ZA200301698B - Pyrazole compounds useful as protein kinase inhibitors. - Google Patents

Description

PYRAZOLE COMPOUNDS USEFUL AS PROTEIN KINASE INHIBITORS

CROSS REFERENCE TO RELATED APPLICATIONS

. This application claims priority to US

Provisional Patent Application 60/232,795 filed September 15, 2000, US Provisional Patent Application 60/257,887 filed December 21, 2000 and US Provisional Patent

Application 60/286,949 filed April 27, 2001, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention is in the field of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositions containing such compounds and methods of use. More particularly, this invention relates to compounds that are inhibitors of

GSK-3 and Aurora-2 protein kinases. The invention also relates to methods of treating diseases associated with these protein kinases, such as diabetes, cancer and

Alzheimer’s disease.

BACKGROUND OF THE INVENTION

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

Protein kinases mediate intracellular signal ’ transduction. They do this by effecting a phosphoryl extracellular and other stimuli cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet ) 5 radiation, bacterial endotoxin, H,0,), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor a (TNF- a)), and growth factors (e.g. granulocyte macrophage- colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF). An extracellular stimulus may effect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle.

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

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

Aurora-2 is a serine/threonine protein kinase that has been implicated in human cancer, such as colon, breast and other solid tumors. This kinase is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-2 may play a role in controlling the accurate segregation of . 30 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 J., 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of o and P ’ 5 isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and

Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)].

GSK-3 has been implicated in various diseases including diabetes, Alzheimer’s disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; and Hag 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 [B-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 - 30 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,

8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (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 : 5 is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood : levels of insulin. This leads to abnormally high blood levels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type II diabetes, GSK-3 is overexpressed [WO 00/38675].

Therapeutic inhibitors of GSK-3 are therefore potentially useful for treating diabetic patients suffering from an impaired response to insulin.

GSK-3 activity has also been associated with

Alzheimer’s disease. This disease is characterized by the well-known PB-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)]1. 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 diseases related to increase in neuronal cell death [Zhong et al., Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993); Pei et al., J.

Neuropathol. Exp, 56, 70-78 (1997)1. ‘ 5 As a result of the biological importance of

GSK-3, there is current interest in therapeutically ) effective GSK-3 inhbitors. Small molecules that inhibit

GSK-3 have recently been reported [WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)].

For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating the same diseases. However, the various protein kinases often act through different biological pathways. For example, certain quinazoline derivatives have been 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-o activity and/or enhanced TGF-fB 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 . 30 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 ’ 5. inhibitors of aurora-2 and GSK-3. These compounds have the general formula I: =

Rr?

HN TN

AN

3 A 6 ~1

I or a pharmaceutically acceptable derivative or prodrug thereof, wherein: : 7! to zZ* are as described below;

Ring A is selected from the group consisting of : x

Gn

RY ® i

RY NON RR RINT, pA a b c d

A A

NN oh NN

ANN PY NAN [

Rr , ANTON , R No? e £ g h

NT

> and R° ; . i : 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', any substitutable non- ortho carbon position on Ring C is independently substituted by -R®, 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®, and at any substitutable ring nitrogen by -R*, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R°® is hydrogen at each ortho carbon position of Ring Dj;

R! is selected from -halo, -CN, -NO,, T-V-R®, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C;.¢ aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo,

oxo, or -R%®, said C,¢ 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 RY are independently selected from T-R?®, or R* and

RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R* and RY is substituted by oxo or T-R?, and any substitutable nitrogen on said ring formed by R* and RY is substituted by R*;

T is a valence bond or a C;.4 alkylidene chain;

R? and R®> are independently selected from -R, -T-W-R®, or

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

R’ is selected from -R, -halo, -OR, -C(=0)R, -CO:R, -COCOR, -COCH,COR, -NO,, -CN, -S(O)R, -S(O)zR, -SR, -N(R*),, -CON(R"),, -SO.N(R”),, -OC(=0)R, -N(R’)COR, -N (R7) CO, (optionally substituted C;.¢ aliphatic), -N(R*)N(R*),, -C=NN(R*),, -C=N-OR, -N(R’)CON(R’), -N(R7) SON (R");, -N(R*)SO;R, or -OC(=0)N(R7),; each R is independently selected from hydrogen or an optionally substituted group selected from Ci. . aliphatic, Cs.10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R* is independently selected from -R7, -COR’, -CO02(Ci¢ aliphatic), -CON(R’),, or -SO;R’, or two R® on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; ’ 5 each R® is independently selected from -R, halo, -OR, -C(=0)R, -COyR, -COCOR, -NO,, -CN, -S(O)R, -SO;R, -SR, _N(R%),, -CON(R%),, -SO.N(R%)., -OC(=O)R, -N(R*)COR, -N (R*) CO, (optionally substituted C;.¢ aliphatic), -N(R*)N(R%),, -C=NN(R%),, -C=N-OR, -N(R®)CON(R*):, -N(R?) SO,N(R*) ,, -N(R*)SO,R, or -OC(=0)N(R*),, or R° and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;

V is -0-, -S-, -80-, -80,-, -N(R®)SO;-, -SO,N(R°)-, -N(R®)-, -CO-, -CO,-, -N(R®)CO-, -N(R®)C(O)O-, -N (R®) CON (R®) -, -N(R®)SO,N(R®)-, -N(R®°)N(R®)-, ~-C(0)N(R®)-, -OC(O)N(R®)-, -C(R®),0-, -C(R®).S-, -C(R®)280-, -C(R®)2802-, -C(R®)280:N(R®)-, -C(R®)N(R®)-, -C(R®),N(R®) C(O) -, -C(R®).N(R®)C(0)O-, -C(R®)=NN(R®)-, -C(R®)=N-0O-, -C(R®),N(R®)N(R®)-, -C(R®),N(R®)SO,N(R®)-, or -C(R®),N(R®) CON (R®) -;

W is —C(R®),0-, -C(R®),S-, -C(R®),S0-, -C(R®)2S0,-, -C(R®),80,N(R®) ~, -C(R®),N(R®)-, -CO-, -CO2-, -C(R®)0OC (0) -, -C(R®)OC(O)N(R®)~, -C(R®),N(R®)CO-, -C(R®),N(R®)C(0)0O-, -C(R®)=NN(R®)-, -C(R®)=N-O-, ~C(R®)N(R®)N(R®) -, -C(R®).N(R®) SON (R®)-, -C (R®) ,N(R®) CON (R®) -, or -CON(R®)-; each R® is independently selected from hydrogen or an optionally substituted C;.4 aliphatic group, or two R® groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; . each R’ is independently selected from hydrogen or an optionally substituted C;.¢ aliphatic group, or two R’ on the same nitrogen are taken together with the : Lo.

nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; each R® is independently selected from an optionally substituted C;.4 aliphatic group, -OR®, -SR®, -CORS®, -S0zR®, -N(R®),, -N(R®)N(R®),, -CN, -NO,, -CON(R®),, or -CO.R®; and

R® is selected from -R, halo, -OR, -C(=O)R, -CO;R, -COCOR, -NO,, -CN, -S(O)R, -SO;R, -SR, -N(R*),, -CON(R%):, -SO,N (R*),, -0OC(=0)R, -N(R*)COR, -N(R*)CO,(optionally substituted Ci.¢ aliphatic), -N(R*)N(R*),, -C=NN(R%),, -C=N-OR, -N(R*)CON(R*),, -N(R*)SO,N(R*)., -N(R*)SO,R, or -0C (=0)N(R*) 5.

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,-C,, 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”, oo 30 “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 straight and branched chains containing two to twelve carbon atoms. The term “cycloalkyl” used alone or as part of a larger moiety shall include cyclic C;-Ci, hydrocarbons which are completely saturated or which ‘ 5 contain one or more units of unsaturation, but which are not aromatic.

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

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

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

The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” as used herein means an aliphatic ring system having three to fourteen members.

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

The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as in a decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring. . The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to aromatic ring groups having five to fourteen members, such as phenyl, benzyl, phenethyl, 1l-naphthyl, 2-naphthyl, l-anthracyl and 2- anthracyl. The term “aryl” also refers to rings that are optionally substituted. The term “aryl” may be used interchangeably with the term “aryl ring”. “Aryl” also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include l-naphthyl, 2-naphthyl, 1l-anthracyl and 2- anthracyl. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used herein includes non-aromatic ring systems having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S. Examples of heterocyclic rings include 3-1H- benzimidazol-2-one, (1l-substituted)-2-oxo-benzimidazol-3- vl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4- tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl, [1,3] -dioxanyl, 2-tetrahydrothiophenyl, 3- tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4- morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4- thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, l-piperazinyl, 2-piperazinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1- phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, and benzothianyl. Also included within the scope of the term

“heterocyclyl” or “heterocyclic”, as it is used herein, is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl, or tetrahydrogquinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. The term “heterocycle”, “heterocyclyl”, or “heterocyclic” whether saturated or partially unsaturated, also refers to rings that are optionally substituted.

The term “heteroaryl”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromatic ring groups having five to fourteen members. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2- imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, l-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2- thiazolyl, 4-thiazolyl, S5-thiazolyl, 5-tetrazolyl, 2- triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, guinolinyl, benzotriazolyl, benzothiazolyl,

Dbenzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzoisoxazolyl. Also included within the scope of the term “heteroaryl”, as it is used herein, is a group in which a hetercatomic ring is fused to one or more aromatic or nonaromatic rings where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolinyl, : tetrahydroisoguinolinyl, and pyrido[3,4-dlpyrimidinyl.

The term “heteroaryl” also refers to rings that are optionally substituted. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heterocarylalkoxy and the like) group may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heterocaralkyl group include a halogen, -R°, -OR°, -SR°, 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, -0(Ph), substituted -O(Ph), -CH, (Ph), substituted -CH, (Ph), -CH,CH, (Ph), substituted -CH,CH, (Ph), -NO,, -CN, -N(R°),, -NR°C(O)R®°, -NRPC(O)N(R°),, -NR°CO,R?, -NR°NR°C(0O)R°, -NR°NR°C(O)N(R°),, -NR°NR°CO.R®, -C(0)C(O)R®°, -C(O)CH,C(O)R®, -COsR°, -C(O)R°, -C(O)N(R°)., -OC(O)N(R°)2, -S(O)3R°, -SOs,N(R®°),, -S(O)R°, -NR°SO;N(R°)., -NR°SO,R°, -C(=S)N(R®),, -C(=NH)-N(R®),, —(CH,)/,NHC(O)R®, - (CH;) NHC (O) CH(V-R°) (R°) ; wherein R° is hydrogen, a substituted or unsubstituted aliphatic group, an unsubgtituted heteroaryl ox heterocyclic ring, phenyl (Ph), substituted Ph, -0(Ph), substituted -0(Ph), -CH, (Ph), or substituted -CH,(Ph); y is 0-6; and V is a linker group. Examples of substituents on the aliphatic group or the phenyl ring of R° include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

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

Examples of suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring include those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: =0, =S, =NNHR", =NN(R"),, =N-, =NNHC(O)R", =NNHCO,(alkyl), =NNHSO, (alkyl), or =NR", where each R" is independently i 5 selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of substituents on the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

Suitable substituents on the nitrogen of a non- aromatic heterocyclic ring include -R*, -N(R"),, -C(O)R", -CO;R*, -C(O)C(O)R*, -C(O)CH,C(O)R*, -SO,R*, -SO,N(R"),, -C(=S)N(R%)2, -C(=NH)-N(R"),, and -NR'SO,R'; wherein R' is hydrogen, an aliphatic group, a substituted aliphatic group, phenyl (Ph), substituted Ph, -O(Ph), substituted -0O(Ph), CH,(Ph), substituted CH, (Ph), or an unsubstituted heteroaryl or heterocyclic ring.

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

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

Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as -NH-, -CH,-, -C(0)-, -C(O)NH-, or a chain of atoms, such as an alkylidene chain. The molecular mass of a linker is typically in the range of about 14 to 200, preferably in the range of 14 to 96 with a length cf up to about six atoms. Examples of linkers include a saturated or unsaturated C;.¢ alkylidene chain which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by ’ 5 -C(0)-, -C(0O)C(0O)-, -CONH-, -CONHNH-, -CO,-, -0C(O)-, ~-NHCO,;~, -0O-, -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -S-, -80-, -80,-, =-NH-, -SO,NH-, or -NHSO,-.

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

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

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., 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 *¥c- or 4c-enriched carbon are within the scope of this invention.

Compounds of formula I or salts thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutical composition. In one embodiment, the composition comprises an amount of the protein kinase inhibitor effective to inhibit a protein kinase, particularly GSK-3, in a biological sample or in a patient. In another embodiment, compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of the protein kinase inhibitor effective to treat or prevent a GSK-3-mediated condition and a pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient.

The term "GSK-3-mediated condition" or "disease", as used herein, means any disease or other deleterious condition or state in which GSK-3 is known to play a role. Such diseases or conditions include, without limitation, diabetes, Alzheimer’s disease,

Huntington's Disease, Parkinson's Disease, AIDS- associated dementia, amyotrophic lateral sclerosis (AML), : multiple sclerosis (MS), schizophrenia, cardiomycete : hypertrophy, reperfusion/ischemia, and baldness.

One aspect of this invention relates to a oo method of enhancing glycogen synthesis and/or lowering : 25 blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula

I or a pharmaceutical composition thereof. This method : is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer’s disease. Another method relates to inhibiting the phosphorylation of B-catenin, which is useful for treating schizophrenia.

Another aspect of the invention relates to inhibiting GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a

GSK-3 inhibitor of formula I.

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

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

I or a pharmaceutical composition thereof.

The term "CDK-2-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which CDK-2 is known to play a role. The term "CDK-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a CDK-2 inhibitor. Such conditions include, without limitation, cancer,

Alzheimer’s disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis. See Fischer, P.M. and Lane, D.P., Current Medicinal Chemistry, 7, 1213-1245 (2000) ; Mani, S., Wang, C., Wu, K., Francis, R. and

Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000);

Fry, D.W. and Garrett, M.D., 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 diseages 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 condition in which ERK is known to play a role. The term "ERK-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a ERK-2 inhibitor. Such conditions include, without } 5 limitation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly,

Alzheimer’s disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone-related diseases. The term “cancer” includes, but is not limited to the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders,

Hodgkin’s, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon- rectum, large intestine, rectum, brain and central nervous system, and leukemia. ERK-2 protein kinase and its implication in various diseases has been described [Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews et al., 1892, 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 90, . 10952; Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science 260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997,

Am. J. Respir. Cell Mol. Biol. 16, 589].

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

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

I or a pharmaceutical composition thereof.

The term “AKT-mediated condition”, as used herein, means any disease state or other deleterious condition in which AKT is known to play a role. The term "AKT-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a AKT inhibitor. AKT-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders. The association of AKT, also known as protein kinase B, with various diseases has been described [Khwaja, A., Nature, pp. 33-34, 1990; Zang, Q. Y., et al, Oncogene, 19 2000;

Kazuhiko, N., et al, The Journal of Neuroscience, 20 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 with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula

I or a pharmaceutical composition thereof.

The term “Src-mediated condition”, as used herein means any disease state or other deleterious condition in which Src is known to play a role. The term "Src-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a Src inhibitor. Such conditions include, without limitation, hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and

Paget's disease. Src protein kinase and its implication in various diseases has been described [Soriano, Cell, 69, 551 (1992); Soriano et al., cell, 64, 693 (1991);

Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli,

Drugs of the Future 2000, 25(7), 717, (2000); Talamonti,

J. Clin. Invest., 91, 53 (1993); Lutz, Biochem. Biophys.

Res. 243, 503 (1998); Rosen, J. Biol. Chem., 261, 13754 (1986) ; Bolen, Proc. Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki, Hepatology, 27, 1257 (1998); Biscardi,

Adv. Cancer Res., 76, 61 (1999); Lynch, Leukemia, 7, 1416 (1993); Wiener, Clin. Cancer Res., 5, 2164 (1999);

Staley, Cell Growth Diff., 8, 269 (1997)].

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 which does not destroy the pharmacological activity thereof.

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

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

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

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

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

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

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

These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s 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- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- oo acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable : dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and : other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

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

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

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

The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including } 30 diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily . prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation

(see above) or in a suitable enema formulation.

Topically-transdermal patches may also be used.

For vopical applications, the pharmaceutical compositions may be formulated in a suitable ointment ’ 5 containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or 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 60, 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,

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

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

A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or 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 (e.g., 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 (e.g., 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, —- 2 7 -

fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- ' 5 naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N' (Cj. alkyl), salts. This invention also envisions the qguaternization 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 the judgment of the treating physician and the severity of the particular disease being treated. The amount of the inhibitor will also depend upon the particular compound in the composition. ’ 5 Depending upon the particular protein kinase- mediated condition to be treated or prevented, additional ) therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, in the treatment of diabetes other anti-diabetic agents may be combined with the GSK-3 inhibitors of this invention to treat diabetes. These agents include, without limitation, insulin or insulin analogues, in injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonyl ureas.

Other examples of agents the inhibitors of this invention may also be combined with include, without limitation, chemotherapeutic agents or other anti- proliferative agents such as adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives; anti- inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti- convulsants, ion channel blockers, riluzole, and anti- : Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents

Claims (1)

1. We claim:

   1. A compound of formule III: SY: Rr? Te HN TN RY “NG IIT or a pharmaceutically acceptable salt, 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 hetercatoms selected from nitrogen, oxygen or sulfur, wherein Ring D 1s substituted at any substitutable ring carbon by oxo or -R%, and at any substitutable ring nitrogen by -R*, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R® is hydrogen at each ortho carbon position of Ring D; R* and R” are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered carbocyclo ring, wherein any substitutable carbon on said fused ring formed by R* and RY is substituted by oxo or T-R3; T is a valence bond or a C;-4 alkylidene chain; R? and R? are independently selected from -R, -T-W-R®, or R® and R? are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R? - 343 - CT AMENDED SHEET 004 05-25 and R*" is substituted by halo, oxo, -CN, -NO,, -R’, or -v-R®, and any substitutable nitrogen on said ring formed by R? and R®* is substituted by R*; R’> is selected from -R, -halo, =0, -OR, -C(=0)R, -COR, ) _COCOR, -COCH,COR, -NO,, -CN, -S(O)R, -S(0O).2R, -SR, -N(R*)2, -CON(R%),, -SO,N(R*),, -OC(=0)R, -N(R*)COR,

   ’ -N (R*%) CO, (optionally substituted Ci_¢ aliphatic), -N(R*)N(R*)2, -C=NN(R%),, -C=N-OR, -N(R*)CON(R%),, -N(R*) SON (R*),, -N(R*)SO;R, or -0C(=0)N(R*),;

   each R is independently selected from hydrogen or an optionally substituted group selected from C;.s aliphatic, Cs.190 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’, -COR’, -CO, (optionally substituted C;.¢ aliphatic), -CON(R’)., or -SO;R7, or two R? on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring;

   each R® is independently selected from -R, halo, -OR, -C(=0)R, -CO3R, ~COCOR, -NO;, -CN, -S{(0O)R, -80:R, -SR, -N(R*),, -CON(R*),, -SO,N(R%),, -OC(=0)R, -N(R*)COR, -N(R*) CO, (optionally substituted C;.¢ aliphatic), -N(R*)N(R*),, -C=NN(R*),, -C=N-OR, -N(R*)CON(R*),, -N(R*) SO,N (R*),, -N(R*)SO,R, or -0C(=0)N(R*).;

   V is -0-, -8-, -S0-, -S0,-, -N(R®)S0,-, -SO.,N(R®)-, -N(R®)-, -CO-, -CO,-, -N(R®)CO-, -N(R®)C(O)O-, -N(R®) CON (R®) ~, -N(R®)SO,N(R®)-, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, -C(R®),0-, -C(R®),S-, -C(R®)280-, -C(R®)280,-, -C(R®)2S0:N(R®)-, -C(R®).N(R®)-, ~C(R®).N (R®) C(O) -, -C(R®),N(R®)C(0)0-, -C(R®)=NN(R®)-,

   -C(R®) =N-0-, -C(R®),N(R®)N(R®)-, -C(R®).N(R®)SO,N(R®)-, or -C(R®) ;N (R®) CON (R®) -;

   W is -C(R®),0-, -C(R®),8-, -C(R®),80-, -C(R®),S0,-, -C(R®) 2SO0;N (R®) -, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)0OC(0)-, —-C(R®)OC(O)N(R®)-, -C(R®),N(R®)CO-, -C(R®),N(R®)C(0)0-, -C(R®)=NN(R®)-, -C(R®)=N-O-, ~C(R®) N(R) N(R®) -, -C(R®)2N(R®)SO.N (R®) -, -C(R®) 2N (R®) CON (R®) -, or -CON(R®)-; each R® is independently selected from hydrogen or an optionally substituted C;., 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;.¢ 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.

   2. The compound according to claim 1, wherein said compound has one or more features selected from the group consisting of: (a) Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; (b) R* and RY are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring; and (c) R* is hydrogen or methyl and R? is T-W-R® or R, wherein W is -C(R®).0-, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)0C(0) -, -C(R®).N(R®)CO-, -C(R®),N(R®)C(0)O-, or -CON(R®°) -, and R is an optionally substituted group selected from C;.¢ aliphatic or phenyl, or R? and R? are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring.

   3. The compound according to claim 2, wherein: ‘ (a) Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; (b) R* and RY are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring; and (c) R* is hydrogen or methyl and R? is T-W-R® or R, wherein W is -C(R®),0-, -C(R®),N(R®)-, -CO-, -CO,-, ~-C(R®)0C(0) -, -C(R®),N(R®°)CO-, -C(R®),N(R®)C(0)O-, or -CON(R®)-, and R is an optionally substituted group selected from C;.; aliphatic or phenyl, or R? and R?* are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring.

   4. The compound according to claim 2, wherein said compound has one or more features selected from the group consisting of: (a) 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;

   (b) R* and RY are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated carbocyclic ring optionally substituted with -R, oxo, halo, -OR, -C(=0)R, -CO;R, -COCOR, -NO;, -CN, -S(O)R, -SO,;R, -SR, -N(R%),, -=CON(R*).,

   -SO.N (R*),, -OC(=0)R, -N(R*)COR, -N(R*)CO, (optionally substituted C;.¢ aliphatic), -N(R*)N(R%),, -C=NN(R%),, -C=N-OR, -N(R*)CON(R%),, -N(R*)SO,N(R%),, -N(R*)SO;R, or -0C(=0)N(R*),; and (c) each R® is independently selected from halo, oxo, CN, NO,, -N(R*),, -CO;R, -CONH(R®), -N(R*)COR, -SO,N(R*)g, -N(R*)SO,R, -SR, -OR, -C(O)R, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Ce¢.10 aryl, or C;.¢ aliphatic.

   5. The compound according to claim 4, wherein: (2) Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4- tetrahydroisoguinolinyl, 1,2, 3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; (b) R* and RY are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated carbocyclic ring optionally substituted with -R, oxo, halo, -OR, -C(=0)R, -CO3R, -COCOR, -NO,, -CN, -S(0O)R, -SO;R, -SR, N(R) 5, -CON (R?) 2, -SO,N (R*),, -0OC(=0)R, -N(R*)COR, -N(R*)CO, (optionally substituted C;_¢ aliphatic), -N(R*)N(R*),, -C=NN(R?).,, -C=N-OR, -N(R")CON(R*),, -N(R*)S0.N(R*),, -N(R*)SO,R, or -0C(=0)N(R%),; and (c) each R® is independently selected from halo, oxo, CN, NO,, -N(R%),, -CO,R, -CONH(R%), -N(R*)COR, -SO,N(R*)., -N(R*) SOR, -SR, -OR, -C(O)R, or a substituted or

   WO (2722644 PCT/US01/28792 unsunsiituted group selected Irom I-& membered : neterocvelyl, Ceo 2¥yl, 0x C..¢ gliphatic.

   &€. Tne compound &CCOYCLInNg IC Cleim £4, whsrzin said compound has one or more features sslecisd from the group consisting of: (ea) R” and RY are taken tocether with their intervening atoms to form a £-mempsred unszturaied ov partially unsaturated carbocyclic ring copticnelly substituted with halo, CN, oxo, Ci.¢ alkyl, C..¢ alkoxy, + (Cig &lkyl)carbonyl, (C..q 2lkyl)suifonyli, mono- or diazlkylamino, mono- or dialkylaminocarbonyl, monc- or Gialkylaminocarbonyloxy, or 5-6 membered heteroaryl; (b) each R® is independently selected from -halo, -CN, -oxo0, -SR, -OR, -N(R®)., -C(O)R, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cg.ip aryl, or Ci.¢ aliphatic; and (c) RY is hvdrogen and R?* is T-¥W-R® or R, wherein W is -C(R®),0-, -C(R®):N(R®)-, -CO-, -CO,-, -C(R®)OC(O)-, -C(R®).N(R®)CO-, or -CON(R®)-, anda R is an optionally substituted group selected from Ci,.¢ aliphatic or phenyl, or R? and R® are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, or partially unsaturated é-membered carbocyclic ring optionally substituted with -halo, -N{(R%),, -Ci.¢ alkyl, -Ci.e haloalkyl, -NO;, -0(Ci.; alkyl), -CO,(Ci_s alkyl), -CN, -80,(Cy., e2lkyl), -SO0.NH,, -0C(C)NH,, -WNH,50,(Ca-q alkyl), -NHC(O) (Ci; alkyl), -C(Q)NH,, or -CO(C.. : ¢ 2lkyl), wherein the (C;., alkyl) is a straight, branched, . or cyclic alkvl group.

   7. The compound according to claim 6, wherein: T348- AMENDED SHEET - 2004 -05- 25

   (a) R* and RY are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated carbocyclic ring optionally substituted with halo, CN, oxo, Cig alkyl, C,.g alkoxy, (Ci-s alkyl) carbonyl, (Ci-6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5- 6 membered heteroaryl; (b) each R’ is independently selected from -halo, -CN, -oxo, =-SR, -OR, -N(R%),, -C(O)R, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, ~ Cg-10 aryl, or Cig aliphatic; and (c) R? is hydrogen and R? is T-W-R® or R, wherein W is ~C(R®)20-, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)OC(0)-, -C(R®),N(R®)CO-, or -CON(R®)-, and R is an optionally substituted group selected from C,.¢ aliphatic or phenyl, or R® and R® are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, or partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -N(R®),, -Ci4 alkyl, -Ci., haloalkyl, - NOz, =O (Cig alkyl), -CO,(Cy.q alkyl), =-CN, -S50;(Cis alkyl), —-SO;NHz, -OC(O)NHz, -NH3SO02(Ci-4 alkyl), =-NHC(O) (Ci.q alkyl), -C(O)NHz, or -CO(Ci.4 alkyl), wherein the (Ci-a alkyl) is a straight, branched, or cyclic alkyl group.

   8. The compound according to claim 1, wherein said compound is selected from the following Table 2 compounds: & = CH, HNN HNN pe ~N SN ~N Cl Cl I17-1 ITI-2 ITI-3 - 349 - AMENDED SHEET ~~ 2004 -05- 23

   CHs & CH: Jo H < NH Ie H HN SN HSN HS “ON SN SN -, A Ao Fig wilig he al “Fel TII-4 111-5 111-6 CHs CHj CH, jal Zp hw HN % HN Nh HN Na ae ae ae _N 111-7 ITI-8 III-9 CHa = CHs nn g Sw HSN HN Na ans HC “OO OL EtNH “CL © cl cl 111-10 TI1-11 TII-12 CH3 CHa, CHs jo J® H fa HN Na HN Na HN No NG YN, eta . © 3 OCHs 111-13 IITI-14 ITI~-15 TOT AMENDED SHEET 2004 -05- 25

   CHj CHj CHy HN Na HN HN Ne ey: . 0 CUR Sn CHEE Sep Oo J CHg 117-16 T1I1T-17 ITT1I-18 CH, CH; CH3 HN Na HN a HN Na jo®: jon jee: NC N’ © CH30 “0 CH30 “OL CHjy Cl CHs ITI-19 111-20 111-21 CHj CH CH3 Chm Ch Jol ’ HN a HN o HN a CH3NH N° CH3SO, NE NN (®) ~ CH; 111-22 111-23 111-24 CHj CHj CH r I In HN vl HN a HN Na ) ol ary EG RORERGRES CHa NcH, | Hye N Hac } 0 III-25 ITI-26 ITII-27 - 351 - AMENDED SHEET 2004 -05- 25

   CHs CH3 CH; In IN In HN Na HN a HN NY ac, ane QH Cl N’ oS N° NE _N _N 111-28 111-26 111-30 CH CHj CH; xr In HN Na HN HN Ne he he! “CG Cl I1I1-31 I1I-32 III-33 CHa CHa CH3 In Is I HNN an HNN OLX Sed SEN “OL OL N’ cl Br Cl Cl III1-34 III-35 III1-36 CHj CH; CH, I I I HNN HN nV HN NY GI G0 a -

   N” . N° ! N° : CN SEt 111-37 III-38 111-39 - 352 - AMENDED SHEET 2004 -05- 25 ve - o [ I B NEN HN a HN Ne SSUES ar ! 48 ) NF SPN cH, SF 0 CHs 111-40 ITI1-41 111-42 CH, CHs CHs rt I I HN Na HN NN HN Nb Ais Ty Cy N” Q N~ N” OMe

   0 . NMe, I1I-43 111-44 III-45 CH o oh - en In HN nN H HN NY : QL Sh d NIN - Liters TC “0 Cl ® CH 11I-4¢6 III1-47 111-48 CHs CH3 CHa I In In HN NY HN Na HN No SVL SYA SV : ZCH : CH 2 F F 111-49 ITII-50 III-51 - 353 - AMENDED SHEET ~~ 2004 -05- 25

   CHs CHa CHs xr I» rl HN NY HN a HN a F JI11I-52 II1I-53 ITII-54 CHa CH3 CHs I 5 J HN v HN nN HN NY i: AF, OG COIS: NOY es NOY NY ers > III-55 III-56 ITI-57 CHa | CHa CHy I I I HN NY HN NY HN Na LL Sed LL CF4 111-58 I1I-59 I11-¢0 oN I ®N HNN HN ol wl ac” g@ SY OOD NY N° S ITTI-61 ITII-62 ITII-63 - 354 - AMENDED SHEET 2004 -05- 25

   CH, CH,CH; Py 2 \ oN 5 N anon HN HN NY ac” SW: ac” SN < “ - N ES NNN N XX he O © ITI-64 111-65 ITTI-66 HaC Hac Hs Hac CHa Pes Re re \ i AY | \ HN NY HN v HN No ary SHY ara’ N° N° N* ~N 111-67 III-68 ITII-69 oO pe - 3 5 I HN Na HN Na HN ar ary Soy 0 O “O ITI1I-70 III1I-71 111-72 CO,CH4 CH,0H CH,OCH; In IN In HN NY HN Na HN No Sod LL LL ie “© ae 111-73 111-74 111-75 ~ 355 - AMENDED SHEET 2004 -05- 25

   WQ 02/22604 PCT/US01/28792 7 OCHs OCH,Ph HN No HN a HN NY sod ced sod SONY NS NN 111-76 111-77 111-78 H4C NH, NHBoc 0° »CHs Pd rd on jo I I HN Ne HN Ne HN Na ay ay acy” ie ae ae III-79 III-80 111-81 CH, OCH; o r~ o rr fo ~~) Pt Po HN Ne HN Na HN No ry ay SP N° N* N° 111-82 III-83 TII-84

   0 J. o_ rCHs 0 ~) } NH N N 2 2 —CHj = CH, HN Ne HN Na HN Na SOU od Sod YO O 0 111-85 III-86 III-87 - 356 - 004 -05- 25 AMENDED SHEET ?

   CHs CHj o o o Pp NH N NH oh Te \ | AY | \

   HNN HNN HN <e oe oF: SONY SNA 5 SUNS & |& 111-88 III-89 TT1-90 Be 0 0 NH CHs N 2 NJ, LT "/CH,OCH; LN LN CHy [HN

   HN HNN HN ac rs oc

   ITI-21 III-92 III-93

   CH3 Ore O 0] 0) 0 SLHs oo oo oo f° 1 IR

   HNN HNN HNN ary” ary” ary “0 O 0 II1I-94 III-95 III-S6 ~ O VAR 0 Ia 0] 0 NCH IR a 3 a2 / N | \ | 3

   ANN HNN HNN QC QC QC

   C ae he

   111-97 III-98 111-99

   - 357 - AMENDED SHEET 2004 -05- 25

   WQ 02/22604 PCT/US01/28792 © NH CH Is 2 Br Br 3 po [A NB HN a Ao HNN ar ary a 9 = ~ ~ NYY NY NY ~~ NF NZ III-100 ITI1I-101 111-102 NC CHj CHa N I I NE HNN HNN QC LE, a NE NNT NNN LO CNH II11-103 III-104 IIT1-105 NC CHj CHs r r I» po HN oh HN NY QL QL OL, NY, NNT vy CH, “Neen, III-106 111-107 ITII-108 CHa CH “ In In 5 HN nN HN v HN a QL, <u: So) OH CH 1711-109 ITII-110 ITII-111 - 358 - AMENDED SH 2004 -05- 25

   WO (02/22604 PCT/US01/28792 CH, CH; CH; xr I I HN NY HN Na HN va A - Pp LD NN OH (OX / . IITI-112 I11-113 III-114 HN No HN NN . HN Na 0 QC, LL, TOO Ty “0 OH III-115 II1-116 ITII-117 HN NG HN NS HN NN QL, OC, OG, OD ey NN OH 111-118 ITII-119 II1-120 0 “ CO,CH; Pas 7 r B HN a HN Na HN NY aed CN, Qed 0) 0) 111-121 } 111-122 III-123 - 358 - AMENDED SHEET ~~ 29p4 -g5- 25

   Pee CONH, CONH, N I r HNN HN NY HN N QC, a, 0, vO ie 0! CH; I1171-124 I11-125 III-126 F FiC YF D) YF °° I ° I HN NY HNN HNN Se QL TL he “0 ie 111-127 ITI-128 ITI-129 F F } 0 I ° HN WY HN NY HN NY QL LL OL ie “0 oe ITI-130 III-131 III-132 SOW QW TN MeO N N N No | N.

   J } - H H HN nV NSN nS aL QE.

   Qo @ he “0 “0 III-133 ITI-134 ITII-135 - 360 ~ AMENDED SHEET 2004 -05- 25

   MeO aL OLR QL N NON FsC N N, / Cl N. J N. ~ NH ~ NH HN WN HN Nak HN NN

   Le. A oN. . 1 | ‘ | i ha MARS MLAS III1-136 111-137 ITI-138 PhO Ci . SW a2 N N . NJ NL { ~ NH ~ NH ~ NH HN n° HN a HN n° GH QP LN “OO “OO NNN = III-139 IIT-140 III-141 ) * ) HN a HN a HN a NENA NSN NN

   =, . III-142 ITI-143 111-144 { HNN ; NH ary” HNN Eve Oy TTD Me Me III-145 I11I-146

   9. A composition comprising a compound according to any of claims 1-8 and a pharmaceutically acceptable carrier. - 361 - AMENDED SHEET ~~ 2004 05-25

   10. The composition according to claim 9, further comprising a second therapeutic agent.

   11. Use of a composition according to claim 9 for inhibiting GSK-3, Aurcra, or Src activity in a patient.

   12. The use according to claim 11 for inhibiting GSX-3 activity in a patient.

   13. Use of a compound according to claim 1 for inhibiting GSK-3, Aurora, or Src activity in a biological sample.

   14. Use of a composition according to claim 8 for treating a disease that is alleviated by treatment with an GSK-3 inhibitor.

   15. The use according to claim 14 in combination with a second therapeutic agent.

   16. The use according to claim 14, wherein said disease is diabetes.

   17. The use according to claim 14, wherein said disease is Alzheimer’s disease.

   18. The use according to claim 14, wherein said disease is schizophrenia.

   18. Use of a composition according to claim 9 for enhancing glycogen synthesis in a patient in need thereof.

   20. Use of a composition according to claim $8 for lowering blood levels of glucose in a patient in need thereof.

   21. Use of a composition according to claim ¢ for inhibiting the production ¢f hyperphosphoryviated Tau protein in a patient in need thereof.

   22. Use of a composition according to claim 9 for inhibiting the phosphorylation of P-catenin in a patient in need thereof.

   23. Use of a composition according to claim 9 for treating a disease that is alleviated by treatment with an aurora inhibitor.

   24. The use according to claim 23 in combination with second therapeutic agent.

   25. The use according to claim 23, wherein said disease is cancer.

   26. Use of a composition according to claim 9 for treating a disease that is alleviated by treatment with a Src inhibitor.

   27. The use according to claim 26 in combination with a second therapeutic agent.

   28. The use according to claim 26, wherein said disease is selected from hypercalcemia, osteoporcsis, osteoarthritis, or symptomatic treatment of bone metastasis.

   2%. The use according to claim 26, wherein said disease is cancer.

   30. Use of a compound according to claim . for inhibiting ERK activity in a patlent wherein in the compound R?’ is hydrogen and R* and RY are taken together with their intervening atoms to form a benzo ring.

   31. Use of a compound according to claim 1 for inhibiting ERK activity in a bioclogical sample wherein in the compound R? is hydrogen and R* and RY are taken together with their intervening atoms to form a benzo ring.

   32. Use of a compound according to claim 1 for treating a disease that 1s alleviated by treatment with an ERK inhibitor wherein in the compound R° is hydrogen and R* and RY are taken together with their intervening atoms to form a benzo ring.

   33. The use according to claim 32, further comprising the step cof administering to said patient a second therapeutic agent.

   34. The use according to claim 32, wherein said disease is selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer’s disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic discrders, inflammation, and neurological disorders. nr - 364 - y - AMENDED SHEET ~~ cout 05° 2°

   35. The use according to claim 34, wherein said disease is cancer.

   36. The use according to claim 34, wherein said disease is restenosis.

   37. Use of a composition according to claim 9 for the treatment of diabetes.

   38. Use of a composition according to claim 9 for the treatment of Alzheimer’s disease.

   39. Use of a composition according to claim 9 for the treatment of schizophrenia. :

   40. Use of a composition according to claim 9 for the treatment of cancer.

   41. Use of a composition according to claim 9 for the treatment of hypercalcemia, osteoporosis, ostecarthritis, or symptomatic treatment of bone metastasis.

   42. Use of a composition according to claim 9 for the treatment of cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer’s disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, and neurological disorders.