AU2004294355B2

AU2004294355B2 - Azole-based kinase inhibitors

Info

Publication number: AU2004294355B2
Application number: AU2004294355A
Authority: AU
Inventors: Xianyong Bu; Christopher John Burns; Andrew Frederick Wilks
Original assignee: YM Biosciences Australia Pty Ltd
Current assignee: YM Biosciences Australia Pty Ltd
Priority date: 2003-12-03
Filing date: 2004-12-03
Publication date: 2011-12-22
Anticipated expiration: 2024-12-03
Also published as: AU2004294355A1

Abstract

A compound of general formula (I) or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof is described. A method of treating kinase-associated disease states using the compound of formula (I) is also described.

Description

WO 2005/054230 PCT/AU2004/001690 1. AZOLE-BASED KINASE INHIBITORS FIELD OF THE INVENTION The present invention relates to the field of inhibitors of protein tyrosine kinases. BACKGROUND OF THE INVENTION 5 Protein kinases are a family of enzymes that catalyse the phosphorylation of specific residues in proteins. In general protein kinases fall into several groups; those which preferentially phosphorylate serine and/or threonine residues, those which preferentially phosphorylate tyrosine residues and those which phosphorylate both tyrosine and Ser/Thr residues. Protein kinases are therefore key elements in signal transduction pathways responsible for 10 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, for example, but are not limited to, members of the Protein Tyrosine 15 Kinase family (PTKs), which in turn can be divided into the cytoplasnic PTKs 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 Idnase family, (including: JAKI, JAK2, JAK3 and Tyk2), the FAK 20 family (including, FAK and PYK2); the Fes family (including FES and FER), the ZAP70 family (including ZAP70 and SYK); the ACK family (including ACKI and ACK2); and the Ab1 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 PDGFRox PDGFRp, CSF1R, KIT, FLK2 25 ); 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, TrRKB, and TRKC); the AXL family (including AXL, MER, and SKY); the TIE/TEK family (including TIE and TIE2/TEK); the EPH family (including EPHA1, EPTHA2, EPHA3, EPHA4, EPHA5, 30 EPHA6, EPHA7, EPHA8, EPHIB1, EPHB2, EPH1B3, EPHB4, EPIHB5, EPHB6); the RYK family (including RYK); the MCK family (including MCK and TYRO10); the ROS family (including ROS); the RET family (including RET); the LTK family (including LTK and ALK); the ROR WO 2005/054230 PCT/AU2004/001690 2. family (including RORI and ROR2); The Musk family (including Musk); the LMR family including LMR1, LMR2 and LMR3); and the SuRTK106 family (including SuRTK106). Similarly, the shrine threoninee specific kinases comprise a number of distinct sub-families, including; the extracellular signal regulated kinases, (p42/ERK2 and p44/ERKI); c-Jun 5 NH2-terminal kinase (JNK); cAMP-responsive element-binding protein kinanes (CREBK); 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 10 protein kinases. For example, the malarial parasite Plasmodium falciparum and viruses such as HPV 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, 15 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 20 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. The JAK family of protein tyrosine kinases (PTKa) play a central role in the cytokine 25 dependent regulation of the proliferation and end function of several important cell types of the immune system. A direct comparison of the four currently known mammalian JAK family members reveals the presence of seven highly conserved domains (Harpur el a, 1992). In seeking a nomenclature for the highly conserved domains characteristic of this family of PTKs, the 30 classification used was guided by the approach of Pawson and co-workers (Sadowski el /, 1986) in their treatment of the SRC homology (SH) domains. The domains have been enumerated accordingly with most C-terminal homology domain designated JAK Homology domain 1 (J1). The next domain N-terminal to JH1 is the kinase-related domain, designated here as the JH2 domain. Each domain is then enumerated up to the JH7 located WO 2005/054230 PCT/AU2004/001690 3. at the N-terminus. The high degree of conservation of these JAK homology OH) domains suggests that they are each likely to play an important role in the cellular processes in which these proteins operate. However, the boundaries of the JAK homology domains arc arbitrary, and may or may not define functional domains. Nonetheless, their delineation ishv a 5 useful device to aid the consideration of the overall structural similarity of this class of proteins. The feature most characteristic of the JAK family of PTKs is the possession of two kinase-related domains (JHI and JH2) (Wilks eta/, 1991). The putative PTK domain of JAKI OHI) contains highly conserved motifs typical of PTK domains, including the presence of a 10 tyrosine residue at position 1022 located 11 residues C-terminal to sub-domain VII that is considered diagnostic of membership of the tyrosine-specific class of protein kinases. Alignment of the human JAK1 PTK domain (255 amino acids), with other members of the PTK class of proteins revealed homology with other functional PTKs (for example, 28% identity with c-fes (Wilks and Kurban, 1988) and 37/ homology to TRK (Kozma e a, 1988). 15 The JH1 domains of each of the JAK family members possess an interesting idiosyncrasy within the highly conserved sub-domain Viii motif (residues 1015 to 1027 in JAK2) that is believed to lie close to the active site, and define substrate specificity. The phenylalanine and tyrosine residues flanking the conserved tryptophan in this motif are unique to the JAK family of PTKs. Aside from this element, the JI-1 domains of each of the members of the JAK 20 family are typical PTK domains. The central role played by the JAK family of protein tyrosine kinases in the cytokine dependent regulation of the proliferation and end function of several important cell types means that agents which inhibit JAK are useful in the prevention and chemotherapy of disease states dependent on these enzymes. Potent and specific inhibitors of each of the 25 currently known four JAK family members will provide a means of inhibiting the action of those cytokines that drive immune pathologies, such as asthma (e.g. IL-13; JAK1, JAK2), and leukenia/lymphoma (e.g. 1L-2: JAK1 and JAK). Furthermore, certain types of cancer such as prostate cancer develop autocrine production of certain cytokines as a selectable mechanism of developing growth and/or m-etastatic 30 potential. An example of this is cancer of the prostate, where IL-6 is produced by and stimulates the growth of prostate cancer cell lines such as TSU and TC3 (Spiotto MT, and Chung TD, 2000). Interestingly, levels of iL-6 are elevated in sera of patients with metastatic prostate cancer. A great deal of literature covers the area of cytokine signalling. The present inventors have 35 focussed on the JAK/STAT pathway that is involved in the direct connection of cytokine WO 2005/054230 PCT/AU2004/001690 4. receptor to target genes (such as cell cycle regulators (e.g. p 21 ) and anti-apoptosis genes (such as Bcl-XL)). The JAK/STAT Pathway The delineation of a particularly elegant signal transduction pathway downstream of the 5 non-protein tyrosine kinase cytokine receptors has recently been achieved. In this pathway the key components are: (i) A cytokine receptor chain (or chains) such as the Interleukin-4 receptor or the Interferon y receptor; (ii) a member (or members) of the JAK family of PTKs; (iii) a member(s) of the STAT family of transcription factors, and (iv) a sequence specific DNA element to which the activated STAT will bind. 10 A review of the JAK/STAT literature offers strong support to the notion that this pathway is important for the recruitment and marshalling of the host immune response to environmental insults, such as viral and bacterial infection. This is well exemplified in Table 1 and Table 2. Information accumulated from gene knock-out experiments have underlined the importance of members of the JAK family to the intracellular signalling triggered by a 15 number of important immune regulatory cytokines. The therapeutic possibilities stemming from inhibiting (or enhancing) the JAK/STAT pathway are thus largely in the sphere of immune modulation, and as such are likely to be promising drugs for the treatment of a range of pathologies in this area, In addition to the diseases listed in Tables 1 and 2, inhibitors of JAKs could be used as immunosuppresive agents for organ transplants and 20 autoimmune diseases such as lupus, multiple sclerosis, rheumatoid arthritis, Type 1 diabetes, autoinnune thyroid disorders, Alzheimer's disease and other autoimmune diseases, Additionally, treatment of cancers such as prostate cancer by JAK inhibitors is indicated.

WO 2005/054230 PCT/AU2004/001690 5. Table 1 Disease Type Cell Types Involved Characteristics Altapy Allergic Asthma (Mast Cells T-cell activation of Atopic Dermatitis (Eczema) (Eosinophils B-cells followed by TgE Allergic Rhinitis (T-Cells mediated activation of (B-Cells resident Mast celLs and Eosinophils Allergic Contact Dermatitis (B-cells T-cell hypersensitivity Hypersensitivity Pneumonitis R/tramaic DiTeses Systemic Lupus Erythematosus (SLE) (Monocytes Cytokine Production Rheumatoid Arthritis (Macrophages (e.g.TNF, IL-1, CSF-1, Juvenile Arthritis (Neutrophils GM-CSP) Sjogten's Syndrome (Mast Cells T-cell Activation Scleroderma (Eosinophils JAK/STAI activation Polymyositis (T-Cels Ankylosing Spondylitis (B-Cells Psoriatic Arthritis VfrnlL)qsess Epstein Barr Virus (EBV) Lymphocytes JAK/STAT Activation Hepatitis B Hepatocytes JAK/STAT Activation Hepatitis C iepatocytes JAK/STAT Inhibition KIV Lymphocytes JAK/STAT Activation HTLV 1 Lymphocytes JAK/STAT Activation Varicella-Zoster Virus (VZV) Fibroblasts JAK/STAT Inhibition Human Papilloma Virus (HPV) Epitheial cells JAK/STAT Inhibition Caricer Leukemia Leucocytes (Cytokine production Lymphoma Lymphocytes (JAK/STAT Activation Aeuradegfeneative Dsease Motor Neuron Disease Neurons Mutated SOD1 Cardio vwlrDis eases Atherosclerosis & Arteriosclerosis (Lymphocytes JAK/STAT Activation (Macrophages JAK/STAT Activation WO 2005/054230 PCT/AU2004/001690 6. (Myoepithelial cells Cardiac Hypertrophy Cardiac Myocytes JAK/STAT Activation Ischemia Cardiac Myocytes JAK/STAT Activation Pulmonary Hypertension Lung Epithelium JAK/STAT Activation WO 2005/054230 PCT/AU2004/001690 7. Table 2:- Diseases Potentially Treata ble By JAK-Base d Drug Therapies Target Disease Cytokine JAK family Strength of member - Association Asthma 1LA4 & IL-9 JA.K1 &JAK3 11L-13 JAK & JAK2 -4±+ JA-K+ 44+ Eczema IL-4 JAKJ. & JAK3 + IFN-a JAMI & JAK2 -4 Food Allergy IL-4 JAKI & JAK3 +4 TInflammnatory Bowel IL-4 JAKI & JAK3 Disease & Crohn'e Disease______ ___ ___ Levtkacmida And (IL-2) JAK3, JAMi & + LymphomaJAK2 Cutaneous GM-CSF & JAMi & JAK2.. Inflammation IL-6 Immune Suppression TL-10 JAKI. & TYK2 +

B

3 y Solid Tumnour ______ Prostate Cancer IL-6 JAKI, JAT(2.. _______ ~&Tyk2 _____ Atherosclerosis & Various JA.K3 ++ arteriosctlerosis Cytokiu ____S__ Cardiac H-ypertrophy Arigiotengin 11 JAK2 + 8. SUMMARY OF THE INVENTION The present inventors have found that a group of compounds based upon the disubstituted pyrazine scaffoled I, are inhibitors of tyrosine kinases. 5 Accordingly, in a first aspect the present invention provides a compound of the general formula W R1 I I A-Q-N N D y N Y I or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or 10 diastereomers thereof, wherein: D is a heterocyclic ring selected from: N N N N R R21 X,-X3 R 21 V R2 R2 where Xi, X 2 , X 3 , X 4 are optionally substituted carbon, or one of XI, X 2 , X 3 , X 4 is nitrogen and the rest optionally substituted carbon; 15 R2 is selected from the group consisting of CN; NR22R23 wherein R22 and R23 are joined to form an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from 0, S, NR6; an optionally substituted 3-8 membered (saturated or unsaturated) ring containing 2-5 nitrogen 8a. atoms; an unsubstituted or optionally substituted 5-membered heteroaromatic ring containing one or more heteroatoms selected from 0, N, S; an unsubstituted or optionally substituted 6-membered heteroaromatic ring containing two or more 5 heteroatoms selected from 0, N, S; R21 is 0-2 substituents independently chosen from H, halogen, C.

4 alkyl, CF 3 ,

OCF

3 , OCHF 2 , CN, aryl, hetaryl, C,.

4 alkylOH, C1.

4 alkylNR3R4, C.4alkylhetaryl, OC. 1 alkyl, OC 1.

4 alkylNR3R4, OC .

4 alkylhetaryl, OC4 .alkylOH, C0 2 R3, CONR3R4, NR3R4, nitro, NR3COR4, NR5CONR3R4, NR3SO 2 R4, 10 C1.

4 alkylNR3COR4, CI- 4 alkylNR5CONR3R4, CI.

4 alkylNR3SO 2 R4; R3, R4 are each independently H, C 1

.

4 alkyl, C .

4 alkylOH, C 1 . 4 alkylNR19R20, CI. alkyl cycloalkyl, C1.

4 cyclohetalkyl, aryl, C- 4 alkylaryl, hetaryl, C1.

4 alkylhetaryl, or may be joined to form an optionally substituted 3-8 membered; 15 WO 2005/054230 PCT/AU2004/001690 9. (saturated or unsaturated) ring optionally containing an atdm selected from 0, S, NR6; and RS is selected from H, C 14 alkyl, aryl or hetaryl; R6 is selected from H, CI 4 alkyl, C 4 alkylNR19R20, aryl, hetaryl, C14 5 alkyl aryl, C 1 4 ailkyl hetaryl; R19, R20 are each independently selected from H, C 14 alkyl; R1 is H, C 14 alkyl, C 14 cycloalkyl, or may form a 5-8 membered ring onto the ortho position of ring A; Q is a bond, CH2, C 14 alkyl; 10 A is aryl, hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C 4 alkyl, CF3, OCF,, CN, NRSR9, aryl, hetaryl, C-laryl, C 1 4 hetaryl, C 4 alkyNR8R9, OCi 4 alkylNR8R9, nitro, NRIOC, 4 NR8R9, NRSCOR9, NR1OCONR8R9, NR8SO 2 R9, CONR8R9, CQ2R8; R8 and R9 are each independently H, C 1 4 alkyl, aryl or together form an 15 optionally substituted 4-8 membered ring which may contain a heteroatum selected from O, 5, NR11; R10 is selected from H, C 14 alkyT; R11 is selected from H, C- 4 alkyl; W is selected from H, C 14 alkyl, C 2 6 alkenyl or may form a 5-8 membered ring onto the 20 ortho position of ring A; where C 14 alkyl or C 2 alkenyl may be optionally substituted with C 14 alkyl, OH, OC4alkyl, NR12R13; R12, and R13 are each independently H, C 14 alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR14; 25 R14 is selected from H, C, 4 alkyl; Y is 0-2 substituents selected from H, C 1 4 alkyl, NR15R16; R15 and R16 are independently selected from H, CI 4 alkyl.

WO 2005/054230 PCT/AU2004/001690 10. In a second aspect the present invention provides a composition comprising a carrier and at least one compound of the first aspect of the invention, In a third aspect the present invention provides a method of treating a tyrosine kinase-associated disease state in a subject, the method comprising administering a 5 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 OF THE INVENTION -The present inventors have found that a group of compounds based upon the disubstituted pyrazine scaffold 1, are inhibitors of tyrosine kinases. 10 Accordingly, in a first aspect the present invention provides a compound of the general formula WRi A-Q-N N D "N Y I or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or 15 diastereomers thereof, wherein: D is a heterocyclic ring selected from: N/N N RL N' N X/ RR2 where Xi, X 2 , X 3 , X 4 are optionally substituted carbon, or one of X 1 , X 2 , XJ, X4 is 20 nitrogen and the rest optionally substituted carbon; 11. R2 is selected from the group consisting of CN; NR22R23 wherein R22 and R23 are joined to fonn an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from 0, S, NR6; an optionally 5 substituted 3-8 membered (saturated or unsaturated) ring containing 2-5 nitrogen atoms; an unsubstituted or optionally substituted 5-membered heteroaromatic ring containing one or more heteroatoms selected from 0, N, S; an unsubstituted or optionally substituted 6-membered heteroaromatic ring containing two or more heteroatoms selected from 0, N, S; 10 R21 is 0-2 substituents independently chosen from H, halogen, C 1

.

4 alkyl, CF 3 ,

OCF

3 , OCHF 2 , CN, aryl, hetaryl, C 1

.

4 alkylOH, CI.

4 alkylNR3R4, C 1

.

4 alkylhetaryl,

OC

1 .4 alkyl, OC 1.

4 alkylNR3R4, OCi.

4 alkylhetaryl, OC .4 alkylOH, C0 2 R3, CONR3R4, NR3R4, nitro, NR3COR4, NR5CONR3R4, NR3SO 2 R4,

C

1

.

4 alkylNR.3COR4, CI.

4 alkylNR5CONR3R4, Ci.

4 alkylNR3SO 2 R4; 15 R3, R4 are each independently H, C 1

.

4 alkyl, C .

4 alkylOH, C 1 . 4 alkylNRI9R20, C 1

.

4 alkyl cycloalkyl, C .

4 cyclohetalkyl, aryl, Ci.

4 alkylaryl, hetaryl, C 1

.

4 alkylhetaryl, or may be joined to form an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from 0, S, NR6; 20 and R5 is selected from H, C 1

.

4 alkyl, aryl or hetaryl; R6 is selected from H, Ci.

4 alkyl, C .

4 alkylNRI9R20, aryl, hetaryl, C 1

.

4 alkyl aryl, C 1

.

4 alkyl hetaryl; R19, R20 are each independently selected from H, CI.

4 alkyl; RI is H, C 1

.

4 alkyl, C 1

-

6 cycloalkyl, or may form a 5-8 membered ring onto the ortho 25 position of ring A; Q is a bond or C 1 4 alkylene; I Ia. A is aryl or hetaryl each optionally substituted with 0-3 substituents independently chosen from halogen, C 1

.

4 alkyl, CF 3 , OCF 3 , CN, NR8R9, aryl, hetaryl, C 1

.

4 aryl, C .

4 hetaryl, C1.

4 alkylNR8R9, OC 1

.

4 alkylNR8R9, nitro, NRIOCI.4NR8R9, NR8COR9, 5 NR 1OCONR8R9, NR8SO 2 R9, CONR8R9, C0 2 R8; R8 and R9 are each independently H, C 1

.

4 alkyl, aryl or together form an optionally substituted 4-8 membered ring which may contain a heteroatom selected from 0, S, NR11; R10 is selected from H, C 1

.

4 alkyl; 10 RII is selected from H, C 1

.

4 alkyl; W is selected from H, C 14 alkyl, C 2

-

6 alkenyl or may form a 5-8 membered ring onto the ortho position of ring A; where C1.

4 alkyl or C 2

-

6 alkenyl may be optionally substituted with C 1

.

4 alkyl, OH, OC 1

.

4 alkyl, NRI2R13; WO 2005/054230 PCT/AU2004/001690 12. R12, and RI 3 are each independently H, C 1 4 alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR14; R14 is selected from H, C1 alkyl; 5 Y is 0-2 substituents selected from H, C,.4 alkyl, NR15R16; R15 and R16 are independently selected from 1-, C 1 -alkyl In the above description it will be appreciated that:

C,.

4 alkyl means an unsubstituted or optionally substituted straight or branched alkyl chain 10 Aryl means unsubstituted or optionally substituted phenyl or naphthyl. Hetaryl means a unsubstituted or optionally substituted 5- or 6-membered heteroaromatic ring containing one or more heteroatorms 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 15 selected from 0, S, NR17, where R17 is H, C4 alkyl, aryl, hetaryl. In a further preferred embodiment the compound is selected from compounds of the general formula II. W A N D Y 20 or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastercomers thereof, wherein; D is a heterocyclic ring selected from- 13. N N X2VX3 R21 R2 where X I, X 2 , X 3 , X 4 are optionally substituted carbon, or one of Xi, X 2 , X 3 , X 4 5 is nitrogen and the rest optionally substituted carbon; R2 is selected from the group consisting of CN; NR22R23 wherein R22 and R23 are joined to form an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from 0, S, NR6; an optionally substituted 3-8 membered (saturated or unsaturated) ring containing 2-5 nitrogen 10 atoms; an unsubstituted or optionally substituted 5-membered heteroaromatic ring containing one or more heteroatoms selected from 0, N, S; an unsubstituted or optionally substituted 6-membered heteroaromatic ring containing two or more heteroatoms selected from 0, N, S; R21 is 0-2 substituents independently chosen from H, halogen, C 1 .4 alkyl, CF 3 , 15 OCF 3 , OCHF 2 , CN, aryl, hetaryl, C.4 alkylOH, Ci.

4 alkylNR3R4, C1.4alkylhetaryl,

OCI.

4 alkyl, OCI.4alkylNR3R4, OC 1 .4alkylhetaryl, OC.4 alkylOH, C0 2 R3, CONR3R4, NR3R4, nitro, NR3COR4, NR5CONR3R4, NR3SO 2 R4,

CI.

4 alkylNR3COR4, Ci.4alkylNR5CONR3R4,

CI.

4 alkylNR3SO 2 R4; R3, R4 are each independently H, C 1 .4 alkyl, C1.

4 alkylOH, C 1 . 20 4 alkylNR19R20, C 1 .4alkyl cycloalkyl, C1.4 cyclohetalkyl, aryl, C.4 alkylaryl, hetaryl, C .

4 alkylhetaryl, or may be joined to form an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from 0, S. NR6; and R5 is selected from H, C1.4 alkyl, aryl or hetaryl; 1 3a. R6 is selected from H, Ci.

4 alkyl, C1.

4 alkylNRI9R20, aryl, hetaryl, Ci.

4 alkyl aryl, CI.4 alkyl hetaryl; 5 R19, R20 are each independently selected from H, Ci.

4 alkyl; RI is H, CI.

4 alkyl, CI- 6 cycloalkyl, or may form a 5-8 membered ring onto the ortho position of ring A; A is aryl or hetaryl each optionally substituted with 0-3 substituents independently chosen from halogen, C 1

.

4 alkyl, CF 3 , OCF 3 , CN, NR8R9, aryl, hetaryl, CI.

4 aryl, C 1

.

4 hetaryl, 10 C 1

.

4 alkylNR8R9, OC 1

.

4 alkylNR8R9, nitro, NR1OC 1

.

4 NR8R9, NR8COR9, NR1OCONR8R9, NR8SO 2 R9, CONR8R9, C0 2 R8; R8 and R9 are each independently H, C 1

.

4 alkyl, aryl or together form an optionally substituted 4-8 membered ring which may contain a heteroatom selected from 0, S, NRI 1; 15 WO 2005/054230 PCT/AU2004/001690 14. R10 is selected from H, C 1

.

4 alkyl; R11 is selected from H, C4 alkyl; W is selected from H, C 14 alkyl, C2,alkenyl or may form a 5-8 membered ring onto the ortho position of ring A; where Cl.

4 akyl or Cualkenyl may be optionally substituted 5 with Ci 4 alkyl, OH, OC alkyl, NR12R13; R12, and R13 are each independently H, Cl-alkyl, or may be joined to form an optionally substituted 3-8 menbered ring optionally containing an atom selected from 0, S, NR14; R14 is selected from H, Cm alkyl; 10 Y is 0-2 substituents selected from H, C. alkyl, NR15R16; R15 and R16 are independently selected from H, CI-.alkyl. In the above description it will be appreciated that:

C

14 alkyl means an unsubstituted or optionally substituted straight or branched alkyl chain 15 Aryl means unsubstituted or optionally substituted phenyl or naphthyl. Hetaryl means a 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 20 selected from 0, S, NR17, where R17 is II, C 14 alkyl, aryl, hetaryl. The compounds of this invention include all conformational isomers (eg. cis and trans isomers). The compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastercomeric forms. This invention relates to the use of 25 all optical isomers and stercoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them. In this regard, the invention includes both the E and Z 15. configurations. The compounds of formula 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 containing prodrugs of 5 compounds of the formula I. This invention also encompasses methods of treating or preventing disorders in a subject that can be treated or prevented by the inhibition of protein kinases, such as JAK comprising administering prodrugs of compounds of the formula 1. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a 10 polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy and carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4 hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta 15 alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methioine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain. Prodrugs also include phosphate derivatives of compounds of formula I (such as acids, salts of acids, or esters) joined 20 through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I. In a still further preferred embodiment the compound possesses S chirality at the chiral carbon bearing W, where W is C 1 4 alkyl. The compound can be used as a 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. 25 In a second aspect the present invention provides a composition comprising a carrier and at least one compound of the first aspect of the invention. In a third aspect the present invention provides a method of treating a tyrosine kinase associated disease state in a subject, the method comprising administering a therapeutically 16. 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. The present invention also provides use of a compound according to the first aspect of the 5 invention or a composition according to the second aspect of the invention in the manufacture of a medicament for treating a tyrosine kinase-associated disease state in a subject. In a further preferred embodiment the disease state involves JAK 1, JAK2, JAK3, or TYK2. In a preferred embodiment of the present invention the disease state is selected from the 10 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, Sjbgren's Syndrome, Scleroderma, Polymyositis, Ankylosing Spondylitis, Psoriatic Arthritis; Other autoimmune diseases such 1 5 as Type I diabetes; autoimmune thyroid disorders, and Alzheimer's disease; Viral Diseases, such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV), Human Papilloma Virus (HPV); Cancer, such as Leukaemia, Lymphoma and Prostate Cancer; Neurodegenerative Diseases such as Motor Neuron Disease; Cardiovascular Diseases such as Cardiac Hypertrophy, Ischemia, Pulmonary Hypertension, 20 Atherosclerosis and Arteriosclerosis. As used herein the term "tyrosine kinase-associated disease state" refers to those disorders which result from aberrant tyrosine kinase activity, in particular JAK activity and/or which are alleviated by inhibition of one or more of these enzymes. In further aspects the present invention provides the use of the compounds described in the 25 preparation of medicaments for the treatment of 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 of JAKI, JAK2, JAK3 and TYK as described herein.

16a. The present invention also provides use of the compounds or composition described herein in the manufacture of a medicament for treating diseases and conditions associated with inflammation and infection in a subject. 5 The present invention provides pharmaceutical compositions comprising at least one of the compounds of the present invention capable of treating a JAK-associated 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 may be formulated, for example, by employing conventional solid or liquid 10 vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavours, etc.) according to techniques such as those well known in the art of pharmaceutical formulation. The compounds of the present invention may be administered by any suitable means, for 15 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 (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit 20 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 WO 2005/054230 PCT/AU2004/001690 17. 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. 'The compounds may also be administered liposomally. 5 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 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 species (e.g., chickens). 10 Diseases and conditions associated with inflammation and infection can 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 15 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 hurnan being, male or female. The term therapeuticallyy effective amount" means the amount of the subject composition that will elicit the biological or medical response of a tissue, system, animal or human that is 20 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 pharmaceuticallyy acceptable" it is meant the carrier, diluent or excipient must be compatible 25 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 individual in need of treatment. The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the 30 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 into association with a liquid carrier or a finely WO 2005/054230 PCT/AU2004/001690 18. 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 5 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. 10 Compositions intended for oral use may be prepared according 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 pharmaccutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with 15 non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be f6r 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 20 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 morostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release. 25 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 watcr or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipiciEts suitable for 30 the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, 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 35 stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for WO 2005/054230 PCT/AU2004/001690 19. example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a heitol 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 5 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 10 paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. 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 15 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. 20 The pharmaceutical compositions of the invention may also be in the form 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 tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters 25 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 emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, 30 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 WO 2005/054230 PCT/AU2004/001690 20. mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane dioL Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, 5 sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or 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 10 mixing the drug with a suitable non-irritating excipient which is solid 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 15 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 multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and 20 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. 25 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 conditions. 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 30 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: WO 2005/054230 PCT/AU2004/001690 21. cyclosporins (e.g., cyclosporin A), CTLA4-lg, antibodies such as ICAM-3, anti-TL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from- CD40 and gp3 9 (CD401g and 5 CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NP-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors lovastatinn 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 10 such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine, VP-16, etoposide, fludarabine, cisplatin and cyclophosphamide, TNF-I I inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof. When other therapeutic agents are employed in combination with the compounds of the 15 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 tyrosine kinase inhibition an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses, Preferably, the 20 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 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0..5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams 25 of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 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. 30 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 combination, the severity of the particular condition, 35 and the host undergoing therapy.

WO 2005/054230 PCT/AU2004/001690 22. Throughout this specification the word "comprise', 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. 5 All publications mentioned in this specification are herein incorporated by reference. Any discussion of documents, acts, 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 10 present invention as it existed in Australia before the priority date of each claim 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. EXAMPLES 15 Materials and Methods Compound Synthesis Compounds are generally prepared in a 2-step process starting from 2,6-dichloropyrazine. The first step is a nucleophilic aromatic substitution to generate a monoamino-monohalo intermediate. (Scheme 1). H C N 0eNCH,(N rC (I -:r base 1 I: 20 N N 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 25 elevated temperature in the presence of excess amine or a non-nucleophilic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate.

WO 2005/054230 PCT/AU2004/001690 23. Alternatively, the amino substituent may be introduced through a transition metal catalysed examination reaction. Typical catalyst systems for such transformations include Pd(OAc) 2 /P(t-5u)a, Pd2(dba)3/BINAP and Pd(OAc) 2 /BINAP. The amines employed in the first step of the synthesis of these compounds are obtained 5 commercially or are prepared using methods well known to those skilled in the art. Of particular interest are a-methylbenzylamines which are obtained commercially or may be prepared through reduction of oximes (Scheme 2). Typical reductants include lithium aluminium hydride, hydrogen gas in the presence of catalytic palladium on charcoal, Zn in the presence of hydrochloric acid, sodium borohydride in the presence of a Lewis acid such 10 as TiC 3 , ZrCh4, NiC2 and MoO 3 , or sodium borohydride in conjunction with Amberlyst 1115 ion exchange resin and LiCi. The oximes are obtained in one-step from the corresponding ketones through condensation with hydroxylarnine. This reaction is generally performed in a protic solvent such as water or ethanol, at temperatures from O*C to reflux. The hydroxylamine is generally used in the form of its hydrochloride salt, and therefore the 15 reaction is performed in the presence of a base such as sodium hydroxide. The ketones employed as starting materials are generally obtained commercially or via procedures well known to those skilled in the art. NgOH [R] NH 2 Scheme 2 20 a-Methyl benzylanines of high optical purity may be prepared from chiral a-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 phthalinide or azide which can then converted to the primary marine using conventional synthetic methods; or, displacement of the hydroxyl with a suitable 25 nitrogen nucleophile under Mitsunobu conditions. The chiral a-methyl benzyl alcohols may be obtained through chiral reduction of the corresponding ketones. Cliral 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 involves a nucleophilic aromatic substitution reaction of the 30 monochloro- mono-amino pyrazine with benzimidazole or indazole. The reaction is WO 2005/054230 PCT/AU2004/001690 24. typically performed using a salt of the benzimidazole or indazole in solvents such as tetrahydrofuran, dimethylformamide, toluene, or xylene from room temperature to reflux. The benzimidazole or indazole salt is prepared by reaction with a metal hydride such as sodium or potassium hydride or by reaction with caesium carbonate. Alternatively, a 5 metal-catalysed coupling reaction can be used to introduce the benzimidazole or indazole ring. The reaction is typically performed using a base such as caesium carbonate, rubidium carbonate, potassium carbonate, sodium tert-butoxide or potassium phosphate in a solvent such as xylene, toluene, and DMF from room temperature to reflux. Auxiliary reagents such as phase transfer agents (e.g. cetrimoniurn bromide) or copper complexing agents (e.g. 10 phenanthroline) may also be employed in the reaction. The benzinidazole or indazole components used in this reaction are obtained commercially or are prepared from commercially available benzimidazoles or indazoles via techniques well known to those skilled in the art. Alternatively, a benzinidazole or indazole derivative may be reacted with the mono-amino 15 mono-chloro pyrazine and the subsequent product further derivatised using methods well known to those skilled in the art. Representative syntheses are reported below. EXAMPLE 1 6-Ckloro-N-/(i5)-7-(4ftoropheyZpyraz/r-2-arite F N IN CI 20 N A solution of S(-)-1-(4-fluorophenyl)-e thylamine (5.0 g, 35.9 rnmol), 2,6-dichloropyrazine (5.90 g, 39.6 mmol), diisopropylethylamine (12.5 mL, 71.8 mmol) in ethoxyethanol (25 mL) was heated at 135 0 C under N 2 overnight. The solvent was removed In uacwo and the residue washed with 1120 (2 x 30 mL) and dried (Na 2

SO

4 ). The solvent was removed under 25 reduced pressure and the residue triturated with hexanes (2 x 10 mL) to give a light brown solid. The washings were combined, concentrated and the residue obtained chromatographed using ethyl acetate-hexane (1:4 - 1:2) to'soparate solid product which, combined with the original solids, gave the total product (7.07 g, 78/).

WO 2005/054230 PCT/AU2004/001690 25. 'li-n.m.r. (CDC1.,) 61,56 (d, 3H-,/== 6.8 H-z, CH 3 ), 4.81-494 (mi, 1H, CH), 5.05 (mn, IT-, NT-I), 6.98-7.07 (in, 2H1, AxH), 7.29-7.36 (mn, 2H1, ArHi), 7.60 (,q, 111, pyraz-H), 7.80 (s, 111, pyiaz-H). EXAMPLE 2 5 H HN NNN NCI ,_N N N N NY To a stirred solution. of benzimidaizole (130 mg, 1.1 mmol) in anhaydrous DMF (5 mL) at O'C under N 2 wa~s added sodium hydride (56 mg, 60% dispersion in oil, 1.45 n-rnot) in portions over 2 min. The miixtuxc was stirred )t 0 0 C for 15 min 8ad at RT for 60 mn To this was 10 added a solution of (6-diloro-pyrazn-2-y)-(1-benzyl)-rniine (220 mng) in D)MF (5 mL) an~d the resulting inixturc was then heatecl at reflux for 1 8h. The DMF was removed under reduced pre~qure and tue residue diluted with chloroform. The orgwiic layer was washed with water, dried (Na 2

SO

4 ) and the solvent removed under reduced pressure to furnish the crude product. Column chromatogaphy using dichlorometane-metlianki (20:1 - 10:1) as etuitt 15 sepaated the product (100mg).

'

1 F-n.r. (COC.L 3 ) 54.66 (d, 2H, /=5.7Hz, CH 2 ), 5.56 (mn, 1H, NH), 7.29-7.39 (mn, 7H, A rH-), 7.78-7.89 (ini, 2H-, ArH), 7.92 (s, 11-1, pyraz-H), 8.16 (s, 1H, pyraz-H), 8.48 (s, I, ArH2), mn/ z (ES) 302 (M±+H). EXAMPLE~ 3 20 and WO 2005/054230 PCT/AU2004/001690 26. N N CINN CN

NH

2 -+ N CK(N N NH, A mixture of 2,6-dichloropyrazine (2.0 g, 13.4 mmol), 1H-benzimidazole-5-carboxamide (2,0 g, 12.3 mmol) and cesium carbonate (5.6 g, 17.2 mmol) in DMF (10 mL) was heated at 90*C for 3h. The solution was cooled to RT and diluted with ethyl acetate (20 mL) and filtered. 5 The solid material was washed with chlorofonm-mnothanol (20mL, 4:1) and the combined flitrates concentrated ir viwuo. The residue thus obtained (3.02 g) was used without further purification. vi/z(EI) 273/275 (M+1) EXAMPLE 4 10 M6-Ch/oropyrq&---y and MY6.e/aropyr;zo2-y-1-bezitit l//-6-arbonr//e CI N N CIyN NN NH N C~ N N C N NN

NH

2 X N An approximately 1:1 mixture of 1-(6-chloropyrazin-2-yl)-1H-benzimidazole-5-carboxamide and 1-(6-chloropyrazin-2-yl)-1H-benzimidazole-6-carboxamide (0.3 g, 1.09 mmol) and 15 thionyl chloride (0.3 mL, 3.3 mmol).in benzene (3 mL) was heated under reflux overnight. Upon cooling to RT the solution was poured onto ice and the resultant mixture basified to pH -11 with solid NazCO0c. The mixture was then extracted with ethyl acetate (2 X 20 mL) and the combined organic layers washed with brine and dried (Na 2

SO

4 ). The solvent was WO 2005/054230 PCT/AU2004/001690 27. removed /hz vacuo and the residue purified by column chromatography using dichloromethanc-methanol (100:0 - 96:4) as eluant to give the desired product as a mitLre of isomers (135 mg). nt/z (EI) 255/257 (M+1) 5 EXAMPLE 5 H H N NC <CI N N N I I N -I N In a procedure analogous to example 2, reaction of 6-chloro-N-I(IR)-1-phenylethylpyrazin-2-amine (240mg, 1.03mmol) and benzimidazole 10 (130mg, 1.10nrol) furnished the product (187mg, 59%). 'I I-n.m.r. (CDC) 61.63 (d, 3H, /= 6.6Hz, CH.1), 4.98-5.20 (mn, 1H, CH), 5.58 (d, 1H, /=6.OHz, NH), 7.25-7.42 (im, 611, Ph-H, ArH), 7.70 (dd, 1H, f= 7.2, 1.0Hz, A rHi), 7.82 (dd, 1-1, =8.0, 1.2Hz, ArH), 7.87 (s, 1H, pyraz-H), 8.11 (s, IH, pyraz-H), 8.38 (s, Il, ArH). m/z (ES) 315 (M*+H), 212, 105. 15 EXAMPLE 6 6-(I1r-Retizimwaza/1-y)-N-/(2IS)-1-phery/ethyIpyrazin-2-aitiwe N CI '., N N N Ny NY In a procedure analogous to example 2, reaction of 6-chloro-N-[(1.)-1 phenylethyllpyrazin-2-amine (140 mg, 0.60 mnol) and benzimidazole (78 mg, 0.66 nmol) 20 furnished the product (71 mg, 38%).

WO 2005/054230 PCT/AU2004/001690 28. 'H-n.mxr. (CDC1 3 )61.,57 (d, 3Hl= 6.9Hz, Cl- 3 ), 4.95 (inITICl-);5.29 (ci, T-I, -J6.01-z, NH), 7,19-7.35 (n-, 7H-, Ph-I-, An-I), 7.63-7-66 (m., 1Ili, ArH), 7,74-7.77 (mn, '1H-, AxrH), 7.78 (s, IH, 1m/rz (ES) 31.6 (M"+H-), 212,105S 5 EXAMPLE 7 ,, C. N C N Tvt an analogous fimshion to example 1, N-methyl-N-L(lS)-1-pheriylethyllamaine (0,27 g, 2.0 irimo) was condensed with 2,6-dichloropyratzine (0.36 g, 2.4 rnrnol), to furriish the desired -10 product as a light brown solid (192 m~g, 39%). 1 1--nm.r. (CDQl.

3 ) 61.56 (d, 3H, f= 6.8 lIz, CI 3 ), 4.81-4.94 (mn, 1H, CH-), 5.05 (mn, 1H, NH), 6.98-7.07 (in, 2H, ArT-I), 7,29-7,36 (irn, 211, ArH), 7.60 (s, 1H, pyraz-H), 7.80 (s, 11-, pyraz-H). EXAMPLE 8 ~ and H N N ~ , N >N / 0 H2N In ant analogoms fashion to Example 3, 0-chloro)-N-[I,-(3-fluorophenyi)ethyllpyrazin-2-arnne (0.25 g, 1 mmol) was reacted witli 1H-benzimidazolc-5-carboxan'dc (0.2 g, 1.2 mniol) to WO 2005/054230 PCT/AU2004/001690 29. afford the product as a mixture of isomers. '.These were separated by chromatography using dichloromethane-methanol (98:2 - 92:8) as eluant to afford from the less polar fractions 1-(6 {[1-( 3 -fluorophenyl)ethyllaminopyrazin-2-yl)-1H-benzimidazole-6-carboxanide (80 ng). 'Ti-n.m.r. (CDCla) 81.64 (d, 311,j= 6.8 Hz, CH,,), 4,97-5.10 (m, IH, CH), 5.47 (d, 1H,1= 6.2 Hz, 5 NH), 6.90-6.99 (n, IH, ArH), 7.09-7.38 (m, 3H, ArH), 7.72 (dd, 1 i-, /= 8.4, 1.6 Hz, ArH), 7.86 (s, 1H, pyraz-H), 7.87 (d, 11-1,/= 8.4 Hz, ArH), 8.22 (s, 1H, pyraz-H), 8.47 (s, 1H, ArH), 8.60 (d, 1H, /= 1.6 Hz, ArH). From the more polar fractions was isolated 1-(6-([l-(3-fuorophenyl)ethyljaminoupyrazin-2 yl)-1 H-bcnzimidazole-5-carboxamide (63 mg). 10 'H-n.m.r. (CDC 3 ) 51.63 (d, 3H,J7= 6.8 lz, Cl- 3 ), 4.94-5.07 (m, 1H, CH), 5.44 (d, 1Hi, J= 6.6 Hz, NH), 6.90-7.38 (n, 4H, ArH), 7.65 (d, 1H,/= 9.0 Hz, ArH), 7.82 (dd, 1H, /= 8.8, 1.6 Hz, ArH), 7.93 (s, 1H, pyraz-H), 8.13 (s, 1H, pyraz-H), 8.25 (d, 11,/= 1.4 Hz, ArH), 8.41 (s, 1H, ArH). EXAMPLE 9 N H N N,_N N/H F N, N N /

NH

2 15 N In an analogous procedure to that reported in Example 4, 1-(6-(I1-(3 fluorophenyl)ethyaminolpyrazin-2-yl)-1H-benziindazole-6-carboxamide (80 mg, 0.21 nmmol) was reacted with phosphorus oxychloride to afford the product as a pale yellow solid (60 mg, 80%). 20 'H-n.m.r. (CDCl 3 ) 51.65 (d, 3H, /= 6.6 Hz, CH 3 ), 4.94-5.09 (m, 1H, CH), 5.57 (d, 1H, /= 6.2 Hz, N-I), 6.92-7.12 (m, 2H, ArH), 7.20-7.25 (m, Ili, ArH), 7.35-7.46 (m, 1H, ArH), 7.59 (dd, 1H, fe= 8.4, 1.4 Hz, ArH), 7.88 (d, 1H,/= 8.4 Hz, Ar-), 7.94 (s, 1H, pyraz-H), 8.12 (s, 1H, pyraz-H), 8.25 (d, 1H, /= 1.4 Hiz, ArH), 8.51 (s, 1H, ArH). EXAMPLE 10 25 -6-34Dyrbrttai-()-przn--/--enni/z/--rbnre WO 2005/054230 PCT/AU2004/001690 30. and clN N N N +N N N \\NN NT N N In an analogous fashion to Example 1, an approximately 1:1 mixture of 1-(6-chloropyrazin-2 5 yl)-1H-benzinidazole-5-carbonitrile and 1-(6-chloropyrazin-2-yl)-1H-benzimidazole-6 carbonitrile (102 mg, 0.4 nmmol) was condensed with 1,2,3,4-tetrahydroisoquinoline (64 mg, 0.48 mmol). The crude product was triturated with cold othyl acetate to separate 1-6-(3,4 dihydroisoquinolin-2(1H)-yl)pyrazin-2-y1]-1H-benzinidazole-5-ca-rbonitrile as an off-white solid (65 mg) 10 111-n.m.r. (CDCl3) 83.05-3.11 (m, 2H, CU 2 ), 3.95-4.02 (m, 211, CH 2 ), 4.85 (m, 2H, CH 2 ), 7.25-7.29 (m, 31-1, ArH), 7.61-7.68 (m, IH, ArH), 7.95 (d, 1H,/= 8.2 Hz, ArH), 8.11-8.21 (in, 1H, Arti), 8.16 (s, II, pyraz-H), 8.23 (s, 1H, pyraz-H), 8.38 (m, IH, ArH), 8.65 (s, 1H, ArH). The ethyl acetate washings were combined and concentrated io rewo to furnish 1{6-(3,4 dihydroisoquinolin-2(1H)-yl)pyrazin-2-ylj-11-bcLzimidazole-6-carbolitrie (41 mg) 15 'H-n.m.r, (CDCla) 63.07 (t, 2H, /t 5.9 Hz, CH 2 ), 3.97 (t, 2H, /= 6.1 Hz, CH-i 2 ), 4.84 (3, 2H, Ch 2 ), 7.24-7.32 (m, 4H, ArH), 7.67 (dd, 1H,/= 8.8, 1.4 Hz, ArH), 8.11-8.21 (m, 1H, 4rH), 8.16 (s, IH, pyraz-H), 8.22 (s, 1 H, pyraz-H), 8.65 (, 1-, ArH). EXAMPLE 11 20 enrbnitrile and cario/4tril WO 2005/054230 PCT/AU2004/001690 31. N CH N NN + N N N~ N +rN + N C N N N N In an analogous fashion to Example 1, an approximately 1:1 mixture of 1-(6-chloropyrazin-2 yl)-1Ti-benzimidazole-5-carbonitrile and 1-(6-chloropyrazin-2-yl)-1H-benzimida zole-6 carbonitrile (100 mg, 0.39 nmol) was condensed with (1S)-1,2,3,4-tetrahydronaphthalen-1 5 amine (69 mg, 0.47 rmmol). '1ie product was obtained as a mixture of regioisoiners which were separated by column chromatography using dichloromethane-methanol (95:5) as cluant. From the less polar fractions 1-{6-[(1)-1,2,3,4-tetrahydronaphthalen-1 ylaminolpyrazin-2-yl}-1H-benzimidazole-6-carbonitrile was obtained as a yellow semi-solid (26 mg). 10 'H-n.m.r. (CDC,) 81.87-1.98 (mn, 2H, CI 2 ), 2.04-2.18 (MI, 2H, CH 2 ), 2.82-2.90 (m, 2H, CH 2 ), 5.18-5.30 (m, 2H, NH + CH), 7.14-7.23 (m, 3H, Ar-i), 7,32-7.38 (m, 1H, ArH), 7.61 (dd, 1H,f= 8.2, 1.4 Hz, ArII), 7.94 (s, 1H, pyraz-H), 8.11 (d, II, /= 8.2 Hz, ArH), 8,14 (s, 1H, pyraz-H), 8.18 (d, 1H,/- 1.4 Hz, ArH), 8.61 (s, 1H, ArH). From the more polar fractions was isolated 1-[6-[(S)-1,2,3,4-tetrahydronaphthalen-1 15 ylaminolpyrazin-2-y1)-1-benzimidazole-5-carbonitrile (19 mg) 'H-n.n.r. (CDCl 3 ) 81.89-2.02 (m, 2H, CH 2 ), 2.10-2,20 (1n, 2H, CH 2 ), 2.83-2.91 (m, 211, CH 2 ), 5.25 (m, 2H, NH + CH), 7.15-7.35 (m, 4HT, ArH), 7.62 (dd, 1H,f= 8.4, 1.4 Hz, ArH), 7.91-7.95 (m, 2H, ArH + pyraz-H), 8.15 (s, 1H, pyraz-H), 8.52 (br s, 1H, ArH), 8.66 (s, 1H, ArH). EXAMPLE 12 20 1ff-ziidazo/e-5-crbow; /e WO 2005/054230 PCT/AU2004/001690 32. N N HN HN OH NH 2 To a stirred suspension of benzimidazole-5-carboxylic acid (5.0 g, 30.8 mmol) in benzene (25 mL) was added thionyl chloride (25 mL) dropwise at room temperature. To this mixture was added DMF (0,1 mL) and it was then heated under reflux for 6h. Benzene and thionyl 5 chloride was evaporated off under reduced pressure and toluene (20 mL) added to the residue. This was removed under reduced pressure and the acid chloride thus obtained suspended in tetrohydrofuran (20 mL). To this was the added 28% aqueous ammonia (20 mL) dropwise at 0*C, and the resultant mixture was then stirred at room temperature overnight. The precipitate was filtered and washed with cold H 2 0 to give the primary amide 10 as a brown solid (3.55 g). H-n.m.r. (de-DMSO) 87.25 (br s, 1H, NH), 7.60 (d, 1H, /= 8.4 Hz, ArH), 7.78 (dd, 111, 8.4 and 1.6 Hz, ArH), 7.97 (br s, 1H, CONH), 8.18 (br s, 1H, ArH), 8.32 (br s, 111, ArH). EXAMPLE 13 i-( 6

-/(

5 )-l-Pkeny/ethy/ainopyrazin-2-y/y7z-bezilns/aIz,-5->mbi anr/ I H I N*~ N,_N N NN H N N N + N N N NH2 To a stirred solution of 5-amino-benziiidazole (290 mg, 2.2 mmol) in anhydrous DMF (10 mL) under N 2 was added caesiun carbonate (980 mug) The resulting mixture was stirred at 70*C for 60 min. To this was added a solution of 20 6-chloro-N-[(13)-1-phenylethyllpyrazin-2-amine (470 mg) in DMF (5 mL) and the resulting mixture was then heated at reflux for 48h. The DMF was removed under reduced pressure -lw WO 2005/054230 PCT/AU2004/001690 33. and the residue diluted with chloroform. The organic layer was washed with aqueous Na 2 CO, dried (Na 2

SO

4 ) and the solvent removed under reduced pressure to furnish the crude product. Column chromatography using dichloromethane-methanol (95:5 - 92:8) as eluant separated two fractions from unreacted starting material. The higher Rf fraction was 5 assigned as the 6-isomer (276mg, 42%). 'l--n.m.r. (CDCb) 51.64 (d, 3H, /= 6.9Hz, CH:,), 2.90 (br s, 2H, NH2), 5.05 (m, 1H, CH), 5.21 (d, 1H, NH), 6.70 (dd, IH, f= 8.7,2.1Hz, ArH), 6.97 (d, 1H,J= 1.8Hz, ArH), 7.28-7.43 (m, 5H, Ph-H), 7.58 (d, 1H,j= 8.4Hz, ArHI), 7.84 (s, IH, pyraz-i), 8.08 (s, 1H, pyraz-H), 8.21 (s, 1H, Ar-I). m/z (ES) 331 (M*+H). 10 The lower fraction was assigned as the 5-isomer (170mg, 26%). 1 H-n.mr. (CDC1) S1.64 (d, 3H, /= 6.9Hz, CH3), 2.85 (br s, 2H, N-i 2 ), 5.01 (m, IH, CH), 5. 19 (d, 1H, NH), 6.70 (dd, 1H, J= 8.7, 2.1Hz, ArH), 7.11 (d, 11, f= 1.8Hz, ArM), 7.29-7.40 (m, 5H, Ph-H), 7.51 (d, 1H,(f=8.7Hz, ArH), 7.81 (s, 1H, pyraz-H), 8.10 (s, 111, pyraz-I), 8.32 (s, 1H, ArH). 15 m/z (ES) 331 (M*+H). EXAMPLE 14 2,2,<bfiety/propanamde fN __C H2H 20 To a stirred solution of 2 -(benzylamino)-6-(5-amino-benzimidazo-1-yi)-pyrazine (33 mg, 0.1mmnol) in anhydrous THF (2 mnL) under N 2 was added triethylamine (38 11, 0.3 mmol). The solution was cooled at 0*C and to this was added pivalic acid (12 mg, 0.11 mmol) and EDC (23 mg, 0.12 mmol) and the resulting mixture then stirred at RT. After 64h the solution was diluted with H20 and the mixture extracted with CHC1 3 (2 x 15 mL). The combined 25 organic layers were washed with10% aqueous Na 2 CO., dried (Na 2

SO

4 ) and the solvent removed in vacuo. The residue was purified by column chromatography using dichloromethane-methanol (100:6) as eluant to separate the pure product (15mg).

WO 2005/054230 PCT/AU2004/001690 34. 'H-n.m.r. (CDC1 3 ) 51.35 (s, 9H, 3CHI), 1.65 (d, 3H,/= 6.6Hz, CH), 5.14 (m, 1H, CH), 5.24 (d, 11-1,/= 5.7Hz, NH), 7.13 (d, 1H-1, f= 8.7 Hz, ArH), 7.29-7.47 (m, 5H, ArH), 7.75 (d, 1H,/= 8.7 Hz, ArH), 7.81 (s, 1H, pyraz-H), 8.17 (s, 114, pyraz-Hi), 8.35 (s, 1H, ArH), 8.69 (s, 1Hk, CONH). EXAMPLE 15 5 NH2 _Y N To a stirred solution of 2-(-methylbenzylamino)-6-(5-amino-benzimidazo-1-yl)-pyra zine (66 mg, 0.2 mmol) in anhydrous THF (2 mL) under N 2 was added triethylarnine (41. mg, 0.4 nmmol). The solution was cooled at O4C and to this was added acetyl chloride (17 mg, 0.22 10 mmol) and the resulting mixture then stirred at RY. After 18h the solution was poured into water (30 mL) and the product extracted into chloroform (2 x 20 mL).'Ihe combined organic layers were dried (Na 2

SO

4 ) and the solvent removed under reduced pressure to furnish the crude product as a pale yellow solid. Column chromatography using dichloromethane-methanol (200:15) as eluant separated the product as a pale yellow solid (38 15 mg). UT-n.m.r. (CDCL:) 51.63 (d, 3H,h6.6Hz, CH1I), 2.21 (s, 311, CH 3 ), 5.00 (m, 1H, CI I), 5.43 (d, 1H,/= 5.7Hz, NH), 7.27-7.38 (m, 5H, ArH), 7.49 (d, U 1,f= 9.0Hz, ArH), 7,61 (d, 1H, /= 9.0Hz, ArH), 7.74 (br s, 1H, CONH), 7.84 (s, 1H, pyraz-H), 7.90 (s, 1 H, Ar-), 8.11 (s, 1H, pyraz--1), 8.36 (s, 1H, ArH). 20 EXAMPLE 16 muethantesu/faamide' NNN NH;

OY+

WO 2005/054230 PCT/AU2004/001690 35. To a stirred solution of 2 -(.Sa-methylbenzylamino)-6-(5-amino-benzimidazo-1-yl)-py razine (33 mg, 0.1 mmol) in anhydrous THF (2 mL) under N2 was added triethylanine (40 mg, 0.4 mmol). The solution was cooled at 0 0 C and to this was added methanesulphoinyl chloride (25 mg, 0.2 mmol) and the resulting mixture then stirred at RT. After 16h the solution was 5 poured into water (30 mL) and the product extracted into chloroform (2 x 15 mL).'The combined organic layers were was washed with 10% Na2CO.,, dried (Na 2

$O

4 ) and the solvent removed under reduced pressure to fuminsh the crude product as a pale yellow solid. Column chromatography, using dichloromethane-methanol (100:6) as eluant, separated the product from the most polar fractions as a pale yellow solid (16mg). 10 'H-n.m.r. (CDC 3 ) 51.65 (d, 311,/= 6.9 Hz, CH.), 3.00 (s, 3H, CH-I), 5.02 (m, 1 H, CH), 5.27 (d, 1H,/= 6.0 Hz, NH), 7.21-7.40 (m, 6H, ArH), 7.64 (d, 1H, /= 8.7 Hz, ArH), 7.69 (d, 1H,f= 1.9 Hz, ArH), 7.88 (s, 1H, pyraz-H), 8.10 (s, IH, pyraz-H), 8-41 (s, 1H, ArH). EXAMPLE 17 2- tS-a-MtyDnyu )6- (5(N-mvethypgivemzin-y/jv-m-ethy/v)-he Nzivi iwa-1-y/)- 15 pymzine N N NNNN N NN: A solution of 3

-[

6 -(Sa-methylbenzylamino)-pyrazin-2-yll-3H-benzoimidazole-5-carboxylic acid N-mothylpiperazinylamide (22mg, 0.05mmol) in dry TF (lmL) was added to a suspension of LiAIH 4 (4mg, 0.1mmol) in THF (1mL) ancl the mixture heated at reflux for 4h. 20 Upon cooling to RT, the solution was treated consecutively with H 2 0 (1mL), aqueous NaOH (1mL, 2M) and H 2 0 (5mL). The resulting mixture was extracted with CHCl, (2 x 1OmL) and the combined organic layers dried (NazSO4). The solvent was removed under reduced pressure and the product purified by flash chromatography using CH 2 C-MeOH (10:1 -+ 1:1) as eluant to afford the product as a yellow solid (11mg, 52%). 25 'H 1 -n.m.r. (CDCis) 81.65 (d, 3H, /= 6.9Hz, CH 3 ), 2.58 (s, 3H, NCH 3 ), 2.81 (br s, 4H, CH 2 ), 2.90 (br s, 4H, CH 2 ), 3.74 (, 2-H, NCH 2 ), 5.03 (m, 1H, CH), 5.33 (d, 1H, /= 6.0 Hz, NH), 7.25-7.42 WO 2005/054230 PCT/AU2004/001690 36. (in, 6H, ArT-I), 7.67 (d, 1H, /= 8.4 Hz, ArH), 7.77 1s H, AffN), 7.87 (s, 1H, pyraz-l 1), 8.12 (s, 11L, pyraz-H), 8.39 (s, 1H-, AnN). EXAMPLE 18 /1~(6//iY~F/t~oap/// 4 ytkhy/Iatzbwiyr4:>l-2-/2-iH1;I:/:dvzI-//m/haNol and 5 F,, N I' Y H N yCI 0 NF H + rN HO In a procedure mnalogous to Example 3, reaction of 6-cliorv-N-[1-(4 ft-orophenyl)cthyllpyrazin-2-amncn (1.84) g, 7.15 Mmc) and 5-hydroxyinethyl, belizimidazole (1.26 g.. 8.5 mmcd) ftunished the two products which were separated by 10 column chromatography using dichloromethane-mcethanot (98:2 - 92:8) as cluant. From the less polar fractions was obtained [1-(6--fl-(4-fluorophenyl)ethylami-olpyazin-2-y)-I benziinidazol-6-yllmethanol as a pale yellow solid (210 mg), 'H--nxm.r. (CDCtj) 81.60 (d, 3H,/= 6.8 Hz, CHIT), 4.93-5.05 (in, 1H-, QI), 5.48 (d, 111L f= 6.2 Hz, Nli-), 6.97-7.07 (in, 7-1, ArH-), 7.29-7.39 (in, 3H, ArH), 7.76 (d, 1H, /9.4 Hz, AdI), 7.79 15 (s, IH, pyraz-H-), 7.89 (s, 11A, ArNl), 8.09 (s, IH, pyraz-H), 8.34 (5, I, ArHi). From the more polar fractions was itiolated [1-(6-([l-(4-fluorophienyl)etlhyljam-inolpyrazin-2 yl)-1H-benzin-idazol-5-ylinmethanol as a yellow -iolid (265 mg). 'H-n,in.r. (CDC 3 ) 81.62 (d, 3H, /= 6.8 H-z, CHI), 4.82 (s, 2H, CH 2 QH), 4.94-5.06 (i, I H, OH), 5.29 (d, 1H, /= 6.0 Hz, WII, 7.02-7.10 (in, 2H, ArH), 7.29-7.40 (mn, 3H-, ArH), 7.68 (d, 111,J 20 8.4 Hz, ArH), 7.80 (d, 1H, /= 1.2 Hz, AnTJ), 7.84 (s, IH, pyraz-T-l, 8.12 (s, IH, pyraz-H), 8.39 (1H T-, ArHI).

WO 2005/054230 PCT/AU2004/001690 37. EXAMPLE 19 N-[-(4F/uropttu/)tky/-6-6-(4-mt/tlpterain--y/mty/J-1h-/>e~z im idazo /-I y//pyratin-2-tuine FH rN FH N N /N N / OH N N 5 A solution of the alcohol (0.18 g, 0,5 mmol) in dichloromethane (5 mL) was cooled to 0 0 C and to this was added diisopropylethylamine (0.13 mL, 0.75 mmol) and methanesulfonyl chloride (46 FlL, 0.59 mmol). After stirring at RT for 2h. a further aliquot of diisopropylethylamine (30 gL) and methanesulfonyl chloride (20 UL) was added. After 1h.

H

2 O (10 nL) was added and the organic layer collected, The aqueous phase was extracted 10 with dichloromethane (3 x 5 mL) and the organic layers combined, dried (Na2SO 4 ) and concentrated in reao. An aliquot of the crude mesylate thus obtained (100 mg) was dissolved in DMF (2 mnL) and to this was added diisopropylethylamine (52 L'L, 0.3 nmmol) and 1-methylpiperazine (25 EDL, 0.45 mmol). The solution was heated at 60*C overnight. The solution was then concentrated /n vacuo and the residue dissolved in dichloromethane (20 15 mL) and washed with H20. The organic layer was dried (NaIS0 4 ) and concentrated and the product purified by chromatography using dichloromethano-methanol-aqueovs annorda (95:5:0: 95:5:1) to furnish the product as a pale yellow semi-solid (34 mg). 'H-n.m.r. (CDCla) 51.63 (d, 3H, /= 7.2 Hz, CH.), 2.26 (s, 3H, NCH 3 ), 2.45 (br s, SH, 4 x CH 2 ), 3.62 (s, 211, CH 2 ), 4.99-5.11 (m, 1H, CH), 5.41 (d, IH, /= 6.4 Hz, N-), 6,99-7.07 (m, 2h, ArH), 20 7.30-7.41 (m, 3H, ArI), 7.76 (d, 1H,/= 8,4 Hz, ArH), 7.82 (s, 1H, pyraz-1-), 7.89 (s, 1H, ArH), 8.17 (s, 1H, pyraz-H), 8.39 (s, 1H, ArH). EXAMPLE 20 1-T/thn-2-/e/nsit 0 NHL, 2

S

WO 2005/054230 PCT/AU2004/001690 38. To a solution of 1-thien-2-ylethanone (505 mg, 4 mmol) and ammonium fonmate (1.26 g, 20 mmol) in methanol (4 mL) under nitrogen was added dichloro(pentamethylcyclopentadienyl)rhodiun (TIl) dimer (14 mg, 0.023 nmmol). The solution was heated at reflux for 7 h. after which time the solution was cooled to room 5 temperature and acidified to pH -2 with 2M Id. The mixture was washed with dichloromethane (3 x 15 mL) and the aqueous phase then basified to pH -12 by addition of 5M NaOH. The aqueous phase was extracted with dichloromethane (3 x 15 mL) and the combined organic layers dried (Na 2

SO

4 ) and concentrated to give a pure product (280 mg, 55%). 10 m/z (EI) 127 (M*), 112 (M-15)' EXAMPLE 21 (R)--(3,4-D'7uorop/toy4)ethanoI 0 OH F F, FD (S,R)-ci -1-amino-2-indanol (284.3 mg, 1.91 mmol, 0.1 eq) was dissolved in tetrahydrofuran 15 (25 mL) in a dry two-necked round-bottomed flask fitted with a dropping funnel and nitrogen inlet. The solution was chilled to approximately 0*C and NN-diethylaniline-borane complex (3.50 mL, 19.2 mmol, 1 eq) added dropwise. The mixture was allowed to stir at 0 0 C for 30 minutes at which time a solution of 3,4-difluoroacetophenone (2.40 mL) in tetrahydrofuran (40 mL) was added via the dropping funnel over approximately 90 minutes. 20 The solution was allowed to-slowly warm to room temperature and stirring continued overnight. Acetone (16 mL) was added to the reaction mixture and the solution allowed to stir for a further hour before being concentrated 4v evcio. The residue was treated with toluene (100 mL) and washed with 1 M sulphuric acid (4 x 50 mL), water (2 x 50 mL) and brine (50 mL). The organic phase was then dried (Na 2

SO

4 ) and concentrated /& vacuao to 25 afford the crude alcohol. Gradient flashmaster chromatography (20 g silica cartridge; 100% petroleum spirits to 10% ethyl acetate) afforded the desired alcohol as a clear oil (2.242 g, 74%). 'H NMR (CDCa, 300 MHz) 8 1.47 (311, d,/=6.4 Hz), 1.80 (1Hl, d, /=3.6 Hz), 4.87 (1 H, dqJ/= 3.6, 6.4 Hz), 7.04-7.14 (2H, m), 7.16-7.24 (1H, i).

WO 2005/054230 PCT/AU2004/001690 39. EXAMPLE 22 61 Chloro-N-(15--4-dif/aarophethVIMefzy/IpyrazIt-2-an tte F F K NH 2 -N CN F FN (1.5)-1-(3,4-Difluorophenyl)ethanamine (977 mg, 6.2 mmol) and 2,6-dichloropyrazine (1.236 g, 5 8.3 mmol, 1.3 eq) was dissolved in dioxane (5 mL) and potassium carbonate (1.73 g, 2.0 eq) added to the solution. The mixture was then heated at reflux (110*C) under a nitrogen atmosphere for 65 hours. The crude reaction mixture was then poured onto cold water (30 mL) and extracted with diethyl ether (3 x 30 mL). The combined organic extracts were concentrated and subjected to flashmaster chromatography (20 g silica cartridge (8:2 10 petroluem spirits:ethyl acetate, followed by ethyl acetate flush) to afford the desired pyrazine-adduct as an off-white solid (587mg, 35%). 'H NMR (CDCis, 300 MHz) 1.56 (3H,d,/=6.9]Hz), 4.88 (1H1, dq,/=6.5, 6.9 Hz), 4.97 (111, brd, /=6.5 Hz), 7.06-7.20 (3H, m), 7.63 (1H, s), 7.82 (1H, s). MS (e.i.) m/z 269 [M'(-Cl), 29%1, ,,/z 271 [M'( 7 Cl), 10%1. 15 EXAMPLE 23 I- (6-([(1)- 1-(3-Fluo rop)henyl)e thylllaminaopyrint-2-p)H-rzide/-6roim : N N QH s e oNH, To a stirred mixture of 6-chloro-N-[(lS)-1-(3-fluorophenyl)cthyllpyrazin-2-amine (242 mg, 0.96 mmol) and 5-benzinidazole carboxamide (318 mg, 1.97 mmol, 2,1 eq) in NN 20 dimethylforinamide (5 mL) was added cesium carbonate (460 mg, 1.41 mnaol, 1.5 eq). This solution was then heated at 120*C under a nitrogen atmosphere for 48 hours at which time a second amount of cesium carbonate (180 mg, 0.6 eq) was added. The mixture w ,as heated at 120 0 C for a further 62 hours before being cooled to room temperature, di-luted with chloroform (15 mL) and filtered. The filtrate was then concentrated b7 Zm'co and subjected 25 to silica column chromatography (stepwise gradient from dichioromethane to 9:1 WO 2005/054230 PCT/AU2004/001690 40. dichloromethane:methanol) to yield the 5-carboxamide product (100.7 mg, 28%) along with the desired 6-carboxamide product (63.7 ng, 18%), 'H NMR (d6-acetone, 300 MIHz) 5 1.64 (3H, d, 1=6.9 Hz), 2.76-2.80 (2H, brm) , 5.35 (1H, n), 6.93 (1H, in), 7.29-7.36 (3H, m), 7.42 (1H, dm, /=7.7 Hz), 7.77 (11i, dd, /=8.5, 0.5 Hz), 7.93 5 (1H, dd,J= 1.7, 8.5 Hz), 8.05 (1H, s), 8,31 (1 H, s), 8.73 (1H, s), 8.40 (1H, dd, /=0.5, 1.6 Hz). MS (e.i.) ,n/z 376 (M+, 89%). Other Compounds prepared through methods analogous to those reported above include: Example Compound Data 24 'H-n.'n.r. (CDCla) 51.67 (d, 3H, f/= 6.9 Hz, FCH), 5.04 (dq, /= 6.9 Hz, 1H, Cli), 5.40 (d, N / 1H, / 6.9 Hz, NH), 6.92-7.12 (m, 2H, Arl), 7.26-7.38 (m, 11H, ArH), 7.40-7.46 (m, 411, N- AH), 7.61 (dd, 1H,J= 8.4, 1.5 Hz, ArH), 7.89 NN (d, 111, /=8.4 Hz, ArH), 7.91 (s, 111, pyraz-H), N 8.10 (s, 1H, pyraz-H), 8.28 (d, 1-, /= 1.4 Hz, ArH), 8.50 (s, 1H, ArH). 2H-n.m~r. (CDC 3 ) 81.66 (d, 3H, /= 6.8 Hz, 25 F CH,), 5.02 (m, 1H, CH), 5.26 (d, 1H, /= 5.8 Hz, N N N Ni), 7,16-7.25 (m, 3H, ArH), 7.91 (d, 1H, /= 8.4 lHz, ArH), 7.92 (d,/=0.4 Hz, 1H, pyraz-H), 8.17 (d, 1H, /=0.4 Hz, pyraz-H), 8.32 (dd, 1H, 7= 1.5,0.7 Hz, ArH), 8.53 (s, 1H, ArH). 'H-n.m.r. (CDQl0) 61.69 (d, 3E,/= 6.6 Hz, 26 N CH.), 5.33 (m, 1II, CH), 5.39 (d, 1H, /= 7.0 Hz, N N N NH), 7.11-7.19 (m, 2H, ArH), 7.26-7.33 (m, 1H1, Ar-), 7.38 (m, IH),. 7.62 (dd, IH, 7= 8.4, 1.5 F N Hz, ArH), 7.91 (dd, /= 84, 0.6 Hz, 1H), 7.94 (d, 1H,/=0.3 Hz, pyraz-H), 8.10 (d, 1H, /= 0.3 N Hz, ArH), 8.26 (1H, in), 8,52 (s, 1H, ArH). 'H-n.m.r. (CDC1a) 81.67 (d, 3H, /= 6.6 Hz, 27 CH3), 5.04 (m, 1H, CH), 5.30 (d, 1H,./= 5.9 Hz, N NH1), 6.99-7.11 (m, 2H, ArH), 7,23 (dm, 1H,/= F 7.8 Hz, ArH), 7.41 (ddd, 1H, J=8.0, 7.9, 5.0 Hz), 7.60 (dd, 1H, /- 8.4,1.5 Hz, ArH), 7,90 , (dd,/= 8.4, 0.7 Hz, 1H), 7.92 (s, 1H, pyraz-H), N 8.14 (s, 1H, pyraz-H), 8.25 (d, 1I 1, /= 1.5, 0.7 Hz), 8.51 (s, 1Hi, ArH).

WO 2005/054230 PCT/AU2004/001690 SCREENING JAK Tyrosine Kinase Domain Production /AK kinase domains were produced in the following manner: /AK1 5 The kinase domain of human JAKI was amplified from U937mRNA using the polymerase chain reaction with the following primers: XHOI-J1 5'-CCG CTC GAG ACT GAA GTG GAC CCC ACA CAT-3' J1-K'NI 5'-CGG GGT ACC TTA TT TAA AAG TGC TTC AAA-3' JAKI FCR products werc cloned into the pFastBac HTb expression vector (Gibco) via the 10 Xho I and Kpn I sites. The JAKI plasmid was then transformed into competent DH1OBac cells (Gibco), and the recombinant baculovirus produced prepared for transfection into Sf9 insect cells, JAK2 The kinase domain of humanJAK2 was amplified from U937mRNA using the polymerase 15 chain reaction with the following primers: SALI-jk2 5'-ACG CGT CGA CGG TGC CTT TGA AGA CCG GGA T-3' jk2-NOTI 5'-ATA GTT TAG CGG CCG CTC AGA ATG AAG GTC ATT T-3' JAK2 PCR products were cloned into the pFastBac HTc expression vector (Gibco) via the Sal I and Not I sites. The JAK2 plasmid was then transformed into competent DHI13ac cells 20 (Gibco), and the recombinant baculovirus produced prepared for transfection into Sf9 insect cells.

WO 2005/054230 PCT/AU2004/001690 42, JAK3 The kinase domain of humanJAK3 was amplified from U937mRNA using the polymerase chain reaction with the following primers: XIIOI-J3 5'-CCG CTC GAG TAT GCC TGC CAA GAC CCC ACG-3' 5 J3-KPNI 5'-CGG GGT ACC CTA TGA AAA GGA CAG GGA GTG-3' JAK3 PCR products were cloned into the pFastBac H-rb expression vector (Gibco) via the Xho I and Kpn I sites. The JAK3 plasmid was then transformed into competent DH10Bac cells (Gibco), and the recombinant baculovirus produced prepared for transfection intc Sf9 insect cells. 10 TYK2 The kinase domain of humanTYK2 was amplified from A549 mRNA using the polymerase chain reaction with the following primers: HT2EK 5'-GGA GCA CTC GAG ATG GTA GCA CAC AAC CAG GTG-3' riTY2.2R 5'-GGA GCA GGA ATT CCG GCG CTG CCG GTC AAA TCT GG-3' 15 TYK2 PCR products were cloned into pBlueBacflis2A (Invitrogen) via the EcoRI site, The recombinant TYK2 baculovirus produced was prepared for transfected into Sf9 insect coils. Large Scale Production Of Kinase Domains Baculovirus preparations from each of the JAK family members were infected into five litres of High Five cells (Invitrogen) grown in High Five serum free medium (Invitrogen) to a cell 20 density of approximately 1-2 X 10 cells/ml. Cells are infected with virus at a MOI of 0.8-30. Cells were harvested and lysed. JAK kinase domains were purified by affinity chromatography on a Probond (Invitrogen) nickel chelate affinity column, Assay Protocols Kinase assays were performed either in a 96 well capture-based ELISA assay or in 384 well 25 Optiplates (Packard) using an Alphascreen Protein Tyrosine Kinase kit. In either casse using approximately 1.5 pg of affinity purified FK domain in the presence of 50mM HEPES, pH 7.5, 10mM MgCl 2 , 150mM NaCI and 10iM-ImM ATP. The biotinylated substrate biotin-EGPWLEEEEEAYGWMDF-NH 2 (final concentration 5pM) was used as substrate - in WO 2005/054230 PCT/AU2004/001690 43, the ELISA assay tyrosine phosphorylation waS quantitated following transfer to an avidin coated ELISA plate using peroxidase-linked anti-phospho-tyrosine antibody PY20. 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 5 Fluorostar, the Alphascreen plates were read on a Packard Fusion A/pha. 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 1%. Results The activity of a range of compounds is shown in Table 3. Compounds that exhibited a 10 capacity to inhibit 50% or greater of enzyme activity at a concentration of 20 pAM (measured under standard conditions, see Methods), are designated as "+". Compounds not tested are designated "NT"; while compounds that did not inhibit enzyme activity by 50% at 20 JtM are designated "-".

WO 2005/054230 PCT/AU2004/001690 Table 3: C4EMIMT1Y J~k2 J310 2a70 1162 MRI abi Mn We bik +~ ~ ~ + NT NT HT HT NT NT NT f25H22N602S + +- +4 Hr NT NT NT + HT - NT NT NT NT HT NT NT fl2HH19N NT - NT NT NT NT NT NT + N NT NT NT NT NT NT + + NT +. + NT + NT C25H28NO0 H 4 T + NT NT NT NT '332H-34fl60 WO 2005/054230 PCT/AU2004/001690 45. Tablc 3 (conit.) CiHEMISTY JMk2 Jaki3 zWO7 tiet hok abiI s kdt btk 'b+ NT NT NT NT N7* NT HT clelN --- + NT NT KT NT NT HT NT - - NT NT NT +- NT NT NT + 4, NT NT NIT NT HT NT 'Cl7HISN5 +~a NT NT NT NT NT NT NT c2IH27N5O2 *l NT NT NT HT NT N NT U~1H1 WO 2005/054230 PCT/AU2004/001690 46. Table 3 (corit,) CHeEMISTRY Jak2 Jaka zap7O -2 Mk 9bi frrw kdr bti( + NY NT NT NT NY + NT C20HIOFNSO M1J~ T NT HT NT NY NT NT G25H1 eFN5O - - NT NT NT NT N4T NT NT C24H27FNO - - NT NT NT NT NT +T NT 024H-26FNe NT NT NTNY + N C2GH29FN7-- - - - - - NT NT NT NT NT + NT C24HZ7FN6 y I N,- - NT NY NT MT NT + NT (C22HO WO 2005/054230 PCT/AU2004/001690 47. Table 3 (cont.) CHEMISTRY Jak2 Jak3 -zap7 tij2 hck abi fmo kdr btk - NT NT NT NT NT NT NT C24H26FN7 - - NT NT NT NT NT NT NT C1BH15FN0 + - NT NT NT NT NT + NT C18H15FN6 r I J' + - NT NT +T NT NT NT C20H18FNS0 r - NT NT NT NT NT NT NT C20HISFN5O - + NT + NT NT NT NT NT C24H26FN7 + - NT NT + NT NT NT NT C24H25FN6O + NT NT NT NT NT NT NT cr C25H27FNe WO 2005/054230 PCT/AU2004/001690 48. Table 3 (cont.) ONEMISTSY JBsd r3pIO Ilc2 hcK abi fm kdr bk + - NT NT NT NT NT NT NT C25H27FNeO + - NT + NT NT NT NT NT C24HZ5FN6 - - NT NT NT NT NT NT NT Q26H31FN6 + - NT NT + NT NT NT NT C24H27FN6o2 - + NT + NT NT NT NT NT C21Hietea + + NT + NT NT NT + NT 021H16NO - - NT NT NT NT NT NT NT C24H18N6 YN - - NT NT NT NT + NT NT WO 2005/054230 PCT/AU2004/001690 49. Table 3 (cont.) CHEMISTRY -Jak2 JaK3 zap7o tio2 rick vbI tms kdr btk + - NT UT NT NT NT NT NT (Q2GH16FrI9 +~L Q. NT NT NT mT NT NT + + UT NT NT NT NT NT NY 4- 4. NT NT NT NT NT NT NT C20HIONO +4 NT NT NY NT + NIT NIT C22H-23N70 -NT NT NT +. HT NT N T + 4- NT NT + UT NT N T NT C1 gf-15N7I WO 2005/054230 PCT/AU2004/001690 50. Table 3 (cont.) CHEMI$Thy J4kZ Jak3 zag70 tiC2 ho~k at 1~ kr b -NT NT NT NT NT NT HT -Cl y-__ HT NT NT NT NT NT NT Or+ + NT NT NT NT NT NT wT + +1 NT NT NT MT NT NT wT CzoH1 4P2NB J + + NT NT 1. NT NT NT HT 020H1 SFN8 + + NT NT NT NT NT NT NT 02QHI5FN5 H T NT NT NT UT NT NT OU2H18N6 + + NT NT NT NT +, HT NT ,C22HiONG WO 2005/054230 PCT/AU2004/001690 51. Table 3 (cont.) OHEMISTnY Jak2 Jvk3 znu7L 1We tAok abI tms kdr bik MY N NT +T NY NT NT NT C2OHl5PN6 __ 14 .. NT NT 4Y NT NY NY NT 02M1 4F2N6- - + - NT NT NT NT NY NY NY - NT NT NT NT NT NT NT C211415F3NB s.t'\ - - NT NT NT NT Nr NT NT + N T NT NT NT NT NT 02OH14CIFN6 '. - - NT NT NY NT NT NT NT jCMI4fsFN60 WO 2005/054230 PCT/AU2004/001690 52. Table 3 (cont.) PHEIMTRYJ Jak3 2ap7O ie2 hck abi tnp kdjr btk - - NT NT NT NT. NT NT NT C21H15F3N6O / N - - NT NT NT NT NT NT NT C21HI6NO -H T NT NT NT NT NT NT C21H1eN8 - NT NT NT NT NT NT NT C21H16N6 - + NT NT NT NT NT NT NT C21Mt6N0 - - NT NIr NT NT NT NT HJT + + NT + NT NT NT T NT C21H18N - NT NT NT NT NT NT NT C10M10NI WO 2005/054230 PCT/AU2004/001690 Table 3 (cont.) CHEMISTRY jl2 JO 70 V62 hck af r no kdr blK o*- -l NY NY NY N-t NTt NT N4T H T HT NT NT NT NY NT ClOH16FNS -) Y NT NY NY NY Nt NT NT + + + NT NT NT NT NT NT + NT NT NT NT NT NT NT '021HIONe + + NT NT NT NT NT +i NT '21HISN6--- __ Oy ). NT NT NT NT T NT NT +y) X + NT NT NY NT NT + NT 54. Table 3 (cuntL) a z701c F FJ!L kd bk + + T HT NT NT HT HT NY -NT NT NT NT NY NY NT ?1 N NT NT NT HT NT NY sa+ NT NT NT NT NT H T ~~5IJ ~NT UT NT NY NY NI HT MY NT T UT UT HT NY N4? NT NIT +T NY NT NY NY M-OH2N1BNQ WO 2005/054230 PCT/AU2004/001690 55. Table 3 (co~nt.) CHEMI*TAY .jok2 Jak3 70o _ti~ Eck abi Ims -kdr boc W f NT N-T NT NT NT NT C2iH1SFN8 __ * t NT + NT 14T NT NT UT G21I415NS - .. NT NT HT T NT NT NT -<7lt - NT NT NT NT NT NT HT CZ1H l58rN8 +4 + HT +4 Nr UT NT NT NI C21Hi7FNG + + N1T NT NT NT HT NT NT v'19H16N? WO 2005/054230 PCT/AU2004/001690 56. 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 enbodiments 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 2005/054230 PCT/AU2004/001690 57 REFERENCES 1. Kozmna SC, Redmond SM, Fu XC, Saurer SM, Groner B, and Hynes NE. (1988) Activation of the receptor kinase domain of the trk oncogene by recombination with two different cellular sequences. EMBO. 7, 147-54 5 2. Spiotto MT, and Chung TD. (2000) STAT3 mediates IL-6-induced growth inhibition in the human prostate cancer cell line LNCaP. ProsMfe 42, 88-98 3. Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zurcher G, Ziemiecki A. (1991) Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Ma/ Cel/ Bial 11, 2057-65 10 4. Wilks AF, and Kurban RR (1988) Isolation and structural analysis of murine c-fes cDNA clones. Orcogen. 3, 289-94 5. Sadowski I, Stone JC, Pawson T. (1986) A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps. Mo/ Ce/B0146, 4396-408

Claims

1. A compound of the general formula (I) W R1 I I A-Q-N N D N: Y or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein: D is a heterocyclic ring selected from: N N N N x X X 2 -X 3 R17 R2 R2 where Xi, X 2 , X 3 , X 4 are optionally substituted carbon, or one of XI, X 2 , X 3 , X4 is nitrogen and the rest optionally substituted carbon; R2 is selected from the group consisting of CN; NR22R23 wherein R22 and R23 are joined to form an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from 0, S, NR6; an optionally substituted 3-8 membered (saturated or unsaturated) ring containing 2-5 nitrogen atoms; an unsubstituted or optionally substituted 5-membered heteroaromatic ring containing one or more heteroatoms selected from 0, N, S; an unsubstituted or optionally substituted 6 membered heteroaromatic ring containing two or more heteroatoms selected from 0, N, S; R21 is 0-2 substituents independently chosen from H, halogen, C 14 alkyl, CF 3 , OCF 3 , OCHF 2 , CN, aryl, hetaryl, Ci. 4 alkylOH, Ci 4 alkylNR3R4, Ci 4 alkylhetaryl, OCi 4 alkyl, OC 1 . 4 alkylNR3R4, OC 1 . 4 alkylhetaryl, OC 1 . 4 alkylOH, C0 2 R3, CONR3R4, NR3R4, nitro, 2870018_2 (GHMatter) P72592.AU.2 59 NR3COR4, NR5CONR3R4, NR3SO 2 R4, C,4alkylNR3COR4, Ci alkylNR5CONR3R4, C14alkylNR3SO 2 R4; R3, R4 are each independently H, CI1alkyl, C1 alkylOH, Ci.4alkylNR19R20, C . 4 alkyl cycloalkyl, ClAcyclohetalkyl, aryl, C 1 4alkylaryl, hetaryl, Cl4alkylhetaryl, or may be joined to form an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from 0, S, NR6; and R5 is selected from H, C Ialkyl, aryl or hetaryl; R6 is selected from H, Cl4alkyl, C]4alkylNR19R20, aryl, hetaryl, C14alkyl aryl, C 1 4alkyl hetaryl; R19, R20 are each independently selected from H, C . 4 alkyl; RI is H, CI.4 alkyl, CI. 6 cycloalkyl, or may form a 5-8 membered ring onto the ortho position of ring A; Q is a bond or C 14 alkylene; A is aryl or hetaryl each optionally substituted with 0-3 substituents independently chosen from halogen, Ci. 4 alkyl, CF 3 , OCF 3 , CN, NR8R9, aryl, hetaryl, CI.4aryl, Cl. 4 hetaryl, C 1 4alkylNR8R9, OC14alkylNR8R9, nitro, NR10C 1 4 NR8R9, NR8COR9, NR 1 OCONR8R9, NR8SO 2 R9, CONR8R9, C0 2 R8; R8 and R9 are each independently H, Cl.4alkyl, aryl or together form an optionally substituted 4-8 membered ring which may contain a heteroatom selected from 0, S, NR 1; R10 is selected from H, C14alkyl; RI 1 is selected from H, C14alkyl; W is selected from H, C14alkyl, C 2 - 6 alkenyl or may form a 5-8 membered ring onto the ortho position of ring A; where C1 alkyl or C 2 . 6 alkenyl may be optionally substituted with CI.4alkyl, OH, OCI1alkyl, NR12R13; R 12, and R 13 are each independently H, CI alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR14; 20700162 (GHMatter) P72592.AU2 60 R14 is selected from H, Ci.alkyl; Y is 0-2 substituents selected from H, CI.4alkyl, NR15R16; R15 and R16 are independently selected from H, CI.4alkyl; or a compound selected from the group consisting of: CI N cC1 NN I H NN H\N=. N N<N Ir N N N N \ N N N -N N21N 7_ 0 r s2T) Nr N 2670010_2 (GHMtt-) P72592AU.2 61 H N N ; N / NH NO; N '§T NH N N 0 0 NJ /N IN '\ / N N N N ~ N N H0 ~ N I~N N 2 ~ RN H ;N / N N PA N N Hl N NT NN NN 267001e 2 (GHIWWo ) P72592 AUJ2 62 F N N 0 ,( 10 - N N N OH NHO N:- ON N. NNN N H r NI NN 267001e_2 (CHL00tem) P72592.AU.2 63 F N N, H NN N ;rN HO H H N.(X N >N HO N N.N 2670016 2 (GHV.01-) P72592AU2 64 N N N N HNJ 0 F r:-N FH N NT fN N N N HO f:.zN H N N :r rN NJ H 2 N HH 2870016_2 (GHMaII-) P72502.AU2 65 F N N N N N/ N N N F N N F, j HFHf NN N N /N N \\ N f:I 'Ni' NN -Z N NN N

2. A compound according to formula (I) of claim 1, wherein the compound is selected from compounds of the general formula (II): W R1 A N NN D YN II or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein: D is a heterocyclic ring selected from: 2870016_2 (GHMatt) P72592.AU.2 66 N N X4 X2 X3 R17 R2 where XI, X 2 , X 3 , X 4 are optionally substituted carbon, or one of X, X 2 , X 3 , X 4 is nitrogen and the rest optionally substituted carbon; R2 is selected from the group consisting of CN; NR22R23 wherein R22 and R23 are joined to form an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from 0, S, NR6; an optionally substituted 3-8 membered (saturated or unsaturated) ring containing 2-5 nitrogen atoms; an unsubstituted or optionally substituted 5-membered heteroaromatic ring containing one or more heteroatoms selected from 0, N, S; an unsubstituted or optionally substituted 6 membered heteroaromatic ring containing two or more heteroatoms selected from 0, N, S; R21 is 0-2 substituents independently chosen from H, halogen, CI4alkyl, CF 3 , OCF 3 , OCHF 2 , CN, aryl, hetaryl, C 1 .4alkylOH, CiaalkylNR3R4, Ci. 4 alkylhetaryl, OC 1 .4alkyl, OCI4alkylNR3R4, OCi4alkylhetaryl, OCI4alkylOH, C0 2 R3, CONR3R4, NR3R4, nitro, NR3COR4, NR5CONR3R4, NR3SO 2 R4, CiAalkylNR3COR4, Ci alkylNR5CONR3R4, C1I4alkylNR3SO 2 R4; R3, R4 are each independently H, CI4alkyl, C 1 .4alkylOH, CI4alkylNR19R20, Ci. 4 alkyl cycloalkyl, C 1 .4cyclohetalkyl, aryl, C 1 . 4 alkylaryl, hetaryl, ClAalkylhetaryl, or may be joined to form an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from 0, S, NR6; and R5 is selected from H, Cialkyl, aryl or hetaryl; R6 is selected from H, Ci4alkyl, C 1 . 4 alkyINR19R20, aryl, hetaryl, C14alkyl aryl, C.4alkyl hetaryl; R19, R20 are each independently selected from H, C14alkyl; 267001_2 (GHMatter) P72592AU.2 67 RI is H, CI.4alkyl, Ci. 6 cycloalkyl, or may form a 5-8 membered ring onto the ortho position of ring A; A is aryl or hetaryl each optionally substituted with 0-3 substituents independently chosen from halogen, C 1 . 4 alkyl, CF 3 , OCF 3 , CN, NR8R9, aryl, hetaryl, C 1 . 4 aryl, Cl. 4 hetaryl, C 1 . 4 alkylNR8R9, OCI. 4 alkylNR8R9, nitro, NR10C 1 .4NR8R9, NR8COR9, NRIOCONR8R9, NR8SO 2 R9, CONR8R9, C0 2 R8; R8 and R9 are each independently H, CIAalkyl, aryl or together form an optionally substituted 4-8 membered ring which may contain a heteroatom selected from 0, S, NR1 1; RIO is selected from H, C 1 4alkyl; R I I is selected from H, Ciaalkyl; W is selected from H, Ci. 4 alkyl, C 2 . 6 alkenyl or may form a 5-8 membered ring onto the ortho position of ring A; where Ciaalkyl or C 2 . 6 alkenyl may be optionally substituted with Ci 4 alkyl, OH, OCIAalkyl, NR I2R 13; R12, and R13 are each independently H, Ciaalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR14; R14 is selected from H, Ci 4 alkyl; Y is 0-2 substituents selected from H, C1.4alkyl, NR 15R 16; R15 and R16 are independently selected from H, CI.4alkyl.

3. A compound according to claim 1 or claim 2 wherein R2 is selected from the group consisting of CN; NR22R23 wherein R22 and R23 are joined to form an optionally substituted 3-8 membered (saturated or unsaturated) ring optionally containing an atom selected from 0, S, NR6; an unsubstituted or optionally substituted 5-membered heteroaromatic ring containing one or more heteroatoms selected from 0, N, S; an unsubstituted or optionally substituted 6-membered heteroaromatic ring containing two or more heteroatoms selected from 0, N, S;

4. A compound according to claim 3 wherein R2 is selected from CN and tetrazole. 2870018_2 (GHMatters) P72592AU 2 68

5. A compound according to claim 1 selected from the group consisting of: NCNNN N N NT N N N N N N NCN N N N H f:K H f7:: N,,(N N/ NTN N I O-Ty N OTN N N H N N ~~ ~ .0,N<TN H f: NN 2870018 2 (GHMft-.) P72592AU.2 69 F F NN" N H~N H N~ NN H N N NN H F FN N 70 F F- /- F N% N~ H N F N~ F NI N H N N NF N Fp( F N N N KrcN C NIXNN 2070010_2 (GHMttem) P7?592AU.2 71 N NNN (Y crN N - N N N N NN NN r N )..N N N 28701_2GH ater)P252.U. 72 H rNN HN NN Nr N H I=N /=N/ iN 2670016h2 (GMLftff.) P72592A.2 73 H N Br-r Ny N HN NN ly N-*,N 26000_ (H~l-P759AU 74 cl N NH11 ~ N N N b-TN/ NIr HN N N0,;_T\ NN N IN tb H I H NH H. N N N N N-) N N N N N NN 26700iB 2 GHMbtt-) P72592.AU.2 75 HO r N H 2 N N 0NN NN N\\ N PH\~1 NN N N~N/ F 7 N N OH

2070016.2 (GHM00.n) P72502AU.2 76 H F N 0, N N H~ N, N HH FR- F HO-./ N N N_ 28700102 (GHIbTtem) P72502AU.2 77 H H N F~.OH N. N% N4 /K N N) 0 HO FyN "rN. 78 HN HH N N N NNH NFiF F N NFN N-N N-N H N0 H FN- F N:'r N F,, N N Pr N N:rN N

6. A compound according to the claim I selected from the group consisting of 1-(6- { [1 -(3 -Fluorophenyl)ethyl]amino} pyrazin-2-yi)- 1 H-benzimidazole-5 carboxamide, 1-(6- {[ -(3-Fluorophenyl)ethyl]amino } pyrazin-2-yl)- I H-benzimidazole-6 carboxamide, 1-(6-{[I-(3-Fluorophenyl)ethyl]amino}pyrazin-2-yl)-IH-benzimidazole-6 carbonitrile, 1-[6-(3,4-Dihydroisoquinolin-2(1H)-yl)pyrazin-2-yl]-IH-benzimidazole-5 2070016_2 (GHMattes) P72592.AU.2 79 carbonitrile, 1-[6-(3,4-Dihydroisoquinolin-2(1H)-yl)pyrazin-2-yl]-1H-benzimidazole-6 carbonitrile, 1-{6-[(IS)-1,2,3,4-Tetrahydronaphthalen-1-ylamino]pyrazin-2-yl}-1H benzimidazole-5-carbonitrile, 1-{6-[(1S)-1,2,3,4-Tetrahydronaphthalen-1 ylamino]pyrazin-2-yl} -1 H-benzimidazole-6-carbonitrile, 2-(S-c-Methylbenzylamino)-6-(5-(N-methylpiperazin-4-yl-methyl)-benzimidazo- l-yl) pyrazine, [1 -(6- {[1-(4-Fluorophenyl)ethyl]amino} pyrazin-2-yl)- 1 H-benzimidazol-5 yl]methanol, and [1 -(6- {[ 1 -(4- Fluorophenyl)ethyl]amino} pyrazin-2-yl)-lH benzimidazol-6-yl]methanol and N-[l-(4-Fluorophenyl)ethyl]-6-{6-[(4-methylpiperazin 1 -yl)methyl]- I H-benzimidazol- 1-yl} pyrazin-2-amine.

7. The compound: H K NN N FI r N or a pharmaceutically acceptable prodrug, salt, hydrate, solvate, crystal form or diastereomer thereof.

8. The compound: H FN N : F N or a pharmaceutically acceptable prodrug, salt, hydrate, solvate, crystal form or diastereomer thereof. 2670016_2 (GHkatters)P72592AU2 80

9. A composition comprising a carrier and at least one compound according to any one of claims 1 to 8.

10. Use of a compound according to any one of claims I to 8 or a composition according to claim 9 in the preparation of a medicament for treating a tyrosine kinase associated disease state in a subject.

11. Use according to claim 10, wherein the disease state involves JAK1, JAK2, JAK3 or TYK2.

12. Use according to claim 10 or 11 wherein the disease state is selected from the group consisting of Atopy, Cell Mediated Hypersensitivity, Rheumatic Diseases, Other autoimmune diseases, Viral Diseases, Cancer, Neurodegenerative Diseases, and Cardiovascular Diseases.

13. Use of a compound according to any one of claims I to 8 or a composition according to claim 9 for use in the preparation of a medicament for the treatment of JAK associated disease states.

14. Use of at least one compound according to any one of claims 1 to 8 or a composition according to claim 9 in the manufacture of a medicament for the treatment of diseases and conditions associated with inflammation and infection in a subject.

15. A compound according to any one of claims I to 8 or a composition according to claim 9 substantially as herein described with reference to the accompanying Examples. 267001_2 (GHMatters) P72592AU2