AU2003232919B2 - Protein kinase inhibitors - Google Patents

Description

WO 03/099796 PCT/AU03/00629 Protein Kinase Inhibitors FIELD OF THE INVENTION The present invention relates to the field of inhibitors of protein kinaes.

BACKGROUND OF THE INVENTION Protein kinases are a family of enzymes that catalyse the phosphoryltion of specific residues in proteins. In general protein kinases fall into several groips; those which preferentially phosphorylate serine and/or threonine residues, those which preferentially phosphorylate tyrosine residues and those which phosphorylite both tyrosine and Ser/Thr residues. Protein kinases are therefore key elements in signal transduction pathways responsible for transducing extracellular signals, including the action of cytokines on their receptors, to the nuclei, triggering various biological events. The many roles of protein kinases in normal cell physiology include cell cycle control and cell growth, differentiation, apoptosis, cell mobility and mitogenesis.

Protein kinases include members of the Protein Tyrosine Kinase family (PTKs), which in turn can be divided into the cytoplasmic PTKs (CTKs) and the receptor PTKs (RTKs). The cytoplasmic PTKs include the SRC family, (including: BLK; FGR; FYN; HCK; LCK; LYN; SRC;YES and YRK); the BRK Family (including: BRK; FRK, SAD; and SRM); the CSK family (including: CSK and CTK); the BTK family, (including BTK; ITK; TEC; MKK2 and TXK), the Janus kinase family, (including: JAKI, JAK2, JAK3 and Tyk2), the FAK family (including, FAK and PYK2); the Fes family (including FES and FER), the ZAP70 family (including ZAP70 and SYK); the ACK family (induding ACK1 and ACK2); and the Al family (including ABL and ARG). The RTK family includes the EGF-Receptor family (including, EGFR, HER2, HER3 and HER4); the Insulin Receptor family (including INS-R and IGF1-R); the PDGF-Receptor family (including PDGFRc, PDGFRD, CSF1R, KIT, FLK2); the VEGF-Receptor family (including; FLT1, FLK1 and FLT4); the FGF-Receptor family (including FGFR1, FGFR2, FGFR3 and FGFR4 the CCK4 family (including CCK4); the MET family (including MET and RON); the TRK family (including TRKA, TRKB, and TRKC); the AXL family (including AXL, MER, and SKY); the TIE/TEK family (including TIE and TIE2/TEK); the EPH family (including EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPI-HA, EPHAS, EPHBI, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6); the RYK family WO 03/099796 PCT/AU03/00629 2 (including RYK); the MCK family (including MCK and TYROO1); the ROS family (including ROS); the RET family (including RET); the LTK family (including LTK and ALK); the ROR family (including ROR1 and ROR2); The Musk family (including Musk); the LMR family including LMRI, LMR2 and LMR3); and the SuRTKi06 family (including SuRTK106).

Similarly, the serine /threonine specific kinases comprise a number of distinct sub-families, including; the extracellular signal regulated kinases, (p42/ERK2 and p44/ERKI); c-Jun NH2-terminal kinase (JNK); cAMP-responsive element-binding protein kinases (CREBK); the cydin dependent kinases (CDKs); cAMP-dependent kinase (CAPK); mitogen-activated protein kinase-activated protein kinase (MAPK and its relatives); stress-activated protein kinase p38/SAPK2; mitogen-and stress-activated kinase (MSK); protein kinases, PKA, PKB and PKC inter alia.

Additionally, the genomes of a number of pathogenic organisms possess genes encoding protein kinases. For example, the malarial parasite Plasmodium falciparum and viruses such as HlfV and Hepatitis viruses appear to bear kinase related genes.

Inappropriately high protein kinase activity has been implicated in many diseases resulting from abnormal cellular function. This might arise either directly or indirectly, for example by failure of the proper control mechanisms for the kinase, related for example to mutation, over-expression or inappropriate activation of the enzyme; or by over- or under-production of cytokines or growth factors also participating in the transduction of signals upstream or downstream of the kinase, In all of these instances, selective inhibition of the action of the kinase might be expected to have a beneficial effect. Diseases where aberrant kinase activity has been implicated include; diabetes; restenosis; atherosclerosis; fibrosis of the liver and kidney; ocular diseases; myelo- and lymphoproliferative disorders; cancer such as prostate cancer, colon cancer, breast cancer, head and neck cancer, leukemia and lymphoma; and, auto-immune diseases such as Atopic Dermatitis, Asthma, rheumatoid arthritis, Crohn's disease, psoriasis, Crouzon syndrome, achondroplasia, and thanatophoric dysplasia.

3 SUMMARY OF THE INVENTION The present inventors have found that a group of compounds based upon a disubstituted pyrazine scaffold are inhibitors of protein kinases.

This invention is therefore directed to compounds that potentially modulate Protein Kinase signal transduction by affecting the enzymatic activity of RTKs, CTKs and/or STKs, thereby interfering with the signals transduced by such proteins. More particularly, the present invention is directed to compounds which modulate RTK, CTK and/or STK mediated signal transduction pathways as a therapeutic approach to cure many kinds of tumor.

Accordingly, in a first aspect the present invention consists in a compound of the general formula R2 W R 1 AQ-N Nr

N

I

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein R1 is H, Ci4alkyl; Q is a bond, or C14alkyl, wherein when Q is a bond W is not present; A is aryl or hetaryl each optionally substituted with 0-3 substituents independently chosen from halogen, Ci4alkyl, CH 2 F, CHF 2

CF

3 CN, aryl, hetaryl, OCF 3 OCi4alkyl, OC 2 -5alkylNR4R5, Oaryl, Ohetaryl, C0 2 R4, CONR4R5, nitro,

C

1 4alkylNR4R5, NR6C 1 -4alkylNR4R5, NR4COR5, NR6CONR4R5, NR4SO 2 R5; and R4, R5 are each independently H, C 1 4alkyl, Cl4alkyl cycloalkyl, Ci4alkyl cyclohetalkyl, aryl, hetaryl, Cl-4alkyl aryl, C.4alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R7; and R6 is selected from H, Ci 4 alkyl and R7 is selected from H, Cl-4alkyl, aryl, hetaryl, P72437.AU.I Specification 2009-1-15

C

14 alkyl aryl, C14alkyl hetaryl; R2 is 0-2 substituents independently selected from halogen, C-4alkyl, OH, OCl4alkyl, CH 2 F, CHF 2

CF

3

OCF

3 CN, Cl4alkylNR8R9, OCl4alkylNR8R9, s CO 2 R8, CONR8R9, NR8R9, NR8COR9, NR1OCONR8R9, NR8SO 2 R9; and R8, R9 are each independently H, Cl 4 alkyl, C 14 alkyl cycloalkyl, C -4alkyl cyclohetalkyl, aryl, hetaryl, Cl4alkyl aryl, C-4alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R11; and R10 is to selected from H, CI-4alkyl, aryl or hetaryl; and RI 1 is selected from H, CI4alkyl, aryl, hetaryl, C- 4 alkyl aryl, C-4alkyl hetaryl; Y is halogen, OH, NR12R13, NR12CORI3, NR12CONR3, N12SO 2 R13; and R12 and R13 are each independently H, Ch 2 F, CHF 2

CF

3 CN, Cl4alkyl, C -4alkyl cycloalkyl, C -4alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R14, and R14 is selected from H, C-4alkyl; N 0-4; W is selected from H, C-4alkyl, C2-6alkenyl; where C14alkyl or C2-alkenyl may be optionally substituted with Cl4alkyl, OH, OC-4alkyl, NRI5R6; and R15, and R16 are each independently H, Cl 4 alkyl, C -4alkyl cycloalkyl, CI- 4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R17, and R17 is selected from H, C -4alkyl; wherein when Y is OH or NHCOCH 3 then R2 is 1-2 substituents and wherein, when Y is NH 2 and R2 is absent then Y is in the para position, or a compound selected from the group consisting of: 01-1

OH

H

N N N P72437.AU.1 Specification 2009-1-15

OH

N

00 c-I OH 0 H O 0~

OH

HNH

O

N

HNO

H

HN 0 CyN

N

N

H

N SO 2 Ph Nl N N

N

N

P72437.AU. I Specification 2009-1-15 IN4 0 0O H

OH

OH N N

N

0O N N

N

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof.

In a second aspect the present invention consists in a composition comprising a carrier and at least one compound of the first aspect of the invention.

In a third aspect the present invention consists in a method of treating a protein kinase-associated disease state, the method comprising administering a therapeutically effective amount of at least one compound of the first aspect of the invention or a therapeutically effective amount of a composition of the second aspect of the invention.

DETAILED DESCRIPTION This invention is directed to compounds that potentially modulate Protein Kinase signal transduction by affecting the enzymatic activity of RTKs, CTKs and/or STKs, thereby interfering with the signals transduced by such proteins. More particularly, the present invention is directed to compounds which modulate RTK, CTK and/or STK P72437.AU.1 Specification 2009-1-15 mediated signal transduction pathways as a therapeutic approach to cure many kinds of tumor.

Accordingly, in a first aspect the present invention consists in a compound of the general formula R2 W R1 ,Q-N

N

Y

N

lo or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein: RI is H, C 1 4alkyl; Q is a bond, or C1 4 alkyl, wherein when Q is a bond W is not present; A is aryl or hetaryl each optionally substituted with 0-3 substituents independently chosen from halogen, C-4alkyl, CH 2 F, CHF 2 CF3, CN, aryl, hetaryl, OCF 3 OC-4alkyl, OC 2 5 alkylNR4R5, Oaryl, Ohetaryl, C0 2 R4, CONR4R5, nitro, NR4R5, C 1 4alkyINR4R5, NR6C 1 4alkylNR4R5, NR4COR5, NR6CONR4R5, NR4SO 2 R5; and R4, R5 are each independently H, C-4alkyl, C14alkyl cycloalkyl,

C

1 4alkyl cyclohetalkyl, aryl, hetaryl, C1 4 alkyl aryl, CI-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R7; and R6 is selected from H, C-4alkyl; and R7 is selected from H, C14alkyl, aryl, hetaryl,Cl4alkyl aryl, C- 4 alkyl hetaryl; R2 is 0-2 substituents independently selected from halogen, C- 4 alkyl, OH,OCl 4 alkyl, CH 2 F, CHF 2

CF

3

OCF

3 CN, C1 4 alkylNR8R9, OCl 4 alkylNR8R9, C0 2 R8, CONR8R9, NR8R9, NR8COR9, NRIOCONR8R9, NR8SO 2 R9; and R8, R9 are each independently H, Cl 4 alkyl, C14alkyl cycloalkyl, C14alkyl cyclohetalkyl, aryl, hetaryl, C14alkyl aryl, Cl 4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with RI1; and RIO P72437.AU.1 I Specification 2009-1-15 is selected from H, Cl4alkyl, aryl or hetaryl; and R11 is selected from H, Ci4alkyl, aryl, hetaryl, Cl4alkyl aryl, Cl4alkyl hetaryl; Y is halogen, OH, NR12R13, NR12COR13, NR12CONR13, N12SO 2 R13; and R12, and R13 are each independently H, CH 2 F, CHF 2

CF

3 CN, C14alkyl, Cl4alkyl cycloalkyl, C1.4alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R14, and R14 is selected from H, C-4alkyl; n 0-4; W is selected from H, Cl 4 alkyl, C2-6alkenyl; where Ci4alkyl or C 2 _6alkenyl may be optionally substituted with C 14 alkyl, OH, OCi4salkyl, NR15R16; and R15, and R16 are each independently H, CI-4 alkyl, C 1 -4 alkyl cycloalkyl, C 1 -4alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R17, and R17 is selected from H, CI-4alkyl; wherein when Y is OH or NHCOCH 3 then R2 is 1-2 substituents and wherein when Y is NH 2 and R2 is absent then Y is in the para position; or a compound selected from the group consisting of: o

OH

H

N

OH

NN0-

N

P72437.AU.1 Specification 2009-1-15 2003232919 09 Feb 2009

H\

zm om m 0 00 00 0 0 N

OH

OH N N 0K

OH

N

K-/

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof.

In the above description it will be appreciated that: Cl4alkyl means a straight or branched alkyl chain; Aryl means unsubstituted or optionally substituted phenyl or naphthyl; Hetaryl means an unsubstituted or optionally substituted 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from 0, N, S; Cycloalkyl means a 3-8 membered saturated ring; Cyclohetalkyl means a 3-8 membered saturated ring containing 1-3 heteroatoms selected from O, S, NR18, where R18 is H, C- 4 alkyl, aryl, hetaryl.

In a further preferred embodiment the compound is selected from compounds of the general formula II.

P72437.AU.I Specification 2009-1-15 R2 N

N

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein: R I is H, C I alkyl A is aryl or hetaryl each optionally substituted with 0-3 substituents independently chosen from halogen, C14alkyI, CH 2 F, CHF 2

CF

3 CN, aryl, hetaryl, OCF 3

OC

14 alkyl, OC 2 -salkyINR4R5, Oaryl, Ohetaryl, C0 2 R4, CONR4R5,

C

1 AalkylNR4R5, NR6CI4alkylNR4R5, NR4COR5, NR6CONR4R5, NR4SO 2 and R4, R5 are each independently H, C I 4 alkyl, C 14alkyl cycloalkyl, C I alkyl cyclohetalkyl, aryl, hetaryl, C14alkyl aryl, Ci 4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from 0, S and N, where N is substituted with R7; and R6 is selected from H, C1 4 alkyl; and R7 is selected from H, CI4alkyl, aryl, hetaryl,

C

14 alkyl aryl, C14alkyl hetaryl; R2 is 0-2 substituents independently selected from halogen, C 14 alkyl, OH, OC14alkyl, CH 2 F, CHF 2

CF

3

OCF

3 CN, C14alkylNR8R9, OC14alkyINR8R9, C0 2 R8, CONR8R9, NR8R9, NR8COR9, NR1IOCONR8R9, NR8SO 2 R9; and R8, R9 are each independently H, C14alkyl, C1 4 alkyl cycloalkyl, C1 4 alkyI cyclohetalkyl, aryl, hetaryl, C 1 4alkyl aryl, C 14 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from 0, S and N, where N is substituted with Ri 11; and RIO0 is selected from H, C1 4 alkyI, aryl or hetaryl; and RI I is selected from H, C1 4 alkyl, aryl, hetaryl, C14alkyl aryl, C1 4 alkyl hetaryl; Y is halogen, OH, NRI2RI3, NR12CORl3, NRI2CONRl3, NI2SO 2 RI 3; and R 12, and R 13 are each independently H, CH 2 F, CHF 2

CF

3 CN, C 1 4 alkyl, C 14alkyl cycloalkyl, C I alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing a heteroatom P72437TAU. I Specification 2009- 1-15 selected from O, S and N, where N is substituted with R14, and R14 is selected from H, Ci 4 alkyl; n 0-4; W is selected from H, C-4alkyl, C2.zalkenyl; where Cl-4alkyl or C2- 6 alkenyl may be optionally substituted with C.4alkyl, OH, OCi4alkyl, NR15R16; and R15, and R16 are each independently H, Cl-4alkyl, Cl-4alkyl cycloalkyl, C14alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R17, and R17 is selected from H, Cl_4alkyl; wherein when Y is OH or NHCOCH 3 then R2 is 1-2 substituents and wherein when Y is NH 2 and R2 is absent then Y is in the para position.

In the above description it will be appreciated that: C14alkyl means a straight or branched alkyl chain; Aryl means unsubstituted or optionally substituted phenyl or naphthyl; Hetaryl means an unsubstituted or optionally substituted 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N, S; P72437.AU. I Specification 2009-1-15 WO 03/099796 PCT/AU03/00629 9 Cycloalkyl means a 3-8 membered saturated ring Cyclohetalkyl means a 3-8 membered saturated ring containing 1-3 heteroatoms selected from 0, S, NRIB, where R18 is H, CI, alkyl, aryl, hetary.

The compounds of this invention include all conformational isomers (e cis and trans isomers). The compounds of the present invention have asymmet ic centers and therefore exist in different enantiomeric and diastereomeric forms. Thisjinvention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositins and methods of treatment that may employ or contain them. The compounds of iormula I may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.

This invention also encompasses pharmaceutical compositions contaiiing prodrugs of compounds of the formula I. This invention also encompasses methods of treating or preventing disorders that can be treated or prevented by the inhibition of protein kinases, such as JAK comprising administering prodrugs of compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy or cdrboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acd residue, or a polypeptide chain of two or more (eg, two, three or fpur) amino acid residues which are covalently joined through peptide bonds to frde amino, hydroxy and carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acds commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demdsine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, orithine and methioine sulfone. Prodaugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbbnyl carbon prodrug sidechain. Prodrugs also include phosphate derivatives of compounds of formula I (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I.

In a still further preferred embodiment the compound possesses Schirality at the chiral carbon bearing W, where W is C, alkyl. The compound can be used as a WO 03/099796 PCT/AU03/00629 purified isomer or as a mixture of any ratio of isomers. It is however preferred that the mixture comprises at least 70%, 80%, 90%, 95%, or 99% of the preferred isomer.

In a still further preferred embodiment the compound is selected froni the compounds set out in Table 1.

In a second aspect the present invention consists in a composition comprising a carrier and at least one compound of the first aspect of the invention.

In a third aspect the present invention consists in a method of treating a protein kinase-associated disease state, the method comprising administering a therapeutically effective amount of at least one compound of the first aspect of the invention or a therapeutically effective amount of a composition of the second aspect of the invention.

In a preferred embodiment the disease state involves a receptor tyrosine kinase selected from the group consisting of EGF, HER2, HERS, HER4, IR, IGP-IR, IRR, PDGFR.alpha., PDGFR.beta., CSFR, C-i C-fms,Flk-lR, Flk4, KDR/IPk-1, Flt 1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R.

In another preferred embodiment, the disease state involves a cellular tyrosine kinase selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes/Fps, Fak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hek, Fgr and Yrk.

In a further preferred embodiment, the disease state involves a tyrosine kinase selected from the group consisting of JAK, JAK2, JAK3 and TYK2.

In a yet further preferred embodiment, the disease state involves a serine/ threoniae kinase selected from the group consisting of ERK2, c-Jun, p38 MAPK, PKA, PKB, PKC, a cyclin-dependent kinase, CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, and CDKI..

In a preferred embodiment of the present invention the disease state is iselected from the group consisting of Atopy, such as Allergic Asthma, Atopic Dermatitis (Eczema), and Allergic Rhinitis; Cell Mediated Hypersensitivity, such as Allergic Contact Dermatitis and Hypersensitivity Pneumonitis; Rheumatic Diseases, such as Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Juvenile Arthritis, WO 03/099796 PCT/AU03/00629 11 SjOgren's Syndrome, Scleroderma, Polymyositis, Ankylosing Spondylitis, Pshriatic Arthritis; Other autoimmune diseases such as Type I diabetes, autoimmune hyroid disorders, and Alzheimer's disease; Viral Diseases, such as Epstein Barr Virs (EIBUV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV), Humau Papilloma Virus (HPV), Cancer, such as Leukemia, Lymphoma and Prostate Cancer.

In one embodiment, the method of the invention is used in the treatmnt of sarcomas, carcinomas and/or leukemnias. Exemplary disorders for which the subject method can be used alone or as part of a treatment regimen include: fibrosardoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdornyosarcoma, colon carcinoma, pancreatic cancer, bIeast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papilldry carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, branchogenic carcinoma, renal cell carcinoma, hepatcma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cAncer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytomna, medulloblastoma, craniopharyngipma, ependymomna, pinealoma, hemangioblastoma, acoustic neuroma, oligodendrbglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

In certain embodiments, the method of the invention is be used to treat disorders such as carcinomas forming from tissue of the breast, prostate, kidrdey, bladder or colon.

In other embodiments, the method of the invention is used to treat hyperplastic or neoplastic disorders arising in adipose tissue, such as adipose cell tumors, e.g,, lipomas, fibrolipomas, lipoblastomas, lipomatosis, hibemomas, hemangiomas' andl or liposarcomas.

As used herein the term "protein kinase-associated disease state" refers to those disorders which result from aberrant protein kinase activity, in particular JAN activity and/or which are alleviated by inibition of one or more of these enzymes.

WO 03/099796 PCT/AU03/00629 12 In further aspects the present invention provides the use of the compounds described in the preparation of medicaments for the treatment of protein kinaseassociated disease states including JAK-associated disease states.

As used herein the term "JAK", "JAK kinase" or "JAK family" refers to! protein tyrosine kinases which possess the characterizing features ofJAK1, JAK2, JAK3 and TYK as described herein.

The present invention provides pharmaceutical compositions comprising at least one of the compounds of the formula I or II capable of treating a protein kinaseassociated disorder in an amount effective therefor, and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain other therapeutic agents as described below, and maybe formulated, for example,'by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.

The compounds of the formula I or II may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such ashy inhalation spray; topically, such as in the form of a cream or ointment; or rectlly such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The compounds may, for example, be administered in a form suitable for immediate release or extended release.

Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.

In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or WO 03/099796 PCT/AU03/00629 13 other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.

However, the method can also be practiced in other species, such as avian sIecies chickens).

Diseases and conditions associated with inflammation and infection dan be treated using the method of the present invention. In a preferred embodiment, the disease or condition is one in which the actions of eosinophils and/or lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response.

The subjects treated in the above methods, in whom which JAK inhibition is desired, are mammals, including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a human being, male or female.

The term "therapeutically effective amount" means the amount of the subject composition that will elict the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The terms "administration of' and or "administering a" compound should be understood to mean providing a compound of the invention to the individuai in need of treatment.

The pharmaceutical compositions for the administration of the compoinds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient

I

WO 03/099796 PCT/AU03/00629 14 into association with a liquid carrier or a finely divided solid carrier or both; and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared accoiding to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

WO 03/099796 PCT/AU03/00629 Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohul. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.

Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the fqrm of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum WO 03/099796 PCT/AU03/00629 16 tragacanth, naturally-occurring phosphatides, for example soy bean, lecithi, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emnilsions may also contain sweetening and flavoring agents.

Syrups and elixirs maybe formulated with sweetening agents,.for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparationimay also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally em ployed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids;such as oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which issolid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.) The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or WO 03/099796 PCT/AU03/00629 17 multilamellar hydrated liquid crystals that ate dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like. The preferred lipids are the phospholipids and phosphatidyl cholines, both natural and synthetic. Methods to form liposomes are known in the art: The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological condititos.

Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles.

The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach:one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.

Examples of other therapeutic agents include the following: cyclosporins cydosporin CTLA4-Ig, antibodies such as ICAM-3, anti-L-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 CD154), fusion proteins constructed from and gp39 (CD401g and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, aspirin, acetaminophen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisolone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine, VP-16, etoposide, fludarabine, cisplatin and cyclophosphanide, TNF-c inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof.

WO 03/099796 PCT/AU03/00629 18 When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

In the treatment or prevention of conditions which require protein kinase inhibition an appropriate dosage level will generally be about 0.01 to 500 mg per kg patientbody weight per day which can be administered in single or multiple doses.

Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.02 to 250 mg/kg per day, about 0,05 to 100 mg/kg per day, or abolit 0.2 to mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0..5 to 5 or 5 to mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0,25.0,30.0, 75.0,100.0, 150.0,200.0, 250.0,300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combinition, the severity of the particular condition, and the host undergoing therapy- Throughout this specification the word "com-prise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element integer or step, or group of elements, integers or steps.

All publications mentioned in this specification are herein incorported by reference.

WO 03/099796 PCT/AU03/00629 19 Any discussion of documents, acs, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each daim of this application.

In order that the nature of the present invention may be more clearly understood preferred forms thereof will now be described by reference to the following non-limiting Examples.

MATERIALS AND METHODS: Compound Synthesis Compounds are generally prepared in a 2-step process starting from 2,6dichloropyrazine.

The first step is a nucleophilic aromatic substitution to generate a monoaminomonohalo intermediate. (Scheme 1).

H

C

CI R1-NHa N CI Ri base Scheme 1 The nucleophilic aromatic substitution is typically carried out by addition of a primary amine to the di-halogenated heterocycle in a solvent such as ethanol, isopropanol, tert-butanol, dioxane, THF, DMF, toluene or xylene. The reaction is typically performed at elevated temperature in the presence of excess amine or a nonnucleophilic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate.

Alternatively, the amino substituent may be introduced through a transition metal catalysed amination reaction. Typical catalysts for such transformations include Pd(OAc) 2 /P(t-Bu)a, Pd,(dba)/BINAP and Pd(OAc),/BINAP. These reactions are WO 03/099796 PCT/AU03/00629 typically out in solvents such as toluene or dioxane, in the presence of bases such as caesium carbonate or sodium or potassium tert-butoxide at temperatures ranging from room temperature to reflux.

The amines employed in the first step of the synthesis of these compounds are obtained commercially or are prepared using methods well known to those skilled in the art. Of particular interest are a-methylbenzylraines which may be prepared through reduction of oximes (Scheme Typical reductants include lithium aluminium hydride, hydrogen gas in the presence of palladium on charcoal catalyst, Zn in the presence of hydrochloric acid, sodium borohydride in the presence of a Lewis acid such as TiCl, ZrCL, NiC1 and MoO 3 or sodium borohydride in conjunction with Amberlyst H15 ion exchange resin and LiC.

OH

Scheme 2 a-Methyl benzylamines of high optical purity may be prepared from chiral c, methyl benzyl alcohols using methods well known to those skilled in the art. Such methods include derivatisation of the hydroxyl as a mesylate or tosylate and displacement with a nitrogen nucleophile, such as phthalimide or azide which is then converted to the primary amine using conventional synthetic methods; or, displacement of the hydroxyl with a suitable nitrogen nucleophile under Mitsunobu conditions. The chiral a-methyl benzyl alcohols may be obtained through chiral reduction of the corresponding ketones. Chiral reducing methods are now well known in organic chemistry and include enzymatic processes, asymmetric hydrogenation procedures and chiral oxazaborolidines.

The second step of the synthesis typically involves a palladium mediated crosscoupling of the monoamino-monochloro intermediate with a suitably functionalised coupling partner. Typical coupling partners are boronic acids (Suzuki coupling: see for example Miyaura, N. and Suzuki, Chem Rev. 1995, 952457) or stannanes (Stille WO 03/099796 PCT/AU03/00629 21 coupling: see for example Stille, Angew. Chem., nt. Ed. Eng., 1986, 25,508) (Scheme 3).

H H

C,

1 R

M

C R YN R2

-RI

R Pd catalyst N base N Scheme 3 The Suzuki coupling is the preferred coupling method and is typically performed in a solvent such as DME, THP, DMF, ethanol, propanol, toluene, or 1,4dioxane in the presence of a base such as potassium carbonate, lithium hydroxide, caesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate.

The reaction may be carried out at elevated temperatures and the palladium catalyst employed may be selected from [Pd(PPh,)41, Pd(OAc), [PdCl,(dppf)], Pd,(dba),/P(t- Bu),.

The products formed from this reaction sequence maybe further derivatised using techniques well-known to those skilled in the art. Alternatively, derivatisation of the mono-amino mono-chloropyrazine may be undertaken prior to displacement of the 6-chloro substituent. This derivatisation typically involves functionality originally present on the amine species and employs methods well known to those skilled in the art.

Representative syntheses are reported below.

WO 03/099796 WO 03/99796PCT/A1103/00629 22 Example 1 V4--phenyk-thyl]prazi-2-fliW Cl N C~I Ny

N

A solution of R-a-mnethylbenzylaiie (0.57g, 4.7mmol) and 2,6dicbloropymazine (0.6388g, 4.29mmol) in dioxane (2.5 ml.) was heated at retlux under

N

2 for 48 hours. The solvent was removed and the product crystallised from toluenehexane (0.82g, 82%).

1 Hnm.r. (CDCI 2 8 1.58 6.6H-z, 3H, CE 3 4.88 (in, 1H, CH), 5.07 (ct if-I, NW-I, 7.24-7.96 (mn, 5H-, Ar-I-u, 7.61 1H, pyraz-H), 7.79 11-, pyxaz--IY Example 2 2-AMfthOAY-4-(6-(/(fRlphenyketyaJ2lo~pyrahi-2-y~phRna Under a nitrogen atmosphere a mixture of 6-cblcro-NR-Ii4phenylethyllpyrazin-2-ainine (0.611g, 2.6irnxnofl, '1-(4,4,5,5-tetrainethyl-i,5,2dioxaborolan-2-yl)phenol (0.765g, S-i4inxol), tetrulcs(triphenylphoaphine)pafladiuin(0) (0.30g, 0.26znzol) and toluene (3inL,) was treated with 2M aqueous sodium carbonate solution (1.6snL, Z6mniol- The resulting mixture was stirredl vigorously whilst being heated undex reflux for 24 hours. Once WO 03/099796 PCT/AU03/00629 23 cool ethyl acetate was added and the mixture dried (MgSO ard filtered. Removal of solvent in vacuo then yielded crude product, which was purified by column chromatography using dichloromethane:diethyl ether (99:1- 90:10) as eluent: (0.619g, 74%).

(CDCa 3 6 1.72 3H, 6.9 Hz, CH 3 4.06 1H, OCH), 4.90 (m, 1H, CH), 5.75 (br s, 1H, NH), 6.98 IH, J= 8.1 Hz, ArH), 7.26-7.46 7H1, Ar-H), 7.97 1H, pyraz-H), 8.20 1iH, pyraz-H) WO 03/099796 WO 03/99796PCT/A1103/00629 24 Example 3 6-Ch~boA-[KIRH-(-methoxphey1eth~tZfl k2&Jaife 7 N In a procedure analogous to Example 1, reaction of R-ct-methylbenzylamine 6.6mniol) and 2,6-dichioropyrazine (0.440& 9 2.95n'mol) furnished the, product (517mg, 67%).

1 H-n.m~r. (GDQ 3 8 1.59 fr6.9Hz, 3H, CU 5 3.81 3H, 0C11), 4.8v (in, l1I, CR), 5.47 (hr liI, NH), 6.79-7.30 (in, 4Xt Ax-H), 7,66 1H-, pyraz-H), 7.79 1Hi, pyraz-H).

i0 Example 4 Z-1N In a procedure analogous to Example 2, reaction of 2-IIR-C-iethyl-3-meffioxybenzylainino)-6-chlore-pyrazine (137-2m&, .S2imol) and 2-inethoxy-4-(4,4,5,5tetrainEthyl-13,2-dioxaborolan-2-ylphenol (143mg, .S7nanol) furnished the product (32mng, 18%).

WO 03/099796 PCT/A1103/00629 'I--nximr. (CDC 3 6 1.6a (4 ,FrG.6Hz, 3F, Cl-S), 3.79 311, OCJ13), 3.94 3H!, 0C11), 4.94 (in, iN, CH), 5.02 (di, j=GF-lz, Ili, NHl), 6.04 (br s, 11,0OH), 6.77-7.48 (mn 7H1, Ar-H), 7.69 iN, pyraz-HY. 8.23 Il-I pyraz-N) m 7 (ES) 352 WO 03/099796 WO 03/99796PCT/A1103/00629 26 Example ,przn2-ann I

O

N

0j 31F N -3 In a procedure analogous to Example 1, reaction of R-cc-inethylbcnzylamine (1.0g, 6.6rnmoI) and 2,6-dichloropyrazine (0.4355S, 2.P2rnil) furnished the product 93%).

'H-n.rn.r. (CDCb3) b 1.36 3K-1,= 6.9H-z, CH3), 3.80 3H1, OCH 3 (mn, 1H1, CR), 5.25 (br s, i, NH), 6.88 (AA'XX', 21-I, Ar-H), 7.28 (A.A'XX, 2H1, Ar-1l), 7.64 (Es, 1H-, pyraz-H), 7.78 1H1, pyraz-E).

Example 6 NT

C,

N

In a procedure analogous to Examnple 2, reaction of 2-(R-cc-nethy1-47methoxybenzylarninoQ)-6-chloro-pyrazine (127.1ing, 0.48nmol) and 2-xnethioxy-4-(4,4,5,5- WO 03/099796 PCT/A1103/00629 teframethyld-d2 ioxabOTOlafl2il)Phflo (145in& .S8mmoI) furnished the product (59.5m&, 'I-i-n.rn.r. (CDC13) 81.59 3HI1- 6.6 Hz, 3.79 3K, OCX,), '3.93 3H, OCH,), 4.97 (in, 2K, C11 and NH), 5.95 (br s, 11,, 01-1), 6.87 2H-, Arfl), 6.97 (d, IN, J= 8.1 Hz ArH-), 7.32 (AA'XX'. 2H4, Ar-H), 7.46 (mn, .2H, ArE), 7.66 111 pyrsz- 8.22 litL pyraz-I-P.

ml/z (ES) 352 WO 03/099796 WO 03/99796PCT/A1103/00629 28 )Example 7 C-Chloro-NjV-(R)-,g,3,4.tetrahydronaphtae-yIprzi2-mn NI:N GI

N

-t H

N'

In a procedure analogous to3 Example 1, reaction of (191234 tetrahydronaphthalen-1-arine (442m& 3.0nmio1) and 2,6-dchioropyrazine 2.72mmol) furnished the product (521mg, 74%).

(CDCI8) 821.89 (in, 2H1, CH 2 C71hArt, 1,97 111, H-

C)HCN

2 CHArX,2.O8 (in, IlII, HC-H-CH 2 CHAr), 2.83 (at, 211, CH 2 Ar), 4.94 (br s, 1K-I NH), 5.15 (in, 1H-, CH), 7.12-7.31 (Itt, 4H1, Ar-Li), 7.76 1H-, pyraz-H), 7.81 1H1, pyraz-H).

Example B 2-Meghoxy4/1-6-r2R)-1,2434-terhydronaphfalen-1-ylaninopyrazn-2-y}phenol Hr

NTIJ

N N In a procedure analogous to Example 2, reaction of 6-chloro-N-(1A ,1,2,3,4tetrahydronaphthaen-1-yIpyrazin-2-amine (139m,-, .S36minol) and 2-rnethoxy-4- (4,4,5,5-tetramethy1-1A32-dioxabarclan-2-y1)phenol (147mg, O59minal) furnished the product (87mg, 47%).

WO 03/099796 PCT/A1103/00629 (CI,1) 8 1.91 (mi, 2H1, CI- 2

CH

2 Ar), 2.09 (in, 2K1 (C (mn, 211i, 011 2 Ar, 5.96 3H,OCM 3 4.87 (d,Jf= 7.8Hz, 1FH, NH), -5.25 (mn, LU, CMH), 6.04 (hr s, 1H1, OH), 6.98-7.73 (in, 7H-, Ar-H), 7.79 11%, pyraz-H), 8.26 Na 1H1, pyraz-H).

m/z (ES) 348 WO 03/099796 WO 03/99796PCT/A1103/00629 so Example 9 6-Chloro-N-K1IR)-2,3-dffydfro-IH-inden1-y]pjrzn 2-ainna

N'

H

Nr In a procedure analogous to Example 1, reaction of (1R1)-2,3-dihydro-iH-inden- 1-ylarnine (1.0g, 7.6rnol) and 2,6-did-doropyrazine (0-45 2 g, 3.O4nirol) furnished the product (673.8mg, 1 H-rum.r. (CDC1 3 6 1.91 (mn, IH, jj-CHICH- 2 Ar), 2.68 (in, HC-fl-CHCHAr), 3.00 (mn, 2U1 CftAr), 5.03 Qxr s, III, NHl), 5.45 (in, IN, OH), 7.18-7.33 (Mn 4R-1Ar-H), 7.82 (bras, 2H4, 2xpyraz-H).

Example to 4 [6 j(1R) -g,3-D~hyd,,,-I-J-mndan-1--yhrnino p-ain 2yJ% 2 -eoxyph. oI In a procedure analogous to Example 2, reaction of 6-chloro-N-[(1A)-2,3dihydro-414-inclen-l-yl]pyrazin-2-amine (136.8mg, 0.S6rmnol) and 2-znethoxyA- (4,4,5,5-tetrainethyl-1,3,2-dioxaborolan-2-yl)pheno (153mg, XO.Glmmol) furished the product (130mg, 707o).

WO 03/099796 PCT/A1103/00629 'H-nL.ntr. (CDCI 3 6 2.00 (in, 1IR HC-U-C-IAr), 2.71 (in, lIH, U-CHCH 2 Ar),3.01 (in, 2K, CH 2 As), 3.96 31-L, OCtj, 4.90 j= 7.8Hz, iN, Nli), 5.57 (in, 114 CHi), 6.06 (br s, IU, OH), 6.98-7,82 (in, 7K4 Ar-H), 7.85 tIN, pymaz-H), 8.29 lI-, pyraz-H); WO 03/099796 WO 03/99796PCT/AIJO3/00629 321 Example ui 6 SC,)IorVA(Rk 1 (4 mthJphenyI~etyIJpyrazin 2-anvhe C) N CA

H

N N 0 In a procedure arnalogous to Example 1, reaction of a-(A-4dimnethylbenzylamnine (230mg,& i.S8iniol) and 2,6-dichioropyrazine (O.251&, 1.67mind) furnished the product (l99.5Smg, 49%).

'W4-n.m.r. (CDCI 3 8 1.56 (di, 3K-3,= 6.9Hz. GCl 3 2.33 3H-, Cr-H), 4,84 (Mn in, CH), 5.05 (br s, 1fl, NH), 7.15 (AA'XX', 2H1, Ar-M), V.24 (AAXXV, 2H-, Ar-I-U, 7.60 (s, 11-, pyraz-H), 7.78 111, pyraz-E-).

Example 12 H

OH

N N N H In a procedure analogous to Examnple 2, reaction of 6-chloro-N-1(Jji)-1-(4inethylpheny1)ethy11pyrazin-2-mnine (56.8mg, O.Q29xurol) and 2-rnethoxy-4-(4,4,5,5teiraimethy-1,3,2-dioxaboroan-2-y)pheno 63mg, 0.2Smmoi) furnished the product WO 03/099796 PCT/A1103/00629 'H-nms. (CDC$) 51.60 6.6 Hz, C11 3 2.33 3K1 CM 3 3.95 31-, OCR,), 4.96 (mn, 2H-, M- and NH), 5.89 (hr s, 11-,0OH), 6.97 111, J= 8.4 liz ArH), 7.14 (AA'XX', 211, AxR),, 7.30 (AA'XX= 211, Ar-Ut, 7.42-7.48 (in, 21-1, Ar-H), 7.67 11-, pyraz-H), 8.62 111, pyraz-H).

S infz (ES) 336 WO 03/099796 WO 03/99796PCT/A1103/00629 )Example 1$ CI N CI

K-

N

H

N N- Ci In a procedure analogous to Example 1, reaction of S';a-methylbenzylan-ine (568.8n-g, 4.72niol) and 2,6-dichloropyrazine (0.6388g, 4.Z9mmol) furnished the product (821mg, 82%P).

'H-n.rn.r. (CDC1,) 6 1.58 (di, J= 6.6Hz, 3H, CKI), 4.88 (in, 1H-, CUF), 5 07 (di, 1$, NH), 7,24-7.36 (in, 5K-I Ar-H), 7-61 1K-I pyraz--1), 7.79 1, pyraz-H).

Example 14 2 Merthoxy-4 (&/KS)-1pheyethylarninjrzin 2 yl)phienol

-;P

In a procedure analogous to Ex'amnple 2, reaction of 6.hooN[1)1 phenylethyllpyrazin-2-amine (717.3mg, 3.O7mmol) and 2-methoxy-4-(4A45,5tetrarnethy1-1,3,2-dioxcaborolan-2-ylphenoI (845mg, 3.S8immol) furnished the~product (689mg, WO 03/099796 PCT/A1103/00629 'H-n.ntr. (CDCI 9 8 2 431166Lz 3.95 311,OC1), 4.99 (a, 21-, Cl-liNH), 5.74 (br s, ff1, OH), 6.97 (di, 111I, J= 9,1 Hz, Ar-fl), 7.24-7.46 (in, M11 Ar- 7.69 1H-, pyraz-H), $.23 1H1, pyraz-H).

WO 03/099796 PCT/A103/00629 36 Example 6-hJoro-N-f0S2 -phennpropyfepw ,jr C1 N CI

H

N I1 In a procedure analogous to Exanple 1, reaction of £a-ethylbenzylannne (558mg, 4.2lmmol) and 2,6-dichloropyrazine (570 mg, 3.B2mznol) furnished the product (655mg, 737).

(CDC

3 8 0.96 3H, 1.90 (ni, 2H, Cr 2 4.59 1H, CI), 5.12 1H, NH), 7.24-7.37 5, Ar-H), 7.60 lI, pyraz-H), 7.78 1H, pyraz-H).

Example16 2 -Mehov#uy~(4(2S)--phenypypnhapyrzy)hz NO H OH N

H

In a procedure analogous to Example 2, reaction of 6-d-loro-N-[(6)-1-' phenylpropyllpyrazin-2amine (135mg, 0.S7mmol) and 2-methoxy-4-(4,4,s,5tetrainethy-1,3,2dioxabrolan-2.yI)phenoI (Smg& O.63mmaol) furnished the product (87mg, 457o).

WO 03/099796 PCT/A1103/00629 'Hnr~.(CDCI,) 5 1.00 31,1= 7.5 Hz, CI-1), 1,94 (dq, 2H,f= 7.5 Hz, CH4 2 3.96 3H4,0QC 3 4.71 (dt, lIH, J' 7.5 Hz, CH), 5.00 (bi s, I, NH), 5.75 (hr s, 1H, OH), 6.97 (di, M 8.4 Hz, ArH), 7.24 (mn, 1IK ArH-), 7.30-7,47 (in, 6K1 ArH), 7.67 (s, 1II, pyr-az-fl), 8.21 114, pyraz-H).

inkz (ES) 336 (NE-iH).

WO 03/099796 WO 03/99796PCT/A1103/00629 38 r]xample 17 2

R

2 PJ(6Chloropyrazin-2-y1)armmo]-2-phenylethanopl C I N C1

H

N N 0r

HON

In a procedure analogous to )Example 1, reaction of (2AZ)-2-arnino-2phenylethanol (420mg, 3J1mmol) and 2,6-dichloropyrazine (413mg& 2.79inmol) furnished the product (261mg, 37%).

t H-n.m.r. (CDCI,,) &80.91 (ci, 1H-, OH), 3.97 (Mn 21-1, CE 2 4.94 (mn, 1H-, 5.56 1H4, NH), 7.30-7.44 (in, 3H1, Ar-H), 7.70 iN, pyraz-H), 7.81 114I, pyraz-H).

ExamnpleIS 4-(61([OE')2Hydro-,y-1-pbeny-lethyflamn opaz-in2yjd)..neth oxvphenoJ OH -N C' ~NOH N N OH N In a procedure analogous to Example 2, reaction of (2A)-2-f(6-chloropyn zin-2yl)aininol.2-phenylethanol (137mg, .S3nnol) and 2-methoxy-4-(4A4,5,5-tetrameffiyl l, 3 2 -dioxaborolan-2%y1)phenol (151mg, 0.G6inmol) furnished the produdt (7Oing 38%).

(OVC1 3 8 1.16 IN, OH), 382 (as, 31-Y, OCi-I), 3.90 (mn, 2H1, 4.92 (in, iN, CHi), 5.50 (br s, 1H-, NH), 6.87 1H-,f= 9 Hz, Armi), 7.15-7,66 (Mn, 8.14 l1H, pyraz-H).

WO 03/099796 PCT/A1J03/00629 mr/z (ES) 338 WO 03/099796 WO 03/99796PCT/A1103/00629 Example 19 6-ChIzarcWA-/(17SJ-(4-methoxphsnyl)ethylJpffazin-2-amine 0 NI N(N)A N'y

NT

In a procedure analogous to Example 1, reaction of 4-methoxy-a-(S)mnethylbenzyl amine (0.70mg, 4.6rnmol) and 2,6-dichioropyrazine (0.6 25 9g, 4.2Ommol) furnished the product (873mng, 79%).

'H-n.mA.r. (CDCI,) 8 1.56 31-, J 6.9Hz, CH), 3.80 (s MCCHq,), 4.84 (in, IMi CH), 5.01 (hr s, IKi NH), 6.88 2H4, Ar-H), 7.28 (AA'X)C, 2K4 Ar-H), 7.61 (s, Example 2D 2-Methoxy-4t-(6-(fS%1I-(-methoxypheny)etyfainojp,,,azin-2-y1)pheno In a proced-ure analogous to Example 2, reaction of 6-chloiro-N-[(t%1-(4inethoxyphenyl)ethyllpyrazin-2-anine (149.4mg, 0.S7inmol) and 2-methoxy-4-(4,4,5,5tetrannthyl-1,3,2-dioxaborolan-2-yl)phenol (156mg. .62rnmol) furnished the product (71mg, WO 03/099796 PCT/A1103/00629 'H-n.mn.r. (CDCL 3 51.59 3H1, J= 6.6 Hz, GH)d 3.79 3H1, 0CM 3 3.95 3H1, 0CH 3 4.95 (mn, 2H1, CHI and NH), 5.98 (br s, 111, OH), 6.87 (AA'XX', 211, ArH), 6.97 (ci, 111 8.1 Hz, ArM), 7.33 (AA'XX', 21-, Ar-rn1, 7.43-7.49 (in, 211, ArK), 7.66, in, pyraz-H), 8.22 111, pyraz-Hi).

WO 03/099796 PCT/AU03/00629 42 Example 21 6-Chloro-N-(pyridin-3-ylmethyl)pyrazin-2-amine

N

01 N 0 H- N N N CI

N:

A mixture 2,6-dichloropyrazine (0.671 runol) and 3-picolylarnine (2.014 nmmol) in xylene (25 mi) was refluxed overnight. The residue obtained after evaporation of the solvent was suspended between CH 2 CI2 (100 ml) and water (100 ml). The organic layer was separated and the aqueous layer was extracted with CH,C, (3 x 50 ml). The combined organic extracts were washed with brine (1 x 100 ml), dried (Na 2 SO4) and the solvent removed in vacuo. The residue was then purified by column chromatography eluting with a hexane:ethyl acetate gradient mixture to afford the desired product H-n.n.r. (CDCIs) 84.61 J= 5.7 Hz, 2 H, NCH 2 5.29 broad, 1H, NH), 7.27 1H, pyrid.-H), 7.30 (mn, IH, pyrid.-H), 7.71 J= 7.8 Hz, 1, pyrid.-H), 7.85 1H, pyrid.-H), 8.54 broad, 1f, pyraz.-H), 8.61 broad, 1H, pyraz.-U).

Example 22 2-Methoxy-6-/(pyridin-$-ylmethyl)aminolpyrazin-2-fl}pheno NN OH Hi

NNY

WO 03/099796 PCT/A103/00629 43 A mixture of 6-chloro-N-(pyridin-3-ylmethyl)pyrazin-2-amifle (49rrt, 0.22 mmol), 2-methoxy-4-(4,S,5-tetramethy-1-t3 1 2-diOXabOrOlar-2-yl)PheOl (52mg, 0.20 rnmol), (PPh,) 4 F (23mg, 0.020 mnol) and a Na 2

CO

5 solution (0.22 rumol of a 2 M solution) in toluene (10 ml) was heated under reflux overnight. After removal of the solvents, the residue was dissolved in C1 2 2 (150 dried (Na 2 S, filtered and the CHClz removed ih vacuo. The residue was purified by column chromatography, eluting with a n-hexane:ethyl acetate gradient mixture to obtain the desired product (62mg, 'H-riinr. (CDCb,) 83.94 (br 9 CH 3 4.70 2H, 1-6.0 Hz, CH2), 5.01 (br a, 1W, Nl), 5.83 (hr s, IN, ON), 6.98 1H, J= 8.7Hz, ArM), 7.29 lH, Ar-H), 7.48 (Mn, 2H, ArH), 7.73 (br d, 1K, J- 8.7 Hz, ArH), 7.83 11-, pyxaz-H), 8.30 ut pyraz-H), 8.54 1, ArH), 8.70 1H, ArM).

r/z 309 (M Example 23 N-Benzyl-6-chloro-N-mnthylpjrazn-2-amife CI N CI I I

N

NX

In a procedure analogous to Example 21, reaction of N-methyl berizylamine and 2,6-dichioropyrazine furnished the product 'N-n.mnr. (CDCIk) 83.11 3 H, NCH), 4.78 2W, ArCH,N), 7.24 1=6.9 Ht, 2 H, ArH), 7.37-7.28 41L ArM), 7-81 IN, pyraz.-M), 7.88 1I, pyraz.-H).

WO 03/099796 WO 03/99796PCT/A1103/00629 44 Example 241 ty)qjnjjrm---ahxpeo In a procedure analogous to Example 22, reaction of N-benzy-6-cloro-Nrnethylpyrazin- 2 -amnife and 2-methoxy-4-(4,4,5,5-tetramethYl-ii3i2-doxaborolanZ2 yl)phenol furnished the product 1 H-n.rn.r. (CDC 3 6 3.20 (br s, 3H, NCH,), 3.91 3H, OC0%I), 4.89 2K1 CH), 5.83 (h-r s, lit OH), 6.98 i 18.1 Hz, ArM), 7.27 (mn, 5H, Ar-H), 7.53 (in, 2H1, ArM), 7.93 IN, pyraz.-H-), 8.28 liH, pyraz.-H).

rn/z (ES) 322 Example 2-(6-Chloropyrazin2y)-l4.3i-etahydroisoquinflOinlC CI N 0

CI

N:

N

N

In a procedure analogous to Example 21, reaction of tetrahydroisoquinoline, and 2,.6-dichaoropytazifle furnished the product WO 03/099796 PCT/A1103/00629 'U-n.mxr. (CDCI 3 52.99 J= 5.7 Hz, 2H-, ArCHz 2 CN), 3.86 h= 5.71 H-z, 211 ArCH 2 Cg 2 4.73 2H1, ArCH 2 7.27-7.19 (xn, 41-1, ArN), 7.82 111, p-vraz.-H),' 8.01 Ili, pyroz.-H-).

WO 03/099796 WO 03/99796PCT/A1103/00629 46 Example 26 4-[6-(3,4-Dhydroisoqidno~Jn -2(1Hj)p zn2yl2-ehxpeo N CI

OH

NI NN

N

N

in a procedure analogous to Example 22, reaction of 2-(6-ahloropyrazirt-2-Yl)- 1,2,3,A-tetrahydroisoquinolhne and 2-inethoxy--4-(4,4,5,5-tetrameth-yl-1,3,2dioxaborolan-2-yl)phenol furnished the product 1 1-1-nar.r. (CDC1,,) 8 3.03 (Mn CJI), 3.96 (mn. 2H, CH), 4,01 OCkI 3 4.83 2K-1 CW), 5.37 (br s, OH), 7.04 (in, 111, ArH), 7.21 (nm, 3H1, Ar-fl), 7.56 (mn, 2H, AwL!), 8.07 (bx s, 1K pyraz.-Tt, 8.28 (hr s, 1M, pyraz.-H-).

rn/z (ES) 374 Example 27 6-C: 'loro-N-($,4-dlclorcbenzyl)pyra4--n-2-arnin e Ci N Ci

N

K-

N

i1 y

H

in a procedure analogous to Example 21, reaction of 3,4-dichlorobenzylantLne and 2,6-dichloropyrazbae furnished the product (07c).

WO 03/099796 PCT/A1103/00629 2 H-n.rn,r. (CVOI 3 54.55 (di, -f-6 X-z, 211 NCH 2 5.01 broad, lIX, NHl), 7.18 (dcl, 2.1, 2.1 Hz, 1H, ArH-), 7.20 2.1, 2.11 Hz, ArE), 7.45-7.41 (ini, 2H1, ArE), 7.77 111 pyraz.-H), 7.86 I, pyraz.-I-l).

WO 03/099796 WO 03/99796PCT/A1103/00629 48 Example 28 4-[6-[ffS-Dkchlorobenzyl)aminolpyrazin-,2-,7]/-2-methoxypbenoI 01I

N

C1 In a procedure analogous to Example 22, reaction of 6-chloro-N-U3,4dichlorobenzyl)pyrazin-2-axnine and 2-inethoxy-4-(4,4,5,5-tetxamethyl-1,3,2dioxaborolan-2-yl)phenol furnished the product (CDC,) 6 3.93 3M, 083), 4.62 (ci, 21J= 6.0 H2, CR 2 (br s, 1H, NH), 5.79 (hr s, M1-,0H), 6.98 (di, F 8.7 Hz, AYH), 7.45 (mn, 48, ArM), 7.68 i.

l1H, Axfl), 7.95 11-L pyrar.-l$, 8.29 1H-, pyraz.-1-f.

nfz (ES) 376 Example 29) 6-Ch1oro-N-($,5-dirneoxbnypraf-anie CI"'

(N)

N:

0H N Nr In a procedure analogous to Example 21, reaction of and 2,6-dichloropyrazine furnlished the product WO 03/099796 PCT/A1103/00629 1H-nnn~r (CDC1 3 33.78 6H1, OCR1,,4,49 J1- 5.4 Hz, 2H1, NCH2) 5.12 (br 114, 6.39 (tf 7.11Hz, IH, ArH), 6.50 j 21 Hz7 7.75 11-1, pyrzaz.

7.82 lI-, pyraz-H-).

WO 03/099796 WO 03/99796PCT/A1103/00629 Example 4-[6 In a procedure anaogous to Example 22, reaction of 6-chloro-N-(3,5dimethoxybenzyL)pyrazin-2-aminie and 2-methoxy-4-(4,4,5,5-tetramTethyl-1,s,2dioxabotolan-2-yl~phenol furnished the product Hnmr.(as inesylate salt) (d&-DMSO) 2.39 3iK -14 3 80 3 ),1369 6W, OCH4D), 3.80 314, CEI 3 4.51 214, 6.36 (di, 11,7= 2,1Hlz, ArK), 6.57 2H, I -2.1 Hz, ArK), 6.83 (d,11-1,f= 8.1 Hz, 7Z54 (in, 214, ArK), 7.S7 11% pyraz.-E-), S.29 11-1 pyraz.-ND.

xnlz (ES) 368 (2v+H).

Example 31 .6Clr- 2Aymty)prn 1=n CI N CI Nr N N C In a procedure analogous to Example 21, reaction Of furturylamnine and 2,6dichloropyrazine furnished the product WO 03/099796 PCT/A1103/00629 'HI-n.mxr. (CDC1 3 64.57 J= 5.7 Hz, 2H-, NCH 2 5.01 broad, IH, NH), 6.30 (dl, f= 3.3 Hz, 1H, furanyl-H), 6,35-6-33 (in, 7B-, furanyl-H), 7.81 1N, pyraz.-H), 7.84 1N, pyraz.-X-).

WO 03/099796 WO 03/99796PCT/A1103/00629 52 Example 82 4-/6-/(2.Puary~nmethy!)amfnojpazih.2-yJ-2-methoxvhenof

H

c N N 01 I

N

CIOH

NtN NI0 In a procedure analogous8 to Example 2, reaction of 6-cbloro-N-(2- ,I furylrnethyl)pyrazin-2-amine and 2-miethoxy-4-(4,4,5,5-tefrainethiyl-1A32dioxaborolan-2-yIphenol furnished the product 1 H-n.ntr. (as xnesylate salt) (d6-DMSQ) 8 2.38 3H, CFT 3

SO

3 3.84 (6,:3H, QC1-14 4.59 2Hf, CH 2 6.33 111, Art!), 6.38 1H-, ArN), 6.87/ 2H-,fJ= 8.1 Hz, ArM), 7.52 (in, 31j. ArH), 7.86 (hr s, flIK pyraz.-It) 0.30 (hr s, It!, pyraz.-H).

m/z (ES) 298 (Mt-H).

Jxample 33 2 lo(6tlS) I-phenylethylamiopradnf-2-J-)p-henol H

N

Oy

N

A solutdon of 4-bromno-2-chlorophenol (246mg, 1.lSMOrno), bis(pinacolato~diboron (332m&, 1.Smrnol), bis(diphenylphospbino)ferrocenelpalladiun(II) chloride (26mg, 0OSSmmol) and WO 03/099796 PCT/AU03/00629 53 potassium acetate (222mg, 2.26mnol) in dry methanol (4mL) was degassed and heated at 65 0 C for 24h. After cooling, the reaction mixture was diluted with ether and filtered through Celite. The solvent was removed under reduced pressure and the residue purified by chromatography using dichloromethane-hexane (90:10) as eluant.

The boronate thus obtained (50mg) was reacted with 6-chloro-N-[(1S)-1phenylethyl]pyrazin-2-amine (50mg, 0,2mmol) under conditions analogous to those of, example 2, to furnish the pure product after chromatography eluting with dichloromethane-ether (90:10) (44mg, 68%).

'H-n.mr. 8 8 1.59 SH, J 6.0 Hz, CHI,), 4.88 1H, CH), 5.08 (br s, 1, NH), 5.69 (br s, 11, NH), 7.07 II, J 8.5 Hz, ArE), 7.27-7.36 (mn, 6, Ar-H), 7.48AS 1IH, F 1.5Hz, ArH), 7.62 1H, pyraz-H), 7.80 II, pyraz-H).

WO 03/099796 PCT/A103/00629 54 Example 34 6-(eAninopenyVN-[(5)--penyiethyljpyrazin-2-amin e

NH,

N N CI r t*a~ y NY

N

A mixture of 6-cbloro-N-[(1S)-l-phenylethy]pyrazin-2-amine (1.1og, 4.71mmol), 4-(MA,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.10g, 5.02nmol), (PPh 3 XPd (580mg, 0.Snnol) and a Na 2

CQ

3 solution 2M solution) in toluene ml) was heated under reflux for 40 h. Upon cooling, the mixture was diluted with water (30mL) and the product extraded with ethyl acetate (3 x 40m1). The organic layers were combined, washed with brine (30nil), dried (Ns 2

SO

4 and the solvent removed in vacuo. The residue was purified by column chronatography, eluting with a hexane-ethyl acetate (nh3) to furnish the desired product from the polar fractions (0.8 6 g, 63%)- (COCt) 81.57 3M, 1= 6.2Hz, 3.80 (hr s, 2H, N- 2 4.92-4.99 2K, CH NH), 6.69 2W, Jt 6.7Hz ArH), 7.21-7.40 3K, ArH), 7.72 2H,/J= 6.7Hiz, ArE), 7.57 1H, pyraz.-EX) 8.16 11-1, pyraz.-H).

n/z (ES) 291 (Mv±H) WO 03/099796 PCT/AU03/00629 Example 6-[4(Ethylamino)plenyl-V-(1S)-1-phenylethylpyrazin-2-arnine

H

H NK r 0 1 N c NN 11N 0 'M1,-AN

NN

A solution of the amide (40mg, 0.12rnmol) in THF (5mL) was treated with solid LiAIH 4 (38mg, Immol), and the mixture stirred at RT for 4h. The reaction was then treated sequentially with 120 (5ml), 2M NaOH (5ml) and water (10m!) and the resulting suspension then extracted with ethyl acetate (3 x 15ml). The combined organic layers were dried (Na,SO 4 and concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane as eluant to give the product as a colorless solid (22mg, 58%).

(CDC13) 81.25 3H, J= 7.01U, CH), 1.57 3H, J= 6.8Hz, CH 3 3.18 2H, J= 7.0Hz, CH 2 3.74 (br s. Il, NH), 4.85-5.01 2, CH NH), 6.59-6.63 2H, ArH), 7.21-740 5H, ArH), 7.54 1, pyraz.-H), 7.73-7.77 2H, ArH), 8.16 1H, pyraz.-H).

m/z (ES)319(M'+H) WO 03/099796 PCT/AU03/00629 56 Example 36 -N-(6-/(1S)-1-Phenylethyl/amnopyrazn-2-yl)phenylJmetbanesulonamide

HH

NHH

NH N N N I 1

N

To a stirred solution of 6-(4-aminophenyl)-N-(1S)-1-phenylethyllpyrazin-2amrnine (58mg, 0.2nmmol) in dry TIHF (3mL) was added triethylamine (70 L, The solutions was cooled to O'C and methanesulphonyl chloride (18.6piL, 0.24mmol) was added dropwise. The mixture was allowed to warm to RT and stirred overnight, before dilution with water (15mL). The product was extracted into ethyl acetate (2 x 15mL) and the combined extracts washed with 10% aqueous Na 2

CO

3 and brine, and then dried (Na 2

SO

4 The solvent was removed under reduced pressure and the product purified by chromatography eluting with ethyl acetate-hexane to afford the product as a pale yellow solid (54mg, 73%).

(COCl) 81.59 3H, J 6.2Hz, 3.01 3, CH), 4.96-5.01 (m, 2, CH- NH), 6.52 (br s, 1H, NHSOO, 7.22-7.40 7H, ArH), 7.70 II, pyraz.-H), 7.85-7.89 2H, ArH), 8.20 1H, pyraz.-H).

rnm/z (ES) 369 WO 03/099796 WO 03/99796PCT/A1103/00629 57 Example 37 -/4-(6-fff1-1S-ph nyethyIm~op~a--y)phycyoppne,-am ide

HH

N N N 1 1

NN

In a method analogous to that reported in example 39, reaction of 6-(4axinophenyl)-N-[(1$)-1-phenylethyllpyrazin-z-amine (58m&. 0.2inmol) and cyclopropanecarbonyl chloride (25mg, 0.24inn-ol) furnished the pure product a~fter chronmatographic purification using ethyl acetate-hexane (46mg, 64%).

'H-njn.r. (GDC 3 1) 60.82-0.88 (mn, 2H, GCH), 1.0-1.10 (mn, 2n1 CH 2 1.49-1.60 (in, 4H, CH, 014) 4.91-4.9 (mn, 2H-, CH NH), 7.23-7.40 (mn, 511, ArH), 7.56 (AA'XX', 2H, AxE-), 7.65 IF!, pyrraz.-kX), 7.85 (AA'XX', 211, Ad-fl, 8.21 1H1, pyraz.-H).

mfz (ES) 359 WO 03/099796 PCT/AU03/00629 58 Example 38 1-Pyidin-S-ylethanone oxine 0 MOMD To a solution of hydroxylamnine hydrochloride (3.44g) in water (20 ml) was S added NaOH (20 yo, 30 ml). The ketone (5g, 42 mmol) was added at once and the resulting mixture was stirred at RT until TLC showed no ketone remained. The solvents were distilled off in vacuo and the residue extracted with CH 2 0 2 (3 x 100 mi) and dried (NaSO 4 After filtration and removal of the solvent the crude ketoxime was recrystallised from CH 2 Cl%/n-hexane.

'H-njn.r, (CDC 3 82.31 3H, CH8), 7.33 (dd, J= 4.8, 4.8 Hz, IH, Arl), 7.97 (ddd, J= 8.1, 1.8, 1.8Hz, 1H, ArH), 8.61 (dd, J= 5.1, 1.8 Hz, XI, ArH), 8.96 1.8 Hz, 1H, ArH), 10.62 1 H, OH).

Example 39 1-(5-ChIlrophenyl)ethanone oxime 11.OH A mixture of the ketone (2.0g, 13mmol), hydroxylamrnine hydrochloride (0.98g, 14mmol), NaOH 4Iml), water (6.2ml) and EtOH (25 ml) was heated under reflux WO 03/099796 PCT/A1103/00629 for 2 houxs. Upon cooling in ice, the ketoxime precipitated and was collected by suction filtration. The crude product was zecrystallised from CH2CI2/n-hexane (1-8Sg, 86%).

(CDC

3 8 2.28 3H, CHS), 7.51 4H,1. 8.67 1H, OH).

WO 03/099796 PCT/AU03/00629 Example 1-(3-ChlorophenyI)ethanamine N OH C1 cl A mixture of the ketoxime (Ig, 6mmnol) and LiA1H 4 (0.27g) in anhydrous TIH (100 ml) was heated at reflux under dry N 2 overnight. The reaction mixture was cooled in ice-water and carefully quenched with HIO (60mL). The mixture was allowed to stir at RT for half an hour, after which time it was filtered through Celite'.

The inorganic salts were washed with EtOAc (3 x 100 ml). The filtrate was concentrated under reduced pressure, diluted with 2M HCI (50ml) and the aqueous phase washed with Et 2 O (2 x 70ml). The aqueous phase was basified with aqueous NaOH and the product extracted with Et 2 O (3 x 50ml). The combined organic layers were washed with brine (50ml) and dried (MgSO 4 The solvents were removed in vacuo to afford the pure amine (0.65g, 71%).

(CDCls) 51.38 J 6.6 Hz, 3H, CH-CHs), 1.63 (br a, 2 H, NH), 4.13- 4.06 1 H, CH-CH-), 7.23-7.18 3 H, ArH), 7.35 1 H, ArH).

WO 03/099796 PCT/AU03/00629 61 Example 41 I-Fyridin-3-ylethnamifne

NN

OH

N To a mixture of the ketoxime (4.85g, 36 mmuol) and Zn powder (12g) at 0 C was slowly added, with vigorous stirring, concentrated HCI (50 rl). When the initial vigorous reaction had subsided, the mixture was heated under reflux until TLC showed all the ketoxime had been consumed. After cooling to RT, the strongly acidic mixture was extracted with CHzCI 2 (2 x 75 nl). The reaction mixture was then made strongly basic with 50% KOH solution. After removal of the solvent, the residue was extracted with boiling MeOH (4 x 100 ml). The MeOH was distilled off to leave the crude amine which was used in the ensuing reactions without further purification.

1 H-n.m.r. (CDCL,) 81.07 J= 6.6 Hz, 3 H, CH), 1.37 (br s, 2H, NH 2 3.84 /f 4.6Hz, 1H, CH-CH 3 6.93 (dd, f= 7.8, 4.8 Hz, 1H, ArH), 7.38 (ddd, f- 7.8,2.1, 1.5 Hz, 1H, ArH), 8.15 4.8, 1.5 Hz, 1H, ArH), 8.27 J1 2.1 Hz, 1H, ArH).

WO 03/099796 PCT/AU03/00629 62

SCREENING

Establishment of TEL:JAK cell lines The coding region encompassing nucleotides 1-487 of TELwas amplified by PCR using the oligonucleotides STEL -GGA GGA TCC TGA TCT CTC TCG CTG TGA GAC-3') and 3TEL (5'-AGGC GTC GAC TTC TTC TTC ATG GTT CTG-3') and U937 mRNA as template. A BamH I site was present into the 5TEL Primer, a Sal I site was incorporated into the 3TEL primer. The regions encompassing the kinase domains of JAK2 (nucleotides 2994-3914;; JAK2F 5'-ACGC GTC GAC GGT GCC TTT CAA GAC CGG GAT-3'; JAK2R 5'-ATA GTT TAG CCCCG CTC AGA ATG AAG GTC ATT T-3' and JAK3 (nucleotides 2520-3469; JAK3F 5'-GAA GTC GAC TAT GCC TGC CAA GAC CCC ACG ATC TT-3' JAK3R 5'-GGA TCT AGA CTA TGA AAA GGA CAG GGA GTG GTG TTT were generated by FCR using Taq DNA Polymerase (Gibco/BRL) and U937 mRNA as template. A Sall site was incorporated into the forward primer of JAK2 and JAK3, a Not I site was incorporated into the JAK2 reverse primer and a Xba I site was added to the reverse primer of JAK3.

A TEL/Jak2 fusion was generated by digestion of the TELPCR product with BamH I /Sal I, digestion of the JAK2 PCR product with Sal I/ Not I followed by ligation and subdoning into the mammalian expression Vector pTRE 2 (Clontech) digested with BamH I-Not I (pTELJAKZ) For JAK3 Sal I/ Not I cleaved kinase domain PCR product was ligated with BamH I /Sal cleaved TELproduct followed by ligation into BamH I/Not I cleaved pTRE2 (pTELJAK3).

The growth factor dependent myelomonocytic cell line BaF3 bearing the pTEToff plasmid (Clontech) was transfected with either pTELJA2 or pTELJAK3 and the cells selected for factor independent growth. BaF 3 wild type cells were cultured in DMEM 10% FCS, 10% WEHI 3B conditioned medium. BaF3 TLJAK cells were cultured in DMEM 10% Tet-System Approved FBS (without WEHI 3B conditioned medium).

Cellular assays were performed as follows: WO 03/099796 PCT/AU03/00629 63 Cell suspensions were prepared by harvesting cells from culture. (Cells used in this test should be in later log phase growth and high viability.) Cells were diluted in correct growth medium to l.1x final concentration (from 50000 celI/mL to 200,000 cell/mL, depending on cell line).

Compounds to be tested were added (10pL, 10X final concentration) to a flat bottom 96-well plate. The cellular suspension (90L per well) was added, and the plate incubated for 40 hr at 37 OC, 5% CO,. MTT (20 gL per well, 5mg/mL in PBS) was added and the plates were returned to the incubator for a further 6 hours. Lysis buffer (100 L per well, 10% SDS, 0.01N H) was added and the plate stored in the incubator overnight. The plate was then read at 590 nm.

Kinase assays were performed either in a 96 well capture based ELISA assayor in 384 well Optiplates (Packard) using an Alphascreen Protein Tyrosine Kinase kit In either casse using approximately 1.5 mg of affinity purified PTK domain in the presence of HEPES, pH 7.5, 10mM MgC12, 150mM NaCI and 10lrM-lmM ATP. The biotinylated substrate biotin?EGPWLEEEEEAYGWMDF?NH2 (final concentration was used as substrate. In the ELISA assay tyrosine phosphorylation was quantitated following transfer to an avidin coated ELISA plate using peroxidase linked anti-phospho-tyrosive antibody FY20. In the Alphascreen assay, Alphascreen phosphotyrosine acceptor beads followed by streptavidin donor beads were added under subdued light. The ELISA plates were read on a BMG Fluorostar, the Alphascreen plates were read on a Packard Fusion Alpha. Inhibitors were added to the assays fifteen minutes prior to the addition of ATP. Inhibitors were added in aqueous DMSO, with DMSO concentrations never exceeding Results The activity of a range of compounds is shown in Table 1. Compounds that exhibited a capacity to inhibit 50% of cell growth at a concentration of (measured under standard conditions, see Methods), are designated as WO 03/099796 PCT/AU03/00629 It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

WO 03/099796 PCT/A1103/00629 Table 1: 2-amino-6-caxba-disubstituted pymazirte and 2-amninc -6-cairbadisubstituted pyridine possessing growth inhibitory activity in transformed cell lines (Tei-JAfl and Tel-Jak3) at 59,M Chemishiv 137 WO 03/099796 WO 03/99796PCT/A1103/00629 OhemLstrv 3is WO 03/099796 WO 03/99796PCT/A1J03/00629 ckx~fr WO 03/099796 PCT/AIJO3/00629 References Spicitto MT, and Chung TI). (2000) STAB3 mediates IL-S-induced growth inhibition in the humnan prostate cancer cell line LNCaP. Pros~ee 42 86-98

Claims (22)

1. A compound of the general formula R2 W R1 1) N or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein RI is H, C14alkyl; Q is a bond, or C14~alkyl, wherein when Q is a bond, W is not present; A is aryl or hetaryl each optionally substituted with 0-3 substituents independently chosen from halogen, CI4alkyl, CH 2 F, CHF 2 CF 3 CN, aryl, hetaryl, OCF 3 0C 1 Aalkyl, OC 2 5 alkylNR4R5, Garyl, Ohetaryl, C0 2 R4, CONR4R5, nitro, C1 4 alkylNR4R5, NR6C14alkylNR4R5, NR4COR5, NR6CONR4R5, NR4SO 2 R5; and R4, R5 are each independently H, C14alkyl, CI4alkyl cycloalkyl, C1 4 alkyl cyclohetalkyl, aryl, hetaryl, C14alkyl aryl, C14alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from 0, S and N, where N is substituted with R7; and R6 is selected from H, C14alkyl and R7 is selected from H, C14alkyl, aryl, hetaryl, C1 4 alkyl aryl, C1 4 alkyl hetaryl; R2 is 0-2 substituents independently selected from halogen, C1 4 alkyl, OH, OC14alkyl, CH 2 F, CHF 2 CF 3 OCF 3 CN, C14alkyINR8R9, OC14alkyINR8R9, C0 2 R8, CONR8R9, NR8R9, NR8COR9, NR IOCONR8R9, NR8SO 2 R9; and R8, R9 are each independently H, C14alkyl, C 14 alkyl cycloalkyl, Ci4alkyI cyclohetalkyl, aryl, hetaryl, C 14alkyl aryl, C 14alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a P72437.AU. I Specification 2009-1-15 heteroatom selected from O, S and N, where N is substituted with R11; and RIO is selected from H, CI-4alkyl, aryl or hetaryl; and RI 1 is selected from H, Cl-4alkyl, aryl, hetaryl, Ci-4alkyl aryl, C i4alkyl hetaryl; Y is halogen, OH, NRI2R13, NR12COR13, NR12CONR13, N12S0 2 R13; and R12, and R13 are each independently H, Ch 2 F, CHF 2 CF 3 CN, Ci4alkyl, Ci-4alkyl cycloalkyl, C 1 I4alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R14, and R14 is selected from H, Ci4alkyl; N 0-4; W is selected from H, Cl4alkyl, C2-6alkenyl; where C14alkyl or C 2 6 alkenyl may 1i be optionally substituted with Cl 4 alkyl, OH, OCI.4alkyl, NR15RI6; and R15, and R16 are each independently H, Cl.4alkyl, Cl.4alkyl cycloalkyl, CI_4alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R17, and R17 is selected from H, Ci 4 alkyl; wherein when Y is OH or NHCOCH 3 then R2 is 1-2 substituents and wherein, when Y is NH 2 and R2 is absent then Y is in the para position; or a compound selected from the group consisting of: 0 o H 0K- N ox OH 9,-N :Y&P P72437.AU. I Specification 2009-1-15 2003232919 09 Feb 2009 0 U0 C0 0 Iz z 0/ Mz Zm Zx ZZ z zz z I _0 0 OH "N N N OH- I -r& N or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof.

2. A compound according to claim 1 selected from compounds of the general formula II R2 W R1 A NN N A- Y N II or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein: RI is H, Cl 4 alkyl; A is aryl or hetaryl each optionally substituted with 0-3 substituents independently chosen from halogen, Cl4alkyl, CH 2 F, CHF 2 CF 3 CN, aryl, hetaryl, OCF 3 OC-4alkyl, OC2-5alkylNR4R5, Oaryl, Ohetaryl, C0 2 R4, CONR4R5, C 1 -4alkylNR4R5, NR6Cl4alkylNR4R5, NR4COR5, NR6CONR4R5, NR4SO 2 and R4, R5 are each independently H, C-4alkyl, C- 4 alkyl cycloalkyl, Cl4alkyl cyclohetalkyl, aryl, hetaryl, Cl-4alkyl aryl, Cl 4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R7; and R6 is selected from H, Cl 4 alkyl; and R7 is selected from H, C- 4 alkyl, aryl, hetaryl, Cl4alkyl aryl, Cl4alkyl hetaryl; P72437.AU.1 Specification 2009-1-15 R2 is 0-2 substituents independently selected from halogen, C-4alkyl, OH, OC-4alkyl, CH 2 F, CHF 2 CF 3 OCF 3 CN, Cl4alkylNR8R9, OCl4alkylNR8R9, CO 2 R8, CONR8R9, NR8R9, NR8COR9, NRIOCONR8R9, NR8SO 2 R9; and R8, s R9 are each independently H, C-4alkyl, C-4alkyl cycloalkyl, C 1 4alkyl cyclohetalkyl, aryl, hetaryl, Cl4alkyl aryl, Cl4alkyl hetaryl, or may bejoined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R 11; and R10 is selected from H, C 14 alkyl, aryl or hetaryl; and R 11 is selected from H, CI4alkyl, aryl, hetaryl, Cl 4 alkyl aryl, Cl 4 alkyl hetaryl; Y is halogen, OH, NRI2RI3, NRI2CORI3, NRI2CONRI3, N12SO 2 RI3; and R12, and R13 are each independently H, CH 2 F, CHF 2 CF 3 CN, Cl 4 alkyl, CI4alkyl cycloalkyl, C-4alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R14, and R14 is selected from H, CI-4alkyl; n 0-4; W is selected from H, Ci.4alkyl, C 2 6 alkenyl; where C- 4 alkyl or C2-6alkenyl may be optionally substituted with Cl 4 alkyl, OH, OC-4alkyl, NRI5R16; and Ri5, and R16 are each independently H, Cl4alkyl, C 14alkyl cycloalkyl, C -4alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing a heteroatom selected from O, S and N, where N is substituted with R17 and R17, is selected from H, Cl-4alkyl; wherein when Y is OH or NHCOCH 3 then R2 is 1-2 substituents and wherein when Y is NH 2 and R2 is absent then Y is in the para position.

3. A compound according to claim I or claim 2 where W is CI4 alkyl wherein the compound possesses S chirality at the chiral carbon bearing W. P72437.AU.1 Specification 2009-1-15

4. A compound according to claim 3 wherein the compound is a midxture of R and S isomers and the mixture comprises at least 707a of the S isomer. A compound according to claim 4 wherein the compound comrnises at Ileast of-the S isomer.

6. A compound according to claim 4 wherein the compound comprises at least of the S isomer.

7. A compound according to claim 4 wherein the compound comprises at least of the S isomer.

8. A compound according to claim 4 wherein the compound comprises at least 1099%o of the S isomer.

9. A compound according to claim I wherein the compound is selected from the group consisting of! 2003232919 09 Feb 2009 2003232919 09 Feb 2009 OH A composition comprising a carrier and at least one compound of any one of claims 1 to 9.

11. A method of treating a protein kinase-associated disease state, the method comprising administering a therapeutically effective amount of at least one compound of any one of claims 1 to 9 or a therapeutically effective amount of the composition of claim

12. A method according to claim 11 wherein the disease state involves a receptor tyrosine kinase selected from the group consisting of EGF, HER2, HER3, HER4, IR, IGF- 1R, IRR, PDGFR.alpha., PDGFR.beta, CSFIR, C-Kit, C-fms,Flk-lR, Flk4, KDR/Flk-1, Fit-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R.

13. A method according to claim 11 wherein the disease state involves a cellular tyrosine kinase selected from the group consisting of Src, Frk, Btk, Csk, Abl, Fes/Fps, Fak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.

14. A method according to claim 11 wherein the disease state involves a tyrosine kinase selected from the group consisting of JAK1, JAK2, JAK3 and TYK2. A method according to claim 11 wherein the disease state involves a serine/threonine kinase selected from the group consisting of ERK2, c-Jun, p38 MAPK, PKA, PKB, PKC, a cyclin-dependent kinase, CDKl, CDK2, CDK3, CDKA, CDK6, CDK7, CDK8, CDK9, CDK10, and CDK1 I.

16. A method according to claim 11 wherein the disease state is selected from the group consisting of Atopy, such as Allergic Asthma, Atopic Dermatitis (Eczema), and 3o Allergic Rhinitis Cell Mediated Hypersensitivity, such as Allergic Contact Dermatitis and Hypersensitivity Pneumonitis; Rheumatic Diseases, such as Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Juvenile Arthritis, Sjogren's Syndrome, Scleroderma, Polymyositis, Ankylosing Spondylitis, Psoriatic Arthritis Other P72437.AU.1 Specification 2009-1-15 1. 79 Alzheimer's disease; Viral Diseases, such as Epstein Barr Virus (EBV) Hepatitis B, Hepatitis Q, Iffy, HTLV 1, Varicella-Zoster Virus (VZV), Human Paplilloma Virus (RPV), Cancer, such as Leukemia, Lymphoma and Prostate Cancer.

17. A method according to claim 11 wherein the protein kinase-associated disease state is selected from the group consisting of one or more of sarcomas, carcinomas and leu~keias.

18. A method according to claim 17 wherein the protein kinase-assoclated disease state is selected from the group consisting of one or more of fibrosarcoma, myxosarcoma, liposarcoxna, chondrosarcoma, osteogerdc sarcoma, chordoma, angiosarcoxna, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyorarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squanmous ceD carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, mnedullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatorna, bile duct carcinoma, choriocarcinoma, semidnorna, embryonal carcinioma, Wilms tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelia] carcinoma, Slioma, astrocytorna, medulloblastoma, craniopharyngoma, ependymonia, pinealoma, hemangioblastoma, acoustic neuroma, oligodendrogliomna, meningloma, melanoma, neuroblastoma, and retinoblastoma.

19. A method according to claim 11 wherein the protein kiriase-associated disease state is a carcinoma formed from the tissue of the breast prostate, kidney, bladder or colon.

20. A method according to claim 11 wherein the protein kinase-associated disease state is a hyperplastic or neoplastic disorder arising in adipose tissue.

21. A method according to claim 20 wherein the hyperplastic or neoplastic disorder is an adipose cell tumour.

22. A method according to claim 21 wherein the adipose cell tumour is one or more of lipoma, fibrolipoma, lipoblastoma, lipomatosis, hibemoma, hemangioma and liposarcoma.

23. The use of at least one of the compounds of any one of claims 1 to 9 in the s preparation of a medicament for the treatment of protein kinase-associated disease states.

24. A pharmaceutical composition comprising at least one of the compounds of any one of claims 1 to 9 capable of treating a protein kinase-associated disorder in an amount effective therefor and a pharmaceutically acceptable vehicle or diluent. The use of at least one of the compounds of any one of claims 1 to 9 for the treatment of protein kinase-associated disease states.

26. A substituted 6-aminyl-2-phenyl-pyrazine compound substantially as herein described with reference to any one of the Examples. P72437.AU. Specification 2009-1-15