ZA200304473B - Pyrazole compounds useful as protein kinase inhibitors. - Google Patents

Description

PYRAZOLE COMPOUNDS USEFUL AS PROTEIN KINASE INHIBITORS i CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to 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

Aurora-2 protein kinase. The invention also relates to methods of treating diseases associated with protein kinases, especially diseases associated with Aurora-2, such as cancer. :

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study is . the protein kinases. : Protein kinases mediate intracellular signal . transduction. They do this by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which 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., 199s, 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 B 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 CEPBo.. 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 ' 30 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, 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 (19%4)].

However, in a diabetic patient where the insulin response 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 therefore are considered to be 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 B-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 B-catenin which is degradated after phosphorylation by GSK-3. Reduced ’ levels of B-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)].

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)]. oo 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- activity and/or enhanced TGF-PB activity. While p38 activity has been implicated in a wide variety of : diseases, including diabetes, p38 kinase is not reported oo 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 roles in cancer and diabetes, respectively. . | 5

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. These compounds have the general formula I: ~

RZ :

Tow

HN” N

BO

NN

I : or a pharmaceutically acceptable derivative or prodrug thereof, wherein: oC Z' is nitrogen or C-R® and 2? is nitrogen or CH, wherein at least one of Z* and z*® is nitrogen;

R* and RY are independently selected from T-R? or L-Z-R?, or R* and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring ' 20 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ] ring formed by R* and RY is independently substituted by oxo, T-R’, or L-Z-R?®, and each substitutable ring nitrogen of said ring formed by R* and RY is independently substituted by R?;

Q is selected from -N(R*)-, -0-, -S-, -C(R%),-, 1,2- cyclopropanediyl, 1,2-cyclobutanediyl, or 1,3- ’ . 5 cyclobutanediyl;

R! is T- (Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carboecyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R®, -or V-Z-R®, and each substitutable ring nitrogen of Ring D is independently substituted by -R%;

T is a valence bond or a C;.4 alkylidene chain, wherein when Q is -C(R®');-, a methylene unit of said Ci. alkylidene chain is optionally replaced by -0-, -S-, -N(R*)-, -CO-, -CONH-, -NHCO-, -SO,-, -8SO,NH-, -NHSO,-, ~~ -C0;-, -0C(0)-, -OC(O)NH-, or -NHCO,-; :

Z is a Cy.4 alkylidene chain;

L is -0-, -S-, -S0-, -S0;-, -N(R®)SO;-, -SO.N(R®)-, -N(R®)-, -CO-, -CO;-, -N(R)CO-, -N(R®)C(0)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®)2802-, -C(R®)2S0.N(R®)-, -C(R®)N(R®)-, -C(R®),N(R®)C(0) -, -C(R®),N(R®)C(0)O-, -C(R®)=NN(R®)-, -C(R®) =N-0-, -C(R®)N(R®)N(R®)-, -C(R®).N(R®)SO:N(R®)-, or -C (R®) 2N (R®) CON (R®) -; x 30 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 ring carbon of said fused ring formed by

R? and R? is independently substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and each substitutable ring nitrogen of said ring formed by R? and R* is independently substituted by R*; . R® is selected from -R, -halo, -OR, -C(=O)R, -CO:R, -COCOR, ~COCH,COR, -NO,, -CN, -S(O)R, -S(0)2R, -SR, } -N(R*),, =-CON(R"),, -SO,N(R’),, -OC(=0)R, -N(R’)COR, © -N(R7)COz(C:i.s aliphatic), -N(R*)N(R*),, -C=NN(R%),, -C=N-OR, -N(R’)CON(R’)2, -N(R7) SON (R")2, -N(R®)SO;R, or -OC (=0) N(R"); each R is independently selected from hydrogen or an optionally substituted group selected from Cig aliphatic, Cs-10 aryl, a heteroaryl ring having 5-10 : ring atoms, or a heterocyclyl ring having 5-10 ring atoms; : each R* is independently selected from -R’, -COR’, -CO, (optionally substituted C;.¢ aliphatic), -CON(R’)., or -SO.R’; each R® is independently selected from -R, halo, -OR, -C(=0)R, -CO;R, -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*) SON (R%)2, -N(R*)SO;R, or -OC(=0)N(R?),;

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(O)N(R®)-, -OC(O)N(R®)-, -C(R®),0-, -C(R®),.S-, -C(R®),80-, -C(R®)2802-, -C(R®),S0,N(R®)-, -C(R®).N(R®)-, © -C(RYN(R)C(0)~, -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®) 2N (R®) CON (R®) -;

W is ~C(R%),0-, -C(R®),S-, -C(R®),80-, -C(R®),50,-, -C(R®),S0,N(R®) -, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)0C(0) =, -C(R®)OC(0)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®),N(R®)SO,N(R®)-, : ~ -C(R®) N(R?) CON (R®) ~, or -CON(R®)-; each R® is independently selected from hydrogen or an + optionally substituted C;., aliphatic group, or two RE : groups on the same nitrogen atom may be taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R® is independently selected from hydrogen or a Cis aliphatic group, or two R® on the same carbon atom are taken together to form a 3-6 membered carbocyclic ring; oo each R’ is independently selected from hydrogen or an optionally substituted Ci-¢ aliphatic group, or two R’ on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and

R® is selected from -R, halo, -OR, -C(=0)R, -CO,R, -COCOR, -NO;, -CN, -S(O)R, -SO,R, -SR, -N(R%);, -CON(R%)a, -S0,N (R*),, -0C(=0)R, -N(R*)COR, -N(R*)CO.(optionally substituted Cp. 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*),. © As used herein, the following definitions shall : apply unless otherwise indicated. The phrase “optionally oo 30 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

) ~-10- 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;-Ci» 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 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;-Cis. hydrocarbons which are completely saturated or which "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. . | 30 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”, : 5 “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, 1-naphthyl, 2-naphthyl, 1-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 1l-naphthyl, 2-naphthyl, l-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 . 30 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- ‘ 5 benzimidazol-2-one, (l-substituted)-2-oxo-benzimidazol-3- yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- Co tetrahydropyranyl, 3-tetrahydropyranyl, a- 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 tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic heterocatom-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, 3-furazanyl, N-

imidazolyl, 2-imidazolyl, 4-imidazolyl, S5-imidazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5- : oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1- pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, l-pyrazolyl, 2- ’ 5 pyrazolyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, S-pyrimidyl, 3-pyridazinyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2- triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indazolyl, 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 tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyridol[3,4-d]lpyrimidinyl.

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

Co the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group include a halogen, -R°, -OR°, -SR°, 1,2-methylene-dioxy, 1, 2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, -O(Ph), substituted -O(Ph), -CH, (Ph), substituted -CH,(Ph), -CH,CH,(Ph), substituted -CH,CH, (Ph), -NO;, -CN, -N(R°),, -NR°C(O)R°, -NR°C(O)N(R°),,

-NR°CO,R°, -NR°NR°C(0)R°, -NR°NR°C(O)N(R°),, -NR°NR°CO,R®, -C(0)C(0)R®°, -C(O)CH,C(O)R®, -CO:R°, -C(O)R°, -C(O)N(R°),, ~0C(0)N(R%) 2, -S(O);R°, -SO,N(R%) 2, -S(O)R°, -NR°SO;N(R°),,

X -NR°SO,R°, -C(=8)N(R°),, ~C(=NH)-N(R®),, -(CH.),NHC(O)R®, - (CH,) yNHC (O) CH(V-R®) (R°) ; wherein each R° is independently . selected from hydrogen, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or : heterocyclic ring, phenyl (Ph), substituted Ph, -O(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, =8, =NNHR', =NN(R%);, =N-, =NNHC(O)R®, =NNHCO, (alkyl), =NNHSO, (alkyl), or =NR", where each R* is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of substituents on the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, 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(0)C(O)R*, -C(O)CH,C(O)R*, -SO;R*, -SO,N(R')a, -C(=S8S)N(R"),, -C(=NH)-N(R*),, and -NR'SO,R*; wherein each R' ) 5 is independently selected from hydrogen, an aliphatic group, a substituted aliphatic group, phenyl (Ph), substituted Ph, -0(Ph), substituted -0(Ph), CH,(pPh), 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-, -CHp-, -C(0)-, -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 a length of 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 -C(0)-, -C(0)C(0)-, -CONH-, -CONHNH-, -CO,-, -0C(O)-, -NHCO,-, -O-, -NHCONH-, -OC(Q)NH-, -NHNH-, -NHCO-, -S-, -S0-, -80;-, -NH-, -SO,NH-, or -NHSO,-. . 30 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. no A combination of substituents or variables is permissible only if such a combination results in a ’ 5 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 8 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 : oo 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 3C- or “C-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 i embodiment, the composition comprises an amount of the protein kinase inhibitor effective to inhibit a protein . 30 kinase, particularly Aurora-2, in a biological sample or in a patient. Compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of the protein Kinase inhibitor effective to treat

Claims (28)

We claim:

1. A compound of formula IV: R2 R? — To HNN X — RY“ Pag Iv or a pharmaceutically acceptable salt, derivative or prodrug . thereof, wherein: z! is nitrogen or C-R® and 2? is nitrogen or CH, wherein one of 2! or 7? is nitrogen; Q is selected from -N(R*)-, -0-, -S-, -C(R%®),-, 1,2- cyclopropanediyl, 1,2-cyclobutanediyl, or 1,3-cyclobutanediyl; R* and RY are independently selected from T-R?® or L-Z-R3, or R*¥ and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R* and RY is independently substituted by oxo, T-R?®, or L-2z-R%® and each substitutable ring nitrogen of said ring formed by R* and RY is independently substituted by RY; R! is T- (Ring D); Ring D is a 5-7 membered mconocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, Amended Sheet — 2004-08-24 heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently ’ substituted by oxo, T-R?, or V-%-R°, and each substitutable ring nitrogen of Ring D is independently substituted by -R*; T is a valence bond or a Cj;.4 alkylidene chain, wherein when Q is -CH(R®)-, a methylene unit of said C;.4 alkylidene chain is optionally replaced by -0-, -S-, -N(R*)-, -CO-, -CONH-, -NHCO-, -SO,-, -SO,NH-, -NHSO,-, -CO3-, -0C(0)-, -OC{O)NH-, or -NHCO,-; Z is a Ci.4 alkylidene chain; L is -0-, -S-, -SO-, -8S0;-, -N(R®)SO,-, -SO0,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®)2802-, -C(R®),SO0.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-0-, -C(R®),N(R®)N(R®)~-, -C(R®),N(R®°)SO,N(R®)-, or -C(R®) N(R?) CON (R®) ~; 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 ring carbon of said fused ring formed by R? and R®* is independently substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and each substitutable ring nitrogen of said ring formed by R?® and R* is independently substituted by R%; R?® is selected from -R, -halo, -OR, -C(=0)R, -COzR, -COCOR, -COCH,COR, -NO,, -CN, -S(O)R, -S(O):2R, -SR,

-N(R*),, -CON(R"),, -SO,N(R’),, -0C(=0)R, -N(R’)COR, -N(R7) CO, (C16 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"),; each R is independently selected from hydrogen or an optionally substituted group selected from Cj. aliphatic, Cs-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R* is independently selected from -R’, -COR’, -CO, (optionally substituted C;.¢ aliphatic), -CON(R’)., or -SO.R’; each R®> is independently selected from -R, halo, -OR, ~C(=0)R, -CO,R, -COCOR, -NO,, -CN, -S(O)R, -SO,R, -SR, -N(R*),, -CON(R%),, -SO,N(R*),, -0C(=0)R, -N(R*)COR, ~N (R*) CO, (optionally substituted Cj_¢ aliphatic), -N(R*)N(R%),, -C=NN(R*),, -C=N-OR, -N(R*)CON(R%),, -N(R*) SO,N (R*) 2, -N(R*)SO,R, or -OC(=0)N(R*),; V is -0-, -8-, -SO-, -80,-, -N(R®)S0,-, -SO0.N(R®)-, -N(R®)-, -CO-, -CO,-, -N(R®)CO-, -N(R®)C(O)O-, -N(R®) CON (R®) -, -N(R®)S0.N(R®)-, -N(R®)N(R®)-, -C(O)N(R®) -, -OC(O)N(R®)-, -C(R®),0-, -C(R®).S-, -C(R®),80-, -C(R®),80;-, -C(R®),S0,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-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®),S0-, -C(R®).S0,-, } -C(R%),80,N(R®) -, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)0C (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®)SO,N(R®)-, -C(R®) ,N (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; each R® is independently selected from hydrogen or a Cis aliphatic group, or two R® on the same carbon atom are taken together to form a 3-6 membered carbocyclic 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 nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and R® is selected from -R, hale, -OR, -C{=0)R, -CO,R, -COCOR, -NO,, -CN, -S(O)R, -SOsR, -SR, -N(R*),, -CON(R%)., -SO,N(R*) 2, -OC(=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?) ,.

2. The compound according to claim 1, wherein Q is selected from -S-, -0-, or -NH-; and said compound has one or more features selected from the group consisting of: (a) R* is hydrogen, alkyl- or dialkylamino, acetamido, or a C;.4 aliphatic group and RY is T-R®> or L-Z-R?, wherein T is a valence bond or a methylene and R® is -R, -N(R%),, or -OR; or R* and RY are taken together with their intervening

. atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, ox nitrogen, wherein each substitutable ring carbon of said fused ring formed by R* and RY is independently substituted by oxo, T-R?, or L-Z- R?®, and each substitutable ring nitrogen of said ring formed by R* and RY is independently substituted by R*; (b) R' is T- (Ring D), wherein T is a valence bond or a methylene unit; (c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d) rR? is -R or -T-W-R® and R?* is hydrogen, or R? and R?*' are taken together to form an optionally substituted benzo ring.

3. The compound according to claim 2, wherein: (a) R* is hydrogen, alkyl- or dialkylamino, acetamido, or a C;.4 aliphatic group and RY is T-R® or L-Z-R3, wherein T is a valence bond or a methylene and R® is -R, -N(R%),, or -OR; or R* and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 - heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R* and RY is independently substituted by oxo, T-R?, or L-2Z- R?, and each substitutable ring nitrogen of said ring formed by R* and RY is independently substituted by R*; "(b) R' is T- (Ring D), wherein T is a valence bond or no a methylene unit;

-. (c) Ring D is a 5-7 membered monocyclic or an 8-10 oo membered bicyclic aryl or heteroaryl ring; and

(d) R® is -R or -T-W-R® and R* is hydrogen, or R?> and R®*' are taken together to form an optionally : substituted benzo ring.

4. The compound according to claim 2, wherein said compound has one or more features selected from the group consisting of: (a) RY is T-R®> or L-Z-R® wherein T is a valence bond or a methylene and R?} is selected from -R, -OR, or -N(R*),, wherein R is selected from hydrogen, Ci-s aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or R* and RY are taken together with their intervening atoms to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by R* and RY is independently substituted by oxo, T-R?, or L-Z-R?, and each substitutable ring nitrogen of said ring formed by R* and RY is independently substituted by R*; (b) R* is T- (Ring D), wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8- membered bicyclic aryl or heteroaryl ring; (¢) R® is -R and R* is hydrogen, wherein R is selected from hydrogen, C;.¢ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;and (d) R® is selected from -R, -halo, -OR, or -N(R?).,, wherein R is selected from hydrogen, Ci.¢ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R?) -.

5. The compound according to claim 4, wherein: (a) RY is T-R? or L-Z-R?® wherein T is a valence bond : or a methylene and R? is selected from -R, -OR, or -N(R*),, wherein R is selected from hydrogen,

Ci. aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or R* and RY are taken together with their intervening atoms to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by R* and RY is independently substituted by oxo, T-R?), or L-Z-R?, and each substitutable ring nitrogen of said ring formed by R* and RY is independently substituted by R*; (pb) R' is T- (Ring D), wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8- membered bicyclic aryl or heteroaryl ring; (c) R?* is -R and R* is hydrogen, wherein R is selected from hydrogen, C;.¢ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;and (Ad) R® is selected from -R, -halo, -OR, or -N{(R%),, . wherein R is selected from hydrogen, Cs aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R*)-.

} 6. The compound according to claim 4, wherein said compound has one or more features selected from the group : consisting of: (a) R* is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and RY is selected from 2-pyridyl, 4-pyridyl,

pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, : isopropyl, t-butyl, alkoxyalkylamino, : alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or R* and RY are taken together with their intervening atoms to form a benzo, pyrido, piperidino, or cyclohexo ring, wherein said ring is optionally substituted with -halo, -R, -OR, -COR, -CO;R, ~CON (R*) 2, cw, -0(CH;) 2_.4-N(R*) 2, -O(CHy)2-4-R, -NO -N(R*),, -NR*COR, -NR*SO;R, or -SO,N(R!),, wherein R is hydrogen or an optionally substituted C;.

6 aliphatic group; (b) R' is T- (Ring D), wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from -halo, -CN, -NO., -N(R*),, optionally substituted C,.¢ aliphatic, -OR, -C(O)R, -COzR, ~CONH(R%), -N(R!)COR, -N(R*)CO.R,

-S0.N (R*) 2, -N(R?)SO,R, -N(R®)COCH,N(R?),, -N (R®) COCH,CH,N (R*) ;, or -N(R®)COCH,CH2CH.N (R*),; (c) R® is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Cig aliphatic group, and R?* is hydrogen; and (d) R?® is selected from -R, -OR, or -N(R%),, wherein R is selected from hydrogen, C; ¢ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and (¢) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO,, -N(R%);, optionally substituted C;.¢ aliphatic group, -OR, -C(O)R, -COsR, -CONH(R'), -N(R®)COR,

~-329- -N(R*) COR, -SO,N(R%),, -N(R*)SO.R, -N (R®) COCH,N (R*),, -N(R®)COCH,CH,N (R*),, or -N (R®) COCH,CH,CH,N (R*) ,, wherein R is selected from hydrogen, C;.s aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

7. The compound according to claim 1, wherein Q is ~C(R%'),-, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl, or 1,3-cyclobutanediyl; and said compound has one or more features selected from the group consisting of: (a) R* is hydrogen, alkyl- or dialkylamino, acetamido, or a C;.4 aliphatic group and RY is T-R?® or L-Z%Z-R’, wherein T is a valence bond or a methylene and R® is -R, -N(R*'),, or -OR; or R* and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R* and RY is independently substituted by oxo, T-R®, or L-Z- R?’, and each substitutable ring nitrogen of said ring formed by R* and RY is independently substituted by R*; (b) R! is T- (Ring D), wherein T is a valence bond or a methylene unit and wherein said methylene unit } is optionally replaced by -0-, -NH-, or ~-S8-; (c¢) Ring D is a 5-7 membered monocyclic or an 8-10 . membered bicyclic aryl or heteroaryl ring; and (d) R® is -R or -T-W-R® and R?' is hydrogen, or R?® and R*' are taken together to form an optionally substituted benzo ring.

-330-~

8. The compound according to claim 7, wherein: ' (a) R* is hydrogen, alkyl- or dialkylamino, acetamido, or a Ci, aliphatic group and RY is T-R? or L.-Z-R?®, wherein T is a valence bond or a methylene and R® is -R, -N(R%),, or -OR; or R* and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R* and RY is independently substituted by oxo, T-R®, or L-Z- R®*, and each substitutable ring nitrogen of said ring formed by R* and RY is independently substituted by R*; (b) R' is T- (Ring D), wherein T is a valence bond or a methylene unit and wherein said methylene unit is optionally replaced by -0-, -NH-, or -8-; (c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d) R? is -R or -T-W-R® and R* is hydrogen, or R? and R*>' are taken together to form an optionally substituted benzo ring.

9. The compound according to claim 7, wherein Q is -C(R%'),- or 1,2-cyclopropanediyl, and said compound has } one or more features selected from the group consisting of: (a) RY is T-R’ or L-Z-R® wherein T is a valence bond or a methylene and R® is selected from -R, -OR, or -N(R*),, wherein R is selected from hydrogen, Ci1-¢ aliphatic, or 5-6 membered heterocyclyl,

phenyl, or 5-6 membered heteroaryl; or R* and RY are taken together with their intervening atoms to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by R* and RY is independently substituted by oxo, T-R?, or L-%-R?, and each substitutable ring nitrogen of said ring formed by R* and RY is independently substituted by R*; (b) R* is T- (Ring D), wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8- membered bicyclic aryl or heteroaryl ring; (c) R® is -R and R* is hydrogen, wherein R is selected from hydrogen, Cis aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (d) R® is selected from -R, -halo, -OR, or -N(R%)., wherein R is selected from hydrogen, Ci. aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, ~-S-, or -N(R*)-.

10. The compound according to claim 9, wherein: (a) RY is T-R® or L-Z-R® wherein T is a valence bond or a methylene and R® is selected from -R, -OR, or -N(R*);, wherein R is selected from hydrogen, Ci-¢ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or R* and RY are taken together with their intervening atomg to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by R* and RY is independently substituted by oxo, T-R?, or L-%Z-R’, and each substitutable ring nitrogen of said ring formed : by R* and RY is independently substituted by R*; (b) R' is T- (Ring D), wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8- membered bicyclic aryl or heteroaryl ring; (c) R*> is -R and R* is hydrogen, wherein R is selected from hydrogen, Cig aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (4) R® is selected from -R, -halo, -OR, or -N(RY)., wherein R is selected from hydrogen, C;_¢ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S5-, or -N(R*)-.

11. The compound according to claim 9, wherein Q is -CH;- and said compound has one or more features selected from the group consisting of: (2) R® is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and RY is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally a substituted phenyl, or methoxymethyl; or R* and RY are taken together with their intervening . atoms to form a benzo, pyrido, piperidino, or cyclohexo ring, wherein said ring is optionally substituted with -halo, -R, -OR, -COR, -CO3R, ~CON(R*) 2, -CN, -O(CHp);-4-N(R*),, -O(CHz):.s-R, -NO,

-333-~ MU) 5, -NR*COR, -NR*SO,R, or -SO,N(R'),, wherein R is hydrogen or an optionally substituted Cj. : aliphatic group; (b) R' is T-(Ring D), wherein T is a valence bond and - Ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from -halo, -CN, -NO,, -N(R%)., optionally substituted C;.¢ aliphatic, -OR, -C(O)R, -COR, -CONH(R*), -N(R*)COR, -N (R*) COR, -SO,N(R*),, -N(R*)SO;R, -N(R®)COCH,N (R*),, -N (R®) COCH,CH,N (R*)., or -N(R®)COCH,CH,CH,N (R*),; (c) R® is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Cis aliphatic group, and R?* is hydrogen; and : (d) R?® is selected from -R, -OR, or -N(R%),, wherein R is selected from hydrogen, C;-¢ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0O-, -8-, or -NH-; and (e) Ring D is substituted by up to three : substituents selected from -halo, -CN, -NO,, -N(R*),, optionally substituted Ci.¢ aliphatic group, -OR, -C(O)R, -CO,R, -CONH(R®), -N(R*)COR, -N(R*) COR, -SO.N(R%),, -N(R!)SO:R, -N (R®) COCH,N (R*) ,, -N(R®)COCH,CH.N (R*),, or -N (R®) COCH,CH,CH,N (R*),, wherein R is selected from hydrogen, C;.¢ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. .

12. The compound according to claim 11, wherein: (a) R* is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and RY is selected from 2-pyridyl, 4-pyridyl,

pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, : isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or R* and RY are taken together with their intervening atoms to form a benzo, pyrido, piperidino, or cyclohexo ring, wherein said ring is optionally substituted with -halo, -R, -OR, -COR, -CO3R, ~-CON (R*),, -CN, -O(CHa)2-2-N(R*),, -0O(CH;):-4-R, -NO; -N(R*),, -NR*COR, -NR®*SO,R, or -SO;N(R'),, wherein R is hydrogen or an optionally substituted Ci; aliphatic group; (pb) R! is T- (Ring D), wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from -halo, -CN, -NO,, -N(R*)., optionally substituted C,.¢ aliphatic, -OR, -C(O)R, -CO.R, -CONH (R*), -N(R*) COR, -N(R*) COR, -SO,N(R*),, -N(R*)SO,R, -N(R®)COCH,N (R*),, ~N (R®) COCH,CH,N (R*) ,, or -N(R®)COCH,CH,CH,N(R*) 2; (¢) R® is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci.¢ : aliphatic group, and R? is hydrogen; and (d) R?® is selected from -R, -OR, or -N(R%),, wherein R is selected from hydrogen, C,.¢ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L. is -O0-, -S-, or -NH-; } (e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO,, -N(R*),, optionally substituted C,.¢ aliphatic group, -OR, -C(O)R, -CO,R, -CONH(R%), -N(R*)COR,

~N(R*)COzR, -SO,N(R%),, -N(R*)SO,R, -N(R®)COCH,N(R?),, ~N (R®) COCH,CH,N (R*) 5, or ~N(R®)COCH,CH,CH,N (R%),, wherein R is oo selected from hydrogen, Ci.¢ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

13. A composition comprising a compound according to any one of claims 1-12, and a pharmaceutically acceptable carrier.

14. The composition according to claim 13, further comprising an additional therapeutic agent.

15. Use of a compound according to any one of claims 1-12 for inhibiting Aurora-2 or GSK-3 activity in a biological sample.

16. Use of a composition according to claim 13 for inhibiting Aurora-2 activity in a patient.

17. Use of a composition according to claim 14 for inhibiting Aurora-2 activity in a patient.

18. Use of a composition according to claim 13 for treating an Aurora-2-mediated disease.

19. The use according to claim 18, wherein said disease is selected from colon, breast, stomach, or ovarian cancer.

20. The use according to claim 19 in combination with an additional therapeutic agent. - Amended Sheet — 2004-08-24

21. The use according to claim 20, wherein said additional therapeutic agent is a chemotherapeutic agent.

22. Use of a composition according to claim 13 for inhibiting GSK-3 activity in a patient.

23. Use of a composition according to claim 14 for inhibiting GSK-3 activity in a patient.

24. Use of a composition according to claim 13 for treating a GSK-3-mediated disease.

25. The use according to claim 24, wherein said GSK-3- mediated disease is selected from 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, or baldness.

26. The use according to claim 25, wherein said GSK-3- mediated disease is diabetes.

27. Use of a composition according to claim 13 for enhancing glycogen synthesis or lowering blood levels of glucose in a patient in need thereof.

28. Use of a composition according to claim 13 for inhibiting the production of hyperphosphorylated Tau protein in a patient. Amended Sheet — 2004-08-24