hz, 7.92 2H), 7.85 3K), 7.56 a 8.1 Hz, 1K), 7.67 J 7.4 Hz, IN), 6.63 lB), 2.27 3H); MS 370.1 (M+HY.

-258- Va Exampe 42 2-(2-Ethylphyl) -quinazolin-4-yl (-Methyl- 2 E-pyrazol-3-'yl).amine (11-42): 1 1UMhM (500 MHz, fMSO-d6) Sa.ao i, 8.02 s, br, 1H), 7.82 J 8.4 Hz, (N S 7.77 1H), 7.62 J 7.6 Hz, 1H), 7.54 (m, 7.41 211), 6.40 1H), 2.75 J 7.1 Hz, 2H1), 2.17 3H), 0.99 J 7.5Hz, 3H); MS 330.1 Examle 43 2 -Biphenyl-2.-yl-quinazoln-4-yl)-(S-methyl- 2 3 -pyrazol-3-yl)..amine (1I-43): 'HNMR (s00 MHz, DMSO-d6) 8.76 Cd, J 7.6 Hz, 1),8.04 11), 7.75 6H), 7.30 Cm, SM), 5.34 1R), 2.14 3H); MS 378.2 Exaaple 4[ r2- (2-Hydroxyphenyl) -quinazolin-4-ylJ Methy-2Hpyrazo.3-yl))-amine (11-44): 'HNMR (500 MHz, DtSO-dG) 810.9 br, 1H), 8.62 J 8.2 Hz, 11), 8.28 Cd, J 7.9 Hz, 1H), 7.87 2H), 7.60 t, J 7.9 Hz, 1H), 7.37 t, J 7.8 Hz, 1H), 6.92 2M),'6.45 (a, 13), 2.27 31); MS 318.1 Example 45 [2-(2-Ethozyphenyl) -quinazolin-4-ylJ- Methyl -2-pyrazol-3 yl)-mine (11-45): 'IflMR (500 MHz, DMSO-dE) 812.1 Cs, br, 1H), 8.75 J 8.3 Hz, 13), 7.97 Ct, J 7.8 Hz, IH), 7.82 J 8.3 Hz, 1H), .7.78 Cd, J 7.5 Hz, 11), 7.70 t, J 7.8 Hz, 7.56 J 7.8 Hz,' 7.22 J 8.4 Hz, IH), 7.12 =7.6 Hz, 11), 6.55 Cs, 13), 4.11 J 6.9 Hz, 2.16 Cs, 3H), 1.22 C 6.9 Hz, 3H); MS 346.1 (14+H).

Example 46 (Thiophen-2-yl) -20-pyrazol-3-ylJ (2trifluoroiethylphenyl).-quinaolin.4y1, -amine (11-46): 1 HMR (500 MHz, DMSO-dG) 88.04 J 8.3 Hz, 1H), 8.05 -259- Va (dd, J 7.3, 8.2 Hz, IS), 7.93 3 .5 Hz, 7.81 Cm, 5H), 7.34 J- 5.0 Hz, 7.25 7.00 Cm, 6.87 MS"438.1 CM+H).

Example 47 (Thiophen-2-yl) -2-pyrazol-3-yll. [2 (2 trifluoroinethylphenyl)-qninazolin-4-yll-amine (11-47): o Prepared according to Method B. 'HNMR (500Mz, DMSO-dE) S (SK 6;97 7.08 Cm, iH), 7.27 iS), 7.36 1W), o 7.66 Cm, 2H), 7.77 7.83 8.00 IW), 8.18 8.62 J 8.2 Hz, 10.7 Cbr. s, IN); El-MS 438.1 WPLC-Method A, Rt 2.97 min.

Example 48 (4-Phenyl-23-pyrazol-3-yl)-[2-(2trifluoroiethylphenyl) -qainazolin-4-y1]-amine (11-48): Prepared according to Method B. 'HNMR (SOOMHz, DMSO-d) S 7.05Sbr. s, IN), 7.14 J 7.8HRz, 1W), 7.25 3H), 7.43 2H), 7.60 2H), 7.73 2H), 7.80 Cd, 1)O 7.95 1W), 8.12 (br. a, 1H), 8.60 aM), 10.6 (br.

0, IS); EI-MS 432.2 HPLC-Method'A, Rt 3.04 min.

Example 49 (S-tert-Butyl-2a-pyrazol-3-yl)-(2-(2triflnoromethyl-phenyl)-quinazolin-4-yll -mine (11-49): 1 HNMR (500 MHz, DMSO-d6) 6 8.76 J 8.3 Hz, IN), 7.94 Cm, 2W), 7.79 4H), 7.70 J 7.6 Hz,,lW), 6.51 (s, 1H), 1.16 s, 9H); MS 412.2 Example 50 (5-Phenyl-2H-razxol-3-yl) (2trif luoromethylpheny) -quinazolin-4-yll -amine (Z1-50): 'HNMR (500MHz, DMSO-d) 6 7.09 IN), 7.36 (td, J 7.8, 1.1 Hz, 11), 7.46 t, J 7.8 Hz, 2W), 7.65 (br. d, J 5.1Hz, 2H), 7.78 7.90 4H), 7.95 Cd, J 7.7 Hz, 1H), 8.00 Ct, J 7.8 Hz, IN), 8.81 J 8.6 Hz, IN), 11.29 (br. a, El-MS 432.1 HPLC-Method A, Rt 3.24 min.

-260- Cl Example5l 4 ,5-Diphenyl-20-ipyrazol-3-yl) -12- (2tritluoromethylphenyi) -quinazolia-4-yl] -amine (XE-Si): __'IWMR (500MHz, DMSO-d6) 8 7.13 IN), 7.18 Cm, 7.36 SE), 7.62 Cin, 3H), 7.73 2H), 7.85 (mi 111), 8.48 J 8 Hz, IN) 10. 02 Cs, iN), 13. 19 Cs, IN); El-MS 508.2 CM-iH); NPLC-Method A, Rt 3.39 muin.

0 Example 52 4 -Carbamoy-2H-pyrazo.s. trifluarcmethylphenyl) -quinazoiin-4-ylJ -amine (11-52): Cl Prepared in 40% yield. 'RHNMR (.500MHz, DMSO-dE): b 12.85 lJfl, 12.77-Cs, 1H1), 11.80 Cs, i1H), 10.80 iN), 8.35-7.42 (in, 9H); MS 399.13 (M4*1) HPLC-Method A, Rt 2.782 min.

Example 53 (20-Pyrazol 3-yl) [2 trifluormethyiphenyl) -quinazolin-4-yl] -amin~e (11-53)- Prepared in 38% yield. 1 MR (500 MHz, DMSO-d6) 8 12.52 1H), 10. 65 iN) 8. 75 Cd, 111), 7.91-7.68 (in, SN), 6.87 Cs, iH) MS: (14+1) 356.27*. HPLC-Method A, Rt 2.798 muin.

Exa~nlej54, (S-Nydroxy-25-pyrazol'3-yl)- (2trifluoromethlylphemyi) -guinazoiin-4-ylJ -amine (11-54): Prepared in 3 6* yield; 'IHIMR (500 MHz,-DMSO-d6) 806 Cs, 111), 8.75 111), 8.03-7.75 Cm, 9H),.5..97 111);, MS 372.18S HPLC-Method A, Rt 2.766 min.

Examaple 55 (5-Cyclopropyl-2H-pyrazol-a-yl) trifiluoroinethyi-phsnyi) -quinazolin-4-y1J -amine 411-55): Prepared'in 30% yield. 'HNMR (500 14Hz, DMSO-d6) 812.21 Cs, iH) 10.'45 11) 8.68 11) 7.89-7.45 BE) -261- Va o 6.48 1K), 0.89 2H), 0.62. 2H). MS 396.18 C HPLC-Method A, Rt 3.069 min.

Example 56 (5-Meth-zymethyl-2-pyrazol-3-yl)-[2-(2triluoramethyl-phenyl)-quinazolin-4-yll -amine (11-56): Prepared in 33% yield; IHNMR (500 MHz, DMSO-d) 8 12.51 0(s, 1K), 10.48 1H), 8.60 1H), 7.81-7.55 7H), 6.71 1H), 4.28 2H), 3.18 3H). MS 400.19 o HPLC-Metod A, Rt 2.881 min.

IND o Example 57 (1E-indazol-3-y1)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine (II-57): Prepared to afford 51 mg (78% yield). as pale yellow solid. 1 HNMR (500 MHz, DMSO-d6) 812.7 1K), 10.4 1H), 8.55 1), 7.81 1I), 7.71 1H), 7.61 1I), 7.58 1H), 7.46 4H), 7.36 1H), 7.22 1H), 6.91 1H) ppm; LC-MS 406.16 404.19 KPLC- Method A, Rt 3.00 min.

Example 58 (4-Chloro-t&-indazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yll-amine (11-58): Prepared in DMF (70% yield) as pale yellow solid. 'HflR (500 MHz, DMSO-d6) 813.3 br, 1H), 10.9 br, 1K), 8.60 1H), 7.97 1H), 7.81 1H), 7.75 1K), 7.67 1H), 7.63 (dd, 1K), 7.57 2K), 7.43 1H), 7.28 (dd, 1H), 7.08 1K) ppm; LC-MS 440.10' 438.12 HPLC-Method A, Rt 3.08 min.

Example 59 (5-Fluoro-1H-indazol-3-yl)-2-(2trifluoromethyl-phenyl)-quinazolin-4-yl] -amine (11-59): Prepared in DMF (34% yield) as pale yellow solid. 'KIaR (500 MHz, DMSO-d6) 813.0 1K), 10.6 1H), 8.72 (d, 1K), 7.99 1H), 7.89 1R), 7.79 1H), 7.75 (t, iS), 7.68 3H),,7.56 (dd, 7.39 1H), 7.28 (t, -262- Va oH) ppm; LC-MS 424.12 r/en 422.13 (M- HPLC-Method A, Rt 3.05 min.

Example SO (7-Fluoro-l-indazol.3-ya) (2 c(2trifluorometbyl-phenyl) -quinazolin-4-yll -amine (11-60): Prepared in DIF yield) as yellow solid. 'HNNR (500 MHz, DMSO-dS) C13.4 10.6 8.68 IN), 7.95 7.85 1H), 7.72 2H), 7.63 Cm, 2H), 7.58 1H), 7.43 II), 7.18 (dd, 1f), 7.00 1H) ppm; LC-MS 424.11 A22.15 CM-H); HPLC- 0 Method A, Rt 3.06 min.

Example 61 (5-ethyl-lH-idazol-3-y1) trifluoromethyl-phenyl) -quinazolin-4-ylJ -amine (11-61): Prepared in DM7 (81% yield) as yellow solid. 1 ffMR (500 MHz, DMSO-d6) 8'13.0 br, 8.79 (br, N) 8.11 Cbr, 1H), 7.96 Cd, 1H), 7.82 5H), 7.46 1H), 7.41 (d, 1H), 7.20 iN), 2.33 3H) ppm; MS 420.15 418.17 CM-H); HPLC-Method'A, Rt 3.07 min.

Example 6 2 6-Dichioro-phenyl) -qninazolin-4-yl3 fluoro-ll-indazol..3.yl) -amine (11-62): Prepared in DMF (37% yield) as yellow solid. '-HNMR-Ct00 MHz, DMSO-d6) 613.0 Cs, 1f), 10.8 8.72 1f), 7.97 t, 1H), 7.90 1R), 7.75 t, 1H), 7.53 3H), 7.43 1f), 7.35 iN), 7.23 Ct, 1) ppm; L0S 424.08 (M+H)L 422.10 CM-H); HPLC-Method A, Rt 3.06 min.

Example 63 (2-Chioro-phenyl) -quinasolin-4-yl] (Ifindazol-3-yl)-amins (31-63): Prepared in 91% yield. HNMR (sobmHz,, DMSO-d6) S 7.06 1H), 7.36 t, 1H), 7.39 tt, iN), 7.52 Cm, 3H), 7.62 7.72 1f), 7.82 Cm, 7.90 1f), 8.'05 Cm, 1H), 8.76 1ff), 11.5 (m, 13.02 E-MS 372.1 HPLC-Method A, Rt.

-263- Va 2.93 min.

Example 64 (5-Trifluoromethyl-2.z-indazol-3-y) (2trifluoromethyl-phenyl)-quinazolin-4-yl -amine (11-64): Cl 5 Prepared in DMF (57% yield) as yellow solid. HNMR (500 MHz, DMSO-d6) 513-.4 br, lW), 11.4 Cbr, lW), 8.72 (d, 0 ZR), 8.12 Cs, lW), 7.98 Ct, 1H), 7.83 IH), 7.76 (d, HlW), 7.73 (dd, 1H), 7.60 4H), 7.52 iN) ppm; LC-MS 474.12 472.17(M-H); HPLC-Method A, Rt V. 10 3.25 min.

Example 65 (4-Trifluorometbyl-H-±ndazoi-3-yl) (2trifluoromethyl-phenyl) -quinazolin-4-yI -amine' (11-65): Prepared in DMF yield) as yellow solid. '1NMR (500 MHz, DMSO-d6) 813.7 br, 1H), 11.2 Cbr, iN), 8.70 (d, IN), 8;05 1H), 7.85 3H), 7.65 Cm, 4H), 7.51 (mi 22) ppm; LC-MS 474.13 472.17 CM-H); HPLC-Method A, it 3.15 min.

Example 66 [2-(2,6-Dichioro-phenyl) -quinazolin-4-yll- (21Eindazol-3-yl)-aane (11-66): Prepared in DMF (30% yield) as yellow solid. 'HNMR (500 M4Hz, DMSO-dE) 812.9 Cs, IW), 11.1 1H), 8.69 IH), 7.95 1H), 7.82 Cd, 1H), 7.73 11), 7.56 Cd, 1H), 7.47 Cs, iN), 7.45 1H), 7.39 Cm, 2H), 7.26 Ct, 1H), 6.92 Ct, 1H) ppm; LC-M$ (ES-) 406.11 404.12 HPLC-Method A, Rt 3.00 min.

Example 67 (1H-indazol-3-yl) (2-methyl-phenyl)quinazolin-4-yiJ-amine (11-67): Prepared in 55% yield.

3 INNR (SOOHz, 'DMSo-ds) 82.15 3H), 7.09 Ct, '7.26 3H), 7.31 JH), 7.39 IIH), 7.42 Cm, 1H), 7.55 (d 1H), 7.64 1H), 7.74 iH), 7.89 IH), 7.96 -264- Va UI), 8.10 1H), 8.81 iN), 12.0 iN), 13.18 iN); El-MS 352.2 HPLC-Method A, 1% 2.93 min.

Example 68 (7-Triluor;:;ethyl:-If lu; trifluorametyl -phenyl) uiazolin 4-yll arine (16) Prepared in DMF (75% yield) as yellow solid. 1HNMR (500 en MHz, DMSO-d6) 813.5 br, 1H), 11.2 br, 8.68 7.97 1H), 7.92 IH), 7.82 iN), 7.74 Ct, iN), 7.70 Cd, iN), 7.68 iN), 7.64 2H), 7.57 m, 11, 7.14 1R) ppm; LC-MS 474.11 472.14 HPLC-Method Rt 3.24 min.

Example 69 (6-Trifuoroinethyl -I-indazol-syi (2trifluornethyl-phenyl)-quinazolin-4-yi]-anine (11-69); Prepared by Method B in DMF (78% yield) as yellow solid.

'HNMR (500 MHz, DMSO-d6) 8 13.4 br, 1H), 11.1 br, iN), 8.67 Cd, 1H), 7.95 7.82 3H), 7.72 Cm, 211), 7.63 Cm, 2H), 7.57 111, 7.23 Cd, IN) ppm; LC-MS 474.12 CM+H), 472.15 CM-H); HPLC-Method A, Rt 3.28 min.

Example 70 (S.-NitroJ.x-indazol-3-yi) (2trifluoromethy1 phenya) -quinazoiin-4-jrl -amine (11-70): Prepared in DMF (82% yield) as yellow solid. 1 flHM43 (500 MHz, DMSO-d) 813.6 br, lH), 11.4 br, 1H), 8.75 Cs, 8.72 1H), 8.09 Cdd, 1H), 7.98 Ct, iN), 7.83 iN), 7.75 Ct, 1H), 7.70 Cm, 2H), 7.61 Cm, 3R) ppm; LC-MS (ES) 451.14 449.12 HPLC-Method.

A, Rt 3.02 min.

Example -71 (5,7-Difuoro-ix-mnaazo13 -yl) 1r2...(2 trifluoromethyl-phenyl) -quinazolizh-4-ylJ -amine (11-71): Prepared in DM2 (60% yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 513.7 Cs, br, 1H), 11.2 br, iN), 8.73 -265- Va Sc(d, 1H), 8.03 1H), 7.88 11), 7.80 2H), 7.70 C' 3H), 7.32 2H) ppm; LC-MS 442.14 (ES- 440.14 HPLC-Method A, Rt 3.11 min.

Example 72 4 -Pyrrol--yl-1-B-indasol-3-yl)- (2trifluoracimethyl-phnyl) -quinazolin-4-yl -amine (11-72): O) Prepared in DMF (33% yield) as yellow solid. lENMR (500 C- MHz, DMSO-d6) 813.4 br, IH), 11.0 br, 12), 8.53 o 1H), 7.98 1H), 7.75 4H), 7.62 23), 7.52 ND 10 1H), 7.43 1H), 7.05 13), 6.80 23), 5.61 o( s, 2H) ppm; LC-MS 471.18 469.18 (M- HPLC-Method A, Rt 3.12 min.

Example 73 (5-Amino-1H-indazol-3-yl)- trifluoromethyl-phenyl)-quinaxolin-4-yl -amine (11-73): A solution of compound 11-70 (70 mg, 0.16 mmol) in MeOH (2 mL) was treated with Raney Ni until solution was colorless (about 1.5 g Raney Ni was added). After stirring at room temperature for 40 min, the mixture was filtered through celite, the resulting celite was washed with MeQH (5 times), and the solvent was evaporated in vacuo to provide a crude product that was then purified by HPLC to give the title compound as a yellow solid mg, m.p. 221-223-C; I 0 NMR (500 MHz, DMSO-d6) 813.2 br, 1H), 10.7 br, 1H), 9.80 (br, 2H), 8.68 1H), 7.97 1H), 7.87 13), 7.75 2H), 7.65 5H), 7.30 11) ppm; MS 421.16 (ES-) 419.17 HPLC-Method A, Rt 2.41 min.

Example 74 (2-Chloro-phenyl) -quinasolin-4-yl] (7fluoro-3a-indazol-3-yl)-amine (I1-74): Prepared in DMF yield) as yellow solid. 1HNMR (500 MHz, DMSO-dS) 813.7 13), 11.7 br, 1H), 8.80 IH), 8.15 (t, 1H), 7.99 13), 7.88 11), 7.68 1H), 7.60 (m, -266- Va o 2H), 7.53 lW), 7.46 7.25 (dd, Ii), 7.04 (m, lH) ppm; LC-MS 390.16 HPLC-Method A, Rt 3.00 min.

Example 75 [2-(2-Chloro-penyl)-quinazolin4.yll-(S.

fluoro-lE-indazol-3-yl)-amine (11-75): Prepared in DMF.

0c 1 iflNM (500 MHz,. DMSO-d) 813.2 lH), 11.7 br, 1H), 8.80 1H), 8.10 Ct, 1H), 7.91 Cm, 2W), 7.70 iS), '7.58 4H), 7.50 1H), 7.29 Ct, 1) ppm; LC-MS (ES+) o 10 390.17 CM+H); HPLC-Method A, Rt 3.00 min.

Example 76 (2-Chloro-phenyl) -quinazolin-4-yl]- (5,7difluoro-1H-indazol-3-yl) -amine (11-76): Prepared in DMF yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 613.8 15), 11.5 br, 1H), 8.76 Cd, 11), 8.08 (t, IH), 7.93 7.84 15), 7.64 1W), 7.55 (d, IH), 7.50 Ct, 15), 7.44 2H), 7.36 1W) ppm; LC-MS 408.15 406.17 CM-H); HPLC-Method A, Rt 3.08 min- Example 77 (2-Chloro-phenyl) -quinasolin-4-yll-

(S-

trifluoromethyl-ru-indazol-3-yl) -amine (11-77): Prepared in DMF (66% yield) as yellow solid.- 1 THNMR (500 MHz, DMSOd6) 513.5 Cs, 15), 11.4 br, 1H), 8.79 1H), 8.29 1H), 8.07 1H), 7.93 no), 7.84 Ct, lH), 7.72 iH), 7.63 2H), 7.53 Cd, 1H), 7.48 Ct, 15), 7.36 15) ppm; LC-MS CES+): r/en 440.16 r/en 438.18 HPLO-Method A, Rt 3.22 min.

Exa le 78 (2-cyano-phenyl)-qainazolin-4-yl]- (1Hindazol-3-yl)-amins (11-78): Prepared in 13% yield. H NR (500 MHz, DMSO) S 12.9 (br, IH), 10.8 (br, 1H), 8.73 Cbr s, 1H), 7.97 4H), 7.74 15), 7.5 4H), 7.42 -267- Va 1H), 7.08 ii) ppm; MS (FIA) 363.2

HPLC-

Method A, Rt 2.971 min.' Example 79 (5-Bram -1H-indazol C 5 tri fluoramethyl -phezyl) -quilazol fa- -yll minie.(T'1- 7 9) Prepared in DMF (64% yield) as yellow solid. 1'2UMR (500 MHz, DMSO-d) 813.4 1H), 11.6 br, 1H), 8.93 (d, C 1H), 8.21 1H), 6.14. s, 1H), 8.05. 1H), 7.95 (m, 7.86 1R), 7.65 1H), 7.59 1IH) ppm; MS 486.10 484.09 CM-H); HPLC-Method A, Rt 3.22 min.

Example 80 (6-Chloro-llr-indazol-3-yl) (2trifluoroethyl.pheeyi)-quinazolin-4-ylJ-amine (11-80): Prepared in DMF (94% yield) as yellow solid. 1HNMR (500 MHz, DMSO-d6) 813.1 1K), 11.2 br, 1H), 8.73 (d, 1H), 8.03 1H), 7.87 1H), 7.79 Cm, 2H), 7.73 (m, 2H), 7.67 2H), 7.58 Cs, 12), 7.04 (dd, 12) ppm. LC-MS (ES+s) 440.14 438.16 CM-H); HPLC-Method A, Rt 3.25 min.

Example 81 7 -Fluoro-6-trifluoromethyl-il-indazo.3-yl) (2 -trifluoromethyl-phenyl) -guinazolin-4-ylJ -amine (II- 81): Prepared in DMF (30% yield) as yellow solid. 1

'NMR

(500 MHz, DMSO-d) 813.9 IH), 11.0 br, 1H), 8.64 Cd, 1H), 7.94 1H), 7.81 7.71. 2H), 7.60 4H), 7.20 (dd, 1H) ppm. LC-MS.CESt) 492.18 490.18 HPLC-Method A, Rt 3.44 min.

Example 82 (6-Bromo-E-indazol-3-yl) 1-(2trifluoriethyl-phenyl)-quinasolin-4-yll-amine (11-82Y: Prepared in DMF (40% yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 813.1 11.2 br, 12), 8.73 (d, 114), 8.03 Ct, 1R), 7.87 Cd, 32), 7.80 Cm, 2H), 7.73 (m, -268- Va 3H), 7.67 (in 1H), 7.61 1H), 7.15 (dd, 1H) ppm; -MS 486.07 HPLC-Method A, Rt 3.28 min.

Example 83 2-(2,4-Bis-trifiuoromethyx.-phenyl)quinaoli-4-yll-(5 ,7-difluro- 1-indaol-3-y -mine (IZ-83): Prepared in DM1 in 28* yield. 2 HNMR (500MHz, MeOH-d4) 6 8.81 J=8.4Hz, 1H), 8.35-8.20 3H), 8.19-7.96 3H1), 7.40-7.34 1H), 7.29-7.14 (in 1); 0 c LC-MS 510.14 HPLC:Method C, Rt 8.29 min.

0~ Example 84 (5,7-Difluoro-1E-indazol-3-yl) -(2-(4-fluoro-2trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (11-84): Prepared in 48% yield. 'SNMR (500MHz, MeOH-64) 88.74- 8.63 iH), 8.23-8.10 1H), 7.99-7.90 2H), 7.89- 7.80 Cm, 1H), 7.71-7.61 15), 7.61-7.50 1H), 7.24- 1H), 7.14-7.02 IH); LC-MS 460.14 HPLC-Method C, Rt 7.59 min.

Example 85 [2-(2-Bromo-phenyl) -qninazolin-4-yl]-(5,7difluoro--indazol-3.ya)..amine (11-85): Prepared in THF (21% yield). 'ENMR (500MHz, MeQH-d4) S8.81 J=8.45z, 11), 8.35-8.20 311), 8.19-7.96 3H), 7.40-7.34 (m, 11), 7.29-7.14 IH); LC-MS 510.14 HPLC- Method C, Rt 8.29 min.

Example 86 (5,7-Difluoro-s-indazol-3-yl)-t2-(-fluoro.2.

trifluormethy.-phenyl) -quinazolin-4-yll-amine (11-86): Prepared in THF yield). 'RMR (5001Hz, MeOH-d4) 8.62 J.4Hz, 1H), 8.16-8.02 15), 7.96-7.73. (m, 7.59-7.48 1H), 7.48-7.35 1H), 7.21-7.09 (m, 7.09-6.89 1W); LC-MS (ES) 460.16 HPLC- Method C, Rt 7.26 min.

-269-

IN

o Example 87 (2,4-Diahloro-phenyi) -quinazolinL-4-yll 0 (5, 7 -DiflUoro-1H4ndazol-3-yl)-amine (11-87): Prepared in TIPF (16% yield). 'ENMR (SOOMHz, HeOH-d4) 8s.8i (d, 3=8.4Hz, 1H), 8.35-8.20 Cm, 3M), 8.19-7.96 3M), 7.40- 7.34 lB), 7.29-7.14 IH); LC-MS 510.14 HPLC-Method C, Rt 8.29 min.

c-i Example 88 t 2 o quinazolin-4-yl]- (5 1 7-DifLuoro-1R-indazol-3-yi) -amine (11-88): Prepared in THF (33% yield). 'HM- (500MHz, o DMSO-dg) 8 10.76 IH), 8.66 3=8.3Hz, lH), 8.06- 7.84 3H), 7.81-7.63 3M), 7.48-7'.,16 2H); IC-MS 476.16 HPLC-Method C, Rt 19.28 min.

Example 89 (4-Fluoro-2Z-indazol-3-yi)-C2-(2trifluoromethyl-phenyl)-guinazolin-4-yl]-amine (11-89): Prepared in NMP (79% yield) as yellow solid. 1 HNMR (500' MHz, DMSO-dE) 513.2 11), 10.8 br, IH), 8.63 (d, 11), 7.97 11), 7.85 IH), 7.74 i, 2H), 7.64 t, IM), 7.57 2H), 7.32 2H), 6.82 iH) ppm; LC-MS 424.17 HPLC-Method A, Rt 3.14 min.

Example 90 (1H-Indazol-3-yl)-[8-methoxy-2-(2tr±luoromethyl-phenyi) -quinazolin-4-yl-amnte (11-90): Prepared usiiig THF as solvent to afford the title compound as a TFA salt (23% yield). HPLC-Method A, It 2.97 miri 1 HNMR (DMSO-d6, 500 MHz)5 12.9 (1R, be), 11.0 -10.7(12, bs), 8.25 7.75-7.50 7.30 (1H, 6.90 (11, 4.0 (3M, MS. 436.2 (M+HJ.

Example 91 (S-Fluoro-ll-indazol-3-yl)-8-methozy-2- (2trifluoromethyl-phenyl)-qainazolin-4-yl]-amine (11-91).

Prepared using TFA as solvent to afford the title compound as a TFA salt (23% yield). HPLC-Method A, Rt -270- Va 3.10 min. 'If1HMR (DMSO-d, 500 MHz): 13.0 (111, be), 11.0 10.7(1, be), 8.25 (1H, 7.75-7.50 (7H, m), 7.35 (111, 7.25 (iN, 4.0 (3H, MS 454.2 (1'kH).

Cl Example 92 7 -Pluoroll-indazol-3-yl)- [B-methoxy-2- (2- 0cr trifluoromethy..phenyl) -quinazolin-4-y1j -amine C Prepared using THF as solvent to afford the title compound as a TA salt (9 8 mg, 58% yield). HPLC-Method A, -Rt 3.20 min HN1R (DMSO-dG, 500 MHz) 5 13.45 (32, be), 11.0 10.7CH, bs), 8.25 7.75-7.60 7.50 (1H, 7.40 (1H, 7.15 (1H, 6.95 m) 4.0 (3H, MS 454.2 Example 93 (5,7-Difluoro-1H-indazol-3-yl) C8-methoxy-z- 2 -trifluoromsthyl.-phenyl) -quinasolin-4-yl -amine (11- 93): Prepared using THF as solvent to.afford the title compound as a TFA salt (36% yield). HPLC-Metbod A, Rt 3.27 win. 1 11P4 (DMSO-dE, 500 MHz): 13.65 (iH, be), 11.0 10.7(11, be), 8.22 (iN, 7.75-7.60 (SN, m), 7.40 (1H,in), 7.35 (11, 7.19 (3H, 4.0 (3H, s)ffMS 472.2 (M+11).

Example 94 (2-Chioro-pyridin-3-yl) -quinazolin-4-yll- (5,7-Difluoro.2s..±ndazol-3-yl)..amine (1r94): Prepared in DMF. 'mMR (SOOMHz, DMSO-d) 8 13.62 (br s, iN, 11.06- 10.71 11), 8.16-7.70 4H), 7.60-7.09 3H); LC- MS 409.14 HPLO-Method A, Rt 2.89 min.

Example 95 (2-Chloro-4-uitro-phenyl -quinazolin-4-ylJ 5 i7-difluoro-ia.. ndazol-3-yl)-aine (11-95): Prepared in lp. IQ'MM4 (500MHz, DMS0-dC) 5 13.35 11), 10.74 (s, 111), 8.67 J=8.4Rz, 1H), 8.29 J=2.OSHz, 1H), 8.18- -271- Va D 8.08 1H), 8.07-7.60 7.53-7.10 LC- Ci MS 453.15 HPLC-Method D, Rt 3.63 min.

Example 96 [2-(4-Amino-2-chloro-phenyl) -quinazolin-4-yll- (r5,7-Difluoro-1a-indazol-3-yl)-amine (11-96): A solution of compound XI-95 (8mg, 0.018mmol) and tin o chloride dihydrate (22mg, 0.lmmol) in ethanol (2mL) was en heated at 100 0 C for 24h. The reaction was diluted with SEtOAc (O10mL), washed with IN NaOH solution (2xlOmL), brine, and dried over anhydrous sodium sulfate to afford the crude product. Purification was achieved by flash cA chromatography on silica gel (eluting with 1-3% MeOH in

CO

2 Cl 2 The title compound was isolated as pale yellow solid (1.2mg, 16% yield). LC-MS 423.12 HPLC-Method C, Rt 13.78 min.

Example 97 (4,5,6,7-Tetrahydro-1H-indazol-3-yl) 2 -trifluoramethyl-phenyl)-quinazolin-4-yl] -amine (11I-97): Prepared in 34% yield. 1 HNMR-(500MHz, DMSO-d6) 8 1.58 2H), 1.66 2E),-2.24 2H), 2.54 (m 2H), 7.63 3H), 7.71 IH), 7.75 1H), 7.78 1H), 7.85 1H), 8.53 12), 9.99 1H), 12.09 1); EI-MS 410.2 HPLC-Method A, Rt 3.05 mii.

Example 98 (lH-PyrazoloE4,3-b]pyridin-3-yl)-r2-(2trifluoromethyl-phenyl) -quinazolin-4-yll -amine (I-98): Prepared in DMF (37% yield) as yellow solid. MM'R (500 MHz, DMSO-dE) 813.1 br, 11H), 11.2 br, 1H), 8.73 1H), 8.54 8.12 12), 8.06 1K), 7.90 1H), 7.84 1i), 7.75 1H), 7.69 2H), 7.65 7.47 (dd, 1H) ppm; LC-MS. 407.18 HPLC-Method A, Rt 2.77 min.

-272o Example 99 (lB-Pyrazolot3,4-bI yridin-3.yl)c..2..2 trifluorcmsthyl.phenyl) -quinazolin-4-ylJ -amine (11-99):- Prepared in DMF C4s% yield). 1 HNMR (500 MHz, DMSO-de) 613.5 hr, 1H1), 11.3 br, lIR), 8.78 IR), 8.49 lB), 8.17 Ii), 8.03 Ct, Ifl, 7.89 7.80 Cm, 2H1), 7.74 2H1), 7.68 1H1), 7.08 Cdd, 111) ppm.

MS 407.16 CM+ffl, 405.16 HPLC-Method A, R 2. 80 min.

Example 100 6 -ethyl- IE-pyrazolo3, 4.b]pyridn.3.yl) [2 0 (2-trifluoromethyl-phenyl) -quinazolinm-4-yl] -am~ine (II- 100) Prepared in D74F (11t yield). 'HNTIR (500 M4Hz, as) 613.2 br, 1H1), 10.8 br, 1H), 8.57 1H1), 7..95 11) 7.82 1H1), 7.72 Ct, 111), 7.65 2H), 7.58 Cm, 2H1), 2.44 Cs, 3H1, buried by DM50) 2.20 3H1) ppm. LC-MS 435.22 433.25 CM-H); HPLCZ" Method A, at 2. 94 min.

Example 10i (6-Oxo-5-phenyl-5,6-dihydro-uE-pyrazolo[4,3..

clpyridazin-3-yl) C2-trifluoromethyl-phenyl) quinazolin-4-y1] -nine 11-101-; Prepared in DMP (6% yield). l'HNMt (500 MHz, DMSO-dG) 812.6 111), 11.0 (a, br,AMk), 8.60 (dyl1H), 7.95 l1H), 7.88 Cd, :lH)#;7..8o d, 1H1), 7.68 Cm, 4H1), 7.40 Cs, 3H1), 7.22.(s, 2H1), 6.61 Cs, 111) ppm. IC-MS (ES+i) 500.-21 498.16 H) HPLC-Method A, Rt 3. 00 Amin.

ExajMle 103 E6-Kethyl-2- (2-trifl.uorometh]oxy-phenyl) pyimidin-4-Yl] (5-phenyl-2H-pyrazol-3'-yl) -am~ine (II- 103): MS 412.13 HPLC-Method 13 Rt 1. 248 mini.

Examle 1,04 (5-Furan-2-yl -2H-pyrazol-3-yl) t6-methyl-2tri fluoronetboxy-pheny1)-pyrimidxn- 4-yl] -amnine (11 104); MS 402.12 HPLC-Method E, Rt 1.188 min.

-2 73- Cl Example 105 E6-Ethyl-2- (2-trifluoromethoxy-pheuy1) pyrimidin-4-yl] -(5-methyl-2H-pyrazol-3-yl) -amine (Ul- 364.14 HPLC-Method E, Rt 1. 112 mlin.

Examle 106 (2-Chioro-phenyl) -pyrido[2,3-djpyrimidin- 4 -Yl]-(S-methyi-25-pyrazol-s-y)-amine

RINMR

Cl (500MHz. DMSO) 512.23 1H), 10.78 111), 7.73-7.47 o (in, 7H1), 6.'72 33), 2.21 311). MS: (14+1) 337.02.

HPLC-Method A, Rt 2.783 min.

Exa mle 107 (5-Fluoro-1E-indazol-3-yl) (2trifluoromethyl-phenxyl) -6,7 -dihydro-SEcyclopentapyrimidin-4yl..amjne (11-107): Prepared in 68% yield. 'UMR (500M~z, DMSO-dE)S6 2.16 2H), 2.88 (m, 2H1), 2.96 2H), 7.21 (td, 1H1), 7.29 (dd, IR), 7.50 Cdd, 1H1), 7.65 Ct, Iii), 7.67 Ct, 1H1), 7.73 Ct, 1H1), 7.79 1H1), 10.22 (br. s, IH), 12.99 (br. s, 1H); El-MS 414.2. CM+H) HPLC-Metbhod A, Rt 2.92 min.

Example 108 (1R-Inxdazol-3-yl) (2-trifluoromethylphaenyl) -pyrido[2,3-dlpyrimidin-4-yll -amine (11-108): EPIC-Method A, Rt 2.78 muin. (95W) 1 1uflMf (DrMso-ds, 500 MI~z): 12.95 (lE, be), 31.45 8511.15(11, be), 9.20 (2H1, mn), 7.85-7.70 (21, mn), 7.70-7.55 (4H1, in), 7.50 (1H, in), 7.35 (111, mn), 7.05 (111, mn); MS 407.03 Examplej09 (5,7-Difluoro-iE'-indazol-s-yl) -r2- (2trifiuoromethyl-phey.) -pyrido (2,3 -dl pyrimidin-4-yl] amine (I1-lo09):t Yellow, di-TFA salt (251 yield). HPLC (method A) 3. 10 min. '!ffMR (DM50-aS, 500 MHz):.

.13 .8-13.6 (in, be), 11.4.- 31.2(11, be), 9.15 (2H, mn), 7.85-7.75 (2H1, mn), 7.75-7.62 (3H1, mn), 7.32 (2H1, mn); MS (in/z) 442.98 (14+1).

-274- Va Examle 110 E2-(2-Chloro-pheny1) -pyrido[2,3-djpyrimidin.

4-ylI (iH-imdazol-3-ya) -amine (11-110): Prepared from 2aminonicotinic acid and 2-chlorobenzoyl chloride afforded S the title. compound as a di-TFA salt (28% yield). HPLC- Method A, Rt 2.85 min. 'HNMR (DMSO-dG, 500 MHz): 0C) 12.90 (1K, 11.10 10.90 (1H, ba), 9.05 (2H, m), 7.75-7.60 (2H, 7.51 (1K, 7.45-7.25 6.95 0 (IH, MS (m/z)372.99(M+a).

0~ Example 111 (5-Fluoro-a-indazol-3-y1) trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydrocycl(-ctapyrimidin-4i-yl-aml). Prepared in 43% yield. 1 HNMR (500MHz, DMSO-d6) 8 1.46 2H), 1.531 (m, 2H), 1.77 4H), 2.95 2H), 3.04 211),'.7.22 (m, 7.50 (dd, 1K), 7.72 3H), 7.80 iN), 10.5 (m, 13.05 (br a, 1K); El-MS 456.2 HPLO-Method C, Rt 11.93 min.

Example 112- (2-Chloro-phenyl) -6,7-dihydro-Sacyclopentapyrimtdin-4.-yl1 fluoro-1H-indazol-3 -yl) amine (11-112): Prepared in 67% yield. 'HNMR (500MHz,.

DMSO-dE) 82.18 2H), 2.89 3.02 2H), 7.24 (td; 7.42 2H), 7.49 (td, 11), 7.52 (dd, 1H), 7.54 1H1), 7.s7 (dd, 15), 10.50 (br. a, 1K), 13.06 (br. a, 1H); El-MS 380.1 HPLC-Method c, Rt 9.68 min.

Example 13 (1H-Indazol-3-yl)-[2- (2-trifluoromethylphenyl) dihydro SI- cyclopentapyrim idin 4 -yl] amine (11-113).: Prepared in 37% yield. 'HNNR (500MHz, DMSO-d6) 82.65 2H), 2.85 2H), 2.99 2H), 7.02 1), 7.32 1H), 7.47 IH), 7.55 1H), 7.68 H) -275-

IN

7.74 Ct, 1H), 7.80 IH), 10.37 (br. s, 1H), 12.91 Cbr.

S, 1R); El-Ms 396.1 HPLC-Method B, Rt 9.88 min.

Example 114 (7-lluoro-1.indazol.-3-yl)- (2- 5 tri f uorome thyl -phanyl) 6, 7 dihydro

SH-

CYCloPentapyrimidi-.4.ylJ-amine (11-114): Prepared in yield. 'IhR (500MHz, DMSO-dG) 8 2.15 2H), 2.87 (m, 2H), 2.97 2H), 6.99 (td, 1H1), 7.17 (dd, 1I1), 7.38 (d, o2), 7.65 Cm, 2H), 7.71 Ct, 2H), 7.78 1H), 10.21 (br.

s 1 1H), 13.40 1H); El-MS 414.1 HPLC-Method C, Rt 9.99 min.

Example 115 (5,7-Difluoro-1H-indazol3-yl) (2trifluorouethyl-phenyl) -6,7-dihydro-5acyclopentapyriidin-4yll -amine (11-115): Prepared according to Method C in 52% yield. 'IfNMR (500MHz, DMSO- -d6) 3 2.16 2H), 2.89 2H), 2.97 2H), 7.19 (dd, 1l), 7.29 (td, 1H), 7.63 1H), 7.66 Cd, 2H), 7.71 Ct, 2H), 7.78 1H), 10.16 Cbr. a, 1H), 13.55 Cbr. s, 11); ZI-MS'432.1 HPLO-Method C, Rt 10.09 min.

Example 116 (2-Choro-phenyl) -6,7-dihydro-SHcyclopntapyrimidin.4..yll-(lE-indazol-3-yl)-amine

(XI-

116): Prepared in 56% yield. 1LNMR (500MHz, DMSO-d6) 52.16 Cm, 2H), 2.95 2H), 3.01 2H), 7.06 Ct, 7.34 1H), 7.40 Ct, 11), 7.48 Cm, 2H), 7.53

H),

7.56 11), 7.63 1R), 10.39-Cbr. a, 11f), 12.91 (a, 11); El -MS 3 62.1 CM+H);.HPLC-Method A, kt 3. 09 min.

EjS 7e (2-Chioro-phenyl) -6,7-dihydro-SEcylopentayrimdiu-4.yl] (7-fluoro-1,H-indazol-3-yu) amine (11-117): Prepared in 63% yield. 'HNMR (SOO1uz, *DMSo-dE) 82.15. 21), 2.87 2H), 3.00 Ct, 2H), 7.01 7.19 (dd, 11), 7.39 1H), 7.45 2H), 7.51 -276- Va 7-.55 lB), 10.35 (br. s, lW), 13.45 (br. s, 1K); El-MS 380.1 HPLC-Method A, Rt Rt 3.15 min.

Example 118 (2-Chloro-phenyl) -6,7-dihydro-5Hcyclopentapyrimidin-4 y1] (5,7-difluoro-1a-indazol-3-y) amine (11-118): Prepared in 60k yield. 'NM (SOOMHz, DMSO-dG) 8 2.18 Cm, 29), 2.91 2H), 3.01 t, 2H), 7.32 t, iH), 7.33 (td, 1H), 7.41 1H), 7.48.(t, 1H), 7.53 1H), 7.55 1W), 10.35 (br. a, In), 13.45 (br. s, 1H); El-MS 398.1 RPLC-Netbod A, Rt Rt 3.24 min.

Example 119 (1H-zndazol-3-yl) (2-trifluoramethylphenyl) -SiG,7,8,9,10-hexahydxo-cyclootapyrimidin4..yll amine (11-119): Prepared in 36t yield. 'HNMR (SOOMHz, IS DMSO-dS) 8 1.47 2W), 1.53 2H), 1.78 4H), 2.96 2H), 3.06 2H), 7.03 t, 1W), 7.47 1W), 7.72 1W), 7.73 1H), 7.72 3H), 7.81 1H), 10.52 1H), 12.97 (br. a, 1H); El-MS 438.2 WPLC- Method A, Rt 3.37 min.

Example 120 (7-Fluoro-1H-indazol-3-y) (2triflnormethyi-phenyL) 6,7,8, 9,10-hexahydrocyciooctapyrimidin-4-yl]-imine (11-120): Prepared in yield. 'HNMR (50OMHz, DMSO-d6) 8 1.46 2H), 1.52 (m, 2H), 1.77LCm, 4H), 2.94 Cm, 2H), 3.04 2K), 7.00 (td, 7.17 (dd, 1H), 7.30 Cd, 1H), 7.70 3H), 7.79 (d, 1W), 10.5 IW), 13.49 (br a, 1H); El-MS 456.1 HPLC-Method A, Rt 3.43 min.

Example 121 (5,7-Difluoro-1H-indazol-3-yl)-(2-(2trifluoromethylephenyx) -5,6,7,9,9,10-hexahydro- Cyclooctapyrzddin-4-yj..mjne (11-121): Prepared in 48% yield. 1 'HW4p (50014Hz, DMSO'd6) 8 1.46 2H), 1.52 Cm, 2H)L 1.77 4H), 2.95 2W), 3.03 2H), 7.14 (d, -277- Va 7.30 Ii), 7.73 3H), 7.80 1K), 10.5 Cm, IH), 13.62 (br. s, El-MS 475.1 HPLC-Method

A,

Rt 3.52 min.

C- 5 Example 122 [6-Cyclohexy1-2-(2-trifluorrmethyl-phnyl).

pyrimidin-4-yl]- (iB-indazol-3-yl) -amine (11-122): 0 Prepared in 45% yield. 'HNM (500 MHz, CDCl3) 8 1.30 (2H, 1.46 (2K, 1.65 (2H, 1.76 (2H, 1.91('2H, 2.1 br 7.08 t, J=7.4 Hz), 7.27 (1W, d, J8.0 Hz), 7.35 (in, t, J= 7.1 Hz), 7.50 (IH, t, Hz), 7.58 (1H, t, J=7.4 Hz), 7.66 (3W, 7.72 (3I, d, J=7.8 Hz), 8.0 (1W, br), 9.87 (1K, br) ppm; HPLC-Method D, Rt 3.57 min; LC-MS 438.17 Example 123 (2-fluoro-phenyl) (2-triflucromethylphenyl) -pyrimidin-4-yll-(3(H-indazol-3-yl)-amine (11-123): Prepared in yield. 2 1 4MR (500 MHz, CDC 3 8 7.18 (3H, 7.37 Cia, 7.43 Ci, t, J-7.9 Hz), 7.51 (1H, d, J=7.9 Hz), 7.55 C(11, t, Jr7.6 Hz), 7.65 (11, t, J=7.4 Hz), 7.79 (IN, d, J-7.9 Hz), 7.85 (1K, d, J= 7.6 Hz), 8.19 (2K, 8.70 (1K, d, JE 8.5 Hz) ppm; HPLC-Method D, Rt 4.93 min; LC-MS 450.13 (M+H) 4 Example 124 (6-Fluoro-iH-indazcl-3-y1)- (2trifluormethyl..phenyl) qunazolin-4-yl -amine (11-124).

Prepared in DMF (87% yield) as yellow solid. 'IENR (500 MHz, DMSO-d) 813.0 IN), 11.1 br, iN), 8.66 (d, 7.95 Ct, IW), 7.80 7.72 Cm, 2H), 7.62 4H), 7.21 Cdd, 1K), 6.84 (td, 1H) ppm..LC-MS 424.15 EPLO-Method A, Rt 3.05 min.

Example 125 3-[2-2 -Trifiuoromethyl-phenyi )-quinasolin-4ylamino] -iH-indazole-s5carboxylic acid methyl ester (1I- 125): To a solution of compourid 11-79 (100 ms 0.21 mmol) -278- Va o in DMF (2 mL) was added MeO (1 mL), DIBA (54 uL, 0.31 mmol) and PdC12(dppf) (4 mg, 0.005 mmol). The flask was flushed with CO three times and then charged with a CO balloon. The reaction mixture was heated at 80 0 C for 14 h then poured into water. The resulting precipitate was collected and washed with water., The crude product was.

n then purified first by flash column (silica gel, ethyl acetate in hexanes) then by preparative HPLC to to 0g afford II-125 as yellow.solid. 'IHNMR (500 MHz, o 10 DMSO-dE) 813.3 1H), 11.3 br, 1H), 8.70 1H), Ci 8.36 1H), 7.97 1H), 7.82 2H), 7.71 3H), 7.58 2H), 7.51 1H), 3.75 3H) ppm; LC-MS (ES+) 464.13 HPLC-Method A, Rt 3.12 min.

Example 208 (5-Methyl-2E-pyrazol-3-yl)-[2-(2-naphthyl-1yl)-quinazolin-4-yl] -amine (11-208): 1 HNMR (500 MHz, DMSOd6) 88.92 1H), 8.73 1H), 8.39 1H), 8.09 (m, 2H), 7.95 3H), 7.62 3M), 6.78 2.32 (s, 3H); MS 352.2 Example 209 [2-(2-Chloro-phenyl) -pyrido[2,3-dpyrinidin- 4-yll.-(7-fluoro-1H-indazol-3-yl)-Emine (11-214): Prepared from 4-Chloro (2-chloro-phenyl) -pyrido 2,3-dl pyrimidine.

(100 mg, 0.36mmol) and 7-Fluoro-1H-indazol-3-ylamine (108mg, 0.72mmol). Purification by preparative RPLC afforded the title compound as a yellow, di-TFA salt (93 mg, 46% yield). HPLC-Method A, Rt 3.04 min; 'H NMR (DMSO, 500 MHz): 8 13.67 (1H, 11.40-11.25 (11, 9.35- 9.25 (2H, 7.95 (1H, 7.80-7.47 (5H, 7.35(21, 7.15 MS EW 391.1.

Example 210 [(2-(2-Chloro-phenyl)-pyrido[2,3-d pyrinidin- 4-yl]- (5-fluoro-1E-indasol-3-yl)-amine (11-215): Prepared from 4-Chloro-2-( 2 -chloro-phenyl)-pyrido[2,3-d] -279o pyrimidine (100 mg, 0.3Emmol) and S-FJluoro-1H-indazol-3- Cl ylamine (108mg, 0.72mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt mg, 22 t u yield). HPLC-Method A, Rt 3.00 mini 1 IH NM (M30O, 500 MHz) 8 13. 0 (1H, 10.90 (11, be), 9.15-9.05 (2H, in), 7.70 (1H1, in), 7.60-7.30. (6H1, in), 7.20 (1H1, in); MS 91.1.

0 Example 211 12- (2-Chioro-phenyl) -pyrido [2,3-dlpyrimidin- 4 -ylJ-(5,7-difluoro-a'-indazol-3-yl)-amine. (11-216): 0 Prepared from 4-Chloro-2- (2-chioro-phenyl) -pyrido dlpyrimidine (100 mng,, 0.3Emmol) and 7-Difluoro-1Hindazol-3-ylamine (112mg, O.66unnol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (130 mng, 621 yield). HPLC-Method A, Rt 3.12 mini 'RH NMR (DM50, 500 MHz): 13.60-13.60 (111, be), 11.30- 11.10 (11, be), 9.20-9.10 (2H1, mn), 7.80 (1H, mn), 7.60- 7.30 (6H1, in); MS MIT' 409.1.

Exaple 2 12 (2-Clloro-phenyl) -pyrido[3,4-dlpyrinidin- 4 -yl]-(lE-indazol-3-yl)-amine (11-217): Prepared from 4- Ohloro-2- (2-chioro-phenyl) -pyrido[3,4-dlpyrimidine (100 mng, 0.3Gmmol) and 1H-indazol-3-ylaine (88mg, 0.S6nimol).

Purification by preparative HPIJC afforded the title compound as a yellow, di-TFA salt (72 ing, 33W yield).

EPLO-Method A, K, r3.21 min; 3-H NMR (DM50, .500 MHz): *12.95 10.90 (1H1, bs), 9.25 (111, 8.75 (111, in), 8.55 (11, mn), 7.65 (111, in), 7.55 (11, in), 7.50-7.30 (511, mn), 7.00(111, in); MS MR* 373.1.

Exlapme 21.3 (2-Chloro-phenyl) -n'rido 4-dI pyrbn~tdin- *4-yl] fluoro-t&-indazol-3.yl) -amine. (11-216): Prepared from 4-Chloro-2- (2-chioro-phenyl) -pyrAido [3,4-djpyriinidine (1oo mug, 0.3Sinmol).and 7-Fluoro-1H-indazol-3-ylanine -280- Va (108mg, 0.72mmol). Purification by preparative

HPLC

afforded the title compound as a yellow, di-TFA salt (48..7 mg, 22% yield). IIPLC-Metbod A, Rt 3.35 min; 1H NMR 500 MHz): 812.95 10.90 (1H, be), 9.25 s (in, 8.75 (11, 8.55 (IH, 7.70-7.35'(5H, n), 1.25(11, 6.95 (1ix, MS MH" 391.08.

Example 214 (2-Chloro-phenyl) -pyrido C3,4-dpyriimidin- 0~l 4-ylJ- (5-fluoro-1E-indazol-3-yl)-amine (11-219): Prepared from 4-chloro-2-(2-chloro-;s-fluoro-1u-indazol.3.ylamine (108mg, 0.72mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (57.2 mg, 26% yield). HPLC-Method A, R 3.27 min; 1H NMR (DMSO, 500 MHz): 8 13.05 (1H, 10.95 (1H, 9.25 (11, 8.75 (11, 8.55 (1H, 7.60 (1H, 7.55 (in, 7.50-7.30 (Sn, 7.25 (11, MS MW 391.1.

Example 215 (2-Chioro-phenyl) -pyrido(3,4-dlpyrimidin- 4-yl l (5,l-difluoro-t&-indazo-3 -yl).am- e (11-220): Prepared from 4-chloro-2-(2-chloro-7-difluoro-1H-inaazol- 3-ylatine (112mg, 0.E6mmol). Purification by preparative HPLC afforded the title compound as..a yellow, di-TFA salt (57.2 mg, 26% yield). HPLC-Method A, Rt 3.45 min; 'H IMER (DMSO, 500 MHz): 8 13.65 (1H, 11.0 (1H, 9.25 (11, 8.80 (11, 8.50 (is, 7..60 (1H, 7.55 (11, 7.50-7.30 (5H, MS NH 409.1.

Example 216 6-Fluoro-- indazol-3-ylamine

'HNMR

(500 MHz, DMSO-d6) 811.4 in), 7.68 (dd, 15), 6.95' (dd, 6.75 (td, 111), 5.45 2H) ppm; LC-MS (ES+) 152.03 HPLC-Method A, Rt 2.00 min.

-281- Va o Ebample 217 5-Fluoro-1-indazol-3-ylamine 1*Th1R (500 MHz, DSO-dG) 811.3 IH), 7.43 ID, 7.22 (im, lH); 7.08 10), 5.29 2H) ppm; LC-MS (ESr) 152.01 HPLC-Method A, Rt 1.93 min.

C Example -21b 5.-7-Diuoro-1HS-ndazol-3-yl-amine

'HNMR

en, (500 MHz, CD 3 OD) 87.22 (dd, 8.45Hz, 1H), 7.04-6.87 10); LC-MS 169.95 (MtH); HPLC-Method c, Rt 2.94 min oN 0 Example 219 7-Pluoro-1s-indazol-3-yaamune HNMR (500 MHz, DMSO-d6) 611.8(s, 10), 7.42 10), 6.97 6.78 1H), 5.40 20) ppm; LCMS 152.01 RPLC-Method A, Rt 2.00 min.

Example 220 7-Fluoro-6-trfluoromethyl-ll-udazol.3.

ylamine (AS):'H-NMR (500 MHz, DMSO) 8 12.5 1H), 7.75 10), 7.25 1H), 5;85 1H) ppin; *MS (FIA) 220.0 (MiH); HPLC-Method A, Rt 2.699 min.

Example 221 G-Bromo-l-indazol-3-ylamine 'H-NMR (500 MHz, DMSO Y811.5 1H), 7.65. 10), -7.40 7.00 10) 5.45 (br a, 1H) ppm; MS (FIA) 213.8 HPLO-Method A, Rt 2.441 min.

Example 222 4-Fluoro-tf-indazol-3-ylamine 1

H-NMR

(500 MHz, DMSO) 8 11.7 lI), 7.17 1H), 7.05 (d, 1H), 6.7 (br, IH), 6.60 (dd, In), 5.20 (br a, 2H) ppm; MS (FIA) 152.0 Method A, Rt 2.256, inm..

Example .223 5'-romo-1- undazol-3-ylamaine 'H-NMR (500 MHz, DMSO) 8 1lS5 (br a, 1H), 7.95 1H), 7.30 (d, -282- Va oD 7.20 1H), 5.45 (br a, 25) ppm; MS (FIA) 213.8 Method A, Rr 2.451 min.

Example 224 5-Nitro-X1-indazol-3-ylamine 'H-NMR (500 MHz, DMSO-d6) 5 9.00 1H), 8.20 1H), 7.45 1R), 6.15 (br 1H) ppm-; Method A, Rt 2.184 min Example 225 4 -Pyrrol--yl-s-indazol-3-ylamine (A10): H- NM im (500 MHz, DMSO) 8 -7.20. 2H), 7.00 2H), 6.75 1H), 6.25 2H), 4.30 iN) ppm; Method A, Rt 2.625 min.

Example 226 4-Chloro-5,6-dimethyl-2-(2-trifluoraomethylphenyl)-pyrimidine Prepared to afford a colorless oil in 75% yield. 'H-NMR (500 MHz, CDC13) 8 7.70 (d, Je7.8 Hz, 1H), 7.64 J=7.6 Hz, 1H), 7.55 J=7.6 Hz, 11), 7.48 J.=7.5 Hz, 11), 2.54 3H), 2.36 3H) ppm; MS (FIA) 287.0 HPLC-Method A, Rt 3.891 min.

Example 227 4-Chloro-2-(2-chloro-phenyl)-5,6-dinmethylpyrinidine Prepared to afford a yellow-orange oil in 71% yield. 1 H..IhI (500 MHz, CDC13) 8-7.73 1H), 7.52 1K), 7.39 2H), 2.66 3H), 2.45 3H) ppm; MS (FIA) 253.0 (M+14H) HPLC-Method A, Rt Rt 4.156 min.

Example 228 4-Chloro-6-methyl-2-(2-trifluoromethylphenyl)-pyrimidine Prepared to affbrd a pale yellow oil in 68% yield. 1H-NMR (500 MHz, CDC13) 8 7.72 (d, J=7.8 Hz, 1i), 7.65 J=7.9 Hz, IH), 7.57 J=7.5 Hz, 7.52 J=7.8 Hz, 1H), 7.16 1H), 2.54 3H) ppm; MS (FA) 273.0 HPLC-Method A, Rt 3.746 min.

-283- Va Example 229 4-Chlaro-6-cyclohexyl-2- (2-trifluoromethylphenyl)-pyrimidine Prepared to afford a yellow oil in 22% yield. 1 H-mtn (500 MHz, CDC13) 8 7.70 2H), 7.57 Ct, J=7.5 Hz, 1H), 7.50 J=7.5 Hz, lB), 7.19 (a, Ci 5 1H), 2.65 JH), :1.9 2H1), 1.8 2H), 1.5 2H), 1.3 1.2 ppm; kS (PIA) 341.0 (M+11).

Example 230 4-Chloro-6-phenyl-2- (2-trifluoroxethylo phenyl) -pyrimidina Prepared to afford a yellow oil IND 10 in 53% yield. H-11NMR (500 MHz, CDC13) 8 8.08 (dd, J=7.9, o 1.6 Hz, 7.80. J-7.6 Hz, 11), 7.77 Cd, J4-7.8 Hz, 111), 7.67 11), 7.61 J=7.S Hz, 1H), 7.54 J-7.6 Hz, 1H), 7.47 Cm, 3H) ppm; MS (FIA) 335.0 HPLC- Method A, Rt 4.393 min.

Example 231 4-Chloro-2-.(2,4-dichloro-phenyl)-s, 6.

dimethyl-pyrimidine Prepared to afford a white solid in 91% yield. 1 H-NMR (500 Mz, CDC13) 8 7.62 (d, J=8.3 Hz, 1H), 7.43 Cd, J=7.0 Hz, 1H), 7.27 (dd, J=8.3, .0 Hz, 1H), 2.55 Cs, 3H), 2.35 3H) ppm; MS (FIA) 287, 289 HPLC-Method A, Rt 4.140 min.

Example 232 4-Chloro-6- (2-cbloro-phenyl) trifluoromethyl-phenyl) -pyrimidine Prepared to affod a yellow oil in 52% yield. 'H-NMR (500 MHz, CDC13) B 7.75 3H), 7.65 Cm, 2H), 7.53 ji, 11), 7.44 11), 7.36 Cm, 2H) ppm; MS (FIA) 369.1 HPLC-Method A, Rt 4.426 min.

Exampe 233 4-Chloro-6-(2-fluoro-phenyl)-2-(2trifluoromethy1 pheny) -pyrimidina (ES):.Prepared to afford a yellow oil in.95% yield. 1 H-NMR (500 MHz, CDCl3) 8 8.24 .7=7.9 Hz, 1R), 7.84 11), 7.78 J=7.7 -284L Va Hz, 1H), 7.76 Cd, J=8.o Hz, IN), 7.60' T=7.5 Hz, 19), 7.53 J-7.6 Hz, 1H), 7.43 Cm, 1H), 7.23 Jc7.6 Hz, 1H), 7.13 Cm, 1H) ppm; MS (FIA) 353.0 Example 234 4 -Chloro-6-pyridin-2-yl-2-(2-trifuoromethy3.

phenyl) -pyrimidine Prepared to afford a pale yellow solid in 50% yield. 11-iMR (500 MHz, CDCX3) S 8.68 (m, 1H), 8.48 (dd, LT=7.9, 0.8 Hz, 1H), 8.38 Cd,*J=2.3 Hz, 1H), 7.84 Cm, 3H), 7.62.(t,.JJ7.6 Hz, IE, 7.55 J'7.6 N 10 Hz, IN), 7.38 1H) ppm; MS (FIA) 336.0 HPLC- Method A, 'R 4.575 min.

Example 235 6-Eenzyl-4-chioro-2-C2-triflnoromethytphenyl)-5,6,7,8-tetrahydro-pyridor4,3dlpyrimidne IS 'HNM (.500 MHz, CDC:l) 87.70 Cd, 1K), 7.62 7.55 1R), 7.48 t, 1H), 7.32 Cm, 4H), 7.25 Cm, 1H), 3.74 2H), 3.66 Cs, 2H), 2.99 t, 2H), 2.80 t, 2R) ppm; LCMS (ESt) 404.17 HPLC-Method A, lt 3.18 min.

Example 236 7-Be'nzyi-4-chloro-2-C2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-pyrido[3,4-dlpyrimmdine (B11): 1 HNMR (S 0 MHz, CDC1 3 87.69 7.60 d, IN), 7.54 Ct, 1H), 7.47 iN), 7.28 Cm, 4H),.7.20 Cm, 1H), 3.68 2H), 3.67 Cs, 2H), 2.86 Ct, 2H), 2.79 Ct, 2H) ppm. MS CES+)404.18 HPLC-Method A, Rt 3.12 min.

Example 237 4-Chloro-2-(4-fluoro-2-trifluoromethyl-' phenyl) -quinazoline (312): 'HNMR (50014Hz, CD30D). 8 8.43 Cd, J=8.1Rz, 1H), 8.20-8.05 Cm, 2H), 8.05-7.82 Cm, 2H), 7.71-7.51 2H). LC-MS 3 27.09 HPLC-Method D, Rt 4.56 min.

-285- Example 238 4 phenyl) -quinazoline. (313) LC-MS 342.97 (MiH) HPLC-Method D, Rt 4.91 min.

Examppe 239 4 -Chloro-2- (2-chloro-4-nitro-phenyl) quinazoline (B14)- LC-MS 319.98 (M±).-HPLC-Method D, RtL4.45 min.

c Example 240 4-Chloro-2-(2-trifluocrnethyl-phenyl)- IND 10 quinazoline (315): Prpared in 57% yield. White Bolid.

HNMR (SOOMHz, DMSO-dE) 8 7.79 1H), 7.86 1H), 7.94 3H), 8.15 Cdd, 8.20 Ctd, 1H), 8.37 1H); E- MS 308.9 Ex@mple 241 4-Chloro-2- (2-trifluoramethy-phny) -6,7.

(316): Prepared in 22% yield. 'mnmm (SOOMHz, DMSO-dG) 8 2.19 3.01 (t, 2H), 3.08 t, 2H), 7.49 7.55 7.62 (d, 1H), 7.71 EI-MS 299.0 Example 242 4-Chloro-2- (2-chloro-phenyl)-6,7,8,9tetrahydro-ss-cycloheptapyrimidindn (B17): Prepared according to Method C in 82% yield to afford a white solid. 1 HNMR (50OMHz, CDCl 3 8 1.67 (m 4H), 1.87 (m 2W), 3.02 (m 4H), 7.28 Cm, 2H), 7.40 7.65 1H); EI-MS 293.0 1ample 243 4-Chloro-2- (2-trifluoroiethyl-phenyl) S,6,7,89,10-hexahydro-cyclooatapyrimidine (B18): Prepared in 38% yield to afford a brown oil. 3HNMR (SOOMHz,,CDC1 3 81.35 Cm 2H), 1.41 (m 2H), 1.76 (m 4H), 2.-96 4K), 7.48 1H), 7.56 1H), 7.66 13), 7.70 1H) El-MS 341.0 -286- Va o Example 244 4-Chloro-8-methozy-2-(2-trifluoromethylphenyl)-quinazoline (819): Prepared from 8-methoxy-2-(2trifluoromethyl-phenyl) -3H-quinazolin-4-one 3.12mmol), triethylamine hydrochloride (472mg, 3.43mmol), and POC1 3 Purification by flash chromatography afforded a white solid (89% yield). HPLC-Method A, Rt 4.10 min, MS 258.08 0 Example 245 2-(4-Chloro-quinazolin-2-yl) -benzonitrile ci N 10 (B20): Prepared to afford a yellow solid in 1.5% yield.

1 H-NMR (500 MHz, CDC13) 6 8.47 1H), 8.24 13), 8.16 1H), 8.07 (impurity), 7.94 18), 7.92 (impurity), 7.86 1H), 7.68 2H), 7.65 (impurity), 7.54 (impurity), 7.49 1H), 4.2 (impurity), 1.05 (impurity) ppm;. MS (LC/MS) 266.05 HPLC-Method A, Rt 3.88 min.

Example, 24 66-Methyl- 2 (2-trifluoronethyl-phenyl) pyrimidin-4-one Prepared to afford a yellow solid in 50% yield. 1 H-NMR (500 MHz, DMSO-d6) 8 12.7 (br s, 13), 7.9 7.8 2H), 7.7 1H), 6.3 1H), 2.21 3H) ppm; MS (FIA) 255.0 HPLC-Method A, Rt 2.578 min.

Example 247 6-Cyclohexyl-2-(2-trifluoromethyl-phenyl)-3Hpyrimidin-4-one Prepared to afford an off-white solid in'54% yield. 'H-MR (500 NHz, DMSO-d6) 8 12.9 (br s, 1H), 7.9 4H), 6.3 2.5 1H), 1.9 (m, 1.4 53) ppm; MS (FIA) 323.1 (M+H);.HPLC-Method A, Rt 3.842 min.

Example 248 2-(2-Chloro-5-trifluoromethyl-phenyl)-38quinazoli-4-one (D10): IENMR (500MHz, CD 3 OD) 8 8.32-8.25 1H), 8.01 1H), 7.91-7.72 13), 7.66-7.55 (m, -287- Va 1H). LC-MS (ESi) 325.01 HPLC-Method D, Rt 3.29 min Example 249 2- (4-Fluoro-2-trifluormetyl-phezyl) quinazolin-4-one (D14): 1 fMR (500MMz, CDOOD) 8.28 (d, 1H), 7.94-7.84 1H), 7.84-7.77 1H), 7.76- 0c, 7.67 2H), 7.65-7.53 Cm, 2H). LC-MS (ESt) 309.06 HPLC-Method'D, Rt 2.88 min.

Example 250 2-(4-Nitro-2-chloro-phenyl) -3H-quinazolin-4one (DiS): LC-MS (ESi) 302.03 HPLC-Method 0, Rt 2.81 min.

Example 251 2-(S-Fuoro-2-trifuormethy.l-phenyl)-30quinazolin-4-one (017): 21NMR (500MHz, CDOOD) 8 8.28 (d, Rt J=8.05z, lB), 7.96 J=5.05, 8.55Hz, 1H), 7.89 (t, J&7.SHz, 1H), 7.78-7.69 7.66-7.46 3H). LC-MS (ESt) 309.14 HPLC-Method D, Rt 2.90 min.

Example 252 (l-hdazol-3-yl).-(2 -pheny-qunazolin-4.-yl).

amine (111-1): Prepared by Method Ain DMF to afford mg (50% yield) as. pale yellow solid. 'H NMR (500 MHz, DMSO-dG) 613.1 br, 1H), 8.48 1H), 7.91 2H), 7.76 (br, 21)Y, 7.45 2H), 7.36 11), 7.20 4H), 6.66 IH) ppm. MS .338.07 (14+11); 336.11-(M- HPLC-Method A, Rt 2.88 min.

Example 253 (S-Methyl-2H-pyrazol-3-y) (2-phenyl-5,6,7,atetrahydroquinazoln-4..yl) -amine (111-7): Prepared according to Method A. 'H NMR (00 MHz, DMSO-d6) 512.1 br, 1iH), 8.70 br, 1H), 8.37 J 6.7 Hz, 2H), 7.54 3M), 6.67 11), .2.82 (mn, 2H), 2.68 2H), 2.37 3M), 1.90 Cs, br, 4H); MS 306.1 -288- Va 0 Example 254 (5-Methyl- H-yrazol-3-yi)- (2-phenyl-s,7,s,9tetrahydro-5acyloheptapyrimdin-.4.y).am 1 jn (111-8): MS 320.48 SPLC-Method E, Rt- 1.124 min.

Example 255 (5-Methyl-2H..pyrazol.s..yl) -(2-pyridin-4-ylqainazolin-4.yl)j-amine. (111-9): Yellow solid, mp 286- 289 0 C, 1H1 NMR (DMSO) 5 2.35 (3H, 6.76 (11, 7.61 (1H, m),-7.89 (2H, 8.32 (2H; 8.70 (11, 8.78 (2H, 10.56 (11, br 12.30 (11, br IR (solid) 1620, 1598, 1571, 1554, 1483, 1413, 1370, 1328; MS 303.2 0~ (M+H) Example 256 7 -Chloro-2-pyridin-4-yl-qinazoln-4-y) methyl-2H-pyrazol-3-yl)-amine (111-28): 'H NMR (DMSO-dS) S 2.35 6.75 (111, 7.65 (11, 7.93 (11, a), 8.30 (2H, 8.73 (11, 8.79 (2H, 10.69 a), 12.33 (1H, MS i/z 337.2 Exmple 257 (6-Chloro-2-pyridin-4-yl.quinazoln.4.y1)-(5- =ethyl -2z-pyrazo1 -3 -y1) -amine (111-29): 1H NMR (DMSO-d) a 2.31 (3M, 6.74 7.89 (IH, 8.30 (2H, d), 8.80 (2H, d) 8.91 (11, s) 10 63 12.29. (1H, a); MS 337.2 Example 258 2 -Cyclohexyl-quinazolin-4-y) (5-methyl-2Hyrazo1-3-y1)-a ue (111-30): NMR (DMSO) 5 2.35 (31, 1.70 (3H, in, 1.87 (2H, 1.99 (2H, 2.95 (1H, 6.72 (11, 7.75 (11, 7.88 7.96 (1H, 8.83 11.95 (11, as), 12.7Q (1H, MS 308.4 4 Example 259 (S-Methyl-2a-pyrazol-3-yl)- (2-phenylquinasolin-4-yl) -amine (II-31)t mp 246 0 OC; 1H NMR (400MHZ) -289-

VO

6 2.35 (3H, 6.70 (1H, br 7.51-7.57 (4H, 7.83- Cl 7.84 (2H, 8.47-8.50 (2H, 8.65 (1H, 10.4 (1H, 12.2 (1H, bs); IR (solid) 3696, 3680, 2972, 2922, 2865; MS 302.1 Example 260 [2-(4-lodophenyl) -quinazolin-4-yl 0 2E-pyrazol-3-yl)-amine (III-32): 'H NMR (DMSO-d6) 8 2.34 (3H, 6.72 (1H, 7.56 (1H, 7.84 (2H, 7.93 C (2H, 8.23 (2H, 8.65 (1H, 10.44 (1H, 12.24 D 10 (1H, MS 428.5 xample 261 (3,4-Dichlorophenyl) -quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-amine (III-33): A suspension of 2- (3,4-dichloro-phenyl) -3H-quinazolin-4-one (1g, 3.43 mmol) in phosphorus oxychloride (4-mL) was stirred at 110°C for 3 hours. The solvent was removed by evaporation and the residue is treated carefully with cold aqueous, saturated NaHCO 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 nit) was added 3-amino-5-methyl pyrazole (396 mg, -2.58 mmol) and the resulting mixture heated at 65 0

C

overnight. The solvents were evaporated and the residue triturated with ethyl acetate, filtered, and washed with the minimum amount of ethanol to afford compound 111-33 as a white solid (311 mg mp 274°C; 'H NMR (DMSO) 8 2.34 (3H, 6.69 (1H, 7.60 (1H, 7.84. d), 7.96 (2H, 8.39 (1H, dd), 8.60 (1H, 8.65 (1H, d), 10.51 (1H, 12.30 (1H, IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5 -290- Va Example 262 (4-Bromophenyl) -quinazioin-4-yij C-i methyly-2pyrazO1-3Yl)-amin. (111-34): p 262-265oc; I'm NMR (DMSO) 8 2.34 6.73 7.55 (1H, m), 7.74 (2H, 7.83 (2H, 8.40 (2H, 8.65 (1H, d), 10.44 (is, 12.25 (an, IR (solid) 1603, 1579, 1546, 1484, 1408,1365; MS 380.1/382.1 E xample 263 2- (4-Chorophenyl) -quinazolin-4-yl] methyl-l2Epyrazol-3-yl)-amine (111-35): tp >300 0 C; 'H NMR (DMSO) 8 2.34 (3H, 6.74 (15, 7.53-7.62 (3H, m), 7.84 (2H, 8.47 (2H, 8.65 10.44 a), 12.26 (15, IR (solid) 1628, 1608, 1584, 1546, 1489, 1408, 1369, 1169; MS 336.2 Example2 264 (3,5-Dichlorophenyl) -quinazolin-4-yJ methyl-2H-pyrazol-3.-yl) -amine (111-36): tp 228 OC; 'H NMR (DMSo) 8 2.34 (3H, 6.69 (1H, 7.96 (15, 8.21 (3H, ni), 8.56 (1H, 8.60 (2H, 10.51 (1H, 12.30 Ia (solid) 1546, 1331, 802, 763, 729, 658, 652, MS 370.5 Example 265 (2-(4-Cyanophenyl) -quinazolin-4-ylJ- methyl-2.pyrazl-3 -yl)-amin (111-37): mp 2630C; 'H NR 8 2.34 6.72 (1H, 7.61 (1H, 7.88 (2H, 8.04 (21H, 8.63 (2H, 8.67 (111, a),.10.52 (is, 12.27 IR (solid) 1739, 1436, 1366, 1229, 1217; MS 32722 (M4H)+.

Exlamle 266 (3-odophenyl) -gyinazoli-4-ylJ 2 E-pyrazo1-3-ya)..-ane (111-38): mp 234-235 0 c; 'H NMR 52.35 (3H, 6.73 7.35 (15, 7.56 (IN, 7.85 (3H, 8.47 (15, 8.65 (1H, 8.86 -291- Va 10.49 (11, 12.28 (19, br IR isolid) 1560, 1541, 1469, 1360; MS 428.1 Example 267 [2-(4-Ethylmulfanylphenyl)-qu.tnasolin-4-yl]- (S-methy1-2H-pyrazoz.-3-yl)amine (111-39): mp 229-231OC; 'E NMR (DMSO) 81.29 2.35. (3H, 3.07 (2EI, q), 0C 6.76 (IH, 7.43 (2H, 7.51 (1H, 7.81 (2H, m), 8.4l- (2R, 8.64 (IH, 10.38'(1H, 12.24(1H, br o a) IR (solid) 158'7, 1574, 1555, 1531, 1484, 1412, 1369; IND 10 MS 362.1 Exap3e 268 (S-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-40): tup 21B-219-C; 1H NMR (DMSo-de) 8 0.70-0.80(2H, 0.90-1.00 (2H, 6.70 7.45-7.55 (4H, 7.80-7.85 (2H, 8.45-8.55 (2H, 8.65 (11, 10.40 (1H, 12.27

IR

(solid) 1624, 1605, 1591, 1572, 1561, 1533, 1479, 1439, 1419, 1361, 1327, 997, 828, 803, 780, 762, 710; MS 328.2 Example 269 12-(4-tert-Butyiphenyl) methy-2H-pyrazol-3 -yl)-amine (111-41); mp >300 0 C; 'H NNR (DMSO-d) 8 1.35 (9H, 2.34 (3H, 6.79 (1H, a), 7.55 (3H, 7.85 (2H, 8.39 (2H, 8.62 (1R, d), 10.35 12.22 (1H, IR (solid) 1603, 1599, 1577, 1561, 1535, 1481, 1409, 1371, 1359, 998, 841, 825, 766,.757; MS 358.3 pkazle 270 E2-(4-Ciorophenyl) -quinasolin-4-ylJ

(S-

cyclopropy-2..pyrazol-3y) -amine (111-42): 'H NMR (DMSOdE) 8 0.77 (4H, br i) ,2.05 (19, 6.59 (11, 7.60 (1I, 7.85 (2H, 7.-91 (2H, 8.22 (2H, 6.65 10.51 12.33 MS 362.1 -292- Va Example 271 2 -Benzo l,3fdioxcl-5-yl quinazolin-4y2) methyl-2-pyraza1.3 7 yl))-ajine (111-43): 'H NM (DM50) a 2.33 (3H, 6.13 (2H, 6.78 7.11 d), 7.80 (1H, 7.94 (1H, 8.09'(3H, 8.25 (1H, d), Cl '5 10.34 (in, 12.21 (in, MS 346.5 (M+H)t.

0Example '272 4 -Dimethylaminophenyl) -quinazolin-4-yl- -methyl-5-pyrazol-3.ayl)-amine (111-44): 1H NE (DMSO- 0~ d) 8 2.02 (6H, 2.39 (3H, 6.83 (in, 7.71 (1H, 7.98 8.04 (21H, 8.33 (2H, 8.67 (1H, 11.82 (1H, 12.72'(1H, MS 345.3 Example 273 (3-Methozyphenyl) -quinazolin-4-ylJ- fethyl-2-pyrazol-3-yl) -aine (111-45): mp 226-C; 'H NMR is (DMSO) 8 2.34 3.92 (3H, 6.72 (11H, 7.21 (11, 7.57 (1H, 7.79 6.02 8.14 (11, 8.79 (in, 10.39 12.'22

IR

(solid) 1599, 1'572,. 1538, 1478, 1427, 1359, 833, 761, 661; MS 332.2 Example 275 (5-Cyclopropyl-2u-pyrazol-3yl). dichiorophenyl) -quinazolin-4-ylJ -amzine (II-46): 'H NMR (DMSO-d6) 8 0.86 (2H, 1.02 1.69 (1i, m), 6.56 (11, 7.57 (11, 7.84 (4H, 8.40 (in, 8.58 (11, s) 8.64 (1H, 10.53 (11, 12.36 a); MS 396.0 Example 276 (2-iphenyl-4-yl-quiazol in.4.yl) (S-methyl- 23 -pyrazol-3-yl)..amine (111-47): To a mixture of bromo-phenyl) -quinazolin-4-ylJ (5-metbyl-2H-pyrazol-3.

yl)-amine (111-34) (196 mg,. 0.51 mmcl) and Phenylboronic acid (75 mg, 0.62 mmcl) in THF:water 4 mL) was added Na 2

CO

3 (219 mg, 2.06 mmoi), triphenyiphosphine (9mg, i/is mol%) and palladium acetate (I mg, 1:135 moli). The -293- 0 resulting mixture was heated at 80°C overnight, the C( solvents were evaporated and the residue purified by t .flash chromatography (gradient of dichloromethane:MeOH) to afford III-21 as a yellow solid (99 mg, 1H NMR C- 5 (DMSO) 8 2.37 (3H, 6.82 (1H, 7.39-7.57 (4H, m), S7.73-7.87 (6H, 8.57 (2H, 8.67 (1H, 10.42 (1H, 12.27 (1H, MS 378.2 (c SExample 277 (4-Ethynylphenyl) -quinazolin-4-yl] IN 10 methyl-2H-pyrazol-3-yl)-amine (III-48): To a mixture of o (4-bromo-phenyl) -quinazolin-4-yl 5-methyl- 2pyrazol-3-yl)-amine (III-34) (114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, 1.5 mmol)in DMF (2 mL) was added Cul (1.1 mg, 1:50 mol%), Pd(PPh) 2 C12 (4.2 mg, 1:50 mol%) and triethylamine (121 mg, 0.36 mmol). The resulting mixture was heated at 120 0 C overnight and the solvent evaporated. The residue was triturated in ethyl acetate and the resulting precipitate collected by filtration. The collected solid was suspended in THF (3 mL) and TBAF (1M in THF, 1.leq) was added. The reaction mixture was stirred at room temperature for 2 hours and the solvent evaporated. The residue was purified by flash chromatography (silica gel, gradient of DCM:MeOH) to afford III-48 as a white solid (68 mg, 'H NMR (DMSO) 5 2.34 (3H, 4.36 (1H, 6.74 (1H, 7.55 (IH, 7.65 (2H, 7.84 (2H, 8.47 (2H, 8.65 (1H, 10.43 (1H, 12.24 (1H, MS 326.1 Example 278 (3-Ethynylphenyl) -quinazolin-4-yll- methyl-2H-pyrazol-3-yl)-amine (111-49): mp 204-207OC; 'H NMR (DMSO) 8 2.34 (3H, 4.28 (1H, 6.74 (1H, s), 7.55-7.63 (3H, 7.83-7.87 (2H, 8.49 (1H, 8.57 (1H, 8.65 10.46 (IH, 12.27 (1H, IR- -294- VO ID O (solid) 1598, 1574, 1541, 1489, 1474, 1422, 1365; MS 326.1 Example 279 [2-(3-Methylphenyl) -quinazolin-4-yll- C- 5 methyl-2H-pyrazol-3-yl)-amine (III-50): A suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POCi 3 en mL, 644 mmol) and N,N-dimethylaniline (8mL, 63.1 mmol) was heated under reflux for 2 h. The excess POC13 was wc removed in vacuo, the residue poured into ice, and the

\O

o 10 resulting precipitate collected by filtration. The crude 0 solid product 2,4-dichloro-quinazoline (6.5 g, 53% yield) was washed with water and dried under vacuum for next step use without further purification. To a solution of the 2 ,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 mL) was added 3-yl amine (3.2 g, 32.9 mrmol)and the resulting mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 4.0 g (93% yield) of (2-chloro-quinazolin-4-yl)-(5-methyl-1Hpyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of the (2chloro-quinazolin-4-yl) (5-methyl-H-pyrazol-3-yl)-amine mg, 0.19 mmol) in DMF (1.0 mL) was added .m-tolyl boronic acid (0.38 mmol), 2M Na2COs (0.96 mmol), and trit-butylphosphine (0.19 mmol). The flask was flushed with nitrogen and the catalyst PdCl 2 (dppf) (0.011 mmol) added in one portion. The reaction mixture was then heated at for 10 hours, cooled to room temperature, and poured into water (2 mL). The resulting precipitate was collected by filtration, washed with water, and purified by HPLC to afford III-50 as a pale yellow solid (61mg, -H NMR (500 MHz, DMSO-d6) 812.3 (br s, 1H), 10.4 (br s, IH), 8.75 1H), 8.30 1H), 8.25 1H), -295- Va 7.78 2H), 7.55 Cm, 11), 7.45 11), 7.35 1H), 6.80 iH), 2.47 Cs, 3H), 2.30 3H); MS 316.1 Example 280 2- (3, 5 -Difluorophenyl) ~l 5 methyl-2H-pyrazol-3-yl)-ami3) (111-51); 'S NMR (500 MHz, DMo-d6) 812.3 (br s, 10.8 Cbr a, 1H), 8.63 Cd, 1), 7.95 2H), 7.85 Cm, 2H), 7.58 Ct, 7.41 11), 6.59 2.27 3H); MS*338.i Example 281 2 -(3-Chloro-4-fluorophenyl) -quinazolin-4ylJ -(S-methyl-2H-pyrazol...yl) -amrine (111-52): 'H NMR (500 MHz, DMSO-dS) 812.4 (br s, 1H), 10.8 (br a, 15), 8.65 (d, 1N), 9.50 Cd, 11), 8.36 Cm, 11) 7.85 (Ms 1H) 7.60 m, 6.62 1H), 2.30 3H); 14 354.1 (14+0).

Example 282 (S-Methy1-2H-pyrazol-3-y1)-[2-(Strifluoromethylphnyl) -quinazolin-4 -ylJ -amine -(111-53): NM (500 MHz, DMSO-d) 812.2' (br, 15), 1O.45(br, 1H), 7.53 Cs, 11), 7.43 J 7.2 Hz, IH), 7.06 Cd, J 8.2 Hz, 1H), 6.65 J 8.3 Hz, 6.57 Ct, J 7.6 Hz, 6.51 J 7.8 Hz, 1H), 6.43 t, J 7.8 Hz; 1H, 6.32 J 7.6 Hz, 15), 5.51 2.03 3W); MS 370.2 (14+H).

Example 283 2 (3-Cyanopheyl) -qunazon.4.yIJ- methyl-2s-pyrazo -3-yl)-amine (111-54): 'H MR (500 MHz, DMSO-dE) 89.01 1H), 8.96 2H), 8.28 J 7.3 Hz, 1H), 8.16 Cs, br, 2H), 8.06 Ct, J 7.8 Hz, 1H), 7.88 (IaH), 6.96-(5, 11), 2.58 Ca, 3M); MS 327.1 Exanple 284 (3-Isopropylphenyl) -quinazolin-4-yjj- methyl-2Z-Wrazol-3-yl)-amine (111-55): 'H NIR (500 MHz, DMSO-d6) 88.89 LT 7.5 Hz, 1H), 8.37 1H), 8.26 -296- Va 8.08 2H), 7.81 Ct, br, 1W), 7.67 Cm, 2H), 6.88 (s,1H) 3.12 lH), 2.40 Cs, 3H), 1.38 Cd, J 6.9 Hz, 6H); MS 344.2 (4t+H).

C' 5 Exmpli 285 (5-Methyl-2H-pyraol-3-yl) -(2-pyidin-3-ylquinasolin-4-yl) -amins (111-56): 3-H NM (500 M4Hz, DMSO-d) 0 39.50 1H) 2 8.84 J 7.3 Hz, l1), 8.80. Cd, J' 4A4 Hz, 1H), 8.66 d, J 8.2 Hz, 1H), 7.87 Cm, 2H), 7.77 m, IH), 7.60 t, JO 7.2 Hz, 1H), 6.67 1H),.2.28 Cs, 3H); MS 303.1 Example 286 [2-(3-Acetyiphenyl) -quinazolin-4-yl] methy1-2s-pyrazo.l-.3-yl)-amie (111-57): IH NMR (500 MHz, DMSO-d6) 88.80 iN), 8.55 J 7.7 Hz, iN), 8.42 J 7.6 Hz, 1H), 8.00 J 7.0 Hz, 11), 7.76 Cm, 2H), 7.58 J 7'7 Hz, 1W), 7.48 Cs, br, in), 6.60 (s, 1W), 2.49 3M), 2.03 Cs, 3M); MS 344.1 CM+H).

Example 287 (355-Ditrifluoromethylpheyl) -quinazolin- 4-yl. (S-msthyl-20-pyrazol-3.yl) -amine (111-58): 'L NMR (500 MHz, DMSO-ds) 810.7 br, 8.95 2H), 8.63 8.2 Hz, 1H), 8.25 Cs, 1W),'7.86 Cm, 2H), 7.58 (t, a' 6.9 Hz, iN), 6.62 aM), 2.26 3H); MS 438.1 Example 288 (3-Hydroymethylphenyl )-qtinazolin-4-ylJ (5-methyl-2r-paZeazo3-yl)-amine (111-59): 'H NMR (500 MHz, DMSO-d6) 88.74 a 7.9 Hz, 11), 8.33 Cs, 11) 8.17 Cs, br, IH), 7.95 br, 1H), 7.89 br, 1W), 7.62 Cm, 3H), 6.72 Cs, 1W), 5.53 Cs, 1H), 4.60 Cs, 211), 2.28 Cs, 3H); MS 332.1 Eample 2 8 9 (S-Methyl-2-pyrazol-3-yl)-(2-(3phenoxyphenyl) -qinazclin-4-yl) -amine JIl-160): nmp 231- -297- Va 232 0 C; 'H NMR (DMSO-d6) 8 2.21 6.59 (1H, s), 7.10-7.22 (42, 7.41-7.45 (2H, 7.54-7.59 (2H; m), 7.81 (2H, 8.09 (12, 8.27 (12, 8.64 (12, m), 10.40 (1H, 12.20 (12, IR (solid); IR (solid) C 5 1589, 1560, 1541, 1536, 1484, 1360, 1227; MS 394.7 on Example 290 (5-Cyclopropyl-2-pyrazol-3-yl)-[2-(3l phienoxyphenyl)-quinazolin-4-yl]-amine (III-61): mp 193- 1950C; 'E NMR (DMSO-d6) 8 0.67 (2H, 0.93 (2H, M),1.87 Cl 6.56 (1H, 7.06-7.20 (4H, 7.40-7.43 (2H, 0 7.55-7.59 (2H, 7.81 (2H, 8.11 8.7 (1H, 8.63 (12, 10.43 12.26 (1H, IR (solid); IR (solid) 1589, 1574, 1527,-1483, 1369, 1226; MS 420.7 Example 291 (5-Methyl-2a-pyrazol-3-yl)-(2-thiophen-3-ylcquinazolin-4-yl)-amine (111-62): 'H NMR (500 MHz, DMSO-d6) 511.78 br, 1H), 8.75 J 8.1 Hz, 1H), 8.68 (s, lE), 7.98 (dd, J 7.9, 7.5 Hz, 1H), 7.89 7.81 1H), 7.68 J 7.5 Hz, IH), 6.69 2.30 (s, 3H); MS 308.1 Example 292 2 -Phenyl-quinazolin-4-yl)-(2E-pyrazol-3-yl)amine (III-63): mp 247-249 0 C; 'H NMR (DMSO) 8 6.99 (12, br 7.49-7.58 (5H, 7.81 br 7.83 (2H, 8.47-8.49 (2H, M) 8.66 (1H, 10.54 (1H, 12.59 (1H,s);.IR (solid) 3145, 2922, 1622, 1597; MS 288.2 Example 293 (2-Pyrazol-3-yl)-(2-pyridin-4-yl-quinazolin- 4-yl)-amine (111-64): mp 285-286 0 C; 'H NMR (DMSO) 6 6.99 br 7.65 (11, 7.81-7.94 (32, nm), 8.3-8.35 (2H, 8.73 (1H, 8.84-8.90 (2H, 10.76 (1H, a), -298- 12.6 (1H, IR (solid) 3180, 2972, 1600, 1574; MS 289.2 Example 294 5-Ethyl-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (III-65): mp 221-2220C; 1H NMR (DMSO) 8 1.31 (3H, 2.68 (2H, 6.80 (1H, 7.50n 7.60 (4H, 8.45-8.55 (2H, 8.65-8.75 (1H, 10.44 12.27 IR (solid) 3190, 1622, 1595, 1575, Ci 1533, 1482, 1441, 1420, 1403, 1361, 758, 711; MS 316.2

NO

o 10 (M+H) 4 Example 295 (2-Phenyl-quinazolin-4-yl)-(5-propyl-2Hpyrazol-3-yl)-amine (111-66): mp 204-205 0 C; 1 H NMR (DMSOd6) 8 1.02 (3H, 1.66-1.75 (2H, 2.69 (2H, 6.80 7.45-7.60 7.80-7.88 (2H, 8.45-8.50 (2H, 8.65 (1H, 10.39 (IH 12.25 (1H, IR (solid) 1621, 1560, 1572, 1533, 1479, 1441, 1421, 1363, 1328, 999, 827, 808, 763, 709, 697; MS 330.2 Example 296 (5-Isopropyl-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-67): mp 218-219 0 C. 1H NMR (DMSO-dG) 8 1.36 (611, 3.05 (11, 6.86 (1H, s), 7.48-7.59 (4H, 7.80-7.88 (2H, 8.49-8.58 (2H, m), 8.66 (1H, 10'.47 (IH, 12.30 (1H, IR (solid) 3173, 2968, 1619, 1593, 1573; 1533, 1478, 1438, 1413, 1398, 1363,.1329, 995, 822, 798, 761, 707, 666, 659; MS 330.2 (M+H) t Example 297 (5-tert-Butyl-2H-pyrazol-3-yl)- (2-phenylquinazolin-4-yl)-amine (11-68): mp 136-137oC; 1H NMR (DMSO-d6) 8 1.38 (9H, 6.87 (1H, br 7.51-7.57 (4H, 7.84-7.85 (2H, 8.49-8.51 (2H, 8.65 (1H, d), 10.43 (1H, 12.21 (1H, br IR (solid) 3162, 2963, 1621,'1590, 1572; MS 3 4 4.2(M+H) -299- Va cr Example 298 (5-tert-Butyl-2H-pyrazol-3-yl) (2-pyridin-4yl-quinazolin-4-yl)-amine (III-69): mp >300 0 C; 1H NMR (DMSO) 8 1.38 (9H, 6.82 (1H, br 7.63 (1H, m), ri 5 7.86-7.91 (2H, 8.32-8.33 (2H, 8.69 (1H, d), 8.75-8.76 1O60 12.31 br IR 0 (solid) 3683, 3149, 2963, 1621; MS 345.2(M+H).

c o Example 299 (5-Cyclopentyl-20-pyrazol-3-yl)-(2-phenyl- V. 10 quinazolin-4-yl) -amine (111-70): mp 240-241C; 'H NMR o (DMSO-d6) 6 1.68-1.89 (6i, 2.03-2.17 (2H, 3.14- 3.22 (11, 6.80 7.50-7.60 (4H, 7.80-7.89 (2H, 8.45-8.52 (2H, 8.67 (1H, 10.52 (11, a), 12.26 (1H, 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 (S-Phenyl-20-pyrazol-3-yl)-(2-phenylquinazolin-4-yl) -amine (111-71): mp 207-209 0 C; 1H NMR (DMSO) 8 7.38-7.40 (1H, 7.50-7.58 (6H, 7.82-7.88 (4H, 8.51 (2H, 8.67 10.58 (1R, 13.11 br IR (solid) 3345, 3108, 1627, 1612; MS 364.2 Example 301 (5-Carboxy-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-72): (5-Methoxycarbonyl-2H- PYrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (111-73) (345mg, 1 mmole in THF, 6 mL) was treated with NaOH (1M, mL), stirred at 50 0 C for 5 hours, cooled to room temperature, and neutralised with IM HC1. The mixture was concentrated in vacuo to remove THF then diluted with water and the resulting precipitate filtered. The residual solid was dried at 80 0 C under vacuum to afford 111-72 as an off-white solid (312 mg, mp 289-2910C -300-

VO

ID

0 IH NMR (DMSO) S 7.45 (1H, br 7.50-7.60 7.80-7.88 (2H, 7.40-7.50 (2H, 8.60-8.70 (1H, 10.70 (1H, 13.00-13.80 (2H, br IR (solid) 1699, 1624, 1607, 1570,1539, 1506, 1486, 1398, 1333, <C 5 1256, 1177, 1004, 827, 764, 705; MS 332.3(M+H) n Example 302 (5-Methoxycarbonyl-2H-pyrazol-3-yl) phenyl-qiinazolin-4-yl)-amine (III-73): mp 271-273oC; H C NMR (DMSO) 8 3.95 (3H, 7.50-7.65 (5H, 7.80-7.98

\O

(2H, 8.40-8.50 (2H, 8.65-8.73 (1H, 10.80 (1H, C 13.80 (1H, IR (solid) 3359, 1720, 1624, 1597, 1561, 1538, 1500, 1475, 1435, 1410, 1358, 1329, 1283, 1261, 1146, 1125, 1018, 1010, 944, 827, 806, 780, 763, 703, 690, 670; MS 346.3(M+H)*.

Example 303 (5-Hydroxymethyl-2H-pyrazol-3-yl)- (2-phenylquinazolin-4-yl)-amine (III-74): A solution of Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4yl)-amine (III-73) (345mg, immol) in anhydrous THF was treated with lithium borohydride (125mg, 5.75 mmol) at 65'C for 5 hours. The mixture was cooled to room temperature then combined with 2M HCl and ethyl acetate.

Solid sodium hydrogen carbonate was added to achieve pH 8 and the resulting mixture extracted with ethyl acetate.

The extracts were dried over magnesium sulphate and concentrated. Purification by flash chromatography (SiO 2 methanol-dichloromethane gradient) afforded III-74 mg, 30%) as an off-white solid: mp 238-239 0 C; 1 H NMR (DMSO) 8 4.58 (2H, d, CH2), 5.35 (1H, s, OH), 6.94 (1H, 7.50-7.60 (4H, 7.85-7.90 (2H, 8.48-8.54 (2H, 8.69 (1H, 1H), 10.40 (1H, 12.48 (1H, IR (solid) 1652, 1621, 1603, 1575, 1558, 1539, 1532, 1480, 1373, 1320, 1276, 1175, 1057, 1037, 1007, 951, 865, 843, 793, 780, 7124; MS 318.2(M+H)*.

-301- Va cl Example 304 (5-Methoxymethyl-2a-pyrazol-3-yl)- (2-phenylquinaolin-4-yl) -amine (111-75): mp 190-1910C; 2H NMR (DMSO) 8 3.34 (3H, 4.45 (2H, 7.00 (13, 7.50- C- 5 7.62 (4H, 7.82-7.90 (2H, 8.45-8.52 (2H, 8.65 (1H, bra 10.50 (11, 12.30 (1H, IR (solid) 3177,.1606, 1589, 1530, 1479, 1441, 1406, 1374, 1363, 1329, 1152, 1099, 999, 954, 834, 813, 766, 707, 691; MS o 332.3(M+H)*.

IND o Example 305 15-(3-Hydroxyprop-1-yl)-2E-pyrazol-3-yl-(2phenyl-quinazolin-4-yl)-amine (111-76): A solution of benzyloxypropyl-2Hpyrazol-3 -yl) (2-phenyl-quinazolin-4yl)-amnine (111-78) (200mg, 0.46mmol) in toluene (4mL) and' acetonitrile (8mL) was stirred with trimethylsilyl iodide (0.64ml, 4.6mmol) at 550C for 3 hours to afford an amber coloured solution. This mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate. The resulting layers were separated, the organic layer was dried over magnesium sulphate and concentrated in vacuo.

Purification by flash chromatography (SiO 2 methanoldichloromethane gradient) affords a yellow oil (115mg).

Trituration with dichloromethane affords IIi-76 as an off-white solid dried at 75 0 C under vacuum (83mg, mp 164-165C; 'H WMR (DMSO) 8 1.80-1.90 (2H, 2.70-2.80 (2H, 3.50-3.60 (21H, 4.59 (1H, .6.80 (1H, a), 7.50-7.60 (4H, 7.82-7.90 8.48-8.53 (2H, m), 8.63 (1H, 10.40 (13, 12.25 IR (solid) 1622, 1587, 1574, 1562, 1528, 1480, 1440, 1421, 1368, 1329, 1173, 1052, 1030, 1006, 952, 833, 762, 734, 706, 690, 671, 665; MS 346.0(M+H).

Example 306 3 -Methoxyprop-1-yl)-25-pyrazol-3-yll phenyl-quinazolin-4-yl)-amine (111-77): mp 169-170OC; 'H -302- Va oD NMR (DMSO-dE) 8 1.86-1.97 (2H, 2.75 (2H, 3.30 (31H, 3.45 (2H, 6.80 (1H, 7.50-7.60 (411, 7.80- 7.90 8.45-8.55 (2H, 8.67 (11, 10.30 (1, 12.25 (1H, IR (solid) 1620, 1591, 1572, 1532, 1476, 1425, 1408, 1373, 1326, 1117, 1003, 831, 764, 714, 695; MS 360.3(M+H)*.

Example 307 15-(3-Benzyloxyprop-1-yl)-2B-pyrazol-3-ylJ- I C( 2 -phenyl-quinazolin-4-yl)-amine (111-78): np 177-178 0

C;

o 10 'H NMR (DMSO) 8 1.92-2.03 (2H, 3.76-3.85 (2H, m), c 3.52-3.62 (2H, 4.51 (2H, 6.82 (13H, 7.28-7.40 (SH, 7.46-7.58 (4H, 7.80-7.85 (2H, 8.47-8.52 (2H, 8.66 (1H, 10.45 (11, IR.(solid) 1621, 1591, 1562, 1532, 1479, 1454, 1426, 1408, 1374, 1101, 1006, 835, 766, 738, 712, 696; MS 436.3(M+H).

Example 308 [5-(3-Aminoprop-1-yl)-2H-pyrazol-3-yll-(2phenyl-quinazolin-4-yl)-amine (II-79): A solution of (3-tert-butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-ylJ- (2-phenyl-quinazolin-4-yl)-amine (111-80) (250mg, 0.56mmol), in dichloromethane (3mL) at CoC was treated with TFA (2imL). The mixture was warmed to room temperature then cbncentrated in vacuo. The residue was triturated and concentrated from dichloromethane (3xmL) and ether, then triturated with dichloromethane to crystallize the TFA salt. The resulting solid was collected by filtration and dissolved in a mixture of ethanol (3mL) and water (3mL). Potassium carbonate was added in portions to achieve pH 8 then the mixture allowed to crystallize. The product was collected by filtration and dried at 80 0 C under vacuum to afford III-79 as an off-white powder (122mg, mp 205-207CC; 12 NMR (DMSO) 5 1.68-1.83 (2H, 2.65-2.80( 4H, 6.80 (11, 7.50-7.60 (4K, 7.80-7.90 (21H, 8.45-8.53 (2H, -303- Va 8.65 (1W, 10.45 (1W, br IR (solid) 1621, 1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 951, 830, 776, 764, 705, 677; MS 345.3(M+H).

C- d5 Example 309 (3-tert-Butoycarbonylamioprop pyrazol-3-yll (2-phenyl-quinazolin-4-yl) -amine (111-80): mp 199-200 0 C; 1H NMR (DMSO) 6 1.37 (9H, 1.71-1.82 C 2.67 (2W, 3.00-3.11 (2H, 7.81 (1w, a), o 7.99 (1I, 7.50-7.60 (4H, 7.80-7.85 (2H, 8.48- 8.52 (2H, 8.63 (1H, 10.40 (1W, 12.26 (1H, m); o IR (solid) 2953, 1687, 1622, 1594, 1573, 1535, 1481, 1441, 1419; 1364, 1327, 1281, 1252, 1166, 1070, 1028, 998, 951, 848, 807, 768, 740, 728, 710,693; MS 445.3 Example 310 5-Isopropylcarbanoy1-2-pyrazol-3-yl)-.(2phenyl-quinazolin-4-yl)-amine (III-81): 1H NMR (500MHz, DMSO-d6) 8 1.20 J 6.6 Hz, 6H), 4.13 1H), 7.42 (br. a, 1W), 7.61 (dd, J 7.0, 7.7 Hz, 2H), 7.66 J 7.1 Hz, 1H), 7.71 1H), 7.99 8.39 8.42 J 7.1 Hz, 2W), 8.74 J 8.2 Hz, 1H), 11.41 (br. a, 1H); EI-MS 373.2 HPLC-Method C, Rt 14.09 min.

Example 311 (5-Allylcarbamoyl-2a-pyrazol-3-yl) (2-phenylquinazolin-4-yl) -amine (III-82): 'H NMR (500MHz, DMSO-d6) S4.02 2H), 5.15 5.23 IH), 5.94 1H), 7.45 (br. a, 1H), 7.60 J =6.9 Hz, 2H),.7.64 1W), 7.72 1Z), 7.98 2H),.8.43 (m 2H), 8.72 J 8.2 Hz, 1i), 8.84 (br. a, 1H), 11.34 (br. B, 1W); EI-MS 371.2 HPLC-Method C, Rt 13.67 min.

Example 312 [5-(2-Methoyethylarbayl)-2-pyrazol-3yl (2-phenyl-quinaolin-4-yl)-amine (111-83): 1H NMR -304- Va o (500MHz, DMSO-d6) 3.32 3H), 3.48 4K), 7.36 (br.

a, 1i), 7.62 2H), 7.63 11), 7.71 1I), 7.98 4m, 2H), 8.41 (dd, J 1.4, 7.0, 2H), 8.70 2H), 11.30 (br. s, 1H); EI-MS 389.2 HPLC-Method C, Rt 12.37 min.

nExample 313 (5-Benzylcarbamoyl-2a-pyrazol-3-yl)-(2phenyl-quinazolin-4-yl)-amine (11I-84): 1 H NMR (500MHz, DMSO-d6) 5 4.52 J 6.0 Hz, 2H), 7.29 1H), 7.38 o 10 J 4.2 Hz, 4H), 7.58 7.5 Hz, 2H), 7.63 (m, C 1iH), 7.72 1H), 7.98 2H), 8.43 J 7 7.7 Hz, 2H), 8.72 J 7.5 Hz, 1H), 9.23 (br. s, 11.34 (br. s, 1H); EI-MS 421.2 HPLC-Method C, Rt 16.76 min.

Example 314 (5-Cyclohexylaarbamoyl-23-pyrazol-3-yl) phenyl-quinazolin-4-yl)-amine (111-85): 1 H NMR (500MHz, DMSO-d6) 5 1.26 1H), 1.34 4H), 1.62 J 2.6 Hz, 1H), 1.76 2H), 1.85 2H), 3.79 1K), 7.43 7.60 J 7.2 Rz, 2H), 7.65 J 7.1 Hz, 1H), 7.71 (ddd, J 2.2, 5.4, 8.2 Hz, 1K), 7.98 2H), 8.35 1K), 8.43 (dd, J 1.4, 7.2 Hz, 2H), 8.72 J 8.2 Hz, 1H), 11.34 EI-MS 413.5 HPLC-Method C, Rt 17.18 min.

Example 315 (5-Diethylcarbamoyl-25-pyrazol-3-yl)-(2phenyl-quinazolin-4-yl) -amine (111-86): 'H NMR (500MHz, DMSO-d6) 8.1.18 (br. a, 31H), 1.25 (br. a, 3K), 3.49 (br.

a, 2H), 3.69 a, 2H), 7.21 1H), 7.59 J 6.9 Hz, 2H), 7.62 1H), 7.70 1K), 7.96 2H), 8.39 J 7.1 Hz, 2H), 8.74 J 8.4 Hz, IH), 11.37 Cbr.

a, 1H); EI-MS 387.2 HPLC-Method C, Rt 14.50 min.

-305- Va Example 316 (Benzyl-methyl-carbamoy) -2I-pyrazol-3- Yll-( 2 -Phenyl-quinazolin-4-yl)-amine (11P897): 1H NMR (SOOMHz, DMSO-dE) 8 3.33 3H), 4.75 2H), 7.26 (im, 1H), 7.31 in), 7.38 4H), 7.58 2H), 7.70 (m, 1H), 7.95 3H), 8.26 IN), 8.40 J 7.8 Hz, 2H), 8.75 IH), 11.2 Cbr. a, IH); El-MS 435.2 HPLC-Method C, Rt 16.77 min.

o ~Example 317 (2-Phenyl-quinazolin-4-yl)-(5- IND 10 propylcarbamyl-2-pyrazol-3-yl)-amine (13-88): 1H NMR (SOOMHz, DMSO-dE) 8 0.94 Ct, J 7.3 Hz, 3H), 1.57 (m, 2H), 3.24 J 6.5 Hz, 2H), 7.39 (br. s, 11), 7.60 (t, J 7.3 Hz, 2H), 7.64 1H), 7.71 (br. t, J 6.5 Hz, IN), 7.98 2H), 8.42 J 7.2 Hz, 2H), 8.61 Cbr. a, 11), 8.72 J 8.5 Hz, 11), 11.34 (br. a, 1N); El-MS 373.3 HPLC-Method C, Rt 13.51 min.

Example 318 (Ethyl-iopropyi-carbamoy1) -20-pyrazol-3yll-(2-phenyl-quinazolin-4-yl) -amine (111-89): 1H NMR (500MHz, DMSO-d6) 8 0.92 J 7.4 Hz, 6H), 1.52 (m, 2H), 1.59 11), 3.79 2H), 7.53 (br. a, 1H), 7.57 J 7.5 Hz, 2H), 7.65 J 7.2 Hz, 1K),.7.71 (m, 11), 7.99 2H), 8.23 (br. d, J .8.8 Hz, 11), 8.46 J 7.5 Hz, 2H1), 8.74 J 8.4 Hz, 1) 11.34 (br. a, 1H); El-MS 401.2 HPLC-Method C, Rt 15.51 min..

Example 319 (5-Cyclopropylcarbamoyl-2a'-pyrazol..3-yl) (2.

phenyl-qunazolj-4 -yl)amine (111-90): 'H NNR (500MHz, DMSO-d) 8 0.60 2H1), 0.74 2H), 2.86 11), 7.34 Cbr. a, 1I1), 7.62 Cmfi, 3E), 7.70 jm, 11), 7.97 2H), 8.41 Cd, 7.9 Hz, 8.63 (br. a, 1H), 8.72 J 7.8 Hz, 114), 1135 (br. a, 1H); El-MS 371.2 (M+H);HPLC- Method C, Rt 12.64 min.

-306- Va Example 320 CS-Iaobutylcarbamoyl-2H-pyrazol-3ya) phenyl-quiazona..4..yl)-amine (111-91): 11 NMR (500MHz, DMSO-d6) 8 0.94 J 6.7 liz, 6H), 1.88 1H), 3.12 Jt, a 6.4 Hz, 7.45 (br. a, 1I), 7.58 J 7.2 S Hz, 3H), 7.64 J 7.1 Hz, 1H), 7.71 11), 7.98 m, 2H), 8.44 (dd, J 1.3, 7.9 Hz, 21), -8.62 (br. a, 1H), CC) 8.72 J 8.3 Hz, 1H), 11.33 Cbr. s, 11); El-MS 387.2 HPLC-Method C, Rt 14.70 min.

Example 321 (5-[(30)-3-Methoxyinethy1-pyrrolidine- carbonylj -2H-pyrazol-3-yl}- (2-phenyl-quinazolin-4-yl) amine (111-93): 'H NNR (500MHz, DMSO-d) 8 2.00 2H), 2.12 11), 3.29 3H), 3.45 J 8.7 Hz, 1), 3.57 (dd, J 3.2, 9.3 Hz, 1H), 3.86 11), 3.92 (m, 4.36 2H), 7.45 Cbr. a, lID, 7.59 J 7.2 Hz, 2H), 7.63 1H), 7.69 1H), 7.97 2H), 8.40 J 7.5 Hz, 2H), 8.74 Cd, J 7.6 Hz, 1H), 11.38 Cbr. a, 1H); El-MS 429.2 (MiH); HPLC-Method C, Rt 13.84 min.

Example 322 (2 -Phenylquinaolin-4 tolylcarbanoyl-a2Hpyrazol-3-yl) -amine (111-94): 'H NMR CSOOMlz, DM4SO-dE) 8 2.33 3M), 6.97 J 7.5 Hz, IH), 7.27 Ct, LTC 7.8 Hz, 7.62 7H), 7.72 (m, IH), 7.98 2H), 8.46 Cdd, J 2.0, 7.9 Hz, 2H), 8.71 Cm, 1H), 10.29 s, iH),,11.31 (br. a, 111); El-MS 421.2 (MiH); EPLO-Method C, Rt 17.11 min.

*Example 323 (2-Phenyl-quinazolin-4-yl). tolYlcarbamoyl-20.pyrazol-3-y.) -amine (111-95): '1 NMR (SOOMHz, DMSO-66) 8 2.30 3H), 7.20 J 8.3 Hz, 2H), 7.62 51), 7.68 J 8.3 Hz, 2H), 7.72 (m, 11), 7.98 Cm, 2H), 8.46 Cdd, J 1.8, 7.0 Hz, 21) 8.72 Cm, 11), 10.31 11), 11.36 (br. S, 1H); El-MS 421.2 EPLO-Method C, Rt 16.95 min.

-307- Cl xample .324 (5-Methylcarbamoyl-.2-pyrazol-3.yl) Phenyl-quinazolin-4-y1') -amne (111-96): 1H NM (500MHz, __DMSO-dE) 8 2.82 J 6 Hz, 3H), 7.31 (br. s, 1-1) Cl S 7.62 (mn, 311), 7.69 (mn, 1H),'7.97 2H1), 8.42 J 7.1 Hz, 211), 8.5S9 (br. s, 8. 71 (dj J =8 .0 HzI 11), 0 11.30 (br. s, 12); El-MS 345.1 11PLC-Method C, Rt 11.02 win.

Va 10 Example 325 (Korpholine-4-carbonyl) -2E-pyrazol-3-ylJ o 2 -phenyl-qinazoin.4.yl).amjne (111-97): 1H NMR (500MHz, .DMSO-ds) 8 3.33 (Mn, 411), 3.83 4H), 7..34 (br. s, 111), .7.53 (in, 4H1), 7.86 22), 9.43 2H1), 8.67 j= 8.6 Hz, IN), 10.70 111), 13.56 111); El-MS 401.2 (14+1) .PLC-Method A, Rt 2.68 muin.

Examle 326 (1-Methylpiperazine-4-carbony.)

-ZN-

pyrazol-3-yl] -(2-phenyl-qu~inazolin-4-yl) -amine (111-98): 'H NMR (50014Hz, DMSO-d6)'8 2.25 311), 2.4 3 411), 3.87 4H1), 7.33 Cbr. 111), 7.53 (in, 411), 7.87 (m, 2H1), 8.45 (mn, 211), 8.67. Z3 7.6 Hz, 10.70 (s, 111), 13.30 111); El-MS 414.2 HPLC-Method A,.Rt 2.38 muin.

.xml 32 (2 -Hydrozyathyloabanoyl -2H-pyrazol -3 -yl] 2 -pheny1-quinazo1±n-4-yj-aine (111-99): NMR (500MHz, DMSO-dE) 8 3.36 211), 3.52 2H), 4.79 (mn, 111), 7.50 (in, 511), 7.83 211), 8.50 411), 10.52 (br. s, 111), 13.-2 5 11); ElI- MS 375S. 1 HPLC -Me tbod A, Rt 2.5 1 muin..

Exaple 328 (5-Carbainoyl-2s..pyrazol-3-y.) (2-phenylqu.±nazolin-4-yl)-aiie (111-100): To a solution of S-(2phenyl -quin'zo in- 4-yl amino) -1H-pyrazole-3 -carboxylic -308- Va o acid 2 ,5-dioxo-pyrro1idin-1-yl ester (270 mg, 0.63 mmol).

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 the solvents, the residue was added to water (20.ml). The resulting precipitate was collected to afford II-100 (168 mg, 80%)as a yellow solid. 1H NMR (sOo500MHz, DMSO-d6) 8 7.77-7.51 6H), 7.86 (br a, 2H), C 8.11 8.50 2H), 8.63 10.52 1H), o 10 11.25 1H); EI-MS 331.1 HPLC-Method A, Rt 2.52 C min.

Example 329 4 -Bromno-2f-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-101): Prepared according to Method A to afford'a yellow solid, mp 189 0 C; 'H NMR (DMSOd6) 8 7.44-7.46 (3H, 7.58 7.87 (2H, 8.15 (1H, 8.31-8.34 (2H, 8.49 (1H, d),.10.08 (1n, a), 13.13 (1H, IR (solid) 3286, 2969, 1738, 1632; MS 366.2/368.2(M+H)+.

Example 330 (4-Bromo-5-methyl-2H-pyrasol-3-yl)- (2-phenylquinazolin-4-yl)-amine (211-102): mp 183-185 0 C; 'H NMR (DMSO) 8 2.33 (3H, br '7.44-7.46 7.57 (1N, im), 7.84-7.87 (2H, 8.31-8:34 (2H, 8.48 (1N, d), 10.05 (1N, 12.91 (1H, br IR (solid) 3362, 3065, 2831, 1619, 1578; MS 380.2/382.2(M+H)t.

Example 331 (4-Cyano-2-pyrazol-3-yl)-(2-phenylquinacolin-4-yl)-amine (111-103): mp >250-C; 1H NMR (DMSO) 7.47-7.49 (3N, 7.64 (11, i 7.91 (2H, 8.40- 8.43 (2H, 8.53 (11, 8.71 10.61 (1N, s), 13.60 IR (solid) 3277, 3069, 2855, 2231, 1625; MS 313.2(M+H)+.

-309- Example 332, (5-Methyl.2.pyrazol.3-.yx) -(2-zorpbolin-4-yl- (N qainazolin-4-y1)..amine (3:11-104) mp 223-224OC; 'H NI' (DM3 0) 8 2.26 (3H1, 3.65 (4H1, 3.75 (4H, mn), '6,44 (1H1, 7.12(mz, 7.33(111, 7..56(1 H, 8.37(111, d), 10.01(1K, ra), 12.13(111, br 1K (solid) 1621, 1578, 1537, 1475, 1434, 1385; MS -311.0 (M+H)t.

CA Examle 333 (SMty-0prza (2-piperazin-1-ylo qainazolin-4-yl) -amine J111-105) lop 179-181OC; 'H 1*1K IND 10 (DMSO). 2. 2 6(3 H, s) 2. 74 (411, bras), 3. 71(4H1, br s) 6.43(111, 7.08(111, 7.30(111, 7.53(1K, t), 8.34(111, .9.50(111, 12.08(111, br ZR (solid) 2853, 1619, 1603, 1566, 1549, 1539;.MS 310.0 (N-iH) 4 Exple%34 (4-Xethylpiperidin-1-yl) -quinazolin-4-ylJ (S-methyl-2s-pyrazol..3.yl) -me (111-106): mp ;.48-150 0

C;

'K NMR (DM30) 8 1..06(3H1, 1.03(2H1, mn), 1.51-1.70(31, mn), 2.26(3H1, 2.86(2H, mn), 4.73(2H1, 6.44(1H, a), 7.06(111, 7.29(111, 7.52(111, 8.32(111, d), 9.92(111, 12.09(111, br 1K (solid) 2917, 2840, 1629, 1593, 1562, 1546, 1486; MjS 323.0 (M+H) 4 Examtple 335 (4-Methylpiperazin-1-yl) -quinazolin-4-yl] -aminte (III-107Y: mp. 105-107*C; "H1 NMR (DM50) 52.21(3H1, 2.26(3H1, 2.34(4H1, m), .3.75(41, mn), 6.45(11, 7.09(111, 7.31(1H, d), 7.54(111, 8.34(111, 9.96(1K, 12.12(111, br a); 111 (solid) 2934, 2844, 2804, 1620, 1593, 1572, 1536, 1476; MS 324.0 (M+K) t Example 336 (5-Methyl-2a-pyrazol-3-yl) -(2-piperidin-1-ylquinazolin-4-yl) -amino (111-108): mp 2940C; 'H Z*R- 81.45-1.58 (4H1, in), 1.63 (2H1, 2.26 (3H1, 3.79 -310- Va o (4H, 6.45 br 7.06 (11, 7.29 (1U, d), 7.52 (1H, 8.33 (1H, 9.92 (iM, 12.11 (1H, br IR (solid) 2929, 2847, 1632, 1591, 1500, 1482, 1437, 1382; MS 309.3 Cl Example 337 (2-Azepan-1-yl)-quinazolin-4-yll- g 2 E-pyrazol-3-yl) -amine (111-109): mp 2690C; 1H NMR (DMSO) 8'1.50 (4H, br 1.76 (4H, br 2.25 (311, 3.78 0 (4H, 6.55 (111, br 7.03 (1H, 7.28 (1H, d), Cl o 10 7.50 (11, 8.33 (iH, 9.92 (1H, 12.09 (1H, br 0 IR (solid) 3427, 2963, 2927, 2909, 2872, 2850, 1623, 1595, 1586, 1568, 1504, 1486, 1468, 1386, 1427; MS 323.3

(M+H)

4 Example 338 [2-(4-(2-Eydroxyethylpiperidin-1-yl)quinazolin-4-yl (5-methyl-2-pyrazol-3-yl)-amine

(III-

110): mp 1750; 1H NMR (DM0SO) 8 1.08 (2H, 1.38 (2H, 1.57-1.83 (3H, 2.26 (3H, 2.85 (2H, 3.47 (2H, 4.38 (1H, 4.75 (2H, 6.45 (1H, br s), 7.06 (1H, 7.29 (1H, 7.52 (1H, 8.32 (1H, d), 9.93 (1H, 12.12 (1H, br IR (solid) 3365, 3073, 2972, 2868, 1622, 1604, .1586, 1568, 1486, 1463, 1440, 1394; MS 353.2 Example 339 (5-Cyclopropyl-2-pyrazol-3-yl)-[2-(4methylpiperidin-1-yl) -qninazolin-4-yll -amine (111-111): To a solution of (S-cyclopropyl-1H-tpyrazol 3 -yl) chloro-quinazolin-4-yl)-amine (118 mg, 0.41 mmol) in tert-butanol (3.0 mL) was added 4-methylpiperidine (0.49 mL, 4.1 mmol) and.the reaction mixture heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in a mixture EtOH:water 4 mL). Potassium carbonate (57mg, 0.41 mmol) was added and the mixture stirred at room temperature for 2 -311- Va hours. The resulting suspension was filtered, washed with water and rinsed with Et20 (x2) to afford IIIct 111 as a white solid (123mg, mp 190 0 C; 'H NMR (DMSO) 8 0.66 (2H, 0.93 (SH, br 1.07 (21, 1.66 (3H, S. 5 1.91 (11, 2.85 (21, 4.72 (2H, 6.33 (1H, 7.06 (11, 7.29 (1H, 7.52 (1i, 8.31 (1H, o 9.95 12.18 (11, br IR (solid) 2925, C 2852, 1622, 1590, 1581, 1558, 1494, 1481, 1453, 1435, o 1394; MS.349.2 0 Example 340 2 -(1,4-Dioza-8-aza-piro[4,5]de-8-y1)quinasolin-4-ylj-(5-methyl-2a-pyrazol-3-yl)-amine

(III-

112): mp 191 0 C; 1H NMR (DMSO) 8 1.65 (4H, 2.26 (3H, 3.90 (4H, 3.93 (4H, 6.43.(1H, br 7.09 (11, 7.32 (1H, 7.54 8.35 (1H, d)L 9.99 (1WH br 12.13 (11H, br s);.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-2-pyrazol-3-yl)-amine

(III-

113): mp 191 0 c; 'H lNMR (DMSO) 5 1.33 (2H11, 1.65 (4H, 1.87 (21, 2.20 (11, 2.26 (3H, 2.49 (2H, 3.00 (2H, 3.36 (2H, 4.61 (2H, 6.45 (11, br 7.07 (1H, 7.31 (1i, 7.52 (1i, 8.33 (1H, 9.94 br 12.12 (1H, br IR (solid) 3371,'2943, 1622,.1600, 1581, 1545, 1509, 1463, 1440, 1390; MS 378.2 Example 342 [2-(4-Hydxoxypiperidin-1-yl)-quinazolin-4- Yl)-(5-methyl-2H-pyrazol-3-yl)-amine (111-114): mp 123OC; 1H lMm (DMSO) 8 1.34 (2H, 1.80 (28, 2.26 (3H, s), 3.24 (2H, 3.72 (1H, br 4.39 (2H, 4.70 (1H, 6.44 (1H, br 7.07 7.30 (in, 7.53 -312- Va o (1H, 8.33 (11, 9.94 (1H, br 12.11 (1H,.br a); IR (solid) 3265, 3151, 2927, 2863, 1622, 1600, 1572, 1540, 1504, 1476, 1440, 1390, 1349, 1066, 1098; MS 325.3 ci Example 343 (5-Cyclopropyl-20-pyrazol-3y cn hydroxy-4-phenylpiperidin-1-yl) -quinazolin-4-yl] -amine (111-115): mp 1310C; 1H NMR (DMSO) 8 0.64 (2H, 0.93 C- (2H, 1.68 (2H, 1.83-1.97 (3H, 3.20-3.45 (2H, Va o 10 4.69 (2H, 5.11 (1H, 6.37 (1H, br 7.08 0g (1H, 7.20 (IH, 7.31 (3H, 7.49 (2H, 7.53 (1H, 8.33 (1H, 9.98 (1H, br 12.18 (1H, br a); 12R (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) (1,3dihydro-isoindol-2-yl) -quinazolin-4-yl -ine (111-116): Prepared according to Method E-1 to afford an off-white solid, mp 2370C; 1H NMR (DMSO-d6) 8 0.79 (2H, 1.00 (2H, 1.99 4.92 (4H, 6.72 (1H, br s), 7.13 (111, 7.33 (2H, 7.30-7.48. (31, 7.58 (1H, 8.40 (1W, 10.12 (13, 12.17 IR (solid) 3449, 3318, 2850, 1623, 1595, 1577, 1541, 1509, 1482, 1432, 1391, 1359, 1141, 1027, 877, 814; MS 369.4 Example 345 (2-Azepan-1-yl)-quinazolin-4-yll-(5cyclopropyl-2H-pyraol-3-y)-amine (III-117): mp 199- 2000C; 3H N1R (DMSO-d6) 8 0.60-0.70 (2H, 0.90-1.00 (2H, 1.45-1.57 (4H, 1.70-1.85 (4H, 1.88-1.97 (1H, 3.75-3.87 (4H, 6.42 (1H, 7.02 (1H, t), 7.27 (1H, 7.49 (1R, 8.29 (1H, 9.91 (1H, a), 12.19 (11, br IR (solid) 2929, 1624, 1595, 1581, -313- Va 1563, 1542, 1498, 1482, 1440, 1426, 1397, 1356, 1305, 1000, 825, 754; MS 349.2-(M+H).

Example 346 (5-Cyclopropyl-20-pyrazol-3-yl)-[2-(3,4- Cl 5 dihydro-1l-isoquinolin-2-yl) -quinasolin-4-yl -amine (III- 118): mp 182-184"C; 'H NMR (DMSO) 8 0.75 (2H, 1.02 0c (2H, 1.96 (1H, 2.89 (2H, 4.05 (2H, 4.94 (2H, 6.46 (1H, 7.10 (1H, 7.21 (4H, 7.37 o. (1H, 7.55 8.36 (1H, 10.05 (1H, 12.23 (1H, br IR (solid) 1621, 1581, 1560, 1537, 1479, o 1456, 1426, 1396, 1374, 1341, 1222; MS 383.3 Example 347 (5-Cyclopropyl-20-pyrazol-3-yl)-[2-(2,3dihydro-indol-1-yl) -quinazolin-4-yll -amine (111-119):.mp 150-153oC; 1H NMR (DMSO) 8 0.74 (2H, 0.98 (2H, d), 1.96 (1H, 3.15 (2H, 4.25 (2H, 6.45 (1H, br 6.88 (1H, 7.09 (1H, 7.20 7.53 (1H, 7.65 (1H, 8.43 (2H, br 10.09 (1H, 12.28 br IR (solid) 1621, 1588, 1577, 1564, 1537, 1487, 1455, 1425, 1386, 1259; MS 369.3 Example 348 (5-Cyclopropoyl-2s-pyrazol-3-yl)-[2-(4hydroxymethylpiperidin-1-yl) -quinazolin-4-yl] -amine (III- 120): mp 142a; 1 H NMR (DMSO) 8 0.67 (2H, 0.96 (2H, 1.10 (2H, 1.55-1.70 (3H, 1.91 (1H, 2.85 (2H, 3.28 (2H, 4.48 (1H, 4.76 (2H, 6.34 7.06 (1H, 7.30 (1H, 7.52 (1H, 8.31 (1H, 9.96 12.19 (1H, IR (solid) 3363, 3000, 2927, 2854, 1618, 1604, 1573, 1536, 1509, 1477, 1436, 1395, 1354, 1314, 1241, 1186, 1091, 995, 941, 823; MS 365.8 Example 349 (5-Cyclopropyl-2-pyrazol-3-yl) dihydro-2H-quinolin-1-yl)-quinazolin4-yll-amine

(III-

-314- Va o 121): mp 137-145 0 C; 1H NMR (DMSO-d6) 8 0.55 (2H, 0.88 (2H, 1.78 (11, mn), 1.92 (2H, 2.75 (2H, 4.04 (2H, 6.20 (11, br 6.97 (1H, 7.14 (1H, m), 7.19 (11, 7.42 (11, 7.61 7.67 (1H, d), 8.43 (11, 10.04 (1i, 12.21 (1H, br IR (solid) 1622,-1572, -1539y 1493,-1454, -1420, 1373, 1249; MS 383.3 C, C Example 350 (5-Methoyearboyl-2-pyrazol-3-yl) [2- (piperidine-I-yl)-quinazolin-4-y1J-amine (III-122): 'H NMR C (500MHz, CDC13) 81.7-1.8(6H, 6 3.8 (4H, 3.9 (3H, 8 5.5 6 7.15. (1H, 8 7.4 (1H, 8 7.6 (1H, 8 8.0 (1H, HPLC-Method.B, (starting with Rt 7.4 min; MS 353.24 Example 351 (Piperidine-1l-carbonyl) -2H-pyrazol-3-yll (2-(piperidine-1-yl)-quinasolin-4-yll-amine (III-123): HPLC-Method B, (starting with 95% H20:0.1% TFA) Rt min; MS 406.30, 404.30.

Example 352 (5-Eydroxymethyl-2H-pyrazol-3-yl)- [2- (piperidin-1-yl)-quinazolin-4-yll-amine (111-124): To a solution of 111-122 (10.0 mg, 0.028 mol) in THF (6 ml) at ambient temperature was slowly added a 1M solution of LiA1* 4 in TUF (0.O mL, 0.05 mmol). After 15 minutes the solution was quenched with water and IN HC1. The product was extracted from the aqueous layer with EtOAc. The organic layer was dried-over MgSO 4 filtered, and concentrated in vacuo. The residue was purified by preparatory HPLC to afford III-124 (4.0 mg, HPLC- Method B, (starting with 95* H20:0.1% TFA) Rt 6.1 min;'MS 325.13 323.13 -315- Va o ~Exmple 353 (5-Carbaoyl-2z-pyrazol-3-yl)- 12- (piperidinl1-yl)-quinaolin-4-yl -amine (II1-125): A solution of II-122 (1.5 g, 4.3 mmol) in 2.0 M WNHA/MeOH (100 mL) was heated at 110 0 C for 2 days. The dark brown reaction C 5 mixture was concentrated in vacuo to afford a viscous oil which was purified by column chromatography to yield 0.7 g of 111-125. H NMR (500MHz, Cf3OD-d 3 81.6 81.7 63.3 (1H, 83.8 68 c- (1H, 6 7.15 (1K, 8 7.45 (1H, 6 7.55 (1i, 8 Va o 10 8.0 (1H, HPLC-Method B, (starting with 95% H 2 0:0.l% 0g TFA) Rt 5.9 min; MS 338.13, 336.15.

Example 354 (5-Carbamoyl-2H-pyrazol-3-yl)- 2-(4metbylpiperidin-1-yl)-quinazolin-4-ylJ -amine (111-126): HPLC-Method B, (starting with 95% H20:0.1% TFA) Rt 6.4 min; MS 352.19, 350.20.

Example 355 (S,7-Difluoro-1-indazol-3-yl)-(2-phenyl- 5,6,7,8-tetrahydroquinazolin-4-yl)-amine (111-127): 3I NMR (500 MHz, DMSO-di) 813.7 1H), 10.3 br, 1H), 7.90 2H), 7.52 1H), 7.45 3H), 7.26 1H), 2:99 2H), 2:75 2H), 1.95 (br, 4H) ppm; MS 378.24 376.23 HPLC-Method A, Rt 3.04 min.

Example 356 (2-Phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)- (5-trifluoromethyl-Z-indazol-3-yl).-amine (111-128): 1H NMR (500 MHz, DMSO-d6) 613.4 1H), 10.2 br, 1H), 8.13 1H), 7.86 2H), 7.78 1H), 7.69 1H), 7.50 1i), 7.35 (dd, 21), 2.89 2H), 2.72 2H), 1.90 br, 4H) ppm; MS 410.24 408.23 HPLC-Method A, Rt 3.19 min.

-316- Example 357 (7-lu oro-ll-±ndazol-3..yi) -(2-phenylquinazolin-4-y1) -amine .(111-129)- "H NMR (500 MHz, DMSOdS) 513.6 flU, 11.1 br, 1N), 8.65 1K), 8.03 2H), 7.95 Cs, 2H), 7.67 1K), 7.45 2H), 7.33 2H), 7.22 (dd, up), 6.99 Ctd, 1K) ppm. MS m/e= 356.20 (M+H);.HPLC-Method A Rt 3.00 min.

Example 358 (S-Fluoro-1- indazol-3-yl)- (2-phenyl- C- quinazolin-4-yl) -amine (111-130): 1H M4R (500 MHz, DMSOo 10 d6) 513.2 1K), 11.3 8.67 8.04 C-i d, 2H), 7.96 2H), 7.70 Cm, 1K), 7.58 (dd, 1K), 7.43 4k), 7.28 (td, 1K) ppm. MS 356.20

EPLC-

Method A, Rt 3.00 min.

Example 359 (5,7-Dffluoro-X-indazol-3.-yl) (2-phenylquinazolin-4-yl) -amine (111-131): :H NMR (500 MHz, DMSOd6) 613.7 Cs, 1K), 8.65 1K), 8.04 2H), 7.95 (s, 2H), 7.68 1K), 7.45 Cm, 1K), 7.35 4K) ppm. MS m/e= 374.17. HPLC-Method A, Rt 3.07 win.

Example 360 (1E-Indazol-3-yl)- (2-(3-trifluoromethylpheryl) -quinazolin-4-ylJ -amine (111-132): 1H NM. (5001Hz, DMSO-d6) 8 7.06 Ct, 1K), 7.42 C(t, 1K), 7.59 1K), 7.63 iN), 7.66 1K), 7.71 1K), 7.80 1K), 7.98 2R), 8.33 1H), 8.46 IN), 8.71 1K), 11.04 (br. s, 1K), 12.97 IH); El-MS 406.1 HPLC- Method A, Rt 3.25 min.

Pxample 361 (2-Phenyl- quinazolin-4-yl)- (1H-pyrazolo 4,3b]pyridin-3-yl) -amine .(111-133): 1H NIR (500 MHz, DMSO-d6) 813.,3 Cs,br, 11.4 br,/i1), 8.78 8.58 (dd, 1K), 8.24 1K), 8.10 2H), 7.95 2H), 7.86 -317- Ct,11),7.56 (in, 2H1), 7.44 2H1) ppm. MS 339.11 HPC-MehodA, Rt 2.63 mini.

Example 362 (3-Methaxy-phenyl) -6-ozo-5, 6-dihydro-lapyrazolo(4,s-cjpyridazin-3-yl] -(2-phenyl-quinazolin-4.

yl)-auine (111-134): 1 K.NMR (5-00 MHz, MeOH-d4) 58.65 Cd, IM), 8.17 3K), 8.10 111), 7.30 Ct, 1H), 7.75 (t, 1K), 7.568m 2H) 7.25 1K), 6.95 Cm, 21) 6.65 (d, o 111H), 6.80 3.64 3H) ppm. MS rn/eu 462.2(4+).

Example 363 (f-Oxo-5-phenyl-s,6-dimydro.1u.pyrazolo4,3.

c~pyridazin-3-yi) -(2-phenyl-quiiazolin-#-yl) -amine C13:I- 135): '1114MR1 (500 MHz, MeOHf-d4) 68.61 -111), 8.13 (m, 3H), 8.05 Cd, 111), 7.85 1H), 7.70 1K), 7.58 Cm, 7.32 51), 6.79 Cs, 1H) jppm. MS m/e= 432.2MiH).

Example 364 [5-(4-Methosy-phenyl) -6-cia-S. 6-dihydro-lapyrabolo(4,3-clpyridazn.3ylJ 2-phenyl-quinazolun-4yl)-amins (111-136): MS 462.2(4+1).

Examle 365. 2 i4-Dichloro-phenyl).-6-oxo-,6-dhyd~o.

lH-pyrazolo [4,3 -cpyr idan-3y11 (2-phenyl-quinazolin-4yl) -amine (Ill- 137): 111 'NR (500 M4Hz, MeOH-d4) 88.6 3 (d, 1K), 8.17 m,411), 7.89 1K), 7.73 Ct, 1K), 7.61 Ct, 2H), 7.57 (di, 111), 7.32 111), 7.21 1H1), 6.84 (s, .1H) ppm. MS m/e= 500.1Mi-).

Exml 366 [6-Oxo-5-(3-trifluormethyl.-phenyl) -5,6dihydro-la-pyrazolo 4 3 -clpyridazin-3-yl] -(2-phenylquinazolin-4-yl) -amine (111-138): 2H1 1041 (500 MHz, MeOK-' d4) 88.55 'Cd, 11) 8.19 2H1), -7.92 2H1), 7.65 (m, -318o 3H), 7.45 2H), 7.25 1K), 7.13 111), 7.05 (t, 1H) 6.75 (a,1KH) ppm. MS m/e='500.2 CM+H).* Example 367 [6-Oxo-S- (4-Phenoxy-phenmyl)-S5,6-dihydro-aH- (N 5 pyrazolo 4 ,3-alpyridait-a-yl] -(2-phenyl-quinazolin-4yl)amie.(111-139).: MS 2 4..3(M+iH).

Exaple368 (4-Chioro-phenyl) -6-oxo-5,6-dihydro-1a- 0 pyrabolo[ 4 ,3-vlpyridazn.s-y1 (2-pheny1-quinazofln-4- IND 10 yl)-aaine (111-140): MS 466.2(MsH).

Examle 369 (2-imidazol-1-y1-quinazolin-4-yl) (iindauol-3-yl)-azmine (13:1-141) 'H 1MR (500Mliz, D)MSO-dE) 8 7.10 111), 7.44 1K), 7.50 (br. s, 1H), 7.60 (d, 1K), 7.72 (in, 211), 7.77 (mr' 11), 7.88 1K), 7.98 (t, 1K), 8.73 1K), 8.96 1K), 11.23 1K), 13.06 (s, 1K) El-MS 328.1 EPLC-Method A, Rt 2.93,mi.

Example 370 (1H-Indazol-3-yl) (2-methyl-imxidazol-1-ylquinaxolin-4-y1] -amine (3131-142) 3H N'M (500MHz, DMSO-d6) 82.48 3H) 7. 1O 1K) 7.43 Ct, 1K) 7.57 1H), 7.60 (di, 1K), 7.67' IH), 7.76 (td, 11) 7.86 1H), 7.91 Cd, 1K), 8.01 (td, 1K), 8.72 1K), 11.15 1H), 13. 10 1K) El-MS 342. 1 HPLC-Method A, Rt 3.06 min.

Example 371 (1R-Indazol-3-yl) -(2-piperidin-1-ylquinazolin-4-y1)-amine (111-143): 'H NNR (500MHz, DMSO-dE) 81.48 Cm, 6H1), 3.60 4K), 7.11 1K),r 7.52 Ct,.H), 7.55 IH), 7.64 Cd,.1K), 7.69 7.75 1K), 7.90 CtH1), 8.58 la), 11.82 Cbr. s, 111), 13.25 1K); El-MS 345.1 CM+1); HPLC-Method A, Rt 3.03 rain.

-319- Va o Example 372 (1H-Indatol-3-yl)-[2-(octahydro-quinlin-1yl)-quinazolin-4-yi]-smine (11-144): 1R NMR (500Mz, DMSO-dG) 8 0.6-1.9 13 3.15 3.25 1H), 11), 7.10 0.5H), 7.12 Ct, 7.55 (m, Cl 5 2H), 7.66 0.5 7.69 0.5 7.77 1H), 7.91 Ct, 1R), 8.55--d,0.5 8.59 0.5 11.46 11.54 0.5 11.78 0.5 11.84 0.5 H), 13.10 0.5 13.12 0.5 EI-MS 399.3 o HPLC-Method A, Rt 3.37 min.

IN o Example 373 (1H-Indazol-3-yl).- (2,6-dimethyl-morpholin- 4 -yl)-qinazolin-4-yl]-amine (II-145): H NMR (0SMHz, DMSO-dG) 8 1.0 6H), 4.0 6H), 7.12 1H), 7.41 (td, 1H), 7.56 Ct, 1H), 7.58 1i), 7.68 (dd, 1H), 7.77 t, IH), 7.93 t, 1H), 8.60 1R), 11.69 1H), 13.16 1H); EI-MS 375.3 HPLC-Method A, Rk 2.93 min.

Example 374 (5-Methyl-2z-pyrazol-3-yl)-(2-phenylpyrinidin-4-yl)-amine mp 245-246*C; 1 NMR (DMSO) 8 2.26 (3H, 6.32 (IH, br 7.07 (1H, br 7.48- 7.54 (311, 8.33-8.39 (3H, 9.87 (1H, 12.03 (1H, IR (solid) 1628, 1589, 1579, 1522, 1479, 1441, 1393, 1336;MS 252.2 Example 375 [6-(4-Acetanidophenylsulfanyl)-2-phenylpyrimidin-4 -yl] (5-methyl-2s-pyrazol-3-yl)-amine (rV-3): A suspension of Penelorim (4,6-dichloro-2phenylpyrimidine)(0.1g, 0.44 mmol), -iethylpyrazole (0.045 g, 0.47 mmol), N, Ndiisopropylethylamine (0.08 ml, 0.47 mol) 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 vacuo and the crude product purified by flash chromatography (silica gel, 3:2 Petrol:EtOAc) to afford -320-

IN

0.037 g (29 yield) of (6-Chloro-2-phenyl-pyrimidin-4yl)-(5-methyl-2-pyrazol-3-yl)-amine as a off-white solid. A suspension of the above pyrimidine (0.037 g, 0.13 mmol) and thioacetamidothiophenol (0.108 g, 0.64 mmol) in tert-butanol was heated at 85 0 C under nitrogen for 2 days. The reaction mixture was cooled to room 0n temperature and the solvent removed in vacuo. The concentrate was dissolved in EtOAc, and washed with NaHC03 0g (sat, The organic layer is concentrated in vacuo, ci o 10 and the crude product by preperative HPLC. The residual 0 disulfide that still remained in the mixture after HPLC may be removed by'precipitation from EtOAc and filtration. The mother liquor was concentrated to afford IV-3 (7mg, 13 1 yield) as an off-white solid: mp 235- 236 0 C; 1HE NMR (DMSO) 8 2.10 (3H, 2.21 (3H, 6.33 (1H, br 7.50 (31, 7.7-7.59 (2H, 7.76-7.78 (2H, 8.25 (2H, 9.72, 10.26 and 11.93 (3 H, 3 x br IR (solid) 1669, 1585, 1551, 1492, 1392, 1372, 1312, 1289, 1259, 1174, 1102, 1089, 1027, 1015, 984; MS 417.3 Example 376 [2-(4-Methylpiperidin-1-yl) -pyrimidin-4-yll- (5-aethyl-2n'-pyrazol-3-yl)-amine mip 215-216 0 C; 32 NMR (CD 3 OD) 8 0.96 (3H, 1.16 (21H, 1.66 (3H, m), 2.27 2.86 (2H, 4.58 (2H, 4.78 (2H, exch.protons), 6.13 (2H, 7.83 (IH, IR (solid) 1593, 1550, 1489, 1436, 1331, 1246, 1231; MS 273.1 Example 377 [2-(4-Methylpiperidin-1-yl)-5-nitropyrimidin- 4 -ylJ-(S-methyl-2B-pyrazol-3-yl)-inne mp 185- 187 0 C; 1H WAR (DMSO) 8 0.93 (3H, 1.06-1.18 (2H, m), 1.68-1.80 (3H, 2.26 (31, 3.01-3.12 (2H, 4.63 (11, 4.80 (1H, 6.39 (11, 9.00. (11, 10.41 -321- Va 12.36 IR (solid) 1589, 1517, 1479, 1446, 1346, 1317, 1246,. 1222, 1055; MS 318.2 (M+H) 4 Example 378 15-Amino-2-(4-Methylpiperidin-1-yl)pyrimidin-4-yll-(5-methyl-2H-pyrazol-3y l)-amine (IV-6): To a solution of. IV-5. (48 mg, 0.151 mmol) in. ethanol o m.L) was added tin dichloride dihydrate (171 mg, 0.756 mmol) and the resulting mixture heated at reflux for 3 o hours. The reaction was cooled to room temperature and c 10 poured onto a mixture of iM NaOH:dichloromethane:.propanol (18:8:4mL) and stirred for 15 minutes. The layers were separated and the aqueous layer extracted twice with dichloromethane.' The combined organic layers were concentrated in vacuo and the residue purified by flash chromatography (silica. gel, gradient dichloromethane:MeoR) to afford Iv-6 as a grey solid (27mg, 1 'H NMR (DMSO) 8 0:88-1.04 1.55-1.62 (3H, 2.21 2.70 (2H, 3.36 (2H, 4.40 (2H, 6.37 (1H, 7.49 (1H, 8.40 (1H, 11.92 (1H, br.s); MS 288.2 Example 379 [5-Amino-6-methyl-2- (4-methylpiperidin-1-yl)- PYrimidin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (IV-7): mp 172-175C; 1H NMR (DMSO) 5 0.90 (3H, 1.03 (2H, m), 1.52-1.62 (3H, 2.13 2.20 (3H, 2.69 (2H, 3.92 (2H1, br 4.44 (2H, 6.35 (11, 8.41 11.85 (11, br IR (solid) 1612, 1589, 1489, 1446, 1317; MS 302.5 Example 380 [6-Methyl-2-(4-methyl-phenyl)-pyrimidin-4- .yl]-(5-phenyl-2-pyrazol-3-yl)-.amine (7V-10): MS 342.34 HPLC-Method E, Rt .1.334 min.

-322oEXample 381, (4-chioro-phenxyl) -6-meth~yl-pyrimidini-4ylJ- (5-furan-2-yl-2pyrazol.3.yl) -amine (IV-11): MS 352. 11 HPLC Method E, Rt 1. 194 mini.

C] S Exa-mle 382 5-Furan-2-y1-2E-pyrazo-3-y)-(6-mthyl.z.

phenyl-pyrimidin-4-y1)-amine (IV-12)s MS 318.21 HPLC-Method E, 1.192 min.

0 Examle 383 [6-Mathyl-2- (4-trifluoromethyl-phenyl) oN 10 pyrimidin-4-yl (5-phenyl-2-yl-2Hf-pyrazol-3-yl) -amine 0 (IV-13)z MS 396.24 HPLC-Method E,.Rt 1.419 min.

Example 384 (5-J'-ran-2-yl-2H-pyrazol-3-yl) 6-moethyl-2- 4 -trifluoromathyl-phenyl) -pyrimidin-4'-yl] -aimine (IV-14): MS 386.08 HPLC-Method E 1.347 mini.

Example 385 (2,3-Dihydra-benzo[1,4ldioxiun-2-yl) -6methyl -pyrimidin- 4-yl] furan- 2-yL- 2N-jyrazo1-3 -yl) amine (fl-is): MS 376.18 (MH;HPLC-Method E, Rt 1.181 min.

Example 386 (2 ,3-Dihydro-bezo [1,41 dioxin-2-yl) -6ethy1-pyrimidin-4-y1 (5-methyl-20-pyrazol-3-yl) -amine (IV-16) M4S 338.17 HPLC-Method E, Rt 1. 082 mini.

Exaple 387 (6-Ethyl-2-phenyl-pyrimitdin-4-yl) (-methyl- 2H-pyrazo1-3-y1)-aminte (3IV-17): MS 280.18 (14tH); HIPLC- Method B, Rt 1. 024 mini.

Examle 388 (6-Methyl-2-phenyl-pyrimidiin-4-yl) (-phenyl- 2 H-pyra~zo1-.3-y1)-amizxe (IV-19): MS 328.51 (MtH); HPLC- Method R, Rt 1.192 min.

-323- Example 389 (6 -Ethyl- 2- (4 -trif luoromethyl-phenyl) (N pyrimidin- 4-ylJ (5 -=ethyl -25-pyrazol-3 -ya) amine MS 348.5 RWLC-Method E, Rt 1.224 min.

Example 390 (5-Puranx-2-yl-2r-pyrazol-s-yl) C-methyl-2- 4 -methy1-pheny1).-pyrimiasn-4-y1J -amine (ZV-21): MS o ~.332.23 HPLC-Method E,,Pt 1.139-min.

Example 391 (6-Methoxymethyl-2-phenyt-pyrimidin..4.yl) methyl-2R-pyrazol-s-yl)..amine MS 296.31 CM-iH); o HPLC-Method E, Ri 0.971 min.

Example 392 (5,6-Diaethy1-2-pheny-pyrimdn.4.yl) methyl-2H-pyrazol-3-yl) -amine*- (IV-23): MS 260.2 HPLC-Method E, Rt 0.927 min.

Example 393 (6-Methyl-2-phenyl-pyrimidin-4 -yl) 2 H-pyrazol-3-yl)..amine (IV-24): MS 266-18 HPLC- Method E, Rt- 0.925 mint.

Exp21e394 [6 -Ethyl -2 (4 -methyl-7phenyl) -pyrimidin- 4-ylJ (S-methyl-2-pyrazol...ya)-.aminei (IV-25): MS 294.46 HPLC-Method E, at 1.174 min.

Example 395 [2 Chioro-phenyl) -6 -ethyl -pyrimidin-4 -ylJ (5-zethy1-2H-pyrazo1'3-y1) -amine (IV-26): MS 314.42 HPLC-Method E Rt 1.213 min.

Example 396 (5-Methyl-1Hf-pyrazol-3-yi) -(6-metliyl-2-ptOlyl-pyrimidin-4-yl) -amine (XV-27): MS 280.45 HPLC-Method E, Rt 1.135 mini.

Examle 397 (1E-Zndazol-3-yl) -(6-methoz-ymethyl-2-phenylpyrinddin-4-yll-amine (IV-28): 'IiNMR (500 MHz, -324- VO ID o 3.57 (3H, 4.65 (2H, 7.23 (1H, J=7.5 Hz, 7.52 (1H, J=7.6 Hz, 7.63 (4H, 7.75 (1H, br), 8.13 (1H, Hz, br 8.44 (1I, J=5.7 Hz, br 10.6 (1H, br), 12.8 (1H, br a) ppm; HPLC-M.ethod A, Rt 2.944 min; MS (FIA) 332.1 r n Example 398 (5-Methyl-2H-pyrazol-3-yl) (2-pyridin-4-ylthieno[3,2-dlpyrimidin-4-yl)-amine (IV-29): 1 H NMR (DMSO) S8 2.34 (3H, 6.66 (1H, 7.53 (1H, 7.84 (1H, d), 8.32 (2H, 8.70 (2H, MS 309.6 Example 399 (5-Methyl-2H-pyrazol-3-yl) (2-phenylpyrido[3,4-d]pyrimidin -4-yl)-amine (IV-30): mp 225°C; IH NMR (DMSO) 8 2.35 (3H, 6.81 (1H, 7.50-7.63 (3H, 8.45-8.52 8.54 (1H, 8.62 (1H, 9.20 (1H, 10.79 (1H, 12.38 (1H, br IR (solid) 2958, 2917, 2852, 1593, 1565, 1524, 1467, 1450; MS 303.2 Example 400 (5-Methyl-2H-pyrazol-3-yl) (2-phenylpyridot2,3-d]pyrimidin-4-yl)-amine (IV-31): To a solution of 4-chloro-2-phenyl-pyrido[2,3d]pyrimidine Pharm. Belg., 29, 1974, 145-148) (109mg, 0.45 mmol) in THF (15 mL) was added pyrazole (48 mg, 0.5 mmol) and the resulting mixture heated at 65 °C 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 (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Si0 2 DCM-MeOH gradient) to afford IV-31 as an off-white solid (69 mg, mp 234 0 C; IH NMR -325-

VO

(DMSO) 8 2.14 (3H, 5.99 (1H, 7.20-7.40 (3H, m), C 7.40-7.50 (3H, 8.60 (IH, 8.79 (1H, 12.82 (1H, Sbr IR (solid) 2957, 2921, 2857, 1644, 1560, 1459, 1427; MS 303.2 Cl Example 401 (5-Cyclopropyl-2H-pyrazol-3-yl)- (2-phenylpyrido[3,4-d]pyrimidin-4-yl)-amine (IV-32): off-white solid, mp 232-233OC; 1H NMR (DMSO) 8 0.70-0.85 (2H, m), C l0.90-1.05 (2H, 1.05-2.07 (1H, 6.75 (1H, 7.50- 7.75 (3H, 8.40-8.70 (4H, 9.20 (1H, 10.80 (1H, s 12.41 IR (solid) 3178, 1601, 1573, 1532, 1484, 1452, 1409, 1367, 1328, 802, 781, 667; MS 329.2 Example 402 [2-(4-Methylpiperidin-l-yl)-purin-4-yll-(5methyl-2H-pyrazol-3-yl)-amine (IV-33): To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-lH-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 Et20 (x2) to afford IV-33 as a white solid (225mg, mp >300oC; H NMR (DMSO) 8 0.91 (3H, 1.10 (2H, 1.65 (3H, m), -326-

NO

o 2.24 2.84 (2H, 4.60 (2H, 6.40 (1H, a), 7.87 (1l, 9.37-9.59 (iH, 12.03-12.39 (2H,

IR

(solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3 (M+H) t Example 403 (5-Cyclopropyl-2-pyrazol-3-yl)r 1 2 (4o methylpiperidin-1-yl) -pyrrolo 2-d]pyrimidin-4-yll -amine (IV-34): white solid; 1 H NMR (DMSO) 8 0.65 (2H, 0.91ci0.96 (SH, 1.08 (2H, 1.58-1.64 (3H, 1.89 (1i, 2.77 (2H, 4.57 (2H, 6.09 (1H, 6.38 (1H, sN 7.33 (1H, 9.42 (1W, 10.65 (1H, 12.02 (1H, br MS 338.3 Example 404 [6-Benzy1-2-phenyl-5,6,7,8-tetracydro- Pyrido(4,3-d]pyriidin-4-yll- (5-fluoro-1E-indazol-3-yl)amine (IV-35): .1H NMR (500MHz,' DMSO-d6) 813.0 1H), 10.4 br, IH), 9.73 1H, TFA-OH), 8.00 2H), 7.64 2H), 7.59 (dd, 1H), 7.52 3H), 7.41 1W), 7.31 3H), 7.14 (dd, 1H),'4.58 2H), 4.35 (br, 2W), 3.74 2H) 3.17 2H) ppm. MS m/e- 451.30 HPLC-Method A, Trt 2.96 min.

Example 405 (5-Fluoro-1-indazol-3-yl)-(2-phenyl-5,6,7,8- .tetrahydro-pyrido[4,3-dpyrinmidin-4-yl) -amine (IV-36): Prepared from IV-35 (0.13 mmol) by treatment with an equal weight of Pd/C in 4.4% HCOOH in MeOH at room temperature for 12 h. The mixture was filtered through celite, the filtrate was evaporated, and crude product was purified by HPLC to afford IV-36.as yellow solid in 35% yield. -1H NMR (500 MHz, DMSO-d6) 812.9 111), 9.06 1W), 7.99 2H), 7.57 (dd, 1W), 7.34 1H), 7.28 3H), 7.22 1k), 3.83 2H), 3.05 2H), 2.72 2H) ppm. MS m/er 361.20 HPLC-Method

A,

Tt 2.68 min.

-327-

VO

CN BExample 406. (5-Methyl-25-pyrazol-3-yl)- (3-phenylisoquinolin-l-yl)-amine To a solution of l-chloro- 3 -phenylisoquinoline Het. Chem., 20, 1983, 121- C 5 128) (0.33g, 1.37 mmol) in DMF (anhydrous, 5 mL) was added 3 -amino-5-methylpyrazole (0.27g, 2.74.mmol) and potassium 0 carbonate (0.57g, 4.13 mmol)and the resulting mixture was (1 heated at' reflux for.6 hours. The reaction mixture was o then cooled and solvent removed in vacuo. The residue ID 10 was extracted twice with ethyl acetate and the combined Sorganic layers washed with brine, dried (MgSO), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, gradient DCM-MeOH) to afford V-1 as a colourless oil; H NMR -(MeOD) 8 2.23 (3H, 5.61 (1H, s),: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 (1-Indazol-3-yl)-[3- (2-trifluoromethylphenyl)-isoquinoline-l-yll-amine A solution of 1chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (100 mg, 0.326 mmoi) 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:dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1 x 25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography (25% to 50% hexane:ethyl acetate) afforded V-2 as a yellow solid (35 mg, ZH NMR (500 MHz, d6- DMSO) 8 9.78 (br s, 1H),.8.62 1H), 7.9-7.85 1H), 7.78-7.72 1H), 7.70-7.68 1H), 7.65-7.62 1H), 7.60-7.55 1H), 7.52-7..45 3H), 7.41-7.38 1H), -328- 7.28-7.25 1H), 7.18 15), 6.95-6.92 (mi 1H), 5;76 15); LC-MS m/e= 405.18 HPLC-Method D Rt 2.74 min.

CA 5 Example 408 (5,7-Difluoro-l-indazol-3-yl) trifluoromethyl-phanyl)-isoquinolin-1-yl -amine Prepared from 5 7 -difluoro-1H-indazol-3-ylamineto afford compound V-3 as a yellow solid (90 mg, 1H NMR (500 c- MHz, d-DMSO) 6 13.25 9.92 (br s, 8.61 (d, 1H), 7.9 7.81-7.49 6H), 7.26-7.2 2H), 7.12-7.10 1H); LC-MS m/e= 441.16 HPLC- Method D, Rt 3.58 min.

Example 409 (5-Methyl-23-pyrazol-3-yl )-(2-phenylquinolin-4-yl)-amine To a mixture of 4-chloro-2phenylquinoline Het. Chem., 20, 1983, 121-128)(0.53g, 2.21 mmol) in diphenylether (5 mL) was added methylpyrazole (0.43g, 4.42 mmol) and the resulting mixture heated at 200 0 C overnight with stirring. The reaction mixture was cooled to ambient temperature then petroleum ether (20 mL) was added and the resulting precipitate was isolated by filtration. The crude solid was purified by flash chromatography (Sio 2 gradient DCM- MeOH) to- afford V-4 as a-white solid: mp 242-244OC; H NMR (DMSO) S 2.27(3H, 6.02(1H, 7.47(2K, 7.53- 7.40(2H, br 7.67(15, 7.92(15, 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 (lB-Indazol-3-yl)-(2-phenyl-quinolin-4-yl)amine 'H NMR (500 MHz, de-DMSO) S 12.78 1H), 9.50 1H), S.65 15), 8.15 1I), 8.04-7.98 (m, 3H), 7.94 1H), 7.78-7.75 (in, 7.60-7.40 6H), -329- Va 7.15-7.10'(m, 1I1). LC-MS (ES) m/e= 337.11 HPLC- Method D, Rt 2.10 min.

Exampple 411 (2-Phenyl-quinolin-4-yl) -(1B-pyrazolo(4,3blpyridin-3-yl) -amine lH WR (500 MSz, DM0-d)' 813.6 1N), 11.4 11)Y, 8.94 11), 8.61 (dd,-1H), 8.23 11), 8.16 (dd, 1N), 8.12 IN1), 7.89 1H), 7'86 1H), 7.65 Cm, 4H), 7.54 11), 7.52 (dd, 1H) 0~ PPm. MS r/em 338.11 HPLC-Method A, HPLC- IND 10 Method D, Rt 2.91 min.

Example 412 (1H-Indazal-3-yl)- (2,-trifluoromethylphenyl) -quinolin-4yll -amine 1 H NMR (500 MHz, d 4 DMSOLS8 12.68 1N), 9.51 1H), 8.7 7.95- 7.89 Cm, 7.83-7.70 Cm, 3H), 7.68-7.62 2H), 7.6b 1H), 7.55-7.52 IN), 7.49-7.45 1H), 7.40-7.37 Cm, 11), 7.12-7.09 1H); LC-MS m/e= 405.15 HPLC-Method D Rt 2.25 min.

Example 423 (5,7-Difluoro-1H-indazol-3-yl)-(2- (2trifluoromethyl-phenyl) -quinolin-4-ylJ -amine 'H NMR (500 MHz, cl-DMSO) 8 13.31 As, IH) 9.49 1H), 8-70- 8.67 Cm, 1H),7.96-7.92 11), 7.85-7.66 7H), 7.63- 7.60 7.42-7.40 1N). LC-MS r/en 441.18 HPLC-Method D Rt 2.39 min.

Example 414 (2-trifluoromethyl-phenyl) -quinolin-4 -yl] (lE-pyrazolo[4,3-blpyridin-3-yl) -amine 1H IhR (500 MHz, DMSO-ds) 813.6 11.6 Cs, br, H, 8.98 (d, 1H), 8.57 (dd, 1H), 8.12 Cm, 3H), 7.97 21), 7.86 (m, 3H), 7.49 (dd, 11), 7.23 11) ppm. MS r/en 406.20 HPLC-Method A Rt' 2.91 min.

-330- Va o Example 415 (2-Phenyl-cpxinaolin-4-yfl'-(2H- 1,[lsZ4ltriazol-3-yl)-amine (IX-154): off-white solid, mp 266 267oC; 1H NTR (DMSO) 8 7.50-7.70 (4H, 7.85-8.00 (2H, 8.15-8.25 (2H, 8.37-8.45 (2H, 8.58 (1H, 13.90 (1H, hr IR (solid) 3344, 3059, 1630, 1609, 1570, 1557, 1543, 1501, 1495, 1445, 1411, 1355, 1326, (fl 1267, 1182, 1053, 1038, 760, 676, 667, 654; MS 289.2 22 N 10 Example 416 (5-Methyl-28-[1,2,4triazol-3-yl).--(.phenyl Cluinazoli-4-yl)-amine (IX-155): 1H NMR (500 MHz- DMSOd6) 88.s 11), 8.42 T 6.7 Hz, 2H), 7.79 (m.

4H), 8.03 2H), 7.74 4H), 2.51 3H1 ppm. MS m/e= 303.08 HPLC-Method A, Rr_ 2.64 min.

E4LaAle 41 7 (25- [1,2,42-Triazol-3-yl)- trifluoromethylphenyl) -quinazolin-4-ylJ -amine (11-47):- Pale yellow solid (52% yield). NMR (500 MHz, DMSO-d6) Se.4 1H), 8.15 br, 11), 7.91 1H), 7.85 (m, 2H) 7.76 Cm, 3H) '7.66 Ct, 1H) ppm. MS m/e= 357.13 m/e= 355.15 HPLC-Method A, Rt 2.81 min.

Examle 418 (S-Iethyl-2-t1,2,4ltriazol-3-yl)- trifluoromethylpheyl) -qainazolin-4-yl -amine (IX-38): Pale yellow solid (54% yield). 'H NMR (5'00 MHz, DMSO-d6) 8.44 br, 11), 7.92 Cm, 3H), 7.84 7.77 (m, 2H), 7.68 1H), 2.28- 3H) ppm. MS m/e- 371.14 m/e= 369.18M-H).; HPLC-Method A, Rt 2'.89 min.

ExQ 4 le 41 9 (S-Metbylsulfaayl-2H- C1,2,4Itriazol-3-yl) -trifluoromethylpbenyl) -quinazolin- 4 -yl] -ains (XX- 156): Pale yellow solid (65t yield). IH NIR (500 MHz, -331- Va F DMSO-ds) 88.56 (br, 1H), 7.90 1H), 7.84 2H), 7.78 Cl 2H), 7.67 2H), 2.51 3H, buried by DMSO) ppm.

MS m/e= 403.12 m/e= 401.16 SHPLC-Method A, Rt 3.20 min.

Example 42 0 -(H-1,2,4Trazol-3-yl)-3-(2oD trifluoromethyl-phenyl) -isoquinolin-1-yl] -amine (IX-175): Cl A solution of l-chloro-3-(2-trifluoromethyl-phenyl)o isoquinoline (0.326 mmol) and IH-[1,2,4]triazol-3-ylamine ND 10 .(0.651 mmol) in ethanol (3 mL) was heated at 160 0 C and.

o the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160 0 C for 18 hours under nitrogen. The resulting melt was dissolved in methanol/dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1 x 25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography afforded IX-175 as a colorless oil (4% yield). 'H NMR (500 MHz, CDC1 3 8 9.18 1I), 8.82 (s, lW), 7.90 i1), 7.85-7.75 7.71-7.62 3H), 7.60-7.55 2H), 4.42-4.35 1i). LC-MS 356.16 HPLC-Method D, Rt 3.55 min.

Example 421 (2-Phenyl-quinolin-4-yl).-(1- f1,2,4]triazol- 3-yl)-amine (IX-176): Pale yellow solid (30% yield). 1

H

NMR (560 MHz, d-DMSO) 8 13.82 1H), 9.91 1H), 8.80 1K), 8.70-8.65 1H), 8.55 15), 8.15-8.12 2H), 8.03-7.98 1H), 7.75-7.72 1H), 7.57-7.49 35). LC-MS m/en 288.11 HPLC-Method D, Rt 1.55 min.

Example 422 (lB- [1,2,4]triazol-3-yl)- trifluoromethyl-phenyl)-quinolin-4-yl]-amine (11-177): Pale yellow solid (46% yield). 1 H NMR (500 MHz, d-DMSO) 6 13.70 15), 9.98 8.70 IH), 8.49 (s, -332-

NO

S1H), 8.30 1H), 7.94-7.88 2H), 7.80-7.68 3H), 7.64-7.56 2H). LC-MS m/e= 356.18

HPLC-

SMethod D, Rt 1.68 min.

N .5 Example 423 (l-H-Indazol-3-yl)- 5-methyl-6-morpholin-4yl-2- 2 -trifluoromethyl-phenyl) -pyrimidin-4-yl] -amine 0 (11-251): Colorless film; 2 yield; I-NMR (500 MHz, CDOD) 8 7..84 2H), 7.71 3H), 7.41 2H), 7.14 0 1H), 3.74 4H), 3.69 4H), 1.24 3H). ppm; cO o 10 HPLC-Method A Rt 3.26 min; MS (FIA) 455.1 BIOLOGICAL TESTING The activity of the compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of the activated protein kinase.

Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/protein kinase complex and determining the amount of radiolabel bound.

Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors.are incubated with the protein kinase bound to known radioligands.

BIOLOGICAL TESTING EXAMPLE 1 Ki DETERMINATION FOR THE INHIBITION OF GSK-3 Compounds were screened for their ability to inhibit GSK-30 (AA 1-420) activity using a standard coupled enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). Reactions were carried out in a solution containing 100 mM HEPES (pH 10 mM MgCl 2 25 mM NaC1, -333o 300 pM NADH, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 20 pM ATP (Sigma cChemicals, St Louis, MO) and 300 pM peptide (HSSPHQS (P03H 2 EDEEE, American Peptide, Sunnyvale, CA).

S, 5 Reactions were carried out at 30 oC and 20 nM GSK-3p.

Final concentrations of the components of the coupled 0 enzyme system were 2.5 mM phosphoenolpyruvate, 300 pM C NADH, 30 pg/ml pyruvate kinase and 10 ug/ml lactate o dehydrogenase.

C0 10 An assay stock buffer solution was prepared o containing all of the reagents listed above with the exception of ATP and the test compound of interest. The assay stock buffer solution (175 jil) was incubated in a 96 well plate with 5 pli of the test compound of interest at final concentrations spanning 0.002 pM to 30 pM at 0 C for 10 min. Typically, a 12 point titration was conducted by preparing serial dilutions (from 10 mM compound stocks) with DMSO of the test compounds in daughter plates. The reaction was initiated by the addition-of 20 p1 of ATP (final concentration 20 pM).

Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 min at The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 JIM for GSK-3: compounds I1-1, II- 105, 11-33, 11-34, 11-36, 11-39, 11-38, 11-39, 11-40, II- 41, 11-42, 11-46, 11-57, 11-59, II-60, II-61, 11-62, II- 63, 11-64, 11-66, 11-67,,II-69, 11-70; 11-53, 11-71, II- 99, 11-73, 11-74, 11-75, 11-76, 11-77, II-7, II-8, 11-9, 11-10, 11-24, 11-19, 11-78, 11-54, 11-79, 11-80, 11-81, 11-82, 11-83, 11-84, 11-56, 11-86, 11-20, 11-25, 11-26, 11-85, 11-21, 11-27, 11-28, 11-87, 11-88, II-29, II-11, 11-12, 11-30, 11-31, 11-13, 11-14, II-15, 11-16, 11-17, -334- Va 11-18, 11-79, 11-23, 11-2, I-90, 11-91, 11-92, 1i1-93, 11-3, 11-4, 11-5, 11-6, 11-94, 11-95, 11-96, 11-107, II- .108, Il-109, 11-110, 11-124, 11-125, 1I-111, 11-112, II- 113, 11-124, II-115, 11-116, 1IL217, I-118, II-119, II- C 5 120, 11-121, II-208, III-8, 111-7, 111-9, 111-37, 111-38, 111-39, III-40,. 111-42, 111-45, 111-46, III-47, 111-48, Cr 111-49, II-51, 111I-52, 111-53, 111-54, 111-55, Il-56, III-57, III-58, 111-59, 111-60, I-61,-111I-62, 111-63, 0 111-30, 111-65, 111-66, 111-67, 111-70, 111-73, 111-31, III-75, 111-76, III-77, III-33, 111-34, III-106, III-108, S111 -109, III-111, 111-35, 111-116, 111-117, III-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 1.0.M for GSK-3: compounds II- 103, 11-104, 11-35, 11-44, 11-45, II-49, II-O50, 11-97, .II-101, 11-22, 11-32, III-41, 111-43, 111-44, 111-28, 11I-50, 111-29, 111-64, 111-71, 111-74, III-78, 111-82, III-88, III-90, 111-102, IIl-105, 111-107, 111-110, III- 112,III-114, 111-115, 111-122, 111-124,,111-124, IV-1, III-1, 111-138, 111-140, 111-142, III-129, 111-132, III- 134, 11-135, 111-136, IV-1, IV-10, IV-11, IV-12, IV-13, IV-14, IV-19, IV-21,1IV-22, IV-23, IV-24, IV-3, IV-4, IV- 6, IV-7, TV-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 ;LM for GSK-3: compounds 11-43, 11-65, 11-48, 11-47, 11-51, 11-68, 11-52, 11-72, II-100, 11-9B, 11-89, III-68, 11-81, III-83, 111-91, 111-94, i1-95, 111-96, 111-97, 111-98, 111-99, II1-100, III-101, 111-103, 111-123, 111-137, 111-139, 111-143, 111-145,

IT-

1 4 6 V-4, V-8, IX-156, and IX-176.

-335- BIOLOGICAL TESTING EXAMPLE 2 CN Ki DETERMINATION FOR THE INHIBITION OF AURORA-2 Compounds were screened in the following manner for their ability to inhibit Aurora-2 using a standard C- 5 coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249).

o To an assay stock buffer solution containing (N 0.1M HEPES 7.5, 10 mM MgC12, 1 mM DTT, 25 mM NaC1, 2.5 mM o phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate M0 10 kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and o 800 pM peptide (LRRASLG, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 pM. The resulting mixture was incubated at 30 'C for 10 min. The reaction was initiated by the addition of 10 pL of Aurora-2 stock solution to give a final concentration of nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over a 5 minute read time at.30 °C using a BioRad Ultramark plate reader (Hercules, CA). The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 gM for Aurora-2: compounds II-33, II-34, 11-36, 11-37, 11-40, 11-41, 11-55, III-7, III-9, III-37, III-38, III-39, III-40, III-4i, III-42, III-44, III-46, III-47, III-48, III-49, III-50, III-51, III-52, I-53, III-54, III-55, III-56, III-57, I-59, 111-61, III-63, III-30, III-65; III-66, III-67, III-31, III-76, III-77, III-78, III-80, III-32, III-33, III-34, III-106, III-108, III-109, III-110, III- 111, III-112, III-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.

-336-

VO

o The following compounds were shown to have Ki values between 0.1 and 1.0 pM for Aurora-2: compounds

II-

1, 11-105, 11-35, II-38, 11-39, 11-42, 11-64, 11-70, II- 53, 11-99, 11-77, II-79, 11-86, 11-20, 11-93, 11-94, III- 28, III-58, III-64, III-71, III-73, III-74 -75, III-75, III- 102, III-105, III-107, III-113, III-124, III-1, III-130, m IV-1, IV-3, IV-4, IV-6, IV-29, IV-33, and V-4.

The following compounds were shown to have Ki C- values between 1.0 and 20 lpM for Aurora-2: compounds II- 103, 11-104, II-57, II-59, 11-61, 11-63, 11-67, 11-69, C 11-75, 11-76, 11-10, II-19, 11-78, 11-54, 11-80, 11-82, 11-21, 11-90, 11-91, II-96, 11-107, III-68, III-79, III- 82, III-101, III-103, III-127, III-141, III-129, III-132, IV-31, V-2, IX-47, IX-154, and IX-177.

BIOLOGICAL TESTING EXAMPLE 3 CDK-2 INHIBITION ASSAY Compounds were screened in the -following manner for their ability to inhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgC1 2 1 mM DTT, 25 mM NaC1, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate kinase, 10 mg/ml-lactate dehydrogenase, 100 mM ATP, and 100 uM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 pM.

The resulting mixture was incubated at 30 OC for 10 min.

The reaction was initiated by the addition of pL of CDK-2/Cyclin A stock solution to give a final concentration of 25 nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over-a 5-minute read time at 30 OC using a BioRad -337-

VO

C Ultramark plate reader (Hercules, CA) The Ki values were C( determined from the rate data as a function of inhibitor c concentration.

Cq 5 BIOLOGICAL TESTING EXAMPLE 4 ERK INHIBITION ASSAY O Compounds were assayed for the inhibition of C( ERK2 by a spectrophotometric coupled-enzyme assay. (Fox et o al (1998) Protein Sci 7, 2249). In this assay, a fixed I\D 10 concentration of activated ERK2 (10 nM) was incubated o with various concentrations of the compound in DMSO for 10 min. at 30°C in 0.1 M HEPES buffer, pH containing 10 mM MgC1 2 2.5 mM phosphoenolpyruvate, 200 pM NADH, 150 pg/mL pyruvate kinase, 50 pg/mL lactate dehydr6genase, and 200 ipM erktide peptide. .The reaction was initiated by the addition of 65 M ATP. The rate of decrease of absorbance at 340 nM was monitored. The ICso was evaluated from the rate data as a function of inhibitor concentration.

The following compounds were shown to have a Ki value of <1M for ERK-2: III-109, III-ill, 111-115, III- 117, 111-118, III-120, and IV-4.

The following compounds were shown to.have a Ki value of between I1M and 12pM for ERK-2: III-63, and III-108.

BIOLOGICAL TESTING EXAMPLE AKT INHIBITION ASSAY Compounds were screened for their ability to.

inhibit AKT using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mM MgCl2, 25 mM NaCI 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 170 pM ATP (Sigma -338- I0 D Chemicals) and 200 pM peptide (RPRAATF, American Peptide, Sunnyvale, CA). Assays were carried out at 30 'C and nM AKT. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, C( 5 .300 pM NADH, 30 ug/ML pyruvate kinase and 10 pg/ml lactate dehydrogenase.

SAn assay stock buffer solution was prepared containing all of the reagents listed above, with the 0 exception of AKT, DTT, and the test compound of interest.

ID 1 0 56 pl-of the stock solution was placed in a 384 well plate followed by addition of 1 1l of 2 mM DMSO stock containing the test compound (final compound concentration 30 The plate was preincubated for about 10 minutes at 30'C and the reaction initiated by addition of 10 pl of enzyme (final concentration 45 nM) and 1 mM DTT. Rates of reaction were obtained using a BioRad Ultramark plate reader (Hercules, CA) over a minute read time at 30*C. Compounds showing greater than inhibition versus standard wells .containing the assay mixture and DMSO without test compound were titrated to determine ICsO values.

BIOLOGICAL TESTING EXAMPLE 6 SRC INHIBITION ASSAY The compounds were evaluated as inhibitors of human Src kinase using either a radioactivity-based assay or spectrophotometric assay.

Src Inhibition Assay A: Radioactivity-based Assay The compounds were assayed as inhibitors of full length recombinant human Src kinase (from Upstate Biotechnology, cat. no. 14-117) expressed and purified from baculo viral cells. Src kinase activity was monitored by following the incorporation of "P from ATP into the tyrosine of a random poly Glu-Tyr polymer substrate of composition, Glu:Tyr 4:1 (Sigma, cat. no.

-339- 0 P-0275). The following were the final concentrations of OC the assay components: 0.05 M HEPES, pH 7.6, 10 mM MgC12, 2.

t mM DTT, 0.25 mg/ml BSA, 10 pM ATP (1-2 pCi "P-ATP per reaction), 5 mg/ml poly Glu-Tyr, and 1-2 units of e< 5 recombinant human Src kinase. In a typical assay, all the reaction components with the exception of ATP were o pre-mixed and aliquoted into assay plate wells.

Ci Inhibitors dissolved in DMSO were added to the wells to o give a final DMSO concentration of The assay plate IN 10 was incubated at 30 oC for 10 min before initiating the o reaction with "P-ATP. After 20 min of reaction, the reactions were quenched with 150 pl of trichloroacetic acid (TCA) containing 20 mM Na 3

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. 200pl of scintillation fluid was then added to each well. The plates were sealed and the amount of radioactivity associated with the filters was quantified on a TopCount scintillation counter. The radioactivity incorporated was plotted as a function of the inhibitor concentration. The data was fitted to a competitive inhibition kinetics model to get the Ki for the compound.

Src Inhibition Assay B: Spectrophotometric Assay The ADP produced from ATP by the human recombinant Src kinase-catalyzed phosphorylation of poly Glu-Tyr substrate was quanitified using coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay one molecule of NADH is oxidised to NAD for every molecule of ADP produced in the kinase reaction. The -340o disappearance of NADH can be conveniently followed at 340 ct nm.

The following were the final concentrations of Sthe assay components: 0.025 M HEPES, pH 7.6, 10 mM MgC12, 2 mM DTT, 0.25 mg/ml poly Glu-Tyr, and 25 nM of recombinant human Src kinase. Final concentrations of the ncomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 200 pM NADH, 30 ug/ml pyruvate 0 .kinase and 10 pg/ml lactate dehydrogenase.

In a typical assay, all the reaction components 0with the exception of ATP were pre-mixed and aliquoted into assay plate wells. Inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of The assay plate was incubated at 30'C for 10 min before initiating the reaction with 100 pM ATP. The absorbance change at 340 nm with time, the rate of the reaction, was monitored on a molecular devices plate reader. The data of rate as a function of the inhibitor concentration was fitted to compettive inhibition kinetics model to get the K± for the compound.

The following compounds were shown to have a Ki value of <100nM on SRC: III-31, III-32, I-33, III-34, 111-47, III-65, III-66, III-37, III-38, III-39, III-42, III-44, III-48, I-49, III-70, III-78, III-76, and IV- 32.

The following compounds were shown to have a K value of between 1oonM and 1pM for SRC: I-63, III-71, III-73, III-72, III-74, III-80, III-50, The following compounds.were shown to have a Ki value of between IpM and 6pM for SRC: III-79, IV-1, and IV-31.

While we have hereinbefore presented a number of embodiments of this invention, it is apparent that our basic construction can be.altered to provide other -341- 00 O embodiments which utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments which have been represented by 5 way of example.

The term "comprise" and variants of the term such as (C "comprises" or "comprising" are used herein to denote the inclusion of a stated integer or stated integers but not to IND exclude any other integer or any other integers, unless in the 1 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.

-342-

Claims (36)

1. A compound of formula IX: Cq R2 SHN 0j A 1 (N Ry- "Z 1 G Cq IX or a pharmaceutically acceptable derivative or prodrug ;as hereinbefore defined, wherein: Z' is nitrogen or CR 9 and Z 2 is nitrogen or CH, provided that at least one of 21 and Z 2 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1, 2 ,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable non- ortho carbon position on Ring C is independently substituted by -R s and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated,

5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R 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 -343- VO O substituted at any substitutable ring carbon by oxo or Cq -R 5 and at any substitutable ring nitrogen by -R 4 Sprovided that when Ring D is a six-membered aryl or Sheteroaryl ring, -R 5 is hydrogen at each ortho carbon r position of Ring D; R 1 is selected from -halo, -CN, -NO 2 T-V-R 6 phenyl, 5-6 Smembered heteroaryl ring, 5-6 membered heterocyclyl ^C ring, or CI- 6 aliphatic group, said phenyl, heteroaryl, Sand heterocyclyl rings each optionally substituted by c0 up to three groups independently selected from halo, oxo, or -R 8 said Ci- 6 aliphatic group optionally C N substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; RX and R Y are independently selected from T-R 3 or RX and R Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by Rx and R Y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by RX and R Y is substituted by R 4 T is a valence bond or a C 1 4 alkylidene chain; R 2 is -R or -T-W-R 6 R 3 is selected from -halo, -OR, -C0 2 R, -COCOR, -COCH2COR, -NO 2 -CN, -S(0) 2 R, -SR, -N(R 4 2 -CON(R 7 2 -SO 2 N(R 7 2 -N(R 7 )COR, -N(R 7 CO 2 (optionally substituted Ci-6 aliphatic), -N(R4)N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 7 )CON(R 7 2 -N(R 7 )SO 2 N(R 7 2 -N(R 4 )SO 2 R, or -OC(=O)N(R 7 )2; each R is independently selected from hydrogen or an optionally substituted group selected from CI-6 aliphatic, Cs-io aryl, a heteroaryl ring having 5-10 -344- Va o ring atoms, or a heterocyclyl ring having 5-10 ring Cl atoms; each R is independently selected from -COR 7 -CO 2 (optionally substituted C.. 6 aliphatic), -CON(R') 2 C or -S0 2 R or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, Q-N(R 4 2 -CON(R 2 -S0 2 N(R 2 -N(R4)COR, o CO 2 (optionally substituted C 1 aliphatic), Cl -N(R 4 )N(R 2 -C=NN(R 2 -C=N-OR, -N(R 4 )CON(R 4 2 -N(R 4 )S0 2 N (R 4 2 -N(R 4 )SO 2 R, or 2 or R 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -SO2-, -N(R 6 -SO 2 -N(R 6 -CO 2 -N(R 6 -N(R 6 -N(R)CON(R 6 -N(R 6 SO 2 N -N(R 6 )N(R 6 -C(O)N(R 6 -OC(O)N(R 6 -C(R) 2 -C(R 6 2 S-, -C(R 6 2 SO-, -C(R 6 2 S 2 -C(R 6 2 S 2 -C(R 6 2 N(R 6 -C 2 N C) -C(R 6 2 N(R 6 C -C(R 6 =NN (R 6 -C(R 6 -C(R 6 2 N(R 6 )N(R 6 -C(R')2N(R 6 )SO 2 N(R 6 or -C(Rt6) 2 N (R 6 CON(R) W is -C(R 6 2 -C(R 6 2 -C(R 6 2 SO-, -C(R 6 2 S 2 -C(R 6 2 S0 2 N(R 6 -C(R 6 2 N(R 6 -CO 2 -C(R 6 )OC -C OC N (R 6 -C (R 6 2 N(R 6 CO-, -C(R) 2 -C(R 6 )=NN(R 6 -C(R6) 2 N(R 6 -C(R 6 )2N(R 6 )SO 2 N (R 6 -C(R) 2 N(R)CON(R6) or -CON(R 6 each R 6 is independently selected from hydrogen, an optionally substituted C1-. 4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; -345- o each R 7 is independently selected from hydrogen or an C- optionally substituted CI-_ aliphatic group, or two R 7 con the same nitrogen are taken together with the Snitrogen to form a 5-8 membered heterocyclyl or C heteroaryl ring; each R 8 is independently selected from an optionally Ssubstituted C2-4 aliphatic group, -OR 6 -SR 6 -COR 6 Ce -S0 2 R 6 -N(R 6 2 -N(R 6 )N(R 6 2 -NO 2 -CON(R 6 2 or o -CO 2 R 6 and Q R 9 is selected from halo, -OR, -CO 2 R, -COCOR, S-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(R4)CO 2 (optionally substituted CI-6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 4 )CON(R 4 2 -N (R 4 )SO 2 N(R 4 2 -N(R4)SO 2 R, or 2; provided that when: Z 1 and Z 2 are both nitrogen; G is Ring D; and Rx and R Y are independently selected from T-R 3 then: R 2 is selected from hydrogen, C 1 -4 aliphatic, alkoxycarbonyl, substituted or unsubstituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, or (N-heterocyclyl)carbonyl. 2. The compound according to claim 1, wherein said .compound is of formula X: -346- CD R 2 N 'NH SHNIN o x RYN or a pharmaceutically acceptable derivative or prodrug thereof, wherein; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, C< 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 non- ortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -Re; R 1 is selected from -halo, -CN, -NO 2 T-V-R 6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or CI-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R 8 said 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; Rx and R y are independently selected from T-R 3 or R and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 -347- VO <D 0 0 Ci ci (N 0 en ci 0 0 ci 0 (O <D 0D 0q 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 RX and R y is substituted by R 4 T is a valence bond or a 1c.4 alkylidene chain; R 2 is -R or -T-W-R 6 R 3 is selected from -halo, -OR, -C02R, -COCOR, -COCH 2 COR, -NO 2 -CN, -S(O) 2 R, -SR, -N(R4)2, -CON(R 7 2 -SO 2 N(R 7 2 COR, CO2 (optionally substituted C1-6 aliphatic), -N(R)N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 7 )CON(R 7 2 -N(R 7 )SO 2 N(R 7 2 -N(R 4 )SO 2 R, or N (R 7 2 each R is independently selected from hydrogen or an optionally substituted group selected from Ci-6 aliphatic, C.-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R 7 -COR 7 -C02 (optionally substituted CI-1 aliphatic), -CON(R 7 2 or -S0 2 R 7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -C02R, -COCOR, -NO 2 -CN, -S0 2 R, -SR, -N(R 4 2 -CON(R 4 2 -SO 2 N(R 4 2 -N(R4)COR, -N(R 4 C02 (optionally substituted CI-6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 4 )CON(R 4 2 -N(R4)SO2N(R 4 2 -N(R 4 )SO 2 R, or -OC(=0)N(R 4 2 or R 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -S02-, -N(R 6 )S0 2 -S0 2 N(R 6 -N(R 6 -C02-, -N(R 6 -N(R 6 -348- Va o CON(R') -N(R 6 )SO 2 N(R 6 -N(R')N(R 6 0 -C(0)N(R 6 -OC(O)N(R 6 -C(R 6 2 0, -C(R 6 2 S-, -C(R) 2 SO-, -C(R 6 2 S 2 2 S 2 N(R 6 2 N(R 6 -C(R 6 2 N(R 6 -C(R 6 2 -C(R 6 )=NN(R 6 -C(R 6 2 N(R 6 -C(R 6 2 N(R 6 )S0 2 N(R 6 or C 2 N (R 6 CON (R 6 W is -C(R 6 -C(R6)2s-, -C(R) 2 SO-, -C(R 6 2 SO 2 Cr -C(R) 2 S 2 -C(R 6 2 N(R 6 -C0 2 -C(R 6 -C(R 6 -C(R 6 )2N (R 6 )CO-, 'i 2 N (R 6 C -C (R 6 =NN(R 6 o -C(R)2N(R 6 )N(R 6 -C(R 6 2 N(R 6 )SO 2 2 N(R)CON(R 6 or -CON(R 6 each R 6 is independently selected from hydrogen, an optionally substituted C 1 4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R 7 is independently selected from hydrogen or an optionally substituted C 16 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R 8 is independently selected from an optionally substituted C 1 4 aliphatic group, -OR 6 -COR 6 -S0 2 R 6 -N (R 6 2 -N(R 6 )N(R) 2 -CN, -NO 2 -CON(R6) 2 or -CO 2 R. 3. The compound according to claim 2, wherein said compound has one or more 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 -349- VO O system, the bicyclic ring system is selected from a C< naphthyl, quinolinyl or isoquinolinyl ring; S(b) Rx is hydrogen or C 1 i- aliphatic and R Y is T- SR 3 or Rx and R Y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring o nitrogens; C-q R is -halo, an optionally substituted CI-6 o aliphatic group, phenyl, -COR 6 -OR 6 -CN, -SO 2 R 6 -S02NH 2 \O -N(R 6 2 -CO 2 R 6 -CONH 2 -NHCOR 6 -OC(O)NH 2 or -NHSO 2 R6; Sand R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 -6 aliphatic group. 4. The compound according to claim 3, wherein: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring; R x is hydrogen or C 1 -4 aliphatic and R Y is T- R 3 or R x and R y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; R 1 is -halo, an optionally substituted Ci-6 aliphatic group, phenyl, -COR 6 -OR 6 -CN, -S0 2 R 6 -S0 2 NH 2 -N(R 6 2 -CO 2 R 6 -CONH2, -NHCOR 6 -OC(O)NH 2 or -NHSO2R 6 and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 6 aliphatic group. -350- VO O 5. The compound according to claim 3, wherein said Ci compound has one or more features selected from the group c3 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 o system, the bicyclic ring system is a naphthyl ring; C- Rx is hydrogen or methyl and R Y is -R, o N(R or -OR, or Rx and R Y are taken together with their 4\ intervening atoms to form a benzo ring or a 5-7 membered o carbocyclo ring, wherein said ring formed by Rx and R Y is optionally substituted with halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO2R, -SR, -N(R4) 2 -CON(R 4 2 -S02N(R 4 2 -N(R 4 )COR, -N(R4)CO 2 (optionally substituted CI-6 aliphatic), -N(R 4 )N(R4) 2 -C=NN(R4) 2 -C=N-OR, -N(R 4 )CON(R 4 2 -N(R 4 )SO2N(R4) 2 -N(R 4 )SO 2 R, or -OC(=O)N(R 4 )2; R 1 is -halo, a Ci-6 haloaliphatic group, a CI-6 aliphatic group, phenyl, or -CN; R 2 is hydrogen or a substituted or unsubstituted group selected from aryl or a Ci-6 aliphatic group; and each R 5 is independently selected from -halo, -CN, -NO 2 -N(R 4 2 optionally substituted Ci-6 aliphatic group, -OR, -C02R, -CONH(R 4 -N(R 4 )COR, -SO 2 N(R 4 2 or -N(R 4 )SO2R.

6. The compound according to claim 5, wherein: 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; Rx is hydrogen or methyl and RY is -R, N(R 4 2 or -OR, or RX and R Y are taken together with their -351- VO 0 intervening atoms to form a benzo ring or a 5-7 membered CA carbocyclo ring, wherein said ring formed by Rx and R Y is Soptionally substituted with halo, -OR, -C02R, -COCOR, -NO 2 -CN, -S02R, -SR, -N(R4) 2 -CON(R 4 2 -SO 2 N(R 4 2 -N(R 4 )COR, -N(R)CO 2 (optionally substituted CI-6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R4) 2 S-C=N-OR, -N(R 4 )CON(R 4 2 -N(R 4 )SO 2 N(R 4 2 -N(R4)SO 2 R, or C( -OC(=0)N(R 4 2 o(c) R is -halo, a. Ci-6 haloaliphatic group, a 0 C.-6 aliphatic group, phenyl, or -CN; o R 2 is hydrogen or a substituted or CA unsubstituted group selected from aryl or a C.-6 aliphatic group; and each R 5 is independently selected from -halo, -CN, -NO 2 -N(R 4 2 optionally substituted Ci-6 aliphatic group, -OR, -C02R, -CONH(R 4 -N(R 4 )COR, -S0 2 N(R 4 2 or -N(R 4 )S0 2 R.

7. The compound according to claim 5, wherein said compound has one or more 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; Rx is hydrogen or methyl and R y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R X and R Y are taken together with their intervening atoms to form an optionally substituted benzo ring or a 6-membered carbocyclo ring; R 1 is -halo, a C-.4 aliphatic group optionally substituted with halogen, or -CN; -352- \O O R 2 is hydrogen or a CI-6 aliphatic group; and C each R 5 is independently selected from -Cl, t -CN, -CF3, -NH 2 -NH(C1- 4 aliphatic), -N(CI-4 aliphatic) 2 -0(CI-4 aliphatic), C1-4 aliphatic, and -C02(CI-4 aliphatic) S8. The compound according to claim 7, wherein: C Ring C is a phenyl or pyridinyl ring, Soptionally substituted by -R 5 wherein when Ring C and two *0 adjacent substituents thereon form a bicyclic ring Ssystem, the bicyclic ring system is a naphthyl ring; C Rx is hydrogen or methyl and R y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or Rx and R Y are taken together with their intervening atoms to form an optionally substituted benzo ring or a 6-membered carbocyclo ring; R 1 is -halo, a C.-4 aliphatic group optionally substituted with halogen, or -CN; R 2 is hydrogen or a CI-6 aliphatic group; and each R 5 is independently selected from -C1, -CN, -CF 3 -NH 2 -NH(Ci-4 aliphatic), -N(C 1 -4 aliphatic) 2 -0(CI-4 aliphatic), C1-4 aliphatic, and -C02(Ci-4 aliphatic).

9. The compound according to claim 1, wherein said compound is of formula XI: -353- SR 2 N"NH C RXt c RY N D D o XI or a pharmaceutically acceptable derivative or prodrug thereof, wherein: SRing D is a 5-7 membered monocyclic ring or 8-10 membered Ci bicyclic ring selected from aryl, heteioaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R s and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; RX and R y are taken together with their intervening atoms to form a fused benzo ring or 5-8 membered carbocyclo ring, wherein any substitutable 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 CI-4 alkylidene chain; R 2 is -R or -T-W-R 6 R 3 is selected from -halo, -OR, -C0 2 R, -COCOR, -COCH 2 COR, -NO 2 -CN, -S(0) 2 R, -SR, -N(R 4 2 -CON(R 4 2 -SO 2 N(R 4 2 -N(R')COR, -N(R 4 C02 (optionally substituted 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 (R 4 )2; each R is independently selected from hydrogen or an optionally substituted group selected from CI-6 -354- VO o aliphatic, C,_Lo aryl, a heteroaryl ring having 5-10 0 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -R7, -COR 7 -CO2(optionally substituted 1-6 aliphatic), -CON(R') 2 or -S0 2 R, or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, c -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2 -CON(R -SO 2 N(R') 2 -N(R 4 )COR, -N(R C02 (optionally substituted C1-6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R) 2 -C=N-OR, -N(R')CON(R 2 -N(R SO 2 N (R 4 2 -N(R')SO 2 R, or N (R 4)2; V is -SO2-, -N(R')S0 2 -SO2N(R 6 -N(R 6 -CO02-, -N(R 6 -N(R 6 -N (R 6 CON(R 6 -N SO 2 N(R 6 -N N -C(0)N(R -C(R 6 2 SO-, 2 SO 2 2 SO 2 2 2 C(0) 2 N C -C(R 6 -C(R) 2 -C(R')2N(R6) SO 2 or -C 2 N CON W is 2 2 -C(R6) 2 SO-, 2 SO 2 -C(R 6 2 SO 2 N 2N(R 6 -CO_ -C02-, OC 0) OC(0)N(R') 2 N(R')CO-, -C(R 6 2 N (R 6 C 2 N N -C(R 6 2 SO 2 N 2 N CON(R') or each R' is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and -355- VO o each R 7 is independently selected from hydrogen or an C< optionally substituted CI-6 aliphatic group, or two R 7 c on the same nitrogen are taken together with the Snitrogen to form a 5-8 membered heterocyclyl or C heteroaryl ring. o 10. The compound according to claim 9, wherein said eC compound has one or more features selected from the group Sconsisting of: V\ 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 and R y are taken together with their intervening atoms to form an optionally substituted benzo ring or 5-7 membered carbocyclo ring; and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 -6 aliphatic group.

11. The compound according to claim 10, 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-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; Rx and R Y are taken together.with their intervening atoms to form an optionally substituted benzo ring or 5-7 membered carbocyclo ring; and -356- VO O R 2 is hydrogen or a substituted or C unsubstituted group selected from aryl, heteroaryl, or a c CI-6 aliphatic group.

12. The compound according to claim 10, wherein said compound has one or more features selected from the o group consisting of: C Ring D is an optionally substituted ring Sselected from phenyl, pyridinyl, piperidinyl, V\ piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4- o tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-IH-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; Rx and RY are taken together with their intervening atoms to form a benzo ring or 5-7 membered carbocyclo ring, wherein said ring formed by Rx and R Y is optionally substituted with oxo, halo, -OR, -CO2R, -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 Ci-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 )S0 2 R, or N (R 4 2 R 2 is hydrogen or a substituted or unsubstituted.group selected from aryl or a Ci-6 aliphatic group; and each R 5 is independently selected from halo,. oxo, CN, NO 2 -N(R 4 2 -CO2R,.-CONH(R 4 -N(R4)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, C 6 10 aryl, or C 1 -6 aliphatic.

13. The compound according to claim 12, wherein: Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, -357- VO O piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4- Cq tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, c 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, Sisoquinolinyl, quinolinyl, or naphthyl; Cg Rx and R Y are taken together with their intervening atoms to form a benzo ring or 5-7 membered o carbocyclo ring, wherein said ring formed by Rx and R y is eC optionally substituted with oxo, halo, -OR, o -C02R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2 -CON(R 4 2 -SO 2 N(R') 2 -N(R 4 COR, o -N(R C0 2 (optionally substituted Ci-6 aliphatic), CI -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 SOzR, or N (R 4 )2; R 2 is hydrogen or a substituted or unsubstituted group selected from aryl or a CI-6 aliphatic group; and each R s is independently selected from halo, oxo, CN, NO 2 -N(R 4 2 -CO 2 R, -CONH(R 4 -N(R4)COR, -SO2N(R') 2 -N(R 4 )SO 2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs- 10 aryl, or Ci-6 aliphatic.

14. The compound according to claim 12, 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 benzo ring or 6-membered carbocyclo ring, wherein said ring formed by Rx and R Y is optionally substituted with halo, CN, oxo, Ci16 alkyl, CI-6 alkoxy, (CI-1 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 -358- VO o substituted or unsubstituted group selected from 5-6 0C membered heterocyclyl, C 6 -jo aryl, or CI_- aliphatic; and S(c) R 2 is hydrogen or a Ci- 6 aliphatic group.

15. The compound according to claim 14, wherein: Rx and R Y are taken together with their Sintervening atoms to form a benzo ring or 6-membered C carbocyclo ring, wherein said ring formed by R x and R Y is Soptionally substituted with halo, CN, oxo, CI-. alkyl, C I -6 N alkoxy, (Cz- 6 alkyl) carbonyl, alkyl)sulfonyl, mono- or Sdialkylamino, mono- or dialkylaminocarbonyl, mono- or C 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 -io aryl, or Ci-6 aliphatic; and R 2 is hydrogen or a Ci-6 aliphatic group.

16. The compound according to claim 1, wherein said compound is of formula XII: R 2 HN NH HN N RY N XII or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or -359- O heterocyclyl ring having 1-4 ring heteroatoms selected c 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 Sposition of Ring D; (C Rx and R y are independently selected from T-R 3 or R x and o R y are taken together with their intervening atoms to V\ form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring is optionally and independently substituted by T-R 3 and any substitutable nitrogen on said ring is substituted by R4; T is a valence bond or a CI-4 alkylidene chain; R 2 is -R or -T-W-R6; R' is selected from -halo, -OR, -C02R, -COCOR, -COCH 2 COR, -NO 2 -CN, -S(0) 2 R, -SR, -N(R 4 2 -CON(R 4 2 -SO 2 N(R 4 2 -N(R')COR, -N(R 4 CO 2 (optionally substituted C_-s aliphatic), -N(R)N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 4 )CON(R 4 2 -N(R 4 )S 0 2 N(R 4 2 -N(R 4 )SO 2 R, or N (R 4 2 each R is independently selected from hydrogen or an optionally substituted group selected from CI- 6 aliphatic, C 6 -i 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R 7 -COR 7 -CO 2 (optionally substituted C1- 6 aliphatic), -CON{R') 2 or -SO 2 R or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; -360- Va S 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 SON(Rf) 2 -N(R)COR, -N(R 4 CO 2 (optionally substituted C..s aliphatic), -N(R)N(R 2 -C=NN(R 4 2 -C=N-OR, -N(R 4)CON(R 4 2 -N(R SO 2 2, -N(R SO 2 R, or -OC(=O)N(R)2; o V is -SO 2 -N(R 6 )S0 2 -SO 2 N -C0 2 S-N(R 6 -N(R')S0 2 N -C(Rt)2S-, 0 2 SO-, 2 SO 2 2 S0 2 -C(R6) 2 N(R 6 -C(R6) 2 -C(R6) 2 2 -C(R) 2 N(R SO 2 N or -C(R 6 2 CON W is -C(R6) 2 2 SO-, -C(R6) 2 S02-, 2 -C0 2 (R6)0C(o)N(R) -C(R 6 2 N(R 6 -C(R 6 )=NN(R -C(R6) 2 -C(R6) 2 N(R')SO 2 2 or -CON(R)-; 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; and each R' is independently selected from hydrogen or an optionally substituted C 1 -6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl ring or heteroaryl.

17. The compound according to claim 16, wherein said compound has one or more features selected from the group consisting of: -361- VO o Ring D is an optionally substituted ring 0< selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or Snaphthyl ring; en R x is hydrogen or C 1 -4 aliphatic and R y is T- R or RX and RY are taken together with their intervening Va atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring C heteroatoms; and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 -6 aliphatic group.

18. The compound according to claim 17, 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 C 1 -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 a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 -6 aliphatic group. -362- VO o 19. The compound according to claim 17, wherein Cq said compound has one or more features selected from the Sgroup consisting of: S(a) Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4- o tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, (S 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, o isoquinolinyl, quinolinyl, or naphthyl; V0 Rx is hydrogen or methyl and R Y is -R, SN (R 4 2 or -OR, or Rx and R 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, -C02R, -COCOR, -NO 2 -CN, -S(0)R, -SO 2 R, -SR, -N(R 4 2 -CON(R 4 2 -SO 2 N(R 4 -OC(=O)R, -N(R 4 )COR, -N(R 4 )C02 (optionally substituted CI-6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R4)CON(R 4 2 -N(R4)SO 2 N(R 4 2 -N(R 4 )SO 2 R, or -OC(=O)N(R4)2; R 2 is hydrogen or a substituted or unsubstituted group selected from aryl or a CI-6 aliphatic group; and each R 5 is independently selected from halo, oxo, CN, NO 2 -N(R4) 2 -CO2R, -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- 1 0 aryl, or CI- 1 aliphatic. The compound according to claim 19, 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, -363- VO O 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, C- isoquinolinyl, quinolinyl, or naphthyl; c Rx is hydrogen or methyl and R Y is -R, G N(R4)2, or -OR, or RX and R Y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, Swherein said ring is optionally substituted with -R, (S halo, oxo, -OR, -C02R, -COCOR, -NO 2 -CN, -S(O)R, o -SO 2 R, -SR, -N(R 4 2 -CON(R4) 2 -S02N(R 4 2 -OC(=O)R, c0 -N(R 4 )COR, -N(R CO2 (optionally substituted C.-6 aliphatic), o -N(R')N(R 4 2 -CNN(R 4 2 -C=N-OR, -N(R 4 )CON(R 4 2 N -N (R SON (R 4 2, -N(R 4 )SO 2 R, or -OC N (R 4 2; R 2 is hydrogen or a substituted or unsubstituted'group selected from aryl or a CI-6 aliphatic group; and each R 5 is independently selected from halo, oxo, CN, NO 2 -N(R 4 2 -C02R, -CONH(R 4 -N(R 4 )COR, -SO 2 N(R4)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 CI-6 aliphatic.

21. -The compound according to claim 19, 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, Ci-6 alkyl, CI-6 alkoxy, (Ci-6 alkyl) carbonyl, (C1-6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R s is independently selected from -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a -364- VO 0 substituted or unsubstituted group selected from 5-6 C( membered heterocyclyl, C 61 0 aryl, or C 1 -6 aliphatic; and t R 2 is hydrogen or a CI-6 aliphatic group. C 22. The compound according to claim 21, wherein: Rx and R Y are taken together with their o intervening atoms to form a 6-membered unsaturated or Ci partially unsaturated ring having 1-2 ring nitrogens, o optionally substituted with halo, CN, oxo, C 1 -6 alkyl, Ci- 6 V0 alkoxy, (CI-6 alkyl) carbonyl, (Ci-6 alkyl)sulfonyl, mono- or o 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-jo aryl, or C 1 -6 aliphatic; and R 2 is hydrogen or a Ci-6 aliphatic group.

23. The compound according to claim 1, wherein said compound is of formula XIII: R 2 N( HN NH Rx-, Z2 XIII or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Z 1 is nitrogen, CR a or CH, and Z 2 is nitrogen or CH; provided that one of Z' and Z 2 is nitrogen; G is Ring C or Ring D; -365- VO o Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, C- pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, c wherein said Ring C has one or two ortho substituents Sindependently selected from -R 1 any substitutable non- g ortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on o Ring C are optionally taken together with their Cg intervening atoms to form a fused, unsaturated or o partially unsaturated, 5-6 membered ring having 0-3 c\ heteroatoms selected from oxygen, sulfur or nitrogen, Ssaid fused ring being optionally substituted by halo, c 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 havihg 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R 5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; R 1 is selected from -halo, -CN, -NO 2 T-V-R 6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or CI-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R 8 said Ci-6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; 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 -366- VO 0 membered ring having 0-3 ring heteroatoms selected from C- oxygen, sulfur, or nitrogen, wherein any substitutable Scarbon on said fused ring formed by Rx and R Y is E 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 o T is a valence bond or a Ci-4 alkylidene chain; R 2 is -R or -T-W-R 6 o R 3 is selected from -halo, -OR, -CO 2 R, S-COCOR, -COCH 2 COR, -NO 2 -CN, -S(0) 2 R, -SR, S-N(R 4 2 -CON(R') 2 -SO 2 N(R 7 2 -N(R')COR, C -N(R')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 7 )CON(R 7 2 -N(R 7 )SO 2 N(R 7 2 -N(R4)SO 2 R, or -OC(=O)N(R 7 )2; each R is independently selected from hydrogen or an optionally substituted group selected from CI-6 aliphatic, C 6 10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R1, -COR 7 -CO 2 (optionally substituted CI-6 aliphatic), -CON(R 7 2 or -SO 2 R 7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2 -CON(R4) 2 -SO 2 N(R4)2, -N(R 4 )COR, -N(R 4 C0 2 (optionally substituted Ci-6 aliphatic), -N(R4)N(R 4 -C=NN(R 4 -C=N-OR, -N(R 4 )CON(R') 2 -N(R4)SO 2 N(R4) 2 -N(R4)SO 2 R, or N(R4) 2 or R 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -SO 2 -N(R6)SO 2 -SO 2 N(R 6 -N(R 6 -C02-, -N(R 6 -N(R 6 )C(0) O -367- O O -N(R 6 )CON(R 6 -N(R 6 )SO 2 -N(R6)N(R 6 S-C(O)N(R 6 -OC(O)N(R 6 -C(R 6 2 -C(R 6 2S-, t -C(R 6 2 SO-, -C(R) 2 SO 2 -C(R 2 S0 2 -C(R 6 2 S-C(R 6 2 N(R 6 -C(R 6 2 N(R 6 -C(R 6 )=NN(R 6 -C(R 6 2 N(R)N(R 6 -C(R 6 2 N(R 6 )SO 2 N(R 6 or -C (R 6 2 N CON (R 6 W is -C(R 6 2 -C(R 6 2 -C(R 6 2 SO-, -C(R 6 2 S 2 -C(R 6 2 SO2N(R 6 -C(R 6 2 ,N(R 6 -C0 2 -C(R 6 OC(o) -C(R 6 )OC(O)N(R 6 -C 2 N (R 6 )CO-, O -C(R 6 )2N(R)C(o0)0-, -C(R 6 =NN(R 6 C(R 6 -C (R 6 2 N(R6)NR 6 2 N(R 6 SO 2 N R 6 -C(R 6 2 N(R 6 )CON(R 6 or -CON(R6)-; each R 6 is independently selected from hydrogen, an optionally substituted C 1 -4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocycly1 or heteroaryl ring; each R 7 is independently selected from hydrogen or an optionally substituted C 1 6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; each Re is independently selected from an optionally substituted C 1 4 aliphatic group, OR, -SR6, -COR 6 S0 2 R 6 -NR 6 2 -N(R 6 )N(R 6 2 -CNi, -NO 2 -CON(R 6 2 or -C0 2 R 6 and Ra is selected from halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2 -CON(R 4 2 SO 2 N (R 4 2 -N(R COR, -N(R4) CO 2 (optionally substituted .C 1 aliphatic), -N(R )N(R4) 2 -C=NN(R) 2 -C=N-OR, -N(R 4 )CON(R 2 SO 2 N(Rt) 2 SO 2 R, -OC 2, or an optionally substituted group selected from CI-6 aliphatic, C5o 10 aryl, a heteroaryl -368- VO o ring having 5-10 ring atoms, or a heterocyclyl ring C- having 5-10 ring atoms. S24. The compound according to claim 1, wherein said compound has one or more features selected from the group consisting of: o Ring C is a phenyl or pyridinyl ring, (g optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring \0 system, the bicyclic ring system is selected from a Snaphthyl, quinolinyl or isoquinolinyl ring, and R 1 is -halo, an optionally substituted C 16 aliphatic group, phenyl, -COR 6 -OR 6 -CN, -SO 2 R 6 -SO2NH 2 -N(R 6 2 -C0 2 R 6 -CONH2, -NHCOR 6 -OC(O)NH 2 or -NHSO 2 R 6 or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; Rx is hydrogen or CI-4 aliphatic and R Y is T- R 3 or Rx and R y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 -6 aliphatic group. The compound according to claim 24, wherein: 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 -369- VO O naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is Cq halo, an optionally substituted C 1 -6 aliphatic group, Sphenyl, -COR 6 -OR 6 -CN, -SO 2 -S02NH 2 -N(R 6 2 -C0 2 R 6 SCONH2, -NHCOR 6 -OC(O)NH 2 or -NHSO 2 R 6 or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, o thienyl, azepanyl, morpholinyl, 1,2,3,4- (C tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, \0 isoquinolinyl, quinolinyl, or naphthyl ring; S(b) RX is hydrogen or C 1 -4 aliphatic and R y is T- C R 3 or R x and R y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 -6 aliphatic group.

26. The compound according to claim 24, wherein said compound has one or more features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R 1 is -halo, a Ci-> haloaliphatic group, a Ci- 6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected-from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; -370- VO o Rx is hydrogen or methyl and Ry is -R, 0g N(R4)2, or -OR, or Rx and R Y are taken together with their intervening atoms to form a benzo ring or a 5-7 membered Scarbocyclo ring, wherein said ring formed by Rx and R y is optionally substituted with halo, -OR, -C02R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R4) 2 -CON(R4) 2 -SO 2 N(R 4 2 -N(R 4 )COR, CO2 (optionally M-q substituted CI- 6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 2 S-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 N(R 4 2; o R 2 is hydrogen or a substituted or C unsubstituted group selected from aryl, or a CI-6 aliphatic group; and each R 5 is independently selected from -halo, -CN, -NO 2 -N(R 4 2 optionally substituted C 1 6 aliphatic group, -OR, -CO 2 R, -CONH(R 4 -N(R 4 )COR, -S02N(R4)2, or -N(R 4 )SO 2 R, and, when Ring G is Ring D, Ring D is substituted by oxo or R

27. The compound according to claim 26, wherein: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R is -halo, a CI-6 haloaliphatic group, a Ci-6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1, 2 ,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; Rx is hydrogen or methyl and R Y is -R, N(R4)2, or -OR, or Rx and R Y are taken together with their -371- o intervening atoms to form a benzo ring or a 5-7 membered (0 carbocyclo ring, wherein said ring formed by Rx and R y is optionally substituted with halo, -OR, -C0 2 R, S-COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2 -CON(R 4 2 -SO 2 N(R 4 2 COR, -N(R 4 )CO 2 (optionally substituted Cie 6 aliphatic) -N(R4)N(R 4 2 -C=NN(R 4 2 S-C=N-OR, -N(R 4 )CON(R 4 2 -N(R4)SO 2 N(R4) -N(R')SO 2 R, or S-OC R 4 2; R 2 is hydrogen or a substituted or Sunsubstituted group selected from aryl, or a C 1 Saliphatic group; and each R 5 is independently selected from -halo, -CN, -NO 2 -N(R 4 2 optionally substituted Ci.- aliphatic group, -OR, -CO 2 R, -CONH(R 4 -N(R 4 )COR, -SO2N(R4)2, or -N(R')SO 2 R, and, when Ring G is Ring D, Ring D is substituted by oxo or R 5

28. The compound according to claim 26, wherein said compound has one or more features selected from the group consisting of: RX is hydrogen or methyl and R Y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or RX and R Y are taken together with their intervening atoms to form a benzo ring or a 6-membered carbocyclo ring wherein said ring formed by Rx and R y is optionally substituted with halo, CN, oxo, C 1 -6 alkyl, CI- 6 alkoxy, (C 1 alkyl)carbonyl, (CI- 6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring -372- VO O system, the bicyclic ring system is a naphthyl ring, and Ci R 1 is -halo, a C1-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally Ssubstituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1, 2 ,3,4-tetrahydroisoquinolinyl, 1,2,3,4- o tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or Mq naphthyl; S(c) R 2 is hydrogen or a Ci-6 aliphatic group; and \4 each R 5 is independently selected from -Cl, S-F, -CN, -CF 3 -NH 2 -NH(CI. 4 aliphatic), -N(C 1 .4 C aliphatic) 2 -O(C1_4 aliphatic), C1-4 aliphatic, and -C02(C1-4 aliphatic), and when Ring G is Ring D, Ring D is substituted by oxo or R 5

29. The compound according to claim 28, wherein: R x is hydrogen or methyl and R y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or Rx and R Y are taken together with their intervening atoms to form a benzo ring or a 6-membered carbocyclo ring wherein said ring formed by RX and R Y is optionally substituted with halo, CN, oxo, Ci-s alkyl, CI-6 alkoxy, (CI-6 alkyl)carbonyl, (CI-6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; Ring C is 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 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, -373- 00 piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1, 2 3 ,4-tetrahydroisoquinolinyl 1,2,3,4- tetrahydroquinolinyl isoquinolinyl, quinolinyl, or naphthyl; R 2 is hydrogen or a C1-6 aliphatic group; and each R 5 is independently selected from -Cl, -CN, -CF 3 -NH 2 -NH(Cl 1 4 aliphatic), -N(Cl 1 4 aliphatic) 2 -O(Cl- 4 aliphatic), C 1 4 aliphatic, and -C0 2 (C 1 4 aliphatic), and when Ring G is Ring D, Ring D is substituted by oxo or R. The compound according to claim i, wherein said compound is selected from the following compounds: CH 3 A N% N -A HN HN "V HNNC 1~hIV H3C N Cl N CI CF3 H 3 C N 91 3 IX-2. IX-2 IX-3 -374- 00 CH 3 N. IX -4 H3C ICH 3 HN J--PH Nx {CH3 HN4P IX -6 N %H CH 3 N (H IX-7 IX- 8 HN J-d INCF3 IX- 9 CH 3 N A IX-12 IX -10 Ix-li CF 3 NH IX- 13 IX-14 -375- 00 ;Z~ HNQCN CF3 IX-16 OH 3 HN IJIP O F 3 H 3 C IX-19 OH 3 HN X N; CXF3 IX- 22 IX-17 OH 3 N A- HN IX -20 OH 3 N A- HN X ci -N OF 3 N HN d CI H 3 CN IX -26 IX -18 OH 3 N A- HN~ IX -21 OH 3 H 3 C N F 3 H 3 C N IX-24 H3C OH 3 H 3 C N C HCS N' IX- 27 IX-2S -37 6- 00 IND CA H 3 C C H I- 28 HN H3N 9NH ~OF IX -31 CH 3 NF IX-31 CH 3 IX-34 H 3 0 N kILK6 c IX- 29 CH 3 HN P LZN 00H 3 N 0 'OCH 3 IX -32 OH 3 HN OH 3 OH 3 HN ,--dH 91 NCF 3 IX-3 8 OH 3 HN -NH OH N~Y IX- 41 OH 3 N IX-3 0 OH 3 N CH 3 O N CC N IX- 33 CH 3 HNV IX- 39 OH 3 HN ;JVH ~CH 2 CH 3 N' IX -42 CH 3 HNP -377- 00 N HN j-d N F IX-43 HN IJP IX-46 HN2 N' IX -52 N? HN -r NCF 3 IX -44 HN P NCF 3 IX-47 HN H C N CF 3 H 3 C CH 3 H HN N? N OH N IX-48 CH 3 HN NH iNO IX- 51 CH 3 N O IX-54 -378- 00 OH 3 HN 3 dJH N S IX -55 CH 3 N QH3CF IX- 58 OH 3 N' IX-61 HNP Qj 4 NOF3 IX-64 OH 3 HN L-.d IX-67 CH 3 HN t-p NCF 3 IX -56 OH 3 HN NCF 3 H 3 C W IX-59 OH 3 HN 4 iI NCI Nk NO 2 IX-62 HN 0F 3 IX-65 OH 3 HN IX- 57 CH 3 N A- HN dP CH 3 N AH HN .NNp IX -63 OH 3 NH HN OCXF 3 113C IX -66 HN d4Hd 91,N CF 3 IX -69 IX-68 -37 9- 00 N? HN Jldq F I- F IX- 70 OH 3 'N'N F 3 C IX-73 IX- 71 HN'N IX-74 IX- 72 IX-7 6 OH 3 HN _)INN H 3 C N N- AcNH F IX -77 OH 3 N-N HN& IX- 8 CH 3 H 3 C 'N MeSO 2 NH cVl IX-78 IX -79 IX-a8 -380- 00 OHS HN)- QN CF3 IX- 82 OH 3 N OH 3 HN NCF 3 (NJ Me IX-83 OH 3 HN IX- 86 OH 3 HN -pH IX-84 OH 3 HN )4 91 N OF 3 IX-87 IX-B88 OH 3 Cbz. ix- 91 OH 3 NH H 3 ONH IX-8 9 CH 3 IX-92. OH 3 1 N OA Cbz'N N IX- 95 OH 3 HN OF 3 p N OH 3 IX-93 OH 3 HN .),tNH Ac N N~ IX-96 IX-94 -381- 00 .N? MeOASN"*J- IX- 97 OH 3 HN AN IX -100 OH 3 HN A' IX-98. IX-99 IX-101 IX-102 IX-103 OH 3 NH N IX- 106 HN IX-104 HN3 IX-107 HNJ!;'3 NN IX -105 H3C CH 3 IX-108 -382- 00 0 IND OH 3 HN ~N(N CF 3 IX-109 N? IX-112 CH 3 IX-115 OH 3 HN I NCF 3 IX -110 OH 3 IX-113 OH 3 N AH HN Mea Me IX-116 OH 3 IN IX-119. OH 3 HN' 1pH N IX-ill CHs IX-114 CH 3 HN ON Me Me IX -117 HOH 3 NOMe IX-120 -383- 00 CH9 HN"' 4I- N OMe IX-121 CH 3 ~NCc(())NH2- IX-124 CH 3 HN a>) 3 i-0 IX-122 CH 3 IX- 125 OH 3 HN 16- NfN H 3 C~ CH 3 IX-123 CH 3 HN 1--dH~ NN NH 2 IX-126 CH 3 SO 2 N(Me) 2 N CN IX-127 IX- 12 8 IX-129 CH 3 HN)1P IX -130 OH 3 N A HN ldl IX-131 HN kt 'N H IX-134 IX-132 OH 3 HNAN %NH EtNHO IX-135 IX-133 -384- CH 3 HN.Jdo NH H 3 C Z4 OOH 3 IX-136 OH 3 NH IX- 13 7 IX -138 IX -139 IX-140 IX-141 NP HN J,.W IX-3142 IX-143 IX-144 CH 3 N 4 NH IX-146 HNi N IX-147 *IX- 145 -38 o CH 2 -tNH HN ANo N H IX-148 OCH 3 p-i IX-149 ix- 15 0 0 -H 3 NN NH IX-1'52 IX -153 HN J/o IX- 154 IX-155 IX-156 N .,CO 2 CH 3 HNAo INH IX- 158, NO IX-159 IX-157 N? HN J--d IX-161 IX- 160 IX-162 3R8 N n- IX-163 IX-164 OH 3 HN ?14H ix -165 HNN n- IX -168 HN _d -NH 'N F 3 C IX-166 IX -167 CH 3 N HN 1,tNH (rN IN' HNN IX-170 CH 3 HN A-P 0 2 N %o %K IX-169 OH 3 NXA,71 HN N N'0H IX-171 IX-1372 IX-173 HNI1IIH aN' N F 3 C IX- 175 IX-176 IX-177. -38 7- 00 O 31. A composition comprising a compound according to any one of claims 1-30 and a pharmaceutically acceptable carrier.

32. The composition according to claim 31 further comprising a CI second therapeutic agent. M 33. A method of inhibiting GSK-3 or Aurora activity in a (N patient in need thereof, comprising the step of administering to C- said patient a therapeutically effective amount of a compound \O according to any one of claims 1 to 30 or the composition of C-I either claim 31 or claim 32.

34. The method according to claim 33, wherein said method inhibits GSK-3 activity in a patient. A method of inhibiting GSK-3 or Aurora activity in a biological sample comprising contacting said biological sample with a compound according to any one of claims 1 to 30 or the composition of either claim 31 or claim 32.

36. 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 a compound according to any one of claims 1 to 30 or the composition of either claim 31 or claim 32.

37. The method according to claim 36 further comprising the step of administering to said patient a second therapeutic agent.

38. The method according to claim 36, wherein said disease is diabetes. -388- 00 O 39. The method according to claim 36, wherein said disease is C Alzheimer's disease. The method according to claim 36, wherein said disease is CI schizophrenia.

41. A method of enhancing glycogen synthesis in a patient in need thereof, which method comprises the step of administering C-i to said patient a therapeutically effective amount of a compound \O according to any one of claims 1 to 30 or the composition of C- either claim 31 or claim 32.

42. A method of lowering blood levels of glucose in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 30 or the composition of either claim 31 or claim 32.

43. 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 a compound according to any one of claims 1 to 30 or the composition of either claim 31 or claim 32.

44. A method of inhibiting the phosphorylation of 9-catenin in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 30 or the composition of either claim 31 or claim 32. A method of treating a disease that is alleviated by treatment with an aurora inhibitor, which method comprises the step of administering to a patient in need of such a treatment a -389- 00 O therapeutically effective amount of a compound according to any C one of claims 1 to 30 or the composition of either claim 31 or claim 32. C 46. The method according to claim 45, further comprising the step of administering to said patient a second therapeutic M agent. C-i 47. The method according to claim 45 wherein said disease is \O cancer.

48. The composition according to claim 31, in combination with an anti-proliferative agent or a chemotherapeutic agent.

49. 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 to 30 or the composition of either claim 31 or claim 32. 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 to 30 or the composition of either claim 31 or claim 32.

51. 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 to 30 or the composition of either claim 31 or claim 32.

52. A method of treating cancer in a patient in need thereof, comprising the step of administering to said patient a -390- 00 O therapeutically effective amount of a compound according to any C one of claims 1 to 30 or the composition of either claim 31 or claim 32.

53. The method of claim 52, wherein said cancer is melanoma or is selected from colon, lung, stomach, or breast cancer. (cN

54. The method of claim 53, comprising the additional step of C-i administering to said patient an anti-proliferative agent or a NO chemotherapeutic agent, wherein said additional therapeutic C-i agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form. A compound of formula IX as defined in claim 1 and substantially as hereinbefore described with reference to one or more of the accompanying examples.

56. A composition comprising the compound according to claim and a pharmaceutically acceptable carrier.

57. A method of inhibiting GSK-3 or Aurora activity in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claim 55 or a composition according to claim 56. Date: 22 August 2008 -391-