AU2005203919B2

AU2005203919B2 - Selective kinase inhibitors

Info

Publication number: AU2005203919B2
Application number: AU2005203919A
Authority: AU
Inventors: Xianyong Bu; Christopher John Burns; Marcel Robert Kling; Michelle Leanne Styles; Herbert Rudolf Treutlein; Andrew Frederick Wilks; Jun Zeng
Original assignee: YM Biosciences Australia Pty Ltd
Current assignee: YM Biosciences Australia Pty Ltd
Priority date: 2004-01-12
Filing date: 2005-01-12
Publication date: 2011-07-21
Anticipated expiration: 2025-01-12
Also published as: AU2005203919A1

Abstract

A compound of the general formula (I) or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein A represents a variety of six membered nitrogen containing heterocyclic rings, Q is a bond, halogen, C alkyl, O, S, SO, CO or CS and X, X, X and X are optionally substituted by 9 specific substituents or one can be nitrogen. Compositions comprising a carrier and at least one compound of formula (I) are also provided. Further provided are methods of treating tyrosine kinase-associated disease states by administering a compound of formula (I) and methods of suppressing the immune system of a subject by administering a compound of formula (I).

Description

WO 2005/066156 PCT/AU2005/000022 I SELECTIVE KINASE INHIBITORS FIELD OF THE INVENTION The present invention relates to the field of inhibitors of protein tyrosine kinases in particular the JAK family 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 Idnases fall into several groups; those which preferentially phosphorylate shrine 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 10 pathways responsible for transducing extracellular signals, including the action of cytokines on their receptors, to the nuclei, triggering various biological events. The many roles of protein kinases in normal cell physiology include cell cycle control and cell growth, differentiation, apoptosis, cell mobility and mitogenesis. Protein kinases include, for example, but are not limited to, members of the Protein 15 Tyrosine Kinase family (PT~s), which in turn can be divided into the cytoplasmic 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 1TK family, (including BTK; IK; TEC; MKK2 and IXK), the Janus kinase family, (including: JAKI, 20 JAK2, JAK3 and Tyk2), the FAK family (including, PAK and PYK2); the Fes family (including FES and PER), the ZAP70 family (including ZAP70 and SYK); the ACK family (including ACKI and ACK2); and the Abi family (including ABL and ARG). The RTK family includes the EGF-Receptor family (including, EGF-PR, HER2, HER3 and I-ER4); the Insulin Receptor family (including INS-R and IGF1-R ); the POGF-Receptor family 25 (including PDGFRa, PDGFRp, CSFIR, KIT, FLK2); the VEGF-Receptor family (including; FLT1, FLK1 and FLT4); the FGF-Receptor family (including FGFRi, FGFR2, FGFR3 and FGFR4); the CCK4 family (including CCK4); the MET family (including MET and RON); the TRK family (including TRKA, TRKB, and-TRKC); the AXL family (including AXL, MER, and SKY); the TIE/TER family (including TIE and TIE2/TEK); the 30 EPH family (including E-HAI, EPHA2, EP HA3, EPHA4, EPHA5, EPH1A6, EPHA7, EPHAS, EPHB1, EPH1B2, EPHB3, EPHB4, EPHB5, EPH36); the RYK family (including' RYK); the MCK family (including MCK and TYRO10); the ROS family (including ROS); WO 2005/066156 PCT/AU2005/000022 2 the RET family (including RET); the LTK family (including LTK and ALK); the ROR family (including ROR1 and ROR2); The Musk family (including Musk); the LMR family including LMR1, LMR2 and LMR3); and the SuRTK106 family (including SuRTK106), Similarly, the serine /threonine specific kinases comprise a number of distinct sub 5 families, including; the extracellular signal regulated kinases, (p42/ERK2 and p44/ERKI); c-Jun NH2-terminal kinase (JNK); cAMP-responsive element-binding protein kinases (CREBK); 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. 10 Additionally, the genomes of a number of pathogenic organisms possess genes encoding . protein kinases. For example, the malarial parasite Plasmodium falciparum and viruses such as 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, 15 for example by failure of the proper control mechanisms for the kinase, related for example to mutation, over-expression or inappropriate activation of the enzyme; or by over- or under-production of cytokines or growth factors also participating in the transduction of signals upstream or downstream of the kinase. In all of these instances, selective inhibition of the action of the kinase might be expected to bave a beneficial effect. 20 Diseases where aberrant kinase activity has been implicated include: diabetes; restenosis; atherosclerosis; fibrosis of the liver and kidney; ocular diseases; myelo- and lymphoproliferative disorders; cancer such as prostate cancer, colon cancer, breast cancer, head and neck cancer, letikemia and lymphoma; and, auto-immune diseases such as Atopic Dermatitis, Asthma, rheumatoid arthritis, Crohn's disease, psoriasis, Crouzon 25 syndrome, achondroplasia, and thanatophoric dysplasia. The JAK family of protein tyrosine kinases (PTKs) play a central role in the cytokine 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 30 reveals the presence of seven highly conserved domains (Harpur et al, 1992). In seeking a nomenclature for the highly conserved domains characteristic of this family of PTKs, the classification used was guided by the approach of Pawson and co-workers (Sadowski et al, 1986) in their treatment of the SRC homology (SH) domains. The domains have been WO 2005/066156 PCT/AU2005/000022 enumerated accordingly with most C-terminal homology domain designated JAK Homology domain 1 (JH1). The next domain N-terminal to J1 is the kinase-related domain, designated here as the JH2 domain. Each domain is then enumerated up to the JH7 located at the N-terminus. The high degree of conservation of these JAK homology 5 (JH) 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 are arbitrary, and may or may not define functional domains. Nonetheless, their delineation is a useful device to aid the consideration of the overall structural similarity of this class of proteins. 10 The feature most characteristic of the JAK family of PTKis is the possession of two kinase related domains (JH1 and JH2) (Wilks et at, 1991). The putative PTK domain of JAKI JH1) contains highly conserved motifs typical of PTK domains, including the presence of a 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 15 Alignment of the human JAM PTK domain (255 amino adds), with other members of the PTK class of proteins revealed homology with other functional FTs (for example, 28% identity with c-fes (Wilks and Kurban, 1988) and 37% homology to TRK (Kozma et al, 1988)). The JH1 domains of each of the JAK family members possess an interesting idiosyncrasy within the highly conserved sub-domain VIlI motif (residues 1015 to 1027 in 20 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 FTKs. Aside from this element, the JH1 domains of each of the members of the JAK family are typical PTK domains. Furthermore, there is high sequence identity in the JAK family particularly in and around the ATP binding site 25 (Figure 1). The central role played by the JAK family of protein tyrosine kinases in the cytokine dependent regulation of the prolferation 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 those enzymes. Potent and specific inhibitors of each of the 30 currently known four JAK family members will provide a means of inhibiting the action of those cytokines that drive immune pathologies, such as asthma and as immunosuppressive agents for, amongst others, organ transplants, lvpus, multiple. sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's 35 disease, Alzheimer's disease, and leukemia/lynphoma.

WO 2005/066156 PCT/AU2005/000022 4 The JAKISTAT Pathway The delineation of a particularly elegant signal transduction pathway downstream of the 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 5 Interleukin-4 receptor or the Interferon y receptor; (ii) a member (or members) of the JAK family of TrKs; (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. 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 10 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 wrnuber of important immune regulatory cytokines. The therapeutic possibilities stemming from inhibiting (or enhancing) the JAK/STAT pathway are thus 15 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 autoimmune diseases such as lupus, multiple sclerosis, rheumatoid arthritis, Type I diabetes, autoimmune thyroid disorders, Alzheimers disease and other 20 autoimmune diseases. Additionally, treatment of cancers such as prostate cancer by JAK inhibitors isiindicated.

WO 2005/066156 PCT/AU2005/000022 Table 1 - Activatiun of the JAK! STAT pathway in various pathologies' Disease Type Cell Types Characteristics Involved Allergic As thma (Mast Cells T-cell activation of B-cells followed by IgE mediated Atopic Dermatitis (Eczi-ma) (E-osinophils activation of resident Mast cells and 'Eosinophids Allergic Rhinitis (T-Cells (B-Cells Allergic Contact Dmatitk& (B-cells T-cell hypersensitivity Hypersensitivity Prumonitii Systemic Lupus~ ETytheratosui (SLE) (Monocytes Cytokie Production Rheumatoid Athritis (e.g.TNF, IL-1, CSF-1, GM Juvenile Arthritis (Macrophages C-sF) Sj~rens Sndrme(Neiifrophils T-cell Activation (Mast Cells JAK/STAT activation Sclercxderma. Polymyositis (oiohl Aiikylosing SpondyUlis (-Cl Psoriatic Arthritis Transplant rejection T-Cells & B-Cdll, JAK/STAT Activation WO 2005/066156 PCT/AU2005/000022 6 Table 1 (cont.) Disease Type Cell Types Characteristics Involved Graft versus Host Disease TCells & B-Cells JAK/STAT Activation ViralDiseases Epstein Barr Virus (EBV) Lymphocytes JAK/STAT Activation Hepatitis B Hepatocytes JAK/STAT Activation Hepatitis C Hepatocytes JAK/STAT Inhibition HIV Lymphocytes JAK/STAT Activation Lymphocytes HTLV 1 JAK/STAT Activation Fibroblasts Varicella-Zoster Virus (VZV) JAK/STAT Tnhibition Epithelial cells Human Papilloma Virus (HPV) JAK/STAT Inhibition Cricer Leukemia Leucocytes (Cytokine production Lymphoma Lymphocytes (JAK/STAT Activation WO 2005/066156 PCT/AU2005/000022 7 Table 2: Diseases Potentially Treatable By JAK-Based Drug Tfherapies Target Disease Cytokine JAK family Strength of member As~sociation Asthima TL-4 &IL-9 JAK1 &JAK3.. ML-13 JAKI & jAK2 + JL5JAK2 + Eczemak IL-4 JAKI &JAK3.. TpN- JAMi & JAK2 Food Allergy TL-4 JAKI & JAK,3 + Infamoatory Bowel IL-4 JAMI & JAK3.. DisCase & Crohn's Disease Leukacinia And (IL-2) JAIK3, JAM ... + Lymphoma & JAK2 Tran-splantation B-C/M~irfzyIL-4 JAKI & JAK3 . ~C~/FokerM~;iTL-2 JAKI & JAK3 + Cuitaneous GM-CSIF&JL-6 JAKI &JAK2 ±1--i h-nflammation WO 2005/066156 PCT/AU2005/000022 8 Table 2 (cont.) Target Disease Cytokine JAK family Strength of member Association Immune Suppression LAO JAK1 & +++ By Solid Tumour TYK2 Prostate Cancer TL-6 JAKI, JAK2 +++ &Tyk2 Jak 3 Signalling Although the other members of the Jak family arc expressed by essentially all tissues, 5 JAK3 expression appears to be limited to hematopoctic cells. This is consistent with its essential role in signaling through the receptors for IL-2, IL4, IL-7, IL-9 and IL-i5 by non covalent association of JAK3 with the gamma chain common to these multichain receptors. Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor gamma chain (gamma c) gene that encodes a shared, 10 essential component of the receptors of interleuin-2 (11-2), L-4, IL-7, TL9, and IL-15; An XSCID syndrome in which patients with either mutated or severely reduced levels of JAK3 protein has been identified, suggesting that immunosuppression should result from blocking signalling through the JAK3 pathway. Gene Knock out studies in mice have suggested that JAK3 not only plays a critical role in B and T lymphocyte maturation, but 15 that JA3 is constitutively required to maintain T cell function. Taken together with the biochemical evidence for the involvement of JAK3 in signalling events downstream of the IL-2 and IL-4 receptor, these human and mouse mutation studies suggest that modulation of immune activity through the inhibiton of JAK3 could prove useful in the treatment of T- cell and B-cell proliferative disorders such as transplant rejection and autoimmune 20 diseases. Prolonged inmunomodulation through inhibition of JAK3 signalling should have great therapeutic potential as long as JAK3 inhibition was achieved selectively and not accompanied by inhibition of other kinase-dependent signalling processes. In particular, the high degree of sequence identity held in common by members of the JAK family of 25 kinases raises the possibility that a compound which inhibits Jak3 would also inhibit other WO 2005/066156 PCT/AU2005/000022 9 members of the family with detrimental long term consequences. For example, prolonged inhibition of Jak2 is likely to lead to erythropenia and thrombocytopenia, since the receptors for both crythropoietin and thrombopoietin use only JAK2 for intracellular transmission of signals. 5 Selective and Irreversible Inhibition A PTK catalyses the transfer of a phosphate group from a molecule of ATP to a tyrosine residue located on a protein substrate. The inhibitors known in the art are usually competitive with either the ATP or the protein substrate of the kinase (Levitzki 2000). Since the concentration of ATP in a cell is normally very high (millimolar), compounds 10 that are competitive with ATP may lack in vivo activity since it is unlikely that said compounds can reach the concentrations within the cell that are necessary to displace the ATP from its binding site. An alternative approach which has been attempted in relation to EGFR is to design or select compounds which-bind to EGFR TK in an irreversible manner, Such compounds 15 are disclosed in Fry 1998; Discafani 1999; Smaill 1999; Smaill 2000; Tsou 2001; Smaill 2001; Wissner 2003. These compounds function as irreversible inhibitors by virtue of the fact that they can form covalent bonds to amino acid residues located at the active site of the enzyme which results in enhanced potency of the compounds in vitro and in the inhibition of growth of human tumors in in vivo models of cancer. A further benefit of 20 such irreversible inhibitors when compared to reversible inhibitors, is that irreversible inhibitors can be used in prolonged suppression of the tyrosine kinase, limited only by the normal rate of receptor turnover. The high homology between members of the JAK family of kinases makes the design of compounds with acceptable selectivity highly challenging. It is believed that by 25 exploiting the minor differences in the amino acid sequence between the members of this family may allow for the identification of selective inhibitors. Alignment of the four members of the JAK family of protein tyrosine kinases reveals that within the amino acids that comprise the ATP-binding pocket of these kinases there are very few amino acid differences that could be used to target potential inhibitors towards one family member or 30 another. Interestingly, JAK3 alone amongst this sub-family of kinases possesses a Cysteine residue close to the front lip of the ATP-binding cavity. It was hypothesised that this may provide a means to develop highly specific irreversible JAK3 inhibitors (Figure 2), by targeting this Cysteine with a functionality bearing an alkylating group such as a Michael acceptor.

10 SUMMARY OF THE INVENTION The present inventors have found that a group of compounds based upon a disubstituted heterocyclic scaffold which include an alkylating group such as a Michael acceptor are 5 irreversible and selective inhibitors of the enzyme Janus Kinase 3 and as will find applications in therapy as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, and other indications where immunosuppression would be desirable. Furthermore, it is believed that 10 these compounds may find application in therapeutic treatments for proliferative diseases and cancers such as Leukemia and Lymphoma where JAK3 is hyperactivated and in diseases such as Alzheimer's disease. Accordingly, in a first aspect the present invention provides a compound of the general formula /N 20 W A x1,, - X3 x 2 or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or 3 0 diastereomers thereof, wherein: XI, X 2 , X 3 , X 4 are each carbon where one is substituted with Z and the rest independently with Y; or one of X I, X 2 , X 3 , X 4 is N and the others are carbon where one carbon is substituted with Z and the rest independently with Y; 35 A is a ring selected from: N N N N N N, N D D N D 2315164_1 (CHMatters) 24/08/10 11 where D is selected from H, C 1

.

4 alkyl, halogen, amino; Q is a bond, halogen, C.4 alkyl, 0, S, SO, SO 2 , CO, CS; 5 W is: (i) NRI R2 where RI and R2 are independently H, C 14 alkyl, C 14 alkylCF 3 , aryl, hetaryl, C.4 alkylaryl, C 14 alkylhetaryl, C3.8 cycloalkyl, C 2 .6 alkenyl, 10 cyclohetalkyl, C 1

.

4 alkylcycloalkyl, CI.

4 alkyl cyclohetalkyl, or RI and R2 are joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR3; and R3 which is selected from H,

C

14 alkyl, aryl, hetaryl, C 14 alkyl aryl, C 14 alkyl hetaryl, COR4 where R4 is selected from H, C 14 alkyl, aryl, hetaryl; 15 OR (ii) H, CI.

4 alkyl, aryl, hetaryl, C 3

.

8 cycloalkyl, cyclohetalkyl, C.4 alkylaryl, C 14 alkylhetaryl, C 3

.

8 cycloalkyl, C 14 alkylcycloalkyl, C 14 alkyl cyclohetalkyl; 20 Y is H, halogen, CN, CF 3 , nitro, OH, C 14 alkyl, C 14 alkylNR5R6, C 14 alkylhetaryl, OC1.4 alkyl, OC 24 alkylOC 14 alkyl, OC 14 alkylNR5R6, OC 14 alkylhetaryl, OC 14 alkylcyclohetalkyl, SC 14 alkyl, SC 24 alkylOC.

4 alkyl, SC 14 alkylNR5R6, NR5R6, NR5COR6, NR5SO 2 R6; and R5 and R6 are each independently H, C 1

.

4 alkyl, or may be 25 joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from 0, S, NR7 and R7 is selected from H, C 1

.

4 alkyl, aryl, hetaryl, C.

4 alkylaryl, C 14 alkylhetaryl; Z is a Michael acceptor selected from: 30 2315164 _1 (GHMattero) 24/08/10 12 R8 R9 R9 R8 R9 N IN"W Ri0 N I I ) N Rio 0 0 0 R8 R9 R9 R9 -HWO -0sNo 'Nroi RIO n n Y n N R1 'N RO .~k ONRO...- R R9 R9 R10 ' 1 R10 R11 n 0 0 5 where R8 is selected from H, C 1 4alkyl; R9 and RIO are independently selected from H, C 1 4alkyl, C 1 4 alkylNR12R]3, C 14 alkylOR12,

C

1 4alkylhetaryl; 10 RI I is selected from OH, OC 1 4alkyl, NR12RI3; n is 0-4; 15 where R12 and R13 are independently selected from H, C 1 4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR14; and R14 is selected from H, C 1 4alkyl. In a second aspect the present invention consists in a composition comprising a carrier and at 20 least one compound of the first aspect of the invention. In a third aspect the present invention consists in a method of treating a tyrosine kinase associated disease state, the method comprising administering a therapeutically effective amount of at least one compound of the first aspect of the invention or a therapeutically 25 effective amount of a composition of the second aspect of the invention. In a further aspect the present invention provides the use of the compounds of the first aspect or the compositions of the second aspect in the preparation of medicaments for the treatment of JAK3-associated disease states. 2315164_1 (GHMaLtera) 24/08/10 13 In a yet further aspect, the present invention provides for a method of suppressing the immune system of a subject, the method comprising administering a therapeutically effective amount of at least one compound of the first aspect of the invention or a therapeutically effective amount of a composition of the second aspect of the invention. 5 BRIEF DESCRIPTION OF THE FIGURES Figure I shows the amino acid sequence alignment of selected Jak Kinases Figure 2 shows a model of the Jak3 kinase ATP binding pocket displaying the Cysteine residue. 10 DETAILED DESCRIPTION OF THE INVENTION Accordingly, in a first aspect the present invention provides a compound of the general formula 15 N N W X4

X

2 25 or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein: 30 XI, X 2 , X 3 , X 4 are each carbon where one is substituted with Z and the rest independently with Y; or one of X I, X 2 , X 3 , X 4 is N, and the others are carbon where one carbon is substituted with Z and the rest independently with Y; 3 5 A is a ring selected from: N N N N N N N D D N D D 2315164_1 (GHMattero) 24/08/10 14 where D is selected from H, C 1 4alkyl, halogen, amino; Q is a bond, halogen, CI.

4 alkyl, 0, S, SO, SO 2 , CO, CS; 5 W is: (i) NR I R2 where Rl and R2 are independently H, C 1 4alkyl, C 1 4alkylCF 3 , aryl, hetaryl, C 1 . 4 alkylaryl, C.4alkylhetaryl, C 3

.

8 cycloalkyl, C 2

.

6 alkenyl, cyclohetalkyl, C 1 . 4 alkylcycloalkyl, C 1 4alkyl cyclohetalkyl, or R I and R2 are joined to form an optionally 10 substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR3; and R3 is selected from H, C,4alkyl, aryl, hetaryl, CI4alkyl aryl, C 1 4alkyl hetaryl, COR4 where R4 is selected from H, C 1 4alkyl, aryl, hetaryl; OR 15 (ii) H, C,4alkyl, aryl, hetaryl, C 3 .gcycloalkyl, cyclohetalkyl, C 1 4alkylaryl, CI.

4 alkythetaryl,

C

3

.

6 cycloalkyl, C.4alkylcycloalkyl, C 1

.

4 alkyl cyclohetalkyl; Y is H, halogen, CN, CF 3 , nitro, OH, C 14 alkyl, C,4alkylNR5R6, C.4alkylhetaryl, OC 1 4alkyl, 20 OC 2 -4alkylOC 1 4alkyl, OC.4alkylNR5R6, OC 1 .4alkylhetaryl, OC,.

4 alkylcyclohetalkyl, SC 1 . 4 alkyl, SC 2 4alkylOC 1

.

4 alkyl, SC,.

4 alkylNR5R6, NR5R6, NR5COR6, NR5SO 2 R6; and R5 and R6 are each independently H, C,.4alkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from 0, S, NR7 and R7 is selected from H, C.

4 alkyl, aryl, hetaryl, C,alkylaryl, C.4alkylhetaryl; 25 Z is a Michael acceptor selected from: 2315164_1 (GHMatter-) 24/08/10 15 R8 R9 R9 R8 R9 R10 >,0 RIO N R10 0 0 0 R8 R9 R9 R9 NO R10 Ri A OJ O~ROR 0 00 R9 R9 R10 I . R10 R11 5 where R8 is selected from H, CIAalkyl; R9 and RIO are independently selected from H, C 1

.

4 alkyl, C 1

.

4 alkylNRl2Rl3, C 1 . 4 alkylOR12, C 1 4alkylhetaryl; 10 RI I is selected from OH, OCI.alkyl, NR12RI3; n is 0-4; where R 12 and R13 are independently selected from H, C .4alkyl, or may be joined to 15 form an optionally substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR 14; and R14 is selected from H, C 1 .4alkyl. In a preferred embodiment the compound is selected from compounds of the general formula II. 20 N w 7X4

X

1

X

3 x 2 2315164 1 (GHMattero) 24/08/10 16 or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein: XI, X 2 , X 3 , X 4 are each carbon where one is substituted with Z and the rest independently with 5 Y; or one of XI, X 2 , X 3 , X 4 , is N, and the others are carbon where one carbon is substituted with Z and the rest independently with Y; A is a ring selected from: N N N N N N N D D D D 10 where D is selected from H, C 1 .alkyl, halogen, amino; Q is a bond, halogen, C 1 4alkyl, 0, S, SO, SO 2 , CO, CS; 15 W is: (i) NRI R2 where R I and R2 are independently H, CI.alkyl, C 1

.

4 alkylCF 3 , aryl, hetaryl, C 1 . 4 alkylaryl, C 1 4alkylhetaryl, C 3

.

8 cycloalkyl, C 2

.

6 alkenyl, cyclohetalkyl, C 1 . 4 alkylcycloalkyl, C1.

4 alkyl cyclohetalkyl, or RI and R2 are joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR3; 20 and R3 is selected from H, C 1 4 alkyl, aryl, hetaryl, CI4alkyl aryl, C 1 4alkyl hetaryl, COR4 where R4 is selected from H, C 1 4 alkyl, aryl, hetaryl; OR 25 (ii) H, CI.4alkyl, aryl, hetaryl, C 3

.

8 cycloalkyl, cyclohetalkyl, C1.

4 alkylaryl, C.4alkylhetaryl,

C

3

.

8 cycloalkyl, C 1

.

4 alkylcycloalkyl, CI4alkyl cyclohetalkyl; Y is H, halogen, CN, CF 3 , nitro, OH, C 1 4alkyl, C,4alkylNR5R6, CI.4alkylhetaryl, OC 1 4alkyl,

OC

2 .alkylOC .

4 alkyl, OC, 4 alkylNR5R6, OCI.4alkylhetaryl, OC.4alkylcyclohetalkyl, SCI. 30 4 alkyl, SC 2

.

4 alkylOC 1 .alkyl, SCI.

4 alkylNR5R6, NR5R6, NR5COR6, NR5SO 2 R6; and R5 and R6 are each independently H, C 1 4alkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from 0, S, NR7 and R7 is selected from H, CI4alkyl, aryl, hetaryl, C 1

.

4 alkylaryl, C 1 4alkylhetaryl; 2315164_1 (GHMatter.) 24/08/10 17 Z is a Michael acceptor selected from: R8 R9 R8 R9 R9 N R0 R11 n Ii 0 0 0 0 where R8 is selected from H, C 1 .4alkyl; 5 R9 and RIO are independently selected from H, C 1 .4alkyl, C 1 4alkylNRl2R13, C,4alkylORl2,

C

1 4alkylhetaryl; R1 I is selected from OH, OC 1 4alkyl, NR12RI3; 10 n is 0-4; where: R12 and Rl3 are independently selected from H, C 1 4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR14; and R14 is selected from H, C 1 4alkyl. 15 In the above description it will be appreciated that:

C

1 4alkyl means an unsubstituted or optionally substituted straight or branched alkyl chain. 20 Aryl means unsubstituted or optionally substituted phenyl or naphthyl. Hetaryl means an unsubstituted or optionally substituted 5-or 6-membered heteroaromatic ring containing one or more heteroatoms selected from 0, N, S. 25 Cycloalkyl means a 3-8 membered saturated ring. Cyclohetalkyl means a 3-8 membered saturated ring containing 1-3 heteroatoms selected from 0, S, NR15, where R15 is H, C 1 4alkyl, aryl, hetaryl. 30 Substituents are chosen from halogen, C 1

.

4 alkyl, CF 3 , CN, nitro, aryl, hetaryl, OCF 3 , OC 1 .4alkyl, 0C 2 .salkylNR I6R17, Oaryl, Ohetaryl, CO 2 RI6, CONR16R17, nitro, NR16R17, NR16COR17, NR16SO 2 RI7; and R16, R17 are each independently H, C 1 4alkyl, C.4alkyl cycloalkyl, C 1 . 4 alkyl cyclohetalkyl, aryl, hetaryl, C 1

.

4 alkyl 2315164_1 (GHMatters) 24/08/10 WO 2005/066156 PCT/AU2005/000022 18 aryl, C 1

.

4 alkylhetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR18; and R18 is selected from H, C 14 alkyl, aryl, hetaryl, C 1 4 alkyl aryl, C 4 alkyl hetaryl. The compounds of formula I may irreversibly inhibit JAK 3. Generally, the strength of 5 binding of reversible inhibitors of an enzyme is measured by the ICwo value which is a reflection of the equilibrium constant of the interaction between the inhibitor and the active site of the enzyme. Irreversible inhibitors display an apparent ICs,) because once the inhibitor is bound it will not leave the active site and the measured ICsu will therefore improve (i.e. number will decrease) over time. For instance, the compound of example 20 10 exhibits an "IC.a" of ~40nM after 20 minute incubation with enzyme (prior to addition of ATP) whereas the "IC50" drops to 7nM after 90 mn pre-incubation. Preferably, the compound of formula I selectively inhibits JAK 3 with respect to JAK 1 or JAK 2. The term "selectively inhibits" is defined to mean that the apparent ICs 1 of the compound for JAK 3 is more than ten-fold lower (i.e. more potent) than the ICao for JAK 1 15 or JAK 2. The compounds of this invention include all confornational 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 all optical isomers and stereoisomers of the compounds of the present invention, and 20 mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them. 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 compounds of the formula I. This invention also encompasses methods of treating or 25 preventing disorders that can be treated or prevented by the inhibition of protein kinases, such as JAK comprising administering prodrugs of compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or moie (eg, two, three or four) amino acid residues which 30 are covalently joined through peptide bonds to free amino, hydroxy and carboxylic acid groups of compounds of formula . 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 alanine, gamnma-aminobutyric acid, citrulline, homocystcine, homoscrine, ornithine and WO 2005/066156 PCT/AU2005/000022 19 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 adds, salts of acids, or esters) joined 5 through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula 1. Where the compound possesses a chiral centre 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. In a still further preferred embodiment the compound is selected from the compounds set 10 out in the Examples. More preferably, the compound is selected from the compounds set out in Table 3. In a second aspect the present invention consists in a composition comprising a carrier and at least one compound of the first aspect of the invention. In a third aspect the present invention consists in a method of treating a tyrosine kinase 15 associated disease state, the method comprising administering a therapeutically effective amount of at least one compound of the first aspect of the invention or a therapeutically effective amount of a composition of the second aspect of the invention. In a further preferred embodiment the disease state involves JAK1, JAK2, JAK3 or TYK2. In a preferred embodiment of the present invention the disease state is selected from the 20 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 25 autoimmune diseases such as Type T 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 Leukemia, Lymphona and Prostate Cancer. As used herein the term "tyrosine kinase-associatcd disease state" refers to those disorders 30 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.

WO 2005/066156 PCT/AU2005/000022 20 In a further aspect the present invention provides the use of the compounds described in the preparation of medicaments for the treatment of JAK3-associated disease states. In a yet further aspect, the present invention provides for a method of suppressing the immune system of a subject, the method comprising administering a therapeutically 5 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. Preferably, the method of suppressing the imnmune system is for the treatment of disease states selected from lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune 10 thyroid disorders, ulcerative colitis, Crohn's disease, and Alzheimer's disease, Preferably, the method of suppressing the immune system is to modify the immune system response to a transplant into a subject. More preferably, the transplant is an organ transplant or tissue transplant. The present invention provides pharmaceutical compositions comprising at least one of 15 the coinpounds of the formula I or II capable of treating a JAK3-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 vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode 20 of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation. The compounds of the formula I or 11 may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; 25 sublinigually; buccally; parenteray, 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 formulations containing non-toxic, pharmaceutically acceptable vehicles or 30 diluents. The compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present WO 2005/066156 PCT/AU2005/000022 21 compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but 5 not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or urine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens). 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 10 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 JAK3 inhibition is desired, are mammals, including, but not limited to, cows, sheep, goats, horses, dogs,. cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and 15 preferably a human being, male or female. The term "therapeutically 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 being sought by the researcher, veterinarian, medical doctor or other clinician. The term "composition" as used herein is intended to encompass a product comprising 20 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, diluont or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. 25 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 methods well known in the art of pharmacy. All methods include the step of 30 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 WO 2005/066156 PCT/AU2005/000022 22 carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to 5 encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily 10 suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. 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 15 provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or 20 algriic acid; binding agents, for example starcb, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may 25 be employed. They may also be coated to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is 30 mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacantb and gum 35 acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for WO 2005/066156 PCT/AU2005/000022 23 example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearatc, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecacthylencoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such 5 as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and bexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose 10 or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, 15 and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixtute with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or 20 wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for.example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emutsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a 25 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 derived from fatty acids and hexitol anhydrides, for example sorbitan monoolcato, and condensation products of the said partial esters with ethylene oxide, for example 30 polyoxyethylene sorbitan monoolcate. The enulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agent, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

WO 2005/066156 PCT/AU2005/000022 24 The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable 5 solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable'vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be empldyed including synthetic 10 mono- or diglycerides. In addition, fatty acids such as olcic acid find use in the preparation of injectables. The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary 15 temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.) 20 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. Uposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any nton-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used. The 25 present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like. The preferred lipids are the phospholipids and phosphatidyl cholines, both natural and synthetic. Methods to form liposomes are known in the art. The pharmaceutical composition and method of the present invention may further 30 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 may act synergistically to effect the treatment or prevention of the WO 2005/066156 PCT/AU2005/000022 25 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: 5 cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD8O, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CDI 54), fusion proteins constructed from CD40 and gp39 (CD401g and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of 10 NT-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA teductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, aspirin, acetaminophen, leflunomide, deoxyspergualin, azathioprine and cyclooxygenase inhibitors such as rofecoxib and celecoxib, steroids such as prednisolone or dexamethasone, gold 15 compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine, VP-16, etoposide, fludarabine, cisplatin and cyclophosphamide, TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNp receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof. 20 When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the treatment or prevention of conditions which require protein tyrosine kinase inhibition an appropriate dosage level will generally be about 0.01 to 500 mg per kg 25 patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 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. 30 For oral administration, the compositions are preferably provided in the fonn of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 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 WO 2005/066156 PCT/AU2005/000022 26 dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including 5 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, and the host undergoing therapy. . In order that the nature of the present invention may be more clearly understood, 10 preferred forms thereof will now be described with reference to the following non limiting examples. EXAMPLES MATERIALS AND METHODS: Compound Sydzhesis 15 Compounds of the general formula I are generally prepared from dibaloheterocycle. When Q is a bond and W is amino, the synthesis may begin with a nucleophilic aromatic substitution to generate a monoamino-monohalo intermediate. The nucleophilic aromatic substitution is typically carried out by addition of an amine to the di-halogenated heterocycle in a solvent such as ethanol, isopropanol, tert-butanol, 20 dioxane, THF, DMP, toluene or xylene. The reaction is typically performed at elevated temperature in the presence of excess amine or a non-nucleophilic base such as trietbylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate. Altematively, the anino substituent may be introduced through a transition metal 25 catalysed amination reaction. Typical catalysts for such transformations include Pd(OAc) 2 /P(t-Bu), Pd2(dba) 3 /BINAP and Pd(OAc) 2 /BINAP. These reactions are typically out in solvents such as toluene or dioxane, in the presence of bases such as caesium carbonate or sodium or potassium tert-butoxide at temperatures ranging from room temperature to reflux.

WO 2005/066156 PCT/AU2005/000022 27 The amines employed in the first step of the synthesis of these compounds are obtained commercially or are prepared using methods well known to those skilled in the art. When Q is a bond and W is aryl, hetary or other similar carbon-linked systems, the synthesis typically begins with a cross-coupling reaction between dihaloheterocycle and a 5 suitably functionalised coupling partner. Typical coupling partners are boronic acids or esters (Suzuki coupling: see for example Miyaura and Suzuki 1995), stannanes (Stille coupling: see for example Stifle 1986), Grignard reagents (Kunada coupling: Kumada, Tamao and Sumitani 1988) or organozinc species (Negishi coupling: Negishi 2002). The Suzuki coupling is the preferred coupling method and is typically performed in a solvent 10 such as DME, THF, DMF, ethanol, propanol, toluene, or 1,4-dioxane in the presence of a base such as potassium carbonate, lithium hydroxide, caesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate. The reaction may be carried out at elevated temperatures and the palladium catalyst employed may be selected from Pd(PPh) 4 , Pd(OAc) 2 , lPdC12(dppf)], Pd 2 (dba) 3 /P(t-Bu) 3 . 15 Where Q is CO, the synthesis begins with the requisite hetaryl carboxylic add bearing a halo group. Amide derivatives of the acid may be readily formed by coupling an amine with the acid using coupling reagents such as dicyclohexylcarbodiinide, 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide, diisopropylcarbodiimide or carbonyldiimidazole in solvents such as dichloromethane, totrahydrofuran or 1,4-dioxane. 20 Alternatively, the acid can be converted to the respective acid chloride using thionyl chloride, oxalyl chloride, is(trichloromethyl)carbonate or cyanuric chloride, or to the mixed anhydride species using, for example, t-butyl chloroformate, using procedures well known to those skilled in the art. The acid chloride or mixed anhydride derivatives can then be reacted with the desired amine preferably in the presence of a base such as 25 triethylamine, diisopropylethylamine or solid phase equivalent in a solvent such as dichloromethane, tetrahydrofuran, dioxane or ethyl acetate at ambient or elevated temperatures, to generate the amide. The acid chloride may also react with the required amine under aqueous conditions preferably in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide or sodium carbonate to generate the desired 30 amide. Thioamides may be prepared from the amides formed above by methods well-known to those skilled in the art and include reaction of the amide with Lawesson's reagent in a solvent such as toluene at elevated temperature.

WO 2005/066156 PCT/AU2005/000022 28 The second step of the synthesis involves a nucleophilic aromatic substitution reaction of the monohalo intermediate with a benzimidazole or azabenzinidazole. The reaction is typically performed using a salt of the benzimidazole or azabenzimidazole in solvents such as TIF, DMF, DMA, NMP, toluene, or xylene from room temperature to reflux. The 5 benzinidazole or azabenzimidazole salt is prepared by reaction with a metal hydride such as sodium or potassium hydride or by reaction with caesium carbonate. A1ternatively, a metal-catalysed coupling reaction can be used to introduce the benziniidazole or azabenzimidazole ring. Typical metal catalysts include Pd(OAC)/dppf, PdCl 2 /dppe, PdAOAc)2/P(t-Bu)a, (CuOTf)2ePhH. The reaction is typically performed 10 using a base such as caesium carbonate, rubidium carbonate, potassium carbonate, sodium tort-butoxide or potassium phosphate in a solvent such as xylene, toluene, or DMF from room temperature to reflux. Auxiliary reagents such as phase transfer agents (e.g. cetrimonium bromide) or copper complexing agents (e.g. phenanthroline) may also be employed in the reaction. 15 Alternatively, the reaction sequence outlined above may be reversed beginning with coupling of the benzimidazole or azabenzimidazole to the dihalobeterocycle using the methods outlined above, followed by introduction of the second substituent onto the heterocyclic nucleus using the procedures outlined above. An alternative route to compounds of the general formula I involves a copper mediated 20 reaction between a benziindazole or azabcnzimnidazole and an organometallic reagent (see for example Finet, 2002). Preferable organometallic reagents are borotnic adds. The thiol reactive moiety (depicted as part of the substituents Z) present in compounds of the general formula I of the invention may be already present in the functionalitics employed in the synthetic processes described above or may be introduced at the final 25 stage of the synthetic procedure. For example, the thiot reactive moiety maybe introduced in compounds bearing a free hydroxyl or amino substituent by coupling with a suitable acid. This is typically achieved using coupling reagents such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-cthylcarbodiimide, diisopropylcarbodiimide or carbonyldiinidazole in solvents such as dichloromethane, 30 tetrahydrofuran or 1,4-dioxane. Alternatively, suitable mixed anhydride species of the acid, formed using, for example, f-butyl chloroformate, using procedures well known to those skilled in the art, or a suitable acid chloride derivative, can be reacted with the amine or alcohol moiety in the presence of a base such as triethylanine, diisopropylethylamine or solid phase equivalent in a solvent such as dichloromethne, WO 2005/066156 PCT/AU2005/000022 29 tetrahydrofuran, dioxane or ethyl acetate at ambient or elevated temperatures, to generate the desired compound. Those skilled in the art will appreciate that the order of the reactions described for the syntheses above may be changed in certain circumstances and that certain functionalities 5 may need to be derivatised (i.e. protected) in certain instances for the reactions described above to proceed with reasonable yield and efficiency. The types of protecting functionality are well-known to those skilled in the art and are described for example in Creene (Greene, 1999). The products formed from the reaction sequences described above may be further derivatised using techniques well known to those skilled in the art. 10 Representative syntheses are reported below. Example I 6-Chloro-N-/(74-R/rnylety/Ipyrazr-2-17ani NCrC Cl N C NN CI N: A solution of R-a-methylbenzylamine (0.57g, 4.7mmol) and 2,6-dichloropyrazine (0.63 8 8g, 15 4.29mmol) in dioxane (2.5 mL) was heated at reflux under N 2 for 48 hours. The solvent was removed and the product crystallised from toluene-hexane (0.82g, 82%). 'H-n.m.r. (CDCl 5 ) 81.58 (d, f=6.6Hz, 3H, CH), 4.88 (w, 1H, CHI), 5.07 (d, 1H, NH), 7.24 7.36 (m, 5H, Ar-H), 7.61 (s, IH, pyraz-H), 7.79 (s, 1H, pyraz-H). Example 2 20 N-(r/-u/yl-6-hlorapyrzkz-2-amine CI% N 01 N C( NN A mixture of /cr/-butylamine (14,9 g, 20 mmol), 2,6-dichloropyrazine (6.0 g, 40 mmol), Hnig's base (1OmL) and ethoxyethanol (6 mL) was heated at 13(C in a sealed tube for 18 WO 2005/066156 PCT/AU2005/000022 30 hours. The solvent was removed & vrcuo and the residue taken up in CH 2 C1 2 (1OmL) and filtered. The filtrate was washed with H20 (2 x 20 mL), brine (20 mL) and dried (Na 2

SO

4 ). Chromatography cluting with CH 2 C1a separated the product as a white solid (5.4 g, 72%). 5 'H-n.m.r. (CDCh) b 1.44 (s, 91-, CH 3 ), 4.68 (br s, I H, NH), 7.71 (s, 1H, pyraz-H), 7.72 (s,1H, pyraz-H). Example 3 6-Ch -(1-(-m/e Mtofxypypkeny/)/ky/Iymz-2a mbz e C N C> N 10 In a procedure analogous to Example 1, reaction of R-a-methylbenzylaraine (1.0g, 6.6mmol) and 2,6-dichloropyrazine (0.4 4 0g, 2.95mmol) furnished the product (517mg, 67%). 'H-n.m.r. (CDCt) 81.59 (d, /= 6.9Hz, 3H, CL,), 3.81 (s, 3H, OCIU), 4.87 (rn, 1H, CH), 5A7 (br s, IH, NH), 6.79-730 (m, 4H, Ar-H), 7.66 (s, IH, pyraz-H), 7.79 (s, iH, pyraz-H). 15 Example 4 6 -Ch/am-N-penylpyazin-2-arnte Cl N C1N N G NY N A solution of 2,6-dichloropyrazine (1 g, 6.7 mnimol) and aniline (1.25 g, 13.4 mmol) in ethoxyethanol (20 mL) containing DIPEA (2.5 mnL, 13.4 mmol) was heated at reflux for 3 20 days under N 2 . The solution was concentrated under reduced pressure and the residue dissolved in EtOAc (50 mL) and washed successively with H2O (50 mL), IM HCI (2 x 50 mL), H2O (50 mL) and bine (50 mL). After drying (Na 2

SO

4 ) the solvent was removed under reduced pressure and the residue chromatographed cluting with EtOAc-hexane (20:80 - 50:50) to separate pure productfrom the lower fractions (230 mg, 17%).

WO 2005/066156 PCT/AU2005/000022 31 'H-n.m.r. (CDC 3 ) 6 6.62 (br s, 1H, NH), 7.11-7.20 (rn, 11A, ArH), 738 (br s, 2H, ArH), 7.40 (s, 2H, ArH), 7.98 (s, IH, pyraz-H), 8.11 (s, 1H, pyraz-H). Example 5 N: NNN 5 In a procedure analogous to Example 1, reaction of c-(R)-4-dimethylbenzylamine (250mg, 1.85mmol) and 2,6-dichloropyrazine (0.251g 1.67mmol) funished the product (199.5mg, 48%). 1 H-n.m.r. (CDCla) 8 1.56 (d, 3H,f 6.9Hz, CH.), 2.33 (s, 31-, CH3), 4.84 (m, 1H, CM), 5.05 10 (br s, II, NH), 7.15 (AA'XX', 2H, Ar-H), 7.24 (AA'XX', 2k-, Ar-H), 7.60 (s, IH, pyraz-), 7.78 (s, 1H, pyraz-H). Example 6 6-Chloro(-N(4-morphelin-4-ylphenyl)pyrazin-2-arnine 01 N CI0 Cl N C) NN NN C N 0 15 In a procedure analogous to Example 1, reaction of 4-morpholinoaniline (2.15g, 12.1mmol) and 2,6-dichloropyrazine (0.756g, 5.03mmol) furnished the product (0.54g, 37%). 'H-n.m.r. (CDCI) 83.25 (br s, 4H, CH 2 ), 3.99 (br s, 4H, CH 2 ), 7.05-7.17 (in, 2H, ArH), 7.42 7.54 (m, 2H, Ar-I), 7.94 (s, 1H, pyraz-H), 8.04 (s, 1R, pyraz-H), 8.06 (s, 1H, NH). 20 WO 2005/066156 PCT/AU2005/000022 32 Example 7 6-Chh/or-N(2/arylhnek/ymrzin-2-am re N C1 In a procedure analogous to Example 1, reaction of fkrfurylamine and 2,6 5 dichloropyrazine furnished the product (98%). 'H-n.m,r. (CDC,) 64.57 (d,/= 5.7 Hz, 211, NCH2), 5.01 (s, broad, 1H, NH), 6.30 (d,= 3,3 Hz, III, furanyl-H), 6.35-6.33 (m, 2H, furanyl-f), 7.81 (s, 1H, pyraz.-IT), 7.84 (s, 1 H, pyraz.-H). Example 8 10 ChkIora-N-(pyrin-3ylre/kl)pymzn--2-arnine N N CQ NZI NN A mixture 2,6-dichloropyrazine (0.671 murol) and 3-picolylamine (2.014 nmol) in xylene (25 ml) was refluxed overnight. The residue obtained after evaporation of the solvent was suspended between CH2C 2 (100 ml) and water (100 nl). The organic layer was separated 15 and the aqueous layer was extracted with CH 2

C

2 (3 x 50 ml). The combined organic extracts were washed with brine (1 x 100 ml), dried (Na 2

SO

4 ) and the solvent removed in vacuo. The residue was then purified by column chromatography eluting with a hexane:cthyl acetate gradient mixture to afford the desired product (93%). 'I-n.m.r. (CDC 3 ) 64.61 (d,/= 5.7 Hz, 2 H, NCH 2 ), 5.29 (s, broad, 1 H, NH), 7.27 (in, 1H, 20 pyrid.-H), 7.30 (m, 1H, pyrid.-H), 7.71 (d, J= 7.8 iz,1H, pyridA{), 7.85 (s, H, pyrid.-IH), 8.54 (s, broad, 1H, pyraz.-H), 8.61 (s, broad, 1H, pyraz.-).

WO 2005/066156 PCT/AU2005/000022 33 Example 9 Menzy-6-chora-IV-met//pyran*-2-amine

<S

0 1 NN MN CI N N N in a procedure analogous to Example 1, reaction of N-methyl benzylamine and 2,6 5 dichloropyrazine furnished the product (70%). 1 H-n.m.r. (CDCb) &3.11 (s, 3 H, NCHI), 4.78 (s, 2H, ArCH 2 N), 7.24 (d, f= 6.9 Hz, 2 H, ArH), 7.37-728 (m, 4H, Arl-T), 7.81 (s, 1H, pyraz.-H), 7.88 (s, 1H,pyrazAT). Example 10 1H-Denzn:dczoab-,wrze 0 2 N N H 2

H

2 NC N \> Pd/C \> 10 H MeOH H A solution of 5-nitrobenzimidazole (10.0 g, 61.3 mmol) in methanol (250 mL) was hydrogenated in the presence of 10% Pd/C (0.40 g) at atmospheric pressure for 20h. The mixture was filtered through Celite* and the solvent removed under reduced pressure to afford the pure product (8.1 g, 100%). 15 'H-n.m.r. (CDIOD) 8 6.75 (dd, 1IH,= 8.4 ind 2.0 Hz, benzimid--), 6.92 (d, 1H,/= 2.YHz, benzimid-H{), 7.36 (d, IH,/= 8.4 Hz, benzirmid-H), 7.92 (s, 1 H, benzimid-H). 20 WO 2005/066156 PCT/AU2005/000022 34 Example 11 I-/6-(terr~t/d/arniopnmzin-2y/J-zH-benznklazoz-5-nme and 7-[6-(ert/-kuty/ain; razin-2-y -be nsuia'azo th4ein N N l HNXNNN Ni~ N H N 5 A mixture of 1H-benziniidazol-5-amine (2.93 g, 22 mmiol), N-(tert-butyl)-6-chloropyrazin 2-amine (3.71g, 20 mmxol) and cesium carbonate (9.12 g, 28 mmol) in DMF (20 mL) was heated under Na for 48h, Upon cooling to RT? the mixture was filtered and the filtrate concentrated /h c'gcuc. The residue was extracted with CH-C1 3 and the solvent removed -under reduced pressure, The residue was chromatographend using CH2CirMeOH (98:2 10 93:7) to give from the less polar fractions 1-6(etbtlmn~yai--1-H benziniidazol-6-amine (1.38 g): 'tI-n.m.r. (CDC13) 5 1.51 (a, 9H-, C(CH- 3

)

3 ), 3.80 (br s, 2H , NH2), 4.84 (br s, lH, NI), 6.74 (dd, I1H,/ f8.4, 2.2Hz, benzimid-H), 7.21 (d, 1H{J= 2.OHz,.benzimnid-E), 7.62 (d, 1H,/= 9.2Hz, benzimid-H), 7.79 (s, 1HI, pyraz-H-), 8.07 (s, 1H-I pyraz-H), 8.17 (s, 11H, benzimid-H). 15 and from the more polar fractions 1-6(ebtlmn~yain2y]1-ezmdzl5 amine (1.54 g): 'I--n.msr. (CDCb 3 ) b1.51 (s, 9H1, C(CH1 3

)

3 ), 3.48 (br s, 21-, NH! 2 ), 4.86 (s, 1Hi, NHT), 6.79 (dd, 1H-,/=8.6, 2 .2H1z, benzimid-H-), 7.14 (di,1H,Jf= 2.0Hz, benzimid-H), 7.70 (d, 1H-, /= 8.6Hz, benzinid-H-), 7.78 (s, 1H-2, pyraz-H), 8.07 (s, IH, pyraz-H), 8A47 (s, IH, benzimid-HI). 20 WO 2005/066156 PCT/AU2005/000022 35 Example 12 1-,(3-tPeye~lek/ym-zia-2-/Hbniilzf5ab and N CIY N N, 0' 5 To a stirred solution of 5-amino-benzimidazole (290mg, 2.2mmol) in anhydrous DMF (IOmL) under N 2 was added caesium carbonate (980mg) 'he resulting mixture was stirred at 70"C for 60 min. To this was added a solution of 6-chloro-N-[(1S)-1 phenylctbyllpyrazin-2-amine (470mg) in DMF (5mL) and the resulting mixture was then heated at reflux for 48h. The DMF was removed under reduced pressure and the residue 10 diluted with chloroform. The organic layer was washed with aqueous Na2CO3, dried (Na2SQ 4 ) and the solvent removed under reduced pressure to furnish the crude product. Column chonatography using dichloromethane-methanol (95:5 - 92:8) as elvuant separated two fractions from unreacted starting material. The higher Rf fraction was assigned as the 6-isomer (276mg, 42%). 15 'H-nmnr. (CDC13) 81,64 (d, 311, = 6.911z, CH 3 ), 2.90 (br s, 2H, NH 2 ), 5.05 (m, IH, CH), 5.21 (d, IH, Nil), 6.70 (dd, 1IH,f= 8.7, 2.1Hz, benzimid-H), 6.97 (d, 1H, /=1.8Hz, benzimid-H), 7.28-7.43 (in, 5H, -Pl-I), 7.58 (d, 1H,f= 8.4Hz, benzinid-), 7.84 (s, 1H, pyraz-H), 8.08 (s, 11H, pyraz-H), 8.21 (s, 1H, benzimid-H). xm/z (ES) 331 (M*+H). The lower fraction was assigned as the 5-isomer (170mg, 26%), 'IH-nm.r. (CDCs) 81.64 (d, 20 3H,J 6.9Hz, C11 3 ), 2.85 (br s, 2H, NH 2 ), 5101 (m, IH, CH), 5. 19 (d, IH, NH), 6.70 (dd, iH, /=8.7,2.1Hz, benzimid-H), 7.11 (d, 1H,/= 1.8Hz, benzimid-H), 7.29-7.40 (m, 51-1, Ph-1), 7.51 (d, 111, /= 8.7Hz, benzimid-H), 7.81 (s, 1H, pyraz-H), 8.10 (s, 1H, pyraz-H), 832 (s, 1H, benzimid-H). m/z (ES) 331 (M*+H).

WO 2005/066156 PCT/AU2005/000022 36 Example 13 i-( 6 -Ck/orrppymzk-2-y)-1H-nznfazol-Samygze and N Nr H + C N NH 2 N H NN N_ N H, 5 A mixture of 1H-benzimidazol-5-aminc (0.8 g, 6 mmol), 2,6-dichloropyrazine (0.9 g, 6.0 mmol) and cesium carbonate (2.73 g, 8A mmol) in DMF (6 ML) was heated under N 2 for 6h. Upon cooling to RT the mixture was diluted with dichloromethane-methanol (6:1, 30mL) and filtered and the filtrate concentrated .Af vacuo. The -residue was chromatographed using C-I 2 ChrMeOH (98:2 - 94:6) to give from the less polar fractions 1 10 ( 6 -chloropyrazin-2-y)-1H-benzinidazol-6-amine (398 mg): 'H-n.m.r. (CDCla) & 6.74 (dd, 1H,J 8.2, 2.2Hz, benzinid-H), 7A (d, 1M,/= 2.2Hz, benzimid-H), 7.51 (d, 1H,/= 8.2Hz, benzinid-H), 8.40 (s, 1H, pyraz-H), 8.48 (s, 1H, pyraz H), 8.83 (s, 1H, benzimid-H). and from the more polar fractions 1-( 6 -chloropyrazin-2-yl)-1i-benzimidazol-&amine (435 15 mg) -nsm,r. (CDCl 3 ) 86.79 (dd, 1H1, /= 8.8, 2.2Hz, benzimid7H), 7.03 (d, 1H, J= 2.2Hz, benzimid-H), 7.86 (d, 1H, f= 9.0 Hz, benzimid-H), 8.44 (s, 1H, pyraz-H), 8.52 (,, 111, pyrtz-H), 8.82 (s, 1H, benzimid-H). 20 WO 2005/066156 PCT/AU2005/000022 37 Example 14 1-/6{{(Cye/opropyknethyI)aminofyyrazbz-2-ylH-betxznklzol-6!nxe N N N N T NHN

NH

2 A solution of 1-(6-chloropyrazin-2-y)-iH-benzimidazol-6-an-ine (1(X) mg, 0.41 nmol) and 5 cyclopropylmethylamine (424 tL, 4.1 mmol) in ethoxyethanoL (2 mL) containing DIPEA (140 IL) was heated at reflux overnight under N 2 . The solution was concentrated under reduced pressure and the residue dissolved in EtOAc (20 mL) and washed successively with H20 (20 mL), IM HCL (2 x 20 mL), H20 (20 mL) and brine (20 mL). After drying (Na2SO 4 ) the solvent was removed under reduced pressure and the residue 10 chromatographed eluting with dichloromethane-methanol (9:1 - 94:6) to separate pure product from the lower fractions (98 mg) H-n,m,r. (CDC1.) 60.28-0.36 (in, 2H, CH 2 ),0.57-0.66 (m, 2H, CH 2 ), 1.08-1.22 (m, 1H, CH), 3.27-3,34 (m, 2H, CH 2 ), 3.79 (br s, 2H, NH 2 ), 5.02 (m, 1H, NH), 6.74 (dd, 1H,J= 8.6,2.2Hz, benzimid-II), 7.33 (d, 1HR; /=2,2Hz, benzimnid-H), 7.61 (d, 1H, J = 9.2Hz, benzimid-H), 7.84 15 (s, 1H, pyraz-H), 8.10 (s, 1H, pyraz-I I), 8.35 (s, III, benzimid-H). Example 15 1-[6-(sopropylamkzo~pyrazik..-yZ/-H-bcnzimklaza-6-amfne C N NN NN NH, N H2 A solution of 1-(6-chloropyrazin-2-yl)-1H-benzimidazol-6-amine (100 mg, 0.41 mmol) and 20 isopropylamine (350 FL, 4,1 mmol) in othoxyethanol (2 nL) containing DIPEA (140 gL) was heated in a sealed tube overnight under N 2 . The solution was concentrated under reduced pressure and the residue dissolved in EtOAc (20 mL) and washed successively with H20 (20 mL) and brine (20 mL). After drying (Na2SO4 the solvent was removed WO 2005/066156 PCT/AU2005/000022 38 under reduced pressure and the residue chromatographed eluting with dichiloromethane methanol (9:1 - 94:6) to separate pure product from the lower fractions (102mg). 'H-n.m.r. (CDC3) 61.33 (d, 6H, f= 6.4Hz, CH 3 ), 3.79 (br s, 2H, NH 2 ), 4.05-4.21 (m, 11, CH), 4.72 (m, 1H,[J= 7.2Hz, NH), 6.75 (dd, 1H, =8.6,2.2Hz, benzimid-H), 732 (d, 1H,/= 5 2.0Hz, benzimid-H), 7.61 (d, 1H, ft 8.4Hz, benzimid-H), 7.79 (s, iH, pyraz-H), 8.09 (s, 1H, pyraz-H), 8.35 (s, 1H, benzimid-H). Example 16 1-[6-(Dth/yknano)pyrazin-2-y1f-111-benzimidazo/-6-,tine CN N ci_ N N_ N___ '.N NW /\N

NH

2 - NH 10 A solution of 1-(6-chloropyrazin-2-yl)-1H-benziimidazol-6-.mrine (100 mg, 0.41 mmol) and diethylamine (430 pt, 4.1 mmol) in ethoxyethanol (2 mL) containing DTPEA (140 pL) was heated in a sealed tube overnight under N 2 . The solution was concentrated under reduced pressure and the residue dissolved in EtOAc (20 mL) and washed successively with HzO (20 mL) and brine (20 mL). After drying (Na 2

SO

4 ) the solvent was removed 15 under reduced pressure and the residue chromatographed eluting with dichioromethane methanol (9:1 - 94:6) to separate pure product from the lower fractions (110 mg). 'H-n.m.r. (CDCh3) 81.28 (t, 6H,f= 7.1Hz, CH 3 ), 3.61 (q, 4H, f= 7.1Hz, CH 2 ), 3.78 (br s, 2,

NH-

2 ), 6.74 (dd, 1H,f= 8.6, 2.2Hz, benzimid-H), 7.32 (d, 11,= 2.4Hz, benzimid-H), 7.61 (d, 1Hf=8.8Hz, benzimid-1), 7.91 (s, 1H, pyraz-H), 8.06 (s, 11, pyraz-H-T), 8.36 (s, 1H, 20 benzimid-H). Example 17 2-(6-tnrdor--yprazn-2-y-1Hf-nzimiazi-6ante N1 N NHz N

NH

2 WO 2005/066156 PCT/AU2005/000022 39 Under a nitrogen atmosphere a mixture of 1-(6-chloropyrazin-2-yl)-1H-benzimidazol-6 amine (50 tng, 0.20 mmol), 4-pyridylboronic add (30 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium(O) (23 mg, 0.02 mmol) in toluene-n-propanol (2 mL, 3:1) was treated with 2M aqueous sodium carbonate solution (0.14 mL, 0.84 mmol). 5 The resulting mixture was stirred vigorously whilst being heated under reflux overnight. Upon cooling, the mixture was diluted with ethyl acetate (10 mL) and washed with 120 (1 x 10 mL). The aqueous phase was extracted with ethyl acetate (10 mL) and the organic layers combined and washed with 0.5M Na 2 COa, brine and then dried (Na 2

SO

4 ). Removal of solvent r vacuo then yielded crude product, which was purified by column 10 chromatography using dichloromethanc-methanol (98:2 - 91:9) as fluent to furnish the product (32 mg). 'H-n.m.r. (CDC1b) 8 3.88 (s, broad, 211, NH 2 ), 6.80 (dd, 1H,/= 8.6 and 2.0 Hz, benzinid-H), 7.46 (d, IH, f 2.0 Hz, benzimid-H), 7.67 (d, 11H, f= 8.6 Hz, benzinid-H), 7.98 - 8,01 (m, 2H, pyrid-H), 8.49 (a, 1H, pyraz-H), 8.84 - 8.87 (in, 2H, pyrid-H), 8.99 (s, 1H, pyraz-H), 9.05 15 (s, 1H, benzinid-H). Example 18 N-fl-6-(tr-Buyliukxopyazin-2-y/1-benzndazo/-5y/pmop-2-ynamni'e N HN NN N(N7 N N NH. 0 To a stirred solution of 1-[6-(tert-butylamino)pyrazin-2-ylj-1H-benzimidazol-6-amine (70 20 mg, 0.25 mmol) in anhydrous dichloromethane (2.5 mL) under N 2 was added triethylanine (86 pl), EDAC.HCI (60 mg), 4-(1-pyrrolidino)pyridine (4 mg) and propiolic acid (18.5 pL). The resulting mixture was then stirred at RT overnight and was the diluted with CH2Cl2 (IOmL) and washed with H2O (2 x 10 mL), 0.5M Na 2 CO (10 mL) and dried (Na 2 SO4). The solvent was removed under reduced pressure and the residue was 25 purified by column chromatography using dichloromethane-methanol (99:1 - 91:9) as cluant to separate the pure product (1.8 mg).

WO 2005/066156 PCT/AU2005/000022 40 'H-n.m.r. (CDCla) 51.52 (s, 9H, CH), 4.76 (br s, 1H, NH), 5.78 (br s,1H, CH), 6.75 (dd, 1H, /=8.4,2.2 Hz, ArH), 7.22 (d, IH,f= 2.2Hz, ArH), 7.63 (d, 1H,/=8S.OHz, Ar-H), 7.79 (s, 1H, pyraz-H), 8.08 (s, 1H, pyraz-H), 8.37 (s, 1H, benzimid-H). Example 19 5 N-Ii-(./(,)4-PkenyfeIhy//arino/pyrainr-2-y/24H-bcnzkn/azo-6-y/IacryIamde NH To a stirred solution of 1-(6-([(1L)-1-phenylfthyljaminolpyrazin-2-y)-iH-benzimidazo-6 amine (67mg, 0.2 mmol) in anhydrous THF (2mL) under N2 was added triethylandne (67 L, 0.48 mmol), DAClIC (46 mg, 0.24 mmol), 4-(1-pyrrolidino)pyridine (cat,) and acrylic 10 acid (17 mg, 0.24 mol). The resulting mixture then stirred at RT overnight and was the diluted with 1120 (10 mL) and the mixture extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with saturated aqueous Na 2 CO, dried (Na 2 SO4) and the solvent removed in vacuo. The residue was purified by column chromatography using dichloromethane-methanol (98:2 - 94:6) as eluant to separate the pure product (25 15 mg). 'H-n.m.r. (CDC 3 ) 81.62 (d, 31i, J =6.8Hk, CH 3 ), 5.01-5.13 (m, 1M, CH), 5,38 (d, 1H,,rf= 6.4Hz, NH), 5.78 (dd, 1H,/= 9.8, 2.0Hz, CH), 6.24-6.52 (m, 2H, 2 x CH), 7.29-744 (m, 6H, ArH), 7.70-7.74 (m, 2H, Ar-H), 7.82 (s, 1H, pyraz-H), 8.11 (s, 11H, pyraz-H), 8.33 (s, 1H, benzimid-H), 8A2 (s, 1H, CONH). 20 Example 20 N-/-[C (cr-Buyninokwyraz-2-y/H-dnznsaz/-6-y//acr/amnlZe H N N N N N N NH)I 0 WO 2005/066156 PCT/AU2005/000022 41' To a stirred solution of 1-[6-(tert-butylamino)pyrazin-2-yl]-1l-bnzinidazol-6-amine (22 mg, 0.08 mmol) in anhydrous dichloromethane (2mnL) under N 2 was added triethylamine (33 9L, 0,24 rmmol), EDACHCI (22 mg, 0.12 mmol), 4-(1-pyrrolidino)pyridinc (cat.) and acrylic acid (8 gL, 0.12 mmol). The resulting mixture then stirred at RT for 3 days and was 5 the diluted with H2O (10 mL), the organic phase separated and the aqueous phase extracted with CH 2

CI

2 (10 ML). The combined organic layers were dried (Na 2

SO

4 ) and the solveit removed / vacuo. The residue was purified by column chromatography using didloromethane-methanol (98:2 - 93:7) as eluant to separate the pure product (10 mg). 'H-n.m.r. (CDCt) 51.50 (s, 9H, C 1 3), 4.89 (br s, 1ET, NH), 5.77 (dd, 1H, /= 10.0, 2.0Hz, CH), 10 6.24-6.51 (m, 2H, 2 x CH), 7.25 (dd, 1IH,f= 8.6,2.0-z, Arl), 7.76 (d, 111,f= 8.8Hz, Ar-H), 7.83 (s, 1HI, pyraz-H), 7.88 (br s, 1H, CONH), 8.13 (s, 1H, pyraz-H), 8.52 (s, 1H, benzimid H), 8.56 (s, 1IH, ArH). Example 21 N-/l-/6-ter/-Bu/merapyrai-2-y/I-zH-bcnzhkmdcus/ncy,,i 15 H N ~N 'U NH, >X NN1~ To a stirred solution of 1-[ 6 -(tert-butylamino)pyrazin-2-y1]-1H-benzimidazol-5-amino (20 mg, 0.08 mmol) in anhydrous dichloromethane (2 mL) under N 2 was added tiethylamine (33 pL, 0.24 mmol), EDAC.HCI (22 mg, 0.12 mmol), 4-(1-pyrrolidino)pyridine (cat.) and acrylic acid (8 ML, 0.12 mmol). The resulting mixture then stirred at RT for 3 days and was 20 the diluted with H2' (10 mL), the organic phase separated and the aqueous phase extracted with CH 2 C2 (10 mL). The combined organic layers were dried (Na 2

SO

4 ) and the solvent removed At Pacuo. The residue was purified by column chromatography using dichloromethane-methanol (98:2 - 92:8) as eluant to separate the pure product (10 mg). 'H-n.m.r. (CDC3) 61.52 (s, 91-1, CH 3 ), 4.87 (br s, 1H, NH), 5.77 (dd, 1Hf= 9.8, 2.0Hz, CH), 25 6.31 (dd, 1H,f= 16.6,9.8Hz, =CHI(H)), 6.48 (dd, 1H,J= 16.6, 2.0Hz, =C-T(H)), 7.73-7.81 (m, 2H, pyraz-H + Ari), 7.89 (d, IH, f/= S.8Hz, ArH), 8.01 (s, IH, Ar 1), 8.10 (s, iH, pyraz-H), 8.55 (s, I H, benzimid-H).

WO 2005/066156 PCT/AU2005/000022 42 Example 22 N-/Z-[6-(/ert-Baiy/amsto~pymzb,-2-y//-ZH-kcnzkmdkaz/--y-2-rnefhyacry/a/tze N N N NN 0 Following a procedure identical to Example 21 however using methacrylic acid in place of 5 acrylic acid, 1-[6-(tert-butylamino)pyrazin-2-yl-1H-benzimidazol-5-amine (57 mg) afforded N-{1-{6-(tert-butylanino)pyrazin-2-yl-l1H-benziddazol-6-y)-2 methylacrylamide (54mg). 1 H-nsn.r. (CDCb+ drMeOD) 81.43 (s, 9H, CH), 2.00 (br s, 3H, CH3), 5.42 (br s, 1H, =CH(H)), 5.77 (br s, 1H, =CH(H-)), 7.32 (dd, 1H, f= 8.2, 2.0 Hz, ArH), 7.67 (d, 1 Hj=8 88 10 Hz, ATH), 7.74 (s, IT-1, pyraz-H), 7.99 (s, IH, pyraz-H), 8.38 (d, 1H,f= 2.0 Hz, Ar-i), 8.46 (s, IH, benzimid-H). Example 23 1-[6&/(2-Me~~/h/ny/2Arnipyraz$;-2-y/-1iH benzbnzaazoa-67rw/e H N Cl, 'NN' N NC NN 15 To a stirred solution of the chloropyrazine (100 mg, 0.40 mrnol) in toluene (2 mL) was added o-toluidine (0,1 mL, 0.93 mnol), Pd[P(/-Bu),]2 (10 rmg) and sodium /-butoxide (58 mg, 0.6 mmol). The solution was heated at 800 overnight and upon cooling to RT was diluted with EtOAc (20 mL). The organic layer was collected and the aqueous layer extracted with EtOAc (20 mL) and the combined organic layers washed with water, brine, 20 and dried (Na2SO4). Removal of the solvent under reduced pressure gave an oily residue which was chromatographed using CH2C2-MeOH (98:2 -> 94:6) to separate the desired product as a pale yellow oil (52mg, 41%).

WO 2005/066156 PCT/AU2005/000022 43 'H-nan.r. (CDC 3 ) 52.34 (s, 31, CH 3 ),3.70 (s, 211, NH 2 ),6.61 (a, 1H, NN), 6.71 (dd; 1,/= 8.6,2.2 Hz, ArH), 7.19-7.36 (n, 4H, Arm), 7.53-7.60 (m, 2H, ArH), 7.99 (s, 1H, pyraz-FT), 8.27 (s, 11-I, pyraz-H), 8,36 (s, 1H, benzinid-H). Example 24 5 (%J-N--/6-dert-uy/amko)pyrazi--y/Hhenzft azots d/-apyrk/di-3 y/acry;/amsde N N N NH NH / \

N~

To a stirred solution of the aikyne (30 mg, 0.07 mmol) in anhydrous ethanol (5 mL) was added Lindlar catalyst (3 mg). The mixture was then purged with hydrogen gas and 10 stirred under H 2 at atmospheric pressure for 3h. The catalyst was removed by filtration through Celite* and the solvent removed A, vano. Flash chromatography using EtOAc MeOH (9:1) separated pure product as a sticky semi-solid (13 mg, 43%). 'H-n.m.r. (CDC%) 81.50 (s, 911, C(CHa) 3 ), 4.93 (s, IH, NH), 6.26 (d, 1H, /=12.6Hz, C=CH), 6.82 (d, !H,f/ 12.6Hz, C=CH), 7.14(dd, 11,f= 8.7,2.1Hz, ArH), 7.25-7.29 (m, 1H, 15 pyridine-HI), 7.74 (d, 1H, f/=8.7Hz, Ari), 7.82 (s, 11-1, pyraz-H), 8.07 (br a, 1H, CONH), 8.09 (s, 1-T, pyraz-H), 8.13-8.16 (n, 1H, pyridine-H), 8.47 (d, IH,f/= 1.8Hz, pyridine-H), 8.50 (s, 1H, benzimid-H), 8.51-8.53 (m, 1H, pyridine-H), 8.63 (d, 1H, J =2.1Hz, ArH). n/z (E): 413 (M). Example 25 20 N-iert-Bt/)6//rprzte2crom/ KO N 0 N01 N>CI N N WO 2005/066156 PCT/AU2005/000022 44 Thionyl chloride (1 mL, 13.7 mmol) was added to a suspension of the acid (315 mg, 2 mmol) in toluene (5 mL). A drop of DMF was then added and after stirring at RT for 10 n'rk. the mixture was heated at reflux for 1h. The reaction was cooled to RT and toluene and excess thionyl chloride were removed under reduced pressure. Toluene (1 mL) was 5 then added to the residue and this was removed under reduced pressure. This process was repeated, and then CH 2 C1 2 (10 mL) was added and the resulting solution cooled to 04C. t-Butylanine (0.45 mL, 4.3 mmol) and triethylamine (1mL, 8.0 mmol) were then added and the solution stirred at RT overnight. The solution was diluted with CH 2 C1 2 (10 mL) and H2O (10 mL) and the organic layer collected and washed with aq. Na2CO3 and 10 then dried (NazSO 4 ). The solvent was removed At racuo and flash chromatography of the residue using CH 2 CIrMeOH (95:5) separated the pure product as an oil (290 ig, 68 %). 2H-n.m.s. (CDC1j) 61.49 (s, 9H, C(CH 3

)

3 ), 7.48 (br s, 1H, NH), 8.72 (s, Ili, pyraz-H), 9.27 (B, IH, pyraz-H). m/z (EL): 413 (M). 35 Example 26 1-t/korypyrikz.-J-yl/-5ntrah4Hbcn;do/e and t-(6metko/rn-3-y)-6 nitro-1H-enztntazo/e NNO+ N HNL NO, NO, Meo N MOO N NO2 A mixture of 5-nitrobenzimidazole (650 mg, 4 mirtol), 2-methoxy-5-pyridyt boronic acid 20 (420 mg, 2.6 mmol), copper (II) acetate (1.09 g, 6 mmol) and powdered 4A sieves was stirred vigorously in CH 2 C12 (40 mL) containing pyridine (0.65 mL) was stirred in the air over 3 days. The mixture was then filtered through Celite and the filter pad washed with H 2 Cl-MeOH (4:1). The filtrate and washings were combined, concentrated /n vacuo and the residue chromatographed using CH 2 ClrMeOH (100:0 4 95:5) to separate 25 the product (as a 1:1 mixture of regiomers) as a ihite solid (272 mg, 37 %4). c/z(EI): 270 (M*).

WO 2005/066156 PCT/AU2005/000022 45 Example 27 .pyst--3-y and 1-(6-meloxypyrkxt-3y/%-H tenzwnzao-o-aminge

NO

2 MeO N MOO N

NO

2 MO t_ NNH 2

NH

2 5 The mixture of regioisomes derived from Example 26 (270 mg, 1 mmol) was hydrogenated following the procedure outlined in Example 10. The crude product was chromatographed eluting with CWzC-MeOH (98:2 -> 95:5) to separate the 6-isomer (84 mg)'from the less polar fractions and the 5-isomer from the polar fractions. (122 mg). 6-isomer: 10 'H-n.n.r. (CDCt3) 6 3.88 (br s, 2H, NH 2 ), 4.01 (s, 3H, OCR 3 ), 6.64 (d, 1IH,f= 2.1Hz, benzimid-HI), 6.72 (dd, 1Hf= 8.7,2.1Hz, benzimid-H), 6.92 (d, 1H,f= 9.OJz, benzimid -1), 7.61-7.68 (m, 211, pyr-H), 7.82 (s, iH, benzimid-H), 8.30 (d, 1H,/= 2,7Hz, pyr-H). 5-isomer: 'H-n.m.r. (CDC) 63.11 (br s, 2H, NI 2 ), 4.01 (s, 311, OCI), 6.75 (dd, 1H,f= 8.4,2,1Hz, 15 benzinid-H), 6.92 (d, 1H, /= 8.7lz, benzimid-H), 7.15 (d, IH,f= 2.1Hz, benzimid--I), 7.18 (d,1H,/= 8.7Hz, pyr-H), 7.68 (dd, 1H, f= 8.7, 2.7Hz, pyr-H), 7.91 (s, 1H, benzimid-H), 8.31 (d, 1IH, /= 2,7Hz, pyr-H). 20 WO 2005/066156 PCT/AU2005/000022 46 Example 28 l-(%9ramropynr~n-pl2-JJI-enzmndazoal-emin and 1-(5bromopyrdfnt-SyV-7H benz/nt iazoZ-S-arn te Br N Br

NH

2 N NH2 5 A solution of 35-dibromopyridine (237g, 10 mmol), 5-aninobenzinidazole (160g, 12 mmol) and caesium carbonate (4.9g, 15 mmol) in DMSO (10 mL) was heated at 150 for 18h. Upon cooling to RT the solution was diluted with CHC1 3 (40 mL) and filtered through Celite" and the filtrate concentrated At racuo. 'The residue was chromatographed (pre-adsorption to silica) eluting with EtOAc-MeO-L (100:0 4 95:5) to separate, from the 10 less polar fractions, the 6-isomer, and from the more polar fractions the 5-isomer. 6-isomer: 'H-n.m.r. (CDCla) a 3.82 (br s, 2H, NH2, 6.75-6.78 (m, 211), 7.64 (d, 1H, f= 9.1Hz, benzimid-H), 7.89 (s, 1H), 8.01 (dd, 1H,f= 2.1Hz, pyr-H), 8.75 (br s, 2H). 5-isomer: 15 1H-n.m.r. (CDClQ) 53.74 (br s, 2H, NH2), 6.79 (dd, 11, f= 8.7,2.1Hz, benzimid-H), 7.15 (d, IH,J= 2.1Hz, benzimid-H), 7.31 (d, H,fm 8.71-z, benzimid-H), 7.99 (s, 1H,benzinid-H), 8.01 (dd, 1H,f:= 2.1, 2.1Hz, pyr-H), 8.74-8.77 (m, 2H, pyr-H). Example 29 Z-(6-romopyr/in-l2-be4nstazol-6'.nbc and 1-(6-bromopyrW/n-2-y/AJH 20 benzndaza/5,anbre 13r N r Br N BrN or',- (I-NY N + N NN

A-NH-

WO 2005/066156 PCT/AU2005/000022 47 Using identical procedures to those outlined in Example 28, reaction of 2,6 dibromopyridine with 5-aminobenzimidazole and caesiun carbonate in DMSO at 150" afforded the two regioisomeric products which were separated by chromatography. 6-isomer: 5 1 1i-nmsn. (CDCl) 5 3,83 (br s, 2H, NH 2 ), 6.75 (dd, 1HJ= B.4, 2.1Hz, benzimid.-H), 7.42 7,47 (m, 3H), 7.60 (d, 1H,/= 8.4Hz), 7.71 (dd, 1H, /= 7.8Hz), 8.33 (s, 1H). 5-isomer: 1 -1-n.m.r. (CDC13) 86.81 (dd, 1Hf= 8.7, 2.1Hz, benzimid-H), 712 (d,1,f =8.1Hz, benzhid-H), 740-7.48 (m, 2H), 7.70 (dd, IH,/= 7.8, 7.8HTz, pyr-H), 7.89 (d, IH, f= 8.7Hz, 10 benzimid-H), 8.46 (s, 1H).

WO 2005/066156 PCT/AU2005/000022 48 The following compounds were prepared using analogous procedures to those described above: Compound Structure Data N-[1-(6-Chloropyrazin-2-yl). N 'H-n.mr. (CDCI 3 ) a5.82 (dd, 1H-benzimidazo-6- Cl N N /TH,,= 9.8,1.8Hz, =CH), 6.24 yjacrylamide 6.54 (m, 21, =CH 2 ),7.33 (dd, NH I,/= 8.8,1.8H z, ArKf), 7.60 (br s, 1H, CONH-), 7.80 (d, IH, fh8.4Hz, Ar-), 8.58 (s,2H, pyraz-H), 8.73 (br s, IH, ArH), 8.94 (b s,IH, Arid). N-{1-16-(4-Mthylpiperazin-1- N N 1 H1-n.m-r. (CDCIa) 62.34 (s, 3H, yl)pyrazin-2-yl-1H- N NCH 3 ), 2.55 (t, 4H, ft 5.1Hz, benzimidazoL-6-y1}acrylamide NCH), 3.74 (t, 4, f= 5.1Hz, NH CH 2

)

1 5Y2 (dd, 1H,/ 9.0, 2.6Hz, C4), 6.25-6.48 (m, 211, =CH2), 734 (dd, IH,/= 8.4, 2.2Hz, ArH), 7.68 (d, 1IH,f 8.6Hz, ArH), 8.04 (s, 1H, pyraz--H), 8.13 (s,211H, pyraz H), 8.38 (br s, 11-, CONH), 8.46 (s, IH, Art), 8.88 (br s, 11-, ArH). N-(-[6- N 1 -n.m.r. (CDOOs) 81.24 (d, 6H, (Diethylamnino)pyrazin-2-y]~ N N N /= 7.OHz, CH 3 ),3.60 (q, 4, /= 1H-benzimnidazol-6- 7,1liz, CH 2 ), 5.72 (dd,1-,f= yljacrylanide N " NH 9.0, 17Hz, CH), 6.25-649 (m, 21H, =CH,), 7.20 (dd, IH, f= 8.9,2.OHz, ArH), 7.71 (d, 1H,/ =8.4iz.. ArH-), 7.91 (s, 1H, pyraz-tI), 8.07 (s, 1H, pyraz H), 8-33 (br s, 1H, CONH), 849 (s, 1H, ArH), 8.6 (br s, IH, ArH).

WO 2005/066156 PCT/AU2005/000022 49 N-{1-6- N'H-n.m.r. (CDC13) 63.11 (d, 3H, (Methyhino)pyrazin-2-y}1- N N / 5.oHz, CHn), 4.9 (br s, 1i, 1H-benzimiidazol-6- N) .8(d1,f96 y~facrlarni I N YNI-I), 5.78 (dd 11i,J. 9.8, NH 2.2Hz, =CHi), 6.23-6,51 (n, 2H, CH1 2 ), 7.15 (dd, 1H,/= 8.4, 2.2Hz, ArH), 7.63 (br s, 1l, CONH), 7.76 (d, 1H,f= 8.6Hz, Ar), 7,86 (s,IM1, pyraz-H), 8.13 (s, 1H4, pyraz-H), 8-.3 (3, 1H, ArHi), 8.90 (s, 1H, Ar-i). N-f1-F6-(Ethylanino)pyrazin- N 'H-n.m.r. (CDCI 3 /de-MeOD) 2-y1j-1H-bcnzimidazoN-6- N N 81.25 (t, 3H,/= 7.3Hz, C13), fllacrylamide N 3.42 (q, 2H,/=7.3Hz, CH 2 ), O NH 5.68 (dd, 1H, /= 7.8,4.6Hz, =CH), 6.23-6.42 (n, 21j, =CH 2 ), 7.24 (dd, 1H, /= 8.6, 2.2Hz, ArH), 7.63 (d, 1H,/=8.8Hz, ArH), 7.73 (s, 1H, pyraz-H), 7.97 (s, 1H, pyraz-H), 8.44 (, 1H, ArH), 8.73 (br s, 1H, Arl). N-L1-(6-piperidin-1- N o/z (ET) 348 (Mi) ylpyrazin-2-y1)-1Hf-N N N benzimidazol-6-yacrylomide N N NH N-l1-(6-morpholin-4- N 1#/z(F2) 350 (M*) y1pyrazin-2-y)-1Hi- N benzimidazol-6-yllacrylamide N

NH

WO 2005/066156 PCT/AU2005/000022 N-1-(6-pyrrlidin-- m/ (E) 334 (M') ylpyrazin-2-yl)--1H-N N N benzimidazol-6-yi]acrylamide NH N--[6- Nrt/z (ET) 308 (M') (dimethylamino)pyfazin-2- N N N yl]-1H-benzimnidazol-6- -' yiacrytlamide N N-(1-(6- N m/(EI) 336 (M*) [isopropyl(wethyl)aminoipyr N N N azin-2-yll-1Hi-benziidazol-1, 6-yl)acrylanide N NH N-{[-[6- N 'H-nmr. (CDC 1 ) 51.32 (d, 6H, (Tfsopropylantino)pyrazin-2- = N 6.2Hz, C-T 8 ), 4.13-4.29 (1m, y cyl-H be mid azal-6~IN, CH), 4.75 (d,IH, /= 7.8Hz, ylacrylamide N N-i NH), 5.78 (dd, 1H, /= 9.8, 2.0Hz, =C-H), 6.22-6.51 (m, 2H, =Cll2), 7.19 (dd, 1H, /=8.6, 2.29-z, ArH), 7.62 (br s, 11, CONH), 7.76 (d, 1H,f= 8.8Hz, ArH), 7.82 (s, 1-1, pyraz-H), 8.13 (s,1IH, pyraz-H), 8.50 (s, 1H, Arli), 8.74 (br s, 1H, ArH). N-{-(-([13-1 'IH-n.m x. (CDCII) W.99 (t, 3H, methylpropyllamrino}pyrazin- N N J= 7.2Hz, CH 3 ),1.27 (d, 3H,J= 2-yl)-1H1-benzimidazol-6- N 6.41 fz, CH.), 1.53-1.73 (m, 21f, yllacrylamide NH CH2), 3.95-4.09 (m, 1i, Cl-), 4.79 (d, 1H,f .Hz, NH), 5.76 (dd, 1H/9.6, 2.0H-z, WO 2005/066156 PCT/AU2005/000022 51 Ci), 6.23-6.50 (im,2, 2CHz), 7.21 (dd, 1H,/= 8.6, 2.2Hz, ArH), 7.74 (d, 11,/= 8.8Hz, ArH), 7.82 (s, 1H, pyraz-H), 7.84 (br s, I, CONH), 8,11 (s, 1i, pyraz-H), 8.49 (s, 11H, ArH), 8.73 (br s, li, Ari). N-(- [(1RH-1- N tH-n.m.r. (CDC ) 60.99 (t, 3H, methylpropylJainojpyrazin. , N / 7.2Hz,CH 3 ) 1.27 (d, 3$,/= 2-yl-1H4-benzimidazo 4-(- 6Aoj .Hz, CH), 1.5 -17( , 2H ylacryland N NH 6.4Hiz. ), 1,3 .7 (m, 2H-, NH Cu 2 ), 3.95-4.08 (n, 1H, CH), 4.81 (d, 11,/:8-Hz, NH-I), 5.75 (dd, 1H, /= 9.6, 2,0Hz, -CH), 6.23-6.50 (m, 21-, =-CH2), 7.22 (dd, IHf= 8.6, 2.2Hz, ArH), 7.73 (d.lh, /=8.8Hz, Ar-I), 7.81 (s, IN, pyraz-H), 7.98 (br s, 1H, CONT-), 8.10 (s, IH, pyraz-H), 8.49 (n, 1H, Ar-1), 8.73 (br 9, 1, ArH). N41-(6-Anilinopyrazin-2-y)- -N 'H-n,m.r. (CDC 3 +d 4 -MeOD) 1H-berizirmidazol-6- N N N 5-79 (dcL1,f=9.0,3.0Hz, yllacrylamide C C), 6.40 (IH, d,/= 9,0Hz, NH =CH(H)), 6.43 (1H, d, /= 3.0Hz, =CH(H)), 7.11-7,15 (m, 11-, ArH), 7.30-7.44 (m,,311, ArH), 7.52-7.56 (m, 2H, ArH), 7.75 (d, 1l-, 1/=8.8Hz, ArH-), 8.20 (s, 1H-, pyraz-H), 8.27 (s, 111, pyraz-), 8.56 (s, IH, ArHi), 8.79 (br s, 1H, ArH). N-[1-(6-Phenylpyrazin-2-yl)-

-

N 2 Hi-n.m.r. (CDC 3 ) 85.70 (dd, 1H-benzimidazol-6- N N 11,/=8.6,2.2Hz, =CH-I), 6.22 y1Jacrylamide 6A6 (m, 2H, =CK 2 ), 7.29 (dd, NH 1H,1~ 8.6,1.4Hz, Ar-i), 7.47 7.57 (rn, 3i, ArH), 7.68 (d, 1I, /= 8.8Hz, ArH), 8.12-8.16 (m, WO 2005/066156 PCT/AU2005/000022 52 2!-TAr) 86 (s, I H, pyroz Wi, .8(s H pyraz-H-), 8.91 _______________________ (s1il, ArH4), 8.97 (s, if!, ArTU). M-{-f-(3cboro4-F N P/Z (ED) M9,395 (-3:1) ~~ fluorophe"y1)pyrtzil.2-yl]- N 11-1benzin~ddazoL-6 yt~acrylamide N N 2-y1)-U-benizimidazo..6- Nr y11acrylan'ddc N NH N-tl(f 211:ln--'-ylprazi-2- 4 /N(EI) 347 (M*) Y Jcrylamnide N NH y ~ ~ y ~ i n - 2 ~ ~ y 3 ~ m( 1~IN N /f ~ E ) 3 3 1 (M ') NN 1-16.3A,$-OMe ,rr~(El ) 431 (M t ) trimetbaxyphlenyi)pyra.zin4. meo N YllIH-berueftidazol-6- mooN yl)avzcyarnide N

NI

WO 2005/066156 PCT/AU2005/000022 53 1-MethylN--1-[6-(- N mr/z (El) 405 (M-) butylanino)pyrazin-2-yl]-1H N(N N benz.imidazol-6-yl}-1,2,5,6- N tetrahydropyridine--3- N carboxamide N N-(-{6(tet-N /z (ET) 3450 (M ) butylamino)pyrazi-2-yl]-1H- N N / benzimidazo-6-yllbut-2- -N enamide NH N-Il-[6-(tr-- H'H-Pm.r.

(CDC

3 ) 61.50 (s, 9H, Butylamino)pyrazim2-yll-1Hi- >(N N N /C(CH3y3),1.98 CH-3), benzimidazol-6-yllbut-2- 4.93 (s, Il, N1-), 7.20 (dd, 1H, ynamide J=8.4,2.0Hz, ArH), 7.76 (d, 1H1, JS.8Hz, ArM), 7.83 (s, 11H, pyraz-H), 7.95 (br s, 1HJ, CONH), 8.08 (s, 1H, pyraz-1-), 8.44 (d, 1H, J = 2.0 Hz, ArH), 8.49 (s, 1H, benzimid-H). m/z (El): 348 (M+). - -N '-n.m.r. CDQjCDjOD methylphenyl)aminolpyrazin N N \ (v/v19/1) 2.35(s, 3H, CH 3 ), N 5.75-5.3 (m, Hi, C=CIH), 6.39 yl)acrylamide NH 6.49 (m, 2H, 2 x C=CH), 7.19 7.34 (m, 3H, 3ArH), 7.41(dd, 1H,/= 7.5,1.4Hz, ArH), 7.71(d, 1H, 1= 8.7Hz, ArH), 7.92 (.s, 1i, pyraz-lH), 8.25 (s, 1H, pyraz-H), 8.57 (s, 1H, benzirnid-H), 8.76 (d, 1H, = 1.8Hz, ArH). m/z (El): 370 (M*).

WO 2005/066156 PCT/AU2005/000022 54 N-(1-(6-[(5-chloro-2- N 'H-njm.r. CDC1 3 /CDOD methylphenyl)amino]pyrazin N N N (v/v=19/1) 82-32 (s,3H, CHi 3 ), -2-yIj-1H-benzimidazo1-6- N 55.77-5.81(m,1H, C=CH),633 yl)acrylamide Ni 649 (m, 21, 2 x C=CH), 7.15 (dd, I-, /=8.1, 2.1Hz, ArH), 7.24 (d, 1H,= 8.1Hz., Ar-1), 7.39 (dd, 114,j=8.7,1.8Hz Arl), 7.62 (d, IM f= 2.1Hz, ArH), 7.98 (s, IH, pyraz-H), 8.31 (9, 1, pyraz-1-), 5.53 (s, 1H, benzimid-H), 8.77 (d, 1H4,1 1.5Hz, ArI). W/z (P-1): 404, 406 (both M*). N-I146-(tert- HNH-n.r. CDCI 3 /Ci 3 OD benzirnidazol-6-yl)-3-pyridin- C(CH3)3),l 7.3-7.42 (m, 21, 3-ylprop-2-ynamide N H ArH + pyrdin-H 7,76 (d, -- 11-1,/=S.MHz, Atli), 78 s N 1H, pyraz-H), 7.90-7.94 (m, 1M, pyridine-H), 8.04 (s, ilH, pyrazr H), 8.48 (d,1Hf21z ArH), 849 (s, 1H, benzinid H), 8.52-8.61 (m, 11, pyridine H), 8.76-8.77 (in, 11H, pyridine /(EU): 411 (M*) N-(1-{6-[(2-chloro6- H N 1 H-n.n.r. CDCI 3 /CDOD methytpheny)aminojpyrazln N N N (v/v19/1) 23(s,31,CU 3 ), -2-yi)yl--benzimidazo6- CI N 5.75-5.79 (m, 114, C=CH), 632 yl)acrylamidde 0o NH 6.48 (m, 2H, 2 x C=CH), 7.18 7.26 (m, 2H, 2ArH ),7.36-7.39 (m, 211,2ArH), 763 (, 1, pyraz-H), 7.69 (d, IH,/= WO 2005/066156 PCT/AU2005/000022 55 8.7Hz, AT-Hi), 8.27 (s, 11, pyraz-H), 8.49 (s, lH, benzimid--i), 8.69 (br s, 1H, ArH). m/z (El): 404,406 (both M*). N-(1-t6-[(3-methylpyridlin-2- N 1 H-n.n.r. CDCl 3 /CDOD yl)aminolpyrazin-2-yl- ii- N > N N / \ (v/v=19/1) 82A4 (9, 3H, CH 3 ), benimidazol-6-yI)acrylamide N N 5.75-5.79 (m, 11, C=CH), 636~ NH 6.48 (m, 2H, 2 x C=C-), 6.97 7.01(m, 1H, pyridine-H), 7.37 (dd, I1,/=8.7,2.,Hz, Arli), 7.39-7.57 (m, 1H1, pyridine-H), 7.73 (d, 1H,/= 8.4Hz, ArH), 8.22-8.24 (n, 1Hk, pyridine-F), 8..47 (s, 1H, pyraz-H), 8.58(s, 1H, pyra-H4), 8.90(d, 1H-Lf 1.5Hz, ArH), 9.44 (s, 1-H, benzimd-H). ,w/z (I): 371 (M*). N-(--(-[(-mehylyriin-- N 'H--nan.r. CDC13/CpaOD yl~minlpyazi-2-lj-H-N (v/V:=4/1) 62.03 (s, 9H, benzimidazol-6-yl)but-2- N

C(CH

3 )), 2.42 (s, 3H, Cl- 3 ), ynamide NH 6.96-7.00 (m, 1-I, pyridine-i), o 7.34(d, 1H,/= 8.1Hz, Ari), 7.54-7.56 (n, 111, pyridine-H), 7.69-7.72 (m, IH, pyridine-H), 8.22-8.24 (m, 11-, pyridine-H), 8.45 (c, IH, pyraz-H), 8.58 (9, 1H, pyraz-H), 8.69 (br s, 1-I, ArH), 9.45 (s, 1H, benzirnid z().

WO 2005/066156 PCT/AU2005/000022 N-(1-{6-[(2-chloro-6- Hm (CDC]:) 82,08 (s,3, methylphenyl)amino]pyrazin N N C r),r2.34 (s, 3, CHA20 657 (s, -2-y1)-1H-benzimidzo-6- C N N , 7.30-732 (m, 2H, yl)but-2-ynamide NH 2ArH), 7.42-7.52 (m, 3-, 0 3ArHl), 7.75 (d, 1H,/8.7Hz, ArH), 7.84 (s, lHI, pyraz-H), 8.06 (br s, IH, CONH), 8.35 (s, 1H, pyraz-H), 8.48 (s, 1H, benzimid-H). m/z (El): 416,418 (both M'). (2A)-N-(1-L6-(jdrl-H N 1 H-n.m-r. (CDC 3 ) 51.51 (s, 9H, Butylamino)pyrazin-2.y]- N N,( N C(CH3)s), 4.81 (s, 1H, NH), 6.66 benmida7zo-6-yl-3-pyridin~ I (d, 1H,/= 15.6Hlz, C=CH), 3-yjacrylamide NNH 7.24-7.33(m, 211, Ar- + pyridine-H), 7.75 (d,1H, /= N-- 15.6k-z, C=CH), 7.78-7.81(m, 31-1, 2ArF + CON-), 7.83 (s, 111, pyraz-H), 8.15 (s, 1., pyraz-H), 8.52 (s, 1H, benzimid-H), 8.58-8,60 (m, 211, 2 x pyridine-H), 8.79 (br s, Il, ArH). m/z (El): 413 (M*). /V-(1(6-[(2,3- N 'H--n.r. CDC4q/CDOD dichlorophenyl)aminolpyrazi N N / (v/v=9/1):5.75-5.79 (i, 1H, n-2-y-1H-bcnzimidazol-6- C=CH), 6.34-6.46 (m, 2H, 2 x yI)acrylamide c NH C=CHA), 7.24-7.26 (m, 211, ci 0 2ArH), 7.28-7.38 (m, 114, ArHi), 7.72 (d, 1H,f= 8.7Hz, ArHi), 7.96-7.99 (n, 1H, ArH), 8.20 (s, 1H, pyraz-1i), 8.40 (s, 1H, pyraz-H), 8.52 (s, 1H, benzimid-H), 8.72 (br s, 1H, ArH). m/z (El): 424,426,428 (all M*).

WO 2005/066156 PCT/AU2005/000022 57 N(-6 H N H-n.m.r. CDCh/CD 3 OD dichlorophenyl)amino]pyrazi N, N N N (v/v=9/1): 5.73-5.79 (n, IH, n-2-yl)-1H-benzimidazol-6- N yN C=CH), 6.40-6.48 (m, 2H, 2 x yl)acrylamide NH C=CH), 7.06 (dd, 1H, /= 8.7, 2.4Hz, ArH), 7.39-7.45 (m, 2H, 2ATHl-), 7.73 (d, 1H-, /= 8.7H7, ArH), 8.21 (d, 1H,/=2.4Hz, ArH), 8.30 (s, 1 H, pyraz-H), 8.44 (s, 1H, pyraz-H), 8.60 (s, 1H, benzimid-H), 8.71 (br s, 1H, ArH). .M/z (El): 424,426,428 (all M+ N-{1-[6-(/r/- N 'H-n.m.r. CDC1 3 /CTJ0D butylanin)pyra7.in-2-yll-IH- N Nm (v/v=19/1): 2.33 (s, 3H, CH3), benzimidazol-6-yl)-3-pyridin- 7.24-7.29 (m, 2H, 2ArH), 7.36 3-ylprop-2-ynamide NNH 7.42 (m, 2H, ArH + pyridine -), 7.51 (dd, 1H,J= 8.7,1.8Hz, N Art-i), 7.73-7.75 (m, 2H, Ar-i + pyraz-H), 7.91-7.95 (m, 11-, pyridine-H), 8.29 (s, 1H, pyraz-H), 8.43 (br s, 1H, ArH), 8.50 (s, 1H, benzimid-H), 8.62 8.64 (m, 1H, pyridine-H), 8.80 (d,1HR, /= LS5Iz, pyridine,-H). ll/Z (El); 479, 481 (both M*). 6-[6-(Acryloylamnino)-1H- N H-.m.r. CDCl661.56 (s, 9H1, be-nzimidazol-1-ylj-N-(tert-N NC(H),5.6d,1,/ 9, butyl)pyrazine-2- .H C(Czi) 3 ), 5.76 (dd, H, d 9.5, carbxamie N1.7Hz, C--Ct'1), 6.31 (4(1, 1H,/, carboxamide NH -16.9 9.5Hz, C=CH), 6.48 (dd, 111, /= 16.9, 1 .8Hz, C=CH), 7.09 (dd, 1H, /: 9.9, 1.9Hz, ArH), 7.62 (br s, II, CONH), 7.76-7.80 (m, 211, 2Arl 1), 8.51 (s, 1H, pyraz-H), 9.10 (br s, 2H, pyraz-H + CONH), 9.33 (s, 1H, benzimid-H).

WO 2005/066156 PCT/AU2005/000022 58 /ll/z (E): 364 (M*). 6-[6-(Acryloylarmino)-1H- p N CDCI 3

/CD

3 OD (v/v=9/1): benzimidazol-1-ylj-N- N N 1.42 (d, 6H, 2 x C 3 ), 4.42 (m, isopropylpyrazinc--2- N IH, CH), 5.75-5.81 (i, 11-, carboxamide N NH C=CkH), 6.35-6.52 (m, 2H, 2 x C C), 7.22 (dd, 1H, f= 9.0, 24Hz, ArI), 7.75 (d, 1H,/= 8.8Hz, ArH), 8.77 (s, 1IH, pyraz-H), 9.25 (s, I, pyraz 1I), 9.34 (s, 11l, benzirnid--i), 9.39 (br s, IH, ArH). m/z (El): 350 (M'). 6-f6-(Acryloylamino)-1H / N 1iH-nxmnr, CDC1 6 3-23 (a, 6H, benzirnidazol-1-yl]-N,N- N N N N(CH-), 5.79-(dd,1Hf=9.5, dimethylpyrazie-2- 2.3Hz,C=CH), 6.33 (dd, ,/ carboxamide N 16.9, 9.5Hz,CCH), 6.47 (dd, NH 1I,./= 16.9, 2.1 Hz, C=Ci), 7.22 (dd, 1H,/= 8.6,2.2Hz, 0 ArHi), 7.72 (d, 111, /= 8.6Hz, Ar-i), 8.05 (br s, 1if, CONH), 8.52 (9, 1, pyraz-H), 8.75 (s, 1Hi, CONE), 8.87 (s, 11H, pyraz-H), 9.02 (s, 1H, benzimid-H). m/z,(EI):. 336 (M'). 6-[6-(But-2-ynoylamino)-1H- / N '1i-nan.r. CDC1 3 8 2.04 (3, 31H, benzinidazol-1-yl]-N,N- N N N N CH 3 ), 3.24, 3.26 (each s, 3H, dimethylpyrazine-2- NNCH), 7,16 (dd,1H, /=8.8, arboxamide N 1.Hz, ArH), 7.75 (br s, I H, NH CONH), 7.80 (d, 311, =8.8Hz, ArH), 8.54 (s, 1IH, pyraz-Hi), 8,74 (d, 1H, /=1.8Hz, Ar), 8.91 (s, 11, pyraz-H), 9.03 (s, 1H, benzimid-H).

WO 2005/066156 PCT/AU2005/000022 59 n/z (El): 348 (M+. N-[1-(6-methoxypyridin-3- N 'H-n,r.n- (CDC1 3 ) 64.01 (s,3H, yl)-1H1-benzimidazol-6. N / OCH 3 ), 5.74 (dd, 114,/= 9-9, yllacrylamide 1.8Hz, C=C4H), 6.29 (dd, 1Hf MeO N =16.8,9.9Hz, C=Ci-), 6.43 (dd, 0 1H, f=16.8, 1.8 Hz, C=CH), 6.91 (d, 1H,f= 8AHz, pyr-H), 7.11 (dd, 1If/= 8.7, 2.1Hz, benzimid-H), 7.70 (dd, IH, J= 8.7, 2.71-z, pyr-H),7.74 '(d, 1H, f= 8AHz, benzimid-H), 7.99 (s, 11-T, benzimid-H), 8.07 (br s, 11, CONH), 8,26 (br s, 1H, benzimiid-H), 8.30 (d, 1H, / 2.1Hz, pyr-H). r/s (El): 294 (M), N-[1-(6-netboxypyridin-3- N I-n.mr. (CDCl 3 ) 81.96 (s, 311, y[)-1H-benzimidazo-6- N CH), 4.01 (s, 3H, OC1 3 ), 6.92 ylbut-2--ymnide (d, 1f,f= 8.7Hz, pyr-H), 7.12 mo N NH (dd,1H,/- 8.7,1.8Hz, benzimid-H), 7.69 (dd, 1H,f= 0 8.7, 2.71-z, pyx-H), 7.76 (d, 1H, /=8.7z, benzimid-H), 7.99 (s, 1H, benimid-H), 8,04-8.05 (m, 2H, CONH + benzimid-), 8.30 (d, 1H,/= 2.4Hz, pyr--). m/z (El): 306 (M*). N-(1-[6-(tert- N 'HNMR (CDC1 3

/CD

1 OD, butylamin)pyrazin-2-y1]-1H- N N / v/v=9/1) 51.51 (9, 9H, -Bu), benzinidazol-6-ylF-4- 2.65 (t, 4H,f= 4.8 Hz, 2 x morpholin-4-ylbut-2-ynamide N NH NC 2 ), 3.5 (s,2H, NCH.) 0 N 3.77 (t, 4H, f=4.8 Hz, 2 x \ OCH 2 ), 7.33 (dd, IH,= 8.7, 1.8 Hz, benzimid-H), 7.75 (d, 1H,/= 8.7 Hz, benzimid-H), WO 2005/066156 PCT/AU2005/000022 60 lit pyraz-H), 8.45 (d, 1H, A 1.8 Hz, benzim id-H), 8.52 s lIH. benzia-ld-H) ff/z 433 (M). NI-46-(trt- 'HNMR (CDC],) 61.52 (s, 9H, butylamino)pyrazxin-2-y1lj-H >j N N ABu), 2.51 (t, 4H,J= 5.1 H7, 2 X benzimidaza-6-ylj-4-(4- NC1 2 ), 2.78 (, ,3k-i, NCH~j), Tnethylplperazin-l-yl)-but-2- N -6(,H =51kz ; ynrrdeNC 2 ), 3.50 03,2, NC-T 2 ), 4 86 (s, 11-, NHl), 7.24 (cid, li, 7.78 (d, ll-T,/ 8.7 Hz, pyraz.H), 8.11 (s, 112, pyrae- 1I), 8.17 (br s, Ifl, CONH), 8.46 (d, 1H,Jf- 1 .8 Hz, beriziinid 1-1), 8.50 (1, IM-, benzirnid-ki). mffz 446 (AC~). butylmino~yrazi-2-ylHN1- (CDCI,) &I Al1 (t, 612-LI but~mio~prazn-2yl)l/ N 7.2 Hz, 2 x C1q), 1.53 (s, 91-4, berizimidazol-6-yl]-4- T ~ -ABu, 2.62 (t, 4H, /= 7.2 l-b, 2 x (diethylamninouk-2-ynamide NNH NCI%), 3.59 (s, 2H, NCH2), N .- ~.4.84 (,, 1H, N-T-), 7.21 (dd, 1H, I= 8-7, 1.8 Hz, bmrziimid-.H), 7.76 (hr s, IH, CONIA), 7.719 (d, lHJk= 8.7 Hz, benzin-tid-H), Ili, pyraz-H). 8.45 (d, 11-f, /= IS81Hz, benziniid-H), 8.51 (s, #l/z 419 (Me).

WO 2005/066156 PCT/AU2005/000022 61 N-{16-(tert- N 'H-NMR(CDC1 3 ): 58.76 (b, 1H), butylamino)pyrimidin-4-yl- NN 8.65 (s, iH), 8.52 (s, I), 7.75 1H-benzimidazol-6- N N (d,f=8.9Hz, 11-), 7.73 (b,1H, yL)acrylarnide NH amide NH), 7.15 (dd,J= 8.6,2.0Hz, iH), 6.58 (s, 1), 0 6.47 (dd, /=16.9,1.7Hz, 1q), 6.30 (dd, = 16.9,9.6Hz, 11H), 5.80 (dd, /=9.6,1.7Hz, 1B), 5.41 (b, iH, NH), 1.52 (s, 9H) ppm. m/z 336.3 N-1-[4-(tert- -N -NMR(CD ) 68,93 (., 2), butylamino)pyrimidin-2-yl]- N N N 8.11 (d,/= 6.0Hz, 1H-), 7.78 (b, 1H-benzimidazol-6- ,I, amide NH), 7.74 (d,/= yllacrylamide NH 8.6Hz, 1H), 7.51 (bm, 111), 6.46 (dcl, / 16.9,1.6Hz, 1H1), 6.32 0 (dd,/= 16.9,10.0Hz, 1H), 6.20 (d,fr 6.0Hz, 1), 5.75 (dd, J= 1).0,i.6Hz, lH), 5.09 (b, 1H, NI-), 1.51 (s, 91) ppm. m/z 336.1 LC-MS: Rr = 7.6min., N-{1-[6-(tert- N /(TNMR (CDC ) S1.53 (s, 9H; butylamino)pyrazin-2-yll-5- N C(CH3)9),4.00 (s, 3H, OCH,), methoxy-1H-benzimidazol-6- N \ 4.78 (s, iH, NH), 5.78 (dd, 1H, yljacrylamide 0 NH /= 9.6, 1.8Hz, C=CH), 6.33 (dd, 11-,= 16.8,9.6Hz, C=CH), 6.44 (dd, 1H,J= 17.0,1.8Hz, CCH), 7.35 (s, IH, Arfi), 7.83 (s, 1H, pyraz-H), 8.09 (br s, iH, CONH), 8.19 (s, 1iT, pyraz-H), . 8.49 (s, 1i, ArH), 9.12 (s, 1i, benzimid-1-1). m /z (El): 366 (M').

WO 2005/066156 PCT/AU2005/000022 62 N41-(5-bromopyridin-3-yl)- N 2 H-n.m.r. (CDC 3 ) S 5.79 (d, 1H-benzimidazol-6- 8r< N /1, If=10.2Hz, C=CH), 6.27 yl]acrylamide | - (dd, 1Hf= 16.8,10.2Hz, N NNH C=CH), 6.45 (d, IH, /= 16.8Hz, o C=CH), 7.16 (dd, 11, = 85, 2.1Hz, benzimid-1), 7.32 (br s, 1H, CONH), 7.80 (d, 1H,I= 8.AHz, benzinid-H), 8.0-.05 (m, 2H), 8.30 (br s, 1H, benzimid-H, 8.77-8.80 (n, 2H, pyr-H). m/z342,344 (M*) N-Il-(6-bromopyridin-2-yi)- N v/z 342,344 (M') 1H-benzimidazol-6- Br N N yljacrylamidc NH 0 SCREENING Compound Dilution For screening purposes, compounds were diluted in 96 well plates at a concentration of 20 5 pM. Plates were warmed at 37'C for 30 minutes before assay. JAK Tyrosine Kinase Domain Production /AK kinase domains were produced in the following manner; /AK1 'he kinase domain of human JAM was amplified from U937mRNA using the polymerase 10 chain reaction with the following primers: XHOI-J31 5'-CCG CTC GAG ACT GAA GTG GAC CCC ACA CAT-3' J1-KPNT 5'-CGG GGT ACC TTA TIT TAA AAG TCC TTC AAA-3' WO 2005/066156 PCT/AU2005/000022 63 JAKI PCR products were cloned into the pFastBac HlTh expression vector (Gibco) via the Xho I and Kpn I sites. The JAKI plasmid was then transformed into competent DH1OBac cells (Gibco), and the recombinant baculovirus produced prepared for transaction into Sf9 insect cells. 5 JAK2 The kinase domain of humanJAK2 was amplified from U937mRNA using the polymerase chain reaction with the following primers: SALL-jk2 5'-ACG CGT CGA CGG TCC CTT TGA AGA CCG GGA T-3' jk2-NOTI 5'-ATA GTT TAG CCG CCG CTC AGA ATG AAG GTC ATT T-3' 10 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 DH1OBac cells (Gibco), and the recombinant baculovirus produced prepared for transfection into Sf9 insect cells. JAK3 15 The kinase domain of humanJAK3 was amplified from U937mRNA using the polymerase chain reaction with the following primers: XHOI-J3 5'-CCG CTC GAG TAT GCC TGC CAA GAC CCC ACG-3' J3-KPNI 5'-CCC GGTACC CTA TGA AAA GGA CAC GGA GTG-3' JAK3 P'CR products were cloned into the pFastBac HTh expression vector (Gibco) via the 20 Xho I and Kpn I sites. The JAK3 plasmid was then transformed into competent DH1OBac cells (Gibco), and the recombinant baculovirus produced prepared for transfection into Sf9 insect cells. TYK2 The kinase domain of humanTYK2 was amplified from A549 mRNA using the 25 polymerase chain reaction with the following primers: HT12BK 5'-GGA GCA CTC GAG ATG GTA GCA CAC AAC CAG GTC-3' 1TY2.2R S'-GCA GCA GGA ATT CCC GCG CTC CCG GTC AA A TCT GG-3' WO 2005/066156 PCT/AU2005/000022 64 TYK2 PCR products were cloned into pBlueBacHis2A (Invitrogen) via the EcoRT site. The recombinant TYK2 baculovirus produced was prepared for transfected into Sf9 insect cells. Large Scale Production Of Kinase Domains 5 Baculovirus preparations from each of the JAK family memberswere infected into five litres of High Five cells (Invitrogen) grown in High Five serum free medium (Invitrogen) to a cell density of approximately 1-2 X 106 cells/mi. Cells are infected with virus at a MOI of 0.8-3.0. Cells were harvested and lysed. JAK kinase domains were purified by affinity chromatography on a Probond (invitrogen) nickel chelate affinity column. 10 Assay Protocols Kinase assays were performed either in a 96 well capture-bascd ELISA assay or in 384 well Optiplates (Packard) using an Alphascreen Protein Tyrosine Kinase kit. In either casse using approximately 1.5 gg of affinity purified PTK domain in the presence of 50mM HEPES, pH 7.5, 10mM MgC 2 , 150mM NaCl and 1OM-mM ATP. The 15 biotinylated substrate biotin-EGPWLEEEEAYGWMDF-NH2 (final concentration 5pM) was used as substrate. In the ELSA assay tyrosine pbosphorylation 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 20 subdued light. The ELISA plates were read on a BMG Fluorostar, the Alphascreen plates were read on a Packard Fusion Ap/r. 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 25 The activity of selected compounds is shown in Table 3. Compounds that exhibited a capacity to inhibit 50% of JAK activity at a concentration of 20pM (measured under standard conditions, see Methods), are designated as "+".

WO 2005/066156 PCT/AU2005/000022 65 Table 3 CHEMISTRY Jak2 Jak3 CHEMISTRY Jak2 JakQ .YIH+ + 014HI1OCINSO ____ ___ =H20Ns0 III C17-iISNGOCoH0lF3 +~ + CITI-118N70 101 H20NO NHH + + C1BNISN6O C15H14NGO WO 2005/066156 PCT/AU2005/000022 66 Table 3 (coift.) CHEMISTRY -Jqk2 Jak3 CHEMISTRY Jak2 Jak3 + + + 020H1460 Ci0H16NO0 rNm - + ~ j<- + C19Fh1N502 ____________ - + - + Cl9H11WOS C19H20N6O ___ + + jC19H21N5O2 -- I 182N6O WO 2005/066156 PCT/AU2005/000022 67. 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 present 10 invention as it existed in Australia or elsewhere before the priority date of each claim of this application. It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present 15 embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

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(2001) 6-Substituted-4-(3 bromophenylamino)quinazolines as Putative Irreversible Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor (HER-2) Tyrosine Kinases with Enhanced Antitumor Activity/Med Chem., 44, 2719-2734. 10 18. 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. Mo? Ce//B/b. 11, 2057-65. 19. Wilks AF, and Kurban RR (1988) Isolation and structural analysis of raurine c-fes cDNA clones. Oncogene 3, 289-94 15 20. Wissner, A.; Overbeek, E.; Reich, M. F.; Floyd, M, B.; Johnson, 13. D.; Mamuya, N.; Rosfjord, E. C.; Discafani, C.; Davis, R.; Shi, X.; Rabindran, S. K.; Gruber, B. C.; Ye, F.; Hallett, W. A.; Nilakantan, R.; Shen, R.; Wang, Y.-F.; Greenberger, L. M.; and Tsou, H.-R. (2003) Synthesis and Structure-Activity Relationships of 6,7-Disubstituted 4 Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible 20 Inhibitor of the Tyrosine Kinase Activity of the Epidermnal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HEUR-2).; Med. Chen. 46, 49-63.

Claims

5-: N W ~X 4 x. X3 x 2 10 or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein: X I, X 2 , X 3 , X 4 are each carbon where one is substituted with Z and the rest independently with Y; or one of X I, X 2 , X 3 , X 4 is N and the others are carbon where 15 one carbon is substituted with Z and the rest independently with Y; A is a ring selected from: N N N N NN N N D D N D 20 where D is selected from H, C.4 alkyl, halogen, amino; Q is a bond, halogen, C,. 4 alkyl, o, S, SO, SO 2 , CO, CS; 25 W is: (i) NRI R2 where RI and R2 are independently H, C.4 alkyl, C,. 4 alkylCF 3 , aryl, hetaryl, C,. 4 alkylaryl, C1. 4 alkylhetaryl, C 3 . 8 cycloalkyl, C 2 . 6 alkenyl, 30 cyclohetalkyl, C1.4 alkylcycloalkyl, C 1 .4 alkyl cyclohetalkyl, or RI and R2 are joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from 0, S, NR3; and R3 which is selected from H, 2315164_1 (GHMattere) 24/08/10 72 C 1 . 4 alkyl, aryl, hetaryl, C 14 alkyl aryl, C 14 alkyl hetaryl, COR4 where R4 is selected from H, C 1 . 4 alkyl, aryl, hetaryl; OR 5 (ii) H, C 14 alkyl, aryl, hetaryl, C 3 . 8 cycloalkyl, cyclohetalkyl, C 1 4 alkylaryl, C 14 alkylhetaryl, C 3 . 8 cycloalkyl, C 14 alkylcycloalkyl, C 14 alkyl cyclohetalkyl; Y is H, halogen, CN, CF 3 , nitro, OH, C 14 alkyl, C .4 alkylNR5R6, C,4 alkylhetaryl, 10 OC.4 alkyl, OC 24 alkylOC,. 4 alkyl, OC.4 alkylNR5R6, OC 14 alkylhetaryl, OC.4 alkylcyclohetalkyl, SC 1 4 alkyl, SC 24 alkylOC 14 alkyl, SC 1 4 alkylNR5R6, NR5R6, NR5COR6, NR5SO 2 R6; and R5 and R6 are each independently H, C 14 alkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from 0, S, NR7 and R7 is selected from H, C 1 . 4 alkyl, aryl, hetaryl, C 1 4 15 alkylaryl, C 14 alkylhetaryl; Z is a Michael acceptor selected from: R8 R9 R9 R8 R9 N Ri0 o RIO -, N Ri0 20 0 0 0 R8 R9 R9 R9 0 R10 0 0 0 R9 R9 R10 R10 R11 n 0 00 0 where R8 is selected from H, C 1 . 4 alkyl; 25 R9 and RIO are independently selected from H, C 1 4 alkyl, C 14 alkylNR12R13, C 1 . 4 alkylOR l2, C 1 . 4 alkylhetaryl; RI I is selected from OH, OC 1 4 alkyl, NR12RI3; 2315164_1 (GHMattere) 24/08/10 73 n is 0-4; where R12 and R13 are independently selected from H, C 1 4 alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom 5 selected from 0, S, NRI4; and R14 is selected from H, C 1 4 alkyl. 2. A compound according to claim I wherein the compound of formula I is a compound of formula II: 10 O /N W X X, X3 x 2 15 or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein: X I, X 2 , X 3 , X 4 are each carbon where one is substituted with Z and the rest 20 independently with Y; or one of X 1 , X 2 , X 3 , X 4 is N, and the others are carbon where one carbon is substituted with Z and the rest independently with Y; A is a ring selected from: N N N N N N N 25 D D N D D where D is selected from H, C.4 alkyl, halogen, amino; Q is a bond, halogen, C 1 4 alkyl, 0, S, SO, SO 2 , CO, CS; 30 W is: 2315164_1 (CHMattero) 24/08/10 74 (i) NR I R2 where RI and R2 are independently H, C 1 .4 alkyl, C1.4 alkylCF 3 , aryl, hetaryl, C,4 alkylaryl, C,.4 alkylhetaryl, C 3 . 8 cycloalkyl, C 2 ., alkenyl, cyclohetalkyl, C 1 .4 alkylcycloalkyl, C,.4 alkyl cyclohetalkyl, or R I and R2 are joined to form an optionally substituted 3-8 membered ring optionally 5 containing an atom selected from 0, S, NR3; and R3 which is selected from H, C1.4 alkyl, aryl, hetaryl, Ci.4 alkyl aryl, C.4 alkyl hetaryl, COR4 where R4 is selected from H, C1. 4 alkyl, aryl, hetaryl; OR 10 (ii) H, C1. 4 alkyl, aryl, hetaryl, C 3 . 8 cycloalkyl, cyclohetalkyl, C]. 4 alkylaryl, C 1 .4 alkylhetaryl, C 3 . 8 cycloalkyl, C 1 .4 alkylcycloalkyl, C.4 alkyl cyclohetalkyl; Y is H, halogen, CN, CF 3 , nitro, OH, C,.4 alkyl, C .4 alkylNR5R6, CI4 alkylhetaryl, 15 OC 1 .4 alkyl, OC 2 .4 alkylOC1.4alkyl, OC1.4 alkylNR5R6, OC,.4 alkylhetaryl, OCI, alkylcyclohetalkyl, SC,.4 alkyl, SC 2 .4 alkylOCI. 4 alkyl, SC .4 alkylNR5R6, NR5R6, NR5COR6, NR5SO 2 R6; and R5 and R6 are each independently H, C,. 4 alkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from 0, S, NR7 and R7 is selected from H, C,. 4 alkyl, aryl, hetaryl, C,. 4 20 alkylaryl, CI4 alkylhetaryl; Z is a Michael acceptor selected from: R8 R9 R8 R9 R9 N Ri0 R10- R1 n n 0 0 0 0 25 where R8 is selected from H, C].4alkyl; R9 and R10 are independently selected from H, CIA alkyl, C 1 .4 alkylNRl2Rl3, C, . 4 alkylOR12, Cl.4alkylhetaryl; 30 RI I is selected from OH, OCI4 alkyl, NR12RI 3; n is 0-4; 2315164 1 (GHMatters) 24/08/10 75 where: R12 and R13 are independently selected from 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, and R14 is selected from H, C 1 . 4 alkyl. 5 3. A compound selected from the group consisting of: H NH NNH N ~Iy $I l~rN 9N HH -. N N H O NH NH NH HN HH NHH H $NH YO H N 7tW9741 1 H(H1attar1 9740A Au t 76 c Ng N>~ yK~? &?NQ NHNH HN 0 >o cl0 NN C Ne ~N Y,~ '-.
27043.1(GH ater) P246.UN 0 0N -ro 2701433 -N~ter)P246A 77 "N HNN HNH 0 H O HH OH N O N NN NH N0 r 0 H NH 2 G P 0 0 NNN 0i - NH0 0 0 aO~ ~ N N~ I iw y >N q ~NH 0 0 0 2708,433.1 (GHMotters) P72490 AU.I 78 H o NH0 NH 0II 0 NH /N 0 o" -- - 0 4. A compound according to any one of claims I to 3 wherein the compound irreversibly inhibits JAK-3. 5 5. A compound according to any one of claims I to 4 wherein the compound selectively inhibits JAK 3 with respect to JAK I or JAK 2. 6. A composition comprising a carrier and at least one compound according to any one of claims I to 5. 10 7. A method of treating a tyrosine kinase-associated disease state, the method comprising administering a therapeutically effective amount of at least one compound according to any one of claims I to 5 or a therapeutically effective amount of a composition according to claim 6. 15 8. Use of the compound according to any one of claims I to 5 or a composition according to claim 6 in the preparation of a medicament for treating a tyrosine kinase-associated disease state. 9. A method of treating a JAK3-associated disease state, the method comprising administering a therapeutically effective amount of at least one compound according to any one of claims I to 5 or 20 a therapeutically effective amount of a composition according to claim 6. 79 10. A method of suppressing the immune system of a subject, the method comprising administering a therapeutically effective amount of at least one compound according to any one of claims I to 5 or a therapeutically effective amount of a composition according to claim 6. 5 I1. A process for the preparation of a compound of the general formula I according to any one of claims I to 5 which comprises coupling a compound of formula LG-A-LG wherein A is as defined in claim I and LG is independently selected from a leaving group with a -Q-W moiety wherein Q and W are as defined in claim I and a - moiety in either order. 0 X,\\ /X X 2 -X 3 12. Compounds of the general formula I, compositions comprising them, methods of treatment or uses involving them or processes for their preparation, substantially as hereinbefore described with reference to any one of the examples and/or drawings. 5 13. A selective JAK3 inhibitor, substantially as hereinbefore described with reference to any one of the examples and/or drawings. 26)9241 1 (GHMattelsI P724968AU.I