ZA200301697B - 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 Aurcora-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 ; 25 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 -1-

SUBSTITUTE SHEET (RULE 26)

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 . radiation, bacterial endotoxin, Hz0.), 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 ) chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, the aurora- 2

SUBSTITUTE SHEET (RULE 26)

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

R al., J. Biol. Chem., 1997, 272, 13766-13771. ‘Glycogen synthase kinase-3 (GSK-3) is a . serine/threonine protein kinase comprised of a 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) 17].

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 Haq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways in which

GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein

Tau, the gene transcription factor P-catenin, the translation initiation factor elF2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c¢-Myb, CREB, and CEPBa. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.

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

SUBSTITUTE SHEET (RULE 26)

phosphorylation and deactivation of glycogen synthase.

The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 393, } 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 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 P-amyloid peptide and the formation of intracellular neurofibrillary tangles. The neurofibrillary tangles contain hyperphosphorylated Tau protein where Tau is phosphorylated on abnormal sites.

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

SUBSTITUTE SHEET (RULE 26)

Another substrate of GSK-3 is P-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)] .

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-a activity and/or enhanced TGF-P activity. While p38 activity has been implicated in a wide variety of diseases, including diabetes, p38 kinase is not reported to be a constituent of an insulin signaling pathway that regulates glycogen synthesis or glucose uptake.

Therefore, unlike GSK-3, p38 inhibition would not be expected to enhance glycogen synthesis and/or glucose uptake. ’ There is a continued need to find new therapeutic agents to treat human diseases. The protein kinases aurora-2 and GSK-3 are especially attractive 5

SUBSTITUTE SHEET (RULE 26)

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

Tt has now been found that compounds of this invention and pharmaceutical compositions thereof are effective as protein kinase inhibitors, particularly as inhibitors of aurora-2 and GSK-3. These compounds have the general formula I: :

R* :

R” ; — pal

HNN _ - Np }

Jy A ~;17 : I or a pharmaceutically acceptable derivative or prodrug thereof, wherein: . 72> to z! are as described below;

Ring A is selected from the group consisting of:

R* rR" Bi REA AL

BB RYN [> vo ~ eZ ~

RY WN RE RTONT YS, ANN } a b c d

A . Ar .

N . . } R NSE 1 i . R AN " EAP N ~ ~

R® “N , RO “N e f g h 2004 -05- 25 6 AMENDED SHEET

SUBSTITUTE SHEET (RULE 26)

NT

0 and RS; 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 oo 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 ririg being optionally substituted by halo, oxo, or -RE;

Ring D is a 5-7 membered monocyclic ring or §-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;

Lo Rr! is selected from -halo, -CN, -NO», T-V-R®, phenyl, 5-6 . a membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci.¢ aliphatic group, said phenyl, heteroaryl,

AMENDED SHEET 2004 -05- 25

SUBSTITUTE SHEET (RULE 26)

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 RY;

T is a valence bond or a Cj;.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 R%;

R? is selected from -R, -halo, -OR, -C(=0)R, -CO;R, -COCOR, -COCH,COR, -NO,, -CN, -S(O)R, -S(O)2R, -SR, -N(R?),, -CON(R"),, -SO,N(R”),, -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(R7) 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 Ci. 8

SUBSTITUTE SHEET (RULE 26)

aliphatic, Ce¢.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:(Ci-e aliphatic), -CON(R7),, or -SO,R’, 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, -COR, -COCOR, -NO,, -CN, -S(O)R, -SOzR, -8SR,

IN(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*) SON (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 Cj; v is -0-, -S-, -S80-, -SO;-, -N(R®) SO,-, -S0,N(R®) -, -N(R®) -, -CO-, -CO,-, -N(R®)CO-, -N(R®)C(O)O-, -N (RS) CON(R®) -, -N(R®)SO,N(R®)-, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, -C(R®),0-, -C(R®)2S-, ~C(R®)280-, -C(R®),80,-, -C(R®),S0;N(R®)-, -C(R):N(R®)-, -C(R)sN(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®) oN (R®) CON (R®) -;

W is -C(R®),0-, -C(R®),S-, -C(R®),S0-, -C(R®);SO;-, -C(R®) ,SO,N(R®) -, -C(R®).N(R®)-, -CO-, -CO,-, _C(RS)OC(0)-, —-C(R®)OC(O)N(R®)-, -C(R®),N(R®)CO-, -C(R®).N(R®)C(0)O-, -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 9

SUBSTITUTE SHEET (RULE 26)

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 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; each R® is independently selected from an optionally substituted C;.; aliphatic group, -OR®, -SR®, -CORS, ~SO,R®, -N(R®),, -N(R®)N(R®),, -CN, -NO,, -CON(R®);, or -CO,R%; and

R® is selected from -R, halo, -OR, -C(=0)R, -CO,R, -COCOR, -NO,, -CN, -S(O)R, -SOR, -SR, -N(R%),, -CON(R*):, -80,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 -OC(=0)N(R%),..

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 10

SUBSTITUTE SHEET (RULE 26)

(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 valkenyl” and “alkynyl” used g 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 C3-Cia hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic.

The terms “haloalkyl”, “haloalkernyl” 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 TI.

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 wcarbocyclic” whether saturated or partially unsaturated, also refers to rings that are optionally substituted.

The terms “carbocycle”, “carbocyclyl”, wcarbocyclo”, or 11

SUBSTITUTE SHEET (RULE 26)

“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 varyloxyalkyl”, refers to aromatic ring groups having five to fourteen members, such as phenyl, benzyl, phenethyl, 1-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 1-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 tetrahydrconaphthyl, 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, (l-substituted)-2-oxo-benzimidazol-3- vl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4- tetrahydropyranyl, [1,3]-dioxalanyl, I[1,3]-dithiolanyl, [1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3- tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4- 12

SUBSTITUTE SHEET (RULE 26)

morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4- thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1- oo 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, 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-pyxrrolyl, 2- pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2- triazolyl, S5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, 13

SUBSTITUTE SHEET (RULE 26)

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 tetrahydroguinolinyl, tetrahydroisoquinolinyl, 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 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, -0(Ph), substituted -O(Ph), -CH, (Ph), substituted -CH, (Ph), -CH,CH;(Ph), substituted -CH,CH, (Ph), -NO,, -CN, -N(R°)a, -NR°C(O)R°®, -NR°C(O)N(R®)2, -NR°CO,R°, -NR°NR°C(O)R°, -NR°NR°C (O)N(R®°),, -NR°NR°CO,R®, -C(0)C(O)R®, -C(O)CH,C(O)R®, -COR°, -C(O)R®°, -C(O)N(R®)., -OC(O)N(R°) 5, -5(0),R°, -SO,N(R%),, -S(O)R®°, -NR°SO.N(R°®), -NR°SO,R°, -C(=8)N(R°),, -C(=NH)-N(R°),, -(CH,),NHC(O)R®, - (CH) yNHC (0) CH (V-R°) (R°) ; wherein R° is 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); vy is 0-6; and V is a linker group. Examples of substituents on the aliphatic 14

SUBSTITUTE SHEET (RULE 26)

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 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)RY, -CO,R*, -C(O)C(O)R*, -C(O)CH,C(O)R*, -SO;R*, -SO,N(R"),, -C(=8)N(R"),, -C(=NH)-N(R'),, and _NR'SO.R*; wherein R* is hydrogen, an aliphatic group, a substituted aliphatic group, phenyl (Ph), substituted Ph, -0 (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, 15

SUBSTITUTE SHEET (RULE 26)

dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, halocalkoxy, 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 of up to about six atoms. Examples of linkers include a saturated or unsaturated C;.s 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-, -COz-, -0C (0) -, -NHCO,-, -O-, -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 16

SUBSTITUTE SHEET (RULE 26)

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 **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 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, ‘ 30 without limitation, diabetes, Alzheimer's disease,

Huntington's Disease, Parkinson's Disease, AIDS- associated dementia, amyotrophic lateral sclerosis (AML), 17

SUBSTITUTE SHEET (RULE 26)

multiple sclerosis (MS), schizophrenia, cardiomycete hypertrophy, reperfusion/ischemia, and baldness.

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

I or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer’s disease. Another method relates to inhibiting the phosphorylation of P-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 18

SUBSTITUTE SHEET (RULE 26)

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 19

SUBSTITUTE SHEET (RULE 26)

oncologic, Endocrine & Metabolic Investigational Drugs, 2, 40-539 (2000).

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

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

I or a pharmaceutical composition thereof.

The term “ERK-mediated condition”, as used herein means any disease state or other deleterious 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 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, 20

SUBSTITUTE SHEET (RULE 26)

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., 1992, Science 258, 478; Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848; Rouse et-al., 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al. 1996; Chen et al., 1993 Proc. Natl. Acad. Sci. USA 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 21

SUBSTITUTE SHEET (RULE 26)

"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, 0. Y., et al, Oncogene, 19 2000;

Kazuhiko, N., et al, The Journal of Neuroscience, 20 20001.

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, 22

SUBSTITUTE SHEET (RULE 26)

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.

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, 23

SUBSTITUTE SHEET (RULE 26)

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 24

SUBSTITUTE SHEET (RULE 26)

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- 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, agueous 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 25

SUBSTITUTE SHEET (RULE 26)

aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. It 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 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 topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical 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 26

SUBSTITUTE SHEET (RULE 26)

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. Altermatively, 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, © 25 pharmaceutically acceptable derivatives or prodrugs of 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 ) 30 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 27

SUBSTITUTE SHEET (RULE 26)

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, penzenesul fonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, : digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanocate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, ’ 30 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 28

SUBSTITUTE SHEET (RULE 26)

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

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

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

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

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 29

SUBSTITUTE SHEET (RULE 26)

Claims (37)

\ We claim:

1. A compound of formula II: R2 R? Tow HNN RY | 0 IT or a pharmaceutically acceptable salt thereof, wherein; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R', 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%; 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’ 350 SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25 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 umsaturated, 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;-. 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 R*;

R?® is selected from -R, -halo, -OR, -C(=O)R, -COR, -COCOR, -COCH,COR, -NO,, -CN, -S(O)R, -S(0)2R, -8SR, -N(R%),, -CON(R"),, -SO.N(R’7),, -OC(=0)R, -N(R’)COR, N(R?) CO, (Cy. aliphatic), -N(R})N(R'),, -C=NN(R?),

: ~C=N-OR, -N(R7)CON(R’),, -N(R7)SO,N(R’),, N(R?) SO,R, oF -OC(=0) N(R") 3; each R is independently selected from hydrogen or an optionally substituted group selected from Cie aliphatic, Ce.10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; 351 SUBSTITUTE SHEET (RULE 26)

each R* is independently selected from -R’, -COR’, -CO, (optionally substituted Ci.¢ aliphatic), -CON(R’)., or -SO0.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, -CR, -C(=0)R, -CO;R, -COCOR, -NO;, -CN, -S(0O)R, -SOzR, -SR, ~N(R*),, -CON(R*)2, -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(=O)N(R%),, or R® and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;

V is -O-, -S-, -SO-, -S0,-, -N(R®)SO,-, -SO.N(R®)-, -N(R®)-, -CO-, -CO,-, -N(R®)CO-, -N(R®)C(O)O-, -N(R®) CON(R®) -, -N(R®)SON(R)-, -N(R®)N(R)-, -C(O)N(R®) -, -OC(O)N(R®)-, -C(R®),0-, -C(R®),S-, ~C(R®) ,80-, -C(R%);S02-, -C(R®),SON(R®)-, -C(R®):N(R®)-, _C(R®),N (RS) C(O) -, -C(RS),N(R®)C(0)0O-, -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")2S802-, -C(R®) ,SO,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)O-, -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;

352 SUBSTITUTE SHEET (RULE 26)

each R’ is independently selected from hydrogen or an optionally substituted Ci.¢ aliphatic group, or two Rr’ on the same nitrogen are taken together with the . nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and : each R® is independently selected from an optionally substituted Ci.s aliphatic group, -OR®, -SR®, -COR®, -SO,R®, -N(R®),, -N(R®)N(R®),, -CN, -NO,, -CON(R®),, or

-CO.R®. :

2. The compound according to claim 1, wherein said compound has one or more features selected from the group consisting of: (a) Ring C is a phenyl or pyridinyl ring, optionally substituted by -R’, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from an optionally substituted naphthyl, quinolinyl or isoquinolinyl ring; (b) R* is hydrogen or C,., aliphatic and RY is T-R’, or R* and RY are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; ) (c) .R' is -halo, an optionally substituted Ci.¢ aliphatic group, phenyl, -COR®, -OR®, -CN, -SO,R®, -SO,NH,, -N(R®),, -CO,R®, -CONH,, -NHCOR®, -OC(O)NH,, or -NHSO.R®; and (d) R* is hydrogen and R? is hydrogen or a ) substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci aliphatic group, or R® and R® are taken together with their intervening atoms to form a 353 SUBSTITUTE SHEET (RULE 26)

substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring.

.

3. The compound according to claim 2, wherein: (a) Ring C is a phenyl or pyridinyl ring, : optionally substituted by -R°, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from an optionally substituted naphthyl, quinolinyl or isoquinolinyl ring; (b) R* is hydrogen or C;., aliphatic and RY is T-R?®, or R* and RY are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; (¢) R* is -halo, an optionally substituted Cie aliphatic group, phenyl, -COR®, -OR®, -CN, -SO:R°, -SO:NH, -N(R®),, -CO,R®, -CONH,, -NHCOR®, -OC(O)NH;, or “NHSO,R®; and (d) R?® is hydrogen and R®> is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci.¢ aliphatic group, 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 C is a phenyl or pyridinyl ring, optionally substituted by -R°, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring 354 SUBSTITUTE SHEET (RULE 26)

system, the bicyclic ring system is selected from an optionally substituted naphthyl ring; (b) R* is hydrogen or methyl and R” is -R,

. N(RY),, or -OR, or R* and RY are taken together with their intervening atoms to form a 5-7 membered unsaturated or : partially unsaturated carbocyclo ring optionally substituted with -R, halo, -OR, -C(=0)R, -CO3R, -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 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, ; (¢) R' is -halo, a Ci.¢ haloaliphatic group, a Ci. ¢ aliphatic group, phenyl, or -CN; (d) BR? is hydrogen and R’ is hydrogen or a substituted or unsubstituted group selected from aryl, or a Ci.¢ aliphatic group, or R® and R? are taken together with their intervening atoms to form a substituted ox unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and : (e) each R® is independently selected from ~halo, -CN, -NO,, -N(R')., optionally substituted Ci. aliphatic group, -OR, -C(O)R, -CO,R, -CONH(R®), -N(R®)COR, -SO;N(R*),, and -N(R)SO:R.

5. The compound according to claim 4, wherein: (a) Ring C is a phenyl or pyridinyl ring, optionally substituted by -R’, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring ' system, the bicyclic ring system is selected from an optionally substituted naphthyl ring; (b) R* is hydrogen or methyl and RY is -R, N(R*),, or -OR, or R* and RY are taken together with their 355 SUBSTITUTE SHEET (RULE 26)

intervening atoms to form a 5-7 membered unsaturated or partially unsaturated carbocyclo ring optionally substituted with -R, halo, -OR, -C(=0)R, -CO;R, -COCOR, -NO,, -CN, -S(0)R, -SO.R, -SR, -N(R'),, -CON(R%), -SO,N(R*)., -0OC(=0)R, -N(R*)COR, -N(R*)CO,(optionally substituted Cig 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*) 2, ; {c) R' is -halo, a Cis haloaliphatic group, a

Ci.¢ aliphatic group, phenyl, or -CN; (d) R* is hydrogen and R® is hydrogen or a substituted or unsubstituted group selected from aryl, or a Ci.¢ aliphatic group, 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; and (e) each R® is independently selected from -halo, -CN, -NO,, -N(R%),, optionally substituted Cj.¢ aliphatic group, -OR, -C(O)R, -CO;R, -CONH(R?), -N(R*)COR, -SO,N(R*),, and -N(R*)SO;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 or methyl and RY is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R* and RY are taken together with their intervening atoms to form a ' 6-membered unsaturated or partially unsaturated carbocyclo ring optionally substituted with -halo, -R, -OR, -COR, -CO;R, -CON(R*),, -CN, or -N(R%), wherein R is an optionally substituted C;.¢ aliphatic group; 356 SUBSTITUTE SHEET (RULE 26)

(b) R' is -halo, a C;.4 aliphatic group optionally substituted with halogen, or -CN; (¢) R? and R? are taken together with their , intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring : optionally substituted with -halo, -N(R%)., -Ci.. alkyl,

-C.i_, haloalkyl, -NO;, -O(Ci-4 alkyl), -CO2(Ci-a alkyl), -CN, -80,(Ci.4 alkyl), -SO.NH,, -OC(O)NH,, -NH250;(Ci-4 alkyl), -NHC (0) (C31. @lkyl), -C(O)NH;, or -CO(Ci.4 alkyl), wherein the (C;., alkyl) is a straight, branched, or cyclic alkyl group; and (d) each R® is independently selected from -C1, -F, -CN, CF, -NH,, -NH(C,., aliphatic), -N(Cj.4 aliphatic), -0(Cy.4 aliphatic), Cj., aliphatic, and -C0O, (Cy1.4 aliphatic).

7. The compound according to claim 6, wherein: (a) R* is hydrogen or methyl and RY is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R* and RY are taken together with their intervening atoms to form a benzo ring or a partially unsaturated carbocyclo ring optionally substituted with -halo, -R, -OR, -COR, -COzR, -CON (R*),, -CN, or -N(R!), wherein R is an optionally substituted C;.¢ aliphatic group; (b) R* is -halo, a C;., aliphatic group optionally substituted with halogen, or -CN; (c) R?® and R? are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R%),, -Cis alkyl,

-C;.s haloalkyl, -NO,, -0(Cy.s alkyl), -CO,(C;.. alkyl), -CN, 357 SUBSTITUTE SHEET (RULE 26)

-80,(C,_, alkyl), -SO,NH,, -OC(O)NH,, -NH,SO,(C,, alkyl), -NHC (0) (C, , alkyl), -C(O)NH,, or -CO(C,, alkyl), wherein the (C,, alkyl) is a straight, branched, or cyclic alkyl group; and (d) each R® is independently selected from -Cl, -F, -CN, -CF,, -NH,, -NH(C,, aliphatic), -N(C,, : aliphatic),, -0(C,, aliphatic), C,, aliphatic, and -CO,(C,, aliphatic).

8. The compound according to claim 7, wherein R® and RY are each methyl or R* and RY are taken together with the pyrimidine ring to form an optionally substituted ring selected from guinazoline or tetrahydroquinazoline, and R? and R? are taken together with the pyrazole ring to form an optionally substituted indazole ring.

9. The compound according to claim 1, wherein said compound is selected from the following Table 1 compounds: F CH3 je H b H 2 H HN N HN NY HN oh HiCAN cl SN Cl SN CF, . |. an. AL “0 he “CO IT-1 IT-2 IT1-3 oy © or _ NH _ NH _ NH HN NY HN NY HN NY oN: Cl oN Cl Cx Cl he he he 11-4 II-5 II-6 358 SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25

F 2 F F b H 2 H b H nN nN nN oP: CF3 oP CF; OC CF; ae he ae IT-7 11-8 II-9 2, H : H HN % HN <\" HN % he ae “0 II-10 TI-11 TI-12 . F b H b H 2 H HN N HN NY HN % oN: CF; Oe CF oN: OCF, he ihe he IT-13 IT-14 IT-15 F F bt H 2 H b H HN NY HN N HN % LOW: CF; SW: CFs QU ®: CFs ae he 0 TI-16 II-17 TI-18 b H 2 H b H HN N HN N HN % j® CFs "SN CFj SN CF 0 EN vaRe N_Z II-19 II-20 II-21 359 SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25

H | H HN Sth HN = HN = SN CFs cl [{°N CFs SCN CFs ba 0 eg I-22 II-23 II-24 F F 2 H bi H b H in ans ann Cr CFs Cy cl Me. CF, H4C NY) HsC NO) HsC NO) II-25 11-26 IT-27 F F F F F - H > H - H HN NY HN % HN NY "Cry CFs "SC cl "Cr cl HsC “OO H,C NO HsC NO 11-28 II-29 II-30

F. _ NH _ NH 7 H nN y= ann Cry cl SO cl ox! CH HaC “OO HC ag! NO) cl II-31 II-32 II-33 Lo jal jal EY nN ans Cry F OW: OCHj3 QP Cl “XQ jae “0 F OCH; 11-34 IT-35 IT-36 360 SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25

CH; CH; CHa ~ NH je H je H = oe oe oxy OCHjs oC! CH; or COCH; “0 Be “0 HsC II-37 IT-38 IT-39 CH; CH; CH, jal jal Low HN % HN NY HN oh QW: CHj QP CF, oe CH,CHj3 “ CH “~ -, TYG ae II-40 II-41 II-42 CH; CH; CH, “1 go =U p= HN " HN =" OXY OL) OH OW OCH,CHj3 “0 “0 II-43 11-44 II-45 S_ Ee J _ NH NH ~ NH HN % HN oh HN oh ory CF, QP: CF, or) CF, N* 0) N°” 0) NO) II-46 11-47 II-48 it ® Eo C) — “NH NH _ NH HN % HN oh HN oh OP CF; QW: CFs QW: CF, ST Id II-49 IT-50 II-51 361 SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25

0 OH oN = r _ NH ~ NH “NH on ne poe oC! CF; oC! CF; OP: CF; he he he II-52 II-53 11-54 Pe OCH Q ~ NH Hu _ NH HN % HN NY HN % Ory CF; QW: CFy OP: CF4 he ihe he II-55 11-56 II-57 F F a2 H H cr, HN =" HN =" HN =" Ory CF3 OW: CF; QW: CF; N° N* NZ II-58 II-59 II-60 HaC F Bb H bl H b H HN N HN % HN % Oxy CF4 OL Cl ory Cl is 0 is cl II-61 11-62 II-63 FaC A, FsC H H HN =" HN =’ HN oh OL! CF, OP CF, OW: Cl “0 “0 0 cl II-64 II-65 II-66 362 2004 -05- 25 SUBSTITUTE SHEET (RULE 26) AMENDED SHEET

CF; CFs C b H b H _ NH HN N HN oh HN NY ory CHgj oC CF; QW: CF, he he ie I1-67 II-68 I1-69 O,N F E “d N 2 y * y < a ’ HN NY HN N HN NY Cry CF; ory CF, QW CFs 0 “0 “0 II-70 II-71 II-72 HN E F 2 H by H b H HN % HN NY HN NY Cry CFs OC! Cl QW: Cl “0 “0 “0 II-73 11-74 II-75 or FC NH D H D H HN % HN NY HN NY Cry cl ory Cl ory CN 0 “0 “0 11-76 11-77 II-78 of CF Br ’c NH NH b H HN oh HN NY HN % ory CFs rN CF; QP: CF; “0 0 is II-79 II-80 II-81 363 SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25

Br F E > or or H - H 5 H HN NY HN NY HN NY ory CFs QW CF; or CF, O “QL “Ql CFs F II-82 II-83 11-84 or or or ~ NH _ NH _ NH HN NY HN NY HN N ory Br QW CF; or Cl NO) NO) "NO F of 1T-85 IT-86 11-87 F F F b H 2 H 2 H HN NY HN N HN % QW cl cry CFs {SN CFy ’ “0 ae OCHj CF; 11-88 II-89 II-90 F F F F A H b H 2 H HN % HN NY HN oh Cs CF; on CF; ox) CF; fe he ] OCH, OCHj OCHg II-91 II-92 II1-93 F F F F b H - H HN J HN NY cry Cl or Cl QL a! NO, NH, 11-95 11-96 364 suBsTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25

7 N 7 °N - _ NH - HN % HN % HN NY LE ape Ce 0 is is I1-97 IT-98 IT-99 QL 9 F o 2 ¢ HsC = NJ NH H - NH HN NY HN \ HN N ory CFj3 OP: CFs CIN he OTD Cli II-100 IT-101 IT-102 © o> CHa Z NH Z NH ja HN N HN N HN N (SN OCF, {SN OCFy "SN OCF, 0 “0 0 CHa CH, H4C IT-103 IT-104 IT-105

F. fo (2 ja ae aC HN NY HN N HN NN "0 <I IT-106 IT-107 IT-108 365 . SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25

F F F ol H > H 2 H HN NY HN oh HN NY QP CFs XN Cl oN: CFs RACINE “Qa I1-109 II-110 I1-111 o F ~ NH b H | " HN NY HN % HN <\" aps as aps 11-112 IT-113 II-114 F - - b H b H b H HN NY HN N HN V CIN CF; cry cl CIN cl “0 “a ie 11-115 11-116 11-117 F - a - H > H H HN NY HN % HN \ CIN cl OF: CF, (ry CF, “O “O 0) II-118 II-119 IT-120 F F 2 H 2 H > H HN V HN NY HN oh Oy CFs SNCF FN CF, he he hs IT-121 IT-122 II-123 366 suBsTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25

F Q MeO,C _ NH > H - H HN N HN N HNN or CF, QP: CF, “Cn CF, “0 “0 0 I1-124 11-125 I1-126

F. F F - H _ NH Pon HN NY HN NY HN” -N NA N_A 5 ae. ae. ae. 0 0 0 FsC F.C Cl IT-127 II-128 II-129 F F F NH H H HNN HN xh oN ~" 0 0 “0 FsC FsC FsC IT-130 11-131 II-132

F. jay _ NH _ NH HN Sh HN % HN % SW IW I 0 ne “YD II-133 II-134 II-135 F F CH; F Con : H - H HN % HN % HN % SI SW a: ne 0 SVD F4C FsC FC TI-136 11-137 II-138 367 AMENDED SHEET 2004 -05- 23 SUBSTITUTE SHEET (RULE 26)

- NH - NH - NH HNN HNN HNN 0 20 he H,N FaC AcNH FaC MeSO,NH lo] II-139 II-140 II-141 - NH - NH - NH HNN HNN HNN "Corn Ore "Or OID WDD we f0 og HNO HaC N F.C 0) II-142 TI-143 II-144 - NH : NH - NH HNN HNN HNN SASCRINS LS CEENINS ANS cozN cl Mesos cl Ho N~ Ec II-145 II-146 T1I-147 F F F ‘NH b H b H HN NY HN J oY HN f [ °N CF; [°N CF; ~My CF, SJ Aa Tl 0) ) o N Me II-148 II-149 II-150 368 AMENDED SHEET 2004 -05- 2 5 SUBSTITUTE SHEET (RULE 26)

. F H ‘NH b H HN % HN oh HN % nN CF, Ne.

CF, SN CF “0 “0 ie HN II-151 I1-152 II-153 F F Me HN-Me b H : H ja H — HN % HN % HN NT or CF, oN CF aw CF, L HN “, -, “0 ie ie II-154 II-155 II-156 F - H : H - H HN NY HN N HN N NSN CF NAN CF; SN CF oY TO La 1° N™°N 2 NN N 0 HN II-157 II-158 II-159 F Q > - H - NH _ NH HN N HN N QN HN N° NY CF, NH CFs SP CF, INE EA “0 II-160 II-161 II-162 EL Q _ NH _ NH ja HN N HN NY HN N SH CFs YN CF, ory CF, Wg YY YY II-163 II-164 II-165 369 SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25 b H b H 2 H HN oh oo HN oh HN J Cbz [SN CF; HaCS SN CF, CH SN CF; N “O) N NO) ( VO) N Cbz II-166 II-167 II-168 2 H b H b H HN oh HN oh HN % H ~N CF; H ~N CF; Me ~N CF3 N “ N ~ N ”, rv YO Ya N N N HyC NO H H II-169 II-170 II-171 2 H b H D H 2 HN \ FP HN % HN NY HCNH SN CF; HC NH [SN CF; NH, SN CFs O70 “0 he II-172 II-173 II-174 : H . H - H INAS HNN HNN SN CFs SN CFy SN CFs Chz Z - bo ‘N YO HoN NO N H HN II-175 II-176 II-177 : H : H : H NSN HNN HNN »: CFs TSN CF; (SN CFy TO “0 “0 H coz N Ac-N II-178 TI-179 II-180 370 SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25

- H - H : H NSN NSN NSN H cl cl c II-181 II-182 II-183 : H - H : H HNN HN SN HNN SN SN SN NN a W AN 0 WOO XO SA HN cry CH NJ cr, 0 II-184 II-185 II-186 & 8 - NH ~ NH : H HNN HNN HNN C I: C2 She cHINS SCI SRDS cozN cFy Me0,sN~" CF; cryN~ cr II-187 II-188 TT-189 bi H b H b H nN nN NSN AcNH ~N CF, MeSO,NH N CF3 NH, ~N CF, II-190 II-191 II-192 - H : H : H ANS H HNN NSN Pe: CFs ZO9. CFs pe CF, 2 N° N’ ~ N° Sa e UO wYO 11-193 11-194 II-195 371 SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25

F : : § ~ NH - NH ~. NH HN a HN a HN % Oh cl rN CFs WO CF; N“ N° N* 0) “OO H 11-196 11-197 II-198 EF - H - H HN NY HN NY HN si 0] “OO ‘N “O H,NO,S O QJ i IT-199 II-200 IT-201 F F F 2 H b H by H HN N HN N HN N SH SW: oF ‘DQ ‘DQ 5 IT1-202 TI-203 IT-204

F. CH, Pi j@ H ~ NH 2 H HN N HN N HN N QW XC) GW 5 5 ITI-208 IT-209 ITI-210 372 sussTITUTE SHEET (RULE 26)AMENDED SHEET 2004 -05- 25

F F F . H b H . H HN «' ea ASN OB, cl an. cl ory ol “N NO) “N 0) NANA < 11-214 11-215 11-216 c F - H - H 2 H HN V HN Sh HN % ON cl OL cl OX cl Ns ) Ns Ig N No 11-217 11-218 IT-219 or F < NH - H a H HN N HN NY HN N Ory Cl OL! -CH ory ~.CH 0 ‘ “0 II-220 11-221 IT-222 ® [ > F F < JH _ NH > H HN oh HN N HN _ Cry com ON or he i v Me Me Me Me 11-223 11-224 IT-225 F a - H D H 2 H HN oh HN % HN nN CI CI rg 0 bs ae I1-226 IT-227 I1-228 373 NE SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25

F F F F b H b H A H HN N HN N HN NY SRE ® 8 “0 0) Y) HO HO I1-229 II-230 11-231

F. NH ‘NH F | H HN N" HN N' HN =" SW SW QW “0 “0 “0 t-Bu t-Bu t-Bu II-232 II-233 II-234 i - H - H HN QW: NH, ox ory C(O)NH, “ VE “0 NH, II-235 IT-236 11-237 F F . A H by H 2 H HN N HN N° HN NN S +S Nes Se + Us he “0 NY

NH. 11-238 II-239 11-240 374 AMENDED SHEET 2004 -05- 25 SUBSTITUTE SHEET (RULE 26)

- H - H 2 HN N HN \ HN =k JRO pO Qe he 0 0 Cc C IT-241 11-242 11-243 F E F - H > H > H HN % HN Sh HN NY ore CR are ie “a ihe OCH; I1-244 II-245 11-246 F F > H : H A, HN NY HN N' HN nN

ON. SO,NH, SW SO,NH, SW: SO,N(Me), he 0 he 11-247 II-248 IT-249 > H - H HN N HN NY SW SO,N(Me), Oy CF, N” NTN? RSENS Re IT-250 and II-251.

10. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

11. The composition according to claim 10 further comprising a second therapeutic agent. 375 DED SHEET -05- SUBSTITUTE SHEET (RULE 26) AMEN 2004 05 23

12. Use of a composition according to claim 10 for inhibiting GSK-3 or Aurora activity in a patient.

13. The use according to claim 12, for inhibiting GSK3 activity in a patient.

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

15. Use of a composition according to claim 10 for treating a disease that is alleviated by treatment with an GSK-3 inhibitor.

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

17. The use according to claim 15, wherein said disease is diabetes.

18. The use according to claim 15, wherein said disease is Alzheimer's disease.

19. The use according to claim 15, wherein said disease is schizophrenia.

20. Use of a composition according to claim 10 for enhancing glycogen synthesis in a patient in need thereof.

21. Use of a composition according to claim 10 for lowering blood levels of glucose in a patient in need thereof. AMENDED SHEET 2004 -05- 25 376 SUBSTITUTE SHEET (RULE 26)

22. Use of a composition according to claim 10 for inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof.

23. Use of a composition according to claim 10 for inhibiting the phosphorylation of B-catenin in a patient in need thereof.

24. Use of a composition according to claim 10 for treating a disease that is alleviated by treatment with an aurora inhibitor.

25. Use of a composition according to claim 24 in combination with a second therapeutic agent.

26. The use according to claim 24 wherein said disease is cancer.

27. A compound of formula A: H ES NH, A wherein R' is one to three substituents that are each independently selected from fluoro, bromo, C,. haloalkyl, nitro, or l-pyrrolyl, selected from the group consisting of: - H CoH Fon F NH, NH, NH, Al A3 A4 AMENDED SHEET 2004 -05- 23 377 SUBSTITUTE SHEET (RULE 26)

Foe H H NH, NH, F NH, AS A6 A7 , Cy © and Al0. :

28. A compound of formula B: Cl “On R' RYN’ ay B wherein: R' is selected from CF,; R®’ is one to three substituents that are each independently selected from H, Cl, F, CF,, NO,, or CN, provided that R' and R® are not simultaneously Cl; 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 optionally and independently substituted by T-R*, and any substitutable nitrogen on said ring formed by R* and RY is substituted by RY; T is a valence bond or a C,, alkylidene chain; R® is selected from -R, -halo, -OR, -C(=0)R, -CO,R, -COCOR, -COCH,COR, -NO,, -CN, -S(O)R, -S(O),R, -SR, -N(R*),, -CON(R’),, -SO,N(R’),, -OC(=0O)R, -N(R’)COR, -N(R’) CO, (optionally substituted C,, aliphatic), SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -03- 25

-N (R*)N(R?),, -C=NN(R*),, -C=N-OR, -N(R’)CON(R’),, -N (R7) SO,N(R7),, -N(R*)SO,R, or -OC(=0)N(R"),; each R is independently selected from hydrogen or an optionally substituted group selected from C, aliphatic, C,,, 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, or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or hetercaryl 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.

29. A compound of formula C: R? Re jal wn Te RY“ SN"CI Cc wherein: 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 R%; R* and RY are independently selected from T-R’, or R* and RY are taken together with their intervening atoms to 379 AMENDED SHEET 2004 -05- 25 SUBSTITUTE SHEET (RULE 26)

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 optionally and independently substituted by 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,, alkylidene chain;

V is -0-, -8-, -SO-, -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®) SON (R®) -, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, -C(R®),0-, -C(R®),S-, -C(R®),SO-, -C(R®),SO,-,

-C(R®) ,SO,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-O-,

-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®),SO-, -C(R®),S0,-,

-C(R%) ,80,N(R®) -, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)OC(O)-, -C(R®)OC (O)N(R®) -, -C(R®),N(R®)CO-, -C(R®),N(R®)C(0O)O-, -C(R®) =NN (R®) -, -C(R®)=N-0O-, -C(R®),N(R®°)N(R®)-,

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

R? is selected from -R, -halo, -OR, -C(=0)R, -CO,R,

-COCOR, -COCH,COR, -NO,, -CN, -S(O)R, -S(O),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 -OC(=0)N(R"),;

each R is independently selected from hydrogen or an optionally substituted group selected from C, aliphatic, C,.,, 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 SUBSTITUTE SHEET (RULE 26) AMENDED SHEET 2004 -05- 25 together to form a 5-8 membered heterocyclyl or heteroaryl ring; 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, wherein R? is other than t-butyl when R* and R' are both hydrogen.

30. The compound according to claim 29, wherein R® and RY are each methyl, or R* and RY are taken together with the pyrimidine ring to form a quinazoline or tetrahydroquinazoline ring.

31. The compound according to claim 30, wherein R? and R? are taken together with the pyrazole ring to form an indazole ring.

32. A compound of formula D: 0 De CFs RY NC D wherein: 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 SUBSTITUTE SET (RULE 26) AMENDED SHEET 2004 -05- 25 carbon on said fused ring formed by R* and RY is optionally and independently substituted by 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,, alkylidene chain; R® is selected from -R, -halo, -OR, -C(=0)R, -CO,R, -COCOR, -COCH,COR, -NO,, -CN, -S(O)R, -S(0O),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(R7) SO,N(R"),, -N(R')SO,R, or -OC(=O)N(R’),; each R is independently selected from hydrogen or an optionally substituted group selected from C,, aliphatic, C,,, 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 -S0O,R’, or two R* on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or hetercaryl ring; and 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(=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 -OC(=0)N(R*),.

33. The compound according to claim 32, wherein R* and RY are each methyl, or R* and R* are taken together with the pyrimidine ring to form a quinazoline or tetrahydroquinazoline ring.

34. Use of a composition according to claim 10 for treating Alzheimer's disease. » AMENDED SHEET 2004 -05- 25 SUBSTITUTE SHEET (RULE 26)

35. Use of a composition according to claim 10 for treating schizophrenia.

36. Use of a composition according to claim 10 for treating diabetes.

37. Use of a composition according to claim 10 for treating cancer. AMENDED SHEET 2004 -05- 25 383 SUBSTITUTE SHEET (RULE 26)