AU2006201264A1 - Pyrazole Compounds Useful As Protein Kinase Inhibitors - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name of Applicant: Address for Service: Invention Title: Vertex Pharmaceuticals Incorporated CULLEN CO Patent Trade Mark Attorneys, 239 George Street Brisbane QId 4000 Australia Pyrazole Compounds Useful As Protein Kinase Inhibitors The following statement is a full description of this invention, including the best method of performing it, known to us: Va ID 0 0

ND

ci

X

ci ci Va

ND

^sD ci 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 usd. More particularly, this invention relates to compounds that are inhibitors of GSK-3 and Aurora-2 protein kinases. The invention also relates to methods of treating diseases associated with these protein kinases, such as diabetes, cancer and Alzheimer's disease.

BACKGROUND OF THE INVENTION The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of enzymes and other biomoleculies 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 -la- N are a number of kinases and pathways through which o extracellular and other stimuli cause a variety of ci cellular responses to occur inside the cell. Examples of Ssuch stimuli include environmental and chemical stress signals osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H202), cytokines (e.g.

tinterleukin-i (IL-1) and tumor necrosis factor a (TNF- CI and growth factors granulocyte'macrophage- 0 colony-stimulating factor (GM-CSF), and fibroblast growth ci S 10 factor (FGF). An extracellular stimulus may effect one 0 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- CD 2 protein has been found to be overexpressed. See C- -Bischoff et al., EMBO 1998, 17, 3052-3065; Schumacher M et al., J. Cell Biol., 1998', 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.

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

o 10 GSK-3 has been implicated in various diseases including C-q 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 D phosphorylation and deactivation of glycogen synthase.

C 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. 303, 21-26 ^c 5 (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 C-I is impaired, glycogen synthesis and glucose uptake fail o to.increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood ^c 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 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 byperphosphorylation of Tau in cells [Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 Therefore, it is believed that GSK-3 activity may promote generation of the neurofibrillary tangles and the progression of Alzheimer's disease..

SAnother substrate of GSK-3 is P-catenin which "C is degradated after phosphorylation by GSK-3. Reduced levels of P-catenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death [Zhong et al., Nature, 395, 698-702 (1998); Takashima et ND al., PNAS, 90, 7789-93 (1993); Pei et al., J.

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

As a result of the biological importance of S 10 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 D targets for the discovery of new therapeutics due to C their important role in cancer, diabetes, Alzheimer's Sdisease and other diseases.

DESCRIPTION OF THE INVENTION It has now been found that compounds of this invention and pharmaceutical compositions thereof are

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C( effective as protein kinase inhibitors, particularly as o inhibitors of aurora-2 and GSK-3. These compounds have ID 10 the general formula I:

R

2

HN'

I

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Z1 to Z 4 are as described below; Ring A is selected from the group consisting of: N R N N R, R 9 R N RYAN) a b c d N N I, N N RK NN

N-

IN

Se f g h 0N

II

and R pc G is Ring C or Ring D;

VO

C Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, 0q pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R; Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or heteroaryl ring, -R s is hydrogen at each ortho carbon position of Ring D;

R

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

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci- 6 aliphatic group, said phenyl, heteroaryl,

VO

0 and heterocyclyl rings each optionally substituted by Ci up to three groups independently selected from halo, Soxo, or -R 8 said C 1 -s aliphatic group optionally Ssubstituted with halo, cyano, nitro, or oxygen, or R" C 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;

R

x and R y are independently selected from T-R 3 or Rx and c- R Y are taken together with their intervening atoms to 0 form a fused, unsaturated or partially unsaturated, 5-8 cO o membered ring having 0-3 ring heteroatoms selected from C oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R" and R Y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by R x and PR is substituted by R'; T is a valence bond or a C.-4 alkylidene chain;

R

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

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R 2 and R 2 '.is substituted by halo, oxo, -CN, -NO 2 7 or

-V-R

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

R

3 is selected from -halo, -OR, -COaR, -COCOR, -COCH 2 COR, -NO 2 -CN, -S(0) 2 R, -SR,

-N(R

4 2 -CON(R 2, -S02N (R) 2 -N (R 7

COR,

C02 (optionally substituted CI-6 aliphatic),

-N(R

4 )N(R 2, -C=NN(R 4 2 -C=N-OR, -N(R 7 CON(R) 2 -N (R SO 2

N(R

7 2 -N (R)SO 2 R, or -OC(=0)N(R 7 2 each R is independently selected from hydrogen or an optionally substituted group selected from C1-.

Va aliphatic,

C

6 1 o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each Rt is independently selected from -itt -00R', -COa(CI-6 c- aliphatic),

-CON(R

7 2 or -80 2 R7; or two R on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each Rs is independently selected from halo, -OR, 0

-CO

2 R, -COCOR, -NO 2 -SO 2 R, -SR, 2 -CON(R4) 2 -S0 2

N(R)

2 -N(R 4

)COR,

-N(R

4

CO

2 (optionally substituted C1_6 aii hatic), -N(R4tN(R) 2

-C=NN(R

4 2 -C-N-OR,

-N(R

4 )CO0N(R) 2

-N(R

4

)SO

2 N(R4) 2

-N(R

4

)SO

2 R, or -OC(=O)N(R 4 2 or It 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -SO2-, -N(R 6 )S0 2

-SO

2

N(R

6 -C0 2 -NCR)CO-, -N(R CONR')-, -N(R')SO 2 2 2

S-,

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

S

2 -C(R6) 2 S0 2 2 _C(R6)jN(R6)C(O)_, -(R6)2N(R6)C(0)0-,

-C(R

6 2 -C(R6)- 2 N(R')S021(R 6 or -C(R6) 2 N CON W is -C(R 6 2 2 -C(R'h2so-, -C(R6) 2 S0 2 2

SO

2 2 N(R6-, -002-,

-C(R

6 2 N(R')oo-, 2 -C(xt6) =NN(R 6) -C(R6) 2 N(a!)N(RpR) 2 N(R) SO 2 N(R6) -C(R6) 2 N(R')C(RON or -CON(R6)-; each R 6 is independently selected from hydrogen or an optionally substituted C.4 aliphatic group, or two R' groups on the same nitrogen atom are taken together -9-

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D with the nitrogen atom to form a 5-6 membered C heterocyclyl or heteroaryl ring; Seach RI is independently selected from hydrogen or an 1 optionally substituted CI-6 aliphatic group, or two R 7 C- 5 on the same nitrogen are taken together with the nitrogen to form a 5-8-membered heterocyclyl or D heteroaryl ring; Seach R 8 is independently selected from an optionally.

substituted CI-4 aliphatic group, -OR 6

-SR

6

-COR

6 0 10 -S 2

R

6

-N(R

6 2 2 -CN, -NO 2 -CON(R6) 2 or 0 -CO 2

R

6 and R' is selected from halo, -OR, -CO 2 R, -COCOR,

-NO

2 -CN, -S 2 R, -SR, -(R 4 2 -CON(R4) 2

-S

2 N (R 4 2

-N(R

4 )COR, -N(R 4 )CO2 (optionally substituted Ci-6 aliphatic), -N(R 4 )N(R4)2, -C=NN(R 4 2 -C=N-OR, -N(R' CON(R 4

-N(R

4

S

2

N(R

4 2 -N(R SO 2 R, or

-OC(=O)N(R

4 2 As used herein, the following definitions shall apply unless otherwise indicated. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted." Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.

The term "aliphatic" as used herein means straight-chain, branched or cyclic Ci-C.2 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

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C (cycloalkyl) alkenyl. The terms "alkyl", "alkoxy", (C "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", used M alone or as part of a larger moiety includes both straight and branched chains containing one to twelve C( 5 carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety shall include both \D straight and branched chains containing two to twelve carbon atoms. The term "cycloalkyl" used alone or as (q part of a larger moiety shall include cyclic C3-C 12

\O

o 10 hydrocarbons which are completely saturated or which C contain one or more units of unsaturation, but which are not aromatic.

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

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

Also the term "nitrogen" includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl) The terms "carbocycle", "carbocyclyl", "carbocyclo", or "carbocyclic" as used herein means an aliphatic ring system having three to fourteen members.

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

The terms "carbocycle", "carbocyclyl", "carbocyclo", or -11-

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0C "carbocyclic" also include aliphatic rings that are fused C( to one or more aromatic or nonaromatic rings, such as in t a decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.

CA 5 The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or D "aryloxyalkyl", refers to aromatic ring groups having Sfive to fourteen members, such as phenyl, benzyl, C phenethyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2o 10 anthracyl. The term "aryl" also refers to rings that are C-q 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, 1-anthracyl and 2anthracyl. Also included within the scope of the term "aryl", .as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.

The term "heterocycle", "heterocyclyl", or "heterocyclic" as used herein includes non-aromatic ring systems having five to fpurteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S. Examples of heterocyclic rings include 3-1Hbenzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2tetrahydropyranyl, 3 tetrahydropyranyl, 4tetrahydropyranyl, -dioxalanyl, -dithiolanyl, [1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4- -12morpholinyl, 2-thiomorpholinyl, 3-.thiomorpholinyl, 4- (N thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3pyrrolidinyl, 1-piperazinyl,'2-piperazinyl, 1- __piperidinyl, 2-piperidinyl, 3-piperidiny., 4-p iperidiny., 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, and benzothiauyl. Also included within the scope of the term N- Theterocyclyl" -or "heterocyclic"f, as it is used herein, o iO is a group in which a non-aromatic heteroatom.-containing c-i ring is fused to one, or more aromatic or non-aromatic rings, suchas in an indolinyl, chromanyl, phenantbridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. The term "heterocycle", ",heterocyclyl", or ',heterocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted.

The tent "heteroaryl", used alone or as part of a larger moiety as in 'teteroaralkyl" or "lheteroarylalkoxy", refers to heteroaromatic ring groups having five to fourteen members. WExamples of heteroaryl rings include. 2-furanyl, 3-furanyl, N-imidazolyl, 2imidazolyl, 4-imidazolyl, 5-iinidazolyl, 3-isoxazolyl, 4isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, S -oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2pyrrolyl, .3-pyrrolyl, 2'-pyridyl,,3-pyridyl, 4-pyridyl, 2pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, qino.inyl, benzotriazolyl, benzotbhiazolyl,, 'benzooxazolyl, benaimidazolyl, isoquinolinyl, indolyl, -13- Va isoindolyl, acridinyl, or benzoisoxazolyt. Also included within the scope of the term "beteroaryl", 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 C 5 radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolinyl, \D tetrahydroisoquinolinyl, and pyrido(3,4-d pyrimidinyl.

The term "heteroaryl" also refers to rings that are C. optionally substituted. The term "heteroaryl" may be o 10 used interchangeably with the term "heteroaryl ring" or Cl 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 0 -ORO, -SRO, 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl substituted Ph, substituted -O(Ph),

-CH

2 substituted -CH 2

-CH

2

CH

2 substituted -CH2CH 2

-NO

2 -CN, -N(RO) 2 -NROC(O)RO, -NROC(O)N(R) 2

-NR

0 CO2R, -NRONRC RO, -NRONROC N (Ro) 2

-NRONRCO

2

R,

-C(O)C(0)R 0

-C(O)CH

2 C(O)R, -C0 1 RO, -C(O)R 0

-C(O)N(RO)

2

-OC(O)N(R

0 2

-S(O)

2 R, -SO 2 -S(O)RO, -NRoS0 2

N(R

0 2 i -NROS0 2 RO, -C(=S)N(Ro) 2 -C(=NH)-N(Ro 2 -(CH)yNHC(O)R,

-(CH

2 yNHC(O) CH (V-RO) wherein R 0 is' hydrogen, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl substituted Ph, substituted -O(Ph),

-CH

2 or substituted -CH 2 .y is 0-6; and V is a linker group. Examples of substituents on the aliphatic -14-

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o 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.

NA 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 C ring include those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: =NNHR*, =NN(R) 2 =NNHC(o)R*, =NNHCO 2 (alkyl),

=NNHSO

2 (alkyl), or 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 nonaromatic heterocyclic ring include 2 -C R,

-CO

2 R, -C(0)C(o)Rt, -C(0)CH 2 C(O)R, -SO 2 -S0 2

N(R

4 2 -C N (R) 2 2 and -NR+SO 2 wherein R+ is hydrogen, an aliphatic group, a substituted aliphatic group, plienyl substituted Ph, -0 substituted -0 CH 2 substituted CH2 (Ph), or an unsubstituted heteroaryl or heterocyclic ring.

Examples of substituents on the aliphatic group or the phenyl ring include amino, alkylamino, dialkylaniino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,

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dialkylaminocarbonyl, alkylaminocarbonyloxy, Cq 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.

0D Linkers are typically comprised of an atom such as oxygen Sor sulfur, a unit such as -CH2-, -C(0)NH-, Ci or a chain of atoms, such as an alkylidene chain. The o 10 molecular mass of a linker is typically in the range of Ci 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 C1-6 alkylidene chain which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced'by -CONH-, -CONHNH-, -CO2-, -NHC0 2 -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -SO2-, -SO 2 NH-, or -NHS02-.

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-

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of the structure; the R and S configurations for CI each asymmetric center. Therefore, single stereochemical ct isomers as well as'enantiomeric and diastereomeric mixtures of the present compounds are within the scope of CA 5 the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which 110 differ only in the presence of one or more isotopically ci enriched atoms. For example, compounds having the c-I present structures except for the replacement of a

INO

hydrogen by a deuterium or tritium, or the replacement of Ci a carbon by a 3 C- or 4 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, without limitation, diabetes, Alzheimer's disease, Huntington's Disease, Parkinson's Disease, AIDSassociated dementia, amyotrophic lateral sclerosis (AML), -17sclerosis schizophrenia, cardiomycete c- hypertrophy, reperfusion/ischemia, and baldness.

One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering c- 5 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 c I or a pharmaceutical composition thereof. This method 0q is especially useful for diabetic patients. Another o 10 method relates to inhibiting the production of 0hyperphosphorylated Tauprotein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of -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 -18deleterious 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, Current Medicinal Chemistry, 7, 1213-1245 (2000); Mani, Wang, Wu, Francis, R. and Pestell, Exp. Opin. Invest. Drugs, 9, 1849 (2000); Fry, D.W. and Garrett, Current Opinion in -19-

VO

0 Oncologic, Endocrine Metabolic Investigational Drugs, (N 2, 40-59 (2000).

cAnother aspect of the invention relates to Sinhibiting CDK-2 activity in a biological sample or a 5 patient, which method comprises administering to the patient a compound of formula I or a composition Scomprising said compound.

ci C_ Another aspect of this invention relates to a 0 method of treating or preventing an ERK-2-mediated O 10 diseases with an ERK-2 inhibitor, which method comprises 0 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,

ID

o papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney t carcinoma, myeloid disorders, lymphoid disorders, SHodgkin's, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colonrectum, large intestine, rectum, brain and central ID nervous system, and leukemia. ER-2 protein kinase and ci Sits implication in various diseases has been described Q [Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science CI 258, 478; Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al.

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

210, 162; Moodie et al., 1993, Science260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, An. 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 ora 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-

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D "AKT-mediated condition" or "disease" also means those (c diseases or conditions that are alleviated by treatment Swith a AKT inhibitor. AKT-mediated diseases or conditions include, but are not limited to, proliferative C 5 disorders, cancer, and'.neurodegenerative disorders. The association of AKT, also known as protein kinase B, with oD various diseases has been described [Khwaja, Nature, 2- pp. 33-34, 1990; Zang, Q. et al, Oncogene, 19 2000; 0 C- Kazuhiko, et al, The Journal of Neuroscience, o 10 2000).

C 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-

VO

SDrugs of the Future 2000, 25(7), 717, (2000); Talamonti, SJ. 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 CN 5 (1987); Masaki, Hepatology, 27, 1257 (1998); Biscardi, Adv. Cancer Res., 76, 61 (1999); Lynch, Leukemia, 7, 1416 ksD (1993); Wiener, Clin. Cancer Res., 5, 2164 (1999); SStaley, Cell Growth Diff., 8, 269 (1997)].

Ci Another aspect of the invention relates to o 10 inhibiting Src activity in a biological sample or a Ci 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- CD for example, the Biological Testing Examples described C below.

Pharmaceutically acceptable carriers that may be'used in these pharmaceutical compositions include, but C 5 are not limited to, ionexchangers, alumina, aluminum.

stearate, lecithin, serum proteins, such as human serum ,D albumin, buffer substances such as phosphates, glycine, sorbic acid,, potassium sorbate, partial glyceride 0g mixtures of saturated vegetable fatty acids, water, salts o 10 or electrolytes, such as protamine sulfate, disodium eC 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, viginally 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- Va

ID

0 o solution or suspension in a non-toxic parenterallyci Sacceptable diluent or solvent, for example as a solution ct in 1,3-butanediol. Among the acceptable vehicles and -solvents that may be employed are water, Ringer's ci solution and isotonic soditim chloride solution. In Saddition, sterile, fixed oils are conventionally employed

N

D as a solvent or suspending medium. For this purpose, any o bland fixed oil may be employed including synthetic monoci or di-glycerides. Fatty acids, such as oleic acid and o 10 its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceuticallyacceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers 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.

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

For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When Va

IND

0 aqueous suspensions are required f6r oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may be administered in the form of ID suppositories for rectal administration. These can be ci prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature o 10 but liquid at rectal temperature and therefore will melt 0 in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol s 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 applicatipn, 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 Isee 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 cain be formulated in a suitable lotion or -26- Va ID 0.

o cream containing the active components suspended or ci jdissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited Sto, mineral oil, sorbitan monostearate, polysorbate cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, Sbenzyl alcohol and water.

IN

Ci For ophthalmic use, the pharmaceutical o compositions may be formulated as micronized suspensions ci ID in isotonic, pH adjusted sterile saline, or, preferably, 0 o 10 as solutions in isotonic, pH adjusted sterile saline, ci either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment' such as petrolatum.

The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be'prepared as solutions in saline, -employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

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

A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester,, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or -27-

VO

0 indirectly, a compound of this invention or an C inhibitorily active metabolite or residue thereof.

Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of C( 5 this invention when such compounds are administered to a patient by allowing an orally administered oD compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a CN biological compartment the brain or lymphatic o 10 system) relative to the parent species.

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

Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfite, 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-

VO

obtaining the compounds of the invention and their (Nq pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal sodium and potassium), alkaline earth (N 5 metal magnesium), ammonium and N+(C.

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

Va o 10 The amount of the protein kinase inhibitor that c-i 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 kinasemediated 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-

VO

ID

o agents may be combined with the GSK-3 inhibitors of this invention to treat diabetes. These agents include, Swithout limitation, insulin or insulin analogues, in injectable or inhalation form, glitazones, alpha C 5 .glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonyl ureas.

ID Other examples of agents the inhibitors of this invention may also be combined with include, without

C

N limitation, chemotherapeutic agents or other anti- O 10 proliferative agents such as adriamycin, dexamethasone, C vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives; antiinflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, .azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti- Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

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

VO

SAlternatively, those agents may be part of a single dosage form, mixed together with the protein kinase Sinhibitor of this invention in a single composition.

SCompounds of this invention may exist in alternative tautomeric forms, as in tautomers 1 and 2 shown below. Unless otherwise indicated, the 0D representation of either tautomer is meant to include the Sother.

ID

VO

R2

R

2 N R'NH Z 22H k z 3 Nz2 3Z z2 A

A

1 2 R and- R y (at positions Z 3 and.Z', respectively) may be taken together to form a fused ring, providing a bicyclic ring system containing Ring A. Preferred RX/R

Y

"rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said RX/R Y ring is optionally substituted.

Examples of Ring A systems are shown below by compounds I-A through I-DD, wherein Z1 is nitrogen or C(R 9 and 22 is nitrogen or C(H).

R

2 *SNH HN

HN

HN-"

Z

I-A I-B

I-C

-31- 1.317 H'17

I-D

I-H I-F 3-G I -H I-1

H??

NIZ

HN-3rtl

H?

I-j I-K I-L HN HN"N r N Z2

Z

I-N I-0 HN377 N

Z,

C-N I so H??"N H??3' I-p I-Q I-R -32- Va HN HN

HN

(t2 txZ2Q I-S I-T

I-U

Va HN HN HN't sS 2- x-z o1N XZ2 Nz NZ'4 R

R

-v I-w I-AA HNH

HN

Preferred bicyclic Ring A systems include I-A, I-B, I-C, I-DR I-K L, and I-M, more preferably I-A, I-B, I-C, I-F, and I-H, and most preferably I-A, I'B, and I-H.

In the monocyclic Ring A system, preferred RX groups, when present, include hydrogen, alkyl- or dialkylamino, acetamido, or' a C.1-4 aliphatic group such as methyl; ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred Ry groups, when present, include T-R 3 wherein T is a valence bond or a methylene, and R 3 is -N1(R 4 2 -33-

VO

O or -OR. Examples of preferred R Y include 2-pyridyl, 4- C pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, aikyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl or halo- CI 5 substituted phenyl; and methoxymethyl.

In the bicyclic Ring A system, the ring formed when R x and R Y are taken together maybe substituted or c-I unsubstituted. Suitable substituents include halo, C -OR, -CO2R, -COCOR, -NO 2 -CN, -S02R, O 10 -SR, -N(R 4 2 -CON(R4'), -SN(R 2

-N(R,)COR,

NC -N(R')C02 (optionally substituted Ci- aliphatic)

-N(R

4

)N(R

4 2

-C=NN(R

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

)CON(R

4 )2,

-N(R

4

)SO

2 N(R4) 2

-N(R

4

)SO

2 R, or -OC(=O)N(R4) 2 wherein R and

R

4 are as defined above. Preferred Rx/R y ring substituents include -halo, -OR, -COR, -C02R,

-CON(R)

2 -CN or -N(R 4 2 wherein R is hydrogen or an optionally substituted C_-6 aliphatic group.

R

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

,HN

'Z NH, N H H

NH

and -34-

IND

0 Pref erred .substituents on the'R 2

/R

2 fused ring *include one or more of the following: -halo, 2 -c 1 3 alkyl, -C 1 3 haloalkyl, -NO 2 3 alkyl), -CO 2

(C

1 3 al~kyl), -Cit -S0 2 3 alkyl), -S0 2

NH

2

-QC(O)NH

2 N11 2 S0 2 3 alkyl) -NHC (C 1 3 alkyl) -C (O)NM 2 and -CO (C 1 3 alkyl), wherein the (C3.-3 aflkyl) is most preferably Va methyl.

When the pyrazole ring system *s monocyclic, preferred R2 grouips include hydrogen, C 1 4 aliphatic, alkoxycarbonyl, (un) substituted phenyl,- hydroxyalkyl, Ci alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaruinoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, *propyl, t-butyl, cyclopentyl, phenyl, CO 2

H,

co 2 Cn 3 cw 2 oH, CH 2 0CH 3

CH

2

CH

2

CH

2 OH, CH 2

CH

2

CH

2 00E 3 C11 2 C11 2 C2CH 2 Ph, CH 2

CH

2

CH

2

NH

2

CH

2

CII

2

CH

2 NECOOC (CE 3 3

CONHCZH(CH

3 j) 2 CONHCi 2 CM=0H 2

CONHCI

2

CH

2 OCZH,, CQNHCH 2 Ph, CONH~cyclohexyl), CON(Et) 2

CONCH

3

)CH

2 P h, CONH(n-C 3 CON (Et) CH 2

CH

2

CH

3

CONHCH

2 CH (CH3) 2 CON(n-C 3

H

7 2 Co (3methoxymethylpyrrolidin-I-yl), CONE (3-tolyl), CONE (4- :tolyl) CONHCH 3 CO(morphiolin-71-yl) CO(4.-methylpiperazin- -yl) CONHCH 2

CW

2 OH,' CONE 2 and CO (piperidin-1-yl). A preferred R 2 group is hydrogen.

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

VO

Rx

R

NH

C thereof, wherein;

NO

SRing C is selected from a phenyl, pyridinyl, pyrimidinyl, C pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R 8 R' is selected from -halo, -CN, -NO 2

T-V-R

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

substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;

R

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

R

Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 -36- VO ID o membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable Scarbon on said fused ring formed by RX and R Y is substituted byoxo or T-R 3 and any substitutable nitrogen on said ring formed by Rx and R Y is substituted by R 4 \O T is a valence bond or a C 1 4 alkylidene chain;

R

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

,R

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

-V-R

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

R

3 is selected from -halo, -OR, -C0 2

R,

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

-N(R

4 2

-CON(R')

2 -S0 2

N(R

7 R, -N (R')COR, C02 (optionally substituted Ci-, aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R

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

-N(R')SO

2

-N(R

4 )S02R, or each R is independently selected from hydrogen or an optionally substituted group selected from C 1 -s aliphatic, C6-o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected..from -R 7

-COR

7 -CO2 (optionally substituted Ci-6 aliphatic), -CON(R 2 or.-S0 2 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; -37- Va each R5 is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, 2

CON(R')

2 -S0N(R) 2

-N(R')COR,

CO

2 (optionally substituted C 1 6 aliphatic),

-N(R

4

)N(R)

2

-C=NN(R

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

)CON(R')

2

-N(R

4

)SO

2

N(R)

2 N(R4)-SO 2 R, or -OC(=O)N(R 4 2 or R 5 and a an adjacent substituent taken together with their intairvening atoms form said ring fused to Ring C; \O V is -502-, -SO 2 N(R6)-,

-N(R

6 -002-, -N(R6)CO-, -N(Rs)C(O)O-, 0 -N(R6)SO 2

N(R

6

-C(R

6 2

C(R

6 )2S, 2 SO-, -C(R 6 2 so 2 -c(RC) 2

SO

2 2

-C(R

6 2 2 =NN(a 6 2

N(R

6

)N(R

6

-C(R

6 2

N(R")SO

2 or -C 2

N(R

6 CON W is 2 2 2 SO-, 2 S0 2

C(R')

2 S0 2

-C(R

6 2

N(R

6 -C02-, 2

N(R')CO-,

2 -C 2 N N 2 N SO 2 N -C(R6) 2 CON or each R' is independently selected from hydrogen, an optionally substituted C3-4 aliphatic group, or two R' groups on the same nitrogen atom are taken tbgether with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each'R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R' on the same nitrogen are taken together with- the nitrogen. to form a 5-8 membered heterocyclyl or heteroaryl ring; and -38m I Va each Re is independently selected from an optionally substituted Qj- aliphatic group,

-COR',

-S0 2

R

6 2 2 -CN, -NOA, -CON(R) 2 or 6

-CO

2

R.

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

FZ2

R

NH

HN> HN

N

I-A II-B II-C HN'3Z HN>' HN3 R 4 II-D II-E II-F HNA HN HN Me Me SI-G I-H Il-I -39- Va HN> HN3'? HN> Z:9 N Nctx q N rt, N

N,

II-J II-K II-L Va HN HNN HN NZ N i cl "I N N" II-M Il-N II-O

HNA

'I-P

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

In the monocyclic pyrimidine ring system of formula II, preferred R t groups include hydrogen, alkylor dialkylamino, acetamido, or a Ca..4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred RY groups include T-R 3 wherein T.is a valence bond or a methylene, and R' is 2 or -OR. Whan

R

3 is -R .or -OR, a preferred R is an optionally substituted group selected from C 16 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred RY include.2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl

VO

o such as phenyl or halo-substituted phenyl, and methoxymethyl.

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

R,

IND -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2 -CON(Rt)2,

-SO

2

N(R)

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

-C=NN(R

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

-N(R)SO

2

N(R

4 2

-N(R

4

)SO

2 R, or

-OC(=O)N(R

4 2 wherein R and R are as defined above.

Preferred RX/RY ring substituents include -halo, -OR, -COR, -CO 2 R, -CON(R -CN, or 2 wherein R is an optionally substituted C 1 -6 aliphatic group.

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

NH

HN N X N N \NN NH NH NH NH RY N N N N Sand Preferred substituents on the R 2

/R

2 fused ring of formula II include one or more of the following: -halo, 4 alkyl, -C-4 haloalkyl, -N02, -O(CNalkyl), -CO2(C Q4 alkyl) -CN, -SO2(C.4 alkyl), -so2NH2, -41-

VO

o -OC(O)NH 2

-NH

2 S0 2 alkyl), -NHC(O) alkyl)

-C(O)NH

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

.When the pyrazole ring system of formula II is monocyclic, preferred R 2 groups include hydrogen, a 0D substituted or unsubstituted group selected from aryl, Sheteroaryl, or a C1-6 aliphatic group. Examples of such CN preferred R 2 groups include methyl, t-butyl, -CH2OC3, o 10 cyclopropyl, furanyl, thienyl, and phenyl. A preferred Ci R 2 group is hydrogen.

More preferred ring systems of formula II are the following, which may be substituted as described above, wherein R 2 and R 2 are taken together with the pyrazole ring to form an indazole ring; and Rx and R Y are each methyl, or R x and R Y are taken together with the pyrimidine ring to form a quinazoline or tetrahydroquinazoline ring: NH NH NH HN N HN HN N N H3C N O H t.

II-Aa II-Ba II-Ha Particularly preferred are those compounds of formula II-Aa, II-Ba, or II-Ha wherein ring C is a phenyl ring and R' is halo, methyl, or trifluoromethyl.

Preferred formula II Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is -42contained in a bicyclic ring system. Preferred fused c rings include a benzo or pyrido ring. Such rings Spreferably are fused at ortho and meta positions of Ring C. Examples of preferred bicyclic Ring C systems include Ci 5 naphthyl, quinolinyl and isoquinolinyl.

An important feature of the formula II \O compounds is the R 1 ortho substituent on Ring C. An ortho position on Ring C or Ring D is defined relative to the- C position where Ring A is attached. Preferred R 1 groups S 10 include -halo, an optionally substituted CI-6 aliphatic cN group, phenyl, -COR 6

-OR

6 S, -SOO 2 R -SONH,, -N(R 6 -C0 2

-CONH

2

-NHCOR

6

-OC(O)NH

2 or -NHSO0R 6 When R 1 is an optionally substituted CI- 6 aliphatic group, the most preferred optional substituents are halogen. Examples of preferred R' groups include -CF 3 -Cl, -CN, -COCH 3 -OCH3, -OH, -CH 2

CH

3

-OCH

2

CH

3

-CH

3

-CF

2

CH

3 cyclohexyl, t- -butyl, isopropyl, cyclopropyl, -CCH, -C C-CH 3 -SO2CH3, -S0 2

NH

2

-N(CH

3 2

-CO

2

CH

3

-CONH

2

-NHCOCH

3

-OC(O)NH

2

-NHSO

2

CH

3 and -OCF 3 On Ring C of formula II, preferred R substituents, when present, include -halo, -CN, -NO 2 optionally substituted Ci- 6 aliphatic group, -OR,

-CO

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

SO

2 R. More preferred R 5 substituents include -Cl, -CN, -CF 3

-NH

2 -NH(CiZ 4 aliphatic), -N(CI-4 aliphatic) 2 -0(C 1 -4 aliphatic), C31 4 aliphatic, and -C0 2 4 aliphatic). Examples of such preferred R substituents include -Cl, -CN, -CF3, -NH 2 -NHMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, .tbutyl, and -CO 2 Et.

Preferred formula II compounds have one or more, and more preferably all, of the features selected from the group consisting of:

VO

Ring C is a phenyl or pyridinyl ring,

C

N optionally substituted by -R s wherein when Ring C and two Sadjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a C 5 naphthyl, quinolinyl or isoquinolinyl ring;

R

X is hydrogen or C 1 -4 aliphatic and R y is VO T-R 3 or R X and R Y are taken together with their Sintervening atoms to form an optionally substituted 5-7 CA membered unsaturated or partially unsaturated ring having O 10 0-2 ring nitrogens; C R- is -halo, an optionally substituted Ci-.

aliphatic group, phenyl, -COR 6

-OR

6 -CN; -S0 2

R

6

-SO

2

NH

2 -N (R 6 2 -C0 2 R, -CONH 2

-NHCOR

6 -QC(0)NH 2 or -NHSO 2

R

6 and

R

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

'More preferred compounds of formula II have one or more, and more preferably all, of the features.

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

R

x is hydrogen or methyl and R Y is -R, N(R)2, or -OR, or Rx and R Y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated carbocyclo ring optionally substituted with halo, -OR, -CO 2 R, -COCOR,

-NO

2 -CN, -S0 2 R, -SR, -N(R 2

-CON(R)

2 -44-

VO

ID

o -SO 2

N(R

4 2

-N(R

4 )COR, -N(R).CO2 (optionally substituted C 1 6 aliphatic), -N(R 4

)N(R

4 2

-C=NN(R

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

-N(R')SO

2

N(R)

2

-N(R)SO

2 R, or -OC N (R 4 2; R' is -halo, a C..

6 haloaliphatic group, a CI-s aliphatic group, phenyl, or -CN; VO R 2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a C 1 -6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and each R 5 is independently selected from -halo, -CN, -N0 2

-N(R

4 2 optionally substituted CI-S aliphatic group, -OR, -CO 2 R, -CONH(R 4

-N.(R)COR,

-SO2N(R 2, .or SO 2

R.

Even more preferred compounds of formula II have one or more, and more preferably all, of.the features selected from the group consisting of: Ring C is a phenyl ring optionally substituted by -R 5 R" is hydrogen or methyl and R Y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or Rx and R y are taken together with their intervening atoms to form an optionally substituted benzo ring or partially unsaturated 6-membered carbocyclo ring;

R

1 is -halo, a C 1 -4 aliphatic group optionally substituted with halogen, or -CN;

R

2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring Va optionally substituted with -halo, 2 -C14 alkyl,

-C

1 4 baloalkyl, -NO 2 4 alkyl), -C0 2

(C,

4 alkyl), -CN,

-SO

2 (C-4 alkyl), -S0 2 Nf 2 -OC(O)NI1 2

-NH

2 SO2 (C.4 alkyl), 9NHC(O) (C 1 4 alkyl), -C(O)NH 2 or -CO(C..4 alkyl), wherein the (C1-4 alkyl) is a. straight, branched, or cyclic alkyl group; and IN each R5 is independently selected from -C1, -CN, -CF 3

-NH

2

-NH(C

1 4 aliphatic), -N(C 1 -4 V aliphatic) 2 -0 (C- 4 aliphatic), C 1 4 aliphatic, and

-CO

2

(C

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

able CH3 \N1 'H T'H

H

HNrK. W'W 2 NjH iHICtN CA (N CI I~ N CF3.

HN

HC N' N N

HN

20-1 II-2 II-3 F F \F F.

H -H H ~N C N'CI N CI II-4 II-5 11-6, -46- 11-7 'I-s

HN

N CF3 C)Ni 11-9

ICF

3 11-12 KhXN OCF 3 11-15 11-13 11-14 11-16 11-17

*N-

N CF 11-20 11-18 11-19 11-21 -47- 11-22 11-23 11-25 KaC ItN- CF 3 11-28

F

11-31

CH

3 HNtPH HaC kN Cl

H

3

C

11-26

CII

HAO

HCtI N CI

H

3 C N' 11-29 Cl 3 OtNOH 8 3 C N -F H3 N' 11-24

H

3

C

H

3 C 'N Us *11-27

HN

H

3 C

NQ

H

3 C N- 11-30

CH

3

CH

3 -48- -I1-34

OH

3 f'J1N OCH 3 11-37 .0K 3

HN

t Plq 11-40 11-35

CH

3

*HN

4

P

H

3 C

N

11-38

OH

3 HN J:H N F 11-41 HN3 .44H

N

11-44

N

11-47

OH

3

HAH

HNkO 11-39

OH

3 H~t cX>)rN$H2CH3 11-42

OH

3

HN*

N DCH 2

CH

3

N)Y

11-45 ItiN CF 3

NIK

11-48

OH

3 HN d 11-43 11-46.

-49-

OH

3

HH

NCF

3 11-49 .0 H2N

H

H-N

CI:

U N

CF

8 11-52

HNH

N

H C4H 11-53

H

HN

ItiN CF 3

NCF

3

NO

11-54 HN&5 2 Nt>63

F

11-59 N CF 3 Nt H N 1-1-60

IN

0

H

3

C

N CF 3 Il-El

F

3

C

NCF3 11-64

HNQ

11-67.

0 2

N

HN.

O N CF 3 11-70 ;N CI 11-63 11-62

NH

HN

NCF3 11-65 CF3 11-71

HNX

Cl 11-66 Cr 3

HZ

N CF 3 N O69

C$

N CF 11-72 -51-

H

2

N

HNV

A, N

CF

3 11-73 F

F

HN

N CI 11-76 Br 11-79 Br

HZ

CF

3 11-82 11-74 Fac

H~

11-77

CI

11-75 ~1H HN CF roo N Cl 11-75 N CN Nr CF3 11-80 1I-81 F

F

N CF3 11-83

<F

F

11-84 -52- N Br N18

FNCF

H

H Nm 11-86 11-87

HN

N CFS 11-88

F

Q N CF 11-91

F

N CI 11-94 rlitrkN

CF

3 OCH3 11-93 F

F

H

11-96 11-92 .II-95 -53- Va 0 0 ci ci N19 11-97 11-98 11-99

CH

3

H

3 04

H

HN

QIN 00F 3 11-100 11-102 11i-101

I

AQtOCFS 11-104

CH

3

'NOCF

3

H

3 C9 '1 '.l

CH

3 HNtt A N CI 11-106

CF

3 11- 107 11-108 -54oZl-II I

N

HH

LtT-I' ra3 NQQA

HH

ZNH

Ht-I 611-I11

QN

13

NZ

9£11 I

HZ

oTT-I' N N% Yt ST1-I' £3

NQ

HH

HD N ji

HH

Sr-I 0 0

HN%

AN CF 3 1112 11-121

F

H

HN

11-124 H?4 11-122 M0O 2C..rq

HN

11-125

YH

N N' )-1 11-123 C.N

CF

3

F

biN

CI

11-129 11-131 11-132 -56- Va 0 0 ci ci

OH

3 11-133

F

3

C

11-135 11-134 CHit

HN

11-136 11-137

H

3

C

AcNH F 3

C

11-140 H3C~k

N>

HNQ cro 11-143 11-138 11-139 11-141 11-142 11 -144 -57- 11-145 11-146 11-247 N CF 3 1 IQNCF3 Me 11-149

F

P,.N CF 3

N'

11-148 11-150

F

HN

1-151 11-152 11-153 -58- HN 'M

NCF

3 11-154 11-155 11-156

H

2

N

HN

11-158 11-157' 11-159, Hg MecA N

H

HN CF 3 4 11-161

HN

11-164

HN

11-162 Me HN J-tNH

"'NCF

3 11-165 11-163 -59-

HN

Cbz IN

C

3 HC 1 N CF 3 eKJ N F3 H3?)

OH

3

N

Cbz 11-168 11-166 11-167

H

3 C%*I

H

11-169 11-170 11-171 0 HaCAkNH 11-172 H3C"NH N CF 3 11-173

HN

2 (N CF 3

H

2 N NAY 11-176

HN

1

N

Cbz'N.

Hf??

YNH

2 ~N CF3

N'

11-174 .Cbz.

11-175 11-177

HN

2 11-178 11-178 11-179 11-180 11-180 H Io 11-181 .HN

RN-

Ac 11-182 11-183 11l-184 11-185 11-186

HNN

CN N CH N&ll CF 3 T-1-189 Cbz-' 11-187 11-188 AcNH 1119 9wH

MS

2 IfkN 11-191 11-192 -61- 11-193

HH

MeINtN CF, 11-194

FF

AcHN Me 9 11-200 11-195 HN CF 3 11-196 0 11-199 11-198 Me

H

2 NOSXN' fJ 11-201

F

11-204 11-202 11-203 -62-

HN

11-205 11-206 11-207 11-208 11-209 11-210

CH

3 H N 11-211

N

11-212

F

11-213 11-216

HN?

tNC 11-214, 11-215 -63- HN NN CI 11-217

F

HN

C2 11-220 11-218 11-219 H N

CH

11-221 11-222

HN

N C(O)NH 2 11-223'

F

Me 11-225 .11-224 11-226 11-227 11-228 -64- 11-229 Izs

I

I-B~

11-232 Fy

HIV

N C(O)NH 2 11-235 11-230 11-231 NH2 11-236 Fq HN2

N

t-Bu2 1-234

NN~

.NH2 11-237

F

gNH2 N NH 11-238 11-239 11-240 Va 0 0O ci 11-241

F

N CN 11-244 F

F

N SO 2

NH

2 11-247 11-242 N 0NH tNOCH 3 11-245 HThV 11-248 OtN N0 2 11-243

F

Qh~N N02 11-246 N S0 2 N(Me) 2 11-249 H H~ N SO 2 N(Me) 2 MsCfN CF 3

N

11-250 11-251 In another embodiment, thisinvention provides a couposition comprising a compound of formula II and a pharmaceutically acceptable carrier.

-66-

IN

o One aspect of this invention relates to a (N method of inhibiting GSK-3 activity in a patient, Scomprising administering to the patient a therapeutically Seffective amount of a composition comprising a compound CA 5 of formula II.

Another aspect relates to a method of treating q0 a disease that is alleviated by treatment with a GSK-3 2 inhibitor, said method comprising the step of 0 administering to a patient in need of such a treatment a IN 10 therapeutically effective amount of a composition C-i comprising a compound of formula II.

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

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

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

One aspect of this invention relates to a method of inhibiting Aurora activity in a patient, -67-

ID

0 comprising administering to the patient a therapeutically C-i effective amount of a composition comprising a compound 3of formula II.

SAnother aspect relates to a method of treating C- 5 a disease that is alleviated by treatment with an Aurora inhibitor, said method comprising the step of administering to a patient in need of such a treatment a c- therapeutically effective amount of a composition 0 comprising a compound of formula II. This method is D 10 especially useful for treating cancer, such as colon, 0 ovarian, and breast cancer.

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula II. This method is.

especially useful,for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid -arthritis.

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

-68- O ID D Each of the aforementioned methods directed to the inhibition of GSK-3, Aurora or CDK-2, or the Streatment of a disease alleviated thereby, is preferably Scarried out with a preferred compound of formula II, as N 5 described above.

Another embodiment of this invention relates to \D compounds of formula III: CR2 0 HN N RK N

III

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

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; Rx and R y are taken together with their intervening atoms to form a fused, benzo .ring or a 5-8 membered carbocyclo ring, wherein any substitutable carbon on said fused ring formed by R x and R Y is substituted by oxo or T-R3; T is a valence bond or a Ci.- alkylidene chain; -69o R and R 2 are independently selected from or N R 2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R 2 7 and R2' is substituted by halo, oxo, -CN, -NO 2 -R or -V-R6, and any substitutable nitrogen on said ring formed by R 2 and RI is substituted by R 4 o 10 R3 is selected from. -halo, -OR, R, -CO 2

R,

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

-N(R

4 2,r -CON(R 4 2

-SO

2 N(Rt) 2

-N(R

4

COR,

-N(R

4 )CO (optionally substituted C 1 6 aliphatic),

-N(R

4 2

-C=NN(R')

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

-N(R)SO

2 N 2

-N(R

4 S02R, or -OC(=O)(R each R is independently selected from hydrogen or an optionally substituted group selected from C-s aliphatic, C6-3o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -R 7

-COR',

-CO

2 (optionally substituted C 1 -s aliphatic), -CON 2 or -SO 2 or two R 4 'on the same nitrogen. are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo,' -OR, -C0 2 R, -COCOR, -NO 2 -CN, -S0 2 R, -SR,

-N(R

4 2 -CON(R4) 2

-SO

2

N(R')

2 -N(Rt)COR, CO2 (optionally substituted Cie- aliphatic),

-N(R)N(R)

2

-C=NN(R)

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

-N(R')SO

2

N(R')

2

-N(R')SO

2 R, or -OC(=O)N(R4)2; V.is -S02-, 6 )S0 2

-SO

2 -CO2-, CO-, -N(R 6 )C Va CON (R 6

SO

2 -N N (R 6 -c(R 6 2 2

S-,

2 SO-, 2

SO

2

-C(R

6 2

SO

2

-C(R

6 2 N(6-, -C(R6) 2N(R6)C() -C(R6)2N(R6)N(R6)-, -C(Ro2N(r)SO2N(RP)-, or -C N (R6) CON (R6) VW is -C(R 6 2

-C(R

6 2

-C(R

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

-C(R

6 2 so 2 2 N (R 6 -CO2-,

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

6 -C 2N(R) CO-, 2 -C(R 6 S-C(R 2N -C(R6) 2N(R6) SO2N R6) r C(R 6)2N(R6) CON(R6)--, or -CON(R)-; each R6 is independently selected from hydrogen or an optionally substituted C1.4 aliphatic group, or two R' groups on the same nitrogen atom are taken together with the nitro!en atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R7 is independently selected from hydrogen or an optionally substituted c2-6 aliphatic group, or two R' on the same nitrogen, are taken together with the nitrogen to form a -5-8 membered heterocyclyl or heteroaryl ring.

Preferred formula III Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings. When two adjacent substituents on Ring D are taken together to form a fused ring, the Ring D system is bicyclic. Preferred formula III Ring D bicyclic rings include 1,2,3,4tetrahydroisoguinolinyli, 1,2,3,4- tetrahydroguinolinyl, 2,3-dihydro-1H-isoindolyl, 2, 3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of -71-

VO

o more preferred bicyclic Ring D systems include naphthyl C and isoquinolinyl.

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

-N(R)

2 -C0 2 R, -CONH(R 4

-N(R

4 )COR, -SO 2 N(R4 2

-N(R

4

)SO

2 R, or substituted or unsbbstituted group selected from 5-6 Smembered heterocyclyl, C6s-o aryl, or CI-6 aliphatic. More preferred R 5 substituents include -halo, -CN, -oxo, -SR, 0 -OR, -N(R 4 or a substituted or unsubstituted OD 10 group selected from 5-6 membered heterocyclyl, C 6 -io aryl, 0 or C1p aliphatic. Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 OH, CH 2

CH

2

OH,

pyrrolidinyl, OPh, CF3, CkCH, Cl, Br, F, I, NH 2

C(O)CH

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

Preferred rings formed when the Rx and R Y groups of formula III are taken together to form a fused ring include a or 7-membered unsaturated or partially unsaturated carbocyclo ring, wherein any substitutable carbon on said fused ring is substituted by oxo or T-R.

Examples of preferred bicyclic ring systems are shown below.

R R

H

HN^' N HN HN Z7 III-A III-B III-C -72- 0H?'1 H3? AZ Kt 2 ot; Preferred substituents on the RX/RY fused ring of formula III include -Ri, oxo, halo, -OR, '-CO 2

R,

-000CR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2

-CON(R

4 2

IN

-SO

2

N(R

4 2 1

-,N(R

4 )C0 2 (optionally subtittedCI,- aliphatic), -N(R 4 2

-C=NN(R

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

)CON(R

4 2

-N(R

4

)SO

2

N(R)

2 -N(R 4

SO

2 R, Or -OC N(W) 2 wherein R. and le 4 are as def ined above.

More preferred substituents- on the eR 2 /R fused ring include halo, CN, oxo, C- 1 6 alkyl, C 1 6 alkoxy, alkyl)'carbonyl, (C3.- 6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or *315 dialkylaminocarbonyloxy, or 5 -6 membered heteroaryl.

Examples of such preferred substituents include methoxy, methyl, isopropyl, methylsulfonyl; cyano, chioro., pyrrolyl, methoxy, ethoxy, ethylamino, acetyl, and acetamido Preferred R.

2 substituents of formula III include *hydrogen, aliphatic, alkoxycarbonyl, (un)substituted phenyl., hydroxyalkyl, alkoxyalkyl, aminocarbonyl, monoor dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylacminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 *substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, 00211, 002 CH 3

CH

2 OH, Q{ 2 00H 3 CWH CR2CH 2 OH, 011 2

CR

2 01 2 00H 3 0H 2

CH

2

CH

2 00H 2 Ph, CH 2 0CH 2

H

2

CH

2

CH

2 CMNwcooc (CH 2 3 CONHOR (OH 2 2

CONHCH

2

CH=CH

2

CONHCH

2

CH

2 0011 3

CONHCH

2 Ph1, -73-

VO

CON(cyclohexyl), 'CON(Et) 2

CON(CH

3

)H

2 Ph, CONH(n-C 3 11 7 N CON(Et)CH 2

CH

2

CH

3

CONHCH

2

CH(CH

3 2 CON(n-C 3

H,)

2 CO(3methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4tolyl) CONHCH 3 CO(morpholin-l-yl) CO (4-methylpiperazin- C 1-yl), CONHCH 2 CH20H, CONH 2 and CO(piperidin-1-yl).

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

/R

2 ring.

systems containing the pyrazole ring include benzo, 0 pyrido, pyrimido, 3-oxo-2H-pyridazino, and a partially unsaturated 6-membered carbocyclo ring. Examples of such preferred R 2

/R

2 ring systems containing the pyrazole ring include the following: H H H and H Preferred substituents on the R 2

/R

2 fused ring of formula III include one or more of the following: -halo, -N(R) 2 -Cl alkyl, -C 1 4 baloalkyl, -NO 2 alkyl) (CO1-4 alkyl), -CN, SO2 (C3-4 al-l) SO2NH2, -OC (O)NH 2 -N2SO2 (C 1 4 alkyl), -NHC (C 1 -4 alkyl), -C NH2, and -CO(C.

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

Preferred formula III compounds have one or more, and more preferably all, of the features selected from the group consisting of: -74- Va o Ring D is an 6ptionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- 5 tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or \D naphthyl ring; RX and RY are taken together with their CA intervening atoms to form an optionally substituted benzo ring or a 5-7 membered carbocyclo ring; and

R

2 is hydrogen or methyl and R 2 is T-W-G or R, wherein W is 2 -CO2-, 2 2

N(R

6 or

-CON(R

6 and R is an optionally substituted group selected from C3, aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstiteutedbenzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula III have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroqinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; RX and RY are taken together with their intervening atoms to form a benzo ring or a,5-7 membered carbocyclo ring optionally substituted with oxo, halo, -OR, -CO 2 R, -COCOR, -NO2, -CN, -S(O)R,

-SO

2 R, -SR, 2

-CON(R

4 2

-SO

2

N(R)

2 -OC(=0)R, COR, -N(R 4 C02 (optionally substituted C1..6 aliphatic), Va o -N(R)N(R) 2

-C=NN(R)

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

)CON(R

4 2 N -N(R')S0 2

N(R')

2

-N(R')SO

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

-N(R

4 2

-CO

2 R, -CONH(R 4

-N(R

4

)COR,

C 5 -SO 2

N(R),

2 -N(R')SO2R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-3.o aryl, or 6 aliphatic.

Even more preferred compounds of formula III 0 have one or more, and more preferably all, of the ci o 10 features selected from the group consisting of: 0 RX and RY are taken together with their .intervening atoms to form a benzo or 6-membered partially unsaturated carbocyclo ring optionally substituted with halo, CN, oxo, C 1 alkyl, C1-.

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

'R

2 is hydrogen and R 2 is selected from R 2 is hydrogen or methyl and R 2 is T-W-R' or R, wherein W is 2 2

N(R

6

-CO

2

-C(R

6

-C(R

6 2 N(Rs)CO-, or and R is an optionally substituted group selected from Cl1s aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, 2 alkyl, -C1-, 4 halalkyl, -N02, -0 (C1.

4 alkyl) -C0 2 4 alkyl) -CN, -S0 2 (C-4 alkyl), -SO 2

NH

2

-OC(O)NH

2

-NH

2 S0 2 (C1- 4 alkyl), -NMC(o) (C 1 4 aikyl), -76- -C(O)NH2, or -Co(C 1 3.

4 alkyl), wherein the (C 1 4 alkyl) is a straight, branched, or cyclic alkyl group.

Representative compounds of formula III are set forth in Table 2 below.

Ill-i 111-2 111-3

CH

3 HN <N1H.

CH

3 0

N

111-4 I-6

OH

3 HN4-H 111-6~

OH

3

HN

N

111-9 M-7

CH

3

HNXO*H

111-10

CH

3

ENHJZZ

111-12 111-11.

-77- CHs

HNJ&

&zx oN NI-is 111-13 111-14

CH

3

%NH

6H 3 111-16 111-17' 111-18

CH

3

CH

3 OAX>%

N

111-19 111-20 111-21

CH

3

HN

CHNHyJKQN.

CH

3 111-22

CH

3 HNtI4

*H

3 CyIZ:N.t-O

CH

3 -NH3

CH

3 H-IN

C-

3 S0 2 Nj 111-23

CH

3

HN~$

111-24 HN#L6

HSN

-78- 111-25

OH

3

HN

111-28 111-26 111-27

CH

3 11<3 111-30 111-29

OH

3

H

OH

3 HN<*1 111L. H 111-31 111-32 111-33

OH

3 HN<14 111-3

CH

3

HI

111-36 111-34

OH

3 HN4 os~ H 111-37 111-38 111-39 -79m o OH 3 HNXl HN *1 HNXt CottH

OH

3 111-40 111-41 111-42 1-3 OH 3

OH

3 HN-* HN<NHN o HH H o~ C(>k1>o WZ!IK OM6 5111-43 111-44 111-45

OH

3 C H 3 HN-0 HNoj~ HN H

N.:

It CH 111-46 111-47 111-48

OH

3

OH

3

OH

3 HN 1HN*$ HN*$ Nj H #N H N

F

111-49 III-so 111-51

OH

3

OH

3

OH

3 KN$ HN'§ N 111-52 111-53 111-54

OH

3 HN4N*

OH

3 HN4*I 91 NH

CF

3

OH

3

HA'

t N H0 111-57

OH

3

HN<N*

H

111-56 0 ci 0 0 ci

OH

3 1'4

,-H

111-59 111-60 111-61

HN'-QH

111-64

H-

3 C

H

HN

Nx

OH

3

HNX

111-62

CH-

2 0H 3

HN<

Nl;' 111-65

OH

3 Z 0H

HNQ'

111-63

OH

3 111-66 -81- 111-67

IHN

111-70 111-68 C0 2

CH

3 NN

H

111-73 111-71

CH

2 0H H4 111-74 111-69 C0 2

H

tN

H

111-72

CH

2

OCH

3

NHH

111-75

OH

HNII

H

111-76 .111-77

OCH

2 Ph HNl; 111-78 H3C-CH3

H

HNI

A, N H HN r Th N

H

111-80 111-79 -82- Va 0O 111-82 111-83 111-84 111-85 0 rCH3 o

-CH

3 HNb HcH

N

CH

3 01-N HNt~ %N-8 111-87 0 HN$0 N N: 111-90 111288 9CH 3 0rtH

&NHLH

HNS

AH

N%

111-92 111-93 -83- -v8'- ON r flNH' CHO,

N

N

Yj k) H N- ow

NH

CHO

SOT-fi H

N>

JNH

£HO

Vol-III 0

N

CHO

H

N

zol-i TOT-II" 00-I"I 66-I11

ON

H0 t H3tNNNH

N-

I--I"I

HI

HO

96-1116-l 1-1 S6-1II T16-:III 111-106

CH

3

HN

111-109 111-107

OH

3

H*

111-110

H

HN

ONH

111-112

H

111-115 111-113 111-108

HNS

0tlN

H

"II-Ill

OH

3

HN<

H

111- 114

HN'

111-117 111-120 111-116 111-119

HNS

111-121

CH

2 0H -N

H

III- 124

F

HN

111-127

HZ

tN

H

111-130

CO

2

CH

3 '4

H

111-122

CONH

2 111-125

F

3

C

H'

NN

111-128

F

HN

111-131 111-123 CON H 2 HN4

H

111-126 HN§Y, N 111-129 111-132 c tN 111-135 111-133 111-134 -86-

HN

111-137 111-136 111-138

HNNO

KN

111-141 111-139 111-140

HZ

N CH3

L--A"NA,

111-142

HZ

me 1;6 Me 111-145 H NN 111-143 F.tq MeZ.

111-146 111-144 -87-

IN

oD In another embodiment, this invention provides ci a composition comprising a compound of formula III and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a c 5 method of inhibiting GSK-3 activity in a patient, comprising administering to the patient-a therapeutically effective amount of a composition comprising a compound of formula III..

ci Another aspect relates to a method of treating

IN

o 10 a disease that is alleviated by treatment with a GSK-3 0inhibitor, said method comprising the step of ci administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula 'In.

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

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

Another aspect relates to a method of inhibiting the phosphorylation of P-catenin in apatient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition -88comprising a -compound of f ormula III. This method is (Nespecially useful for treating schizophrenia.

*method of inhibiting Aurora activity in a patient, (N 5 comprising administering to the patient a therapeutically effective amount of 'a composition comprising a compound of formula III.

Another aspect relates to a method of treating c-ia disease that is alleviated by treatment with an Aurora o 10 inhibitor, said method compSrising the step of c-i administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula III. This method is especially useful for treating cancer, such as colon, ovarian, and breast cancer.

one aspect of this invention relates to a method of inhibiting C2fK-2 activity in a patient, cbmprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula Ill.

Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 inhibitor, said method comprising the'step of administering to a patient in need of such a treatment a.

therapeutically effective amount of- a composition comprising a compounid of formula Ill.. This method is especially useful -for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia., and autoimmune diseases such as rheumatoid arthritis.

One aspect of this invention relates to a method of inhibiting*Src activity in a patient, -89- Va comprising administering to the patient a therapeutically effective amount.of a composition comprising a compound of formula III.

Another aspect relates to a method of treating a disease that is alleviated by treatment with a Src inhibitor, said method comprising the step of Va administering to a patient in need of such a treatment a ci therapeutically effective amount of a composition comprising a compound of formula III. This method is o 10 especially useful for treating hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and Paget's disease.

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

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

Compounds of formula III, wherein R 2 is hydrogen and RX and RY are taken together with the pyrimidine ring to form an optionally substituted quinazoline ring system, are also inhibitors of ERLK-2 and AKT protein kinases.

Accordingly, another method of this invention relates to a method of inhibiting ERK-2 or AKT activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition

ID

o comprising a compound of formula III, wherein R 2 is hydrogen and Rx and R y are taken together with the pyrimidine ring to form an optionally substituted quinazoline ring system.

Another aspect relates to a method of treating a disease that is alleviated by treatment with a ERK-2 or VD AKT inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition S 10 comprising a compound of formula III, wherein R 2 is ^C hydrogen and Rx and R Y are taken together with the pyrimidine ring to form an optionally substituted quinazoline ring system. This method is especially useful for treating cancer,. stroke, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, restenosis, psoriasis, allergic disorders including asthma, inflammation, and neurological disorders.

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

R

2 R

'!NH

HN N R'

N

IV

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Ring-D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or -91heterocyclyl ring having 1-4 ring heteroatoms selected C from nitrogen, oxygen or sulfur, wherein Ring D is csubstituted at any substitutable ring carbon by oxo or

S-R

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

R

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

R

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

R

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

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8-membered, unsaturated or partially unsaturated, ring containing 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein said fused ring is optionally substituted by up 'to three groups independently selected from halo, -oxo, -CN, -NO 2

-R

7 or -V-R 6

R

3 is selected from -halo, -OR, -C02R, -COCOR, -COCH 2 COR, -NO 2 -CN, -S(0) 2 R, -SR,

-N(R

4

-CON(R')

2

-SO

2

N'(R)

2 -N(R4)COR,

-N(R

4 C02 (optionally substituted CI-6 aliphatic),

-N(R

4

)N(R

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

)CON(R)

2 -N(R SO 2

N(

R4 2

-N(R

4 )S02R, or -OC(=0)N(R4)2; each R is independently selected from hydrogen or an optionally substituted group selected from. Ci -92- Va aliphatic, aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -RU, -COR (N -C0 2 (optionally substituted C2_6 alipatic) )2, or -S0 2 R, Or two R 4 on the same nitrogen are taken Va together to form a 5-8 membered heterocyclyl or 2 heteroaryl ring; each R 5 is independently selected from -R,.halo, -OR,

-CO

2 R, -COCORi

'-NO

2 -CN,

-SO

2 R, -SR, Ci -NCR 4 2

-CON(R

4 2

-SO

2

N(R')

2 -N(RtCOR, -N(R4)C02 (optionally substituted C 1 6 aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R)

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

)CON(R'),

N(R

4

)SO

2

N(R

4 2 -N(R4)50 2 R, or _OC(=O)N(R4)2; V is

-SO

2 -N(R')S0 2

-SO

2

N(R

6

-NR

6

-CO

2

-N(R

6

-N(R

6 -N (R 6 CON(R') -N(R 6 S02N(R 6

-N(R

6

-OC(O)N(R

6

-C(R

6 2

-C(R

6 2

S-,

-C(R

6 2 so-, '-CCR 6 )2So 2

-C(R

6 )2So 2 N(RI) 2 N(R6)C(O) 2 -CtR 6 h=NN(R)-,

-C(R

6

-C(R)

2 -C(R 2 N(R)S0 2 N (R 6 or

-C(R

2

N(R

6 )CON W is -C(R 6 2

-C(R

6 2

-C(R'

2 SO-, 2 S0 2 2 S0 2

-C(R

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

-C(R

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

N(R

6 )S0 2

NN(R

6 -C (R 6 2 N(R)CON(R)-, or -CON(R) each R6 is independently selected from hydrogen or an optionally substituted C 1 -4 aliphatic group,, or two R' groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl1 ring; and -93-

VO

o each R' is independently selected from hydrogen or an C( optionally substituted C.1- aliphatic group, or two R 7 on the same nitrogen are taken together with the.

nitrogen to form a 5-8 membered heterocyclyl ring or C( 5 heteroaryl.

Preferred formula IV Ring D monocyclic rings \D include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, C- azepanyl, and morpholinyl rings. Preferred formula IV

\O

o 10 Ring D bicyclic rings include 1,2,3,4- Cq tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-IH-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples -of more preferred Ring D bicyclic rings include naphthyl and isoquinolinyl.

Preferred substituents on Ring D of formula IV include halo, oxo, CN, -NO 2

-N(R

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

N(R

4

-N(R

4 )SOaR, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-io aryl, or Ci-6 aliphatic. More preferred R 5 substituents include -halo, -CN, -oxo, -SR, -OR, -N(R4) 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-o0 aryl, or C1-6 aliphatic. Examples of Ring D substituents include -OH, phenyl, methyl, CH2OH, CH2CH20H, pyrrolidinyl, OPh, CF 3 C-CH, C1, Br, F, I, NH 2 C(0)CH3, i-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene dioxy, and ethylene dioxy.

When the Rx and R groups of formula IV are taken together to form a fused ring, preferred RX/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 1-2 heteroatoms. This provides a bicyclic ring system containing the pyrimidine -94ring. Examples of preferred pyrimidine ring systems of formula IV are the mono- and bicyclic systems shown below.

IV-I,

IV-!

IV- J?

H>N

Met~oL

'V-G

HN

TV-K

N

'v-B

IV-L.

HN>3? flY-H IV- 0 IV- P Iv- Q HNA3r

IV-R

HN"N '0'

N

N Iv- S IV-T HN-3 Iv-x

HNA

I N

N-

IV-A

N

NN

R1

IV-AA

IV-V IV-W

HNA

IV-Y

HNA

IV-BB

HN'31

HN

N N

IV-Z

HNc

IV-CC

HNA

N

0~2

TV-DD

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

In the monocyclic pyrimidine ring system of formula IV, preferred Rx. groups include hydrogen, amino, nitro, alkyl- or dialkylamino, acetamido, or a CQ 4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl. Preferred RY groups include T-R 3 wherein T is a valence bond or a methylene, and R 3 is -R, -96-

ID

-N(R4)2, or -OR. When R 3 is -R or -OR, a preferred R is C an optionally substituted group selected from C 1 Saliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. ,Examples of preferred R Y groups 5 include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, \O acetamido, optionally substituted phenyl such as phenyl, Smethoxyphenyl, trimethoxyphenyl, or halo-substituted C-i phenyl, and methoxymethyl.

o 10 In the bicyclic pyrimidine ring system of C formula IV, the ring formed when R x and R Y are taken.

together may be substituted or unsubstituted. Suitable substituents include halo, -OR, -CO 2

R,

-COCOR, -NO 2 -CN, -S02R, -SR, 2

-CON(R

4 2 -SO2N(R 4 2

-N(R

4 COR, -N CO2 (optionally substituted C 1 -6 aliphatic) -N(R N (R 2

-C=NN(R

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

-OC(=O)N(R

4 2 wherein R and R 4 are as defined above for compounds of formula IV. Preferred PR/R Y ring substituents include -halo, -OR, -COR, -CO2R,

-CON(R

4 2 -CN, or 2 wherein R is a substituted or unsubstituted Ci-6 aliphatic group.

The R 2 and R 2 groups of formula rv may be taken together to form a fused ring, thus providing a.bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-iembered carbocyclo ring. These are exemplified in the following formula IV compounds having a pyrazole-containing bicyclic ring system: -97-

VO

0I

NN

HN N N N\ NH NH NH NH ,and Preferred substituents on the R 2

/R

2 fused ring 0 Ci of formula IV include one or more of the following:

O

o 5 halo, -N(R 4 b2, -C14 alkyl, haloalkyl, -NO 2 -O(C-4 CA alkyl), -C02 (C-4 alkyl), -CN, -SO 2

(C-

4 alkyl), -SO 2

NH

2

-OC(O)NH

2

-NH

2 SO2(C- 4 alkyl), -NHC(O) (C1-4 alkyl),

-C()NH

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

When the pyrazole ring system of formula IV is monocyclic, preferred R 2 groups include hydrogen, a substituted or unsubstituted group selected from aryl, heteroaryl, or a C-6 aliphatic group. Examples of such preferred R 2 groups include methyl, t-butyl, -CH 2 0CH 3 cyclopropyl, furanyl, thienyl, and phenyl. A preferred R2 group is hydrogen.

Preferred formula IV compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from a phenyl,.pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quiiolinyl, or naphthyl ring; -98-

VO

o Rx is hydrogen or C1i- aliphatic and R Y is T- (C R 3 or R x and R Y are taken together with their intervening atoms to form an optionally substituted 5-7. membered unsaturated or partially unsaturated ring having 1-2 ring C( 5 heteroatoms; and

R

2 is hydrogen or methyl and R 2 is T-W-R 6 or \0 R, wherein W is -C(R 6 2 2

N(R

6 -CO2-, 2

N(R

6 CO-, 2 or 0C -CON(R 6 and R is an optionally substituted group o' 10 selected from Ci-6 aliphatic or phenyl, or R 2 and R 2 are C- taken together with their intervening atoms to form a substituted or upsubstituted benzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring.

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

R

x is hydrogen or methyl and R Y is -R,

N(R

4 2 or.-OR, or R x and R Y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, wherein said ring is optionally substituted with -R, halo, oxo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -S(O)R, -S0 2 R, -SR, -N(R 4 2

-CON(R

4 2

-SO

2

N(R)

2 -OC(=0)R, COR, -N (R 4 CO (optionally substituted aliphatic),

-N(R

4

)N(R

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

)CON(R

4 2 -N (R SON (R 2, -N (R 4

)SO

2 R, or -OC(=O)N(R 4 2 and -99-

IO

0 each R 5 is independently selected from halo, c oxo, CN, NO 2

-N(R

4 2

-CO

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

S

2

N(R)

2

-N(R')SO

2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-io aryl, or C-G aliphatic.

Even more preferred compounds of formula IV OD have one or more, and more preferably all, of the ci Sfeatures selected from the group consisting of: Ci R x and R Y are takeni together with their

VO

o 10 intervening atoms to form a 6-membered unsaturated or Ci partially unsaturated ring having 1-2 ring nitrogens, optionally substituted with halo, CN, oxo, C1-6 alkyl, Ci-6 alkoxy, (Ci-6 alkyl) carbonyl, (Ci-s alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R 5 is independently selected from halo, -CN, -oxo, -SR, -OR, -N(R 4 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-o aryl, or C 1 -6 aliphatic; and

R

2 is hydrogen and R 2 is T-W-R 6 or R, wherein W is -C(R 6 20

-C(R

6 2

N(R

6 -CO2-,

-C(R

6 -C(R6) 2 or and R is an optionally substituted group selected from Ci-6 aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, oxo, -N(R 4 2 -C alkyl, -CI-4 haloalkyl, -NO 2 -0(C14 alkyl), -C0 2 (C.4 alkyl), -CN, -S0 2 (Ci-4 alkyl), -S0 2

NH

2

-OC(O)NH

2 -NH2

S

O2 (C-4 alkyl) -NHC(O) (CI-4 alkyl), -C(O)NH 2 or -CO(C 1 .4 alkyl), wherein the 4 alkyl) is a straight, branched, or cyclic alkyl group.

-100- Representative compounds'of formula IV are Bet fortb in Table 3 below.

Table 3.

Va ci 0 ci Va 0 0 ci

OH

3

IHN

C113 H Nt MeO Kq MeO -1 'LI.c OMe IV- 2 IV- 1

OH

3 AcNH~c.S I.tN I[V-3I

OH

3 IV-6

OH

3 HNAJ4NH IV- 4 IV- S

OH

3 HN )4NH H2NtN

H

3

C.

IV- 7

CO

2 Me IV- B

OH

3 Iv- 9 IV- 10 IV-11 IV- 12 -101- IV-13 IV- 14TVi

CH

3 HN Itt'

H

3

C

IV- 16

UN?

H

3 C N IV-19

CH

3 IV-22

CH

3 IV-17

CH

3

HN

IV- 18

CH

3 HN~r IV- 20 IV-21

CH

3

HN

I-

3

I

IV-24 IV- 23 2-

H

3

C,

CH

3

HNN

HaC N IV-26 IV-27 MeO e' IV-28

CH

3

SHN

IV-29

CH

HN3 H

N

N-3

CH

3

HN

4 N H IV-31

HN&N

Nt2 IV-32 IV-33 In another embodiment, this invention provides a composition comprising a compound of formula IV and a pharmaceutically acceptable carrier.

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a -103-

IN

SD therapeutically effective amount of a composition c'I comprising a compound of formula IV.

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of c-i 5 glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula c-i IV. This method is especially useful for diabetic 0 patients.

o 10 Another aspect relates to a method of 0q inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful in halting or slowing -the progression of Alzheimer's disease.

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

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula IV. This method is -104- Va

ID

0 o especially useful for treating cancer, such as colon, Sovarian, and breast cancer.

X One aspect of this invention relates to a Smethod of inhibiting CDK-2 activity in a patient, ci comprising administering to the patient a therapeutically Seffective amount of a composition comprising a compound q* of formula IV. ci O Another aspect relates to a method of treating ci a disease that is alleviated by treatment with a CDK-2

IND

S 10 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus., HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

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

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

Another embodiment of this invention relates to compounds of formula V: -105-

VO

c R2

NH

HN

Rx z2 RY' Z VO v ci C or a pharmaceutically acceptable derivative or prodrug

NO

0 thereof, wherein: C Z .is N, CR a or -CH and Z 2 is N or CH, provided that one of Z i and Z 2 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently.

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

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or -106-

VO

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

R

1 is selected from -halo, -CN, -NO 2 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl.

C- 5 ring, or aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by 7 up to three groups independently selected from halo, Soxo, or -R 8 said Ci-6 aliphatic group optionally C substituted with halo, cyano, nitro, or oxygen, or RI O 10 and an adjacent substituent taken together with their C intervening atoms form said ring fused to Ring C; R" and RY are independently selected from T-R 3 or Rx and Ry are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by Rx and R Y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by Rx and R y is substituted by R'; T is a valence bond or a C-.

4 alkylidene chain;

R

2 and R 2 are independently selected from or

.R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said .fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO 2 or and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R 4

R

3 is selected from -halo, -OR,

-CO

2

R,

-COCOR,

-COCH

2 COR, -NO 2 -CN,

-S(O)

2 R, -SR,

-N(R'

4 2

-CON(R

7 2 -SO2N(R 2 -OC(=0O)R, -N(R COR, -107- Va -N (R 7 C02 (optionally substituted C3._ aliphatic), 0~ -N(R')N(Rt 2 -C=NN(f 2 -C=N-OR, -N(R 7

)CON(R')

2

-N(R

7 S0 2

N(R

7 2 -N(R)S0 2 R, or -OC(-)N(R72; each R is independently selected from hydrogen or an optionally substituted group selected from aliphatic, C-.o 1 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocycly. ring having 5-10 ring atoms' o each R' is independently selected from -COR 7 o -C0 2 (optionally substituted C1.6 aliphatic), -CON(R) 2 0 or -SO 2 or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyi or S heteroaryl ring; each R 5 is independently selected from halo, -OR, -C0 2 R, -COCOR, -NC 2 -CN, -SO 2 R, -SR, 2

-CON(R')

2 -S0 2

N(R

4 2

-N(R

4

)COR,

-N(R')C02 (optionally substituted C.1-6 aliphatic), -N(R4)N(R 4 2 -C=1N(R 4 2 -C=N-CR, -N(R 4

)CON(R')

2 -N(R4fS 2

N(R')

2

-N(R

4 )S0 2 R, or -OC(=0)N(R) 2 or R 5 and an adjacent substituent taken together with their *intervening atoms form said ring fused to Ring C; V is -S- -N(R)S0 2

-SO

2

-N(R

6 -C02-,

-N(R

6

-N(R

6 )CoN(R 6

-N(R

6

-N(R

6

)N(R

6 2 -C(R6) 2

S-,

2 S0 2

-C(R

6 2 S0 2

-C(R)

2 N -C(R 6

)N(R

6

-C(R

6 -C(R6) 2

N(R

6

)N(R

6

-C(R

6 2 N(R)S02 (R 6 or

-C(R

6 2 N.(R)CON(R6)-; w is -C(R 6 2 2 -C(R6) 2 S0-, 2 S0 2

-C(R

6 2 S0 2 2

N(R

6

-C(R

6

-C(R

6

)OCC()N(R

6 2

N(R

6

)CO-,

-R(R

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

=NN(R

5

-C(R

6 -108-

O

O -C(R6)N(R')N(R 6 2

N(R

6 N -C(R 6 2

N(R

6

)CON(R

6 or -CON(R 6 Seach R' is independently selected from hydrogen, an optionally substituted C:.

4 aliphatic group, or two R 6 Cl 5 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered Sheterocyclyl or heteroaryl ring; each R 7 is independently selected from hydrogen or an 0 optionally substituted Ci-S aliphatic group, or two R 7 O 10 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 8 is independently selected from an optionally substituted Ci-4 aliphatic group, -OR 6

-SR

6

-COR

6

-SO

2

R

6 -N(R6) 2

-N(R

6

)N(R

6 2 -CN, -NO 2

-CON(R

6 2 or -C0 2

R

6 and Ra is selected from halo, -OR, -CO 2 R, -COCOR,

-NO

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

-CON(R)

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

CO

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

)N(R

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

)CON(R

4 2 -N(RSN() S R 4 2

-N(R

4

)SOR,

-OC(=0)N(R 4 or an optionally substituted group selected from Ca.

6 aliphatic, C-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

Compounds of formula V may be represented by specifying Z 1 and Z 2 as shown below: -109

IO

oF R2 R2 R c-NH rNH rCNH HN'N H NN HN N

R

x RX N RK NI

N

SR' N R R G G G \D Va Vb Vc Ci When the R x and R Y groups of formula V are taken

VO

D 5 together to form a fused ring, preferred RI/R Y rings C include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said RX/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Examples of preferred bicyclic ring systems of formula V are shown below.

NH

HN HN

HNN

HN N Va-A Vb-A Vc-A HN HN HN-

N

sVaB VbB V-B Va-B Vb-B Vc-B -110- HNZ HN Z Va-C yb-C Vc-C HN>~ HN> oCN SVa-D yb-fl Vc-D HN HN>17 HN>3% Va-R 4- Vc- NN Va-F vb-F Vc-F HN)1PHN~z

NN

O.

N

Va-J Vb-.J Vc-J -111- Va 0 0 ci ci HN3 Va-K HN Z Vb-K Vc--K Va-L vb-L Vc-L HN Z Va -M Vb-M ye -M HN31

N

Va-N HN r Nv

NSS

Va-C Vb-N HN> Z vib-o ye-N ye -0 -112-

VO

HN0 HN> HN4r

NN

Va-P Vb-P Va-P Va C More preferred bicyclic ring systems of formula o 5 V include Va-A, Vb-A, Vc-A, Va-B, Vb-B, Va-B, Va-D, Vb-D, IN Vc-D, Va-E, Vb-B, Vc-E, Va-J, Vb-J, Vc-J, Va-K, Vb-K, 0 o V-K, Va-L, Vb-L, Ve-L, Va-M, Vb-M, and V-M, most preferably Va-A, Vb-A, Va-A, Va-B, Vb-B, and Vc-B.

In the monocyclic pyridine ring system of formula V, preferred RX groups include hydrogen, alkyl- or dialkylamino, acetamido, or a C 1 -4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred RY groups include T-R' wherein T is a valence bond or a methylene, and R 3 is -N(R 2 or -OR. When

R

3 is -R or -OR, a preferred R is an optionally substituted group selected from C1.-6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred R include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isbpropyl, t-butyl, .alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl, and methoxymethyl.

In the bicyclic ring system of formula V, the ring formed when RX and RY are taken together may be substituted or unsubstituted. Suitable substituents include halo, -OR, -C0 2 R, -COCOR, -NO 2

-CN,

-SO

2 R, -SR, 2

-CON(R')

2

-SO

2

N(R

4 2

-N(R

4 )COR, -N(R 4

CO

2 (optionaily substituted C1aliphatic), -N(R 4

)N(R)

2

-C=NN(R

4 2

-C=N-OR,

-N(R')CON(R

4 2

-N(R

4

)SO

2

N(R)

2

-N(R

4 )SOR, or -113-

VO

-OC(=O)N(R)

2 wherein R and R 4 are as defined above.

C Preferred RX/RY ring substituents include -halo, -OR, -COR, -CO 2 R, -CN, or -N(R)2 wherein R is an optionally substituted Ci.. aliphatic group.

C 5 The R 2 and R 2 groups of formula V may be taken together to form a fused ring, thus providing a bicyclic \0 ring system containing a pyrazole ring. Preferred fused c( Srings include benzo, pyrido, pyrimido, and a partially Ci unsaturated 6-membered carbocyclo ring. These are

VO

o 10 exemplified in the following formula V compounds having a 0 Ci pyrazole-containing bicyclic ring system:

NH

HN N N N 'NH NH NH 'NH R" z G -fN N N fN and Preferred substituents on the R/R 2 fused ring of formula V include one or more of the following: -halo,

-N(R

4 2 -C1- 4 alkyl, -C- 4 haloalkyl, -NO 2 -0(CI-4 alkyl),

-CO

2

(C

1 -I alkyl), -CN, -S02 (C 1 4 alkyl), -SO 2

NH

2 -OC(0)NH 2

-NH

2

SO

2

(C

1 -4 alkyl) -NHC(O) (C 1 -4 alkyl), -C(O)NH 2 and

-CO(C

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

When the pyrazole ring system is monocyclic, preferred R 2 groups include hydrogen, C1- 4 aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (N- -114- Va o heterocyclyl) carbonyl. Examples of such preferred R2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO2H,

CO

2

CH

3 CH20H, CH 2 0CH 3

CH

2 CH2CHaOH, CH 2

H

2 CH20CH 3 CS 5 CH2CH 2

CH

2 0CH 2 Ph, CH22MN 2

CH

2

CH

2

CH

2 NHCOOC H 3 3,r

CONHN(CH)

2

CONHCH

2

CH=CH

2

CONHCH

2

CH

2 0CH 3

CONHCH

2 Pb, SCONH(cyclohexyl), CON(Et) 2

CON(CH

3

)CH

2 Ph, CONH(n-C 3

H

7 CON(Et) CH2CH2MH,3, CONHCH 2 CH (CM3)2, CON (-n-C 3

H

7 2 CO (3- 0 methoxymethylpyrrolidin-1-yl), CONH (3 -tolyl), CONH (4o 10 tolyl), CONHCH 3 CO (morpholin-l-yl), CO (4-methylpiperazin- C 1-yl) CONHCH 2

CH

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

More preferred ring systems of formula V are the following, which may be substituted as described above, wherein R 2 and R2' are taken together with the pyrazole ring to form an optionally substituted indazole ring; and RX and RY are each methyl, or RX and RY are taken together with the pyridine ring to form an optionally substituted quinoline, isoquinoline, tetrahydroquinoline or -tetrahydroisoquinoline ring: I I I HH NDH HN N HN N HN

H

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

Preferred fused rings include a benzo or pyrido ring.

-115o.Such rings preferably are fused at ortho and meta 0 Ci positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred R3 .groups include -halo, an optionally substituted C1_6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -S0 2

R

6

-SO

2

NH

2 2

-CO

2 R6, -CONH 2 -NHCOR, -OC(O)NHa 2 or -NHSO 2 R6.

When R is an optionally substituted C3., aliphatic group, the most preferred optional substituents are halogen.

0 Examples of preferred R1 groups include -CF 3 -Cl, -F, -CN, -COCH3, -OCH 3 -OH, -CH 2

CH

3 -OCH2CH3, -CH 3

-CF

2

CH

3 0 cyclohexyl, t-butyl, isopropyl, cyclopropyl, -C=CH,

-CC-CH

3 -S02CH3, -S0 2

NH

2 -N(CH3) 2

-CO

2

CH

3

-CONH

2

-NHCOCH

3 -OC(0) NH 2

-NHSO

2

CH

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

-N(R

4 optionally substituted C-s aliphatic group, -OR, -CO 2

R,

-CONH(R

4

-N(R

4 )COR, -SO 2 2 and -N(R')SO 2 R. More preferred R 5 substituents include -Cl, -CN, -CF 3 -NH2, -NH (C3-4' aliphatic) -N(C1-4 aliphatic) 2 -0 (Cl.4 aliphatic), C1.4 aliphatic, and -C02(C.4 aliphatic).

Examples of such preferred R5 substituents include -C1, -CN, -CF 3

-NH

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

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

When two adjacent substituents on Ring D are taken together to form a fused ring, the Ring D system is bicyclic. Preferred formula V Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-if-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and -116- Va naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

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

-CO

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

-SO

2

N(R

4 2 -N (R')SOR, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C-.0 aryl, or C1-6 aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, 2 -C(O)R,:or a substituted or unsubstituted group selected from 5-6 Ci membered heterocyclyl, C6-31 aryl, or aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 0H, CH 2 CH20H, pyrrolidinyl, OPh, CF 3 CiCH, Cl, Br, F, I, NH 2

C(O)CH

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

Preferred formula V compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent-substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R is -halo, an optionally substituted C36 aliphatic group, phenyl, -COR', -OR, -CN, -S0 2

R

6

-SO

2

HN

2 2

-CO

2

R',

-CONH2, -NHCOR6, -OC(O)NH 2 or -NHSO 2

R

6 or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; -117-

VO

CD R x is hydrogen or C-.

4 aliphatic and R Y is T- Ci R 3 or R x and R Y are taken together with their intervening Satoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring Ci 5 nitrogens; and

R

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

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

R

1 is -halo, a Ci- haloaliphatic group, a CI-. aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; Rx is hydrogen or methyl and R Y is -R, N(R)2, or -OR, or R x and R Y are taken together with'their intervening atoms to form a benzo ring or a 5-7 membered partially unsaturated carbocyclo ring, said benzo or carbocyclo ring optionally substituted with halo, OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2

R,

-SR, -N(R 4 2

-CON(R

4 2

-SO

2

N(R

4 2, -N(R 4

)COR,

-118-

VO

o -N(R')C0 2 (optionally substituted Ci- 6 aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R

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

-N(R)SO

2

N(R

4 2

-N(R

4

)SO

2 R, or -OC(=O)N(R 4 2 S(c) R 2 is hydrogen and R 2 is hydrogen or a C( 5 substituted or unsubstituted group selected from aryl, or a C 1 -6 aliphatic group, or R 2 and R 2 are taken together \O with their intervening atoms to form a substituted or Sunsubstituted benzo, pyrido, pyrimido or partially Cq unsaturated 6-membered carbocyclo ring; and

VO

o 10 Ring D is substituted by oxo or R

S

wherein Ci each R 5 is independently selected from -halo, -CN, -NO 2 -N(R4) 2 optionally substituted C 1 6 aliphatic group, -OR,

-CO

2 R, -CONH(R 4

-N(R

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

R.

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

R

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

R

x is hydrogen or methyl and R Y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or RX and R y are taken together with their intervening atoms to form a -119- Va o benzo ring or a 6-membered partially unsaturated ci carbocyclo ring optionally substituted with halo, CN, oxo, C 1 6 alkyl, C._6 alkoxy, alkyl) carbonyl, (C.-6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono-.or dialkylaminocarbonyloxy, or 5-6 meibered heteroaryl; a R2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido,.pyrimido or 0q partially unsaturated 6-membered carbocyclo ring ci o 10. optionally substituted with -halo, -CI- 4 alkyl, S-C1,.

4 haloalkyl, -NOz, 4 alkyl), -CO02(C.-4 alkyl), -CM,

-SO

2

(C

1 4 alkyl) -S02NH 2 -OC(O)NH2, -NH 2 SO2 (C1- 4 alkyl), -NHC(O) alkyl), -C(O)NH 2 or -CO(C.- 4 alkyl), wherein the 4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R. is independently selected from -Cl, -CN, -CF 3

-NH

2

-NH(C,.

4 aliphatic), -N(C.

4 aliphatic)2, 4 aliphatic), CI- 4 aliphatic, and -C02(C3.

4 alipbhatic).

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

Table 4.

CH

3 H H H HN HN HN CF6F V-1 V-2 V-3 -120- 2006201264 21 Mar 2006 c r w z z X 3: o o/ ~z z Zr Li o Zr Cf L C)48 0 Q z z n Z 0 -n ~-n z z 0n -n 00~ n4j z 1 Z-

N

V-i16 H 3

N

HN

V-17

I-ISONNH

HN

V-20 V-1 8 V- 19

F

HN

HN

I-

H

3

C'N'-

ci N V- 21 V-22 V-23 V- 24 V- 26 V- 27 -122-

HN

2 V-28 V-29 V-31 V- 32 V-33 CI 0.

V-34 V-35 V-36 V-37 V-38 V-39 -123o

F

c~IH 3 C oc;cCco V-41 V-42 HN2 2 HN$ Va

NHN

F

NZ

F

3 C clF 3

C

5V-43 V-44 HN pHH HHPt

F

3

C

V-46 V-47 V-48 4.F V-49 V-5O V-51, -124- V-52 V-5 ~V-53V-4 V-54 V-56 V-57

SF

3

C-

NH

2 V-58 v-s59 V-so V-El1 V-62 V- 63 -125- Va 8

CH

3 CH3 j H HM HNH

H

H HN HNAC C- "N3l N^ ,r3> V-64 V-65 V-66

F

oH 0 H? H

(N

FC

3

F

3 C V-67 V-68 In another embodiment, this invention provides a composition comprising a compound of formula V and a pharmaceutically acceptable carrier.

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

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

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective 2 amnimnt of a comnosition comnrisincr a compound of formula -126- V. This method is especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula V. This method is especially useful in halting or 0 slowing the progression of Alzheimer's disease.

o) 10 Another aspect relates to a method of Ni inhibiting the phosphorylation of P-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula V. This method is especially useful for treating -schizophrenia.

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

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

One aspect of this invention relates to a method of inhibiting CDK-2 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of f ormula V., -127-

ID

o Another aspect relates to a method of treating 0 C( a disease that is alleviated by treatment with a CDK-2 Sinhibitor, said method comprising the step of r administering to a patient in need of such a treatment a CN 5 therapeutically effective amount of a composition comprising a compound of formula V. This method is especially useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, 0 cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis,

ID

alopecia, and autoimmune diseases such as rheumatoid C arthritis.

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

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

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

R

2 HN v

VI

-128- S' or a pharmaceutically acceptable derivative or prodrug C thereof, wherein: SG is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, CN pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents \O '5 independently selected from any substitutable none ortho carbon position on Ring C is independently Cq substituted by and two adjacent substituents on o Ring C are optionally taken together with their C intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, .said fused ring being optionally substituted by halo, oxo, or -R 8 Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon .position of Ring D; R' is selected from -halo, -CN, -NO 2

T-V-R

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

6 aliphatic group, said phenyl, beteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R 8 said Ci- 6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R- -129o and an adjacent substituent taken together with their c- intervening atoms form said ring fused to Ring C;

SR

Y is T-R 3 ST is a valence bond or a Ci- 4 alkylidene chain; C- R 2 and R 2 are independently selected from -T-W-R 6 or

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or c partially unsaturated, ring having 0-3 ring heteroatoms C .selected from nitrogen, oxygen, or sulfur, wherein each O substitutable carbon on said fused ring formed by R 2 0 and R 2 is substituted by halo, xo, -N0 2

-R

7 or

-V-R

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

R

3 is an optionally substituted group selected from C 1 aliphatic, C3-10 carbocyclyl, C-o 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally substituted group selected from C 1 -6 aliphatic, C-Io0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R 7

-COR

7

-CO

2 (optionally substituted C 1 .i aliphatic), -CON (R 2 or -SO 2

R

7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR,

-N(R)

2

-CON(R')

2 -SO0N(R') 2

-N(R')COR,

N (R 4 C02 (optionally substituted C 1 aliphatic),

-N(R)N(R

4 2

-C=NN(R

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

CON(R

4 2 -N(R)SN()S2R') 2

-N(R

4

)SO

2 R, or -OC(=O)N(R 4 2 or R 5 and -130- Va an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -802-, -N(R')S0 2

-SO

2

-N(R

6 CO-, -CO2-,

-N(R

6 CA 5 -N(R')s0 2 -N(R)N(R 2 2

S-,

-C(RR)

2 SO-, 2 SO0 2 -C(R')2S 2 2 -C 2 2

N(R

6 0 2 2

N(R')SO

2 or

NO

-C(R 2

N(R

6 )CON(R6)-; w is 2 2 2 SO-, 2

SO

2 2

SO

2 -C02-, 2

CO-,

2 C (R6)2N (R6) N (R6) -C (RG) 2N (RI) SO2N C N (R CON(R or -CON(R 6 each R 6 is independently selected from hydrogen, an optionally substituted C1_.4 aliphatic group, or two R' groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R 7 is independently selected from hydrogen or an optionally substituted aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R 8 is independently selected from an optionally substituted C-4 aliphatic group,

-COR,

-SO

2 -N 2

(R)

2 -CN, -NOZ, -CON(R 6 2 or

-CO

2

R'.

Preferred Ry groups of formula VI include T-R 3 wherein T is a valence bond or a methylene, and R31 is an optionally substituted group selected from aliphatic, -131-

VO

o C 3 1 0 carbocyclyl, C-j0o aryl, a heteroaryl ring having 5-10 0 Ci ring atoms, or a heterocyclyl ring having 5-10 ring Satoms. A preferred R 3 group is an optionally substituted Sgroup selected from C3-6 carbocyclyl, phenyl, or a 5-6 C 5 membered heteroaryl or heterocyclyl ring. Examples of preferred R Y include 2-pyridyl, 4-pyridyl, piperidinyl, Smorpholinyl, cyclopropyl, cyclohexyl, and optionally substituted phenyl such as phenyl or halo-substituted 0 phenyl.

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

NH

HN N -NN N N $NH NH NH NH N NN H. and Preferred substituents on the R 2

/R

2 fused ring include one or more of the following: -halo, 2

-C

1 -4 alkyl, -CI-4 haloalkyl, -NO2, -0(CI-4 alkyl) -CO2 (C-4 alkyl), -CN, SO2(C1-4 alkyl), -S0 2

NH

2 -OC (0)NH 2

-NH

2

SO

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

-132-

IND

o When the pyrazole ring system is monocyclici 0R ri preferred R 2 groups of formula VI include hydrogen, C1..4 Ct aliphatic, alkoxycarbonyl, bin) substituted phenyl, hydroxyalkyl, alkoxyalkyt, aminocarbonyj., mono- or diallcylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylarninocarbonyl, and (Nheterocyclyl)carbonyl.. Examples of such preferred R 2 substituents' include methyl, cyclopropyl,.ethyl, 0 isopropyl, propyl, t-butyl, cyclopentyl, phenyl, 002%, 002043, CH 2 OH, CH 2 0CB 3

CM

2

CH

2

CH

2 0H, C%2CH 2

CH

2 00H 3 0 CM2

C

H

2 0COcPh, CH 2

CH

2

CH

2

NH

2

CH

2

CH

2

CH

2 NHCOOC (CH 3 3 COIQHCH (CHb) 2

CONHOH

2

CH=CH

2 CoNHCH 2

OH

2 0CH 3

CCNHOH

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

CON(CH

3

)CH

2 pb, CONH(n-C 3

H-

7 CON(Et)OH 2

OH

2

OH

3 CONHc~icH(cHi 3 2 CON(n-C 3

H

7 2 00(3methoxymethylpyrrolidin-a-ya), CONH(3-tolyl), CONH(4tolyl), CONHCH,, CO (morpholin-l-yl), CO (4-methylpiperazinl-yl), CONHCI 2

CH

2 OH, CON%4, and CO(piperidin-1-yl).

A

preferred R 2 group is hydrogen.

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

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably ar~e fused at ortho and meta positions of Ring C. Examples of preferred bicyclic Ring C systems include naplithyl and isoquinolinyl Preferred

R

1 groups include -halo, an optionally substituted C1..6 aliphatic group, phenyl, -OR6, -ONC, -S0 2 RG, -S0 2

NH

2 -N()2,-CO 2 Rr, -CONH 2 -NHCOR', -OC(O)'H 2 or -IN2S0 2

R

6 When R' is an optionally substituted CI- aliphitic group, the-most preferred optional substituents are halogen.

Examples of preferred R' groups include -CF 3 -Cl, -F; -ciq, -docH 3 -Cog 3

-CH

2

CH

3 -OCIHzCH 3

-CH

3

-CF

2

CH

3 -133- O cyclohexyl, t-butyl, isopropyl, cyclopropyl, -eCH, -CEC-CH3, -S0 2 CH3, -SOaNH 2 -N(CH3) 2 -CO2CH3, -CON 2

-NHCOCH

3

-OC(O)NH

2

-NHSO

2 CH,, and -OCF On Ring C preferred R 5 substituents, when present, include -halo, -CN, -NO 2 2 optionally substituted CI- aliphatic group, -OR, -C0 2

R,

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

N(R')

2 and -N(R')80 2 R. More preferred R 5 substituents include -C1, -CN, -CF, N -NH2, -NH(C1-4 aliphatic), -N(C1_4 aliphatic) 2, -0 (CI- O 10 aliphatic) C11 aliphatic, and -CO2 1-4 al 9 tlc) C Examples of such preferred R 5 substituents include -C1, -CN, -CF, -NH 2 -NHMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -C0 2 Et.

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

When two adjacent substituents on Ring D are taken together 'to form a fused ring, the Ring D system is bicyclic. -Preferred formula VI Ring D bicyclic rings include 12,3,4-tetrahydroisoquinolinyl 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

Preferred substituents on formula VI Ring D include one or more of the following: halo, oxo, CN, -NO 2 2 -COR, -CONH(R'), -N(R')COR, -SO 2 -N(R')So 2

R,

-SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-o aryl, or C1-6 aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted group selected from 5-6 -134-

VO

D membered heterocyclyl, Cs-o 0 aryl, or C1- 6 aliphatic.

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

CH

2 OH, pyrrolidinyl, OPh, CF', CCH, C1, Br, F, I, NH 2 C(O)CH3, i-propyl, tert-butyl, SEt, OMe, Ci 5 N(Me) 2 methylene dioxy, and ethylene dioxy.

Preferred formula VI compounds have one or 0D more, and more preferably all, of the features selected Sfrom the group consisting of: Cq Ring C is selected from a phenyl or o 10 pyridinyl ring, optionally substituted by -R 5 wherein Cq when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is -halo, an optionally substituted C1-l aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2

R

6 -S0 2

NH

2

-N(R

6 2

-CO

2

R

6

-CONH

2

-NHCOR

6

-OC(O)NH

2 or -NHSO 2

R

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

R

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

R

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

More preferred compounds of formula VI have one or more, and more preferably all, of the features selected from the group consisting of: -135-

\O

0 Ring C is a phenyl or pyridinyl ring, Cq optionally substituted by -R 5 wherein when Ring C and two Sadjacent substituents thereon form a bicyclic ring Ssystem, the bicyclic ring system is a naphthyl ring, and C- 5 R' is -halo, a C 1 z- haloaliphatic group, a C.1- aliphatic group, phenyl, or -CN; or Ring D is an optionally Ssubstituted ring selected from phenyl, pyridinyl, c- piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, o. 1,2,3,4-tetrahydroisbquinolinyl, 1,2,3,4o 10 tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- Sdihydro-IH-indolyl, isoquinolinyl, quinolinyl, or naphthyl;

R

Y is wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from C 1 6 aliphatic, C3-6 carbocyclyl, C 6 1 o aryl, a heteroaryl. ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

R

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

-N(R

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

-CO

2 R, -CONH(R 4

-N(R

4 )COR, -SO 2

N(R

4 2 or

-N(R

4

SO

2

R.

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

R

Y is T-R 3 wherein T is a valence bond or a methylene and R 3 is an optionally substituted group -136selected from C 1 -4 aliphatic, Caj- carbocyclyl, phenyl, or

NO

o a 5-6 membered heteroaryl or heterocyclyl ring; 0q Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two 5 adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and Ci R' is -halo, a C--4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, C 10 piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, o 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- 0 tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or o naphthyl; Cl R and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R' 2

-C

1 4 alkyl,

-C

1 -4 haloalkyl, -N0 2 -O(CI-4 alkyl),- -CO 2 (C.4 alkyl), -CN, -SO2 (Ci- alkyl), -S0 2

NH

2 -OC (O)NH2, -NH 2 S02 4 alkyl), -NHC(O) (Ci- 4 alkyl), -C(O)NH2, or -CO(Ci.

4 alkyl) wherein the (Ci-4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -Cl, -CN, -CF 3

-NH

2 -NH(Ci-4 aliphatic), -N(Ci-4 aliphatic) 2 -0(Ci-4 aliphatic), C- 1 aliphatic, and -C0 2 4 aliphatic)'.

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

R

2

\O

o fNH C(

HN

NN

Cl VIa or a pharmaceutically acceptable derivative or prodrug

\O

C l thereof, wherein: o G is Ring C or Ring D;

N

O Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, Cl wherein said Ring C has one or two ortho substituents independently selected from any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R; Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having. 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or beteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; I R 1 is selected from -halo, -CN, -NO 2 phenyl, 5-6 O membered heteroaryl ring, 5-6 membered heterocyclyl C ring, or Ci-s aliphatic group, said phenyl, heteroaryl, and beterocyclyl rings each optionally substituted by 5 up to three groups independently selected from halo, oxo, or -R 8 said Ci- aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R and an adjacent substituent taken together with their 0 intervening atoms form said ring fused to Ring C; C T is a valence bond or a Ci- 4 alkylidene chain; o 10 R 2 and R 2 are taken together with their intervening atoms I\D to form a fused, 5-8 membered, unsaturated or partially o unsaturated, ring having 0-3 ring heteroatoms selected (N from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO 2 or

-V-R

6 and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R'; each R is independently selected from hydrogen or an optionally substituted group selected from C 1 6 aliphatic, Cs-o 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -COR 7

-CO

2 (optionally substituted Ci-s aliphatic), -CON(R') 2 or -SO2R 7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R s is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO2, -CN, -S02R, -SR,

-N(R

4 2

-CON(R)

2

-SON(R)

2

-N(R

4

)COR

-N (R C2 (optionally substituted C .6 aliphatic), 2

-C=NN(R

4 -C=N-OR, -N(R')CON(R) 2 139

IND-N(R'

4 0 2 2

-N(R')SO

2 R, or -OC N 2 or R 5 and o an adjacent substituent taken together with their C intervening atoms form said ring fused to Ring C; V is -S02-, -N(R)SO 2

-SO

2 S0 2 2 2

S-,

2 So-, 2

SO

2 2 -C(R6) 2 2

-C(R

6 c 10 2 2 N (R)SO 2 or -C 2N IDW is 2 2 So-, -C(R 6 2

SO

2 -c(R')SO 2 2

-CO

2 N 2

N(R

6

)CO-,

2 2

-C(R

6 )2N(R')SO 2 CON(R) or -CON(R 6 each R' is independently selected from hydrogen, an optionally substituted C.4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R7 is independently selected from hydrogen or an optionally substituted C 1 -6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to -form a 5-8 membered heterocyclyl or beteroaryl ring; and each R' is independently selected from an optionally substituted C 1 4 aliphatic group, -COR', -S0 2 -N(R6) 2

-CON(R')

2 or

*-CO

2

R'.

Preferred rings formed by the R 2 and R 2 groups of formula Via include benzo, pyrido, pyrimido, and a 140 partially unsaturated 6-membered carbocyclo ring. These o are exemplified in the following formula VIa compounds 0 C- having a pyrazole-containing bicyclic ring system: N H HI N

N

ks N N N H NH NH NH

NO

and NO Preferred substituents on the R /R 2 fused ring o include one or more of the following: -halo, -C-.4 alkyl, haloalkyl, -N02, -0(Ci-4 alkyl) -CO (CI-4 .alkyl), -CN, -SO 2 (Ci- 4 alkyl), -S0 2

NH

2 -OC(O)NH2,

-NH

2 SO2(C-.

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

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

Preferred fused rings include a benzo or pyrido ring.

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

R

1 groups include -halo, an optionally substituted C 1 aliphatic.group, phenyl, -COR 6 -CN, -SO 2 -SOaNH 2 -N(R6)2, -CO 3

R

6

-CONH

2

-NHCOR

6

-OC(O)NH

2 or -NHSO 2

R'.

When R 1 is an optionally substituted Ci-. aliphatic group, the most preferred optional substituents. are halogen.

Examples of preferred R 1 groups include -CF 3 -Cl, -F, 141 -CN, -COCH 3 -OCH3, -OH, -CH 2

CH

3 -OCH3CH, -CH 3

-CFCH

3 0 cyclohexyl, t-butyl, isopropyl, cyclopropyl, -CcHI,

-CEC-CH

3 -S02CMs, -SO 2

NH

2

-N(CH

3 2

-CO

2 CHI, -CONH 2

-NHOOCH

3 -OC(0)NH2, -NHSO 2

CH

3 and -OCF 3 On Ring C preferred R' substituents, when present, include -halo, -CN, -NO 2 optionally substituted C--6 aliphatic group, -OR, -C02R, -CONH(R'), -N(R')COR, -SON(R') 2 and -N(R')SO 2 R. More INDpreferred R 5 substituents include -Cl, -CN, -C? 3 -NH, -NH(CQ 1 4 aliphatic), -N(C.

4 alipbatic) 2

-O(C

1 .4 0 aliphatic), C 1 4 aliphatic, and -CO 2

(C

1 .4 aliphatic).

INDExamples of such preferred Rs substituents include -Cl, o -CN, -CF 3

-NH

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

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

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

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

-NO

2 2

-CO

2 R, -CONH(R'), -N(R')COR, -SO2N(R') 2

-N(R')SO

3 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C-o 10 aryl, or C 1 6 aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted group o selected from. 5-6 membered heterocyclyl, Cs-lo aryl, or CI 3 6 aliphatic. Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 OH, CH 2

CH

2 OH, pyrrolidinyl, OPh, CF 3 CCH, Cl, Br, F, NH 2

C(O)CH

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

Preferred formula Via compounds have one or more, and more preferably all, of the features selected from the group consisting of: C 10 Ring C is a phenyl or pyridinyl ring, o optionally substituted by -R 5 wherein when Ring C and two )s adjacent substituents thereon form a bicyclic ring Ssystem, the bicyclic ring system is selected from a Ci naphthyl, quinolinyl or. isoquinolinyl ring, and R 1 is -halo, an optionally substituted Ci.. aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2

R

6

-SO

2

NH

2 -N(R6) 2 -C0R 6 S-CONHK, -NHCOR', -OC(O)NH 2 or -NHSO 2 or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl; 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; and

R

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

More preferred compounds of formula Via have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring 143 system, the bicyclic ring system is a naphthyl ring, and o R 1 is -halo, a C 1 -s haloaliphatic group, a C 1 i- aliphatic Sgroup, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- C tetrahydroquiholinyl, 2,3-dihydro-iH-isoindolyl, 2,3dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl; C< 10 R 2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or C^ partially unsaturated 6-membered carbocyclo ring

NO

Soptionally substituted with -halo, -N(R 4 2 alkyl, Cl -Ci- 4 haloalkyl, -N02, -O(C1- 4 alkyl) -C0 2

(C-

4 alkyl), -CN,

-SO(CI-

4 alkyl) -S02NH 2 -OC(O)NH2, -NH2S0 2 4 alkyl), -NHC(O) alkyl), -C(O)NH 2 and -CO (C.

4 alkyl) wherein the (C3- 4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R s wherein each R s is independently selected from -halo, -CN, -NO 2 optionally substituted C 1 -6 aliphatic group, -OR,

-CO

2 R, -CONH(R'), -N(R 4 )COR, -SO 2 1(R 4 2 or

SO

2

R.

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

R

1 is -halo, a C..

4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, 144 piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinoinyl, 1,2,3,4o tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; S k 2 and R" 2 are taken together with their intervening atoms to form a benzo, pyrido, or partially C unsaturated 6-membered carbocyclo ring optionally substituted with -halo, alkyl, -C 14 haloalkyl, -NO 2 -0(C.

4 alkyl), -CO 2 4 alkyl), -CN,

-SO

2 4 alkyl), -SO 2

NH

2

-OC(O)NH

2 -NH2SO 2

(C

1 4 alkyl), -NHC(0) alkyl), -C()Ni 2 or -CO(C.

4 alkyl), wherein ci the (C 1 4 alkyl) is a straight, branched, or cyclic alkyl

VO

oN group; and Ring D is substituted by oxo or Rs, wherein each R 5 is independently selected from -Cl, -CU, -Cr 3 -NH2, -NH(CI-4 aliphatic), -N (CI4 aliphatic)2, -0{CI.4 aliphatic), C 14 aliphatic, and -c0 2 (c1- 4 aliphatic).

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

Table S.

CH

3 HNI* HN HN H~iN N N N 4 N N N

F

3 C F 3 0 VI-1 VI-2 VI-3 145

OH

3 HN Z VI -7 Pr N AlpN vi-lo OMe HN

J

NV-N

VI-13

OH

3 VI -5

HNZX

N 6N VI -8 Pr HNctv N

O~N

VI -14

OH

3

HN

4

VH

NN

VI -6 N A-N 4rA ®koCI VI -9 But HNr4 N J-N 1 0 f 2 LN!' j %0 vi HN

NN

JN

VI-1E

HN%_

IN

VI -19

N--N

VI -22 N A4 ONjt)4Me.

VI VI- 17 2NH 0N

AIN:

VI -23 ctt VI- 26

H

HgT-

N.N

F

3

C

VI-21

NAIN

0N3CYz VI -27 .147

N

F

3 CC VI -28 HN2? VI -31

I.

VI -34

HNACDQ

VI -29 N -N VI -32 HN2

NN

VT3D 9I3

HNX

N F 3

C"

VI -33

HNJ?

F

3

CV

V-1-36 HNJ14N .VT-39 Cg N

JN

VI -35 Cg N aN VI -38

NNH

N ~N

N

N4l VI -41

N

NI -44- F3 VIa -2 J F 3 C jo

NH

2 VI -42

NA

F

3 0 VI N Vla -3

H-N

N6N CN via- 4 F l N IN Me Vla-5

N

N AlN CF 3 Vla-6 HN HN HN '14H v.0HN~

N'J

4 N CN NN Me N'N 3 NHMe SVIa-7 VIa-8 Vla-9 0

MCNN

SH ;PH

H

H HN9 1

HN

N-IN N*IN N'-N IN 1" N vl H e 9 NHMe NH0 NHe VIa-10 VIa-11 VIa-12 In another embodiment, this invention provides a composition comprising a compound of formula VI or VIa and a pharmaceutically acceptable carrier.

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

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

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising 150 administering to said patient a therapeutically effective IND amount of a composition comprising a compound of formula o VI or Vla. This method is especially useful for diabetic patients.

St Another aspect relates to a method of inh ibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amhount of a composition comprising a compound of formula IND 10 VI or Vla. This method is especially useful in baiting Ni or slowing the progression of Al~zheimer's disease.

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

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula V3: or Via. This method is especially useful for treating cancer, such as colon, ovarian, and breast cancer.' One aspect of this invention relates to a method of inhibiting.CDK-2 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound k0 O of formula VI or Via.

SAnother aspect relates to a method of treating ci a disease that is alleviated by treatment with a CDK-2 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a Cil therapeutically effective amount of a composition comprising a compound of formula VI or Via. This method Sis especially useful for treating cancer, Alzheimer's Va Cl 10 disease, restenosis, angiogenesis, glomerulonephritis, Scytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, N alopecia, and autoimmune diseases such as rheumatoid o arthritis.

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

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

Another embodiment of this invention relates to compounds of formula VII: tN H R 2 R Z R I H HN N NR JN

RY®

152

VII

O ID O or a pharmaceutically acceptable derivative or prodrug thereof, wherein: G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, (C pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable non-

VO

C' ortho carbon position on Ring C is independently Ssubstituted by -R s and two adjacent substituents on C Ring C are optionally taken together with their

VO

o 10 intervening atoms to form a fused, unsaturated or 0 C-i partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 .is hydrogen at each ortho.carbon position of Ring D;

R

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

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci- 6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to' three groups independently selected from halo, oxo, or said Ci-, aliphatic group optionally 153 substituted with halo, cyano, nitro, or oxygen, or R 1 IN and an adjacent substituent taken together with their O intervening atoms form said ring fused to Ring C;

R

y is hydrogen or T-R"; T is a valence bond, hydrogen, or a alkylidene chain;

R

2 and R2' are independently selected from -T-W-R 6 or C .5 R 3 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms

VO

ci selected from nitrogen, oxygen, or sulfur, wherein each Ssubstitutable carbon on said fused ring formed by R 2 Ci 10 and R 2 is substituted by halo, oxo, -CN, -NO 2

-R

7 or 0 and any substitutable nitrogen on said ring ^C formed by R 2 and R 2 is substituted by R4; R is selected from an optionally substituted group selected from C3- 10 carbocyclyl, Cs-3o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally substituted group selected from CI-6 aliphatic, Cs6-o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -COR', -'CO (optionally substituted Ci-s aliphatic), -CON (R 7 2 or -S0 2

R

7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R is. independently selected from halo, -OR, -C02R, -COCOR, -NO2, -CN, -SOzR, -SR, N(R)2, -CON(R') 2 -SO2N(R')2, -N(R')COR, -N (R)C0 2 (optionally substituted Ci-6 aliphatic),

C=NN(R')

2 -C=N-OR, CON

-N(R

4

)SO

2

N(R

4 2

-N(R

4 )S0 2 R, or -OC(=0)N(R 4 2 or R 5 and IND an adjacent substituent taken together wtith their intervening atoms form said ring fused to Ring C; V is -S- 1 -SO2-, -N(R')S 2

-SO

2 -CO- -C0 2 -N(R6)CO-, -N(R9)C(O)O-, -N(R6)CON(R6) -(R6)SO 2 N(R) -N(PY)N(R6) -c(R6) 2 2

S-,

-C(R6) 2 -c(R) 2 S0 2 2 S0 2 -C(R6)N 2 -C(R6) 2 IND 10 )2W -C(R6) 2 N (R')SON (R or -C(R6) N (Rr) C64(RG) 1 is -0(R 6 2 -C(R6) 2 S0-, -C(R')2S0 2 2 S0 2 -C(R6) 2 N(R6) -F -CO-, -0(R 6 )00 -C(R6) 2 -C 2 N -0(R -0(R 6 -C(RG) 2 N (R6)N(R) -t 2 N(R6) SO 2 N (R6)- 2 or each R6 is independently selected from hydrogen, an optionally substituted 01.4 aliphatic group, or two It groups on' the same nitrogen atom are taken together with the nitrogen atom-to form a S-6 membered heterocyclyl or heteroaryl ring; each I 7 is independently selected from hydrogen or an optionally substituted C3,- aliphatic. group, or two I7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; each It is independently selected from an optionally substituted 0I-4 aliphatic group, -OR, -S9t, -COR6,

-SO

2 R6, 2 -N(R6)N(R6) 2 -ON, -NO 2

-OON(R')

2 or -CR; and

R

9 is selected from halo, -OR, -C(tO)I, -00 2 R, -COCOR,

-NO

2

-SO

2 R, -SR, 2

-CON(

4 2 155

-SO

2

N(R)

2 -N(R')COR, -N(R 4 )C0 2 (optionally substituted C.

6 aliphatic), -N(R)N(R) 2 -CtNN(R') 2 0 -C=N-OR, -N(R)CON(R') 2 -N(R)80 2

N(R)

2 -N(R)SO2R, or N (R) 2 Preferred RY groups of formula VII include T-R" wherein T is a valence bond or a methylene. Preferred R" Ci groups include an optionally substituted group selected from C 3 6 s carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred RY

O

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

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

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

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

H

N N NH NH H NH RY G.NN 6 N I and Preferred substituents on the R 2

/R

2 fused ring include one or more of the following: -halo, 2

-CI-.

4 alkyl, C1.

4 haloalkyl, -NO 2 -0 (C1.

4 alkyl) -CO2 (C1.

4 alkyl), CN, -S02(C.

4 alkyl), -S02NH 2

-OC(O)NH

2

-NH

2

SO

2

(C

1 4 alkyl) -NHC(O) (C3- 4 alkyl), -C(O)N NR 2 and 156

-CO(C.

4 alkyl), wherein the (C.

4 alkyl) is a straight, INDbranched, or ;cyclic alkyl group. Preferably, the (C 1 o alkyl) group is methyl.

When the pyrazole ring system of formula VII is monocyclic, preferred R2 groups include hydrogen, C 1 4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, C hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nbeterocyclyl)carbonyl. Examples of such preferred R 2 substituents,include methyl, cyclopropyl, ethyl, Ci isopropyl,.propyl, t-butyl,.cyclopentyl, phenyl, CO 2

H,

\O CO 2

CH

3

CM

2 0, CH20CH 3

CH

2 CH2C 2 0H, CH 2

CH

2

CH

2 0CH 3 SCH2CH2CH20CH 2 PI, CH 2

CH

2 2N 2

N

2

CM

2

NHCC(C

3 3 CONHH (c 3 a) 2 CONHc 2

CH=CM

2 cONHCH2CH 2 0CH 3

CONHCH

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

CON(C

3

)CMH

2 Ph, CONH(n-C 3

H

7 CON(Et)CH2CH2CH3, CONHHCH(CH) 2 CON(n-C 3

H

7 2 CO (3methoxymethylpyrrolidin-l-yl), CONH(3-tolyl), CONH(4tolyl), CONHCH 3 CO(morpholin-1-yl), CO(4-methylpiperazinl-yl), CONHC 2

CH

2 0HI, CONH 2 and CO(piperidin-l-yl). A preferred R 2 group is hydrogen.

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

Preferred fused rings include a benzo or pyrido ring.

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

1 -s aliphatic group, phenyl, -COR6, -OR 6 -CN, -S0 2 -S0 2

NH

2 2, -CO 2

-CONH

2 -NHCOR', -OC NH 2 or -NHSO 2

R'.

When R is an optionally substituted C 1 6 aliphatic group, 157 the most preferred optional substituents are halogen.

IND Examples of preferred R' groups include -CF3, -C1, -F, 0 o0 -CN, -COCH 3 -0CH 3 -OH, -CH 2

CH

3

-OCH

2

CH

3

-CH

3

-CF

2

CH%,

cyclohexyl, t-butyl, isopropyl, cyclopropyl, -CCH, -CeC-CH 3 -S0 2

CHM

3 -02NH2, -N(CH 3

-CO

2

CH

3

-CONH

2 -NHICOCH, -OC NH 2 -NHS02CH 3 and -OCF 3 On Ring C preferred R5 substituents, when present, include -balo, -CN, -NO 2

-N(R

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

R,

\O

-CONH(R'), -N(R')COR, -302N(R 4 2 and -N(R')SO2R. More preferred R5 substituents include -Cl, -CN, -CF3, -NH2, -NH(Cl-4 aliphatic)', N(CQ.4 aliphatic)2, -O(cI-4 0aliphatic), aliphatic, and -CO(Cl-, aliphatic).

CA Examples of such preferred R 5 substituents include -Cl, -CN, -CF, -NH2, -NHMe, -NMe,, -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -CO2Et.

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

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

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

-N(R

4 -CO02R, -CONH(R'), -N(R')COR, -SO2N(R) 2

-N(R

4 )SO2R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-3o aryl, or CI- 6 158 aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, 2 or a o substituted or uinsubstituted group selected from 5-6 membered heterocyclyl, Cs-,o aryl, or C,- 6 aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CH20H, CH 2 CH20H, pyrrolidinyl, OPh, CF 3 CECH, Cl, cl Br, F, I, NH 2 C(O)CH, i-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene dioxy, and ethylene dioxy.

Preferred formula VII compounds have one or Va C 10 more, and more preferably all, of the features selected from the group consisting of: Cl Ring C is a phenyl or pyridinyl ring,

NO

o optionally substituted by -R 5 wherein when Ring C and. two Cl adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl 'ring, and R is -halo, an optionally substituted C,.

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

-SO

2

NH

2 -N11(R 6 2 -C0 2

R,

-CONH

2 -NHCOR', -OC(O)NH 2 or -NHSO 2 or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; RY is wherein T is a valence bond or a methylene; and

R

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

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

R

1 is -halo, a C1-6 haloaliphatic group, a C 1 -s aliphatic Sgroup, phenyl, or -CN; or Ring D is an optionally

\O

Ci 10 substituted ring selected from phenyl, pyridinyl, Spiperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, C' 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4o tetrahydroquinolinyl, 2,3-dibydro-1H-isoindolyl, 2,3- C dihydro-iH-indolyl, isoquinolinyl, quinolinyl, or naphthyl;

R

Y is wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from C3-. carbocyclyl, phenyl, or a 5-6 membered .heteroaryl or heterocyclyl ring;

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a C 16 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and Ring D is substituted by oxo or R 5 wherein each R s is independently selected from -halo, -CN, -NO 2 optionally substituted Ci-6 aliphatic group, -OR, -CO0R, -CONH(R 4

-N(R

4 )COR, -S02N(R 2, or

-N(R')SO

2

R.

Even more preferred compounds of formula VII have one or more, and more preferably all, of the features selected from the group consisting of: 160

R

Y is T-R 3 wherein T is a valence bond or O a methylene and R 3 is an optionally substituted group 0selected from phenyl, or a 5-6 membered beteroaryl or heterocyclyl ring; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two C< adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R1 .is -halo, a Ci-4 aliphatic group optionally substituted IN 10 with halogen, or -CN; or Ring D is an optionally S'substituted ring selected from phenyl, pyridinyl, C piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,

IO

o 1,2,3,4-tetrabydroisoquinolinyl, 1,2,3,4- 0 tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl;

R

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

-C

1 -4 alkyl,

-C

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

(C-

4 alkyl), -CN,

-S

2 (C 4 alkyl), -S0 2

NH

2 -OC(0)NH 2

-NH

2 SO2 4 alkyl), -NHC(O) (CI- 4 alkyl), -C(O)NH 2 or -CO(C 1 4 alkyl), wherein the (Ci- 4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -Cl, -CN, -CF 3

-NH

2 -NH(C3-4 aliphatic), -N(CI- 4 aliphatic) 2 -0(Ci-4 aliphatic), Ci-4 aliphatic, and -C0 2 4 aliphatic).

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

2006201264 21Mr06 21 Mar 2006 S2 x

C)

0 z oz z 0z 0 I t C,3z C; C)z

-ZI

3) VII -13 F

F

N

4 VII-16 Hg3 N -N

H

VII -22 N

.N

HN2

NN

N 'JN VII

HN

4 N YN VII -23 HN

N

VII

CH

3 H A J N J-%N V1I -18 HN2P N J%%N VII -21

HN

NA"N CF 3 VII -24 .163 N'-N CF 3

CH

3 HN*t

F

3

C

VII-28

HN

N-N

VII-31

CH

3 HNAjP

H

NVIN

VII -34 nl HN

I

NAN I VII- 26

CH

3

HNP

N~N

QAC

VII-29

H

'A-

VII-32

CH

3 N -N VII-3S HN2V N)N CI VII-27

HN#S

N N VII-

CH

3

HNP

VII-33 Et

N~N

VII1-36 In another embodiment, this invention provides a composition comprising a compound.of formula VII and a pharmaceutically acceptable carrier.

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with'a GSK-3 inhibitor, said method comprising the step of Sadministering to a patient in need of such a treatment a Va C 10 therapeutically effective amount of a composition o comprising a compound of formula VII.

Cl 0 Another aspect relates to a method of enhancing Sglycogen synthesis and/or lowering. blood levels of Cl glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective am6unt of a composition comprising a compound of formula VII. This method is especially useful for diabetic patients.

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

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

One aspect of this invention relates to a method of inhibiting Aurora activity in a patient, 165 N comprising administering to the patient a therapeutically o effective amount of a composition comprising a compound 0 c-i of formula VII.

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

VO

Cl 10 especially useful for treating cancer, such as colon, o ovarian, and breast cancer.

Cl| D One aspect of this invention relates to a Smethod of inhibiting CDK-2 activity in a patient, Cl comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VII.

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

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

Each of the aforementioned methods directed to

NO

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

Another embodiment of this invention relates to compounds of formula VIII: R 2

HN

VIII

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

Z

1 is N or CR 9

Z

2 is N or CH, and Z 3 is N or CR, provided that one of Z' and Z 3 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -Re 167 Ring D is a 5-7 membered monocyclic ring or 8-10 membered o bicyclic ring selected from aryl, heteroaryl, 0 C-i heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by halo, q oxo, or -R s and at any substitutable ring nitrogen by provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho N 10 carbon position of Ring D;

SR

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

T-V-R

6 phenyl, 5-6 membered heterparyl ring, 5-6 membered heterocyclyl Sring, or Cie6 aliphatic group, said phenyl, heteroaryl, C( and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R said Ci-e aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; R is T-R 3 T is a valence bond or a C 1 i- alkylidene chain;

R

2 and R 2 are independently selected from or

R

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

-R

7 or

-V-R

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

R

3 is selected from -halo, -OR, -C0 2

R,

-COCOR, -COCH 2 COR, -NO 2 -CN, -S(0) 2 R, -SR, -N(R 2, -SO 2 N(R 2, -N(R')COR, 168 -N C0 2 (optionally substituted C 1 6 aliphatic),

IND

o 2

-C=NNR)

2 -C-N-OR, -N(R')CON(R) 2 -Nq(R7) SO 2 N (R7) 2

-N(R

4

)SO

2 R, or O=)NR)2 each.R is independently selected from hydrogen or an optionally substituted group selected from C 1 6 aliphatic, Cg..

10 aryl, a heteroary. ring having 5-10 Cl ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from _R 7 coR 7

IND

Cl -CO 2 (optionally substituted C 1 6 aliphatic) -CON (R 7 2 o ~~Or -S0 2

R

7 ,o w R 4 on the same nitrogen are taken together to form a 5-B. membered heterocyclyl or o heteroaryl ring; Cleach R' is independently selected from halo, -OR,

-CO

2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, 1.N(RW) 2 -CON(R'h), -SO,2N(R 4 2

-N(R

4

)COR,

-NU(R

4 C0 2 (optionally subst ituted C 2 6 aliphatic), -NCR)N(Rt 2 -C=lqN(Rt) 2 -C=N-OR, -N(RtCONR) 2 2 -N(R4)S0 2 R, Or -OC(=O)N(R) 2 or R 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; -C0 2

-N(R

6 -N(R6)C(O)O-, CON (R 6 -NCR') SO 2

N(R

6 6

-C(R

6 -C(R6) 2 -C(R 2 o -C(a) 2

N(R)CO(R

6 -;(62(6C00, CR)N(6- W Is, -c (a'Lo2-, -C (Rf)l 2 C 2 so-, -C (R6) 2 S0 2 -C(R6)aSO2N(R') 2 rC02r, 2

N(R

6

I)CO-,

-C(R'h2N(R6)C(O)O-, rC(R)N0O, .169 2

-C(R

6 2

N(R')SO

2 o 2 or 0 each R' is independently selected from hydrogen, an optionally. substituted aliphatic group, or two R' S groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R' is independently selected from hydrogen or an optionally substituted C 1 -6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or O heteroaryl ring; O each Re is independently selected from an optionally (N substituted C 1 aliphatic group, -SR, -COR6',

-SO

2 R6, 2 2 -CN, -NO 2

-CON(R')

2 or

COR

6 and R9 is selected from halo, -OR, -CO2R, -COCOR, -NOC, -CN, -SO 2 R, -SR, 2

-CON(R

4 2

-SO

2

N(R

4 2 -N(R')COR, -N(R4)CO 2 (optionally substituted aliphatic), -N(R 4

)N(R

4 2

-C=NN(R')

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

-N(R

4

)SO

2

N(R

4 2

-N(R')SO

2 R, or N 2 Accordingly, the present invention relates to compounds of formula VIIIa, VIIIb, VIZIc and VIId as shown below: Fe R2 F2R 2 RF, R2 RF F H H tNH HN HN HN HN N N N N N N G GNK r and ~~Rt~YrY Tr ~r ~~lld Svi.L.L.La V.J..L V.LJ.I VI.L.LQ 0 (C Preferred Rx groups of formula VIII include T-R 3 wherein T is a valence bond or a methylene and R 3 is CN, or -OR. When R 3 is preferred R 3 groups include an optionally substituted group selected from C 16 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. When R 3 is -OR, preferred R groups include an k\ optionally substituted group C4-6 aliphatic group such as C_ 10 alkyl- or dialkylaminoalkyl and aminoalkyl. Examples of o preferred R* include acetamido, CN, piperidinyl,

CA

.0 piperazinyl, phenyl, pyridinyl, imidazol-1-yl, .imidazol- S2-yl, cyclohexyl, cyclopropyl, methyl, ethyl, isopropyl, C t-butyl, NH 2 CCH2CNH, and NH 2

CH

2

CH

2 0.

Preferred R 9 groups of formula VIII, when present, include R, OR, and N(R 4 2 Examples of preferred

R

9 include methyl, ethyl, NH 2

NH

2

CH

2

CH

2 NH, N(C 3 )2CH 2

CH

2

NH,

N(CH

3

CH

2

CH

2 0, (piperidin-l-yl) CH 2

CH

2 O, and NH 2

CH

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

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

These are exemplified in the following formula VIII compounds having a pyrazole-containing bicyclic ring system: HN 1 .N

N

I f ,N H H NH I H NH" and 171

IND

o Preferred substituents on the formula VIII (N R 2

/R

2 fused ring include one or more of the following: Ct ~-halo, -N(R 4 2

-C!

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

-O(C

3 4 alkyl), -C0 2

(C

1 4 alkyl), CN, S02 (C 1 4 alky:l), -S0 2

NH

2 -Oc(O)qH 2

-NN

2

SO

2 4 Lalkyl), -1*IC(o) 4 elyl), 7C N 2 and -CO (C 1 4 alkyl) where in the (Ci- alkyl) i.L aL straight, branched, or cyclic alkyl. group. Preferably, IND the (C2_.4 alkyl) group is methyl.

When the pyrazole ring system of formula VIII o is monocyclic, preferred R 2 groups include hydrogen, C 1 4 IND aliphatic, alkoxycarbonyl, (un) substituted phenyl, o hydroxyaflcyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminiocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, Cogi,

CO

2 Cl 3

CII

2 OH, CH 2

OCH

3

CN

2

CH

2

CH

2 OH*, 01 2 0? 2

CH

2 Oal 3

CH

2 a! 2 Cd1 2 0CH 2 Ph, CH 2 0 2

CH

2

RH

2

CH

2 aI 2 cH 2 qHCoOc(C%4) 3 CONHcH COmrCH 2 i=Ci 2

CONHO

2

CH

3 00I 3

CONHC!HZPI,

CONH(cyclohenyl), CON(Et) 2 CO(0 3 )cltPh, CONH(n-C 3 1 7 CON(Et)CH 2 aI 2 CH3, CoNRC! 2 a!(cH 2 2 CON(n-C 3

H)

2 CO(3methoxymethylpyrrolidin-l-yl), CONHi3-tolyl), COIIH(4tolyl), CONHCH 3 CO (morpholin-l--yl), CO (4-methylpiperazinl-yl), CONHCH 2

CH

2 OH, COrNH 2 and CO(piperidin-l.-yl). A preferred R 2 group is hydrogen.

When G is Ring C, preferred formula VIII Ring C groups are phezyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system.' Preferred fused rings include a benzo orpyrido ring.' Such rings preferably are fused at ortho-and meta .172 IND positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred

R

1 groups include -halo, an optionally substituted C 1 6 aliphatic group, phenyl, -COR', -OR, -CN, -SQ2R', -80 2

NH

2 3 -COC2R, -CONH 2 -NHCOR', -OC(O)NH21, or -NHS0 2

R'

When R' is an optionally substituted C3-g aliphatic group, the most preferred optional substituents are halogen.

Examples of preferred R groups include -CF 3 -Cl, -F, IN -CN, -COCH 3 -OCH, -OH, -CH 2

CH

3

-OCH

2

CH

3

-CH

3

-CF

2

CH

3 10 cyclobexyl, t-butyl, isopropyl, cyclopropyl, -CmCH, -Zn-CHi 3 -S0 2

CH

3

-SO

2

NH

2

-NCH

3 2

-CO

2

CH

3

-CONH

2

-NHCOCH

3 -OC(0)NH 2

-NHSO

2

CH

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

N(R')

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

R,

-CONH(R

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

N(R')

2 and -N(R')SO 2 R. More preferred R 5 substituents include -Cl, -CN, -CPF 3

-NH

2

-NH(C

1 4 aliphatic), -N(CI.

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

Examples of such preferred R5 substituents include -C1, -CN, -CF 3

-NH

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

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

When two adjacent substituents.on Ring D are taken together to form a fused ring, the Ring D system is bicyclic. Preferred formula VIII Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-M1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and S173 INDnaphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

Preferred RS substituents on Ring D of formula VIII include halo, oxo, CN, -NO 2

-N(R)

2

-CO

2

R,

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

-N(R)SO

2 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, CG-10 aryl, or C-6 aliphatic. More preferred R5 substituents include -halo, S-CN, -oxo, -SR, -OR, -N(R) 2 or a substituted or unsubstituted group selected from 5-6 membered o heterocyclyl, C 6 so aryl, or Ct- 6 aliphatic. Examples of IN Ring D substituents include -OH, phenyl, methyl, o2 O2CH120H, pyrrolidinyl, OPh, CF 3 CCH, Cl, Br, F, I, NH 2 C(o) CH 3 i-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene dioxy, and ethylene dioxy.

Preferred formula VIII compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -Rs, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and RI' is -halo, an optionally substituted C 1 aliphatic group, phenyl, -COR', -CN, -SO 2

R

6

-SO

2

NH

2 2

-CO

2

R',

-CONH

2 -NHCORG, -OC(O)NH 2 or -NHSO 2

R

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

R

X is T-R 3 wherein T is a valence bond or a o methylene; and ^C R 2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C2.

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

.More preferred compounds of formula VIII have

VO

Cl 10 one or more, and more preferably all, of the features Sselected from the group consisting of: C\ Ring C is a phenyl or.pyridinyl ring, Soptionally substituted by -R 5 wherein when Ring C and two Cl adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and

R

1 is -halo, a C.- 6 haloaliphatic group, a C 1 -6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl;

R

x is T-R 3 wherein T is a valence bond or a methylene and R 3 is CN, -R or -OR;

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a C 1 i. aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and each R s is independently selected from -halo, -CN, -NO2, optionally substituted Ci- 175 aliphatic group, CO 2 R, -CONH(R'), -N(R' COR, O -SO 2

N(R

4 or -N(R 4 )SO2R.

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

R

x is T-R 3 wherein T is a valence bond or a methylene and R 3 is -R or -OR wherein R is an optionally substituted group selected from C.-6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; C 10 Ring C is a phenyl or pyridinyl ring, o optionally substituted by -R 5 wherein when Ring C and two \O adjacent substituents thereon form a bicyclic ring Ssystem, the bicyclic ring system is a naphthyl ring, and C' R' is -halo, a Ci- 4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl;

R

2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R 4 2 -CI.4 alkyl, haloalkyl, -NO, alkyl), -CO 2 (Ci-4 alkyl), -CN, -S0 alkyl), -S02NH2, -OC(O)NH2, -NHSO (CI- 4 alkyl), -NHC(O) (CI.

4 alkyl), -C(O)NH2, or -CO(C1.

4 alkyl), wherein the (CI- 4 alkyl) is a straight, branched, or cyclic alkyl group; each R 5 is independently selected from -Cl, -CN, -CF 3 -NH2, -NH(Ci.

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

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

176 Ce) R 9 is R, OR, -Or NCR 4 3 Representative compounds of formula VIIX are set forth in Table 7 below.

HNZH

VIII -1 HNt$ VIII -4 VIII -2

HN

4

H

VIII-5 Me VIII-3

HN

N )Me VIII-6

BU

N

Pr

HN*H

N

OMe

VIII-B

IF

ArN NMe VIII -9 Me

HN

4

PH

rN

N

DMe

NN

vill-lo VIII-11 VIII-12 VIII -13 VIII -14 HN2V Me-NJ M e VIII -17 HNZ4

N'-NCF

3 Me VIII-20 HN2H N CF 3

HN

N

4 -N CF 3 VI 11-21 94H N C VI 1 -24 VIII -16 N N C F, VIII- 19:

MN

N J1N CF3 VtiI-22

HN

NON CI VIII- 23 178

H

NN CN HN94

A'

N)N CI VIII-26 FZ

H

N'N CI VIII-27 VIII-28 VIII-29 9I_

NH

Me VIII-34

?~H

H NI DN J CF 3 VIII-32 9XNH N CF 3 Me) VIII-35 VIII-33 N F Me VIII-36 179 NN CI Me'N JOt- Me VIII -39 VIII-37 VIII-38 MN4 NtA VIII -40 VIII-41 VIII -42 9NH CNIQ TN CF 3 VIII1-43 37111-44 VI 46VIII-47 311-148 VIII-46 HN N^ HN HN O N CFe N N CFI kY'N CF3

CF

3 YN N CF 3

N

VIII-49 VIII-50 VIII-51 O

V

H

VIII-52 VIII-53 VIII-54 Me HHN N HNN' HN C o S '9 N CF, H2N 'l-O N CF VIII-55 VIII-56 VIII-57 In another embodiment, this invention provides a composition comprising a compound of formula VIII and a pharmaceutically acceptable carrier.

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

Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 181 IND inhibitor, said method. comrprising the, step of o administering to a patient in need of such a treatment a ci therapeutically effective amount of a composition Ct ~comprising a compound of formula VIII3.

S Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula VIII. This method is especially useful for diabetic patients.- IND Another aspect relates to a method of o inhibiting the production of hyperphosphoryiated Tau Cl protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula VI:11. This method is especially useful in halting or slowing the progression of Alzheimer's disease.

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

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

Another aspect relates to a method of treating a disease that is alleviated by tr eatment with an Aurora inhibitor, said method comprising the step of, administering to a patient. in need of -such a treatment a D therapeutically effective amount of a composition o comprising a compound of formula VIII. This method is 0 c-i especially useful for treating cancer, such as colon, ovarian, and breast cancer.

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

Another aspect relates to a method of treating Sa disease that is alleviated by treatment with a CDK-2 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a N1 therapeutically effective amount of a composition comprising a compound of formula VIII. This method is especially useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

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

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

The above formula I compounds contain a pyrazole ring bearing the R 2 and R 2 substituents. In 183 \DO their search for further inhibitors of the protein O kinases GSK and Aurora, applicants sought to replace the CN pyrazole moiety of formula I with other heteroaromatic Srings. One of the more effective pyrazole ring replacements was found to be a triazole ring. Inhibitors having this triazole ring are otherwise structurally similar to the formula I compounds and are represented by the general formula IX: o RR 2 SN NH I

HNN

R

Ix or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

1 is nitrogen or CR' and Z 2 is nitrogen or CH, provided that at least one of Z 1 and Z 2 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or'nitrogen, 184 said fused ring being optionally substituted by halo,

\O

o oxo, or -R 8 Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected Sfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by -R 4 (C 10 provided that when Ring D is a six-membered aryl or Sheteroaryl ring, -R 5 is hydrogen at each ortho carbon \0 position of Ring D;

SR

1 is selected from -halo, -CN, -NO2, T-V-R 6 phenyl, 5-6 C( membered heteroaryl ring, 5-6.membered heterocyclyl ring, or C-s aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R e said Ci-6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 20 and 1 an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;

R

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

R

Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by Rx and R Y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by R x and R Y is substituted by R'; T is a valence bond or a Ci-. alkylidene chain;

R

2 is -R or -T-W-R6; 185 Ra is selected from -halo, -OR, -C(tO)R, -00 2

R,

o -00002, -COCH 2 COR, -NC 2 -01, -5(0)22, -SR, ci -NWR) 2 -CON(R'b2, -SC 2

N(R')

2 -CC(nC)R, -N(R')COR, -M (R7) C02 (optionally substituted C 1 6 aliphatic),

-N(

4

W)N(R

4 2 -C=NN(Rd)h, -C=N-OR, -N (R7500NW) 2

-N(R')SC

2 R, or -C=)(72 each 2 is independently selected from hydrogen or an optionally substituted group selected from 01-6 aliphatic, C6.1 aryl, a heteroaryl ring having 5-10 (N ring atoms, or a heterocyclyl rin-g having 5-10 ring o atoms; each R" is independently selected from -R7, -OR?, o -C0 2 (optionally substituted C1..6 aliphatic), 7OON(2') 2 Ci Or -SO 2 or two U' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or S heteroaryl ring; each Rs is independently selected from halo, -OR, -00 2 R, -00002, -NO 2 -oN, -SC 3 R, -SR,

-N(R

4 2 -COI1(R')2, -SC 2 N(2fl 3

-N(R')OR,

-N (Ri) C02 (optionally substituted C1_.6 aliphatic), -C=ZqNCR') 2 -0=11-OR, -N(R')CON(2 4 h2, -N(RtSO 2 N(Rt 2 -N(Rt)SO 2 R, or -0C(=0)N(R) 2 Or RS and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C, V is -502-, -N(RflSC 2 -S0 2 -N(R')CON(R) -N(R 6 )50 2

-N(R

6 2 2

S-,

-C(2 6 2 N(R6)C(0) -C(R 6 2

N(R

6 -CR6) =NN(0)

-C(R

6 2 2

N(R

6 )S0 2 Or INDW is 2 2

-C(R

6 2 SO-, -C(R6)2S2-, o -C(R6)SO 2 2 -C0 2 2

N(R

6 2 2

N(R')SO

2 2 N or -CON(R 6 each R 6 is independently selected from hydrogen, an optionally substituted CI-4 aliphatic group, or two R' INDgroups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered 0 heterocyclyl or heteroaryl ring; IN each.R' is independently selected from hydrogen or an optionally substituted CI-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; each R 8 is independently selected from an optionally substituted C.-4 aliphatic group, -COR',

-SO

2 2 2 -CN, -NO 2

-CON(R')

2 or

-CO

2 and

R

9 is selected from halo, -OR, -C0 2 R, -COCOR,

-NO

2 -CN, -SO2R, -SR, 2

-CON(R

4 2

-SO

2

N(R')

2 -N(R)CO, C2-N(R C(optionally substituted Cl-s aliphatic), 2

-C=NN(R)

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

-N(R

4

)SO

2 R, or 2.

Compounds of formula IX may exist in alternative tautomeric forms, as in tautomers 1-3 shbwn below. Unless otherwise indicated, the representation of any of these tautomers is meant to include the other two.

IN R 2 R R N N

HN

C HNAl HN HN Z2H l 2 Rt2 SRY 4 RY a Z R y

Z

(C 1. 2 3 The R x and R Y groups of formula IX may be taken

\O

C- 5 together to form a fused ring, providing a bicyclic ring o- system containing Ring A. Preferred Rr/RY rings include a C(l or 8-membered unsaturated or partially o unsaturated ring having 0-2 heteroatoms, wherein said

SR'/R

Y ring is optionally substituted. Examples of.Ring A systems are shown below by compounds IX-A through IX-DD, wherein Z 1 is nitrogen or C(R 9 and Z 2 is nitrogen or

C(H).

SZ2

NH

IX-A IX-B IX-C HN HN HN

IX-DZ

2 IX-E Xz-F IX-D IX-E IX-F 188 IND HN,31? M.? ZX-G IX-li IS-1 Ci S I-j IS-K I1-L

IND

NW>

IX-14 IS-N 11-0 HN>?Z HN.V>?

H

IS-P IS- f-R

HN>

ISSIX-T 1x-u is \O -HN HN/2 HNA IX-V II-W IX-X HN/? HNL HNX

INNN

CA

flZ-v fI- Il-S HN HMN HN 2Z IX-BB I-CC IX-DA Preferred bicyclic Ring A systems of formula IX o~11 NKz2 N I W include I-A, Ix-B, Ix-C, IX-D, IX-E, fl-F, fIX-G, l-E, fL-I, IX-J, IX-K, IX-L, and IS-N, more preferably IX-A, fl-B, IX-C, IX-F, and IX-H, and most preferably fl-A, IX- B, and IS-H.

In the monocyclic Ring A system of formula IX, preferred RX. groups include hydrogen, alkyl- or dialkylamino, acetamido, or a C..

4 aliphatic group such as methyl, ethyl, cyclopropyl, .isopropyl or t-butyl.

Preferred RY groups, when present,..include T-R' wherein T is a valence bond or a methylene, and R 3 is R, -N(RI) 2 or -OR. Examples of preferred R 7 include 2-pyridyl, 4pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substit ted phenyl such as phenyl or halosubstituted phenyl, and methoxymethyl.

IND In the bicyclic Ring A system of formula IX, the ring f ormed by e~ and a 7 Y taken together may be substituted or unsubstituted. Suitable substituents Ct include halo, -OR, -CO 2 R, -COCOR, -NO 2 -aP -S0 2 R, -S9R, -N(R, 4 2

-CON(R

4 h,1 -S(0%N1W) 21 -OC -N (a 4 )COR, -N CR) CO 2 (optionally substituted Cl..

6 -N(RtCON(Rt 2

-N(R)SO

2

N(R)

2

-N(R

4

)SO

2 RZ, Or -OC(=0)N(R) 2 wherein R and R' are as defined above.

Preferred eRY ring substituents include -halo, -OR, o -COW, -CO 2 -CON(Rt 2 -01, or -N(R 4 wherein R is an IND optionally substituted C 1 6 aliphatic group.

0Pre ferred R 2 groups of formula IX include hydrogen, C 1 4 aliphatic, alkoxycarbonyl, (unj substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, monoor dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminloalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, C0 2 11, Co 2 cn 3

CH

2 0H, 012001,3, 01,12012202, CH2CH 2 CH2OCH,'

CH

2

CH

2

CR

2 OC%2Ph, C%2CH 2 C%2NH 2 C4 2 0{ 2

CH

2 NHCOOC (CH 3 )3, CONHCH (CH3d2, CONH4CH 2

CH=CH

2 CONHCH201,0CH3, CONHCH, Ph, CONH(cyclohexyl), CONCMth, CON(CH,)CH2Ph, CONH~n-C3H, CON(Et)o1,012 3 c, 'CoNHa 2 co4(a1,h, CON(n-CiH7)2, COD3methoxymethylpyrrolidin-1-yl), CONE (3-tolyl), CONH (4tolyl), COFIHCH3, Co (morplaolin-l-yl), CO (4-methylpiperazin-

CONHCH

2

CH

2 OHi, CONH,, and CO (piperidin-l-yl).

A

more preferred R2 group for formula IX compounds is hydrogen.

An embodiment that is particularly useful for treating 05K3 -mediated diseases relates to compounds of formula S wherein, ring A is a pyrimidine ring:

O

HN

N

R"L N A N RY N x c or a pharmaceutically acceptable derivative or prodrug thereof, wherein; LC 5 Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, Spyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, C wherein said Ring C has one or two ortho substituents independently selected from -Rx, any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, OxO, or -R; Ra is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C3.6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -Re, said Ci-a aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their intervening atoms form said ring fused to.Ring C;

R

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

R

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

VO

CI T is a valence bond or a CI- alkylidene chain;

SR

2 is -R or -T-W-R 6 C* R 3 is selected from -halo, -OR, -CO 2

R,

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

-CON(R

7 2

-SO

2

N(R

7 2

-N(R

7

)COR,

-N(R

7

)CO

2 (optionally substituted C 1 -6 aliphatic),

-N(R

4

)N(R

4

-C=NN(R

4 2 -C=N-OR, -N(R 7

CON(R')

2

-N(R

7 S0 2

-N(R

4 SO2R, or -OC (=O)N(R 7 2; each R is independently selected from hydrogen or an optionally substituted group selected from CI-.

aliphatic, Cs-.o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -COR,

-CO

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

-CO

2 R, -COCOR, -NO2, -CN, -SO2R, -SR,

-N(R)

2

-SO

2

N(R')

2

-N(R

4

)COR,

N(R

4 C2 (optionally substituted C.

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

-C=NN(R

4 2 -C=N-OR,

CON(R')

2

-N(R)SON(R

4 2

-N(R')SO

2 R, or -OC(=0)N(R 4 or R 5 and 193 an adjacent substituent taken together with their

NO

intervening atoms form said ring fused to Ring C; V is -S 0 4U(R')S 2 -N(R6)CO-, S -N(R')SO 2 -N(R6)N(R6)-,

-C(R

6 2 C~l -C(R 6 2 S0-, -C(R 6 2 S0 2

-C(R

6 2 S0 2

N(R

6

-C(R

6 2

-C(R

6

-C(R

6 2

-C(R

6

-C(R

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

N(R

6

)SO

2 or c~ t10 C WR) 2N (16) CON W) o is 2

-C(R

6 2 2 SO-, -C(R'bS0 2 IN -C(R6) 2 S0 2

-C(R

6 2

N(R

6 -C2-, o -7C(R)0C(O)N(R 6 -C(R6)bN(R')CO-, cl -C(R) 2 -C(R6) 2 -C(R6) 2

N(R

6

)SO

2 N(R6)

-C(R)

2 1NT(R)CON(R) -or -CON(R6) each R' is independently selected from hydrogen, an optionally substituted C-4 aliphatic group, or two R' groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or hetercaryl ring; each R7 is independently selected from hydrogen or an optionally substituted 01.6 aliphatic group, or two RC on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each It is independently selected from an optionally substituted C-4 aliphatic group, -OR 6 -SR6, -OOR, -S0 2 aR6, -N(R6) 2

-N(R')NUR')

2 -CN, -NO 2

-CON(R)

2 or -CO0R6.

Compounds of formula x are structurally similar to compounds of formula IX except for the replacement of the pyrazole ring moiety. by the triazole ring moiety.

0 'Preferred

R

2 R, R Y and Ring C groups of formula X are as 0 described above for the formula II compounds. Preferred formula X compounds have one or more,' and more preferably Sall, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring; o

R

x is hydrogen or 4 aliphatic and Ra is T- L

R

3 or R x and R y are taken together with their intervening o atoms to form an optionally-substituted 5-7 membered (c unsaturated or partially unsaturated ring having 0-2 ring nitrogens;

R

1 is -halo, an optionally substituted C., aliphatic group, phenyl, -COR', -CN, -S0 2

R

s

-SO

2

NH

2

-N(R

6 2

-CO

2

R

6

-CONH

2

-NHCOR

6 -OC(0)NH 2 or -NHSO 2

R';

and

R

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

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

R

x is hydrogen or methyl and R 7 is -R, N(R4)2, or -OR, or R x and R 7 are taken together with their intervening atoms to form a benzo ring or a 5-7 membered carbocyclo ring, wherein said ring formed by R x and R

Y

is \OD optionally substituted with halo, -OR, -C02R, S-COCOR,

-NO

2 -CN, -SO 2 R, -SR, 2

-CON(R

4 Cl -SO 2

N(R')

2 -N(R')COR, -N(R')CO (optionally t substituted C 1 -6 aliphatic), -N(R 4

-C=NN(R'

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

-N(R

4 )S0 2

N(R

4

-N(R'SO

2 R, or -OC(=0)N(R 4 2;

R

1 is -halo, a C haloaliphatic group, a C 1 6 aliphatic group, phenyl, or -CN;

R

2 is hydrogen or a substituted or Cl 10 unsubstituted group selected from aryl or a Ci-c aliphatic o group; and Cl IN each R 5 is independently selected from S-halo, -CN, -NO 2

-N(R

4 2 optionally substituted CI-s Cl aliphatic group, -OR, -CO2R, -CONH(R) -N(R 4

)COR,

-SO

2

N(R')

2 or -N(R')SO 2

R.

Even more preferred compounds of formula x have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring; -R is hydrogen or methyl and R Y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R x and R

Y

are taken together with their intervening atoms to form an optionally substituted benzo ring or a 6-membered carbocyclo ring; R is -halo, a C.4 aliphatic group optionally substituted with halogen, or -CN;

R

2 is hydrogen or a C,-6 aliphatic group; and 196 \D each R 5 is independently selected from -Cl, o. -CN, -CPF, -NH 2

-NH(C

1 4 aliphatic), -N(Cz.

4 C-I aliphatic) -O(C.

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

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

R

2 HN "N

R

N

0

XI

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

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; R* and R Y are taken together with their intervening atoms to form a fused benzo ring or 5-8 membered carbocyclo ring, wherein any substitutable carbon on said fused ring formed by R x and R is substituted by oxo or T-R3; T is a valence bond or a Cq.

4 alkylidene chain;

R

2 is -R or -T-W-R 6 197 IND RK 3 is selected from -halo, -OR, -00 2

R,

o -_COCOR, -COCH 2 00R, -NO 2 -Cli, -S(O) 2 R, -SR, Cl -NCR) 2

-CON{R')

2 -80 2 N(R'b, -N(RtCOR, Ct C% (optionally substituted C 1 aliphatic), 2

-C=NN(R')

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

-N(R

4

)SO

2

N(R')

2 '-N(R4lSO 2 R, Or 0=0ZR)2 each R is independently selected from hydrogen or an optionally substituted group selected from C3..

6 IND aliphatic, CG..

10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring 0 atoms; IND each R" is independently selected from -R7, -CQR', o -CO 2 (optionally substituted C 1 6 aliphatic), -CON 2 or -SO 2 R7, or two II' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; is independently selected from halo, -OR, -C0 2 a, -COCOR, -CN, -SO 2 R, -SR,

_NC(R)

2

_-CON(R')

2 -SO2N(R') 2

-NCR')CO)R,

-N optionally substituted a aliphatic), -N i NtI CNO,-N OON(R') 2 -N(RtS 2 -N(R')SOR, or O=)NV2 V is -SO 3 -N(Rg)s0 2 -S0 2 -C0 2 -N(R')CON(R -N(R 6

-N(R

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

S-,

-C (R 6) 2 S0-, -C(R')SO 2 -C(R6VSO 2 N(a 6

-C(R

6 b2N(R') 2 2 2 -C(Rr' 2 N(Rr)S0 2 N(s 5 or C(W) 2 N CON (RY) W1 is -C(R'hOC-, 2 2 S0-, 2 S0 2

-C(R

6 2 50 2 2

-CO

2 -C OC (O)N (Rs) C- .198 D -C(R e 1(R b -C (R')NN(R 6 -C (R 6

N-O-,

S-C(R' N (R 6 -C(R' N (R 6

SO

2

N(R

6 S-C(R (R CON (R 6 or -CON(R 6 each R 6 is independently selected from hydrogen or an optionally substituted C 1 -4 aliphatic group, or two R 6 C groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and \0 each R 7 is independently selected from hydrogen or an e-l 10 optionally substituted C1- 6 aliphatic group, or two R' 0 on the same nitrogen are taken together with the ND nitrogen to form a 5-8 membered heterocyclyl or Sbheteroaryl ring.

Compounds of formula XI are structurally similar to compounds of formula III except for the replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred R 2

R

x RY, and Ring D groups of formula XI are as described above for the formula III compounds. Preferred formula XI compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring'D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;:

R

x and RY are taken together with their intervening atoms to form an optionally substituted benzo ring or 5-7 membered carbocyclo ring; and 199 IN a 2 is hydrogen or a substituted or o unsubstituted group selected from aryl, heteroaryl, or a

C..

6 aliphatic group.

More preferred compounds of formula XI have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, IN piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, C) isoquinolinyl, quinolinyl, or naphthyl; o RX and RY are taken together with their intervening atoms to form a benzo ring or 5-7 membered carbocyclo ring, wherein said ring formed by R' and RY is .optionally substituted with oxo, halo, -OR, -C2R, -COCOR, -NO 2 -CN,

-SO

2 R, -SR, 2

-CON(R)

2

-SO

2

N(R

4 2

-N(R)COR,

-N(R

4

)CO

2 (optionally substituted C 1 6 aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R')

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

)CON(R'

4 2

-N(R

4 )So 2

N(R

4 2 -N(R')So 2 R, or -OC(=O)N(R)2; R' is hydrogen or a substituted or unsubstituted group selected from aryl or a C 1 aliphatic group; and each R 5 is independently selected from halo, oxo,01 CN, N02, 2 -CO2R, -CONH(R'), -N(R')COR, -SO2N(R 4 -N(R')SO2R, -SR, -OR, or a substituted or unsubstituted group selected from' 5-6 membered heterocyclyl, C 6 0 aryl, or C 1 alipbatic.

Even more preferred compounds of formula X1 have one or more, and more preferably all, of the features selected from the group consisting of: 200 D Rx and R Y are taken together with their o intervening atoms to form a benzo ring or 6-membered 0 carbocyclo ring, wherein said ring formed by R x and R Y is optionally substituted with halo, CN, oxo, C.-s alkyl, CI.alkoxy, (C 1 alkyl) carbonyl, (C1-6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R 5 is independently selected from -halo, -CN, -oxo, -SR, -OR, 2 or a

VO

substituted or unsubstituted group selected from 5-6 Smembered heterocyclyl, C 6 s-o aryl, or C 1 aliphatic; and 0 R 2 is hydrogen or a Ci-g aliphatic group.

SAnother embodiment of this invention relates to Ci compounds of formula XII:

R

2 R" N

HN

RYN

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

-R

s and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or 201 heteroaryl ring, -R 5 is hydrogen at each ortho carbon

VO

o position of Ring D; RX and R Y are independently selected from T-R 3 or R X and

R

7 are taken together with their intervening atoms to Sform.a fused, unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ring heteroatoms selected from CN oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring is optionally and Sindependently substituted by T-R 3 and any C- substitutable nitrogen on said ring is substituted by O R 4 \0 T is a valence bond or a Ci-, alkylidene chain; o

R

2 is -R or -T-W-R6; C\ R 3 is selected from -halo, -OR, -CO 2

R,

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

-N(R

4 2

-CON(R

4 2 -SOzN(R 4 2

-N(R

4

COR,

-N(R

4 )C0 2 (optionally substituted C1;6 aliphatic),

-N(R)N(R

4 2

-C=NN(R

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

-N(R')SO

2

N(R

4 2 -N(R')S0 2 R, or 2 each R is independently selected from hydrogen or an optionally substituted group selected from C 1 6 aliphatic, Cg-o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -R 7

-COR',

-CO

2 (optionally substituted CI.- aliphatic), -CON R 7 2 or -SO 2

R

7 or two .Ri on the same nitrogen are taken together to form a 5-8 membered heterocyclyi or heteroaryl ring; each R 5 is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR,

-N(R

4

-CON(R

4 2

-SO

2

N(R'

2

-N(R

4

)COR,

-N(R

4 CO (optionally substituted C6 aliphatic), S202 2

-C=NN(R

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

N(R

4 2

-N(R')SO

2 R, or -C=)(42 0V is -S- 1 -S02-, -N(R')S0 2

-SO

2

-N(R

6 -C0 2

-N(R

6

-N(R')CON(R

6 -N(-R6)SO 2 2 2

-C(R

6

)=NN(R

6 2

-C(R

6 2

N(R

6 )S0 2 or -CC(R),N (R)CON (R 6 W is -C(1I6)20-, -C(R 6 2

-C(R

6 2 s0-, 2 50 2 -c(R6) 2 -C(R6) 2

N(R

6 -C0 2 o

-C(R

6 2 Cl 2

-C(R

6 is -C(R 6 2

N(R

6

},N(R

6 -C(R 6 2

N(R

6 S0 2 N (R6)- 2 'or -CON(R'6); each R 6 is independently selected f rom hydrogen or an optionally substituted C 1 4 aliphatic group, or two R' groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each k 7 is independently selected from hydrogen or an optionally substituted C 1 6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocycly. ring or h~eteroa-ryl Compounds of formula XII are structurally similar to cdmpounds of formula IV except for the replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred R 2 RY, and Ring D groups of formula XII are as described above for the formula IV compounds. Preferred formula X11 compounds have one or .203 IND more, and more preferably all, of the features selected 0 from the group consisting of: c Ring D is an optionally substituted ring cselected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3dihydro-IH-indolyl, isoquinolinyl, quinolinyl, or C) naphthyl ring; 10 Rx is hydrogen or C 1 -4 aliphatic and R Y is To R 3 or Rx and R are taken together with their intervening N0 atoms to form an optionally substituted 5-7 membered o unsaturated or partially unsaturated ring having 1-2 ring heteroatoms; and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl,.heteroaryl, or a Ci- aliphatic group.

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

R

x is hydrogen or methyl and R y is -R,

N(R')

2 or -OR, or R x and R Y are taken together with their intervening.atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, wherein said ring is optionally substituted with -R, halo, oxo, -OR, -C0 2 R, -COCOR, -NO 2 -CN, -S(O)R,

-SO

2 R, -SR, -SO 2

N(R')

2

-OC(=O)R,

ND -N(R COR, -N(R)C0 2 (optionally substituted C-6. aliphatic), O 2

-C=NN(R

4 2 -C=N-OR, -N(R')CON(R 4 )2, 0q -N(R)SO 2 N -N(R')SO 2 R, or -OC N 2;

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl or a C.L aliphatic group; and c each Rs is independently selected from halo, oxo, CN, NO 2 2 -COR, -CONH(R 4 -N(R COR,

S-SO

2

N(R')

2

-N(R

4

SO

2 R, -SR, -OR, or a substituted -or unsubstituted group selected from 5-6 membered Sheterocyclyl, C 6 o aryl, or Ci-6 aliphatic.

Ci I\ Even more preferred compounds of formula XII 0 have one or more, and more preferably all, of the C features selected from the group consisting of:

R

x and R y are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, optionally substituted with halo, CN, oxo, C,- 6 alkyl, C.-6 alkoxy, (Cij- alkyl)carbonyl, (Ci- 6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R 5 is independently selected from -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C-io aryl, or C 2 -6 aliphatic; and

R

2 is hydrogen or a Ci-, aliphatic group.

Another embodiment of this invention relates to compounds of formula XIII: 205 ID R2 0 NA 0NH HN

N

Rx Z2

XIII

or a pharmaceutically acceptable derivative or prodrug C thereof, wherein:

SZ

1 is nitrogen, CR, or CH, and Z 2 is nitrogen'or CH; ND provided that one of Z 1 and Z' is nitrogen; oG is Ring C or Ring D; Cl Ring C is selected from' a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently substituted by -R s and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R 8 Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen.or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

-R

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

heteroaryl ring, -R 5 is hydrogen at. each ortho carbon position of Ring D; R is selected from -halo, -CN, -NOa, T-V-R 6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci- aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or said Ci., aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; R and R Y are independently selected from T-R 3 or R x and

R

Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring beteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R3 and R Y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by R x and R Y is substituted by R'; T is a valence bond or a CI-4 alkylidene chain; R

R

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

R,

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

-N(R

4 2

-CON(R

7 2

-SO

2

N(R

7 2

-N(R')COR,

-N(R

7

CO

2 (optionally substituted Ci.. aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R

4 2 -C=N-OR, -N(R 7

CON(R

7 2 -N (R SON (Ri 7 2

-N(R')SO

2 R, or 2; each R is independently selected from hydrogen or an optionally substituted group selected from Ci-s aliphatic, Cs- 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; 207 IND each R 4 is independently selected f rom -R 7

-COR

7 0 -Co 2 (optionally substituted C 1 4 aliphatic), -CON 2 or -S0 2 R, or two It 4 on the same nitrogen are taken Ct together to form a 5-8 membered heterocyclyl or S heteroaryl ring; each R' is independently selected from -It, halo, -OR, -C0 2 It, -COCOR, -NO 2 -CN, -80 2 R, -SRt,

-N(R

4 2

-CON(R)

2 -SO2N(R 4 2 -N(It)COR, IND -N (R 4 C0 2 (optionally substituted C 1 6 aliphatic),

-N(R')N(R

4 2 -C=NN(R'b2,. -C=N-OR, -N(R 4

)CON(R

4 -N(RlS 2 N(t) 2 N(Rt)SO 2 R, Or -OC(=O)N(Rl, or It and an adjacent substituent taken together with their o. initerve ning atoms form said ring fused to Ring C;.

V is -S02-, -NCR')S0 2

-SO

2 CON(R") K -NCR') SN(R) 2 2 s-,

-C(R)

2 S0-, 2 80 2 2 S0 2 2 -C (It) 2 N (R6) C(0) C(R') 2 N -C CR') -CCR') 2 -C 2 502N R6) or -C CR') 2 N (R6) CON CR') W is 2 3 -C(R 6) 2 50-, 2 S0 2 -C(It') 2 S0 2 2 Nq(It)-, -C0 2 -C OCCO)-, -C(R6) OC N -C (RE) 2 N (R6) co-, 2 =NN 2 -C(6;6S0NJ6- -C (R6) 2 NWR'CON or -0011(R')-; each R6 is independently selected from hydrogen, an optionally substituted C 1 4 aliphatic group, or two It' groups on the same. nitrogen atom are taken togeth .er with the nitrogen atom to form a 5-6 membered heterbcyclyl or heteroaryl ring; INDeach

R

7 is independently selected from hydrogen or an o optionally substituted C- 6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; each R is independently selected from an optionally substituted C1-.

4 aliphatic group, -COR,.

-SO

2 -N(R6) 2 -N(R6)N(R") 2 -CN, -NO2, -CON(R 6 or 7 -CO2R'; and N 10 Ra is selected from halo, -OR, -CO 2 R, -COCOR,

-NO

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

IND-SON(R)

2 -N(Rf)COR, -N(R')CO(optionaliy substituted C- 6 aliphatic), -C=NN(R 4 )2, -C=N-OR, -N(R4)CON(R 4

-N(R')SO

2

N(R')

2

-N(R')SO

2

R,

or an.optionally substituted group selected from C 1 6 aliphatic, Coso aryl, a heteroaryl ring having 5-10 ring atoms, or a beterocyclyl ring having 5-10 ring atoms.

Compounds of formula XIII may be represented by specifying Z' and Z 2 as shown below: R2

R

H N -A

NNNH

HN: HNAN HN'N R R R RF N N RYX'o RY RY G G G ad Re G and G ZIla IIIb SIIc Compounds of formula XIII are structurally similar to compounds of formula V except for the replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred RX, RY, a 8 and Ring G groups D of formula XIII are as described above for the formula V o compounds. Preferred formula XIII compounds have one or 0 C- more, and more preferably all, of the .features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a Snaphthyl, quinolinyl or isoquinolinyl ring, and R 1 is LN -halo, an optionally substituted Ci-6 aliphatic group, Sphenyl, -COR 6 -CN, -so 2

R

6

-SO

2

NH

2

-N(R

6 2 -C02R 6 S-CONH, -NHCOR 6

-OC(O)NH

2 or -NHSO 2 R6; or Ring D is an o optionally substituted ring selected from a phenyl, C( pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dibydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

R

x is hydrogen or Ci-, aliphatic and R Y is T-

R

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

R

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

More preferred compounds of formula XIII have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and 210 RI is -halo,. a C2- haloaliphatic group, a CI., aliphatic o group, phenyl, or -CN; or Ring D is an optionally 0 C- substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, -1,2,3,4-tetrahydroisoquinoinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; '4 RX is hydrogen or methyl and RY is -R, 10 N(R) 2 or -OR, or RX and RY are taken together with their o2 intervening atoms to form a benzo ring or a 5-7 membered carbbcyclo ring, wherein said ring formed by RX and R is 0 optionally substituted with halo, -OR, -co 2

R,

N -COCOR, -NO 2 -S0 2 R, -SR, -CON(R') 2 -S02N(R') 2 COR, CO2 (optionally substituted 01-6 aliphatic), 2

-C=NN(R')

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

-N(R)SO

2

N(RY

2

-N(R

4

)SO

2 R, or R is hydrogen or a substituted or unsubstituted group selected from aryl, or a C1-6 aliphatic group; and each Rs is independently selected from -halo, -CN, -NO 2 2 optionally substituted aliphatic group, -OR, -C0 2 R, -CONH(R'), -N(R')COR,

-SO

2

N(R)

2 or -N(R)SO 2 R, and, when Ring G is Ring D, Ring D is substituted by oxo or R 5 Even more preferred compounds of formula XIII have one or more, and more preferably all, of the features selected from the group consisting of:

R

1 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 e and Ry INDare taken together with their intervening atoms to form a o benzo ring or a 6-membered carbocyclo ring wherein said C ring formed by R" and RY is optionally substituted with halo, CN, axo, C., 6 alkyl, 0C 1 6 alkoxy, (C1- alkyl)carbonyl, alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; Ring C is a phenyl or pyridinyl ring, optionally substituted by -Rs, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring o system, the bicyclic ring system is a naphthyl ring, and IO R. is -halo, a C3.. aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally C substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl;

R

2 is hydrogen or a C 1 6 aliphatic group; and each R 5 is independently selected from -C1, -CN, -NH 2

-NH(C

1 4 aliphatic), -N(C 1 4 alipatic)2, -O(C.1-4 aliphatic), CI.4 aliphatic, and -C0 2

(C

1 4 aliphatic), and when Ring G is Ring D, Ring D is substituted by oxo or Rs Representative compounds of formula IX are shown below in Table 8.

Table-8.

CH

3 HN H HN"rH HN H HN. HN l HN*H N CI N CI N CF 3 HJC~N N HN

H

3 C N 4 -j~ 212 IX- 1

CH

3

NASH

HN;

IX-4 HN C

NCF

3 IX-7 .IX-2

IX-S

IX- 3 MN AN IX- 6 Ny HNAXdl IX- 9

CH

3 N AH IX- B

CHS

HN 6

N~

9 j[N CF 3 IX- 12 X-li.

HNA

NICF

iX- 13

CF

3 GPN

CF

3 IX- 14

OH

3 MN

H

NCH

3 fl-is IX-I1S IX-17"-l IX-18

OH,

NA(

HN

'_X

H3C ix- 19

OH

3

N

4

A

HN 4W N

F

IX -22 H 3 C cH3

HAH.

HNC

HC N IX- 25

OH

3 N A

HN

IX-20

OH,

N A HN

IX

TX- 23 HNl I-X-26

OH

3

-NA

4

NO

IX -21 08, N H

HN-"

KSC jN OF, IX -24 N

H

HN'

HCtI N ON

HC

IX-27 214 IX- 28 HN LN HaCt.,N

CA

H

3

C

IX- 29 MNt IX- 32

CM

3 MN

H

ON F IX- 31

OH

3 .Ot) "N OCHS IX-34 .Cl-I

HN;PH

cJ N CH 3 N~tfM IX- 37

NH

HN*t lclN

CH

3 IX -3 B

CH

3 Nt HN

P

N'

TX- 41

NZ

O H 3 n-3D

OH

3

HN*

IX-33

CH

3 NkH MN

NCOCH

3 IX- 36 C H 3 N

H'

NCH

2

C-

3 IX- 39 OH3 N OCH CH 3

NO

IX- 42

CM

3 IX -40 .215

HNA_

IX -43 hN-

NA

IX-46' N

H

IX- 49

HN-H

N9 IX-52

HN-

ON CF3 IX -44 HNAPd O N CF3 IX- 47

HNI

N CF IX-so

OH

HN d4

NCF

3 IX- 48

OH

3 NkH HN*r gNa ICr

OH

3

HN*"

KJN ON IX-54 IX-53 .216

OH

3 HN 4 NBr

CH

3

N-A

HN

VH

-NCF

3

H

3 IX -61

HN

HN!'

IX- 67

CH

3

HNAIPN

N

I5X-56 H3XOH4 IX-59 tH 3 IX-62 HN N NtCF3

IS-E

OH

3 HN NC I IX- 57

CIA

3 N A HN -i4H

CF

3 IX- CH-3

NH

2 1X5-53

OH

3

HNA

9{~NOF3

H

3

C

IX-66

CH

3 N A HN 4

X

N

15-68

NH

HN

N CF3 N N IX-69 217 IX- 72 IX-71

CM

3 N, 'NH

HNN

F

3

C

IX-73

HNA

FC

IX- 74

CH

3

H

2 NJrF3 IX-7G

CH

3

HNA~

Nc AcN H>1 F IX -77

CH

3 HNt H 3C IWS0 2 NH Cl IX- 78

CH

3 HN A

F

3

CN

0.

IX-81

CM

3 HN Ar4N IX-79

CM

3

N-

4 IX- 80 .218

CH

3

H

HN

4 P H 3

NCF

3 reN- F Me 2IX-82 IX- 83 Cl-l CH3I N A H-

HN;%PH

1 jN CFa Nhf kN CF, Nt *IX-BS IX-86 0T HNA' ONtN

CFS

IX- 84 OH3 HN

;P

IX- 87

OH

3 NA

H

tx-88 tX-89 CH3

HN

1 N OF, Cbz. NN

OH

3 N k HN N N N

F

IX-94 OH3 IX-92 OCH3 HN4

HN-NN

I NCF 3 Cbz* IX-95 IX-93

MNA

'NCF

Ix- 96 *219

N

2 M0 2 SN.l.Qi IX-97

CH

3 HN

IN

I 'N CI IX- 100

CH

3 -HN _4%WH A c ~N U Ona IX- 99

OH

3 HN4 H7,- 1 'N CF, IX-102 IX- 101

OH

3 Ix- 103

HN$

IX-104 ICs

HN

ON

nc-i107 IX- 105

HN"

Nt

IN

IX- 108

CH

3 IX-3106 .220

CH

3

N

C 1N CF 3 rzA 0 IX- 109 IX-112

CH

3 QN CFS ix- 110

C

3 IX- 116

CH

3 *N k HN -I's

CH

3 HN4;

OH

3

NH

ONe

CH

3

NAH

NC(O)NH

2 IX-115

OH

3

HNA

IX- 118 IX-120 .221

CM

3

HNA*

rON OMe IX -121 CMs

NIL

HN

MOMo IX -122

OH

3

NA

MN

IX-123

OH

3

NAM

HNAX-d N C(O)NH 2 IX-124

CM

3

NA--

N

IX- 127

OH

3

CH

3 N-

NAMH

HN XH HN*

NH

2 IX-125 IX-126

CH

3 N H 3

H

HN*H HNN 3

'NOS

2

NM)

2 -Z N CN NNI~jN IX-128 IX- 129 IX-130

CM

3

N

MN

IX 31 *HN t.

N tH

CH

3

H

N

IX- 132

N

CM

3 UM NS-,( IX-133

CH

3 HNJp N H;

H

3 0 IOCX-3 IX-136 IX-134 IX -137

OH

3

HNA"NN

IX-140

OH

3 HN Jd.J

N

0t 1 tIX-140 IX-135 IX-139 IX-138

CH

3 HN Adj

H

O NH 2

OH

3 IX-141

OH

3

N-(

HN J,-t4

HWP

IX-144 IX-142

CH

3

NS(

HN

IX- 146

N'H

IXC-147 IX-145 223 IX- 148

OCH-

3

HN$

IX -149 o ,-CH 3 HNA4' IX- 152

CH

3

HNAN

H

flas 0% I H IX- 153 fl-iS 1 Ni IM- 154 Nt DC- 157t sme HNA'It IX-156

CO

2

CH

N

-'H

N HN

'CH

3 N

H

.224 IX -160IX-6I 12 IX-161 IX-162 IX-164

OH

HNX*H

IX- 165 IX- 163 IX-166 IX- 167 IX- 168 IX-169

CH

3

MN

it CN N

HN..

CH

3 HN rX

N

IX- 37 3

CH

3 NoH

MNN

F 3

C

IX- 171-

CH

3

HNWH

&CLH3 IX-172 IX- 174 .225 Va IND NN,.H-% AHNXW HN* HN N N

F

3 C

F

3

C

IX-175 IX-176 IX-177 ci In another embodiment, this invention provides IN 5 a composition comprising a compound of formula IX and a pharmaceutically acceptable carrier.

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

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

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

Another aspect relates to a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, cohptising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula 226 ID Ix. This method is especially useful in halting or o slowing the progression of Alzheimer's disease.

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

k One aspect of this invention relates to a 10 method of inhibiting Aurora activity in a patient, o comprising administering to the patient a therapeutically ID effective amount of a composition comprising a compound 0 of formula IX.

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

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

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

IQD The compounds of this invention may be prepared o as illustrated by the Synthetic Methods below, by the rC Synthetic Examples described herein and by general Smethods known to those skilled in the art.

General Synthetic Methods The general synthetic methods below provide a series of general .reaction routes that were used to prepare compounds of_this invention. Methods A-F below 10 are particularly useful for preparing formula II 0 compounds. In most cases, Ring C is drawn as a phenyl Cs ring bearing an ortho R 1 substituent. However, it will be Sapparent to one skilled in the art that compounds having other Ring C groups may be obtained in a similar manner.

Methods analogous to methods A-F are also useful for 'preparing other compounds of this invention. Methods F-I below are particulary useful for preparing compounds of formula III or IV.

Method A C H Re (HO)2B R R 2 I H 2 HN O H(HotB RRd 0

RX

4 N R 1 Ry We N Pdo

NR

1 R N I RY' N 2 .l Method A is a general route for the preparation of compounds wherein ring C is an aryl or heteroaryl ring. Preparation of the starting dichloropyrimidine 1 may be achieved in a manner similar to that described in Chem. Pharm.'Bull., 30, 9, 1982, 3121-3124. The chlorine in position 4 of intermediate 1 may be replaced by an aminopyrazole or aminoindazole to provide intermediate 2 228 \D in a manner similar to that described in J. Med. Chem., 0 38, 3547-3557 (1995). Ring C is then introduced using a (c boronic ester under palladium catalysis (see Tetrahedron, S48, 37, 1992, 8117-8126). This method is illustrated by the following procedure.

A suspension of lH-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POC13 (60 mL, 644 mmol) and N,Ndimethylaniline (8mL, 63.1 mmol) is heated under reflux S* for 2 h. Excess POCI 3 is evaporated under vacuum, the '10 residue is poured into ice, and the precipitate is o collected by filtration. The crude solid 2,4- ND dichloroquinazoline product may be used without further Spurification.

To a solution of 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 mL) is added methyl-lH-pyrazol-3-yl amine (3.2 g, 32.9 mmol). The mixture is stirred at room temperature for 4 h, and the resulting precipitate is collected by filtration, washed with ethanol, and dried under vacuum to afford (2-chloroquinazolin-4-yl) (5-methyl-lH-pyrazol-3-yl) -amine.

To a solution of (2-chloro-quinazolin-4-yl)-(5methyl-1H-pyrazol-3-ylY-amine (50 mg, 0.19 mmol) in DMF mL) is added the desired arylboronic acid (0.38 mmol), 2M Na2CO3 (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). Under-nitrogen, PdCl 2 (dppf) (0.011 mmol) is added in one. portion. The reaction mixture is then.

heated at 80OC for 5 to 10 hours, cooled to room temperature, and poured into water (2 mL). The resulting precipitate :is collected by filtration, washed with water, and purified by HPLC.

Method B 229 Rx NH R poc S Rx N R1 H2N RNR

N

3 4 0,CO 2

H

NH R' NH2 2- (ii) 5 6

OONH

1 0 R 1 0 R k;NHI I 2N OI

H

S A 6 (iii) 7 Methods B through F describe routes where the pyrazole ring system is introduced after Ring C and the pyrimidine ring portion are first constructed. A versatile intermediate is the 4-chloropyrimidine 4, which is readily obtained from pyrimidinone 3- as shown in Method This reaction sequence is generally applicable for a variety of Ring C groups including aliphatic, aryl, beteroaryl, or heterocyclyl. See J.

Med. Chem., 38, 3547-3557 (1995).

For quinazoline ring systems (where Rx and RY are taken together to form a benzo ring), the useful intermediate 6 may be obtained by .condensing an anthranilic acid or its derivative with a benzamidine as shown in Method B(ii) or by condensing a benzoylchloride with an anthranilamide as shown in Method B(iii). Many substituted anthranilic acid, anthranilamide, benzamidine and benzoylchloride starting materials may be obtained by 230 Sknown methods. See Aust. J. Chem., 38, 467-474 and J.

0 Med. Chem., 38, 3547-3557 (1995). Method B(iii) is C( illustrated by the following procedure.

t To a solution of anthranilamide (33 mmol) in THF and CH 2 C1 2 70 mL) is added the desired benzoylchloride (33 mmol), and triethylamine (99 mmol) at room temperature. The mixture is stirred for about 14 hours. The resulting precipitate is collected by k\ filtration, washed with CH 2 Ci 2 and water, and dried under vacuum. The crude 2-benzoylaminobenzamide may be used o directly for the next step without further purification.

To a solution of the above crude product (13 S- mmol) in ethanol (50 mL) is added NaOEt (26 mmol) at room temperature. The mixture is heated under reflux for 48 to 96 h. The solvent is evaporated and the residue is neutralized using concentrated HC1 to pH 7. The product is then collected by filtration and dried under vacuum to -provide 2-phenyl-3H-quinazolin-4-one that may be used without further purification.

To a suspension of the above product (12 mmol) in POCl 3 (120 mmol) is added tri-n-propylamine (24 mmol) The mixture is heated under reflux for 1h. After removal of the excess POCl 3 by evaporation, the residue is dissolved in ethyl acetate, and washed with IN NaOH (twice) and water (twice). The organic layer is .dried over MgSO 4 the solvent is evaporated under vacuum, and the crude product is purified by flash chromatography (eluting with 10% of ethyl actetate in hexanes) to give 4-chloro-2-aryl quinazoline.

To a solution of 4-chloro-2-aryl quinazoline (0.16 mmol) in DMF (or THF, ethanol) (1 mL) is added the desired aminopyrazole or aminoindazole (0.32 mmol). The mixture is heated in DMF. (or THF under reflux) at 100 to 231 \D 110°C for 16 h (or in ethanol at 130-160oC for 16 hours) o and then poured into water (2 mL). The precipitate is Cl collected by filtration and purified by HPLC.

Method

C

NHR'

H2N1C0 o RY NH R RyA -C02EI 8 91 IND Method DWi) Y NH R 1 Rx COEt PO 11 Methods C and D(i) above employ P-ketoesters 8 and 10, respectively, as pyrimidinone .precursors. The substitution pattern of the R and R Y groups on the pyrimidinone ring will be reversed if a chlorocrotonate 11 (Synth. Comm, (1986), 997-1002), instead of the corresponding P-ketoester 10, is condensed with the desired benzamidine. These methods are illustrated by the following general procedure.

To a solution of a P-ketoester mmol) and amidinium chloride (5.7 mmol) in ethanol (5 mL).is added sodium ethoxide (7.8 mmol). The mixture is heated under reflux for 7-14 hours. After evaporation the resulting residue is dissolved in water, acidified with concentrated HC1 to pH 6, and then filtered to obtain a solid product 2-aryl-3H-pyrimidin-4-one (yield 75-87%), 232 \D which may be purified by flash column chromatography if 0 needed. To this pyrimidinone (3.7 mmol) is added POC13 (4 (N mL) and n-Pr 3 N (1.4 mL) The mixture is heated under Sreflux for 1 hour. After evaporation of the excess POCl 3 the residue is dissolved in ethyl acetate, washed with IN NaOH solution (three times) and NaHCO0 (once), and dried over MgSO 4 The solvent is removed under vacuum and the residue is purified by flash column chromatography eluting with 10% of ethyl acetate in hexanes to give 2f_ 10 aryl-4-chloro-pyrimidine as a pale yellow syrup. This o crude product may be treated with a 3-aminopyrazole or 3- IND aminoindazole as described above.

Method D(ii) NH R' H2N O POCI 3

CI

R cc 1 nPr 3 N R EtO YCO2EL R 1 nN 0 reflux Cl N 36 37 38 k2'" R 2 R2 R 2 CI RNNH H morphouine, H2 R Wl

N

MeOH Rx NH R N R' 38 0reflux I reflux is) rfux OCN 39 Method D(ii) above shows a general route for the preparation of the present compounds, such as compound 40, wherein R Y is N(R 4 2 See II Farmaco, 52(1) 61-65 (1997). Displacement of the 6-chloro group is exemplified here using morpholine. This method is illustrated by the following procedure.

To a solution of 2-methylmalonic acid diethyl ester (5 mmol) and sodium ethoxide (15 mmol) is added the N0D appropriate amidine salt (5 mmol) in ethanol (10 mL) and O the reaction heated at reflux for 2-24 hours. The residue is dissolved in water and acidified.with 2N HC1.

t The resulting precipitate is filtered off and further purified by flash chromatography (yield 5-35%) to afford the pyrimidinedione 37. To 37 (1.6 mmol) is added Pocl 3 (32 mmol) and tri-n-propylamine (6.4 mmol) and the reaction refluxed is for Ih. After evaporation of excess ND POCl 3 the residue is dissolved in ethyl acetate, basified with IN NaOH, separated and the aqueous phase twice more C( extracted with ethyl acetate. The combined organics are

LO

dried (sodium sulfate) and evaporated. Purification by Sflash chromatography .provides the dichloropyrimidine (38) as a yellow oil in 23% yield.

A solution of 38 (0.33 mmol) in methanol (5 mL) is treated with an amine, exemplified here using morpholine (0.64 mmol) and refluxed 1 hour. After evaporation of solvent, the residue is purified by flash chromatography to provide the mono-chloropyrimidine 39 as a colorless oil in 75% yield.

The mono-chloropyrimidine, 39, (0.19 mmol) may be treated with a 3-aminopyrazole or 3-aminoindazole compound in a manner substantially similar those described above ih Methods A and B.

Method E R' 0 0 i N=CO 0 R CH 2 H R NH4OAc, R' N 12 AcOH, reflux (R =H) As shown by Method E, an acyl isocyanate 12 may be condensed with an enamine to provide Pvrimidinone 9 I Org. Chem (1993), 58, 414-418; J.Med.Chem., (1992), 0 35, 1515-1520; J.Org.Chem., 91967, 32, 313-214). This method is illustrated by the following general procedure.

The enamine is prepared according to W. White, et al,.J. Org Chem. (i967), 32, 213-214. The acyl C isocyanate is prepared according to G Bradley, et al, J Med. Chem. (1992), 35, 1515-1520. The coupling reaction then follows the procedure of S Kawamura, et al, J. Org.

SChem, (1993), 58, 414-418. To the enamine (10 mmol) in tetrahydrofuran (30 mL) .at O°C under nitrogen is added C( dropwise over 5 min a solution of acyl isocyanate

VO

D ommol) in tetrahydrofuran (5 mL). After stirring for o h; acetic acid (30 mL) is added, followed by ammonium acetate (50 mmol). The mixture is refluxed for 2 h with continuous removal of tetrahydrofuran. The reaction is cooled to room temperature and is poured into water (100 mL). The precipitate is filtered, washed with water and ether and dried to provide the 2-aryl-3H-pyrimidin-4-one.

Method F O O 7H NH 4 0H NH 2 Heat N NH, N N ot 13 14 Method P shows a general route for the preparation of the present compounds wherein R x and R Y are taken together to form a 5-8 membered partially unsaturated saturated or unsaturated ring having 1-3 heteroatoms. The condensation of a 2-amino-carboxylic acid, such as 2-amino-nicotinic acid 13, and an acid chloride 7 provides an oxazinone 14. Treatment of 14 .with ammonium hydroxide will furnish the benzamide 235 ND which may be cyclized to a 2-(substituted)-pyrido[2,3o d] [l,3]pyrimidin-4-one 16. This method is illustrated by N the following procedure.

t2-(Trifluoromethyl)benzoyl chloride (4.2 ml, 29.2 mmol) is added dropwise to a solution of 2aminonicotinic acid (2.04g, 14.76 mmol) in 20 ml of pyridine. The reaction mixture is.heated at 158 C for min then cooled to room temperature. The reaction is NO poured into 200 ml of water and an oil forms which solidifies upon stirring. The solid is collected by Cq vacuum filtration and washed with water and diethyl IN ether. The product is dried to give 2-(2o trifluoromethyl-phenyl)-pyrido 2,3-dI [1,3]oxazin-4-one (2.56 g, 60% yield) which may be used -in the next step without further purification.

(2-Trifluoromethyl-phenyl) -pyrido[2,3d [1,3]oxazin-4-one (2.51g) is stirred in 30% ammonium hydroxide (25 ml) at room temperature overnight. The resulting precipitate is filtered and rinsed with water and diethyl ether. The precipitate is dried under vacuum at 50 C overnight to give 2-(2-trifluoromethylbenzoylamino)-nicotinamide (850 mg, 33% yield) 2-(2-Trifluoromethyl-benzoylamino)-nicotinamide (800mg, 2.6mmol) is dissolved in 10ml of ethanol.

Potassium ethoxide (435mg, 5.2mmol) is added to the solution which is heated to reflux for 16 h. The reaction mixture is evaporated in vacuo to afford a gummy residue that is dissolved in water and acidified with sodium hydrogen sulfate to pH 7. The resulting precipitate is filtered and dried under vacuum at 50 C to give 2- (2-trifluoromethyl-phenyl) -3H-pyrido [2,3d] pyrimidin-4-one.

236

O

O Method G is analogous to Method B(i) above.

0 This method is illustrated by the following general procedure.

2- (3,4-Dichloro-phenyl) -3H-quinazolin-4-one (1g, 3.43 mmol) is suspended in phosphorus oxychloride (4 mL) and the reaction mixture was stirred at 110 0 C for 3 hours. The solvents are then evaporated and the residue is treated carefully with an ice cold aqueous saturated c s 10 solution of NaHCO 3 The solid is collected by filtration o and washed with ether to give 4-chloro-2-(3,5-dichloro- IN phenyl)-quinazoline as a white solid (993 mg, 93%).

To 4-chloro-2- (3,5-dichloro-phenyl) -quinazoline 1 (4.00mg, 1.29 mmol) in THF (30 mL) is added methyl pyrazole (396 mg, 2.58 mmol) and the reaction mixture is heated at 65 0 C overnight. The solvents are then evaporated and the residue triturated with ethyl acetate, filtered and washed with a minimum amount of ethanol to give (3,4-dichlorophenyl) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine as a white solid (311 mg mp 274"C; 'H NMR (DMSO) 8 2.34 (3H, 6.69 (1H, 7.60 7.84 (1H, 7.96 (2H, 8.39.(1H, dd), 8.60 (1H, 8.65 (1H, 10.51 (1H, 12.30 IR (solid) 1619, 1600, 1559, 1528,'1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5 The THF solvent used in" the previous step may be replaced by other organic solvents such as ethanol, N,N-dimethylformamide, or dioxane.

Method H S (HO)B 5

R

2 SRPdo R N Ry R

Y

17 18 ci R2Z R 2 R R 2 N HN$ (CH 3 3 SI---H HN

N

Cul o rEN -RY N (ii) 17 19 Method H shows routes in which a Ring D aryl group bearing a halogen (X is Br or I) may be converted to other formula III compounds. Method H(i) shows a phenylboronic acid coupling to Ring D to provide compound 18 and Method H(ii) shows an acetylene coupling to provide compound 19. Substituent X in compound 17 may be bromine or iodine. These methods are illustrated by the following procedures.

Method To a mixture of [2-(4-bromophenyl) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl) -amine (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol) in THF/water 4 mL) is added Na 2

CO

3 (219 mg, 2.06 mmol), triphenylphosphine (9mg, 1/15..mol%) and palladium acetate (1 mg, 1/135 mol%). The mixture is heated at*80°C overnight, the solvents are evaporated and the residue is purified by flash chromatography (gradient of.CH 2 C1 3 /MeOH) to give (2-biphenyl-4-yl-quinazolin-4-yl) (5-methyl-2H-pyrazol-3-yl)-amine as a yellow solid (99 mg, NMR (DMSO) 6 2.37 (3H, 6.82 (1H, 7.39- 238 IN 7.57 7.73-7.87 (6H, 8.57.(2K, 8.67 (11, 0 O 10.42 (11, 12.27 (11, MS 378.2 Method H(ii). To a mixture of [2-(4-bromophenyl) -quinazolin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, mmol)in DMF (2 mL) is added Cul (1.1 mg, 1/50 molt), Pd(PPh,),C1l (4.2 mg, 1/50 mol%) and triethylamine (121 mg, 0.36 mmol). The mixture is heated at 120 0 C overnight and IDthe solvent is'evaporated. The residue is triturated in 10 ethyl acetate and the precipitate is collected by C filtration.

\O

To the above precipitate.suspended in THF (3 o iL). is added tetrabutylammonium fluoride (LM in THF, 1.eq). The reaction mixture- is stirred at room temperature for two hours and the solvent is evaporated.

The- residue is purified by flash chromatography (gradient of 0H 2 C1 2 /MeOH)' to give (4-ethynylphenyl) -quinazolin-4yl]-(5-methyl-2H-pyrazol-3-yl)-amine as a white solid (68 mg, 70%) 1 NMR (DMSO) 6 2.34 (31, 4.36 (11, 6.74 (1H, 7.55 (11, 7.65 (2H, 7.84 (2H, 8.47 (2H, 8.65 (11, 10.43 (1H, 12.24 MS 326.1 (M+H) Method I Q Re

HN>

I 1 N R I N RY Y"4"-CN 2. Method I above shows a general route for the preparation of the present compounds wherein.ring D is a heteroaryl or heterocyclyl ring directly attached to the 239 ND pyrimidine 2-position via a nitrogen atom. Displacement 0 o of the 2-chloro group, exemplified here using piperidine, may be-carried out in a manner similar to that described Sin J. Med. Chem., 38, 2763-2773 (1995) and J. Chem. Soc., 1766-1771 (1948). This method is illustrated by the C following procedure.

To a solution of (2-chloro-quinazolin-4-yl) (1H-indazol-3-yl)-amine (1 equivalent, 0.1-0.2 mmol) in O N, N-dimethylacetamide (1 ml) is added the desired amine e-4 10 (3 equivalents). The resulting mixture is maintained at 0 C- 100oC for 6 h and then purified by reverse-phase HPLC.

O

Method J

R

2

R

2 C HY:H H H .R

R.

(i) 21 22 R H

H

R2 R R2 (ii) H2N 23 24 Method J above shows the preparation of compounds of formula V via the displacement of a chloro group from an appropriately substituted pyridyl ring.

Method J(i) is a route for preparing compounds of formula Va (see-Indian J. Chem. Sect.B, 35, 8, 1996, 871-873).

Method J(ii) is a route for preparing compounds of 240 IND formula Vb (see Bioorg. Med. Chem.,6, 12, 1998, 2449o 2458). For convenience, the chloropyridines 21 and 23 ^C are shown with a phenyl substituent corresponding to Ring 3 D of formula V. It would be apparent to.one skilled in the art that Method J is also useful for preparing compounds of formula V wherein Ring D.is heteroaryl, heterocyclyl, carbocyclyl or other aryl rings. Method J is illustrated by the following procedures.

.0 Method (5-Methyl-2H-pyrazol-3-yl)-(2- 10 phenyl-quinolin-4-yl)-amine.' To 4-chloro-2- -C phenylquinoline Het. Chem., 20, 1983,- 121-128) (0.53g, IO 2.21 mmo-l) in diphenylether (5 mL) was added 0 methylpyrazole (0.43g, 4.42 mmol) and the mixture was heated at 2000C overnight with stirring. To the cooled mixture was added petroleum ether (20 mL) and the resulting crude precipitate was filtered and further washed with petroleum ether. The crude solid was purified by flash chromatography (SiO 2 gradient DCM-MeOH) to give the title compound as a white solid: mp 242-244°C; 1H NMR '(DMSO) S 2.27(3H, 6.02(1H, 7.47(2H, 7.53- 7.40(2H, br 7;67(1H, 7.92(1H, 8.09(2H, d), 8.48(2H, 9.20(1H, 12.17(1H, br IR (solid) i584, 1559, '1554, 1483, 1447, 1430, 1389; MS 301.2 Method (5-Methyl-21-pyrazol-3-yl) (3phenyl-isoquinolin-l-yl)-amine. To 1-chloro-3phenylisoquinoline Het. Chem., 20, 1983, 121- 128) (0.33g, 1.37 mmol) "in dry DMF (5 mL) was added 3- (0.27g, 2.74 mmol) and potassium carbonate.(0.57g, 4.13 mmol)and the mixture was heated under reflux for 6 hours. The mixture was cooled and the bulk of DMF was evaporated. The residue was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO 4 filtered and ND concentrated. The crude was purified by flash O chromatography (SiO 2 gradient DCM-MeOH) to give the title C1 compound as a colourless oil; 1H NMR (MeOD) 8 2.23 (3H, Cs 5.61 7.41 (1H, 7.52(2H,. 7.62(1H, m), 7.81(1H, 8.07(1H, 8.19(2H, 8.29(1H, 8.54 (1H, MS 301.2 Cl Method K lR2 CI C1 CI H CI "NCI CI N R' IN'3 25 26 27 Method K shows a route for the preparation of compounds of formula VI. A versatile starting material is 2,4,6-trichloro-[1,3,5]triazine 25 in which the chlorine substituents may be sequentially displaced. The displacement of one of the chlorines by an aryl Grignard reagent or an aryl boronic acid is described in PCT patent application WO 01/25220 and Helv. Chim. Acta, 33, S1365 (1950). -The displacement of one of the chlorines by a heteroaryl' ring is described in WO 01/25220; J. Bet.

Chem., 11, 417 (1974); and Tetrahedron 31, 1879 (1975).

These reactions provide a 2,4-dichloro-(6substituted) [1,3,5]triazine 26 that is a useful intermediate for the preparation of compounds of formula VI. Alternatively, intermediate 26 may be obtained by constructing the triazine ring by known methods. See US k patent 2,832,779; and US patent 2,691020 together with J.

Am. Chem. Soc. 60, 1656 (1938). In turn, one of the chlorines of 26 may be displaced as described above to provide 2-chloro-(4,6-disubstituted)[1,3,5]triazine 27.

242 The treatment of 27 with an appropriate aminopyrazole provides the desired compound of formula VI.

0 28 urea CF 3 POCd 3 N Y NH O 0 N N

CI

'H

2 N H HgN

R

2

HNN

N N .4;3 Method L shows a route for preparing compounds of 'formula VII. For illustration purposes the trifluoromethylchalcone 28 is used as a starting material; however, it would be apparent to one skilled in the art that other rings may be used in place of the trifluoromethylphenyl and phenyl rings of compound 28.

Substituted chalcones may be prepared by known methods, for example as described in the Indian J. Chemistry, 32B, 449 (1993). Condensation of a chalcone with urea provides the pyrimidinone 29, which may be treated with POC13 to give the chloropyrimidine 30. See J. Chem. Eng.

Data, 30(4) 512 (1985) and Egypt. J. Chem., 37(3), 283 243 \NO (1994). In an alternative approach to compound 30, one O of the aryl rings attached to the pyrimidine is CA introduced by displacement of of the 4-chloro group of t 2,4-dichloro-(6-aryl)-pyrimidine by an aryl boronic acid using a palladium catalyst such as (Ph 3

P)

4 Pd in the presence of a base such as sodium carbonate as described Ci in Bioorg. Med. Lett., 1057 (1999).- Displacement of the chlorine of compound 30 by an appropriate s0 aminopyrazole provides compounds of this invention, such 10 as 31. The last step of this method is illustrated by o the following procedure.

\IN (4-Methylpiperidin-l-yl) -pyrimidin-2-yl] O methyl-2H-pyrazol-3-yl)-amine. To a solution of 2chloro-4-(4-methylpiperidin-l-yl)-pyrimidine (prepared using a procedure similar to the one reported in Eur. J.

Med. Chem., 26(7) 729(1991))(222 mg, 1.05 mmol) in BuOH mL) was added 3-amino-5-methyl-2H-pyrazole (305mg, 3.15 mmol) and the reaction mixture was then heated under reflux overnight. The solvent was evaporated and the residue dissolved in a mixture ethanol/water 4 mL).

Potassium carbonate (57mg, 0.41 mmol) was added and-the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with'water twice and rinsed with ether twice to give the title.

compound as a white solid (143mg, mp 193-195°C; 1 NMR (DMSO) 8 0.91 (3H, 1.04 (2H, 1.67 (3H, m), 2.16 (3H, 2.83 (2H, t),.4.31 6.19 (2H, m), 7.87 (1H, 8.80 (IH, br 11.71 (1H, IR (solid) 1627, 1579, 1541, 1498, 1417, 1388,.1322, 1246; MS 273.3(M+H) 244 IND R2 R2

H

2

N

SVIIIa 32 Cl1

CI

pg VIIfb 33 lOC

N

34 C4

WNN

.8 io ""oVII'Id Method M provides routes for obtaining compounds of formula VIII. A general procedure for displacing the chlorine of a 4-chloro-6-substitutedpyridazine, 32, with an appropriately substituted pyrazole to provide VIIIa is described in J. Ret. Chem., 1473 (1983). Analogous reactions may be carried out as.follows: with 33, to provide VIIb is described in J. Med. Chem., 41(3), 311 (1998); with 5-chloro-3-substituted- 245 [1,2,4]triazine, 34, to provide VIIc is described in 0 Heterocycles, 26(12), 3259 (1987); and with 3-chloro- [1,2,4]triazine, 35, to provide VIIId is described in Pol. J. Chem., 57, 7, (1983); Indian J.

Chem. Sect. B, 26, 496 (1987); and Agric. Biol. Chem., 54(12), 3367 (1990). An alternative procedure to compounds of formula VIIIc is described in Indian J.

Chem. Sect. B, 29(5), 435 (1990).

SCompounds of formula IX are prepared by methods cN 10 substantially similar to those described above for the 0 pyrazole-containing compounds of formula I. Methods A-J Ci IN may be used to prepare the triazole-containing compounds Sof formula IX by replacing the amino-pyrazole compound Ci with an amino-triazole compound. Such methods are specifically exemplified by Synthetic Examples 415-422 set forth below. The amino-triazole intermediate may be obtained by methods described in J. Org. Chem. USSR, 27, 952-957 (1991).

Certain synthetic intermediates that are useful for preparing the protein kinase inhibitors of this invention are new. Accordingly, another aspect of this invention relates to a 3-aminoindazole compound of formula A:

H

NH

2

A

where R 10 is one to three substituents that are each independently selected from fluoro, bromo, CI-~ haloalkyl, nitro, or 1-pyrrolyl. Examples of such compounds include the following:

H

F-04

NH

2 Al pF F H

NH

2

H

0 2 N Y

NH

2 A9

H

F 04

NH

2 A2

H

NH

2 A6

H

,N NH 2 F H F N

NH

2 A3 F H 6

NH

2 A4 H H F .NH 2

NH

2 A7 AS Al 0 Another -aspect of 4-chloropyrimidine compound this invention relates to a of formula B:

B

wherein RX and R are as defined above; R 1 is selected from C1, F, CF 3 CN, or NO 2 and is one to three substituents that are each independently selected from H, Cl, F, CE 3

NO

2 or CN; provided that R 1 and R 5 are not simultaneously C1. Examples of compounds-of formula B are shown below: C1 Me tN CF Me N

BI

CI

Me N CI Me N B2

C

N CF, Me B3 247 Cl CI rN CF,

N

38 B9 'Cl

CF

3 B13

CI

CF

3 312.

CI

N 'CA B14 B17 cXN CN Bl 320

CI

N CF 3 312 1 'N CF 3 c I

CFS

B16 cl

CF

3 B19

CF

3 318 248 Another aspect of this invention relates to compounds of formula C: R z,

HN*

INN

RY N-'CI

C

wherein RX, Y, R 2 and R 2 are as defined above. Examples of compounds of formula C are shown below: F H Cl r1 HN4H

.N

tN

U

H

HN

C2

HH

CH

3 k

HN

C3 H3 H

HN

F

H9H

HNN

C7 11 21H

HN

C8

FZ

IN

C1C 249

HH

HNf* C10 N C- fci

NN

C13.

Yet another a compounds of' formula D:

F

H

HNS

C11

HNCU

C14

HN

N

C12 Me CHN H N C %N 1I spect of this invention relates to

O

INYH CF DR N

D

where R, R and RY are as defined above. Examples of formula D copmpounds and other useful pyrimidinone intermediates are shown below: 0 i H3C I NH CFs 3

H

3 C N H3C INH CI

H

3 C Nt D2 0 CF NH

CF

3 D3 0 H CF 0 CI 'NH CF, D7 Da D9 D11 DI2 o c(NH ai NrN 13 D14 0

%%NH

D1s 0

NHCF

DIB D16 D17 0 "INH CF3 In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be constried as limiting this invention in any manner.

251

O

o0 SYNTHETIC EXAMPLES C' The following HPLC methods were used in the analysis of the compounds as specified in the Synthetic Examples set forth below. As used herein, the term "Rt" refers to the retention time observed for the compound using the HPLC method specified.

SHPLC-Method A: Column: C18, 3 um, 2.1 X 50 mm, "Lighting" by Jones o Chromatography.

ND Gradient: 100% water (containing 1% acetonitrile, o 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) min, hold at 100% acetonitrile for 1.4 min and return to initial conditions. Total run time min. Flow rate: 0.8 mL/min.

HPLC-Method B: Column: C18, 5 ur, 4.6 X 150 mm "Dynamax" by Rainin Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) over 20 min,-hold at 100% acetonitrile for 7.0 min and return to initial conditions. Total run time 31.5 min. Flow rate: 1.0 mL/min.

iPLC-Method C: Column: Cyaio, 5 um, 4.6 X 150. mm "Microsorb" by Varian.

Gradient: 99% water TFA); 1% acetonitrile (containing 0.1% TFA) to 50% water TA), acetonitrile (containing 0.1% TFA).over 20 min, hold for 8.0 min and return to initial conditions. Total run time 30 min. Flow rate: 1.0 mL/min.

O

o HPLC-Method D: 0 Column: Waters (YMC) ODS-AQ 2.0xSOmm, SB, 120A.

Gradient: 90% water Formic acid), acetonitrile (containing 0.1% Formic acid) to water formic acid), 90% acetonitrile (containing 0.1% formic acid) over 5.0 min, hold for 0.8 min and return to initial conditions. Total run time 7.0 min.

C 10 Flow rate: 1.0 mL/min.

0 HPLC-Method E: Column: 50x2.mm Hypersil C18 BDS;5 jm Gradient: elution 100% water TFA), to 5% water TFA), 95% acetonitrile (containing 0.1% TFA) over 2.1 min, returning to initial conditions after 2.3 min.

Flow rate; 1 mL/min.

Examle 1 [2-(2-Clorophenyl)-5,6-dimethylpyrimidin-4-yll- (5-Methyl-22-pyrazol-3-yl)-amine 'NMR (500 MHz, DMSO-d6) 810.4 br, 7.74 2H), 7.68 1H), 7.60 1i), 6.39 1H), 2.52 3H), 2.30 3H), 2.22 3H); MS 314.1 Example 2 [2-(2-Chloro-phenyl)-6,7, 8,9-tetrahydro-5u-.

cycloheptapyrimidin-4-yll -(-indazol-3-yl)-amine (11-2): Prepared in 30% yield. 'HNMR (500MHz, DMSO-d6) 6 1.72 (m, 4H),.1.91. 2H), 3.02 4H), 7.05 1H), 7.33 (t, 1H), 7.39 7.47 7.55 3H), 7.59 (d, 1i), 10.4 11), 13.11 (br. a, 1H);-EI-MS 390.2 HPLC-Method A, Rt 2.99 min.

253 IND xamp 3 (5-Fluoro-1E-indazol-3-yl)-(2-(2o trifluoromethyl-phenyl) 8-tetrahydro-pyrido (3,4d pyrimidin-4-yl]-amine Compound I-18 (90 mg, 0.17 mmcl) was treated with an equal weight of Pd/C (lot) in 4.4% formic acid in MeOH at room temperature for 14 h.

The mixture was filtered through celite, the filtrate was evaporated, and crude product was purified by HPLC to provide 18 mg (241) of the desired product as pale yellow solid'. 1 HNMR (500 MHz, DMSO-d6) 512.9 11), 9.51 (s, 9.26 2H), 7.72 7.63 1N), 7.58 (t, 12), 7.49 21), 7.21 (td, 11), 7.15 (dd, 1H), 4.24 (s, -ND 2H), 3.56 2H), 2.95 ppm. MS i/e= 429.22 HPLC-Method A, Rt 2.88 min.

Exampi 4. [2-(2-Chlorc-phenyl) -6,7,B,9-tetrahydro-5Hcycloheptapyrimidin-4-yl (7-fluoro-1- indazol-3-yl) amine Prepared in 52% yield to afford a white solid. 'NNMR (500MHz, DMSO-dG) 8 1.72 42), 1.92 (m, 2H), 3.00 41),.7-.02 (td, lR),.7.20 (dd, 11),.7.40 (m, 1H), 7.42 1H), 7.52 3H), 10.5 1H), 13.50 (br.

a, 1H); El-MS 408.2 HPLC-Method A, Rt 3.00 min.

(2-Chioro-phenyl) -6,7,8,9-tetrahydro-5Hcycloheptapyrimidin-4-yl] (5-f luoro-lH-indazol-3-yl) amine Prepared in 51% yield. 1 ImMR (500MHz, DMSOd6) 8 1.71 41), 1.91 2H), 3.01 4H), 7.24 (td, 1H), 7.41 2H), 1.54 4H), 10.5 1H), 13.1 (br.

a, IN); El-MS 408.2 HPLC-Method A, Rt 3.05 win.

Exa=Le_ (2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5Hcycloheptapyriiidin-4-yl (5,7-difluoro-lHf-indazol-3-yl) amine Prepared according to Method C in 72% yield. 'HNMR (50MHz', DMSO-d) 8 1.72 4H), 1.91 (m, IND~2H) 3.-01 (mn, 4H) 7.231 (mn, 2H) 7.41. (in, 12), 7.54 (mn, o 10.5 (mn, 12), 10.6 (br. s, XE); El-MS 426.2 (14+1); 0 RHPLC-lMethod A, at 3.21 mini ct Eaml1n.? (7-Pluoro-1Bf-indazol-3-yl)-[2-(2- 'trifluoromethyl-phenyl) -5,6,7,8 -totrahydroqniinazolin-4 y13-amine Prepared in 621- yield. 1 'M (500 M4Hz, DMS0-d6) 813.5 br, iH), 10.1 lE), 7.75 (mn, 7.33 211), 7.17 (dd, 12), 7.00 (td, 111), 2.80 (in, 211), 2.71 (mn, 22), 1.89 (br, 4H) ppm; LC-MS 428.44 o 426.43 RPLC-Method A, Itt 3.02 min.

o ~Fxapla... (S-Fluoro-XHf-indazol-3-yl)t[2-(2trifluaromethyl-phenyl) B-tetrahydroqniinazolin-4yl]-anme Prepared in 53t yield. 'hNeAR (500 M4Hz, DMSo-dS) 813.1 12), 10.2 br, 12), 7.75 (mn, 42), 7.50 (dd, 12), 7.27 (dd, 1H), 7.21 (td,1IH), 2.BO (in, 2H), 2.72 (mn, 2H), 1.88 (mn, 4H) ppm; MS 428.43 426.43 HPLC-Method A, &t 3. 01 min.

Sxamlp .9 (5,7-IDifluoro-1H-iLndazo:l-3-y1) (2trif luoroxuethyl-phenyl) 5, 6,7, ,8-tetralaydroquinazolin-4 yll-amIne Prepared in 37%k yield. 'HNM (500 MHz, DMSO- dS) 813.7 1H), 10.2 bri 12), 7.80 1H), 7.76 12), 7.69. (mn, 2H), 7.3-1 12), 7.18 11) 2.81 br, 22), 2.72 br, 22), 1.90 (mn, 42) ppm; MS 446.42 444.37 RPLC-MethodA, t 3.09 muin.

Examne 10 (5-Trifluoromethyl-1H-indazol-3-yl) -2 2 tErifluoromethyl-phenyl) 8-tetrahydroquinazolin-4 yl] -amine (11-10): Prepared by Method C in ethanol in yield. 1 HNM (500 MHz, DMS0-d6) 81.3.2 12), 10.1.

255 br, 111), 8.01 1H) 7.76 Cd,.1H) 7.66 CM, 4H), O7. 57 .Cd, 1H) 2. 79 28) 2. 73 2H) 1. 89 Cm, 4H) c-i ppm. MS CES+t) 478.45 476.42 CM-H); HPLC- Method A, Rt: 3.21 min.

ExJml 115,7-dlifluoro-iH-indazol-3-yl) (2tr:iluoromethyl-phenyl) cycloheptapyrimidin-4-yl] -amine (11-11): Prep&red in yield. white solid. 1 fl~pbf (500MHz, DMSO-dE) 8 1.72 (m, 4H), 1.91 2H), 3.01 Cm, 4H), 7.15 (dd, 18), 7.30 (td, o 18I), 7.66 Cm, 2H), 7.72 18), 7.78 18) 10.2Cm IND 1H), 13.5 Cbr. a, 18); El-MS 460.2 HPLC-Method A, o Rt 3.13 man.

gxamip1ej2 (6-Benzyl-2- (2-trifluoromethyl-phenyl) 5,6,7, 8-tetrahydro-pyrido 3-dlpyrimidin-4-y1) fluoro-2R-indazol-3-yl)-amifle (11-12): Prepared in 49% yield. ',HI4R (500 MHz, DMSO-dE) 812.8 Cs,. 1H), 9.11 Cs., 18) 7.68 18) 7. 58 18) 7.53 Ct, 18) 7.44Cm 7.37 Ct, 2H), 7.29 Ct, lH), 7.19 2H), 3.78 Cs, 28), 3.61 Cs, 28), 2.81 br, 4H) ppm; LC-MS (ES+) 519.2.4 M1+H); HPLC-Method A, Rt.3.11 min.

Exame13U (lE-Ilndazol-3-yl) (2-trifluoromethylphenyl) 8,9-tetrahydro-5H-cycloheptapyrimidin-4-y1] amine (11-13) :jYrepared in 40% yield. 'HNMR (500MHz, DMSO-d6) 8 1. 70 (mt, 4H) 1. 90 (in, 2H) 3. 00 Cm, 4H) 7. 01 Ct, 18), 7.3 0 (td, 18), 7.44 18), 7.49 18), 7.68 3H), 7.77 1H), 40O.01 (mn, 12.83. Cs, 18); El- MS 424.2 CM-iH) HPLC-Method A, Rt 3.17- min.

E2~Mnet-14 C7-Fluoro-JfU-indazo1-3-y1) C2trif luoromethyl -phenyl) 6,.7,86, 9 -tetrahydro- SH- S256 aycloheptapyrimidin-4-yl -amine (11-14): Prepared in 78% yield. 'HNIMR (500MHz, DMSO-d) 8 1.71 4H), 1.991 (m, N 2H), 3.00 4H), 6.98 (td, 1H), 7.16 (dd, 11), 7.31 (d, 111), 7.68 3H), 7.77 1H), 10.25 1H), 13.40 (br. a, 11); El-MS 442.2 HPLC-Method A, Rt: 3.12 min.

Fp&ti 1 (5-Pluoro-LH-indazol-3-yl)- (2- IN trifluoromethyl-phenyl)-6,7, 8,9-tetrahydxo-5SH- Ci 10 cycloheptapyrinddin-4- yl)-amine (11-15): Prepared in 63% yield. 1 HN1R (5;0MHz, DMSO-d6) 8 1.71 4H), 1.91 (m, IN 2H), 3.00 4H), 7.20 (td, 1H), 7.25 1H), 7.49 (dd, 11H), 7.69 (br. t, 2H), '7.74 1H), 7.79 1H), 10.35 1H), -13.00 Cbr. s, IH); El-MS 442.2

HPLC

t -Method A, Rt 3.21 min.

Exawe 16 (5-Fluoro- l-indazol-3-yl)- (2trifluoromethyl-phenyl) -5,6,7,8-tetrahydro-pyrido[4,3d3pyrimidina4-y13 -amineA(II-16) A solution of compound 11-12 (45mg, 0.087 nmol) in methanol HCOO) was treated with an equal weight of Pd/c at room temperature for 14 h. The mixture was filtered through celite, the filtrate evaporated, and the crude product was purified by preparative HPLC to provide 15 mg (411) of the desired product as yellow solid. 1 HNMR (500 MHz, DMSO-d6) 812.9 9.52 1K), 9.32 21, TFA- OH), 7.72 11), 7.59 2Hj, 7-.49 7.21 (m, 11), 7.15 1H), 4.31 21), 3.55 Cs, 21), 3.00 (m, 2H) ppm; LC-MS 429.20 HPLC-Method A, Rt 2.79 min.

Examptle 1 (iH-ndazol-3-yl) (2-trifluoromethylphenyl)-5,6,7,8-tetrahydroquinazolmn-4-yl]-amine (11-17): 257 IN Prepared in 58% yield. '1QMM (500 MHz, DMSO-d6) 813.0 1H), 10.3 Cs, br, Wi), 7.74 4H), 7.51 1H), 7.47 1H), 7.32 Ct, 11), 7.03 1N), 2.82 2H), 2.73 2H), 1.90 4H) ppm; LC-MS (ESt) 410.21 HPLC-Metbod A, Ut 2.99 min.

Expmvl-eJ 1 (7-Benzyi-2 -(2-trifluoronethyl-phenyl)- 6,7,B-tetrahydxo-pyrido(4,3-dpyrimidn-4yl) INDfluoro-LH-indazol-3-yl)-amine (11-18): Prepared from compound Bl in 92W yield. 1 HNMR (500 MHz, DMSO-dE) 812.9. 11), 10.5 br, in), 9.58 IN, TEA-OH), 7.71 1H), 7.52 91), 7.19 2H), 4.57 2H), o 4.20 Cm, 2H), 3.70 2H), 3.00 2N) ppm; LC-MS* (ES+) 519.23 HPLC-Method A, Ri: 3.23 min.

Ecalle 1. (1H-Zndazoi-3-yl)- [6-methyl-2- (2trifluoroiethyl -phenyl) -pyrimidin-4 -ylJ -amine (11-19): Prepared in 42W yield. Melting point 235-237 0 c; HNMR (500'MHz, DMSO) 8 2.44 (32, 7.09 (IH, J=7.5 Hz, t), 7:40 (1R, J=7.1 Hz, 7.49 J=8.3 Hz, 7.70 (3H, 7.79 (11, J=7.3 Hz, 7.87 (1H, J=8.3 Hz, 8.03 (11, J=7.7 Hz,* 10.3 (1N, 12.6 (11, as) ppm; HPLC- Method A, Rt 2.958 min; MS (PIA) 370.2 Example 20 (1H-Indazol-3-yl)- t6-phenyl-2- (2trifluoromethyl -phenyl) -pyrimidin-4-ylj- amine (12-20): Prepared in 32% yield. 'NMo (500 MHz, DMSO) 8 6.94 (1H J=7.4 Hz, 7.24 (1H, J=7.4 Hz, 7.33. (ifir J=8.4 Hz, 7.42 (3H, 7.57 (11, J=7.3 Hz, t),-7.68 (21S, n), 7.75 (111, J=7.9 Hz, 7.93 8.18 (11, br a), 10.45 (11, br 12.5 br a) ppm; HPLC-Method A, Rt min;;MS (FIA) 432.2 INDaiiale 21 (1-Indazol-3-yl) -16- (pyridin-4-yl) (2o trifluoronmethyl-phenyl) -pyrimidin-4 -ylJ -amine (11-21): Prepared in 12% yield. 'mQMR (sOo MHz, DMSO) 8 7.16 (H, J=7.4 Hz, 7.46 (1W, J-7.6 Hz, 7.56 (IH, 3=8.3 Hz, 7.80 (1H, J=7.2 Hz, tL, 7.90 (2H, 7.97 (1H, J=7.8 Hz, 8.09 brl, 8.22 (2H, J=4.9 Hz, 8.45 (IH, br 8.93 (2H, J=4.8 Hz, 10.9 (11, br 12.8 (1H, br s) ppn" HPLC-Method A, Rt 3.307 min; MS (FIA) 433.2

IND(M+H)+

.Exajj1j.je 22 (1H-Indazol-3-yl)- [6-(pyridin-2-yl) (2trifluoroiethyl-phenyl) -pyrimidin-4-ylJ-amine (11-22): o Prepared in 42% yield. HNMR.(500 MHz, DMSO) 7.07 (lB.

J=7.4 Hz, 7.36 (1H, J=7.4 Hz, 7.46 (iN, 3=7.4 Hz, 7.53 (lB, J=5.0 Hz, 7.70 (1H, J=7.4 Hz, 7.79 (IH, 37.1 Hz, 7.83 (iS, J=7.4 Hz, 7.88 iH, J=7.8 Hz, 7.97 (11, J=7.7 Hz, 8.02 (1H, J=5.5 Hz, br 8.36 (iN, J=7.8 Hz, 8.75 (2H, J=4.1 Hz, d), 10.5 (IN, br 12.7 (1H, br s) ppm; HPLC-Metlod A, Rt 3.677 min; MS (FIA) 433.2 Eampxa...2.a 16- (2-Chlorophenyl) (2-trifluoroiethylphenyl)-pyrimidin-4-yll-(JA-indazol-3-yl)-amine (11-23): Prepared in 44% yield; HNMR (500 MHz, DMSO) '8 7.08 (3-H, 3=7.5 Hz, 7.37 (iN, J=7.5 Hz, 7.45 (iN, J=8.4 Hz, 7.51 (2H, m) 7.61 (1H, J=7.4, 1.9 Hz, ad), 7.69 (2H, 7.79 (2H, J=4.0 Hz, 7.86 (3H, J=7.8 Hz, 8.04 (2H, J=6.2 Hz,br 10.7 (iN, br 12.6 (iN, br a) ppm; HPLC-Method A, Rt 3.552 min; MS (PTA). 466.2 (Mi-H) 4 EZ1t 21 6-Dimethyl-2- (2-trifluoromethyl-phenyl) pyrimidin-4-yll- (I-indazol-3-yl) -amine (11-24): Prepared in 35t vield: MD 183-186-C: 'RNMR (500 MHz. DMSO) 8 2.14 259 IND (3H, sI, 2.27 I, 6.85 (1H, J=7.5 Hz, 7.15 -1H, J=7.6 Hz, 7.32 7.38 (1H, J=7.5 Hz, 7.42 (12, J-7.4 Hz, 7.53 (12, J=7.6 Hz, 8.88 (IH, B), 12.5 (12, e) ppm; HPLC-Method A, Rt 2.889 min.; MS (VIA) 384.2 Example 25 6-Dimethyl-2- (2-trifluoromethyl-phenyl) pyrimidin-4-yl (5-fluoro- 1-indazol-3-yl)'-aaine (11-25): Prepared in 441 yield. Melting point 160-163 0 C; 1

HNMR

(500 MHz, nMSO) 8 2.27 (3H, 2.40 (3H, 7.16 (2H, 7.44 (2H, m)l 7.52 (IH, J=7.4 Hz, 7.57 (iR, 3=7.4 Hz; 7.67 (12, J=7.8 Hz,, 9.03 (12, 12.75 (iH, C a) ppm;- HPLC-Method A, Rt 2.790 min; MS (VIA) 402.2 Egmpjle 2i Chiorophenyl) -5,6-dimethyl-pyrimtdin- 4ylJ- (1 -indazol-3-yl)-aaine (11-26): Prepared in .yield. 1 DHNMR (500 MHz, DMSO) 8 2.14 (3H, 2.33 (3H, 6.84 (12, J=7.4 Hz, 7.13 (12, J=7.4 Hz, 7.19 (12, JE.9 Hz, br 7.27 (1H, J=7.4 Hz, 7.32 (3H, hr 7.37 (12, J=7.1 Hz, 10.0 (12, br), 12.8 (1H, br a) ppm; 8 2.919 min; MS (VIA) 350.1 Examle 27 [S,6.Dimety1-2- (2-trifluromethyl-phenyl) pyrimidin-4-yl] (7-fluoro -IB-indazol-3-yl) -amine (11-27): Prepared in 921 yield. 1 HNMR14 (500 MH, DMSO) 8 2.33 (3H, 2.50 (3H, 6.97 (12, 7.15 (12, 7.30 (12, Jc8.1 Hz, 7.65 (3H, 7.16 (1H, J=7.5 Hz, d), 10.0 (1K, 13.4 (12, s) ppm; HPLC-Method A, Rt 3.053 min; MS (VIA) 402.2 (M+H)4.

Bxaum-e 28 (5,7-Dif luoro-.lf-indazol- 15,6-DiiIiethyl- 2-(2-trifluoramethyl-phenyl)-pyrimiidun-4-y]-amine (II- 260 NO Prepared in 50O yield. 'IHNMR (500 MHz, DMSO) 5 2.42 (3H, 2.63 (3H, 7.22 J-7.6 Hz, 7.38 (1H, J=9.3, 1.7 Hz, dt), 7.11 (1H, 7.75 (1H, J=7.0 Hz, d), 7.79 3=6.7 Hz, 7.86 (12, J=8. 0Hz, 10.0. (LH, 13.2 (12, a) ppm; HPLC-Method&A, Rt 3.111 min; MS (FIA) 420.2 Example 29 [2-(2-Chiorophenyl) -5,6-dimethyl-pyrimidin-4- NO yll 7-difluoro- 1H-indazol-3-yl) -amine (11-29): Prepared in 58% yield. 1HNMR (500 MHz, DMSO) 52.47 (3H, 2.66,(3H, 7.44 (2H, in), 7.53 (12, 7.64 (3H, No in), 10.4 (12, br), 13.8 (12, br a) ppm; HPLC-Method A, R' 2.921 min; MS (FIA) 386.1 (MiH)*.

Example 30 12-(2-Chlorophenyl) -5,6-dimethyl-pyrimidin-4ylJ-(7-fluoro-1H-indazol-3-yl) -amine (11-30): Prepared in yield. 1 HNMR (500 MHz, DMSO) 5 2.35 (32; 2.51 (3H, 7.03 (12, J=7.8, 4.4 Hz, dE), 7.22 (12, 7.33 J=7.4 Hz, 7.42 (1H, 9.19 (11, 13.3 (1H, a) ppm; HPLC-Method A, at 2.959 min; MSAFIA) 368.2 Eparrjle 32 (2-Chiorophenyl) 6-dimethyl-pyrimidin-4yl] (5-fluoro-IH-indazol-3-yl) -amine (11-31): Prepared in -86% yield. 1 HNMR (500 MHz, DMSO) 8 2.49 (3H, 2.68 (32, 1.38 (1H, 3=9.0 Hz, 7.54 (2H, 7.67 (4H, 10.5 (iH, br), 13.2 (11H, br a) ppm; HPLC-Method A, Rt 2.850 min; MS (FTA) 368.1 Zxmkae 12 [2-(2,4-Dichlorophenyl)-5,6-dimethylpyrimidin-4-ylJ- (H-indazol-3-yl)-amine (11-32): Prepared in 52% yield. '1'HNMR (500 MHz, DMSO) 8 2.46 2.64 261 (3H, 7.1-6 CaM, J=7.5 Hz, 7.46 In, J-7.6 Hz, t), o 7.61 (211, 7.68 (2H, J=8.2 Hz, 7.82 (iN, 10.2 (1H, br), 13.0 (IH, br s) ppm; HPLC-Method A, Rt 2.983.

min; MS (FA) 384.1 Rxnij2g 33 (5-Methyl-23-pyrazol-3-yl) (2methylphenyl) -quinazolin-4-y] -amine (11-33): 3I.flR (DMSO) 8 1.21 2.25 (3H, 6.53.(iN, 7.38 (4H, i), 7 .7.62 (XM, 7.73 7.81 (in, 7.89 (1H, t), 8.70 (iN, 12.20 (1H, MS 316.3 (M+N)4.

IND Exin2le 34 12-(2,4-Difluorophenyl) -quinazolin-4-yi]- methyl-20-pyrazol-3-yi)-amjne (11-34): '1HNMR (500 MHz, DMSO-d6) 512.4 Cbr a, 1H), 10.8 Cbr a, 8.58 7.97 8.36 iN), 7.85 aM), 7.60 iM), 6.62 IH), 2.30 3H); MS 338.07 35 (2,5-Dimethosyphenyl) -quinazolin-4-yi] methyi-20-pyrazol-3-yl)-amine (11-35): 1 HNMR (500 MHz, DMSO-d) 512.5 (br a, IH), 8.68 IH), 7.92 J Hz, 7.86 'J 8.2,Hz, iH), 7.65 Ct, J .Hz, 1H), 7-45 Cs, iN), 7.14 2H), 6.51 Cs, in), 3.79 3M), 3.67 Cs,'3H), 2.14 Cs, 3M); MS 362.2 xampe 3j (2-Chiorophenyl) -quinazolin-4-yll- wethyl-2H-pyrazol-3-yl)-amune (11-36): 1 HNMR -(500 MHz, DMSO-d6) 511.8 Cbr, in), 8.80 J Hz, 11), 8-.00 Ct, J 7.6 Hz, IH), 7.82 J 8.3 Hz, 1H),'7.78 (m, 2H), 7.67 Cd, J 7.8 Hz, 1H), 7.61 -Ct, J Hz, 1H), 7.55 Ct, J 7.4 Hz, IN), 6.56 Cs, IN), 2.18 Cs, 3H); MS 336.1 262 NO EamE.e 57 (2-Kethoxyphenyl) -qtdDazolin-4-ylJ- methyl-2H-pyrazol-3-yl) -amne (11-37) 1 HN"R (500 MHz, DMSO-d) 88.78, br, 1H), 8.00 J 7.4 Hz, 1K), 7.90 2H), 7.74 J t 7.5 Hz, 1H), 7.63 t, J 7.3 Hz, 1N), 7.30 J 8.4 Hz, IH), 7.18 J 7.5 Hz, 1K), 6.58 br, 1K), 3.90 3H), 2.21 31); MS 332,1 CM+H).

Examle 12- (2,6-Dimetbylpheny1) -quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-amine (11-38): 'mH (500 M'z, DMSO-d) &512.2 br, 2H), 8.88 J 7.7 Hz, 1H), 8.05 J 7.7 Hz, iN), 7.80 2K), 7.37 t, 3 7.6 Hz, 1H), 7.21 J 7.7 Hz, 2H), 6.36 IH), 2.16 (s, 3H), 2.15 Z6H);.MS 330.1 (MiH).

gmWale 3 (2-Acetylphenyl) -quinazalin-4-yl]l methyl-2H-pyrazol:3-yl)-amine (11-39): 'HN4R (500.1Hz, DMSO-d6) 812.35 br, 1K), 8.93 Cd, J 6.4 Hz, IH), 8.37 3 T 8.6 Hz, 8.20 J =7.6 Hz, 11), 8.11 J 8.0 Hz, 2H), 7.89 2H), 7.77 2H), 6.93 (a, 2.33 3H), 2.04 3H).,MS 344.1 EXmmlg 40' (2,3-Dimethyiphenyl) -quinazolin-4-yl] methyl72H-pyrazol-3-yl)-amine (11-40): '1HMM (500 MHz, DMSO-d) 812.6 br,-1H), 12.1 br, iH), 8.91 J 7.7 Hz, IK), 8.14 Ct, J 7.2 Hz, 1H), 7.95 J 8.4 Hz;' 7.89 3 7.7.Hz, 1H), 7.58 3 7.6 Hz, IH), 7.53 J R 7.0 Hz, 1K), 7.42 7.6 Hz, 1K), 6.60 IH) 2.43 31), 2.35 3H), 2.32 3H); MS 330.1 EpJ.m fl 41(5-ethyl-2H-pyrazol-3-yl)- (2-L trifluoromethylphenyl)-qninazoiin-4-ylJ -amine (11-41): 263 IND 1 1NM (500 MHz, DMdO-d6) 812.3 1H), 10.5 XE), 8.77 Cd, 8.2 Hz, aM), 7.92 2H), 7.85 3M), 7.56 J 8.1 Hz, 1H), 7.67 Ct, J 7.4 Hz, 11), 6.63 IH), 2.27 3M); MS 370.1 axmple :J2, (2-Ethylphenyl) -quinazolin-4-yll-( S-Methyl- 2H-pyrazol-3-yl) -amine (11-42): lHMR (500 M~z, DMSO-d6) 88.80 1H), 8.02 Cs, br, 1H), 7.82.Cd; J 8.4 Hz, IND IH), 7.77 1H), 7.62 J 7.6 Hz, IH), 7.54 Cm, IN), 7.41 2H), 6.40 1H), 2.75 J 7.1 Hz, 2H), 2.17 3M), 0.99 J 7.5 Hz, 3M); MS 330.1.

IND Bs2mle 43 (2-Bipheyl-2-yl-quinazolin-4-yl) CS-methyl- 1S 2H-pyrazol-3-yl)-amine (11-43): 1 HNMR (00 MHz, DMSO-dG) S 8.76.(d. J1. 7.6 Hi, 1H), 8.04 11), 7.75 EN), 7.30 Cm, 5H), 5.34 in), 2.14 Cs, 3M); MS 378.2 (MiH).

ExaAle A (2-Hydrozyphenyl) -quinazolin-4-yl]- Methyl-2H-pyrazol-3-y)-aminm e (11-44): 'MOM (500 M41z, DMSOd6) 510.9 br, 11), 8.62 J 8.2 Hz, 1H), 8.28 J 1H), 7.87 2H), 7.60 Ct, J =-7.9 Hz- 1H), 7.37 Ct, 7.8 Hz, 1H), 6.92 2H), 6.45 (s, iH)L, 2.27 3H); MS 318.1 Example 45 P- (2-Ethaxyphenyl) -qainazolin-4-yi] Methyl-2H-pyrazol-3-yl)-amine (11-45): 'HNMR (00 MHz, DMSO-d6) 812.1 br, 1H), 8.75 J 8.3 Hz, IN), 7.97 J 7.8 Hz, 1H), 7.82 Cd, J 8.3 Hz, 1Hj, 7.78 J 7.5 Hz, 1H), 7.70 J 7.8 7.56 Ct, J 7.8 Hz, 7.22 J3= 8.4 Hz, 1H),.7.12 C(t, J =.7.6 Hz, 111), -655 lB), 4211 J 6.9 Hz, 2H) 2.16 (a, 3M), 1.22 Ct, -J 6.9 Hz, 3H); MS 346.1 264 Va ~a l.t4' (Thiophen-2-yl) -25-pyrazol-3-yl] (2- (N trifluoromethyiphenyl) -quinazolim-4-yl] -amie (11-46): 1 HNMR.(SOD MHz, DMSo-d6) 58.04 J 8.3 Hz, in), 8.05 {dd, J 7.3, 8.2 Hz, 7.93 Cd, J 6.5 Hz, 11), 7.8 5H), 7.34 Cd, J 5.0 Hz, IN), 7.25 Cm, 11), 7.00 (M, 1N), 6.87 Cs, MS 438.1 Va Eamle 47 [4-(Tbiophen-2-yl) -23-pyrazol-3-yl 12- (2trifluoromethylphenyl) -qulnazalin-4-yl] -amine (11-47): Prepared according to Method B. 1 HlQMR (500MHz, DMS0-d6) 6.97 11), 7.08 11), 7.27 IH), 7.36 IH), 7.66 2H), 7'.77 3H), 7.83'Cm, 11), 8.00 Cm, 1N), 8.18 Cs, 8.62 J Hz, 10.7 (br. lH); El-MS 438.1 HPLC-Metbod A, Rt 2.97 min.

xampe 48 (4-Phenyl-2H-pyrazol-3-yl)- (2trifluoroethylphenyl) -quinazolin-4-yll -amine (11-48): Prepared according to Method B. 1 HNMR (5OHz, DMSO-d) 8 7.05 (br. s, 11), 7.14 Ct, J 7.8 Hz, 7.25 Cm, -311), 7.43 2H), 7.60 -Cm, 2H), 7.73 2H), 7.80 1H), 7.95 8.22 (br. s, 11), 8.60 1H), 10.6 (br.

1H); El-MS 432.2 CM+H); HPLC-Method A, Rt 3.04 min.

B2Larle 49 {5-tert-Eutyl-2Hpyrazol-3-yl)-[2-C2trifluoroiethyl-phenyl) -quinazolin-4-yl] -amine (11-49): RMNMR (SOO MHz, DMS0-d) 8 '8.76 Cd, :j 8.3 Hz, 1H), 7.94 21), 7.79 Cm, 41), 7.70 Ct, J 7.6 Hz, 11), 6.51 (s, 11), 1.16 Cs, 9H); MS 412.2 Ex* .p Ea (5-Phenyl-2H-pyrazol-3-yl)- 12- (2trifluroethylphenyl) -quinazolin-4 -yl] -amine (11-50): 1 HNNR (50OMHz, DMSO-d) 7.09 Cs, iH) 7.36 Ctd, J 7.8, IND 1.1 Hz, 7.46 Ct, J 7.8 Hz, 2H), 7.65 (br. d, J o 8.1 Hz, 2H), 7.78 2H), 7.90 4H), 7.95 J 7.7 Hz, 1H), 6.00 J 7.8 Az, 1H), 8.81 Cd, J 8.6 Hz, 1K), 11.29 (br. s, 1H); El-MS 432.1 CM+H); HPLC-etbod A, R 3.24 min.

Example 51 (4,5-Diphenyl-2H-pyrazol-3-yl)-[2-(2trifluoromethylpbenyl)-quinazolin-4-yl]-nine (11-51): 'HNMR (500MHz, D1SO-dS) 8 7.13 Cm, 1H), 7.18 5K), 7.36 Cm, 5H), 7.62 Cm,, 3H), 7.73 2H), 7.85 1K), 8.48 J 8.7Hz, 1K), 10.02 1H), 13.19 1H); El-MS NO ,508.2 HPLC-Metbod A, Rt 3.39 min.

inplt.52 C4-Carbamoyl-2R-pyrazol-3-yl)-[2-(2trif3uoromethylphenyl) -quinazolin-4-yl] -amine (11-52): Prepared in 40% yield. 'KNMR (500MHz, DMSO-dG): 8 12.85 Cs, 1H), 12.77 Cs, iN), 11.80 1H), 10.80 1K), 8.35-7.42 9H); MS 399.13 (M+11) HPLC-Method'A, Rt 2.782 min.

gxamlpj53 (2H-Pyrazol-3-yl) trifluoromethylphenyl)-quinazolii-4-yl]-amine (11-53): Prepared in 38% yield. 1 HNMR (500 MHz., DMSO-d) 5 12.52 1H), 10.65 1H), 8.75 7.91-7.68 K), 6.87 1H). MS: 356.17. KPLC-Metbod A, Rt 2.798 min.

BN=pI&34 5(5-Hydroxy-22-pyrazol-3-yl)- trifluoromethylphenyl)-quinazoli:n-4-yl]-amine (11-54): Prepared in 36k yield; 1 HNMR (500 MHz,,DMSO-dS) 8 10.61 110, 8.75 iH), 8.03-7.15 9H), 5.97 1H); MS 372.18 HPLC-Method A,'Rt 2.766'min.

266 INDppl g...55 (5-Cyclopropyl-2a-pyrazol-3-yl)- (2o trifluoromethyl-phenyl) -qaunazolin-4-yl] -amine (11-55): Prepared in 30% yield. '1HNMR (500 MHz, DMSO-d) 812.21 1H), 10.45 iN), 8.68 3M), 7.89-7.45 OH), 6.48 0.89 2H), 0. 2 2H). MS 396.18 HPLC-Method A, lt 3.069 min.

Erxa.. SAE (5-Methoxymethyl-21-pyrazol-3-yl)-[2-(2tr3fluoroiethyl-phenyl) -quinazolin-4-ylJ -amine (11-56): Prepared in 33% yield; 'HNMR (500 MHz, fMSO-d6) 8 12.51 10.48 1H), 8.60 7.81-7.55 7H), 6.71 11), -4.28 2H), 3.18 3H). MS 400.19 HPLC-Method A, Rt 2.881 min.

9x2 fle 51 (1H-indazal-3-yi) (2-trifluoroiethylphenyl) -quinazolin-4-yl] -amine (11-57): Prepared to afford 51 mg (78W yield) as pale yellow solid. 'HNMR (SOO MHz, DMSO-d6) 812.7 1H), 10.4 in, 8.55 il), 7.81 Ct, 1H), 7.71 iN), 7.61 1H, 7.58 iN), 7.46 4H) 7.36 1H), 7.22 iH), 6.91 Ct, iH) ppxnj LC-MS 406.16 tM-iH), 404.39 CM-H); HPLC- Method A, lt 3.00 min.

Zxae '5B- (4 -Chloro- indazol- 3 -yI) (2 trifluoromethyl-phenyi)--quinazoiin-4-yl -amine (1l-58); Prepared in DMP (70% yield) as pale yellow solid. lIrp (500 MHz, DMSO-d) 813.3 Cs, br, 11), 10.9 br, In), 8.60 1H), 7.97 iN), 7.81 iN), 7.75 iN), 7.67 iH), 7.63 (dd, IH), 7.57 2H), 7.43 iN), 7. 8 (dd, IH), 7.08 IH)*ppm; LC-MS 440.10 (MiH), 438.12.(M-H); HPLC-Method A, Rt, 3.08 min.

267 IND xap1t..i5 (5-Fluoro-2.H-indazol-3-yl).- (2o trifluoromethyl-phenyl) -quinazolin-4-yl -amine (11-59): Prepared in DMF (34W yield) as pale yellow solid. HuNMR (500 MHz, DMSO-d) 813.0 LH), 10.6 1H), 8.72 (d, 1H), 7.99 1H) 89 1H) 7.79 1H), 7.75 (t, 1H), 7.66 31), 7.56 (dd, iN), 7.39 iH), 7.28 (t, 11) ppm; LC-MS 424.12 r/e= 422..13 (M- HPLC-Method A, Rt 3.05 min.

Va Examnie 60 (7-Fluoro-iH-indazol-3-yl)-[2-(2- 0 trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (11-60): Prepared in DMP (511 yield) as yellow solid. 'HNMR (500 M~z, DMSO-d6) 813.4 IN), 10.6 11), 8.68 11), 7.95 in), 7.85 (di1H), 7.72 2H), 7.63_ 2H), 7.58 1H), 7.43 1H), 7.18 (dd, 1H), 7.00 1H) ppm; LC-MS 424.11 422.15 HPLC- Method A, Rt 3.06 min.

&iat.&e 61 (5-Methyl-1E-indazoi-3-yl)- (2trifluoromethyl-phenl) -guinazolin-4-yl] -amine (11-61Y: Prepared in DMF (811 yield) as yellow solid. 'HNNR (500 MHz, DMSO-d) 813.0 br, in), 8.79 (br, 11), 8.11 (Sr, 1H), 7.96 1H), 7.82 51), 7.46 IH), 7.41 (d, 1H), 7.20 11), 2.33 3H) ppm; M. (ESt) 420.15 418.17 HPLC-Method A, Rt 3.07 min.

Eample 62 12-(2. 6-Dichloro-pheny) -quinazolin-4-ylJ- fluoro-2H-indazol-3-yl) -amine (11-62): Prepared in DMF (371 yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 813.0 1H), 10.8 1H), 8.72 7.97 7.90 1H), 7.75 11), 3H), 7.43 iN), 7.35 7.23 1H) ppm; LCMS 424.08 422.10 HPLC-method A, Rt 3.06 min.

268 Va 0x e k 63 12-(2-Chloroo-phenyl) -quinazolin-4-y1 (1N- C- ±indazoi-3-yl)-amine (11-63): Prepared in 91t yield. 'NMRm (S00MHz, DMSO-d) 8 7.06 IM), 7.36 IH), 7.39 (t, 7.52 3M), 7.62 XH), 7.72 in), 7.82 (m, IH) 7.90 11), 8,05 8.76 iH), 11.5 (m, IH), 13.02 IR); El-MS 372.1 HPLC-Method A, Rt 2.93 min.

IN

Example 64 (5-Trifluoromethyl-lfl-indaaol-3-yl)- (2- 0 trif luoromethyl-phenyl) -cuiazolin-4-y] -amine. (11-64): IN Prepared in'DMF.C57% yield) as yellow solid. 1HNMR (500 MHz, DMSO-d6) 513.4 Cs, br, IH), 11.4 (br, 1H), 8.72 (d, 1H), 8.12 Cs, i14), 7.98 Ct, UH), 7.83 IH), 7.76 d, 1H), 7.73 Cdd, iH), 7.60 Cm, 4H), .7.52 Il) ppm; LC-MS 474.12 CM+H), 472.17 RPLC-Method A, Rt 3.25 min.

gmpae 65 (4-TrifluoromethyI- 1HE-undazol-3-yl)- 1 -(2 trifluoromethyl-phenyl) -quinazolin-4-yl) -amine (11-65): Prepared in DM7 (Bt yield) as yellow solid- 'n-NMR (500 MHz, DMSO-dE) 813.7 Cs, br, 1H), 11.2 Cbr, il), 8.70. (d, 1H1), 8.05 7.85 3H), 7.65 Cm, 4H), 7.51 (m, 2H).ppm; LC-MS 474.13 472.17 CM-H); HPLC-Hethod A, Rt 3.15 min.

Example [2-(2,6-Dichloro-phenyl)-quinasolin-4-yll (2indazoi-3-y1) -amine (11-66): Prepared in DM7 (30% yield) as yellow solid. 1 HNMR (500 MHz, DMSO-d) 812.9 in), 11.1 Cs, 211), 8.69 1H) 7.95 t, iH) 7.82 1H) 7.73 Ct, iH), 7.56 11), 7.47 Cs, 110, 7.45. Cs, lID, 7.39 2H), 7.26 Ct, iH), 6.92 Ct, 11) ppm; LC-MS, (ES+) 269 406.11 404.12 HPLC-Method A, Rt 3.00 min.

xanle 67 i1UH-indazol-3-yl) (2-methyl-phenyl) quinazolin-4-ylJ -amine (11-67): Prepared in 55 yield.

'HNM (S00{MHz, DMSO-d6) 8 2.15 3H), 7.09 Ct, 1H), 7.26 1K), 7.31 Ct, 1K), 7.39 1H), 7.42 7.55 Cd 1H), 7.64 1H), 7.74 Cd, 1H),!l.89 Cm, 1H), 7.96 Cd, 1H), 8.10 Cm, 1H), B.81 11), 12.0 1H), 13.18 Cs, 1H); El-MS 352.2 HPLC-Method A, R, 2.93 min.

IND Eamtle 68 (7-Trifluoromethyl-1E-indazoi-3-yl)- trifluoromethyl-phenyl) -uinazolin-4-yl] -amine (11-68): Prepared-in DMF (75% yield) as yellow solid. lHNMR (500 MHz,' DMSO-d6) S13.5 Cs, br, 1H), 11.2 Cs, br, 1H), 8.68 1H), 7.97 11), 7.92 Cd, 1K), 7.82 1H), 7.74 IN), 7.70 IH), 7.68 1H), 7.64 Cm, 1H), 7.57 Cm, 1K), 7.14 1K) ppm; LC-MS CES+) 474.11 472.14 (M-H);fHPLC-Method A, Rt 3.24 min.

Examle 69 (6-Trifluoromethyl-H-indazol-3-yl)-[2-(2trifluoromethyl-phenyl) -quinazolin-4-yl -amine (11-69): Prepared by Method B in DMF (78% yield) as yellow solid.

HNMR (500 MHz, DMSO-d) 8 13.4 Cs, br, 1K), 11.1 br, 1H), 8.67 d, 1H), 7.95 IH), 7.82 3H), 7.72 Cm, 2H), 7.63 2H), 7.57 Ct, 1H),-7.23 Cd, 1K) ppm; LC-MS CES+) 474.12 472.15 CM-H); HPLC-Method A, Rt 3.28 'min.

Exagmje 74 (5-Nitro-i- indazol-3-yl)- 12- (2trifluoromethyl-phenyl) -quinazolin-4-yll-amine (11-70): Prepared in DM' 1(821 yield) as yellow solid. 1 )luom (500 MHz, DMSO-d) 613.6 Cs, br, 1H), 11.4 br, 1H), 8.75 270 IND 1H), 8.72 1H), 8,09 (dd, 1H), 7.98 18), 7.83 0 IH), 7.75 1iH), 7.70 2H), 7.61 3H) ppm; LC-MS 451.14 449.12 HPLC-Method A, Rt 3.02 min.

Example 71 (5,7-Difluoro-1H-indazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yl]-amine (11-71): Prepared in DMF (60% yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 813.7 br, 1H), 11.2 br, IH), 8.73 1iH), 8.03 11), 7.88 1H), 7.80 2H), 7.70 0 3H), 7.32 2H) ppm; LC-MS 442.14 (ES- IN 440.14 HiPLC-Method A, Rt 3.11.min.

Example 72 (4-Pyrrol-1-yl-lB-indazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yl -amine (I1-72): Prepared in DMF (33% yield) as yellow dolid. 1 HN4MR (500 .MHz, DMSO-d6) 613.4 br, 1I), 11.0 br, 1H), 8.53 1H), 7.98 1H), 7.75 4H), 7.62 2H), 7.52 1H), 7.43 1iH), 7.05 11), 6.80 2H), 5.61 2H) ppm; LC-MS 471.18'(M+H), 469.18 (M- HPLC-Method A, Rt 3.12 min.

Example 73 (5-Amino-LE-indazol-3-yl)- 12-(2trifluoromethyl-phenyl)-quinazolin-4-yll-amine (11-73): A solution of compound II-70 (70 mg, 0.16 mmol) in MeOH (2 mL) was treated with Raney Ni until solution was -colorless (about 1.5 g Raney Ni was added). After stirring at room temperature for 40 min, the mixture was filtered through celite, the resulting celite wa.s washed with MeOH (5 times), and the solvent was evaporated in vacuo. to provide a crude product that wasthen purified by HPLCto give the title compound as a yellow solid mg, m.p. 221-223C; 1 HNMR (500 MHz, DMSO-d6) 271 ID 813.2 br, 110, 10.7 hr, LH), 9.80 2H), 8.68 1H), 7.97 3n), 7.87 (d 7.75 2H), 7.65 5H), 7.30 in) ppm; MS 421.16 (ES-) 419.17 ;'HPLC-Method A, Rt 2.41 min.

ThcEaile 74 (2-Chioro-phenyl) -quinazolin-4-yl- (7fluoro-lR- indazol-3-yi)-amine (11-74): Prepared in DMF (351 yield) as yell6w solid. 1 HNMR (500 MHz,' DMSO-d6) IND 813.7 iH), 11.7 br, 1H), 8.80.(d, 1H), 8.15 (t, 1H), 7.99 iH), 7.88 in), 7.68 1H), 7.60 (m, 2H), 7.53 1H), 7.46 LH), 7.25 (dd, iH), 7.04 (m, IND 1H) ppm; ILC-MS 390.16 RPLC-Method A, at 3.00 min.

Example 75 [2-(2-Chloro-phenyl) -quiaazolin-4-yiJ- fluoro-1-indazol-3-yl) -aaine (11-75): Prepared in DMF.

'HNMR (500 MHz, DMSO-d6) 813.2 Cs, 1H), 11.7 br, 11), 8.80 8.10 iN), 7.91 2H), 7.70 7.58 4H), 7.50 1H), 7.29 IH) ppm; LC-MS (ES+) 390.17 CM+H); HPLC-Method A, Rt 3.00 min.

Exam2le 7§ (2-Chioro-phenyl) -quinazolin-4-yiJ-(5,7difluoro- 1E-indazol-3-yl) -amine (11-76): Prepared in DM yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 813.8 IH), 11.5 Cs, br, 1H), 8.76 iN), 8.08 (t, 1H), 7.93 in), 7.84 Ct, iN), 7.64 1H), 7.55 (d, 7.50 in), 7.44 Cm, 2H), 7.36 Ct, 11) ppm; LC-MS 408.15 406.17 HPLC-Method A, R, 3.08 min.

Ezan3.&Z 77[2- (2-Chioro-phenyl) -quiazolin-4-yl] trifluoromethyl-1i-indazo1-3--yi)-amine (11-77): Prepared in DM' (66% yieid) as yellow solid. 1 'HNM (500 MHz, DMSO- 272 IND d6) 823.5 Ce, 1H3), 11.4 Ca, br, lx), 8.79 1H), 8.29 o(s, In) 8. 07 l1H, 7. 93 1K) 7. 84 11) 7. 72.

(N d, 113), 7,6 3 2 7. 53 13), 7. 48 7 .3 6 Ct t, 113) ppm; LC-MS rn/en 440.16 CM-iH); rn/em.

438.18 CM-H) HPLC-Method A, Rt 3.22 min.

Exmple 7!1 (2-cysno-phenyl) -quinazoiin-4-yl indazol-3-yl)-amine Prepared in 13t yield. 113- Va .NMRAS0O MHz, DM50) 8- 12.9 Cbr, 113), 10.8 Cbr, 113), 8.73 (br s, 113), 7.97 Cm,,413), 7.74 (mn, 113), 7.5 (mn, 413), 7.42 7.08 Cm, 113) ppm; MS -(PIA) 363.2 HPLC- IND Method A, Rt 2.971 Thin.

Eaina1t.7Th (5-Bromo-3M-inmdazal-3-yi) (2trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (11-79): Prepared in DMF (64W yield) as yellow solid. 1 'LHNRP (500 M4Hz, DMSO-dG) 813.4 In), 11.'6 Cs, br, lID, 8.93 (d, 1H3), 8.21 113), 8.14 (8,113), 8.05 113), 7.95 (in, 4H3), 7.86 Ct, 113), 7.65 Cd, 113), 7.59 Cd, 113) ppm; MS- 486.10 CES-) 484.09 HPLC-Method A, Rt 3.22 Min- EiiaJIC (6-Chloro-1H-indazol-3-yl) (2trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (11-80): Prepared inDM2 (94% yield) as yellow solid. lfIHNR~ (500 M413, -DMSO..dE) 813.1 113), 11.2 Cs, br, 113), 8.73 (d, 1H1), 8.03 Ct, 113), 7.87 113), 7.79 *Cm, 2H3), 7.73 Cm, 213), 7.67 Cm, 213), 7.58 Cs,. 113), 7.04 Cdd, 113) 'ppm. LC-MS CES+) 440.14 438.16 CM-H); HPLC-Metlaod A, R, 3.25.mml.

Rxanpl 1 7-Fuo-6-trifluoromethy1-1lf-indazo1-3-yx) 12- (2-trifluoromeathyl-phenyl) -quinazoiin-4-yl] -nine (II- .273 I 81) Prepared in DM7 (30t yield) as yellow solid. IH~ o (500 J'Sz Dms0-d6) 513.9 (s,1H) "'11.0 (s br 3 1H), 8.64 Cl 111), 7.94 Ct, 1H), 7.81 111), 7.71. Cm, 2H1), 7.60 ct 4H1), 7.20 Cdd, 111) ppm. LC-MS 492.18 490.18 .1 M-H) MPLC-Method A, Rt 3.44 min.

EXAM~pet82(6-3romo-1H-indazol-3-y1) 2- (2trifluoromethyl-phenyl) -quinazolin-4-ylJ -amine (11-82): Prepared in DM7 (40% yield) as yellow solid. 'HNMR (500 M'Hz, DMS0-aG) 613.1 1H), 11.2 br, 11), 8.73 (d, 1H), 8.03 Ct, 7.87 Cd, 1H1), 7.80 (Mn, 211), 7.73 (in, IND3H1), 7.67 1H1), 7.61 111), 7.315 (dd, 1H1) PPM; MS o(ES+) 486.07 HPLC-Method A, R, 3.28 min.

Exile 83 (2.4-Bis-trifluoromethyl-phenyl) quinazolin-4-yll 7-difluoro-2.R-indazol-3-yl) -aiaine (II-83) Prepared in DM7 in 28% yield. j'RN4j (500MHZ, MeOH-d4) 8 8.81 J=8.4Hz, 8.35-8.20 3M), 8.19-7.96 3H1), 7.40-7.34 111), 7.29-7.14 1H1); LC-MS 510.14 HPLC-Method C, R, 8.29 min.

ExiupIti84 C5,7-Difluoro-lHU-indazol-3-yl) -[2-(4-fluoro-2trifluoroinethyl-phenyl) -quinazolin-4-ylJ -amine (1:1-84): Prepared in 481k yield. 1 }'NM (500MH'Z, MeOH-d4) 68.74- 8. 63 C m, 11), 8S.23-8.10 Cm, 111), 7.99-7.90 2H), -7.89- 7.80 (in, 7.71-7.61 Cm, 21H), 7.61-7.50 Cm, 111), 7.24- -7.15 Cm, 111), 7.14-7.02 Cm, 1H); LC-MS (ESt) 460.14 HPLC-Metho~d C, R, 7.59 min.

Exml U(2- (2-Eroino-phenyl) -quinazolin-4-yl (5,7difluoro-1Hf-indazol-3-yl)-amiine (11-85): Prepared in TSP (21t yield). 1 HNMR (500wi2z, MeOH-d4) 86a.a81 3=8.4Hz, 111), 8.35-8.20C(m, 8.19-7.96 3M), 7.40-7.34 (m, .274 IN I'XH), 7.29-7.14 (uT, IH); LC-MS 510.14 HPLC- Method C, Rt 8.29 min.

gg R=le 8jj (5,7-Difluoro-1N-indazo1-3-y1) -[2-(5-fluoro-2trifluroiethyl-pheny) -quinazolin-4-yl -amine (11-86): Prepared in THY (26% yield). 'HNMR (500MHz, MeOH-d4) 88.62 J-8.41z, Il), 8.16-4.02 Cm, 12), 7.96-7.73 (m, 3H), 7.59-7.48 iN), 7.48-7.35 7.21-7.09 (m, 12), 7.09-6.89 Cm, IN); LC-MS 460.16 CM+H); PLC- Method C, Rt 7.28 min.

IND &ampC 8.f [2-(2,4-Dickloro-phenyl) -quinazoin-4-yl- (5,7-Difluoro-1H- indazol-3-y1)-amine (11-87): Prepared in THF yield). 1 HNMR (500MHz, MeOH-d4) 88.81 (d, J=8.4Hz, I2), 8.35-8.20 3H), 8.19-7.96 3H), 7.40- 7.34 12), 7.29-7.14 LC-MS 510.14 HPLC-Method C, Rt 8.29 min.

BxainrJe 2 quinazoiin-4-y11-(5 ,7-Difluoro-1H- indazol-3 -yl)-amine (11-88): Prepared in THF (33% yield). 1 HNMR (500MHz, DMSO-dE) 8 19.76 Cs, IE), 8.66 Cd, J=8.3Hz, 1H), 8.06- 7.84 7.81-7.63 3M); 7.48-7.16 2H); LC-14S 476.16 HPLC-Metbod C, Rt 19.28 min.

ERa.le 89 (4-Fluoro-1- indazo1-3-y) -[2T(2trifluoromethyl-phenyl) -quinazolin-4-yll -amine (11-89): Prepared in NMP (79% yield) as yellow solid. 'HNMR (500 MHz, DMSO-d) 613.2 12), 10.8 Cs, br, 8.63 (d, 12), 7.97 Ct, 1H), 7.85 1H), 7.74'Am, 22), 7.64 Ct, 7.57 m, 2H),.7.32 6.82 12) ppm; LC-MS 424.17. IPLC-Method A, Rt 3.14 min.

275 IND xanl Q 0 (1A-Indazol-3-yl)- E8-methosy-2-(2o trifluoromethyl-phenyl) -quinazolin-4 -yll -amine Prepared using THF as solvent to afford the title compound as a TPA salt (23% yield). HPLC-Method A, Rt 2.97 ftin lHNMR (DMSO-d, 500 MRZ)$ 12.9 (11, be), 11.0 -10.7(11, ba), 8.25 7.75-7.50 (BI, 7.30 6.90 4.0 (3H, MS (mlz) 436.2 Va .Example 91 (5-Fluoro-1I-indazol-3-yl)- [8-iethoxy-2-(2trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (U-91): 0 Prepared using TPA as solvent to afford the title IN compound as a TFA salt (23% yield). HPLC-Method A, Rt 3.10 min. 1 4HN (DMSO-d, 500 MHz): 13.0 ba), 11.0 10.7(1!, be), 8.25 (1H, 7.75-7.50 (7H, m) 7.35 7.25 (11, 4.0 (3H, MS 454.2 Examle 92 (7-Fiuoro-HJ-indazol-3-yl)- [8-iethocy-2-{trifluoromethyl-phenyl)-quinazolin-4-yl-amine (11-92): Prepared, using THI as solvent to afford the title compound as a TFA salt (98 mg, 58% yield). HPLC-Method A, Et 3.20 min 1 HNMR (DMSO-d6, 500 MHz) 8 13.45 (1H, be), 11.0 10.7(1, be), 8.25 (1H, 7.75-7.60 (SH, in), 7.50. 7.40 (1H, 7.15 (11, 6.95 (1H, i) 4.0 (31, MS 454.2 Ex* plie-2 (5,7-Difluoro-15f-indazol-3-yi)- f8-iethoxy-2- (2-trifiuoromethyl-phenyl) -quinazciin-4-yl] -amine (11- 93): Prepared using THF as solvent to afford the title compound as a TFA salt. (36% yield). HPLC-Method A, Rt 3.27 win. HI4MR (DMSO-dG, 500 MHz): 13.65 bs), 11.0 10.7(10 ba), 8.22 7.75-7.60 m), 276 IND7.40 (11, 7.35 (11, 1.19 4.0 (3H, s)j MS 472.2 (14+H).

BxEant2ie 94 12- (2-Chloro-pyridin-3-yl) -qinazolin-4-yll- (5,7-Difluoro-H-indazol-3-yl)-amine (11-94): Prepared in DMF. 'HNMR (500MHz, DMSO-d) 8 13.62 (hr a, 1H, 11.06- 10.71 1H), 8.16-7.70 41), 7.60-7.09 3H); LC- MS 409.14 HPLC-Method A, Rt 2.89 min.

Va Exgmle 9a (2-Chloro-4-nitro -phenyl) -quinazolin-4-yl (5,7-difluoro-1H-indazol-3-yl) -amine (11-95): Prepared in THF. '1NMR (500MHz, DMSO-d) 8 13.35 Cs, 1H), 10.74 (s, 8.67 J=8.4Hz, 1H), 8.29 Cd, J=2.OSHz, IH), 8.18- 8.08 11), 8.07-7.60 (mi 4H), 7.53-7.10 2H). -LC- MS 453.15 RPLC-Method 1, 1I 3.63 min.

Exm 2le 96 [2-(4-Amino-2-chloro-phenyl)-quinazolin-4-yll- (5,7-Difluoro-JM-indazol-3-yl)-amine (11-96): A solution of compound 11-95 (8mg, 0.01Smol) and tin chloride dihydrate (22mg, 0.lmmol) in ethanol (2mL) was heated atio 0 00c for 24h. The reaction was diluted with EtOAc OmL), washed with IN NaOH solution CanxOaL), brine, and dried over anhydrous sodium-sulfate to afford the crude product Purification was achieved by flash chromatography on silica gel (eluting with 1-3% MeOH in 012012.) The title compound was isolated as pale yellow solid (1.2mg, 16% yield). LC-MS 423.12 HPLC-Hethod C, Rt 13.78 min.

amp 9 (4,5,6,7-Tetrahydro-lR-indazol-3-yi) -[2-(2-trifluoromethyl-phenyl)-quinazolin-4-ylJ-amine (11-97): Prepared in 34% yield. '-HNMR (500MHz, DMSO-d) 8 1.58 2H), 1.66 2H), 2.24 21), 2.54 (m 2H), 277 IND7.63 m, 3H), 7.71 t, i 7.75. 7.78 o 7.85 iH), 8.53 1H), 9.99 1H), 12.09 1H); EI-MS 410.2 HPLC-Method A, Rt 3.05 min.

Exa.le 98 (1R-Pyrazolc[4,3-b]pyridin-a-yx) trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (11-98): Prepared in DMF (37% yield) as yellow solid. 1 fNMR (00 MHz, DMSO-d6) 613.1 br, 1H); 11.2 br, 1H), 8.73 IND 1H), 8.54 1H), 8.12 15), 8.06 Ct, 7.90 1H), 7.84 Ct, 11), 7-75 IH), 7.69 2H), 7.65 1H), 7.47 (dd, 1H) ppm; LC-MS 407.18 NO HPLO-Method A, Rt 2.77 min.

0 0 Exampt 99 (2 -Pyrazolo(3,4-b pyridi- 3 -yl) [2 (2trifluoromethyl-phenyl) -quinazolin-4-yl -amine (11-99): .Prepared in DMF (45% yield). 'HNMR (500 MHz, DMSO-d6) 513.5 br, in), 11.3 Cs, br, 15), 8.78 8.49 8.17 1H), 8.03 Ct, 7.89 1H), 7.80 2H), 7.74 (in, ZN), 7.68 1H), 7.08 (dd, 1H).ppm.

MS 407.16 405.16 CM-H); HPLC-MethodA, Rt.2.80 min.

xamle Igo (6-Methyl- l-pyrazoloE3,4-blpyridin-3-yl) [2- (2-trifluorometyl-phenyl)-quilnazoiin-4-yll-amine

(II-

100): Prepared in DMF (11% yield). HNMR (500 Mz, DMSOd6) 813.2 br, 1H), 10.8 Cs, br, 15), 8.57-(d, 1H), 7.95 Ct, in), 7.82 1H), 7.72 1H),"7.65 7.58 2H), 2.44 Cs, 35, buried by DMSO), '2.20 3H) ppm. LC-MS 4P5.22 CES-) 433.25 SM-H); HPLC- Method A, Rt 2.94 min.

xamP&lI (6-0xo-5-phenyi-5s-dihydro-1u-pyrazolor4f3' a]pyridazin-3-yl)-(2-(2-trifluoromethyl-phenyl)quinazolin-4-yll -amine 11-101: Prepared in DMF (6t o yield). lgHNt f (500 Maiz, DMS0-d6l 8 12.6 iH) 11. 0 (B, 0 Cl r, iN), 8.60 1H) 7. 95 Ct, 111), 7.88 1N), 7.80 ct (Cd, iN), 7.68 411) 7. 40 3M), 7.22 211), 6.61 Cs,11) ppm. LC-MS 500.21 498.16 CM- H) HPLC-Method A, R, 3. 00 min.

Enmpe103~ (6-Methyi-2- (2-trifluoromethoxy-phenyl) pyrimidin-4-ylJ (5-phenyl-2H-pyrazol-3-yl) -amine (11- 103):. MS 412.13 (4411) HPLC-Method E R, 1. 248 win.

INDEgmnp1L2Q04 CS-Furan-2-yl-2H-pyrazol-3-yl) 6-methyl-2-.

o (2-trifluoromethoxy-phenyi) -pyrimidin-4-yiJ -amino (3I1- Cl104); MS 402.12 (M+H1) HPLC-Method E, Rt 1. 188 min.

£JL1Qe I U16 -Ethyl- 2- (2 -trif luoromethoxy-phenyl) pyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (II- 105): MS 364.14 HPLC-Method-E, Rt 1.112 min.

"xample 106 2-Cloro-phenyl) -pyrido[2,3-dlpyrimidin- 4-yl (5-methyl-2H-pyrazoi-3-yl) -nine (31-:L06): 1

HNMR

(500 MHz, DM50) 812.23 111), 10.78 111), 7.73-7.47 Cm, 7H), 6.72 1H1), 2.21' 311). 14S: (144.H) 337.02.

11PLC-Metbod A, Rt 2.783 min.

Exmp12 J-Floro-1H-±ndazol-3-yl) (2trifluoromethyl-pheiyl).- 6,7 cyclopentapyrimidin-4-yl) -amine (11-107): Prepared in 68% yield. 1 11N14R (500MHz, DMSO-d6) 8 2.16 2H1), 2.88 (in, .211), 2.98 Ct, 211), 7.21 (td, 111), 7.29 (dd, 3M), 7.50 (dd, 111), 7.65 t, 11) 7.67 t, 1H1), 7.73 1H1), 7.79 1111,10.22 Cbr. s, 111), 12.99 (hr. s, 1H1); El-'MS 414.2 HPLC-Method Rt 2.92 muin.

o ~Exarfl.e 0. (hH-lndazol-3-yl) (2-trifluoromethylci phenyl)-,pyrido[2,3-dlpyrimidtn-4-ylJ-anine (11-108): RPLC-Method A, Rt 2.78 min. 1 H1NIR (DMSO-dE, 500 M4Hz): 12.95 hO), 11.45 8 11.15(11?, be), 9.20 (2H?, 7.85-7.70 mn), 7.70-7.55 (4H, 7.50 i), .7.3-5 mn), 7.05 in); MS (rn/z) 407.03 (14+1).

&J&pl 12 (5,7-fitluoro-1H-indazol-3-y.) -12- (2- .tritluoromethyl-phenyl) -pyrido 3-dWpyrimidin-4-yl] o amine (11-109): V ellow, di-TFA salt (25% yield). HPLC IND(Method A) 3.10 Tminf. 'HfMMt (DMSO-dG, 500 MHz) o 13.8-13.6111?, be), 11.4 11.2(11?, bs) ,9.1S nO, C] 7.85-7.75 in), 7.75-7.62 7.32 mn); MS 442.98 (14tH).

E~mxt.23 1 2- (2 -Chioro-phenyl) -pyrido [2,3 -dl pyriinidin- 4-yl]-(1H-indazol-3-yl)-amitne (u1-hO): Prepared from 2aminonicotinic acid and 2-chlorobenzoyl chloride afforded the title compound as a di-TFA salt (28% yield). HPLC- Method A, Rt 2.85 min. (95t) 1NM (DMSO-d6, 500 MHz): 12.90 11.10 10.90 be), 9.05 (2H,j n), 7.75-7.60 rn), 7.51 mn), 7.45- 7.25 in), 6.95 MS (in/z) 372.99(4+1).

L'aml *l,(-Flucro-1H-indazol-3-y1l) (2trifluoroinethy~1-phenyl) 6,7,9,9,10-hexahydrocyclooctapyrinidin-4-ylJ -amine (11-111). 'Prepared in 43tyield. 1?HJ14 (50014Hz, DMSO0-d6l 8 1.46 (in, 1.53 (in, 1.77 (mn, 2.95 (mn, 3.04.(m, 7.22 (mn, 7.50 (dd, 1H), 7.72 (mn, 7.80 IN), 10.5 (in, 13105 ()Dr s, El-MS 456.2 HPLC-Method C, Rt 11. 93 min.' .290 0 ~xamW~e, 112 12- (2-Chiaro-phenyl) -6,1-diydro-$o- (N ocyclopentapyrimidin-4-yl] {-fluoro-1H-indazol-3-yl) Ct amine (zr-112): Prepared in 67% yield. 1flMR (500MHz, DMSO-d6) 52.18 Cm, 211), 2.89'(in, 210, 3.02 2H1), '7.24 (td, 1H1), 7.42 Cm,.2H), 7.49 Ctd, iH), 7.52 (66, iN), '7.54 1H), 7.57 (66, 1H), 10.50 Cbr. s, 1H) 13.06 Cbr. a, 111); El-MS 380.1 HPLC-Method C, Rt 9.68 min 01 E~gUlp.A113 (1H-Indascl-3-yl) -(2-trifinoromethyl- Va phaenyl) 7-dihydto-SE-cyclopentapyrimidin-4 -yl] -amine o (11-113) :-Prepared in 37% yield. 'iuMm CSQOMiflz, DMSQ-d6) 8 2.65 Cm, 2H) 2.85 2H1), 2.99 Ct, 2H), 7.02 IN), 7.32 Ct, iN) 7.47 1H1), 7.55 Cd, 110, 7.68 Ct, Ii), 7.74 111), 7.80 iN), 10.37 Cbr. s, 111), 12.91 (br.

s, 1H1); El-MS 396.1 CM-iH); HPLC-Method B, Rt 9.88 min.

Exanl114l (7-Flnoro-1N-indazoi-3-yi) -12- (2trifluormethyl-phenyl) -6,7 -dihydro-Sifcyrclopentapyrimidin-4-yll -amine (11-114): Prepared in yield. 1 LHNIMR (500MHz, DMS0-dS) .852.15 2H1), 2.87 (m, 2H), 2.97 2H1), 6.99 7.17 (66, 7.38 (d, 7.65 Cm, 211), 7.71 IMH), 7.78 in), 10.21 C(br.

s, IN), 13.40 (br. s, El-MS 414.1 HPLC-Method C, Rt 9. 99 min Exml-1 (5,7-Difluoro-1H-indazol-3-yl)- (2trifluormbethyl-phenyl) -6,7 cyciopentapyritidin-4-yll -amine (11-115)- Preparid.

.according to Method C in 52% yield. l1lHNMR (500MHz, 66)' 8 2.16 2H)0, 2. 89 -2H) 2. 97 CtI 211), .7.19 (66, 7.29 (td, 3-H) 7.63 iN), 7.66 111), 7.71 Ct, 1H), 7.78 IN), 10.16 Cbr. 6, IH), 13.55 (br. a, l); El -MS 432.1 HPLC-Method C, Rt 10.09 min.

*tau.XIe aIf (2-Chioro-phenyl) 7-dihydro-SEcyclopentapyrimidin-4-ylJ -(1-indazol-3-yl) -amine (II- 116): Prepared in 56% yield. 1 'HNMR (501Hz, DMSO-d6) C 2.16 2H), 2.85 2H), 3.01 2H), 7.06 Ct, 1K), 7.34 1H), 7.40 IH), 7.48 Cm, 2H), 7.53 IH), IND7.56 7.63 10.39 (br. s, 1H), 12.91 (s, 1H); El-MS 362.1 KPLC-Method A, Rt 3 .09 min.

Ia NDnR J&le 17 (2-Chioro-phenyl) -6,7-dihydro-50cyclopentapyrimidin--ylJ -(7-fluoro-2M-indazol-3-ylamine (11-117): Prepared in 63W yield. 'HNMR (500MHz, .DMSO-d6) 82.15 Cm, 2H), 2.87 2H), 3.00 Ct, 2H), 7.01 (td, 1H), 7.19 (dd, 11H), 7.39 1K), 7.45 Cm, 2H), 7.51 1H), 7.55 Cd, 1H), 10.35 a, 1H), 13.45 (br. a, 11); El-MS 380.1 HPLC-Method A, Rt Rt 3.15 min.

ExgJ~le Ila(2-(2-Chioro-phenyl) -6,7-dihydro-sHcyolapentapyrimidin-4-yl]- (5,7-difiuoro-1i-indazol-3-yl)amine (11-118): Preparedin 60% yield. 1 gHNMR (500MHz, DMSO-dS) 8 2.18 2H), 2.91 2H), 3.01 Ct, 2H), 7.32 11), 7.33 Ctd, 7.41 1H), 7.48 Ct, 11), 7.53 Cd, 1H), 7.55 Cdd, 10.35 (br. a, 11), 13.45 Cbr. s, 1H); El-MS 398.1 KPLC-Method A, at Rt 3.24 min.

E(ampLe11 H-Tndazal-3-y1)-[2-{2-trifluoromethylphenyl) Br9, 1-hexahydro-cyclooctapyrimidin-4-yl] amine (11-119): Prepared in 36% yield. 'HNMR (5001Hz, DMo-dE) 8 1.47 21), 1.53 2H), 1.78 4H), 2.96 2H),.3.06 Ct, 2H), 7.03 Ct, 1H), 7.47 11), 7.72 IH), 7.73 1H), 7.72 31), 7.81 3H),.10.52 IND 12.97 (br. a, 1H); El-MS 438..2 HPLC- 0 Method A, Rt 3.37 min.ct BmpIt 12Q C7-Fluoro-1EH-indazol-3-yl) (2trifluoromethyl-phenyl) 6,7,8,9,*10-hexahydrocyclooctapyrimidin-4-yl-amitne (11-120): Prepared ini yield. 1 1flM'9 (50014Hz, DMSO-dE) 8 1.46 (mn, 2H) 1. 52 (mn, 2H), 1.77 414), 2.94 21H), 3.04 (mn, 2H), 7.00 (td, IND111), 7.17 (dd, 1H), 7.30 7.70 3H), 7.79 (d, 1K), 10.5 114), 13.49 (br s, 1K); El-MS 456.1 (14+1); 0 KHPLC-Method.A, Itt 3.43 min'.

ox~l 12 (5,7-Difluoro-1B-indazoi-3-yl) (2trifluoromethyl-phenyl) 6,7,8,9, cylooctapyrimidiun-4-yll-amine (11-121). Prepared in 48t yield. 'HN~m (500MHz, DMSO-de) S 1.46 2H), 1.52 (m, 2H), 1.77 4H), 2.95 Cm, 2H4), 3.03 2H4), 7.14 (d, 7.30 iN), 7.73 (mn, 3H), 7.80 114), 10.5 (m, 114), 13.62 (br. s, iH) El-MS 475.1 KPLC-Method A, Rt 3.52 mini.

E~a~t 22Z [6-Cycloheryl-2- (2-trifluoromethyl-phenLyl) pyrimidiin-4-yl] C1H-iudzol-3-yl) -amine (11-122): Prepared in 45% yield. 'IjH441i (500 MHz, ODC13) 8 1.30 (2H, zm), 1'.4 6 (2H, mn), 1.65 (2H, mn), 1.76 (2H, mn), 1.91 (2H4, mn), 2.61,(1K,- br mn), 7.08 (iN, t, J-7.4 Hz), 7.27' (1H4, d, 7.3 5 (114, t, 1Hz),. 7. 50 (Iii, t, 9=7. 0 Hz), 7.58 (114, t, J=7.4 Hz) 7.66 (3H4, in), 7.72 (1K, d, 3T=7.8 Hz), 8.0 (1H, br), 9.87 (114, br) ppm; -HPLC-Method D, Itt 3.S7 rain; LC-MS 438.17 Fxml 1i~a23 (2-Pluoro-phenyl) (2-trifluoromethylphenyl) -pyrinidin-4-yl] (1K-ndazol-3-yl) -amine (11-123): Prepared in 8% yield. 1HNR (500 MHz, CDC1 3 7.18 (3H, 7.37 7.43 (1H, =7.9 Hz), 7.51 (1H, d, J=7.9 Hz), 7.55 (1H, t, J=7.6 Hz), 7.65 (1i, t, Jn7.4 Hz), 7.79 (1H, d, J=7.9 Hz), 7.85 d, J= 7.6 Hz), 8.19 (2H, 8.70 (1H, d, J= 8.5 Hz) ppm; HPLC-Method D, Rt 4.93 min; LC-MS 450.13 (M+H)4 Example 124 (6-Fluoro-1H-indazol-3-yl)-E2-(2trifluoromethyl-phenyl)-quinazolin-4-yll-amine (11-124).

Prepared in DMF (87% yield) as yellow solid. 'HNMR (500 MHz, DMSO-dG) 813.0 1H), 11.1 br, 1N), 8.66 (d, 1H), 7.95 (tj 11), 7.80 1H), 7.72 2H), 7.62 (m, 4H), 7.21 (dd, 1H), 6.84 (td, 1N) ppm. LC-MS 424.15 HPLC-Method A, Rt 3.05 min.

Examrnple p125 3- [2-(2-Trifluoromethyl-phenyl)-quinazolin-4y1amino]-1HN-indazole-5-carboxylic acid methyl eater (II- 125): To a solution of compound 11-79 (100 mg 0.21 mmol) in DMP (2 mL) was added MeOH (1 mL), DIEA (54 uL, 0.31 mmol) and PdCl 2 (dppf) (4 mg, 0.005 mmol). The flask was flushed with CO three times and then charged with a CO balloon. The reaction mixture was heated at 800C for 14 h then poured into water. The resulting precipitate was collected and washed with water. The crude product was then purified first by flash column (silica gel, .ethyl acetate in hexanes) then by preparative HPLC to to afford II-125 as yellow solid. 'HNMR (500 MHz, DMSO-d6) 813.3 1N), 11.3 br, 11), 8.70 iH), 8.36 7.97 1H), 7.82 2H), 7.71 3H), 7.58 2H), 7.51 1H), 3.75 3H) ppm; LC-MS (ES+) 464.13 HPLC-Method A, Rt 3.12 min.

284 IND MM~e208(5-Methyl-20-pyrazol-3-yl) (2-napbthyl-1- 0yli -qainasolin-4-yl] -ine (11-208):- 1 *HMR (500 MG~z, d6) 58.92 111), 8.73 (Mn, IH), 8.39 1H1), 8.09 (mn, Ct2H), '7.95 (in, 311), 7.62 (mn, 3M) 6.78 s,1H1), 2.32 s 3H1); MS 352.2 (M H).

Ex~A..ZQ (2-Chioro-phenyl) -pyrido [2 ,3-dl pyrinidin- 4.-yl (7-flnoro-XH-indazol-3-yl) -amine (11-214). Prepared IND from 4-Chloro-2- (2-obloro-phenyl)-pyrido 3-dlprmidine 2210 (100 mg, 0.36mmol) and 7-Fluoro-1Hi-indazol-3-ylamine 0(108mg, O.72mmol). Purification by peatieHPLC IND afforded the title compound as a yellow, di-TFA salt (93 o rng, 46% yield)'. RPLC-Nethod A, Rt 3.04 in; 'H.NMR, 500 MHz) :513.67 (1H, 11.40-11.25 (1H, 9.35- 9.25. (2H1, in), 7.95 (111, mn), 7.80-7.47 (511, Mn), 7..35(1H, in), 7.15 (11, mn); MS MHW 391.1.

Expt6210 (2-Chioro-phenyl) -pyrido[2,3-dlpyrimidin- 4-ylJ -(5-fluoro-lHE-indazol-3-yl) -amine (11-215)- Prepared from 4-Chloro-2- (2-chloro-phenyl) -pyrido 3-dJ pyriinidIne (100 mg, 0.S3inmol)'arid 5-Fluoro-lIi-indazol-3- -ylamine (108mg, 0.72inmol). Purification by preparative RPLC afforded the title comnpound as a yellow, di-TPA salt Ins, 22% yield). HPLC-Metbod A, Rt 3.00 win; 1H NMR (DMSO, 500 MHz) 613. 0 (1H1, 10.90(1H, bs), 9.15-9.05 (2H, 7.70 (18, mn), 7.60-7.30 (6H, mn), 7.20 (1H1, m); MS MH+ 391.1.

E~an-221 (2-Chioro-phenxyl) -pyrido[2,3-dlpyrimidin- 4-71] -(5,7-diflnoro-la-indazol-3-yl)-enine (11-216): Prepared from 4-Chloro-2- (2 -chioro-phenyl) -pyrido [2,3d) pyriinidine (100 mng, 0.3Gminol) and 7-Difluoro-1Hindazol- 3-ylamine.. (112mg, 0 .G6nuol) Purif ication by .285 IND preparative HPLC afforded the title compound as a yellow, o di-TFA salt (.30 mg, 621 yield). EPIPC-Method A, Rt 3.12 0 min; 1 H NMR (DMSO, 500 MHz): 13:80-13.60 (1H, be), 11.30- 11.10 (iii; be), 9.20-9.10 (2H, 7.80 (11, 7.60- 7.30 (6H, MS ME 4 409.1.

Eamle 2[ I2- (2-Chioro-phenyl) -pyrido [3,4-dIpyrimidin- 4-ylJ-(1H-indazol-3-yl)-amine (11-217): Prepared from 4lChloro-2- (2-chloro-phenyl) -pyrido[3,4-d pyriidine (100 mg, 0.36mmol) and 1H-indazol-3-ylamine (88mg, 0.66mmol) Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (72 ig, 33W yield).

HPLC-Method A, aRt 3.21 mii; AR NMR (DMSO, 500 MHz): 8 12.95 (1H, 10.90 (1H, bs), 9.25 (IN, 8.75 (iH, 8.55 (iH, 7.65 (iH, 7.55 (lE, 7.50-7.30 7.00(H, MS E 373.1.

Exarle 213 12- (2-Chioro-phenyl) -pyrido[3, 4-d]pyrimidun- 4-yll]-(7-fluoro-2R-indazol-3-yl)-amine (11-2i8): Prepared from 4-Chloro-2-(2-chloro-phenyl) -pyrido [3,4-dlpyrimidine (100 mg, 0.36mmoi) and 7-Fluoro-lI-indazoi-3-yiamine (108mg, 0.72mmol). Purification by preparative HPLC.

afforded the title compound as a yellow, di-TFA salt (48.7 mg, .22% yield). .HPLC-Method A, Rt 3.35 min; 1 H NMR (DMSO, 500 MHz): 8 12.95 (lE, 10.90 (1H, 9.25 (iN, 8.75 (iN, 8.55 (lE, 7.70-7.35 (5H, i), 7.25(1H, 6.95 (ii, MS MH+ 391.08.

ExAMpg 224 [2-(2-Chloro-phenyl )-pyrido[3,4-djpyrimidin- 4-yl]- (5-fluoro-1Hf-indazol-3-yl)-amine (11-219): Prepared from 4-chloro-2-(2-chloro-s-fluoro-ur-inazo-3-ylinine (108mg, 0.72mnmol). Purification by preparative HPLC.

afforded the title compound as a yellow, di-TFA salt 286 IND (57.2 mg, 26W yield) HPLO-Method A, Rt 3.27 mhin; 1 H NMR o (DM80, 500 IMHz): 13.05 (111, 10.95 (lE, 9.25 Cl (Ui, 8.75 (XE, in), 8.55 (in, in)' 7.60 (YE, Mn), 7.55 ct (il, ifi), 7.50-7.30 (Sn, Mn), 7.25(iH, mn); MS MHW 391.1.

Exall 25[2- (2-Chioro-phenyl) -pyrido pyrimidin- 4-yl (S, 7 -difluoro-1H-indazol-3-y)...mine (11-220): Prepared fr6in 4-chloro-2- (2-chloro-7-difluoro-in'-indazo>- Cl 10 3-ylainine C112mg, 0.G66miol). Purif'ication by preparative Cl HPLC afforded the title compoiund as a yellow, di-TFA salt Va(57.2 mg, 26%- yield) HPLC-Method A, Rt 3.45 mhin; 1H NMR 500 MHz): 513.65 (iH, s) 11. 0 (in, -9.25 (in, 8.80 (iN, in), 8.50 7.60 (In, mn), 7.55 (iN, mn), 7.50-7.3 0 (SN, mn); MS (mix) M t 40.9. 1.

Rx&mnJgt21i 6 -Fluoro-1H-indazol-3-ylIamine (Al) 'HNMR (500 M4Hz, DMS0-aS) 511.4 IH), 7.68 (dd, iN), 6.95 (dd, IN) 6. 75 (td, 545 2H1) ppm; LC-MS (ES+) 15-2.03 HPLCSMethod A, Rt 2. 00 min.

Examie 217 'S-Pluoro-tH -indazol.-3-yiamine

'I'I

(500 MHz, DMSO-dS) 511.3 Cs, 1H), 7.423 12) 7.22 (m, iN), 7.08 iH), 5.29 la, 2H1) ppm; LC-MS (ESi) 152.01 HPLC-Me-thod A, Rt 1. 93 Thin.

S7 -Difiluoro-lH-indazo- -y..-amino 'HNMR (500 MHz, C 0D) 87.22 (dd, J=2.0, 8.45Hz, iN), 7.04-6.87 (in, 11); LC MkS 169. 95 (14+H1) HPLC-Metho. C, Rt 2.94 min Eaplet2l2.7-Fluoro-1H9-indazol-3-ylamine lfflQMR (5-00 MHz, DMSO-dE) 611.8 in), 7.42 1H), 6.97 (in, 111), ID 6.78 11), 5.40 21H) ppm;-LC4S 152.01 HPLC-Method A, R 2.00 min.

Example 22Q 7-Fluoro-6-trifluoromethyi-10-indazol-3ylsmine 'H-NMR (500 MHz, DM50) 512.5 1H),'7.75 In), 7.25 Cm, 1H), 5.85 1H) ppm; MS (FIA) 220.0 HPLC-Method A, Pt 2.899 min.

Examjle 221 6-Eromo-211-indazol-3-ylanne 'H-NMR (500 MHz, DMSO) 11.5 (sF 1H), 7.65 1H), 7.40 1), 7.00 1H), 5.45 (br a, 1H) ppm; MS.(FIA) 213.8 HLC-Method A, Rt 2.441 min.

ExangXe....222 4-Fluoro-1H-iudazol-3-yiamine 1

H-NMR

(500 MHz, DMSO) S 11.7,Cs, 11), 7.17 1H), 7.05 (d, 1H), 6.7 (br, 1H), 6.60 Cdd, 1H), 5.20 (bra, 21) ppm; MS (FIA) 152.0 Method A, Rt 2.256 min.

BamplJ 223 5-Eromo-2fI-indazoi-3-ylamine 'H-NMR (500 MHz, DMSO) 5 11.55 (br a, 11), 7.55 Cs, 11), 7.30 (d, 111), 7.20 111), 5.45 (br S, 2H) ppm; MS (FZA) 213.8 Method A, Rt 2.451 min.

Exai~e 224 5-Nitro-1 H-undazol-3-ylamine 'H-NMR (500 MHz, DMSO-d6) 8 9.00 Cs, 11), 8.20 11), 7.45 1H), 6.15 (br s, 1H-) ppm; Method A, Rt 2.1B4 min ExaLmp 22i 4-Pyrrol-1-yl-a-indazol-3-yaine

IH-

NMR (500 MHz, DMSO) 8 7.20 Cst21), 7.00 Cs, 2H), 6.75 111), 6.25 21), 4.30 Cd, 11) ppm; Method A, Rt 2.625 min.

IND Zaxt.226g 4-Chloro-5,6-dlmethyl-2- (2-trifluoromethylo phenyl)-pyrimidine Prepared to afford a colorless Cl oil in 75% yield. 1 H-N1R (500 MHz, CDC13) 8 7.70 (d, 3=7.8-Hz, lH), 7.64 3=7.6 Hz, iH), 7.55 J=7.6 Hz, S H11), 7.48 Js7.5 Hz, 2.54 3H), 2.36 Cs, 3H) ppm; MS CFIA) 287.0 HPLC-Method A, Rt 3.891 min.

ramale 222 4-Chloro-2- (2-chioro-phenyl) 6-dimethyl- IND pyrimidine CE2): Prepared to afford a yellow-orange oil in 71% yield. 1 H-NMR (500 MHz, CDC13) 8 7.73 111), 7.52 Cm,l 7.39 Cm, 2H), 2.66 Cs, 31), 2.45 Cs, 3M) INDppm; MS (FIA) 253.0 HPLC-Method A, Rt Rt 4.156 min.

Example 22i 4-Chloro-6-methyi-2-(2-trifluoromethyl- 1S phenyl)-pyrinidine Prepared to afford a pale yellow oil'in 68% yield. 'H-NMR (500 MHz, CDC13) 8 7.72 (d, J=7.8 Hz, iN), 7.65 Cd, J=7.9 Hz, 1H), 7.57 J=7.5 Hz, 11), 7.52 3=7.8 Hz, iN), 7.16 11), 2.54 3H) ppm, MS (PIA) 273.0 CM+H); HPLC-Method.A, R, 3.746 min.

Bxakple 222 4-Cbloro-6-cyclohexyl-2-(2-trifluoromethylphenyl)-pyrimidine Prepared to afford a yellowoil in 22% yield. 1 H-NMR (500 MHz, CDCI3) 8 7.70 2H), 7.57 Ct, J-7.5 Hz, IH), 7.50 Ct, J=7.5 Hz, IN), 7.19 (s, 11), 2.65 Cm, LM), 1.9 21), 1.8 Cm, 2H), 1.5 2H), 1.3 2H) 1.2 Cm, 2H) ppm; MS (FIA) 341.0 Exa2le. 4-Chloro-6-phenyl-2-(2-trifluoromethylphenyl)-pyrimidine (ES):-Prepared to afford'a yellow oil in 53% yield. 1 H-NMR (500 MHz, CDCl3) 8 8.08 (dd, 3=7.9, 1.6 Hz, 2H), 7.80 3=7.6 Hz, 1H), 7.77 Cd, J=7.8 Hz, IH), 7.67 Cs, 11), 7.61 Ct, J=7.5 Hz, IH), 7.54 3=7.6 Hz, 1H), 7.47 3H) ppm; MS (FIA) 335.0 CM+H); HPLC- Method A, Rt 4.393 min.

Rxamj&.231 4-Chloro-2- (2,4-dibloro-phenyl) -5,6dimethyl-pyriziddine Prepared to afford a white solid in 91% yield. 'H-4MR (500 MHz, CDC13) 8 7.62 (d, %7=8.3 Hz, lI), 7.43 J-7.0 Hz, 1H), 7.27 (dd, J=8.3, Hz, 1H), 2.55 3H), 2.35 3H) ppm; MS (PtA) 287, 289 HPLC-Method A, Rt 4.140 min.

oxanmle aJ2f 4-Chloro-6- (2-chioro-phenyl) IND triflucromeehyl-phenyl) -pyrimidine Prepared to 8 affod a yellow oil in.52%cyield. 'H-NMR (500 1Hz, CDC13) 8 7.75'(m, 31), 7.65 2H), 7.53 11), 7.44 Cm, 1H), 7.36 2H) ppm; MS (FIA) 359.1 HPLC-Method A, Rt 4.426 min.

£xample 233 4-Chloro-6-(2-fluoro-phenyl)-2-(2trifluoromethyl-phenyl) -pyrimidine Prepared to afford a yellow oil in 95t yield. 'H-NMR j500 MHz, CDC13) 8 8.24 J=7.9 -Hz, IN), 7.84 iH), 7.78 J=7.7 Hz, iH),-7.76 Cd, J=80 Hz, 1H), 7.60 Ct, J=7.5 Hz, 1H), 7.53 J=7.6 Hz, 11), 7.43 11), 7.23 J=7.6 Hz, 1H), 7.13 1H) ppm; MS (FA) 353-0 CM+H).

carmle 234 4-Chloro-6-pyridin-2-yl-2- (2-trifluoroiethylphenyl) -pyrimidine Prepared to afford a pale yellow solid in 50% yield' 1H-NMR (500 MHz, CDC13) 8 8.68 (m, 11), 8.48 Cdd, J=7.9,.0.8 Hz, IH), 8.38 Cd,'3=2.3 Hz, iR), 7.84 3H), 7.62 J=7.6 Hz,l1iR, 7.55 J=7.6 Hz, 1H), 7.38 1H) ppm; MS (FIA) 336.0 CM+H); HPLC- Method A, Rt 4.575 min.

290 IND ka~t..235 6-Eanzyl-4-ohloro-2- (2-trifluoromethyl- S phenyl -SI 6 7 ,B-tetrahydro-pyrdo[4,3-lpyrimin±e (ala): Cl 'HNMR (500 MHz, CDC1,) 87..70 7.62 n1), 7.55 Ct t, 111), 7.46 111), 7.32 4H1), 7.25 (Mn, 111), 3.74 Cs, 211), 3.66 2H1), 2.99 Ct, 2H1), 2.80 Ct, 2H1) ppm; LQAS 404. 17 HPLC-Methcd A, Rt 3. 18 main.

gx~e 3 7-Eenzyl-4-chloro-2-(2-trifluoromethy.- INDphenyl) 5 6 ,?;G-tetrahydro-pyridoc3,4-czjpyrimiajn 0 (B11): 'KNMR (500 M4Hz, CDC 3 87.69 111), 7.60 111), 7.54 c-I 11), 7.47 11R), 7.28 411), 7.20 Cm, 111), 3.68 IN (s 2H1), 3.67,(s, 211), 2.86 Ct, 211), 2.79 211) ppm. Ms o CES+) 404.18 RPLC-Method A, Rt 3.12 muin.' lbumle2n2 4-Chloro-2- C4-fluoro-2- trifluromethy..

phenyl)-q inazoline (312): 'HNMR (50014Hz, CD 3 0D) 58.43 J=8.1Hz, 111), 8.20-8.05 211), 8.05-7.82 C,2H1), 7.71-7.51 Cm, 2H1). LC-MS 327.09 CM+11). HPLC-Method Rt 4. 56 mini.

Exml 3 4-Cbhloro-2- thenyl)-qu.nazoline (313): LC-MS 342.97 (14+1).

HPLC-Method D, Rt 4.91 muin.

£xarapi 2zf 4 -Chloro-2-(2-chloro-4-nitro-paenyl).

quinazoline (314): LC-MS (ES+i) 319.98 HPLC-Method Rt 4.45 muin.

ExpJ&le2t 4-Chloro-2-. (2 -trifluorometyl-penyl) qunazoline Prepared in 57% yield. W~hite Bolid.

NMiR (50014Hz, DMSO-dE) 5 7.79 Ct, 111), 7.86 Ct, 111), 7.94.

311), 8.15 Cdd, 1H1), 8.20 Ctd, 111), 8'.37 El- MS 308.9 (M4).

.291 Va 0 EExaple241 4-Chloro-2-(2-trifluoromethyl-phenyl)-6,7dihydro- 5H-cyclopentapyrimidine (316): Prepared in 22% yield. HNMR (SOOMHz, DHSO-d6) 8 2.19 3.01 (t, 2H), 3.08 2H), 7.49 1H), 7.55 IH), 7.62 (d, IN), 7.71 Cd, 1H). El-MS 299.0 E=mple.242 4-Chloro-2-(22-chloro-phenyl)-6,7,8,9- Va tetrahydro- 5H-cycloheptapyrimidine (317): Prepared according to Method C in 82% yield to afford a white 0 solid. 'HNMR (50MHz, CDC1 3 8 1.67 (m 4HB 1.87 (m 2H), 3.02 m 4) 7.28 Cm, 2H), 7.40 m, 7.65 i); E-MS 293.0 -Example 243 4-Chloro-2-(2.-trifluoramethyl-phenyl) 5,6,7,8,9,1D-hexahydro-cyclooctapyrimidine (B18): Prepared in 38% yield to afford a brown oil. 1

HNMR

(SOOMHz, CDC1 3 8 1.35 (m 2H), 1.41 (m 2H), 1.76 (m 4H), 2.96 Cm, 7.48 Ct, 1H), 7.56 1H),.7.66 Cd, IH), 7.70 IN); El-MS 341.0 Exame 2sA 4-Chloro-8-methoxy-2- (2-trifluoromethylphenyl)-quinazoline (B19): Prepared from 8-methoxy-2-C2trifluoromethyl-phenyl)-3H-qiinazolun-4-one 0g, 3.12mmol), triethylemine hydrochloride (472mg, 3.43mmol), and POC1 3 Purification by flash chromatography afforded a white solid (89% yield). HPLC-Method A, Rt 4.10 min, MS (mlz) 258.08 EampJe 2i5 (4-Chioro-qninazolin-2-yl) -benzonitrile Prepared to afford a yellow solid in 1.5% yield.

'H-NMR (500 MHz, CDC13) 8 8.47 1H), 8.24 1M), 8.16 IH), 8.07 (impurity), 7.94 Ct, iN), 7.92 (impurity), IND7.86 1H), 7.68 2H), 7.65 (impurity), 7.54 o (impurity), 7.49 111), 4.2 (impurity), 1.05 (impurity) ppm; MS (LC/MS) 266.05 HPLC-Method A, Rt 3.88 min.

Enin-le.24i 6-Methyl-2-( 2 -trifluoromethyl-phenyl) -3Mpyrimidin-4-one Prepared to afford a yellow Bolid in 50% yield. 'H-NMR (500 MHz, DMSO-d) 8 12.7 (br s, in), 7.9 1H), 7.8 2H), 7.7 1H), 6.3 IH), IN 2.21 3H) ppm; MS (FTA) 255.0 HPLC-Method A, Rt l1 2.578 min.

IND Exale 247 6-Cyolohexyl-2 (2 -trifluoroietbyl-phenyl) -3Mpyrimidin-4-one Prepared to afford an off-white solid in 54% yield. H-NMR (500 MHz, DMSO-d) 8 12.9 (br s, 1H), 7.9 4H), 6.3 1H), 2.5 1H), 1.9 (Im,.

511), 1.4 511) ppm; MS (FIA) 323.1 HPLC-Method A, Rt 3.842 min.

amPle 248 2-(2-Chloro-5-trifluoromethyl-phenyl) -311qainazoli-4-one (D10) 'HIMR (5001Hz, OD 3 OD) B 8.'32-8.25 1H), 8.01 IM), 7.91-7.72 1H), 7.66-7.55 (in, 1H). LC-MS (ESt) 325.01'M+H). HPLC-Method D, Rt 3.29 min.

ExaPle 249 2-(4-Fluoro-2-trifluoromethy-phenyl)--3H quinazolin-4-one (D14): 'HNIR (5001Hz, CD 3 OD) 8 8.*28 (d, 1H), 7.94-7.84 IH), 7.84-7.77 11), 7.76- 7.67 (in, 2H), 7.65-7.53 2H). LC-MS (ESt) 309.06 HPLC-Method DPRt 2.88 min.

"Lxamnet250 2- (4-Nitro-2-choro-phenyl) -3H-quinazolin-4one (DtS): LC-MS 302.03 HPLC-Method D, Rt 2.81 min.

Va Exam e 251 2- (5-Fluoro-2-trifluormethyl-phenyl) Cl quinazolin-4-one' (D17): 1 HNMR (500MHz, CD 3 OD) 8 8.28 (d, Rt J=8.OSHz, IH), 7.96 (dd, J=5.05, 8.55Hz, 1H), 7.89 (t, J=7.9Hz,.1H), 7.78-7.69 7.66-7.46 3H). LC-MS 309.14 HPLC-Method D, Rt 2.90 min.

ExaiJe.252 (1H-Indazol-3-yl)- (2-phenyl-quinazolin-4-yl)- Va amine Prepared by Method A in DMF to afford mg (50% yield) as pale yellow solid. 1 H NMR (500 MHz, DMSO-d) 813.1 br, lH), 8.48 7.91 2H), IND7.76 (br, 2H), 7.45 2H), 7.36 1H), 7.20 4H), 6.86 Ct, lH) ppm. MS 338.07 336.11 (M- HPLC-Method'A, R 2.88 min.

Exaple 253 (5-Jethyl-2H-pyrazol-3-yl)- (2-phenyl-5,6,7,8tetrahydroqainazclin-4-yl)-ine (111-7): Prepared according to Method A. 1 H NMR (500 MHz, DMSOAd6) 812.1 br, 1H), 8.70 br, 1H), 8.37 J 6.7 Hz, 2H),' 7.54 Cm, 31), 6.67 1H),-2.82 21), 2.68 21), 2.37 1.90 br, 44); MS 306.1 Example 254 C5-Methyl-20-pyrazol-3-yl) (2-pheny1-6,7,8,9tetrahydro-5-cycloheptapyrimidin-4-yl)-amine (111-8): MS 320.48 CM+H); HPLC-Method E, Rt 1.124 min.

Fx&We 255 (5-Methyl-2H-pyrazol-3-yl)-(2-pyridin-4-ylquinazolin-4-yl)-amine (111-9): Yellow solid, mp 286- 289 0 C, 1H NMR (DMSO) 8 2.35 (3H, 6'.76 7.61 (1H, 7.89 (2H, 8.32 (2H, 8.70 (11, 8.78 (2H, 10.56 br 12.30 *br IR (solid) 1620, 1598, 1571, 1554, 1483, 1413, 1370, 1328; MS 303.2

CM+H)+

294 Va o aml-e-25 (7-Chloro-2-pyridln-4-yl-quinaolin-4-yl)-(5iethyl-23-pyrazol-3-yl)-azinme (111-28): 'H NMR (DMSO-dE) B 2.35 6.75 7.65 (1H, d)L.7.93 (1H, a, S 8.30 (2H, 8.73 (1H, 8.75 (2H, 10.69 (1H, a), 12.33 (1H, MS m/z 337.2 Eiinn2.t22. (6-CbJloro-2-pyridin-4-yl-quinazolin-4-y1)-(5methyl-2R-pyrazol-3-yl)-amine (111-29): 'H NMR (DMSO-d6) S 2.31 (3H, 6.74 7.89 (il, 8.30 (2H, d), 8.80 (2H, 8.91 (11, 10.63 (11; 12.29 (1H, s); MS 337.2'AM+H).

Examwle 25a (2-Cyclohexyl-quinazolin-4-yl)- (5-methyl-2Npyrazol-3-yl),-amine (111-30): 'H NMR (DMSO) 8 2.35 (3H, 1.70 (3H, 1.87 (2H, 1.99 (2H, 2.95 (1H, 6.72 (11, .7.75 (21, 7.88 (111, 7.96 (1, 8.83 (11, 11.95 12.70 (1N, MS 308.4 (M.iH) Examble 259 (S-Methyl-2H-pyrazol-3-yl) -(2-phenylquinazolin-4-yl)-aminie (111-31): np 246 0 C; 'H NMR (400MHz) a 2.35 (3H1, 6.70 br 7.51-7.57 14H, 7.83- 7.84 (2H, 8.47-8.50 (2H, 8.65 (11, 10.4 (11, 12.2 (114, ba); IR (solid) 3696, 3680, 2972, 2922, 2865; MS 302.1 BsamSle 260 [2-(4-lodophenyl)-quinazolin-4-yl]-(5 -methyl- 2H-pytazol-3-yl) -amine (111-32): 'H !MR (DMSO-dG) 8 2.34 (3H, 6.72 (11, 7.56 (11, 7.84(2, d),.7.93 8.23 (2H, dl, 8.65 (11, 10.44 (111, 12.24 (11, MS 428.5 Example 261 (3,4-Dichlorophenyl)-quinazolin-4-yl] \O methyl-25-pyrazol-3-yl)-anine (111-33): A suspension of Cl~ 2-(3,4-dichloro-phenyl)-3H-quinazolin-4-one (1g, 3.43 mmol) in phosphorus oxychloride (4 mL) was stirred at 110 0 C for 3 hours. The solvent was removed by evaporation and the residue is treated carefully with cold aqueous, saturated NaHCO 3 The resulting solid was collected by filtration and washed with ether to afford 4-chloro-2as a white solid (993 mg, To the above compound (400mg, 1.29 mmol) in o THF (30 mL) was added 3-amino-5-methyl pyrazole (396 mg, IND2.58 mmol) and the resulting mixture heated at 65 0

C

0overnight. The solvents were evaporated and the residue C triturated with ethyl acetate, filtered,rand washed. with the minimum amount of ethanol to afford compound III-33 as a white solid (311 mg mp 274 0 C; 1H NMR (DMSO) 6 2.34 (3H, 6.69 (1H, 7.60 7.84 (1H, d), 7.96 (2H, 8.39 (IH, dd), 8.60 (1H, 8.65 (1H, d), 10.51 12.30 (1H, IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5 Ea.ple 262 (4-Bromophenyl) -quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-amine (111-34): mp 262-265 0 C; 2H NMR (DMSO) 8 2.34 (35, 6.73 (11, 7.55 (IH, m), 7.74 (21, d),.7.83 (211, 8.40 (2H, 8.65 (1H, d), 10.44 (11, 12.25 (1H, IR*(solid) 1603, 1579, 1546, 1484, 1408, 1365; MS 380.1/382.1 Exmaple 263 [2-(4-Chlorophenyl)-quinazolin-4-yll-(5methyl-2H-pyrazol-3-yl)-amine (111-35): mp >300 0 C; 11 NMR (DMSO) 8 2.34 (3H, 6.74 7.53-7.62 (3H, m), 7.84 (2H, 8.47 (2H, 8.65 10.44 s), 12,26 (1H, IR (solid) 1628, 1608, 1594, 1546, 1499, 1408, 1369, 1169; MS 336.2 Exaule264 (3,5-Dichlorophenyl) -quinazolin-4-yl) methyl-20-pyrazol-3-yl)-amine (111-36): mp 228-C; 'H NMR (DMSO) 62.34 6.69 (11, 7.96 (1H, 8.21 (3H, 8.56 (11, 8.60 (2H, 10.51 (11, 12.30 (1H, IR (solid) 1546, 1331, 802, 763, 729, 658, 652; MS 370.5 o 2mx le 2 (4-Cyanophenyl) -quinazolin-4-yl]- IND methyl-2H-pyrazol-3-yl)-amine (111-37): mp 263 0 C; 2- NMR (DMSO) 8 2.34 (3H, 6.72 7.61 (1H, 7.88 (2H, 8.04 8.63 (21, d) 8.67 10.52 (1H, 22.27 (11, ZR (solid] 1739, 1436, 1366, .1229, 1217; MS 327.2 Exampe 2jS- [2-.(3-Iodopheny1) -quinazolin-4-Yl] (S-methyl- 2H-pyrazol-3-yl)-amne (111-38): np 234-23S-C; 'H NMR (DMSO) 8 2.35 (3H, 6.73 (11, 7.35 (11, 7.56 7.85 (3H, 8.47 (1H, 8.65 (1H, 8.86 10.49i(1H, 12.28 (1H, br ZR (solid) 1560, 1541, 1469, 1360; MS 428.1 Examrnle 2i2 (4-Etbylsulfanyiphenyl) -quinazolin-4-yl] (5-methy1-2H-pyrazo1-3-y1)-amin6 (111-39): np 229-231 0

C;

'H NMR (DMSO) 6 1.29 (31, 2.35 (3H, 3.07 (2H, q), 6.76 (11, 7.43 (2H, 7.51 (1H, 7.81 (2H, m), 8.41 8.64 (11, 10.38 H, 12.24 br IR (solid) 1587, 1574, 1555, 1531,- 1484, 1412, 1369; MS 362.1 297 NDEz it.e 2i (5-Cyclopropyl-2-pyazol-3-yl)- (2-phenylquinazolin-4-yl) -amine (111-40): nip 218-219 0 C; 'H NMR (DMSO-d6) 8 0.70-0.80(2, 0.90-1.00 (2H, 6.70 (11H, 7.45-7.55 (4H, 7.80-7.85 (2H, 8.45-8.55 (2H, in), 8.65 (111, 10.40 (11, 12.27 (11, IR (solid) 1624, 1605, 1591, 1572, 1561, 1533, 1479, 1439, '1419, 1361, 1327i 997, 828, 803, 780, 762, 710; MS 328.2 Example 2E2 [2-(4-tert -Butylphenyl) -quinazolin--yll (So met3hyl-2H-pyrazol-3-yl)-amine (111-41): ip >300 0 C; 2H NMR IND(DMSo-ds) 5 1.35 2.34 (3H, 6.79 e), 7.55 (3H, 7.85 (2H, 8.39 (2H1, 8.62 (11, d), 10.35 (114, 12.22 (111, IR (solid) 1603, 1599,.

'1577, 15611 1535, 1481, 1409, 1371, 1359, 998, 841, 825, 766, 757; MS 358.3 Lxian~1t.2270 (4-Chlorophenyl) cyclopropyl-2R-pyrazol-3-yl)-amine (111-42): 'H NMR (DMSOd6) 5 0.77 (4H, br m) ,2.05 (1H, 6.59 (1H, 7.60 (11, 7.-85 (2H, 7.91 (2H, 8.22 (2H, 8.65 (1H, 10.51 12.33 MS 362.1 2gmnjle 221 (2-BenzoEl,3dioxol-5-yl-quinazolin-4-yl)-(5methyl-2H-pyrazol-3-yl) -amine (111-43): 'H 1MR (DMSO) 2.33 6.13 6.78 (1Hs), 7.11 d), 7.80 (1H, 7.941111, 8.09 (3H, 8.25 d), 10.34 (11, 12.21 (11, MS 346.5 (M+H)H 8smle 272 (4-Dimethylaminophenyl)'-quinazolin-4-yJ- (5-rethyl-2H-pyrazol-3-yl) -amine (111-44): 1 NMR (DMSOd6) 8 2.02 (61, 2.39 (31, 6.83 (11, 7.71 (1H, 298 IDd), 7.98 (2H, 8,04 (2H, 8.33 (2H, 8.67 (1H, o 11.82 (15, 12.72 (15, MS 345.3 0 ExmoJeZ273 Jt2-(3-Methoxyphenyl) -quinazolin-4-yl] methyl-2H-pyrazol-3-yl) -amine (111-45): mp 226-C; 'H NMR (DMSO) 8.2.34 3.92 (3H, 6.72 (1I, 7.21 (1H, 7.57 (1I, 7.79 (15, 8.02 (3H, 8.14 8.79 (18, 10.39 12.22 (15, IR V (solid) 1599, 1572, 1538, 1478, 1427, 1359, 833, 761, 661; MS 332.2 0 ID Example 275 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4o dichlorophenyl)-quinazolin-4-yll-amine (1I1-46): 'H NMR (DMSO-d6) 8 0.86 (2H, 1.02 (2H, 1.69 (15, m), 6.56 (1M, 7.57 (15, 7.84 mn), 8.40 (1H, d), 8.58 (15, 8.64 (15, 10.53 (15, 12.36 (1H, a); MS 396.0 Example 276 (2-Biphenyl-4-yl-quinazoin-4-yl) 2H-pyrazol-3-yl)-amine (III-47):.To a mixture of bromo-penyl)-quinazolin-4-yll-(5-methyl-2H-pyrazol-3yi) -amine (111-34) (196 mg, 0.51 mmol) and phenyiboronic acid (75 mg, 0.62 mmol) in.THF:water 4 mL) was added Na 2

CO

3 (219.mg, 2.06 mmol), triphenylphosphine (9mg, 1/15 mol%). and palladium acetate (1 mg, 1:135-mol%). The resulting mixture was heated at 80 0 C overnight, the solvents were evaporated and the residue purified by flash chromatography (gradient of dichloromethane:MeOH) to afford III-21 as a yellow solid (99 mg, 5 NMR (DMSO) 8 2.37 (31, 6.82 (1H, 7.39-7.57 (4H, m), 7.73-7.87 (6H, 8.57 (2H, 8.67 (1I, 10.42 (1H, 12.27 (15, MS 378.2 299 r~C INDExase 222 .[2-(4-Ethynylphenyl)-quinazolin-4-yl]-(5o methyl-20-pyrazol-3-yl)-amine (111-48): To a mixture of (N [2-(4-bromo-phenyl) -quinazolin-4-yl]-( 5-methyl-2Hpyrazol-3-yl)-amine (111-34) (114 Mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, 1.5 mmol)in DMF (2 mL) was added Cul (1.1 mg, 1:50 molt), Pd(PPh) 2 C1 (4.2 mg, 1:50 mol%) and triethylamine (121 mg, 0.36 mmol). The resulting mixture was heated at 120 0 C overnight and the V solvent evaporated. _The residue was triturated in ethyl acetate and the resulting precipitate collected by o filtration. The collected solid was suspended in THF (3 IO mL) and TBAP (IM in THF, 1.leq) was added. The reaction 8 mixture was stirred at room- temperature for 2 hours and the solvent evaporated. The residue was purified by flash chromatography (silica gel, gradient of DCM:MeOH) to afford III-48 as a white solid (68 mg, 3

H-NMR

(DMSO) 6 2.34 (3H, 4.36 (iN, 6.74 (l1H, 7.55 (1H, 7.65 (2H, 7.84 (2H, 8.47 8.65 (IH, 10.43 (1H, 12.24 (1H, MS 326.1 xampe 278 (3-Ethynylphenyl) -quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-aine (I111-49): mp 204-207 0 C; IH NMR .(DMSO) 8 2.34 (3H, 4.28 (12, 6.74 (IH, 8), 7.55-7.63 (3H, 7.83-7.87 (2H, 8.49 (1H, 8.57 (1N, 8.65 (1H, 10.46 (1H, 12.27 (11, IR (solid).1598, 1574, 1541, 1489, 1474, 1422, 1365; MS 326.1 Example 279 [2-(3-Methylphenyl)-quinazolin-4-yl-(5methyl-2H-pyrazol-3-yl)-amine (III-50): A.suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POCl 3 mL, 644 mmol) and N,N-dimethylaniline (8mL, 63:1 mmol) was heated under reflux for 2 h. The excess POC1 3 was O0 removed in vacuo, the residue poured into ice, and the S resulting precipitate collected by filtration. The crude solid product 2,4-dichloro-quinazoline (6.5 g, 53% yield) Swas washed with water and dried under vacuum for next step use without further purification. To a solution of ^C the 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 mL) was added 5-methyl-1H-pyrazol- 3 -yl amine (3.2 g, 32.9 mmol)and the resulting mixture NO was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 4.0 g (93% NO yield) of (2-chloro-quinazolin-4-yl)-(5-methyl-1H- 0 pyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of the (2chloro-quinazolin-4-yl) (5-methyl-iH-pyrazol-3-yl) -amine mg, 0.19 mmol) in DMF (1.0 mL) was added m-tolyl boronic.acid (0.38'mmol), 2M Na 2

CO

3 (0.96 mmol), and trit-butylphosphine (0.19 mmol). The flask was flushed with nitrogen and the catalyst. PdCl 2 (dppf) (0.011 mmol) added in one portion. The reaction mixture was then heated at 0 C for 10 hours, cooled to room temperature, and poured into water (2 mL). The resulting precipitate was collected by filtration, washed with water, and purified by HPLC to afford III-50 as a pale yellow solid (61mg, 'H NMR (500 MHz, DMSO-d6) 812.3 (br s, 1H), 10.4 (br s, 1H), 8.75 1H), 8.30 1H), 8.25 1H), 7.78 2H), 7.55 1H), 7.45 1H), 7.35 1H), 6.80 1H), 2.47 3H), 2.30 MS 316.1 Example 280 [2-(3,5-Difluorophenyl)-quinazolin-4-yl]- miethyl-2H-pyrazol-3-yl)-amine (III-51): 1H NMR (500 MHz, DMSO-d6) 612.3 (br s, 1H), 10.8. (br-s, 1H), 8.63 1H), 301 IND7.95 Id, 7.85 Cm, 211), 7.58 It IH), 7.41 It, 1H), 8 6.59 1H), 2.27 3H); MS 338.1 1M+H).

ct En~le 281 C3-Chloro-4-fiuorophenyl).-quinazolin-4- S y1J- (S-methyl-2H-pyrazol-a -yl)-amine (111-52): 1H NR (500 MHz, DMSO-d) 812.4 (hr s, 1H), 10.8 (hr s, 11), 8.65 Id, 11), 8.50 Id, 111), 8.36 1H), 7.85 11), 7.60 (m, 1H), 6.62 Cs, 1H), 2.30 Is, 3H); KS 354.1 CM+H).

Va Exame 282 (5-Methyl-2H-pyrazoi-3-yl)--[2- (3trifluoromethyiphenyl) -quinazolin-4-ylJ -amine 31 oN NMR (500 MHz, DMSO-d.d) 812.2 (hr, 1H), 10.45(br, 11), 7.53 1H), 7.43 J 7.2 Hz, IF), 7.06 Id, J 8.2 Hz, im), 6.65 J 8.3 Hz, 1H), 6.57 It, J 7.6 Hz, IH), 6.51 j c 7.8 Hz, iH),.6.43 J 7.8 Hz, 1H), 6.32 It, J 7.6 Hz, 1H), 5.51 Cs, 11), 2.03 Cs, 31); MS 370.2 xminme 283 (3-Cyanophenyi) -quinazoiin-4-ylJ-15methyl-2H-pyrazcl-3-yl)-amine (111-54): "H NMR (500 MHz, DMSO-dE) 89.01 Is, 1H), 8.96 21), 8.28 Id, J 7.3 Hz, 111), 8.16 bt, 2H), 8.06 It, J 7.8 Hz, 1H), 7.88 Cm, 6.96 15 IH), 2.58 31); MS 327.1 Examle 284 (3-Isopropyiphenyl) -quirdazolin-4-yl]- methyl-2H-pyrazol-3-yl)-amine (111-55): 'H NMR (500 MHz, DMSO-d) 88.89 a.7 7.5 HZ, 111), 8.37 Cs, 8.26 Is, 1H), 8.08 2H), 7.81 It, br, .67 2H), 6.88 Cs, IX), 3.12 in), 2.40 3H), 1.38 Id, J 6.9 Hz, 6H); MS 344.2 xame 285 (5-flethyl-2E-pyrazol-3-yl) C2-pyridin-3-ylquinazolin-4-yl) -amine (111-56): 'H NMR (500 MHz, DMSO-d6) 302 IND89.50 lI), 8.84 J 7.3 Hz, 1H), 8.80 J 4.4 0 z, 1H), 8.66 J 8.2 Hz, lI), 7.87 7.77 (m, C lH) 7.60 J 2Hz, 1H), 6.67 Cs, iH), 2.28 (s, 3H); MS 303.1 C BX=IC 28 62- (3-Acetyiphenyl) -quinazolin-4-yi] methy3.-2H-pyrazol-3-yl)-amine (111-57): 1H NMR (500 M4Hz, DMSO-dE) 58.80 Cs, 1H), 8.55 Cd, J 7.7 Hz, 1H), 8'.42 IND J 7.6 Hz, 8.00 J 7.0 Hz, 11), 7.76 (m, 2H), 7.58 Ct, J 7.7 Hz, Ix), 7.48 br, lH), 6.60 (s, 2.49 3H), 2.03 3H); MS 344.1 CM+H).

o ELarnle 287 £2-(3,S-Ditrifluoromethylphenyl) -quinazolin- 4 -ylJ-(S-methyl-2-pyrazo-3-yl)-ami)±e (111-58): 'H NR is (500 MHz, DMSO-d) 810.7 br, 11), 8.95 2H),.8.63 Cd, J 8.2 Hz, 8.25 1H), 7.86 Cm,, 2H), 7.58 (t, J 6.9 Hz, IH),>6.62 11), 2.26 Cs, 3H); MS 438.1

CM+H).

Exmple 288 C3-Hydroxyiethylpheny) )-quinazolin-4-yl]- (S-methyl-2B-pyrazol-3-yl)-amne (111-59): 'H NMR (500 MHz, DMSO-d) 8 8.74 Cd, J 7.9 Hz, 1H), 8.33 Cs, 11W, 8.17 br, lI), 7.95 Cs, br, 1H), 7.89 br, 3-H), 7.62 Cm, 3H), 6.72 Cs, ix), 5.53 Cs, lI), 4.60 2H), 2.28 Cs, 3H); MS 332. 1 (M+H)j gxamle 23- (S-Methyl-2s-pyrazo-3-yl)- 12-(3phenoxyphenyl) -quinazolin-4-yll -amine (111-60): mp 231- 232CC; H NMR(DMSO-d6) 8 2.21 (3H, 6.59' (lI, a), 7.10-7.22 (4H, .7.41-7.45 (2H, 7.54-7.59 (21 i), 7.81 (2H, 8.09 (lH, 8.27 (IH, 8.64 (In, i), 10.40 (IH, 12.20 lm, (solid); ID (solid) 1589, 1560, 1541, 1536, 1484, 1360, 1227; MS 394.7 (M+H) 4 Va Eampale 2 (5-Cyclopropyl-2H-pyrazol-3-yl)- (3phenoxyphenyl) -quinazolin-4-yl]-amine (111-61): mp 193- 195 0 C; 3H NR (DMSO-d6) 8 0.67 (2H, 0.93 (22, i) ,1.87 S (lH,m) 6.56 (1H, el, 7.06-7.20 (4H, ml, 7.40-7.43 (2H, 7.55-7.59 (2H, 7.81 (2H, 8.11 (1H, 6.27 A12, 8.63 10.43'(11, 12.26 (12, s)b IR (solid); IR (solid) 1589, 1574, 1527, 1483, 1369, 1226; IN MS 420.7 Example 291 (5-Methyl-2R-pyrazol--yl) (2-thiophen-3-yl- INDquinazolin-4-yl) -amine (II1-62) r "H NMR (500 MHz, DMSO-d) 811.78 br, 1H), 8.75 J 8.1 Hz, 12), 8.68 (s, IH), 7.98 (dd, 7.5 Hz, 11), 7.89 2H), 7.831 1H), 7.68S J 7.5 Hz, 1H) 6.69 1H), 2.30 (s, 3H); MS 308.1 name .292 (2-Phenyl-qainazolin-4-yl) (2H-pyrazol-3-yi) amine (111-63): mp 247-249 0 C; 'H NMR (DMSO) 8 6.99 (12, br 7.49-7.58 (SH, 7.81 (1H, br 7.83 (22, m), 8.47-8.49 (2H, 8.66 10.54 (12, 12.59 (12, IR (solid) 3145, 2922, 1622, 1597; MS 288.2 Example 293 (2H-Pyrazol-3-yl)- (2-pyridin-4-yl-4juinazolin- 4-yl)-amine (I-64)l-np 285-286aC; 'H NMR (DMSO) S 6.-99 (11, br 7.65 (12, 7.81-7.94 (3H, 8.3-8.35 (2H, 8.73 8.84-8.90 (2H, 10.76 (12, a), 12.6 (1H, ZR (solid) 3180, 2972, 1600, 1574; MS 229.2 ExIanP2e 294 .5-Ethyl-ZR-pyrazol'-3-yl) (2-phenylquinazolin-4-yl) -amine (111-65): mp 221-222OC; NMR 304 ID (DMSO) 8 1.31 (3H, 2..68 (2H, 6.80 (1H, 7.50- 0 7.60 (4H, 8.45-8.55 (2H, 8.65-8.75 (1H, 10.44 12.27 IR (solid) 3190, 1622, 1595, 1575, 1533, 1482, 1441, 1420, 1403, 1361, 758, .711; MS 316.2

(M+H)

t Example 295 (2-Phenyl-quinazolin-4-yl)-(5-propyl-2Hpyrazol-3-yl)-amine (111-66): mp 204-205C; 1H NMR (DMSO- IN dE) 8 1.02 (3H, 1.66-1.75 (2H, 2.69 (2H, 6.80 (18H, 7.45-7.60 7.80-7.88 (2H, 8.45-8.50 ci (2H, 8.65 (1H, 10.39 (18, 12.25 (1H, IR

\O

(solid) 1621, 1560, 1572, 1533, 1479, 1441, 1421, 1363, S.1328, 999, 827, 808, 763, 709, 697; MS 330.2 Exaple 296 (5-Isopropyl-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (IXI-67): mp 218-219 0 C; 1H NMR (DMSO-d6) 8 1.36 (6H, 3.05 (11, 6.86 a), 7.48-7.59 (4H, 7.80-7.88 (2H, 8.49-8.58 (2H, m), 8.66 (1H, 10.47 (1H, 12.30 (1H, IR-(solid) 3173, 2968, 1619, 1593, 1573, 1533, 1478, 1438, 1413, 1398, 1363, 1329, 995, 822, 798, 761, 707, 666, 659; MS 330.2 Examele 297 (5-tert-Butyl-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-68): mp 136-137 0 C; I'H NMR (DMSO-d6) 8 1.38 (9H, 6.87 (11, br 7.51-7.57 (4H, 7.84-7:85 (2H, 8.49-8.51 (28, 8.65 (1H, d), 10.43 (1H, 12.21 (18, br IR (solid) 3162, 2963, 1621, 1590, 1572; MS 344.2(M+H) 4 Exaptle298 (5-tert-Butyl-2E-pyrazol-3-yl)-(2-pyridin-4yl-quinazolin-4-yl)-amine (111-69): tp >300C; 'H NMR (DMSO) 8 1.38 (9H, 6.82 (3M, br 7.63 (IH, m), 305 IND7.86-7.91 (2H, 8.32-8.33 (2H, d),8.69 (1H, d), o 8.75-8.76 (2H, 10.60 (1i, 12.31 (1H, br IR (solid) 3683, 3149, 2963, 1621; MS 345.2(M+H)+.

Example 299 (5-Cyclopentyl-2H-pyrazol-3-yl) -(2-phenylquinazolin-4-yl)-amine (111-70): mp 240-241-C; 1H NMR (DMso-d.6) 1.68-1.89 (6H, 2.03-2.17 (2H, '.14- 3.22 (1H, 6.80 (1H, 7.50-7.60 (4H, 7.80-7.89 IN (2H, 8.45-8.52 (2H, 8.67 (1H, 10.52 (1H, s), 12.26 (1H, IR (solid) 2957, 1621, 1591, 1571, 1531, 01476, 1438, 1405, 1370, 1325, 999, 951, 801, 775, 761, NO 747, 710695, 668, 654; MS 356.2(M+H)+.

Example 300 (5-Phenyl-25-pyrazol-3.3-yl)-(2-phenylquinazolin-4-yl) -amine (111-71): mrrp 207-209 0 C; 'H NMR (DMSO) 5 7.38-7.40 (11, 7.50-7.58 7.82-7.88 (4H, 8.51 (2H, 8.67 (1H, 10.58 13.11 br IR (solid) 3345,' 3108, 1627, 1612; MS 364.2 Exramnle 301 (5-Carboxy-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-72): (5-Methoxycarbonyl-2Hpyrazoi-3-yl)-(2-penyl-quinazolin-4-yl)-amine .(111-73) (345mg, 1 mmole in THF, 6 mL) was treated with NaOH (IM, 4.0 Lt), stirred at 50 0 C for 5 hours, cooled to room temperature, and neutralised with IM HC1. The mixture was concentrated in vacuo to remove THF then diluted with water and the resulting precipitate filtered. The residual solid was dried at 80 0 C under vacuum to afford 111-72 as an off-white solid (312 mg, mp 289-.291oC "H NMR (DMSO)'6 7.45 (1H, br 7.50-7.60 7.80-7.88 (21, 7.40-7.50 (2H, 8.60-8.70 (1H, 10.70 (11, 13.00-13.80 (2H, br IR (solid) IN 1699, 1624, 1607, 1570,1539, 1506, 1486, 1398, 1333, 0 o 1256, 1177, 1004, 827, 764, 705; MS 332.3(M+H)*.

c( SExample 3Q0 (5-Methoxycarbonyl-2f-pyrazol-3-yl)- (2phenyl-quinazolin-4-yl)-amine (III-73): mp 271-273oC; 1H NMR (DMSO)-. 3.95 (3H, 7.50-7.65 (5H, 7.80-7.98 (2H, 8.40-8.50 (2H, 8.65-8.73 (1H, 10.80 (1H, Ss), 13.80 (1H, IR (solid) 3359, 1720, 1624, 1597, I 1561, 1538, 1500, 1475, 1435, 1410, 1358, 1329,-1283, 10 1261, 1146, 1125, 1018, 1010, 944, 827, 806, 780, 763, N 703, 690, 670; MS 346.3(M+H).

\O

o Example 303 (5-Hydroxymethyl-2B-pyrazol-3-yl)- (2-phenylquinazolin-4-yl)-amine (III-74): A solution of Methoxycarbonyl-2H-pyrazol-3-yl) (2-phenyl-quinazolin-4yl)-amine (III-73) (345mg, Immol) in anhydrous THF was treated with lithium borohydride (125mg, 5.75 mmol) at 650C for 5 hours. The mixture was cooled to room temperature then combined.with 2M HC1 and ethyl acetate.

Solid sodium hydrogen carbonate was added to achieve pH.8 and the resulting mixture extracted with ethyl acetate.

The extracts were dried over magnesium sulphate and concentrated. Purification by flash chromatography (Sio 2 methanol-dichloromethane gradient) afforded III-74 mg, 30%) as an off-white solid: mp 238-2390C; 'H NMR (DMSO) 6 4.58 (2H, d, CH2), 5.35 (1H, s, OH), 6.94 (1H, 7.50-7.60 (4H, 7.85-7.90 (2H, 8.48-8.54 (2H, 8.69 (1H, 1H), 10.40 (1H, 12.48 (IH, IR (solid) 1652, 1621, 1603, 1575, 1558, 1539, .1532, 1480, 1373, 1320, 1276, 1175, 1057., 1037, 1007, 951, 865, 843, 793, 780, 7124; MS 318.2(M+H)+.

307 Examle 304 (5-Methoxymethyl-2H-pyrazol-3-yl) -(2-phenyl- Squinazolin-4-yl)-amine (111-75): mp i90-191OC; 'H NMR (DMSO) 8 3.34 (3H, 4.45 (2H, 7.00 (1H, 7.50- 7.62 (4H, 7.82-7.90 (2H, 8.45-8.52 (2H, 8.65 (1H, br 10.50 (11, 12.30 (1H, IR (solid) 3177, 1606, 1589, 1530, 1479, 1441, 1406, 1374, 1363, 1329, 1152, 1099, 999, .954, 834, 813, 766,. 707, 691; MS 332.3(M+H)

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Example 305 [5-(3-Hydroxyprop-1-yl)-2H-pyrazol-3-yl]-(2phenyl-quinazolin-4-yl)-amine (III-76): A solution of C) benzyloxypropyl-2H-pyrazol-3-yl) (2-phenyl-quinazolin-4yl)-amine (13I-78) (200mg, 0.46mmol)' in toluene (4mL) and acetonitrile (8mL) was stirred with trimethylsilyl iodide (0.64ml, 4.6mmol) at 55 0 C for 3 hours to afford an amber coloured solution. This mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate.. The resulting layers were separated, the organic layer was .dried over magnesium sulphate and concentrated in vacuo.

Purification by flash chromatography (Si0 2 methanoldichloromethane gradient) affords.a yellow oil (115mg).

Trituration with dichloromethane affords 111-76 as an off-white solid dried at 75 0 C under vacuum (83mg, mp 164-165OC; 'H NMR (DMSO) 6 1.80-1.90 (2H, 2.70-2.80 (2H, 3.50-3.60 (2H, 4.59 (1H, 6.80-(1H, s), 7.50-7.60 (4H, 7.82-7.90 (2H, 8.48-8.53 in), 8.63 (1H, 10.40 (1H, 12.25 (1H, IR (solid) 1622, 1587., 1574, 1562, 1528, 1480, 1440, 1421, 1368, 1329, 1173, 1052, 1030, 1006, 952, 833, 762, 734, 706, 690, 671, 665; MS 346.0(M+H)'.

Example 306 [5-(3-Methoxyprop-1-yl)-2-pyrazol-3-yll- (2phenyl-quinazolin-4-yl)-amine (III1-77): mp 169-170OC; 1H 308 '1! IN NMR (DMSO-d) 8 1.86-1.97 (2H, 2.75 (2H, 3.30 (3H1, 0 o 3.45 (2H, 6.80 (IH, 7.50-7.60 7.80- 7.90 (2H, 8.45-8.55 (2H, 8.67 10.30 (1H, 12.25 (1H, IR (solid) 1620, 1591, 1572, 1532, S 1476, 1425, 1408, 1373, 1326, 1117, 1003, 831, 764, 714, 695; MS 360.3(M+H).

Examptle 7 (3-Benzyloxyprop-1-yl)-2-pyrazol-3-yll IND(2-phenyl-quinazolin-4-yl)-amine (111-78): mp 177-178OC; H NMR (DMSO) 8 1.92-2.03 (2H, 3.76-3.85 (2H, m), 3.52-3.62.(2H, 4.51 (2H, 6.82 7.28-7.40

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7.46-7.'58 (4H, 7.80-7.-85 (2H, m, 8.47-8.52 (2H, 8.66 (1H, 10.45 (1H; IR (solid) 1621,.

1591, 1562, 1532, 1479, 1454, 1426, 1408, 1374, 1101, 1006, 835, 766, 738, 712, 696; MS 436.3(M+H)+.

ExanMple 308 (5-(3-Aminoprop-1-yl)-2H-pyrazol-3-yl]- (2phenyl-quinazolin-4-ylI-amine (111-79): A solution of (3-tert-butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-yl]- (2-phenyl-quinazolin-4-yl)-amine (111-80) (250mg, O.56mmol), in dichloromethane (3mL) at 0 0 c was treated with TFA (2mL). The mixture was warmed to room temperature then concentrated in vacuo. The residue was triturated and concentrated from dichloromethane and ether, then triturated with dichloromethane to crystallize the TFA salt. The resulting solid was collected by filtration and dissolved in a mixture of ethanol (3mL) and water (3mL). Potassium carbonate was added in portions to achieve pH 8 then the mixture allowed to crystallize. The product was collected by filtration and dried at 80OC under vacuum to afford III-79 as an off-white powder (122mg, mp 205-2070C; 18 NMR (DMSO) 8 1.68-1.83 (2H, 2.65-2.80( 4H, 6.80 (1H, INa), 7.50-7.60 (4H, 7.80-7.90 (21, in), 8.45-8.53 (2H,.

o 8.65 (1H, 10.45 (1H, br IR (solid) 1621, 1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 951, 830,' -776, 764, 705, 677; MS 345.3(M+H).

Examle 309 [5-(3-tert-Butoxycarbonylaminopropo-1-yl)-25pyrazol-3-yl ]-(2-phenyl-quinazolin-4-yl) -amine (111-80): mp 199-100.; EH NMR (DMSO) 8 1.37 1.71-1.82 IN 2.67 (2H, 3.00-3.11 (2W, 7.81 (1W, a), 7,99 (1W, 7.50-7.60 (4H, 7.80-7.85 (2H, 8.48- 8.52 (2H, 8.63 (1H, 10.40 (1W, 12.26 (LH, m); N DIR (solid) 2953, 1687, 1622, 1594, 1573, 1535, 1481, o 1441, 1419, 1364, 1327, 1281, 1252, 1166, 1070, 1028, 998, 951, 848, 807, 768, 740, 728, 710,693; MS 445.3 Examnle 31Q 5-Isopropylcarbamoyl-2H-pyrazol-3-yl) (2phenyl-quinazolin-4-yl)-amine (311-81): IH NMR (500MHz, DMSO-d6) 8 1.20 J 6.6 Hz, 6H), 4.13 11), 7.42 (br. a, 1H), 7.61 (dd, 7.0, 7.7 Hz, 2H), 7.66 J 7.1 Hz,. IH), 7.71 7.99 2H), 8.39.(m, 1H), 8.42 J n 7.1 Hz, 2H), 8.74 J 8.2 Hz, 1H), 11.41 (br. s, 1H); EI-MS 373.2 HPLC-Method C, Rt 14.09 min.

Exampe 311 (5-Allylcarbamoyl-20-pyrazol-3-yl) (2-phenylquinazolin-4-yl)-amine (III-82): 1 H NMR (500MHz, DMSO-d6) 8 4.02 2H), 5.15 5.23 ZW), 5.94 1H), 7.45 br;. s, 1H), 7.60 J 6.9 Hz, 2H), 7.64 i), 7.72 1H), 7.98 2H), 8.43 (m 2H), 8.72 J 8-.2 Hz, IH), 8.84 (br. a, 1H), 11.34 (br. s, 1H); EI-MS 371.2 HPLC-Method C, Rt 13.67 min.

310 INxDntle (2-Kethoxyethylcarbambyl) -2R-pyrazol-3yll (2-phenyl-quinazolin-4-yl) -amine (111-83) 'H NMR (500Mz, DMSO-d6l 6 3.32 Ce, 3.48 Cm, 4H), 7.36 (Br.

a, 1H), 7.62 Cm, 2R), 7.63 1H), 7.71 14), 7.98.

2H), 8.41 (dd, 1.4, 7.0, 2H), 8.70 2K), 11.30 (br. a, IH); El-MS 389.2 HPLC-Method c, at 12.37 min.

Ep 313 (5 -Eenzylcarbamoyl-2R-pyrazol-3 phenal-qunazolin-4-yl)-amine (111-84): 'H NMR DMSO-d) 8 4.52 Cd, J 6.0 Hz, 2H), 7.29 7.38 Cl Id, J 4.2 Hz, 4H), 7.58 Ct, J 7.5 Hz, 2H), 7.63 (m, o 1K), 7.72 1H), 7.98 2H), 8.43 T 7.7 Hz, 2H), 8.72 Cd. 3 7.5 Hz, 1H), 9.23 (br. a, 2H), 11.34 (Br. s, 1H); El-MS 421.2 HPLC-Method C, Rt 16.76 min.

flamntj 31g (5-Cyclohexylaarbamoyl-23-pyrazol-3-yl)-(2phenyl-quinazolin-4-yl)-amine (111-85): 'H NMR (500MHz, DMSO-d) 6 1. 16 1H), 1.34 4H), 1.62 J 2.6 Hz, 1K), 1.76 2H). 1.85 Cm,'2H), 3.79 1H), 7.43 Cm,lH), 7.60 J 7.2 Hz, 2H), 7.65 Ct, J 7.1 Hz, 1K), 7.71 (ddd, J 2.2, 5.4, 8.2 Hz, 1K), 7.98 2H), 8.35 Cm, IH), 8.43 (dd, J 1.4, 7.2 Hz, 2H), 8.72 J 8.2 Hz, 1K), 11.34 (br. a, 1K); EI-MS 413.5 HPLC-Method c, Rt 17.18 Tin.

Example 315 (5-Diethylcarbamoyl-2R-pyrazol-3-yl) phenyl-qninazolin-4-y)-amine (111-86): 'K NR DMSO-dE) 6 1.18 (Br. a, 3H), 1.25 s, 3H), 3.49 (Br.

3.69 a, 2H), 7.2i Cs, 1K), 7.59 Ct, J- 6.9 Hz, 2H), 7.62 1H), 7.70 1H), 7.96 Cm, 2H),.8.39 Id, J 7.1 Hz, 2H), 8.74 J 8.4 Hz, 1H), 11.37 Cbr.

No S, 1H); El-MS 387.2 HPLC-Metbod C, Rt. 14.50 min.

Bxamle 316 t5- {Eenzyl-methyl-carbamoyl) -2R-pyrazol-3yl]-(2-phenyl-quinazolin-4-y1)-amine (111-87): 1H NMR (500MHz, DMSO-d) 8 3.33 3M), 4.75 2H), 7.26 (m, 1H), 7.31 1H), 7.38 Cm, 4H), 7.58 2H), 7i70 (m, 1H), 7.95 31), 8.26 Cm, 1H), 840 J 7.8 Hz, 2H), 8.75 iH), 11.2 Cbr. a, 1H) El-MS 435.2 HPLC-Method C, Rt 16.77 min.

a Es le S_2 Phenyl-qainazolin-4 -yl) propylcarbamoyl-2H-pyrazol-3-yl) -amine (111-88): H NNR (500MHz, DMSO-d6) 8 0.94 J 7.3 Hz, 3H), 1.57 (m, 3.24 3 6.5 Hz, 2H), 7.39 (br. s, 7.60 Ct, J 7.3 Hz, 2HY, 7.64 im, 11), 7.71 (br. t, 3 6.5 Hz, 11), 7.98 2H), 8.42 J 7.2 Hz, 2H), 8.61 (br. a, 1H), 8.72 J 8.5 Hz, 1H), 11.34 (br. s, iH); El-MS 373.3 HPLC-Method C, R, 13.51 min.

S31- (Ethyl- isoprcpyl-carbaioyl) -2R-pyrazol-3 yl] (2-phenyl-quinazolin-4-yl) -amine (111-89): 'H NM (500MHz, DMSO-d) 8 0.92 J 7.4 Hz, 6H), 1.52 2H), 1.59 3.79 2H), 7.53 Cbr. a, iN), 7.57 J 7.5 Hz, 2H), 7.65 J 7.2 Hz, 1H), 7.71 (m, 1H), 7.99- 210, 8.23 (br. d, J 8.8 Hz, 1H), 8.46 (d, 3 7.5 Hz, 2H), 8.74 J 8.4 Hz, 1H), 11.34 (br. s, 1N); El-MS 4.01.2 HPLC-Method C, Rt 15.51 win.

Example 31 (5-Cyclopropylcarbamoyl-2H-pyrazol-3-yl) (2phenyl-qainazolin-4-yl)-amine (111-90): 1H NMR (500MHz, DMSO-d6)8& 0.60 2H), 0.74 2H), 2.86 1H), 7.34 (br. a, Ii), 7.62 Cm, 3H), 7.70 lkD, 7.97 2H), IND 8.41 J 7.9 Hr, 2H), 8.63 (br. a, iH), 8.72 J m 7.8 Hz, 1H), 11.35.(br. s, 12); RI-MS 371.2 HPC- Method C, Rt 12.64 min.

Rxamle'32Q (5-aobutylcarbamoyl-2W-pyrazol-3-yl) phenyl-quinazoln-4-yl)-amine (111-91): '2 NM R (SOOMHz, DMSO-d) 6 0.94 J 6.7 Hz, 1.88 1H), 3.12 J 6.4 Hz, 2H), 7.45 (br. s, 12), 7.58 Ct, J 7.2 IND Hz, 3H), 7.64 J 7.1 Hz, 1H), 7.71 7.98 (m, 22), 8.44 (dd, J 7 1,3, 7.9 Hz, 22), 8.62 (br. a, 1H), 8.72 J 8.3 Hz, 1H), 11.33 (br. a, El-MS 387.2 HPLC-Method C, Rt 14.10 min.

amle 3,21 S- -3-Methoxymethyl-pyrrolidine-1carbonyl -2H-pyrazol-3-yl}- (2-phenyl-quinazoiin-4-yl)amine (111-93): 1H NMR (5OMHz, DMSO-d6) 6 2.00 Cm, 2H), 2.12 12), 3.29 32), 3.45. J 8.7 Hz, is), 3.57 (dd, J 9.3 Hz, 12), 3.86 12), 3.92 (m, 12), 4.36 22), 7.45 (br. a, 1H), 7.59 J Hz, 22), 7.63 12), 7.69 12), 7.97 2H), 8.40 J 7.5 Hz, 22), 8.74 J 7.6 Hz, lB), 11.38 (br. a, 12); El-MS 429.2 (M+H;-HPLC-Method C, Rt 13.84 min.

pxale 322 (2-Phenyl-quinazclin-4-yl) -CS-mtolylcaarbamoyl-2E-pyrazol-3-yl)-aine (111-94): IH NMR (500MHz, DMSO-d6) 6 2.33 3H), 6.97 J 7.5 Hz, 12), 7.27 J 7.8 Hz, 1H), 7.62 72), 7.72 (m, 1H), 7.98 2H), 8.46 (dd, J 2.0, 7.9 Hi, 2H), 8.771 12), 10.29 Cs, 1H), 11.31 (br. S, 1H); El-MS 421.2 HPLC-Method C, Rt 17.11 min.

Eample 323 (2-Phenyl-quinazolin-4-yl)- tolylcarbamoyl-2H-pyrazol-3-yl)-amine (111-95): 'H NMR IND (500OMHz, DMSO-dS) 82.30 Cs, 3H).7.20 J 8.3 z' o 211), 7.62 Sn), 7.68 J 8.3 Hz, 2H), 7.72 (m, Cl 1H), 7.98 2H), 8.46 (dd, J 1.8, 7.0 Hz, 2H), 8.72 1H), 10.31 12), 11.36 (br. a, 12); El-MS 421.2 S HPLC-Method C, Rt 16.95 min.

ExWz1le 324 (5-Methylcarbamoyl-20-pyrazol-3 (2phenyl-quinazolin-4-yl)-amine (111-96): 2 H NMR -(SOMHz, DMSO-d6) 8 2.82 J 4.6 Hz, 3H), 7.31 (br. s, iH), 7.62 3H), 7.69 1H), 7.97 2H), 8.42 J 7.1 Hz, 22), 8:59 (br. a, 1H), 8.71- d, J 8.0 Hz, 1H), IND 11.30 (br. s, 1H); El-MS 345.1 HPLC-Method C, Rt 11.02 min.

Example 325 (lorpholine-4-carbonyl) -2H-pyrazol-3-yl]- (2-phenyl-quiriasolun-4-yl)-amine (111-97): 'H bMt (501MHz, DMSO-d) 3.33 Cm, 42), 3.83 (m 4H), 7.34 (Br. a, 12), 7.53' m, 41), 7.86 Cm, 2H), 8.43 Cm, 2H), 8.67 Cd, J= 8.6 Hz, 10.70 j(s, 13.56 1H); El-MS 401.2 HPLC-Metaod A, Rt 2.68 min.

Example 326 (1-Methylpiperazine-4-carbonyl)-2Hpyrazol-3-yl] -(2-phenyl-quinazolin-4-yl) -amine (111-98): 'H NR (5004Hz, DMSO-d) 8 2.25 3H), 2.43 C(m, 4H), 3.87 (m 4H), 7.33 (Br. a, 12), 7.53 41), 7.87 Cm, 8.45 2H), 8.67 J 7.6 Hz, 111), 10.70 1H), 13.30 12); El-MS 414.2 (M+H);HPLC-Metbod A, Rt 2.38 min.

Exarp2le 32. 15-(2-Hydroxyethylcarbanoyl-2R-pyrazcl-3-yl)- (2 phenyl-quinazolin-4-yl)-amine 'H NMR CSOOMHz, DMSO-d) 6 3.36 211), 3.52 2H), 4'79 7.50 Cm, SH), 7.83 Cm, 2H), 8.50 10.52 Cbr. a, 12), 13.25 1H); El-MS 375.1 HPLC-Method A, Rt 2.51 o min.

Cg Bfle 328 (5-Carbamoyl-20-pyrasol-3-yl)- (2-phenylquinazolin-4-yl)-amine (111-100): To a-solution of 5-(2phenyl-quinazolin-4 -ylamino) -1H-pyrazole-3 -caboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (270 mg, 0.63 mnol) in DMF (20 ml) was added a solution of ammonia in 1,4- IND dioxane (0.5 M, 10 ml). The resulting mixture was stirred at room temperatuie for 24 h. After o concettration of the solvents, the residue was added to' INDwater (20 ml). The resulting .precipitate was collected to afford II-100 (168 mg, 80%) as a yellow solid. 1H NMR DMSO-dG) 8 7.77-7.51 6R), 7.86-(br s, 2H).

8.11 12), 8.50 2H), 8.63 12), 10.52 IN), 1125 El-MS 331.1 RPLC-Method'A, Rt 2.52' min.

Enamplt-f29 (4-Dromo-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amne (II-101): Prepared according to Method A to afford a yellow solid, mp 189CC; '1H NMR (DMSOdE) 8 7.44-7.46 (32, 7.58 (12, 7.87 (2H, 8.15 (lI, 8.31-8.34 (2H, 8.49 (12, 10.08 (12, S), 13.13 IR (solid) 3286, 2969, 1738, 1632; MS 366.2/368.2(M+H) Exapl 330 4 -Eromo-5-methyl-2H-pyrazol-3-yl)-(2-phenylqiinazolin-4-yl) -aimine (111-102): mp 183-185-C; 1H NMR (DMSO) 8 2.33 32, br 7.44-7.46 (3H, in), 7.57 (1H, 7.84-7.8. (2H, 8.31-8.34 (2H, 8.48 (1H, d), 10;05 12.91 <12, br IR (solid) 3362,..3065, 2831, 1619, 1578; MS 38Q.2/3B2.2(M+H)+.

315 IND gaMn2-t.331 {4-Cyano-2H-pyrazol-3-yl) (2 -phenylo quinazolin-4-yl)-amine (111-103): mp >250CC; 11i NM (D?4SD) Cl 5~ 7.47-7.49 (3H1, mn), 7.64 (1H1, mn), 7.91 (2H1, in), 8.40ct8.43 (211, 8.53 (11, 2.71 (111, 10.61 (11, s), 13.60 (11, IR (solid) 3277, 3069, 2855, 2231, 1 625; MS 3 13. 2(M+1) t Exinp2.t3iZ (5-ZMethyl-2H-pyrazol-3-yl) -(2-morpbolin-4-ylquinazolin-4-yI) -amine (111-104): mp 223-224 0 C; 111i NMR ADMSoY' 8 2.26(311, 3..65(4H1, in), 3.75(4H, in), 6.44(11, 0 ~7.12(111, 7.33(111, 7.56(111, 8.37(111, d), 10.1(11,s), 12.13(111, br Ill (solid) 1621, 1578, o 1537, 1475, 1434, 1385; MS 311.0 (M+EP*.

-Exianple-3af (5-Methyl-ZH-pyrazol-3-yl) -(2-piperazin-1-ylqainazolin-4-yl) -nine (111-105): mp 179-181 0 C; 11H IMR (DMSO) 8 2. 2 6(31, s) 2.-74 (4H1, br s) 3. 71(41, br s) 6.43(111, 7.08(111, 7.30(111, 7.53(111, 8.34(111, 9.50(111, 12.08(111, br. IR (solid) 2853, 1619, 1.603, 1566, 1549, 1539; MS 310.0 (M+1i)+ Examnlt.334i 2- (4-Methylpiperidin-1-yl) -guinazolin-4-ylJ (5-methyl-2H-pyrazol-3-yl) -amine (111-106): nip 148-1500C; NHIUR (DM50) 8 1.06(3H1, 1.03(2H' inm), 1.51-1.70(3H1, in), 2.26(3H, 2.86(21, 4.73(2H,.d), 6..44(1H, S), 7.06(111, 7.29(111, 7.52(111, 8.32(111, d), '9.92(111, 12.09(111, br IR (solid) '2917, .2840, 1629, 1593, 1562, 1546, 1486; MS 323.0 4.

Exam~ 12(-Methylpiperazin-1-yl)-qiaoiin-4-yl] (5-methyl-2H-pyraLzol-3-yl) -amnine (111-107): mp 105-107WC; 'H 1Thfl (DMS0) 8 2. 21 (3H, 2. 2 6(3H, 2. 3 4(4 H, in), 3.75(41, in), 6.45(111, 7.09(111, 7.31(111, d), .316 IN 7.54(12, 8.34(1H, 9.96(1H, 12.12(12, br s); S IR (solid) 2934, 2844, 2804, 1620, 1593, 1572, 1536, 1476; MS 324.0 &c 3 5ityl2-Przl3y)-2pprdn1y1 quinazolin-4-yl)-amine (I11-108): mp 2.94C; NM (DMSO) 6 1.45-1.58 (4H, 1.63 (2H, 2.26 (MH, 3.79 (4H, 6.45 (1H, br 7.06 (1I 7.29- (1H, d), 7.52 (1H, 8.33 (1H, 9.92 (1H, 12.11 (1H, br IR (solid) 2929, 2847, 1632, 1591, 1500, 1482, 1437, 0 1382; MS 309.3

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o Example 337 (2-Azepan-1-yl) -quinazolin-4-yll 25-pyrazol-3-yl) -amine (III-109): anp 269 0 C; IH NMR (DMSO) 81.50 (42, br 1.76 (42, br s),.2.25 (3H, 3.78 (4H, 6.55 (12, br 7.03 (1H, 7.28 (1H, d), 7.50 (12, 8.33 9.92 (12, 12.09 (12, br IR (solid) 3427,.2963, 2927, 2909, 2872, 2850, 1623, 1595, 1586, 1568, 1504, 1486, 1468, 1386, 1427; MS 323.3 Example 338 [2-(4-(2-Eydroxyethylpiperidin-1-yl)quinazsolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine

(III-

110): mp 175 0 C; 12 NMR (DMSO) 8 1.08 (2H, 1.38 (2H, 1.57-1.83 (3H, 2.26 (3H, 2.85 (2H, 3.47 (2H, nm), 4.38 (12, 4.75 (2H, 6.45 (12, br s), 7.06 (12, 7.29 (IH, 7.52(1, 8.32 (12, d), 9.93 (IH, 12.12 (12, br IR (solid) 3365, 3073,.

2972, 2868, 1622, 1604, 1586, 1568, 1486, 1463, 1440, 1394; MS 353.2 (M+H) 4 Examplte 3392 (5-Cyclopropyl-2R-pyrazol-3-yl)- 2-(4methylpiperidin-1-yl)-quinazolin-4-ylJ -amine (II-111): 317 INDTo a solution of (5-cyclopropyl-1H-pyrazol-3-yl)-(2o chloro-quinazolin-4-yl)-amine (118 mng, 0.41 mmol) in tert-butanol (3.0 mL) was added 4-methylpiperidine (0.49 mL, -4.1 mmol) and the reaction mixture heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in a mixture EtOH:water 4 niL). Potassium carbonate (57mg, 0.41 mmol) was added and the mixture stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water and rinsed with Et 2 0 (x2) to afford III- 111 as a white solid (123mg, mp 19000; H MR (DMSO) IN8 0.66 (2H, 0.93. (5H, br 1.07 (2H, 1.66 (3H, Ss), 1.91 (12, 2.85 (2H, 4.72 (2H, 6.33 (1H, 7.06 (1H, 7.29 (1H, 7.52 (1H, 8.31 (1H, 9.95 (IH, 12.18 (12, br IR (solid) 2925, 2852, 1622, 1590, 1581, 1558, 1494, 1481, 1453, 1435, 1394; MS 349.2 Exampie 340 [2-(1,4-Dioxa-8-aza-spiro[4,.S dec-8-yl)quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (III- 112): mp 191-C; 'H NMR (DMSO) 8 1.65 (4H, 2.26 (3H, 3.90 (4H, 3.93 (4H, 6.43 (1H, br s),.7.09 (12, 7.32 (Zi, 7.54 (12, 8.35 (1H, 9.99 (12, br 12.13 (1H, br IR (solid) 3069, 2964, 2927, 2868, 1618, 1581, 1568, 1540, 1495, 1481, 1435, 1390; MS 367.3 Examle 341[2-(4-Cyclopentylamino-piperidin-1-yl)quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (III- 113): mp 19100; 'H NMR (DMSO) 1.33 (2H, 1.65 (4H; 1.87 (2H, 2.20 (12, 2.26 (3H, 2.49 (2H, 3.00 (2H, 3.36 (22, 4.61 (2H, 6.45 (IH, br 7.07 (12, 7.31 (12, 7.52 (12, 8.33 ID(I, 9.94 (3N, br 12.12 (1H, br IR (solid) 3371, 2943, 1622, 1600, 1581, 1545, 1509, 1463, 1440, 1390; MS 378.2 xample 34 (4-Hydroxypiperidin-1-yl) -quinazolin-4yl]-(S-methyl-2H-pyrazol-3-yl)-amine (111-114): mp 123 0

C;

'H NMR (DMSO) 6 1.34 (2H, 1.80 (2H, 2.26 (3H, s), 3.24 (2H, 3.72 (1H, br 4.39 (2H, 4.70 (1H, IND 6.44 (1H, br 7.07 (1H, 7.30 (11, d),.7.53 8.33 9.94 (1H, br 12.11 (1H, br s);

O

IR (solid) 3265, 3151, 2927, 2863, 1622, 1600, 1572, 1540, 1504, 1476, 1440, 1390, 1349, 1066, 1098; MS 325.3 Example343 (5-Cyclopropyl-20-pyrazol-3-yl)- hydroxy-4-phenylpiperidin-1-yl) -quinazolin-4-yll -amine (111-115): mp 131OC; 1H NMR (DMSO) 8 0.64 (2H, 0.93 (2H, 1.68 (21, 1.83-1.97 (3H, 3.20-3.45 (2H, 4.69 (2H, 5.11 6.37 (1H, br 7.08 (1H, 7.20 (1H, 7.31 (3H, -7.49 (2H, 7.53 (1H, 8.33 (11, 9.98 (1H, br 12.18 (1H, br s); IR (solid) 3362, 2952, 2934, 2911, 2870, 2825, 1618, 1584, 1570, 1559, 1536, 1481, 1459, 1431, 1372, 1336, 1213, 994; MS 427.6. Example 344 (5-Cyclopropyl-2H-pyrazol-3-yl) dihydro-isoindol-2-yl)-quinazolin-4-yll.-amine (111-116): Prepared according to Method E-I to afford an off-white solid, mp 237.C; 1H NMR (DMSO-d6) 8 0.79 (2H, 1.00 (2H, 1.99 (1H, 4.92 (4H, 6.72 (1H, br a), 7.13 (1H, 7.33 (2H, 7.30-7.48 (3H, 7.58 (1, 8.40. (1H, 10.12 (1H, 12.17 (1H, IR (solid) 3449, 3318, 2850, 1623, 1595, 1577, 1541, 1509, 319 1482, 1432, 1391, 1359, 1141, 1027, 877, 814; MS 369.4 oC 0 Example 34 (2-Azepan-1-yl)-quinazolin-4-yl]-(5cyclopropyl-25-pyrazol-3-yl)-amine (111-117): mp 199- 200 0 C; 'H NMR (DMSO-d6) 6 0.60-0.70 (2H, 0.90-1.00 (2H, 1.45-1.57 (4H, 1.70-1.85 (4H, 1.88-1.97 3.75-3.87 (4H, 6.42 (1H, 7.02 (1H, t), IN 7.27 (1H, 7.49 (1H, 8.29 (1H, 9.91 a), 12.19 (1H, br IR (solid) 2929, 1624, 1595, 1581, o 1563, 1542, 1498, 1482, 1440, 1426, 1397, 1356, 1305, IN .1000, 825, 754; MS 349.2 Exampe 34 (5-Cycopropyl-2H-pyrazol-3-yl)-[2-(3,4dihydro-1f-isoquinolin-2-yl)-quinazolin-4-yl] -amine (III- 118): mp 182-184W; 'H NMR (DMSO) 8 0.75 (2H, 1.02 (2H, 1.96 (1H, 2.89 (2H, 4.05 (2H, 4.94 (2H, 6.46 (1H, 7.10 (1H, 7.21 (4H, 7.37 (iH, 7.55 (1H, 8.36 (1H, 10.05 (1H, 12.23 (1H, br IR (solid) 1621, 1581, 1560, 1537, 1479, 1456, 1426, 1396, 1374, 1341, 1222; MS 383.3 (M+H)4.

Examnple 3247 (5-Cyclopropyl-2ff-pyrazol-3-yl)- dihydro-indol-1-yl)-quinazolin-4-yl -amine (111-119): mp 150-153 0 C; 1H NMR (DMSO) 8 0.74 (2H, 0.98 (2H, d), 1.96 (1H, 3.15 (2H, 4.25 (2H, 6.45 (1H, br 6.88 (1H, 7.09 (1H, 7.20 (2H, 7.53 (1H, 7.65 (1H, 8.43 (2H, br 10.09 (1H, 12.28 (1H, brs); IR (solid) 1621, 1588, 1577, 1564, 1537, 1487, 1455, 1425, 1386, 1259; MS 369.3 Example 3A48 (5-Cyclopropyl-2H-pyrazol-3-yl)-12-(4hydraxymethylpiperidin-1-yl) -quinazolin-4-yl] -amine (III- 320 IND120): Inp 142CC; 'H NMR (DMSO) 8 0.67 (2H, 0.96 (2H, 1.10 (2H, 1.55-1.70 (3H, in), 1.91 (11, 2.85 c' (2H, 3.22 (2H, 4.48 (1H, 4.76 (2H, 6.34 (1H, 7.06 (1H, 7.30 (1H, 7.52 (1H, 8.31 9.96 (1H, 12.19 (1H, IR (Bolid) 3363, 3000, 2927, 2854, 1618, 1604, 1573, 1536, 1509, 1477, 1436, 1395, 1354, 1314, 1241, 1186, 1091, 9959 941, 823; MS 365.8 Va Ecaumle 349 (S-Cyclopropyl-2-pyrazol-3-yl)-[2- (3,4dihydro-2r-quinolin--yl) -quinazoli-4-ylJ -amine (III- IND 121): mp 137-145 0 C; 'H NMR (DMSO-d6) 5 0.55 (2H, 0.88 o (2H, 1.78 1.92 (2H, 2.75 (2H, 4.04 (2H, 6.20 (1H, br 6.97 (1H, 7.14 (11, 7.19 (1H, 7.42 (11, 7.61 (11H, 7.67 (1H, d), 8.43 10.04 (1H, 12.21 (1H, br IR (solid) 1622, 1572, 1539, 1493, 1454, 1420, 1373, 1249; MS 383.3 BxaJnVje (5-Methoxcycarbony-2-pyazo1. [2- (piperidine-r1-yl) -quinazolin-4 -yl] -amine (111-122): 'H NMR (5001Hz, CDC1 3 5 1.7-1.8(sH,in), 153.8 853.9(3H, 55.5 (1H, 8 7.15 (1K, 8 7.4 (1H, 5 7.6 (1H, 5 8.0 (1H, HPLC-Methad B, (starting with H20) Rt 7.4 min; MS 353.24 Eane 5 (Piperidine-1..carbonyl)-2H -pyrazol-3-yll- [2-(piperidune-1-yl)-quinazolin-4-y]-amine (111-123): HPLC-Method B, (starting with 95% H10:0.1% TFA) R, min; MS 406.30, 404.30.

-Examn1raiae (5-Hydroxymethyl-2H-pyrazol-3-yl) [2- (piperidin-1-yl)-quinazolin-4.yl]-amine (111-124): To a 321 I solution of III-122 (10.0 mg, 0.028 mmol) in THF (6 mL) o at ambient temperature was slowly added a 1M solution of Cl LiA1H 4 in TEF (0.05 mL, 0.05 mmol). After 15 minutes the solution was quenched with water and IN HC1. The product was extracted from the aqueous layer with EtOAc. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by preparatory HPLC to afford III-124 (4.0 mg, HPLC- Method B, (starting with 95% HO20:0.1% TFA) Rt 6.1 min; MS 325.13 323.13 INDExamle 353 (5-Carbamoyl-2H-pyrazol-3-yl)-[2-(piperidin- 01-yl)-quinazolin-4-yll-amine (111-125): A solution of C 11I-122 (1.5 g, 4.3 mmol) in 2.0 M 11H 3 /Me0H (100 iL) was heated at 1100C for 2 days. The dark brown reaction mixture was concentrated in vacu to afford a viscous oil which was purified by column chromatography to yield 0.7 g of III-125. 1H NMR (500MHz, CD30D-d) 51.6 (4H,m) 51.7 8 3.3 (1H, 8 3.8 (4H, 8 (1H, 8 7.15 (IS, .8 7.45 (1H, 6 7.55 (1H, 6 (1H, RPLC-Method B, (starting with 95% H20:0.1% TFA) Rt 5.9 min; MS 338.13, 336.15.

xampe 354 (5-Carbamoyl-2-pyrazol-3-yl)- methylpiperidin-1-yl)-quinazolin-4-yl] -amine (111-126): HPLC-Method B, (starting with 951 H20:0.1% TFA) Rt 6.4 min; MS 352.19, 350.20.

Rxamp1e 355 (5,7-Difluoro-t-indazol-3-yl) (2-phonyl- 5,6,7,8-tetrahydroquinazolin-4-yl)-amine (111-127): 'H NMR (500 MHz, DMSO-d6) 813.7 1H), 10.3 br, 1H), 7.90 2H), 7.52, 1H), 7.45 3H),.7.26 1H), 2.99 (Mn, 2H1), 2.75 (Mn; 2H1), 1.95 (hr, 411)pm;M (S+'382 (Mt-H} .376.23 HPLC-IMethod A, Et 3.04 min.

2 -Phenir1-5D6I7Is-ttrahydrot±na~o±n 4 yl) (S-trifluorOmethy.cw..±ndzo.3.yl)..minl (I1I1-128): l1H NMhI (500 M01z, DMSO-d6) 613.4 111), 1.0.2 br, 231), 8'.13 111)', 7.86 211), 7.78 1H1), 7.69 111), 7.50 111), 7.35 (dd, 211), 2.89 (in, 2H1), 2.72 (Mn, 2H)', 1.90 br, 411) ppm; MS 410.24 408.23 (M4-H) HPLC-Method A, Rt 3.19 min.

kgwAPits.2M (7-Pluoro-1H-indazol.3.yt) (2-phenylguin4zolin'-4-yl) -amine (111-129): 1H NMR (500 MHz, dE) 613.6 111), 11.1 br, 8.65 111), 8.03 211), 7.95 211), 7.67 (mn, 111), 7.45 211 7.33 2H1), 7.22 (dd, 111), 6.99 (td, 111) ppm. MS m/e= 3520(M+H); HPLO-Method A at 3.00 win.

ExaiiP1e isi (S-Fluoro-Js-inazol.3yl) -(2-phenylquinazonin-4-yl) ramine (111-130): 'H NMR .(500 MHz, dG) 6 13.-2 11) 11. 3 br, 1H)I, 8. 67 11) 04 211), 7.96 211), 7.70 (mn, 111), 7.58 (dd, 111), 7.43 (in, 4H1), 7.28 (td, 111) ppm. MS 356.20

HPLC-

Method A, Rt 3. 00 min.

Enmpla..3E2

(S

1 7-Difluoro-H-na~o.3-y1) -(2-pheny:lquinazolin-4-yl)-amjne. (111-1331). NMR (500 mHz, ~Ms0-' diG) 61-3.7 111), 8.65 111), 8.04 211), 7.95 (S, 211), 7.68 (in, 1H), 7.45 111), 7.3.5 411) ppm. MS m/e= 374.17 HPLC-MethodA, Rt 3.0*7 min.

;apej3jQ (]M9-Indazol-3-yl) 3 -trifluoromethy1pheny1)-quinazoln.4.yllJ..min 6 (111-132): NmtR (500mHz, IND DMSO-d6) 8 7.06 Iii), 7.42 -Ct, 1H), 7.59 iN), 7.63 o(t, 1H) 7. 66' iH) 7. 7 1 (mn, 11U, 7. 80 12) 7.9 8 22), 2.33 CS, iN), 8.46 12), 8.71 12), 11.04 (br. s, iN), 12.97 1H); El-MS 406.1 CM+1); 2PLC- Method A, Rt 3.15 mini.

(2-Phenyl-quinazolin-4-yl) CI-pyrazcic [4,3blpyridun-3-yl) -amine (111-133): 'H INMR (500 MHz, DMS0-dS) 8 13.3 br, 12) 11. 4 Cs, br, 12), 8.78 12), 8.58 C110 (dd, 12), 8.24 12), 8.10 (mn, 22), 7.95 22), 7.86 o(t, iR), 7.56,(in, 2H1), 7.44 22-) ppm. MS (ES4-) 339.11 CM+H) RPLC-Method A, Rt 2.63 mini.

Exampe362 (3-Methoxy-phenyl)-6-oxo-5,6-dihydro-iapyrazolo 3-c] pyridazin-3-yl (2-phenyl-quin:azolin-4yl)-amine (111-134): 'H INMR (500 MHz, MeOH-d4) 88.65 (d, 1H), 8.17 3H), 8.10 7.90 Ct, 12), 7.75 (t, 12), 7.58 (mn, 2H), 7.25 iN), 6.95 (mn, 2H1), 6.85 (d, 12), 6.80 IH), 3.64 ppm. MS in/e= 462.2CM+N).

Eam~t..363 (6-Oxo-5-phenyl-5,6-dihydro-1H-pyrazolo[4,3ci pyridazin-3,-yl) -(2-phenyl-quinazolin-4-yi) -amine (III- 135): 3H N~M (500 M4Hz, MeOH-d4) 88.61 12) 2.13 (m, 32), 9.05 12), 7.55 Ct, 12), 7.70 (t 1 12), 7.58 (m, 22), 7.32 (in, 52, 6.79 12) ppm. MS in/e= 432.2 CM+H).

EKinpi 364 (4-Methoxy-phenyl) -6-oxo-S, 6-dihydro-lipyrazolo pyridazin-3-yl] (2-phenyl-quinazolin-4yl).-amins (II1-136): MS 462.2(14+2).

IND uml 3 (2,4-Dichloro-phienyl) -6-oo-s, 6-dihydroo lER-pyrazolo 43-cpyridazin-3-yll (2-Phenyl-qunrazoltn.4 Cl yl)-amnne (111-137): 'M MMa Csoo 1Hz, MeOH-d4) 88.63 (d, ct IH), 8.17 Cm, 4H4), 7.89 Ct, iN) 7.73 Ct, 14) 7.61 Ct, 7.57 Cd, 1IN), 7.32 12H); 7.21 Cd, 31X)-, 6.84 Cs, 1H4) ppm. MS CES+): rn/en 500.i(4.i-).

BcAinpet366 [6-Oxo-5- (3-triflnoromethyl-phenya) 6dihydro-lE-pyrazolo 3-cipyridazin-3-yI (2-phenylquinazoiin-4-ylJ -mine (11-138) '1K WAR (500 MHz, MeON'- 0d4) 58. 55 I1H4), 8. 19 2H4), 7. 92 CM, 2H) 7.65 (m, IND3H),.*7.45 2H4), 7.25 Ct,,iN), 7.13 Ct, in), 7.05 Ct, o114), 6.75 Cs, 1H1) ppm. MS CES+) 500. 2 CM+H).

pjam.e j [6-Oxo-5- (4-Phenoxy-phenyl) 6-dihydro-lEpyrazolo 3-c]pyridazin-3-yl) (2-pheny1-guinazolin-4yl)-amine (111-139): MS 524.3(4+1).

gxgamjj (6 5- (4-Ohioro-phe~nyl) -6-oxo-5 ,6-dihydro-aupyrazolo[4,3-clpyridazin-a-y) 2 -phenyl-quinazolin-4yi)-amine (111-140). MS (ES+i) 466.2(MiH).

Example 3692 C2-imidazol-1-yl-qu~inazolin-4-y1) Cuf-.

±ndazol-3-yl)-amine (111-141): 'H NMR C500rMnz, DMSO-dG)6 7.10 Ct, IJU, 7.44 Ct, iH), 7.50 {br. s, in), 7.60 (d, 114), 7.72 Cm, 2H4), 7.77 111), 7.88 Cd, IH), 7.92 Ct, 114), 8.73 1H4), 8.56 in), 11.23 Cs, in), .13.06 Cs, iH) -El-MS 328. 1 CM+1) HFLC-Method A, Rt 2.93 min.

Excamne 370 (1R-Indazol-3-yl)- (2-nethyl-imdaol-.y.quinazoiu-4-yl3-amine (111-142): "H4 NMR CSOOMnz, DNSO-dS) 82'.48 (C3, 3H4), 7.10 Ct, 114), 7.43 Ct, 114), 7.57 114), 7.60 flU', 7.67 in), 7.76 in), 7.86 1-H), 7.91 lH), 8.01 (td, IH), 8.72 Cd,.lIH), 11.15 C8, 1H), 13.10 il); El-MS 342.1 (Mi1); RPLC-Method A, Rt 3.06 -min.

S B2p1m e3am (H-Indazol-3-yl)- C2-piperidin-1-y1quinazoln-4-yl) -amine- (111-143): 'H NMR (501Hz, DMSO-d6) 8 1.48 6H), 3.60 4H), 7.11 t, IH), 7.52 1H), 7.55 1H), 7.64 1H), 7.69 aM), 7.75 Ii), 7.90 Ct, 1H), 8.58 Cd, 1H), 11.82 (br. a, IH), 13.25 Cs, 1H); El-MS 345.1 HPLC-Method A, Rt 3.03 min.

Mxgaule 31a (CH-Indazol-3-yl) Coctehydro-quinolin-1yl)-quxinazoiin-4-y1]-amine (111-144): 'H NKR (500MHz, DMso-dE) 8 0.6-1.9 13 3.15 Cm, iH), 3.25 Cm, Ir), 4.0 1H), 7.10 0.5H), 7.12 Ct, 0.SH), 7.55 (m, 2H), 7.66 0.5 7.69 0.5 7.77 11), 7.91 1H), 8.55 0.5 8.59 0.5 11.46 11.54 Cs, 0.5 11.78 0.5 11.84 Cs, 0.5 H), 13.10 0.5 13.12 Cs, 0.5 El-MS 399.3 HPLC-Method A, Rt 3.37 min.

aExU.le 3 (3 1-Indazol-3-yl) 6-dimethyl-morpholin- 4-yl) -quinazolin-A-y11 -amine (111-145): 'H NMR (500MHz, DMSO-d) 8 1.0 6H), 4.0 6H1), 7.12 1H), 7.41 (td, 1H), 7.56 Ct, 1H), 7.58 1H), 7.68 (dd, 1H), 7.77 IH), 7.93 Ct, IH), 8.60 Cd, lI), 11.69 IH), -13.16 Cs, 1H); El-MS 375.3 HPLC-Metlod Rt 2.93 min.

Exgm e 374 5-ethyl-2-pyrazol-3-yl)-(2-phenylpyrimidin-4-yl)-amina np 24SL246 0 C; 'H NMR (DMSO) 82.26 6.32 (Cl, br 7.07 (11, br 7.48- 7.54 (3H, 8.33-8.39 (3H, 9.87 CiM, 12.03 Ci, QD IR (solid) 1628, 1589, 1579, 1522, 1479, 1441, 1393, O 1336;MS 252.2 ci Exale 37 6- (4-Acetamidophenylsulfanyl) -2-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IV-3): A suspension of Fenclorim (4,6-dichloro-2phenylpyrimidine) (0.1g, 0.44 mmol), methylpyrazole (0.045 g, 0.47 mmol), N, N- \D diisopropylethylamine (0.08 ml, 0.47 mmol) and sodium 10 iodide (0.067 g, 0.44 mmol) in n-butanol (5 ml) were C heated at 117 °C for 18 hours. The solvent was removed in IN vacuo and the crude product purified by flash o chromatography (silica gel, 3:2 Petrol:EtOAc) to afford 0.037 g (29 yield) of (6-Chloro-2-phenyl-pyrimidin-4yl)- (5-methyl-2H-pyrazol-3-yl)-amine as a off-white solid. A suspension of the above pyrimidine (0.037 g, 0.13 mmol) and thioacetamidothiophenol (0.108 g, 0.64 mmol) in tert-butanol was heated at 85 °C under nitrogen for 2 days. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The concentrate was dissolved in EtOAc, and washed with NaHCO 3 -(sat, The organic layer is concentrated in vacuo, and the crude product by preperative HPLC. The residual disulfide that still remained in the mixture after HPLC may be removed by precipitation from EtOAc and filtration. The mother liquor was concentrated to afford IV-3 (7mg, 13 yield) as an off-white solid: mp 235- 236°C; 1H NMR (DMSO) 6 2.10 (3H, 2.21 (3H, 6.33 (1H, br 7.50 (3H, 7.7-7.59 (2H, 7.76-7.78 (2H, 8.25 (2H, 9.72, 10.26 and 11.93 (3 H, 3 x br IR (solid) 1669, 1585, 1551, 1492, 1392, 1372, 1312, 1289, 1259, 1174, 1102, 1089, 1027, 1015, 984; MS 417.3 (M+H)f.

327

VO

oP Example 376 [2-(4-Methylpiperidin-1-yl)-pyrimidin-4-yl] 0 (S-methyl-25-pyrazol-3-yl)-amine mp 215-216 0 C; 3H NMR (CDO30D) 6 0.96 (3H, 1.16 (2H, 1.66 m), 2.27 (3H, 2.86 (2H, 4.58 (2H, 4.78 (2H, exch.protons), 6.13 (2H, 7.83 (1i, IR (solid) 1593, 1550, 1489, 1436, 1331, 1246, 1231; MS 273.1 xamle 377 [2-(4-Methylpiperidin-1-yl)-5-nitropyrimidin- 10 4-yll-(5-methyl-2H-pyrazol-3-yl)-amine mp 185- O 187 0 C; 3H IM (DMSO) 5 0.93 (3H, 1.06-1.18 (2H, i), Ste 1.68-1.80 (3H, m),-2.26 (3H, 3.01-3.12 (2H, 4.63 o (1H, 4.80 (1i, 6.39 (1i, 9.00 (1K, 10.41 (1H, 12.36 (1H, IR (solid) 1589, 1517, 1479, 1446, 1346, 1317, 1246, 1222, 1055; MS 318.2 Examle 3782 [5-Amino-2- (4 -Methylpiperidin-1-yl)pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IV-6): To a solution of IV-5 (48 mg, 0.151 mmol) in ethanol mL) was added tin dichloride dihydrate (171 mg, 0.756 mmol) and the resulting mixture heated at reflux for 3 hours. The reaction was cooled to room temperature and poured onto a mixture of IM NaOH:dichloromethane:propanol (18:8:4mL. and stirred for 15 minutes. The layers were separated and the aqueous layer extracted twice with dichloromethane. The combined organic layers were concentrated in vacuo and the residue purified by flash chromatography (silica gel, gradient dichloromethane:iMeoH) to affprd IV-6 as a grey solid (27mg, 'HNMR (DMSO) 6 0.88-1.04 (5H, 1.55-1.62 (3H, 2.21 (3H, 2.70. (2H, 3.36 (2H, 4.40 (2H, i),.6.37 (1I, 7.49 8.40 (1H, 11.92 (1H, br MS 288.2 (M+H) 4 o ~Eanmit.379 [5-,Amino-6-methyl-2 -(4-metbylpiperidin-1-yl) c-i pyrimidin-4-yl (5-methyl-2Hf-pyrazol-3-yl) -amin~e (IV-7): ctnip 172-175 0 C; 1 H NM (D)MSO) 8 0.90 (3H, 1.03 (2H, it), 1.52-1.62 (3H1, in). 2.13 (3H, 2.20 (3H, 2.69 (2H, in), 3.92 (2H, br 4.44 (2H, 6.35 (1H, 8.41 (is, 11.85 br ID. (solid) 1612, 1589, 1489, 1446, 1317; MS 302.5 Fxnam~--3Q [6-Methyl-2-(4-methyl-phenyl)-pyrimidin-4oyl]-(5-phenyl-2H-pyrazol-3-yl).-amLne- (iV-i0): MS 342.34 V.0 HPLC-Method E, Rt 1. 334 min.

Example&2Ii (4-Chioro-phenyl) -6-methyl -pyrimitdin-4yl]- (5-furan-,2-yl-2E-pyrazol-3.-yl) -amine (IV-11): MS 352.11 HPLC Method E, Itt 1.194 min.

£a~Ml1t 3fa 5-Furan-2-yl-2H-pyrazoi-3-yl) -(6-methyl-2phenyl-pyrimidin-4-yl)-amine (IV-12)t- MS 318.21 HPLC-Method E, 1.192 main.

gxapet383 [6 -Methyl-2- (4 -trifluoromethyl-phenyl) pyrimidin-4-y1 (S-phenyl-2-y1-2B-pyrazol-3-yl) -amine (IV-13): MS 396.24 HFLC-Metaod E, Rt 1.419 min.

Bxatmn..egi (5-Furan-2-yl-2H-pyrazol-3-yl)- 16-methyl-2-.

tri fluoromethyl -phenyl) -pyrinddin- 4-yl] -amine (IV- 14):.

MS 386.08 HPLC-Method E 1.347 main.

Exmpe~j 18 2-(2,3-DihydXo-benzo[1,4]dioxin-2-yl)-Gmethyl-pyrimidin-4-yll -(5-furaa-2-yi-2R-pyrazol-3 -yl) nmine (iV-15) MS 376.18 HPLC-Method E, Rt 1.181 main.

.329 o ~~Eajg. .386j[2- (2,3-fihydro-bezoEl4]dioxin-2-yl) -6ethyl-pyrimidi in-4-yl (5-methyl-20-pyrazol-3-yl) -amine (IV-16) M$ 338.17 HPLC-Method E, Rt 1. 082 mini.

Exampleal- (6-Ethyi-2-phenyl-pyrimidin-4-yl) 28-pyrazol-3-yl)-amine MS 280.18 HPLC- Method E, Rt 1. 024 mini.

xg I 38 i (6-Methyl-2-phenyl-pyrimidin-4-yl) o2Rw-pyrazol-3-yl) -amine MS 328.51 IIPLC- Method E, Rt 1. 192 mii.

~an~te 3 16-Ethyl-2- (4-trifluoromethyl-phenyl) pyrimidiun-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (IV-2 0): MS 348.5 (M+14) UPLC-Methodl E, It~ 1.224 muin.

Exmlaa 39{5-Furan-2-yl-211-pyrazol-3-yl) E-methyl-2- (4-methyl-phxenyl) -pyrimiclun-4-ylJ -amine MS 332.23 MPLC-Method E, Rt 1.139 ruin.

Example.391 {6-Metho ymethy-2-pheny1-pyrimidin-4-y1) methyl-2H-pyiazol-3-yl)-aaine (ITV-22):. MS 296.31 (NMiH); HPLC-Method BRt 0. 971 mini.

Zxmple 32 6-Dimethyl-2-phenyl-pyrimidin-4-yl)- methyl-2H-pyrazol--3-yl)-amine (IV-23): MS 280.2 HPLC-Metbhod E, Rt 0.-927 mini.

&a=p __393 (6-Methyl-2-phenyl-pyrimidin-4-yl) 2E.-pyrazol-3-yl)-amLne (IV-24): MS 266.18 HPLC- Method E, Rt 0.925 mini.

.330 IND BxuEmp2 1 t324 [6 -Ethyl -2 (4 -methyl -Phenyl) -PYrimidin- 4-yl] (5-mthy-25pyrzol--yl-amne{IV-25): ms '294.46 X le 3,5 (4-Chicro-phenyl) -6-et-hy1-pyrimidin 4-yxJ (S-methyl-2a'-pyrazol-3-ylp-amine (XV-26): MS 314.42 HPLC-Method R Rt 1.213 min.

R~x1le 2i (5-Methyl-1R-pyrazol-s.-p) (6-methyl-2-p- 10 tolyl-pyrimidin-4-yl)-amine (IV-27): MS 280.45 (M+eH); o HPLC-Metbhod E, Rt 1. 135 min.

Exml (1Er-Indazol-3-yl) -(6-methoxymethyl-2-phenyl.

pyrimidin-4-yl) -amine (IV-28): 'H NMM (500 MHz, flMSO) 8 3.57 (3H1, 4.65 (2H1, 7.23 (114, J=7.5 Hz, 7.52 (111, J=7.6 Hz, 7.63 (4H, mn), 7.75 (111, br), 8.13 (111, ,7=5.5 Hz, br 8.44 (111, J=5.7 Hz, br L0.6 (111, br), 12-8 (iM, br a) ppm: HPLC-Method A, Rt 2.944 min; MS (FIA) 332.1 (M+H) t Exm61 9 (5-N4ethy1-2H-pyaz1-3.y1) 2-pyridin-4-y1thieno[3,2-dlpyrimidin-4-y1)..ajne (lIt-29): 'H NMR (DMS0) 8 2.34 13H1, 6.66 (1Hi, 7.53 (lIH, 7.84 (111, d), 8.32 (2H1, d),,8.70 (2H1, MS8 309.6 Exmle.S99, (S-Methyl-2H-pyrazol-3-yl) -(2-phenylpyrido[3,4-d~pyrimiamn -4-y1)-ainine MI-30): mp.225 0 C; 1H NqM (DM80) 8 2. 35 (3H, S) 6. 81 (111, a) 7.5 0 63 (3 H, in), 8.45-8.52 (2H4, 8.54 (111, B8'62 (Ift, .9.20 (111, 10.79 (1H4, 12.38 (111, bra); ZR (solid) 2958, 2917,'2852, 1593, 1565, 1524, 1467, 1450; MS 303.2

(M+H)

4 .331 IO EaMple 400 (5-Methyl-2-pyrazol-3-yl)-'(2- phenylo pyridot2,3-d]pyrimidin-4-yl) -amine (IV-31): 0 To a solution of 4-chloro-2-phenyl-pyrido[2,3d]pyrimidine Pharm. Belg., 29, 1974, 145-148) (109mg, 0.45 mmol) in TF (15 mL) was added pyrazole (48 mg, 0.5 mmol) and the resulting mixture heated at 65 0 C overnight. The mixture was cooled to room temperature and the resulting suspension was filtered and washed with Et 2 O. The solid was dissolved in a mixture EtOH:water and the pH adjusted to pH 7. The aqueous was o extracted twice with ethyl acetate and the combined IND organic layers were dried (MgSO 4 filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO 2 DCM-MeOH gradient) to afford IV-31 as an.off-white solid (69 mg, mp 234OC; 1H NMR (DMSO) 8 2.14 (3H, 5.99 7.20-7.40 (3H, m), 7.40-7.50 (3H, 8..60 (1H, 8.79 (1H, 12.82 (1H, br IR (solid) 2957, 2921, 2857, 1644, 1560, 1459, 1427; MS 303.2 xamle 401QJ (5-Cyclopropyl-2s-pyrazol-3-yl)-(2-phenylpyridol3,4-d]pyrimidin-4-yl)-amine (IV-32): off-white solid, mp 232-233 0 C; 1H NMR (DMSO) 8 0.70-0.85 m), 0.90-1.05 (2H, 1.05-2.07 6.75 (1H, 7.50- 7.75 8.40-8.70 (4H, 9.20 (1H, 10.80 (1H, 12.41 IR (solid) 3178, 1601, 1573, 1532, 1484, 1452, 1409, 1367, 1328, 802, 781, 667; MS.329.2 Example 42 [2-(4-Hethylpiperidin-1-yl)-purin-4-yl]-(5methyl-21-pyrazol-3-yl)-amine (IV-33): To a suspension of 2,4-dicloro- 7 purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-1B-pyrazol-3-yl amine (2.05 g, 21.2 mmol). The-resulting mixture was stirred IND at room temperature- for 48 h. The resulting precipitate 0 was collected by filtration, washed with ethanol, and dried under vacuum to afford 1.524 g (58% yield) of (2chloro-purin-4-yl) (5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification.

To a solution of (2-chloro-purin-4-yl)-(5-methyl-1Hpyrazol-3-yl)-amine (200 mg, 0.80 mmol) was added 4methylpiperidine (4 mL, 8.01 mmol) and the reaction IND mixture heated at reflux overnight. The solvent was 10 evaporated and the residue dissolved in a mixture 0 EtOH:water 4 mL). Potassium carbonate (57mg, 0.41 IND mmol) was added and the mixture was stirred at room o temperature for 2 hours. The resulting suspension was filtered, washed with water (x2) and rinsed with Et 2 O (x2) to afford IV-33 as a white solid (225mg, mp >3000*C; H AMR (DMSO) 8 0.91 (3H, 1.10 (2H, 1.65 (3H, m), 2.24 (3H, 2.84 (2H, 4.60 6.40 (1H, s), 7.87 (1H, 9.37-9.59 (1H, 12.03-12.39 (2H, ER (solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3 Example 403 (5-Cyclopropyl-2H-pyrazol-3-yl)- methylpiperidin-1-yl)-pyrrolo[3,2-dpyrimidin-4-yll-amine (IV-34): white solid; 'H NMR (DMSO) 8-0.65 (2H, 0.91- 0.96 (5H, 1.08 (2H, 1.58-1.64 1.89 (1H, 2.77 (2H, 4.57 (2H, 6.09 (1H, 6.38 (1H, 7.33 (1H, 9.42 (1H, 10.65 (1H, 12.02 (1H, br MS 338.3 Example 404 [6-Benzyl- 2 -phenyl-5,6,7,8-tetrahydropyrido [4,3-dpyrimidin-4-yll-(5-fluoro-1H-indazol-3-yl)amine (IV-35): 'H NMR (5004MHz, DMSO-d6) 813.0 1H), 10.4 br, 1H), 9.73 1H, TFA-OH), 8.00 2H), 333 ND 7.64 2H), 7.59 (dd, 1H), 7.52 3H), 7.41 1H), O 7.31 3H), 7.14 (dd, 1H), 4.58 2H), 4.35 (br, 2H), C<1 3.74 2H), 3.17 2H) ppm. MS m/e= 451.30 t HPLC-Method A, Trt 2.96 min.

Sxamle 405 (5-Fluoro-lH-indazol-3-yl) (2-phenyl-5,6,7,8-.

Cl tetrahydro-pyrido pyrimidin-4-yl) -amine (IV-36): Prepared from IV-35 (0.13 mmol) by treatment.with an equal weight of Pd/C in 4.4%-HCOOH in MeOH at room 10 temperature for 12 h. The mixture was filtered through o celite, the filtrate was evaporated, and crude product Cl I\ was purified by HPLC to afford IV-36 as yellow solid in 0 o 35% yield. 1H NMR (500 MHz, DMSO-d6) 812.9 IH), 9.06 1H), 7.99 2H), 7.57 (dd, 1H), 7.34 1H), 7.28 3H), 7.22 1H), 3.83 3.05 2H), 2.72 2H) ppm. MS m/e= 361.20 HPLC-Method A, Tt 2.68 min.

Example 406 (5-Methyl-2H-pyrazol-3-yl) (3-phenylisoquinolin-l-yl)-amine To a solution of 1-chloro- 3-phenylisoquinoline Het. Chem., 20, 1983, 121- 128)(0.33g, 1.37 mmol) in DMF (anhydrous, 5 mL) was added (0.27g, 2.74 mmol) and potassium carbonate (0;57g, 4.13 mmol)and the resulting mixture was heated at reflux for 6 hours. The reaction mixture was then cooled and solvent removed in vacuo. The residue was extracted twice with ethyl acetate and the combined organic layers washed with brine, dried (MgSO0), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO 2 gradient DCM-Me0H) to afford V-i as a colourless oil; H NMR (MeOD) 8 2.23 (3H, 5.61 (IH, 7.41 (1H, 7.52(2H, m), 334 I 7.62(1H, 7.81(1H, 8.07(1, 8.19(2H, m), 8.29(1H, 8.54' (1H, MS 301.2 Examle 407 (1H-Indazol-3-yl)- 13-( 2 -trifluoromethylphenyl)-isoquinoline-1-yl]-aine A solution of 1cbloro-3-( 2 -trifluoromethyl-phenyl)-isoquinoline (100 mg, 0.326 mmol) and lM-indazol-3-ylamine (86 mg, 0.651 mmol) in ethanol (3 mL) was heated at 160 C and the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160 C for 18 hours under nitrogen.

o The resulting melt was-dissolved in O methanol: dichloromethane (50 mL), washed with saturated 0 aqueous sodium bicarbonate x 25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography (251 to 50% hexane:ethyl acetate) afforded V-2 as a yellow solid (35 mg, 271). 'H NMR. (500 MHz, d- DMSO) 6 9.78 (br s, 1H), 8.62 1H), 7.9-7.85- 1H), 7.78-7.72 10), 7.70-7.68 1H), 7.65-7.62 1H), 7.60-7.55 1K), 7.52-7.45 3H), 7.41-7.38 1H), 7.28-7.25 1H), 7.18 1H), 6.95-6.92 1H), 5.76 1H); LC-MS m/e= 405.18 (M+H);.HPLC-Method D R, 2.74 min.

ex le 408 (5,7-Difluoro-1a-indazol.-3-yl)- trifluoromethyl-phenyl)-isoquinolin-1-yl] -anine Prepared from 5,7-difluoro-H-indazol-3-ylamineto afford compound V-3 as a yellow solid (90 mg, .H NMR (500 MHz, d 6 -DMSO).8 13.25 1K), 9.92 (br s, 1H), 8.61 (d, 1H), 7.9 1K), 7.81-7.49 6H), 7.26-7.2 2H), 7.12-7.10 1H); LC-MS m/e= 441.16

HPLC-

Method D, Rt 3.58 min.

335 Exa le 409 (5-Methyl-2H-pyrazol-3-yl) (2-phenyl- \O quinolin-4-yl)-smine To a mixture of 4-chloro-2phenylquinoline Het. Chem., 20, 1983, 121-128)(0.53g, 2.21 mmol) in diphenylether (5 mL) was added methylpyrazole (0.43g, .4.42 mmol) and the resulting mixture heated at 200 0 C overnight with stirring. The reaction mixture was cooled to ambient temperature then petroleum ether (20 mL) was added and the resulting precipitate was isolated by filtration. The crude solid 10 was purified by flash chromatography (Si0 2 gradient DCMo MeOH) to afford V-4 as a white solid: mp 242-244CC; IH NMR \C (DMSO) 2.27(3H, 6.02(1H, 7.47(2H, 7.53- O '7.40(2H, br 7.67(1H, 7.92(1H, 8.09(2H, d), 8.48(2H, 9.20(1, 12.17(1H, br IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 (M+H) 4 Examle 410 (1H-Indazol-3-yl)-(2-phenyl-quinoli-4-yl)amine 3H NMR (500 MHz, d 6 -DMSO) 8 12.78 1H), 9.50 1H), 8.65 8.15 1I), 8.04-7.98 (m, 3H), 7:94 1H), 7.78-7.75 1H), 7.60-7.40 6H), 7.15-7.10 1H). LC-MS m/e= 337.11 HPLC- Method D, Rt 2.10 min.

Exagmle 41 (2-Phenyl-quinolin-4-yl)-(C2-pyrazolo[4,3b]pyridin-3-yl)-amine 3H NMR (500 MHz, DMSO-d6) 613.6 1H), 11.4 1H), 8.94 11), 8.61 (dd, 1H), 8.23 8.16 (dd, 1H), 8.12 1H), 7.89 1H), 7.86 11H), 7.65 4H), 7.54 1H), 7.52 (dd, 1) ppm. MS m/e= 338.11 HPLC-Method A, HPLC- Method D, Rt 2.91 min.

Examle 412 (18-Indazol-3-y) (2-trifluoromethylphenyl)-quinolin-4-yl]-amine 3H NMR (500 MHz, d6- 336 IND DMSO) 12.68 1H), 9.51 LH),,8.7 12), 7.95- 7.9 Cm, 2H), 7.83-7.70 3H), 7.68-7.62 m, 21), 7.60 1H), 7.55-7.52 3B), 7.49-7.45 12), 7.40-7.37 7.12-7.09 1H); LC-MS /en 405.15 S HPLC-Rethod D Et 2.25 min.

c Eple113 (5,7-Diluoro-la-indazol-3-yl)- 2-(2trifluoromthyl-phenyz) -quinolin-4-yll -amine 1fl NMR D (500 MHz, d 6 -DMSO) 8 13.31 s, 1H), 9.49 IH), 8.70- 8.67 IH), 7.96-7.92 (in; 1H), 7.85-7.66 71), 7.63- 7.60 7.42-7.40 m, 1H). LC-MS ES+) i/e= 441.18 HPLC-Method D Rt 2.39 min.

ta~1~ej1 2 -triflluoromethyl-phenyl) -qinolin-4-yll- (LH-pyrazolo[4,3-bpyridin-3-yl)-amine 'H NMR (500 MHz, DMSO-d6) 813.6 Cs, 12), 11.6 Cs, br, 11), 2.98 (d, 1H), 8.57 (dd, 1H), 8.12 3H), 7.97 22), 7.86 (m, 3H), 7.49 (dd, 12), 7.23 11) ppm. MS i/e= 406.20 HPLC-Method A Pit 2.91 min.

Exan~le 415 2 -Pheny1-quinazolin-4-yl)- (2K- [l,2,4]triazol-3-yl) amine (I1-154): off-white solid, mp 266-267oC; 'H NMR (DMSO) 8 7.50-7.70 (4H, 7.85-8.00 (2H, 8.15-8.25 (22, 8.37-8.45 (22, 8.58 (ia, 13.90 (11, br IR (solid) 3344, 3059, 1630, 1609, 1570,.1557, 1543, 1501, 1495, 1445, 1411, 1355, 1326, 1267, 1182, 1053, 1038, 760, 676; 667, 654; MS 289.2 CM+H) K Exg2 .jgAtj (5-Methyl-28-11, 2,4]triazol-3.y1) (2-phenyl-.

quinazolin--y1) -amine CXX-155) 1H NMR (500 MHz, DMSOdG) 88.59 12), 8.42 J 6.7 Hz, 2H), 7.79 (m, 337 IND 41), 8.03 (in, 2H1), 7.7 .4 Cm, 4H1), 2.51. 3H) ppm. MS 303. 08 RPLC-Method A, flt 2.64 min.

gimpkt4fl (ZR- -Triazol-3-yl) (2trifluoromethylphenyl) -quinazolin-4-yl] -amine (11-47): Pale yellow solid yield) 'H NISR (500 M4Hz, DMSO-dE) C~~1 88.54 1K), 8.15 br, 1H), 7.91. 111), 7.85 (in, 211), 7.76 3H1), 7.66 Ct, IH) ppm.- MS rn/e= *357.13 (14tH); 355.15 CM-H); HPLC-Method A, Rt ('110 2.81 min.

8 trifluoromethylphenyl) -qninazolia-4-yl] -amine (11-39); ClPale yellow solid (54% yield) '3H NMR (500 MHz, DMSO-d6) 88.44 br, 1IN), 7.92 (mn, 311), 7.84 (in, I11), 7.77 (m, 211), 7.68 111), 2.28 311) ppm. MS m/e= 371.14 in/e= 369.18 HPLC-Method A, Rt 2.89 min.

Example 419 (5-Methy'lsulfanyl-2H- [l,2,4jtriazol-3-yl)-(2- (2-triflnorometbylphenyl) -qnuinazolin-4-yi] -amine (IX- 156): Pale yellow solid (65t. yield) 'H NT4H (500 MHz, DMSO-d6) 68.56 111), 1.90 1H1), -7.84 (mn, 211), 7.78 (mn, 2H1), 7.67 211), 2.51 Cs, 3M, buried by DM80) ppm.

MS rn/e= 403.12. r/e= 401.16 CM-H); HPLC-Method A, Rt 3.20 min.

trifluaroinethyl-phenyl) -isoquinolin-l-yl) -amine (11-175): A solution of l-ch~loro-3- (2-trifluxoromethyl-phenyl) isoquinoline (0.326 inmol) and lH-f1,2,4jtriazol-3-ylamine (0.651 minol) in ethanol (3 mL) was heated at.160CC and the solvent evaporated with' a stream bf nitrogen. The 338 remaining oil was then heated at 160 0 C for 18 hours under Va nitrogen. The resulting melt was dissolved in methanol/dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1 x 25 mL) then dried over magnesium sulfate., Purification by silica gel chromatography afforded 11X-175 as a colorless oil (4% yield). 'H NMR (500 MHz, CDC 3 8 9.18 1E), 8.82 (s, 11), 7.90 1H), 7.85-7.75 3H), 7.71-7.62 3H), 7.60-7.55 2H), 4.42-4.35 1H). LC-MS 356.16 HPLC-Method D, Rt 3.55 min.

Sxcampe 421 (2-Phenyl-quinolin-4-yl) (K-[1,2,4]triazol-

NO

8 3-yl)-anine (IX-176): Pale yellow solid (30% yield). 'H NMR (500 MHz, d4-DMSO) 8 13.82 1H), 9.91 1H), 8.80 8.70-8.65 1H),.8.55 11), 8.15-8.12 2H), 8.03-7.98 1H), 7.75-7.72 1H), 7.57-7.49 3H). LC-MS m/e= 288.11 HPLC-Method D, Rt 1.55 min.

Examle 422 (1f-[1,2,4]triazol-3-yl)- t2-(2trifluoromethyl-phenyl)-quinolin-4-yll-amine (1X-177): Pale yellow solid (46% yield). 1H NMR (500 MHz, d 6

-DMSO)

6 13.70 1H), 9.98 1H), 8.70 1H), 8.49 (s, 11), 7.94-7.88 2H), 7.80-7.68 3H), 7.64-7.56 LC-MS m/e= 356.18 HPLC- Method D, Rt 1.68 min.

E2ampe 423 (1-H-Indazol-3-yl) [5-methyl-6-morpholin-4yl-2- (2-trifluoromethyl-phenyl)-pyrimidin-4-yll -amine (11-251): Colorless film; 2 yield; 'R-NMR (500 MHz, CDwoD) 8 7.84 21), 7.71 3H), 7.41 2H), 7.14 3.74 4H), 3.69 4H), 1.24 3H) ppm; HPLC-Method A Rt 3.26 min; MS (FIA) 455.1 339

VO

0 BIOLOGICAL TESTING o ^c The activity of the compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity or C ATPase activity of the activated protein kinase.

Alternate in vitro assays quantitate the ability of the Sinhibitor to bind to the protein kinase. Inhibitor binding may be measured by radiolabelling the inhibitor o prior to binding, isolating the inhibitor/protein kinase \D complex and determining the amount of radiolabel bound.

o Alternatively; inhibitor binding, may be determined by C( running a competition experiment where new inhibitors are incubated with the protein kinase bound to known radioligands.

BIOLOGICAL TESTING EXAMPLE 1 K4 DETERMINATION FOR THE INHIBITION OF GSK-3 Compounds were screened for their ability to inhibit GSK-3p (AA 1-420) activity using a standard coupled enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). Reactions were carried out in a solution containing 100 mM HEPES (pH 10 mM MgC12, 25 mM NaC1, 300 pM NADH, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 20 pM ATP (Sigma Chemicals, St Louis, MO) and 300 .M peptide (HSSPHQS(POsH 2 )EDEEE, American Peptide, Sunnyvale, CA).

Reactions were carried out at 30 °C and 20 nM Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 AM NADH, 30 pg/ml pyruvate kinase and 10 pg/ml lactate dehydrogenase.

340 An assay stock buffer solution was prepared o containing all of the reagents listed above with the (N exception of ATP and the test compound of interest. The tassay stock buffer solution (175 was incubated in a 96 well plate with 5 A1 of the test compound of interest at final concentrations spanning 0.002 AM to 30 AM at 0 C for 10 min. Typically, a 12 point titration was conducted by preparing serial dilutions (from 10 mM compound stocks) with DMSO of the test compounds in 10 daughter plates. The reaction was initiated by the oaddition of 20 p1 of ATP (final concentration 20 AM).

ci Rates of reaction were obtained using a Molecular Devices o Spectramax plate reader (Sunnyvale, CA) over 10 min at C. The &L values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 pM. for GSK-3: compounds 11-1, II- 105, 11-33, 11-34, 11-36, 11-39, 11-38, 11-39, 11-40, II-- 41, 11-42, 11-46, 11-57, 11-59, 11-60, I-61, 11-62, II- 63, 11-64, 11-66, 11-67, 11-69, 11-70, 11-53, I-71, II- 99, 11-73, 11-74, 11-75, 11-76, 11-77, 11-7. 11-8, 11-9, 11-10, 11-24, 11-19, 11-78, 11-54, 11-79, 11-80, 11-81, 11-82, 11-83, 11-84, 11-.56, 11-86, 11-20, 11-25, 11-26, 11-85, 11-21, 11-27, 11-28, 11-87, 11-88, 11-29, I-l, 11-12, 11-30, 11-31, 11-13, 11-14, Il-15, 11-16, 11-17, Il-18, 11-79, 11-23, 11-2, 11-90, 11-91, 11-92, 11-93, 11-3, 11-4, 11-5, 11-6, 11-94, 11-95, 11-96, 11-107, IIiI-109, 11-110, 11-124, 11-125, Ii-111, 11-112, 11- 113, 11-114, 11-115, 11-116, 11-117, 11-118, 11-119, II- 120, II-121i I-208, 111-8, 111-7, 111-9, 111-37, 111-38, 111-39, 111-40, 111-42, 111-45, 111-46, 111-47, 111-48, 111-4-9, .1-51, 111-52, 111-53,- II1-54, 111-55, Ill-56, 111-57, II1-58, 111-59, 111-60, 111-61, 111-62, 111-63, 111-30, 111-65, 111-66, III-7, 111-70, 111-73, 111-31, o 111-75, 111-76, 111-77, 111-33, 111-34, 111-106, 111-108, S111-109, 1-111ll, 111-35, 111-116, 11I-li7, 111-118, III- 119, I11-120, 111-121, III-127, III-128, 111-141, III- 130, 111-131, V-15, IV-16, IV-17, IV-20, IV-25, IV-26, IV-34, V-3, and 11-47.

The following compounds were shown to have Ki values between 0.1 and 1.0 pM for GSK-3: compounds II- IN 103, 11-104, 11-35, 11-44, 11-45, 11-49, Il-50, 11-97, 11-101, 11-22, 11-32, III-41, 111-43, 111-44, 111-28, 11-50, 111-29, 111-64, 111-71, 111-74, 111-78, 111-82, IDIII-88, 111-90, 111-102, 111-105, 111-107, 111-110, IIIo 112, 111-114, 111-115, 111-122, 111-124, 111-124, fV-i, 111-1, 111-138, III-140, II1-142, 111-129, 111-132, III- 134, 111-135, 111-136, IV-1, V-10, IV-11, IV-12, IV-13, IV-14, fV-19, IV-21, IV-22, IV-23, IV-24, IV-3, IV-4, IV- 6, IV-7, IV-8, IV-29, IV-31, IV-32, IV-33, IV-36, V-2, V- 7, IX-38, X-154, and IX-177.

The following compounds were shown to have K 1 values between 1.0 and 20 pM for GSK-3: compounds 11-43, 11-48, 11-47, 11-51, II-68, 11-52, 11-72, II-100, 11-98, 11-89,- 11I-68, 111-81, 111- 8 3 111i-91, 111-94, 111-95, 111-96, 111-97, 111-98, 111-99, III-100, II1-101, II1-103, 111-123, 111-137, 111-139, 111-143, 111-145, 111-146, V-4, V-8, IX-156, and IX-176.

BIOLOGICAL TESTING EXAMPLE 2 K, DETERMINATION FOR THE INHIBITION OF AURORA-2 Compounds were screened in the following manner for their ability to inhibit Aurora-2 -using a standard cbupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249).

IND To an assay stock buffer solution containing o 0.1M HEPES 7.5, 10 mM MgC1 2 1 mM DTT, 25 mM NaCl, 2.5 mM (C phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate Skinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and 800 pM peptide (IRRASLG, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 pM. The resulting mixture was incubated at 30 C for 10 min. The IN reaction was initiated by the addition of 10 pL of Aurora-2 stock solution to give a final concentration of nM in the assay. The rates of reaction were obtained k0 by monitoring absorbance at-340 nm over a S minute read Stime at 30 oC using a.BioRad Ultramark plate reader (Hercules, CA). The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 pM for Aurora-2: compounds 11-33, II-34, 11-36, 11-37, 11-40, 11-41, 11-55, III-7, 111-9, III-37, III-38, III-39, III-40, 1-41, III-42, III-44, III-45, III-46, III-47, III-48, III-49, III-50, III-51, III-52, III-53, III-54, III-55, III-56, III-57, III-59, III-61, 1-63, 111-30, III-65, III-66, III-67, 1-70, III-31, III-76, 1-77, III-78, III-80, III-32, III-33, III-34, III-106, III-108, III-109, III-110,

III-

111, II-112, 111-114, III-35, III-115, 111-116, 11I-117, III-118, III-119, III-120, III-121, IV-7, IV-30, IV-32, and IV-34.

.The following compounds were shown to have Ki values between 0.1 and 1.0 pM for Aurora-2: compounds

II-

1, 1-105, 11-35, 11-38, II-39, 1-42,. 11-64, II-70, II- 53, II-99, 11-77, 11-79, II-86, 11-20, II-93, 11-94, III- 28, III-58, III-64, III-71, 111-73, III-74, III-75, III- 343 ID 102, III-105, III-107, III-113, 111-124, III-1, III-130, 0 IV-1, IV-3, IV-4, IV-6, IV-29, IV-33, and V-4.

cN The following compounds were shown to have K Svalues between 1.0 and 20 PM for Aurora-2: compounds II- 103, II-104, 11-57, 11-59, 1-61, II-63,. 11-67, 11-69, 11-75, 11-76, II-10, 11-19, 11-78, 11-54, 11-80, II-82, 11-21, 11-90, 11-91, 11-96, 11-107, III-68, III-79, III- 82, III-101, III-103, III-127, III-141, III-129, III-132, IN IV-31, V-2, IX-47, IX-154, and IX-177.

ci 0 BIOLOGICAL TESTTG EXAMPLE 3 N CDK-2 INHIBITION ASSAY O Compounds were screened in the following manner for their ability to inhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998) Protein. Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgCl 2 1 mM DTT, 25 mM NaCi, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and 100 pM peptide (MAHHHRSPRRAKKK, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 AM.

The resulting mixture was incubated at 30 oC for 10 min.

The reaction was initiated by the addition of AL of CDK-2/Cyclin A stock solution to give a final concentration of 25 nM in the assay. The rates of reaction-were obtained by monitoring absorbance at 340 nm over a 5-minute read time at 30 °C using a BioRad Ultramark plate reader (Hercules, CA). The Ki values were determined from the rate data as a function of inhibitor concentration.

L\ BIOLOGICAL TESTING EXAMPLE 4 0 ERK INHIBITION ASSAY N Compounds were assayed for the inhibition of ERK2 by a spectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay, a fixed concentration of activated ERK2 (10 nM) was incubated with various concentrations of the compound in DMSO for 10 min. at 30°C in 0.1 M HEPES buffer, pH 0 containing 10 mM MgC1 2 2.5 mM phosphoenolpyruvate, 200 iM NADH, 150 pg/mL pyruvate kinase, 50 pg/mL lactate <c dehydrogenase, and 200 pM erktide peptide. The reaction

\O

was initiated by the addition of 65 iM ATP. 'The rate of decrease of absorbance at 340 nM was monitored. The was evaluated from the rate data as a function of inhibitor concentration.

The following compounds were shown to have a Ki value of <IpM for ERK-2: III-109, III-111, 111-115, III- 117, III-118, III-120, and IV-4.

The following compounds were shown to have a Ki value of between IpM and 12pM for ERK-2: III-63, and III-108.

BIOLOGICAL TESTING EXAMPLE ART INHIBITION ASSAY Compounds were screened for their ability to inhibit AKT using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assays were carried out in a mixture of 100 mM HEPES 10 mM MgC12, 25 mM NaC1 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 170 pM ATP (Sigma Chemicals) and 200 pM peptide (RPRAATF, American Peptide, Sunnyvale, CA). Assays were carried out at 30 .C and nM AKT. Final concentrations of the components of the 345 ND coupled enzyme system were 2.5 mM phosphoenolpyruvate, 0 300 M NADH, 30 pg/ML pyruvate kinase and 10 ug/ml (C lactate dehydrogenase.

tAn assay stock buffer solution was prepared containing all of the reagents listed above, with the Sexception of AKT, DTT, and the test compound of interest.

56 pi of the. stock solution was placed in a 384 well plate followed by addition of 1 1l of 2 mM DMSO stock ND containing the test compound (final compound S 10 concentration 30 pM). The plate was preincubated for 0 about 10 minutes at 30 C and the reaction initiated by IN addition of 10 il of enzyme (final concentration 45 nM) Sand 1 mM DTT; Rates of reaction were obtained using a BioRad Ultramark plate reader (Hercules, CA) over a minute read time at 30 C. Compounds showing greater than inhibition versus standard wells containing the assay mixture and DMSO without test compound were titrated to determine IC 0 values.

BIOLOGICAL TESTING EXAMPLE 6 SRC INHIBITTON ASSAY The compounds were evaluated as inhibitors of human Src kinase using either a radioactivity-based assay or spectrophotometric assay.

Src Inhibition Assay A: Radioactivity-based Assay The compounds were assayed as inhibitors of full length recombinant human Src kinase (from Upstate Biotechnology, cat. no. 14-117) expressed and purified from baculo viral cells. Src kinase activity was monitored by following the incorporation of. 33 from ATP into the tyrosine of a random poly Glu-Tyr polymer substrate of composition, Glu:Tyr 4:1 (Sigma, cat. no.

P-0275) The following were the final concentrations of the assay components: 0.05 M HEPES, pH 7.6, 10 mM MgC1 2 2 IND mM DTT, 0.25 mg/mil BSA, 10 iM ATP (1-2 pCi 3P-ATP per o reaction), 5 mg/ml poly-Glu-Tyr, and 1-2 units of (C recombinant human Src kinase. In a typical assay, all cthe reaction components with the exception of ATP were S pre-mixed and aliquoted into assay plate wells.

Inhibitors dissoived in DMSO were added to the wells to give a final DMSO concentration of The assay plate was incubated at 30 °C for 10 min before initiating the V0 reaction with 33 P-ATP-. After 20 min of. reaction, the -i 10 reactions were quenched with 150 pi of 0 trichloroacetic acid (TCA) containing 20 MM Na 3 P04. The IND quenched samples were then transferred to a 96-well o filter plate (Whatman, UNI-Filter GF/F Glass Fiber Filter, cat no. 7700-3310) installed on a filter plate .vacuum manifold. Filter plates were washed four times with 10% TCA containing 20 mM Na 3

PO

4 and then 4 times with methanol. 200 pl of scintillation fluid was then added to each well. The plates were sealed and the amount of radioactivity associated with the filters was quantified on a TopCount scintillation counter. The radioactivity incorporated was plotted as a function of the inhibitor concentration. The data was fitted to a competitive.

inhibition kinetics model to get the Ki for the compound.

Src Inhibition Assay B: Spectrophotometric Assay The ADP produced from ATP by the human recombinant Src kinase-catalyzed phosphorylation of poly Glu-Tyr substrate was quanitified using a coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay one molecule of NADH is oxidised to NAD for every molecule of ADP produced in the kinase reaction. The disappearance of NADH can be conveniently followed at 340 nm.

IN The. following were the final concentrations of o the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgC12, (C 2 mM DTT, 0.25 mg/ml poly Glu-Tyr, and 25 nM of Srecombinant human Src kinase. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 200 pM NADH, 30 pg/ml pyruvate kinase and 10 Ag/ml lactate dehydrogenase.

In a typical assay, all the reaction components O with the exception of ATP were pre-mixed and aliquoted into assay plate wells. Inhibitors dissolved in DMSO o were added to the wells to give a final DMSO' concentration IND of The assay plate was incubated at 30 C for 10 min o before initiating the reaction with 100 pM ATP. The Sabsorbance change at 340 nm with time, the rate of the reaction, was monitored on a molecular devices plate reader. The data of rate as a function of the inhibitor concentration was fitted to compettive inhibition kinetics model to get the Ki for the compound.

The following compounds were shown to have a Ki value of <100nM on SRC: III-31, III-32, III-33, .111-34, 111-35, III-47, III-65, III-66, III-37, III-38, III-39, I-42, III-44, III-48, III-49, III-70, III-78, I-76, and IV- 32.

The following compounds were shown to have a Ki value of between 100nM and 1pM for SRC: III-63, III-71, 111-73, III-72, III-74, III-80, III-50, The following compounds were shown to have a Ki value of between 1IM and 6pM for SRC: III-79, IV-1, and IV-31.

While we have hereinbefore presented a number of embodiments of this invention, it is apparent that our basic construction can be altered to provide other embodiments which utilize the compounds and methods of 348 ND this invention. Therefore, -it will be appreciated that o the scope of this invention is to be defined by the ri appended claims rather than by the specific embodiments cwhich have been represented by way of example.

0 0 0 349

Claims (24)

1. 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by Rx and R Y is \0 substituted by oxo or T-R 3 and any substitutable C nitrogen on said ring formed by R7 and RY is 0 substituted by R 4 \0 T is a valence bond or a CI-4 alkylidene chain; R 2 and R 2 are independently selected from -T-W-R 6 or R 2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO 2 or -V-R 6 and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R'; R. is selected from -halo, -OR, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 -CN, -S(O) 2 R, -SR, 2 -CON(R 7 2 -SON (R 7 2 -N(R 7 COR, -N (R 7 CO2 (C aliphatic), -N(R 4 )N(R 2 -CtNN(R') 2 -C=N-OR, CON(R) 2 -N(R 7 )SO2N(R 7 2 -N(R')SO2R, or -OC N(R 7 each R is independently selected from hydrogen or an optionally substituted group selected from CI- aliphatic, C 6 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; 351 IND ~each R' is independently selected from -RL -00KCO 7 o -C0 2 (optionally substituted C 1 6 aliphatic), -CON(Ri 7 2 or -S0 2 R 7 or two Rt 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each Rt 5 is independently selected from -It, halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(Rt) 2 -CON(R'h2, -SC N(R') 2 -N(R 4 )COR, 7 -N (R 4 C02 (optionally substituted CI-6 aliphatic), C']-M(RtN(K') 2 -C=NN(Rt 3 -C=N-OR, -N(R 4 )CON(R 4 2 o-N (RI)SO 2 N 2 -N (R4) SO 2 R, or -OC(zzO)N(R 4 2 or R 5 and IND an adjacent substituent taken together with their 0 intervenin'g' atoms form said ring fused to Ring C; C']V is -502-, -N(R6)S0 2 -SO 2 -00O-, -N (R6) CON -N(R6)S0 2 N(RG) NR)NR)- -C(O)Nfli) -C(R6) 2 2 S-, -C(R6) 2 S0-, -C(Rt') 2 S0 2 2 S0 2 2 -C -C 2 -C (It) 2 N (R')SO 2 or -C (WS) 2 N (ItS) CON W is 2 -C(R6) 2 2 S0-, 2 S0 2 2 sO 2 2 -002-, 2 N(R')CO-, -C (It) 2 1(R 6 -C(W),2NV(R) NcR)-, 2 N (E')So 2 -C(R6) 2 N(R')CON(R6)-, or each It' is independently selected from hydrogen or an optionally substituted C1..4 aliphatic group, or two groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 menmbered heterocycly). or heteroary). ring; \O each R' is independently selected from hydrogen or an 0 optionally substituted CI- 6 aliphatic group, or two R 7 C' on the same nitrogen are taken together with the Cnitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R' is independently selected from an optionally substituted C1-4 aliphatic group, -SR 6 -COR 6 -SOR', 2 -CN, -NO 2 -CON(R') 2 or \O -co0R 6 ci 2. The compound according to claim 1, wherein said IND compound has one or more features selected from the group o -consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -Rs, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from an optionally substituted naphthyl, quinolinyl or isoquinolinyl ring; R is hydrogen or Ci- aliphatic and R Y is T-R 3 or RX and R Y are taken together with their intervening .atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; .R 1 is -halo, an optionally substituted C.-s aliphatic group, phenyl, -COR 6 -CN, -SOR', -S0 2 NH 2 2 -C0 2 R 6 -CONH 2 -NHCOR 6 -OC(0)NH 2 or -NHSO 2 R 6 and R 2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a 3.53 ND substituted or unsubstituted benzo, pyrido, pyrimido or o partially unsaturated 6-membered carbocyclo ring. 3. The compound according to claim 2, wherein: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from an optionally substituted naphthyl, quinolinyl or isoquinolinyl ring; o R x is hydrogen or Ci,- aliphatic and R Y is NO T-R 3 or Rx and R Y are taken together with their Sintervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; R 1 is -halo, an optionally substituted Ciz- aliphatic group, phenyl, -COR 6 -OR 6 -CN, -SO 2 R 6 -S02NH 2 -N(R 6 2 -CO 2 R 6 -CONH 2 -NHCOR 6 -OC(O)NH 2 or -NHSO 2 R 6 and R 2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci.- aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring. 4. The compound according to claim 2, wherein said compound has one or more features selected from the group consisting of: Ring C is a phenyl or pyridinyl-ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring 354 D system, the bicyclic ring system is selected from an S optionally substituted naphthyl ring; CA RX is hydrogen or methyl and R Y is -R, c 2, or -OR, or R X and BR are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated carbocyclo ring optionally substituted with halo, -OR, -CO 2 R, -COCOR, -NO 2 -CN, -S0 2 R, -SR, -N(R 4 2 -CON(R 4 2 IN -S0 2 N(R 4 2 -N(R 4 COR, C02 (optionally substituted C 1 -6 aliphatic), -N(R')N(R 2 -C=NN(R 4 2 C -C=N-OR, -N(R')CON(R 4 2 -N(R 4 )SO 2 N(R') 2 -N(R')SOaR, or IN -OC(=O)N (R 4 2,; o R 1 is -halo, a Ci.- haloaliphatic group, a C., Saliphatic group, phenyl, or -CN; R 2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a C 1 -6 aliphatic group, or R 2 and are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and each R 5 is independently selected from -halo, -CN, -NO, -N(R 4 optionally substituted C- aliphatic group, -OR, -CO2R, -CONH(R) -N(R COR, -SO2N(R 4 and -N(R')SO2R. The compound according to claim 4, wherein: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from an optionally substituted naphthyl ring; R x is hydrogen or methyl and R Y is -R, or -OR, or R X and R Y are taken. together with their intervening atoms to form a 5-7 membered unsaturated or o partially unsaturated carbocyclo ring optionally C- substituted with halo, -OR, -C02R, -COCOR, -NO 2 -CN, -SO2R, -SR, 2 -CON(R 4 2 -S0 2 N(R 4 2 -N(R')COR, -N(R')C0 2 (optionally substituted C 1 -s aliphatic), -N N 2, -C=NN 2 CNI -C=N-OR, -N(R')CON(R 4 2 -N(R')SO 2 N(R') 2 -N(R')SO 2 R, .or 2 S(c) R 1 is -halo, a Cz- 6 haloaliphatic group, a N Ci- aliphatic group, phenyl, or -CN; o(d) R 2 is hydrogen and R 2 is hydrogen or a k\ substituted or unsubstituted group selected' from aryl, or S. a CI-6 aliphatic group, or R 2 and R 2 are taken together C with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and- each R 5 is independently selected from -halo, -CN, -NO 2 2 optionally substituted Ci-6 aliphatic group, -OR, -C0 2 R, -CONH(R 4 -N(R 4 COR, -SO0 2 N(R' 2, and -N(R')SOR.
2. 6. The compound according to claim 4, wherein said compound has one or more features selected from the group consisting of: R X is hydrogen or methyl and R Y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R and R 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, -COR, -CON(R') 2 -CN, or -N(R) 2 wherein R is an optionally substituted C,-6 aliphatic group; 356 IND is -halo, a C 1 aliphatic group o optionally substituted with halogen, or -CN; C R 2 and R 2 are taken together with their Sintervening atoms to form a benzo, pyrido, pyrimido or Spartially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R 4 2 -CI-4 alkyl, -C-4 haloalkyl, -NO2, -0(C1.4 alkyl), -CO2(C -4 alkyl), -CN, -SO, alkyl), -SO2NH2, -OC(O)NH, -NH2S02 (C.4 alkyl), ID -NHC(O) (C. 4 alkyl), -C(O)NH 2 or -CO(Ci. 4 alkyl) wherein the (Ci 1 4 alkyl) is a straight, branched, or cyclic alkyl Sgroup; and V0 each R 5 is independently selected from -Cl, o -CN, -NH 2 -NH(C. 4 aliphatic), -N(C 1 aliphatic) 2 -O(CI-4 aliphatic), C 1 -4 aliphatic, and -C0 2 (C 1 4 aliphatic).
3. 7. The compound according to claim 6, wherein: R x is hydrogen or methyl and R Y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R* and R Y are taken together with their intervening atoms to form a benzo ring or a partially unsaturated carbocyclo ring optionally substituted with -halo, -OR, -COR, -C02R, -CON(R 4 2 -CN, or -N(R) 2 wherein R is an optionally substituted C 1 -6 aliphatic group; R' is -halo, a C1-4 aliphatic group optionally substituted with halogen, or -CN; R 2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R 4 2 -C 1 -4 alkyl, -CI-4 haloalkyl, -NO2, -O(C 1 L 4 alkyl), -CO (C 1 -4 alkyl), -CN, 357 D -SO2 4 alkyl) -SO 2 NH 2 -OC(0)NH 2 -NH 2 S0 2 (C 1 4 alkyl) 0 -NHC(O) (CI- 4 alkyl), -C(0)NH 2 or -CO(C-. 4 alkyl), wherein <CA the (C 1 4 alkyl) is a straight, branched, or cyclic alkyl t group; and S each R 5 is independently selected from -Cl, -CN, -CF 3 -NH 2 -NH(Ci- 4 aliphatic), -N(C3. 4 aliphatic) 2 -0(CI-4 aliphatic), C.. 4 aliphatic, and -C0 2 aliphatic). e-
4. 8. The compound according to claim 7, wherein R x and 0* RRY are each methyl or R x and R Y are taken together with IN the pyrimidine ring to form an optionally substituted Sring selected from quinazoline or tetrahydroquinazoline, and R 2 and R" are taken together with the pyrazole ring to form an optionally substituted indazole ring.
5. 9. The compound according to claim 1, wherein said compound is selected from Table 1. A composition comprising a compound according carrier.
6. 11. The composition according to claim 10 further comprising a second therapeutic agent.
7. 12. A method of inhibiting GSK-3 or Aurora activity in a patient comprising the step of administering to said patient a therapeutically effective amount of the composition according to claim
8. 13. The method according to claim 12, wherein said method inhibits GSK3 activity in a patient. 358
9. 14. A method of inhibiting GSK-3 or Aurora activity in a biological sample comprising contacting said biological with the compound according to claim 1. A method of treating a disease that is alleviated by treatment with an GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of the composition according to claim
10. 16. The method according to claim comprising the step of administering to second therapeutic agent.
11. 17. The method according to claim disease is diabetes.
12. 18. .The method according to claim disease is Alzheimer's disease. 15 further said patient a 15, wherein said 15, wherein said
13. 19. The method according to claim 15, disease is schizophrenia. wherein said A method of enhancing glycogen synthesis in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of the composition according to claim
14. 21. A method of lowering blood levels of glucose in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically IND effective amount of the composition according to claim oD <ID
15. 22. A method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of the composition according to claim VO
16. 23. A method of inhibiting the phosphorylation of o j-catenin in a patient in need thereof, which method ID comprises the step of administering to said patient a otherapeutically effective amount of the composition. according to ,claim
17. 24. A method of treating a disease that is alleviated by treatment with an aurora inhibitor, which method comprises the step of administering to a patient in need of such a treatment a therapeutically effective amount of the composition according to claim The method according to claim 24, further comprising the step of administering to said patient a second therapeutic agent.
18. 26. The method according to claim 24 wherein said disease is cancer.
19. 27. A compound of formula A: H NH 2 A 360 \O wherein R"1 is one to three substituents that are each o independently selected from fluoro, bromo, C~.s haloalkyl, C- nitro, or 1-pyrrolyl. S28. A compound of formula B: R N R RR I B wherein: Ci R 1 is selected from Cl, F, CF, CN, or NO 2 VO O R 5 is one to three substituents that are each Cs independently selected from H, Cl, F, CF 3 NO 2 or CN, provided that R 1 and R 5 are not simultaneously Cl; RX and R Y are independently selected from T-R 3 or R x and R Y are taken together with their intervening atoms to form a fused, .unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from .oxygen, sulfur, or nitrogen, wherein any substitutable carbon on. said fused ring formed by RX and R Y is optionally and independently substituted by T-R 3 and any substitutable nitrogen on said ring formed by R x and R Y is substituted by R 4 T is a valence bond or a CI- 4 alkylidene chain; R 3 is selected from -halo, -OR, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 -CN, -S(O) 2 R, -SR, -N(R 4 2 -CON(R 7 2 -S0 2 N (R) 2 -N(R')COR, CO, (optionally substituted C2-s aliphatic) -N(R')N(R 4 2 -C=NN(R 4 2 -C=N-OR, CON(R') 2 -N(R')S0 2 N(R 7 2 -N(R)S0 2 R, or N(R) 2; each R is independently selected from hydrogen or an optionally substituted group selected from C. aliphatic, C-i 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring 0 atoms; C' each R 4 is independently selected from -COR 7 C -C0 2 (optionally substituted Ci-j aliphatic), -CON(R') 2 i or -SO 2 R 7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered beterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an optionally substituted aliphatic group, or two R' C' on the same nitrogen are taken together with the 0 nitrogen to form a 5-8 membered heterocyclyl or IO heteroaryl ring.
20. 29. The compound according to claim 28 wherein R 1 is CF 3 A compound of formula C: Rr R 2 HN H RY NW'-Cl C wherein: R 2 and R 2 are independently selected from -T-W-R 6 or R 2 and R 2 are-taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO 2 -R 7 or and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R4; NO ~RX and RY are independently selected from, T-R 3 orean o RY are taken together with their intervening atoms to (N form a fused, unsaturated or partially unsaturated, 5-8 Ct membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by RK and RY is optionally and independently substituted by and any substitutable nitrogen on said ring f ormed by Re and. RY is substituted by R.; is a valence bond or a CaL-g alkylidene chain;- o Th~~~Vis -N(R')SO 2 IND -IQ(R)co-, -N(R6)C(O)o-, 0 -N(R')So 2 N(Rn) (N-c -00(0) C(RG) 20; -C(R 6) 2 S0-, 2 So 2 -C(R'bs 2 N21') 2 -C(R'6) 2 -C(Rt)=NN(RY)-, 2 2 or 2 N CON WP.) W is 2 2 3 S0-, 2 S0 2 -C(R'h2SO 2 -003-, -C(R6) 2 N(R')CO-, -C 2 NCR') -OCR') zNN(R') -C N-O-, 2 -C(RGY 2 N(RY)so 2 or P. 3 is selected from -halo, -OR, -CO 2 R, -COCOR, -COC3 2 00R, -CN, S(0)R, -S(o) 2 R, -SR,. -NCR') 2 -CON(R- 7 2 -S0 2 fl(R') 2 -N(R7)COR, '-N(RW)C0 2 (optionally substituted C3_6 aliphatic), -N(R')N(Rt) 2 -C=NNC,, -0=11-OR, -N(R'7)OON(R7) 3 2, -N (R')5S0 2 N (R 7 2 -N (R4) Sc R, or C=ONR72 each R is independently selected from hydrogen or an optionally substituted group selected .from C,-6 aliphatic, Cc3 aryl, a heteroazyl. ring having 5-10 I ring atoms, or a heterocyclyl ring having 5-10 ring o atoms; each R' is independently selected from -R 7 -COR 7 -CO 2 (optionally substituted Ci- 6 aliphatic), -CON(R')2, or -S0 2 R 7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring. each R 6 is independently selected from hydrogen or an optionally substituted 4 aliphatic group, or two R 6 (N groups on the same nitrogen atom are taken together o with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and o each R 7 is independently selected from hydrogen or in (C optionally substituted C3. aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
21. 31. The compound according to claim 30, wherein RX and R y are each methyl, or eR and R Y are taken together with the pyrimidine ring to form a quinazoline or tetrahydroquinazoline ring.
22. 32. The compound according to claim 31, wherein R 2 and R 2 are taken together with the pyrazole ring to form an indazole ring.
23. 33. A compound of formula D: 0 Rl NH CF3 RYwherein: wherein: R X and R Y are independently selected from T-R 3 or R* and o R Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by Rx and R' is "C optionally and independently substituted by T-R 3 and any substitutable nitrogen on said ring formed by is substituted by R 4 Cl T is a valence bond or a Ci-4 alkylidene chain; SR 3 is selected from -halo, -OR, -CO 2 R, 0 -COCOR, -COCH 2 COR, -NO 2 -CN, -S(0)2R, -SR, S-N(R4)2, -CON(R 7 2 -SO2N(R) 2 -N(R 7 )COR, Cl -N(R 7 C02 (optionally substituted C1-6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N(R 7 )CON(R 7 )a, -N(R 7 )SO 2 N(R') 2 -N(R')S0 2 R, or N(R) each R is independently selected from hydrogen or an optionally substituted group selected from CI-s aliphatic,, Cs-. aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -COR 7 -CO 2 (optionally substituted CI-s aliphatic), -CON 2 or -SO 2 R 7 or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R 5 is independently selected from halo, -OR, -CO2R, -COCOR, -NO 2 -CN, -SOR, -SR, 2, -CON(R') 2 -SO 2 N(R') 2 -N(R')COR, -N(R 4 )C0 2 (optionally substituted CI-. aliphatic), -N(R')N(R4) 2 -C=NN(R') 2 -C=N-OR, -N(R')CON(R) 2 -N(R')SO 2 N(R4) 2 -N(R4)SOaR, or 2
24. 34. The compound according to claim 33, wherein R X O and Ry are each .methyl, or R X and R Y are taken together C' with the pyrimidine ring to form a quinazoline or S- tetrahydroquinazoline ring. o DATED this 21 s t day of March 2006 Vertex Pharmaceuticals Incorporated 0 By their Patent Attorneys O SCULLEN CO. O' 366