ZA200602138B - Azole-based kinase inhibitors - Google Patents

Description

@® ® PCT/AU2004/0031690

AZOLE-BASED KINASE INHIBITORS

FIELD OF T HE INVENTION

The present invention relates to the field of inhibitors of proteix= tyrosine kinases.

BACKGROUND OF THE INVENTION

Protein kinases arc a family of enzymes that catalyse the phosphorylation of specific residues in proteins. In gencral protein kinases fall into several groups those which preferentially : phosphoryl ate serine and/or threonine residues, those which gpreferentially phosphorylate tyrosine resajdues and those which phosphorylate both tyrosinee and Ser/ ‘Thr residues.

Protein kinzascs are therefore key elements in signal transduction pathways responsible for trensducings extracellular signals, including the action of cytoksines on their receptors, to the nucle, triggering various biological events. ‘The many roles off protein kinases in normal cell physiology Include cell cycle control and cell growth, differen tiation, apoptosis, cell mobility - and mitoge=mnesis.

Protein kirmases include, for example, but are not limited to, members of the Protein Tyrosine

Kinase fanmily (PTKs), which in turn can be divided into the cwytoplasmic PTKs and the ’ receptor PKs (RTKS). The cytoplasmic PTKS include the SRCC family, (including: BLK; FG;

FYN; HCE; LCK; LYN; SRC;YES and YRK); the BRK Family (including: BRK: ERK, SAD; and

SRM); the =CSK faraily (including: CSK and CTK); the BTK family, (including BTK; ITK; TEC:

MKK?2 anc TXK), the Janus kinase family, (including: JAK, J-AK2, JAK3 and Tyk2), the FAK family (including, FAK and PYK2); the Fes family (including FES and FER), the ZAP70 family (including ZAP70 and SYK); the ACK family (includirmg ACK1 and ACK2); and the

Abl family (including ABL and ARG). The RTK family includes the EGF-Reccptor family (including, EGFR, HER2, HER3 and HER4); the Insulin Rece=ptor family (including INS-R and IGF1-"R ); the PDGF-Receptor family (including PDGEFRoe, PDGFRB, CSFIR, KIT, FLK2 ); the VEGSF-Receptor family (including; FLT1, FLK1 and FL=T4); the PGF-Receptor family (includings; FGFR1, FGFR2, FGFR3 and FGFR4 ); the CCK4 fasmily (including CCK4); the

MET fami: ly (including MET and RON); the TRK family (including TRKA, TRKB, and

TRKC); thme AXL family (including AXL, MER, and SKY); the TIE/TEK family (including TIE "and TIE2 ~ TEK); the EPH family (including EPHA), EPH A2,, EPHA3, EPHA4, EPHAS,

EPHA6, EEPHA7, EPHAS, EPHB1, EPHB2, EPHB3, EPHB4, E PHB, EPHBS6); the RYK family (includingz RYK); the MCK family (including MCK and TYRRO10); the ROS family (including

ROS); the RET family (including RET); the LTK family (inchoading LTK and ALK); the ROR

BE ee A ® PCT/AUI2004/001690

WO omrsosisn ® PCT/AU2004/0016 90 2. famil®y (including ROR1 and ROR); The Musk family (including Musk); the LMR family inducing LMR1, LMR2 and LMRR3); and the SuRTK106 family (awcluding SuRTK106). . Similarly, the scrine /threonine specific kinases comprise a number of distinct sub-familics=, inclu=ding; the extracellular sigrmal regulated kinases, (p42/ERK2 and p44/ERKI); Jun

NH2—terminal kinase (JNK); cA_MP-responsive element-binding protein kinases (CREBK); ¢AMP-dependent kinase (CAPEK); mitogen-activated protein kinmse-activated protein kina=se ] (MATI7K and its relatives); stresea-activated protein kinase p38/SA_PK2; mitoen-and stres=s-activated kinase (MSK); gprotein Kinases, PKA, PKB and PIC inter alia.

Additionally, the genomes of a number of pathogenic organismss possess genes encoding : 10 protein kinases. For example, Ee malarial parasite Plasmodium falciparum and viruses seach as HEPV and Hepatitis vimses appear to bear kinase related gene-s.

Tnap>propriately high protein Icinase activity has been implicated in many diseases resultiryg fromm sbriormal celular functicen, This might arise either directly or indirectly, for example= by . failure of the proper control m_cchanisms for the kinase, related #for example to mutation, ovemr-expression or inappropriate activation of the enzyme; or bygr over- ur under-producticon of cytokines or growth factors also participating in the transduceion of signals upstream oor dowernstream of the kinase, In all of these instances, selective inbibition of the action of thee kinzage might be expected to haave a beneficial effect. Diseases where aberrant kinase activity has been implicated include: tiabetes; restenosis; atherosclerosizs; fibrosis of the liver and kidmney; ocular diseases; myelc-and lymphoprolifcrative disord_ers; cancer such as prosta—t¢ can_cer, colon cancer, breast cancer, head and neck cancer, leuke mia and lymphoma; and, auteo-immune diseases such ass Atopic Dermatitis, Asthma, rheuxmatoid arthritis, Crohn's disease, psoriasis, Crouzon sy=ndrome, achondroplasia, and thasnstophoric dysplasia.

The JAK family of protein tyr-osine kinases (PTKs) play a centram] role in the cytokine dependent regulation of the proliferation and end function of sarsveral important cell type~s of thes immune system. : A cirect comparison of the four currently known mammalian J~AK family members reveeals thes presence of seven highly «conserved domaing (Harpur e224, 1992). In seeking a nomenclature for the highly conserved domains characteristic of this family of PTKs, thes 30 . classification uscd was guide by the approach of Pawson and co-workers (Sadowski ef a/, 19636) in their treatment of thez SRC homology (SH) domains. The domains have been enwancrated accordingly with most C-terminal homology domain designated JAK Homology domain 1 (Il). ‘The next dozmain N-terminal to JH1 is the Kinzase-related domain, deasignated here as the JH2 demain, Each domain is then enun—crated up to the JH7 located

® PCT/A_U2004/001690 1 at the N-terminus. The high degree of conservation of these JAK homology 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 arc © arbitrary, and may or may not define functional domains. Nonetheless, their delineation 1sa useful device to aid the consideration of thes overall structural similarity of this class of proteins. : ‘ © The feature most characteristic of the JAK family of PTKs is the possession of two

Kinase-related domains GH1 and JH2) (Wilks e44/, 1991). The putative PTK domain of |A=K1 (JH1) contains highly conserved motifs typdcal of PTK domains, including the presence oof a tyrosine residue at position 1022 located 11 residues C-terminal to sub-domain VII that ies considercd diagnostic of membership of th_e tyrosine-specific class of protein kinases.

Alignment of the human JAK] PTK domai=n (255 amino acids), with other members of tree

PTK class of proteins revealed homology vith other functional PTKs (for example, 28% identity with c-fes (Wilks and Kurban, 1988) and 37% homology to TRK Kozma ¢f a/, 15388).

The JH1 domains of cach of the JAK familys members possess an interesting idiosyncrassy/ within the highly conserved sub-domain \W/11t motif (residucs 1015 to 1027 in JAK?2) that 1s believed to He close to the active site, and Clefine substrate specificity. The phenylalanin-e and ! tyrosine residues flanking the conserved taryptophan in this motif are unique to the JAK family of PTKs. Aside from this clement, he JH1 domains of each of the members of thet JAK family are typical PTK domains.

The central role played by the JAK family of protein tyrosine kinases in the cytokine dependent regulation of the proliferation nd end function of several important cell typ=es means that agents which inhibit JAK arc 1aseful in the prevention and chemotherapy of disease states dependent on these enzymes. Potent and specific inhibitors of each of the currently known four JAK family membe as will provide a means of inhibiting the actiomn of those cytokines that drive immune pathoRogics, such as asthma (e.g. 1L-13; JAK], JAK2)®, and leukemia /tymphoma (c.g. IL-2: JAKT andl JAKS).

Furthermore, certain types of cancer suchm as prostate cancer develop autocrine product=jon of certain cytokines as a selectable mechanism of developing growth and/or metastatic potential. An example of this is cancer of the prostate, where IL-6 is produced by and stimulates the growth of prostate cancer cell lines such as TSU and TC3 (Spiotto MT, ard

Chung TD, 2000). Interestingly, levels of IL-6 are elevated in sera of patients with meteastatic prostate cancer. ’

A great deal of literature covers the area of cytokine signalling. The present inventors “have focussed on the JAK/STAT pathway that is involved in the direct connection of cytokine ee —————————————————————————E EE

® ® PCT/AU2004/0016520 receptor to target genes (such as cell eycle regulators (e.g. p21) and anti-apmaptosis genes (such amas Bcl-X)). . The JAaK/STAT Pathway , | }

The de=lineation of a particularly elegant sIgnal transduction pathway downstream of the non-pmrotein tyrosine kinase cytokine recegptors has recently been achieve. In this pathway the key components are: (i) A cytokine receptor chain (or chains) such as Sthe Interleulin-4 receptor ot the Interferon y receptor; (ii) a member (or members) of the JAK family of PTKs; (iii) a smember(s) of the STAT family of transcription factors, and (iv) a secsjuence specific

DNA =element to which the activated STAT will bind. .

A revimew of the JAK/STAT literature offcers strong support to the notion tthat this pathway is important for the recruitment and marshalling of the host immune respo=Tse to envircormental insults, such as viral and bacterial infection. This is well exemplified in Table land Table2. Information accumulated from gene knock-out experimer—its have underlined the importance of members of the JAK family to the intracellular signallizng triggered by a numbmcr of important immune regulatory” cytokines. The therapeutic possibilities stemming * from inhibiting (or enhancing) the JAK/ STAT pathway are thus largely Hn the sphere of immuzzne modulation, and as such are like:ly to be promising drugs for thee treatment of a range= of pathologies in this area, In addition to the diseascs listed in Tables 1and 2, inhibitors of JAKs could be used #9 immuinosuppresive agents for organ transplants and autoimmmune discases such as lupus, mulltiple sclerosis, rheumatoid arthmritis, Type I diabetes, autoimmmune thyroid disorders, Alzheinmer's disease and other autoimmune diseases.

Additionally, treatment of cancers such es prostate cancer by JAK inhibi—tors is indicated.

® PCT/AU2004/001690

Table 1

Atopy . . :

Allergic Asthma (Mast Cells Tell activation © -f

Atopic Dermatitis (Eczema) (Eosinophils Bells followed bey IgE

Allergic Rhinitis (T-Cells mediated activati=on of (B-Cells resident Mast cells and - Eosinophils

Cell Mediated Hyporsensittorty (I-cells .

Hypersensitivity Pneumoniti=s Co ’

Rirenmatic Diseases . :

Systemic Lupus Erythematos=us (SLB) (Monocytes Cytokine Production

Rheumatoid Arthritis (Macrophages (e.g TNE, IL-1, CSF-1,

Juvenile Arthritis (Neutrophils GM-CSF)

Sjtgren’s Syndrome (Mast Cells T-cell Activatiorm

Scleroderma (Eosinophils JAK/STAT activation

Palymyositis (T-Cells

Ankylosing Spondylitis (B-Cells

Psoriatic Arthritis . :

Viral Diseases

Epstein Barr Virus (EBV) Lymphocytes JAK/STAT Activation ’ . | Hepatitis B Hepatocytes JAK/STAT Acti vation

Hepatitis C Hepatocytes JAK/STAT Inhibition

HIV Lymphocytes JAK/STAT Activation

HTLV 1 Lymphocytes JAK /STAT Act®vation

Varicella-Zoster Virus (VZV™) Fibroblasts JAK/STAT Inhibition

FHuman Papilloma Virus (FH Epithelial cells JAK/STAT Inhsbition

EE

Leukemia Leucocytes (Cytokine prod_uction

Lymphoma Lymphocytes AK/STAT Ac=tivation

EE lee

Motor Neuron Disease Neurons Mutated SOD1

Cardiovascular Diseases

Atherosclerosis & Arteriosczlerovis | (Lymphocytes JAK/STAT Activation acrophages JAK/STAT Activation ee ————————— EEE

— 7 ——_— Vea [ ® PCT/AU20048/001690 6. (Myoepithelial cells

Cardiac Hypertrophy Cardiac Myocytes J—AK/STAT Activation oo

Ischemia Cardiac Myocytes J AK/STAT Activation

Pulmonary Hyperte.xsion Lung Epithelium BWAK/STAT Activation

-—

PS Py PCT/AU2-004/001690 7

Table 2: Dise ascs Potentially Treatable By JAK-Based Drug Therapies

Targget Disease Cytokine JAK family Strength of member Association © Asthma | MAK JAKiGgARG| +i]

JAKL&JAES2| abd] rena | wa] NGAJAR| eh]

AKIGJAXZ| err]

Toflammatory Bowel m4}! JAK1&JA K3 +t

Disease & Crohn's

Disease ‘ Leukaemia And (IL-2) | JAK3,JAKD & +++

Lymphoma JAK2

Cutancous | GM-CSF &| JAK1 & JAK2 . .. Inflammation IL-6 “Immune Suppression I-10) JAKL & TWK2 +++

B By Solid Tumour

Prostate Cancer JAK, JAK2 +t &Tyk2 n arteriosclerosis kittes ee —————————————sseESEEEEEEEREEEEEEER

® ® PCT/AU2004/001690 . SUMMARY OF THE INVENTION : ‘I'he present inventors have found that a group c»f compounds based upon the disubstituted pyrazine scaffold 1, are inhibitors of tyrosine kinases. : :

Accordingly, in a first aspect the present inventi«on provides a compound of the general formula yo i A—Q—N N D » ry

Y N

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

D is a heterocyclic ring selected from: -— ~~ NX b y kel : R2 2 where Xi, Xa, X3, X4 are optionally substituted carbon, or one of X,, Xa, Xa, Xy is . nitrogen and the rest arc optionally substituted carbon;

R2 is 0-3 substituents independently chosen from H, halogen, Ciaalkyl, CE, OCF,

OCHEF,, CN, aryl, hetaryl, C,4alkylOH, CiialkyINR3R4, Cy alkylhetaryl, OCi4alkyl,

OCy4alkyINR3R4, OC) alkylhetaryl, OC 4 alkylOH, CO:R3, CONR3R4, NR3R4, nitro, . NR3COR4, NRSCONR3R4, NR3SO:R4, €C)4alkyINR3ICOR4, Ci4alkyINRSCONR3R4,

R3, R4 are each independently Hl, Cy alkyl, Cy 4alkylOH, C,,alkyINR19R20,

Ci alkyl cycloalkyl, C., cyclohe-talkyl, aryl, C14 alkylaryl, hetaryl, C, } alkylhetaryl, or may be joined tow form an optionally substituted 3-8 membered

CC ————————————————————————————————

® ® PCT/A.U2004/001690 (saturated or ursaturated) ring optionally containing an atom selected from 0, S, NR6; and RS is selected from H, Ciyalkyl, aryl or heotaryl; Co

R6 is selected from H, Cy 4 alkyl, Crualky=INR19R20, aryl, hetaryl, C4 alkyl ary BR, Ciualkyl hetacyl;

R719, R20 are each independently selected from H, Caalkyl;

Rl is H, Cy alkyl, C4 «cycloalkyl, or may form a 5-8 renembered ring onto the ortho position of ring A;

Q isa bond, CH, Cia alkyl; :

A is ary), hetaryl opticonally substituted with 0-3 subsstituents independently chosen from halogen, Ci alksy], CF; OCFy, CN, NRSR9, aryl! hetaryl, Ciqaryl, Cyzhetaryl, Cy alkyINRSR9, OCy4alkcyINRER9, nitro, NR10C, JNREERY, NRSCOR9, NR1I0OCONRERRY,

NR8SQ,R9, CONRSRS, CORE; :

RS and R9 are each independently H, Cy alley, aryl or together form an uptionally sulostituted 4-8 membered ring wilhich may contain a heteroatorm selected from OQ, 5, NR11;

R10 is selectect from H, Cry alkyl;

R11 is mlected from H, Craalkyl; : W is selected from H,. Cy4alkyl, Caealkenyl or may feom a 5-8 membered ring onto the ortho position of rings A; where Cy salkyl or Ca calkemnyl may be optionally substitLated with Ciqalkyl, OH, OCalkyl, NR12R13; : . R12,and R13 are each independently H, C;.malkyl, or may be joined to foram an optionally sulbstituted 3-8 membered ring optionally containing an atom selected fromm O, S, NR14; ~ R14 is selected from H, Cy alkyl;

Y is 0-2 substituents ssclected from H, Cy 4 alkyl, NREL5R16;

R15 and R16 are independently sclected fromm H, Cy alkyl.

Co ———————————————————————————

® ® PCT/AUTI2004/001690

In a second aspect the present invention provides a composition comprising a carrier and a least one compound of the first aspect of thee invention. oo

Tn a third aspect the present invention provides a method of treating a tyrosine :

Kkinasc-associated disease state In a subject, the method comprising administering a therapeutically effective amount of at least one compound of the first aspect of the inventicon or a therapeutically effective amount of a ceomposition of the second aspect of the inventiorwm,

DETAILED DESCRIPTION OF THE INV=ENTION ~The present inventors have found that a group of compounds based upon the disubstituted pyrazine scaffold I, are inhibitors of tyrosire kinases.

Accordingly, in a first aspect the present ira vention provides a compound of the general formula yr

A—Q=N Ny DP

TT v § or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or 1.5 diastereomers thereof, wherein: -

D is a heterocyclic ring selected fromm:

SE i oY N

NTN NTS

=

Ny

XE, . R=2 Re where Xy, Xa, Xs, X, arc optiomnally substituted carbon, or one of Xi, Xz, Xs, Xs fis nitrogen and the rest optionamlly substituted carbon; ——————— EE ————

® ® PCT/AU2004/001690 . = 3% 2 is 0-3 substituents independently chosen from H, halogen, Ci4alkyl, CCF, OCF, «OCHF,, CN, ary), hetaryl, C,4 alkylOF], C.4alkylNR3RS, Cy aalkylhetaryl~ OCs alkyl, “OC,.4alkyINR3R4, OC,qalkylhetaryl, COC alkylOH, CO:R3, CONR3R4, I™NR3R4, nitro, “NR3COR4, NRSCONR3R4, NR350,R~4, C,.ialkyINR3COR4, Ci1calkyINRSSCONR3R4,

CiaalkyINRISO:RE;

R3, R4 are each independently~ H, C14 alkyl, CralkylOH, C: salky=INR19R20, : - C4 alkyl cycloalkyl, Ci cyclohetalkyl, aryl, Cia alkylaryl, hetary 1, Cig alkylhetaryl, or may be joined. to form an optionally substituted =-8 membered (saturated or unsaturated) rin_g optionally containing an atom scBllected from 0, S, NRé; and R5 is selected from H, Cy alkyl, aryl or hetaryl;

R6 is selected from H, Cj ,alkyl, Cy4alkyINRI9R20), aryl, he=taryl, Cia alkyl aryl, Cy alkyl hetanyl; :

R19, R20 arc cach independently selected from H, C.alkyl;

Rl is H, Cy alkyl, Cys cycloalkyl, or mnay form a 5-8 membered ring ont the ortho position of ring A;

Q isa bond, CH,, Cia alkyl; : A 1s aryl, hetaryl optionally substituteed with 0-3 substituents independently chosen from halogen, Cy alkyl, CB, OCF, CN, NR8RY, ary], hetaryl, Criaryl, Chehetaryl, Coy

Lo 20 alkyINRSR9, OC alkyINRSR9, nitrom, NR10C, {NRSRI, NRSCORY, NRL. QCONRER9,

NR8SO,R9, CONRER9, CO;R8;

RS and R9 are each independently H, Ciyalkyl, aryl or together form an optionally substituted 4-8 me=mbered ring which may contain a . heteroatom salected from O, S, NR11; 2% R10 Is selected from 11, Cy aAkyl;

R11 is selected from H, Ciyalkyl;

W is selected from H, Chaatkyl, Cr.4a Bkenyl or may form a 5-8 membered ring onto the ortho position of ring A; where Cy ymmlkyl or Cy ¢alkenyl may be optionally substituted with Ci4alkyl, OH, OC,.alkyl, NR122R13; . ee —

I SR. ® Py PaCT/AU2004/001690 12.

R12, and R13 ave each indepmendently H, Cuaalkyl, or may be joined tc form en optionally substituted 3-8 amembered ring optionally containing an artom selected from O, $5, NR14; -

R14 is selected from F3, Cia alkyl;

Y is 0-2 substituents selected from 1, C,., alkyl, NR15KR16;

R15 end R16 arc independently selected from H, Cysalkyl.

In the above description it will be appreciated that:

Ch28lkyl means an unsubstituted wor optionally substituted straight or braneched alkyl chain

Aryl means unsubstituted or opticonally substituted phenyl or naphthyl.

Heotaryl means a unsubstituted ox= optionally substituted 5- or 6-memberec®® heteroaromatic ring containing omne or more heteroatoms sclected from ©, N,S.

Cycloalkyl means a 3-8 membered saturated ring

Cyclohetalkyl means a 3-8 membmwered saturated ring containing 1-3 heterom atoms selected from O, S,NR17, where R17 is H, C14 alkyl, ary), hetaryl.

In a further preferred embodiment the compound is sclected from corapounds of the general formula IL . : vv

A N N D

J vy? N i or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms. or diastercomers thereof, wherein: } : D is a heterocyclic ring selected from:

A

® PCT/~AU2004/001690

J

2 wheree X,, Xz, Xs, Xs fire optionally substituted carbon, or one of Xi, Xa Xa Xa is N and tThe rest optionally substituted carbon; ’ R2ig 0-3 substituents independently chosen from F, halogen, Cr alkyl, CP, OCT, - OCHE,, CM, aryl, hetaryl, Cy 4alkylOH, C,.calkyINIR3R4, Cyalkylhetaryl, OCiqalikyl,

OC 4alkylINR3R4, OC alkylhetaryl, OCy.4alkylOFN, CO:R3, CONR3R4, NR3R4, mitro,

NR3COR4_, NRSCONR3R4, NR3S0;R4, C,:alkyINFR3COR4, CalkyINRSCONRTIS RS,

Ci4alkyINERISO:RS;

R3, R4 are each independently H, Ciqalkyl, Ch.alkylOH, CyinlkyINRI9RZ20,

Cra alky] cycloalkyl, C4 ¢yclohctalkyl, aryl. Ci4alkylaryl, hetaryl, Cy alk ~ylhetaryl, or may be joined to form an opotionally substituted 3-8 memkered (sa®turated or unsaturated) ring optionally ¢- ontaining an atom selected from

O, 55, NR6; ancl R5 is selected from H, Cig alkyl, aryl or= hetaryl;

R6 1s selected from H, C, 4alkyl, C;al KyINR19R20, aryl, hetaryl, C: -a alkyl aryl, Ciqalkyl hetaryl; .

R19, R20) are each independemntly selected from H, Cy qalkyl >

Rl1is H, C,_4aky}, Cy cycloalkyl, or may form a 5-88 membered ring onto the orth .o position of xing A;

A is aryl, h-etaryl optionally substituted with 0-3 substituents independently chos-en from halogzen, C,4alkyl, CF, OCF, CN, NRSRY, are], hetaryl, Ciqaryl, Ci ihetaryll, Cy alkyTINRBR_9, OC; alkyINRSRY, nitro, NR10C, 4NRER9, NRECORY, NR1I0CONRS_RY,

NRSSO,R9., CONRSRY, CORS;

RB and RJ arc cach independently H, Cy.4al kyl, aryl or together form an opt=ivnally substituted 4-8 membered ring werhich may contain a heteroatossm selected from O, 5, NR11; eect tog

® ® TPCT/AU2004/001690

R10 is selected from H, Cy. alkyl;

Ril is selected from H, Cau alkyl; : . WW is selected from H, Ciqalkyl, Caalkenyl or renay form a 5-8 membered rina g onto the « ortho pusition of ring A; where Ci.alkyt or C2_galkenyl may be optionally sebstituted with Cy alkyl, OH, OC, _aalkyt, NR12R13; "R12, and R13 are each independently 4, Crualkyl, or may be joined to form an optionally substituted 3-8 membered riding optionally containing an atom selected from O, S, NR14;

R14 is sclected from H, Cha alkyl= “Y's 0-2 substituents selected from H, Ci alkyB, NR15R16;

R15 and R16 are independently selecte=d from H, Ciqalkyl.

In the &bove description it will be appreciated that:

C,4alkyl means an unsubstituted or optionally substituted straight or bran-ched alkyl «<hain _ Aryl means unsubstituted or optionally substituted phenyl or naphthyl.

Hetaryl means a unsubstituted or optionally ssubstituted 5- or 6-memberedt heteroaromatic ring containing une or more heeternatoms selected from O, BN, S.

Cycloalkyl means a 3-8 membered saturated ing

Cyclohctalkyl means a 3-8 membered saturated ring containing 1-3 heteroatoms selected from O, S, NR17, } where R17 is 11, C4 alkyl, ary], hetaryM. .

The commpounds of this invention include all conform: ational isomers (eg, cis and txxrang : isomerzss). The compounds of the present invention haave asymmetric centers and t=herefore exist inm different enantiomeric and diastercomeric for—ms. This invention relates too the use of all apti cal isomers and stereoisomers of the compoun ds of the present invention, sand mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employe or contain them, In this regard, the invention includes both the Eand Z

FE

PS . PY PCT/AU2004/%001690 configurations. The compounds of formula I may also exist aas tautomers, This invention relates to the use of =mall such tautomers and mixturcs thereof, . 1his invention also encompasses pharmaceutical compositiormy containing prodrugs of compounds of the feormula I. This invention also encompasses methods of treating or preventing disordexss in a subject that can be treated or preve=nted by the inhibition of protein kinases, such as JAF< comprising administeting prodrugs of ccompounds of the formula I,

Compounds of fornia [ having free amino, amido, hydroxy or carbuxylic groups can be converted into procrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain Of two or more (eg, two, three or four) amreeino acid residues which are covalently juincd thmxough peptide bonds to free amino, hydr=oxy and carboxylic acid groups of compounds of fomymula I. The amino acid residues includee the 20 naturally occurring amino acids commonly designated by three letter symbols a=nd also include, 4+ hydroxyproline, hy=droxylysinc, demosine, isodemosine, 3-rexwthylhistidine, norvlin, beta- alanine, gamma-an—vinobutyric acid, citrulline, homocysteine=, homoserine, omithine and methioine sulfone. Prodrugs also include compounds wherwein carbonates, catbamates, amides and alkyl casters which are covalently bonded to the - above substituents of formula I ’ through the carburmyl carbon prodrug sidechain. Prodrugs ealso include phosphate derivatives of comgoounds of formula I (such as acids, salts ©f acids, or esters) joined through a phosphorus-oxygmen bond to a free hydroxyl of compound_s of formula I.

Tn a still further preaferred embodiment the compound possesses Schirality at the chiral carbon bearing W, where W is C4 alkyl. The compound carn be used as a purified isomer or © as a mixture of any ratio of isomers. It is however preferred that the mixture comprises at east 70%, 80%, 90%%, 95%, or 39% of the preferred isomer.

In .a second aspect the present invention provides a compos -ition comprising a carrier and at : least one compourmd of the first aspect of the invention.

In a third aspect thme present invention provides a method o=f treating a tyrosine : . kinase-associated cliscase state in a subject, the method cormaprising administering a therapeutically effacctive amount of at least one compound «of the first aspect of the invention or a therapeutically effective amount of a composition of thee second aspect of the invention.

In a further prefermred embodiment the disease state involveesJAKI, JAK2, JAKS or TYK2.

In a preferred embwodiment of the present invention the discz2ase state Js selected from the group consisting oof Atopy, such as Allergic Asthma, Atopic Dermatitis (Eczema), and

Allergic Rhinitis; Cell Mediated Hypersensitivity, such as Am llergic Contact Dermatitis and tg =

Claims (14)

1. A compound of the ggeneral formula (I) vor A—Q —N N D AN T YT y N I or pharmaceutically acceptabl e prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, whereim: D is a heterocyclic rings selected from: ~~ PAS — PAN N N N X4 Xa \ SE \} ’r / hr \7 R17 R2 R2 where X;, X,, X=, X, are optionally substituted carbon, or one of X;, X,, Xs, X4 1s nitroge n and the rest optionally substituted carbon; R2 is selected from thes group consisting of CN; NR18R19 wherein BR18 and R19 are joined to form an optionally substituted 3-8 membered (saturate=d or unsaturated) ring optionally containing an atom selected from O, S, NR6; an optionally substituted 3-8 membered (saturated or unsaturated) ring containing 2- AME=NDED: 24 APRIL 2007

5S nitrogen atoms; an unsubstituted or optionally substituted 5-membered eteroaromatic ring containing one or more hete=roatoms selected from O, IN, S; an unsubstituted or optionally substituted 6-menbered heteroaromatic ring containing two or more heteroatoms selected frosm O, N, S; MR 17 is 0-2 substituents independently chosen from H, halogen, C4 alkyl, CFs, COCF;, OCHF,, CN, aryl, hetaryl, C, 4 alkylOH, &C,_jalkyINR3R4, CC ialkylhetaryl, OC, 4 alkyl, OC,_salkyINR3R4_ OC, salkylhetaryl, OC,.4 alkylOH, CO,R3, CONR3R4, NR3R4, nitro, NER3COR4, NR5CONR3R4, INR3SO;R4, C,4alkyINR3COR4, C, 4alkyINRS&CONR3R4, C; 4alkyINR3S O,R4; R3, R4 are each independently H, C,.4 al kyl, C,.4alkylOH, C,. 4alkyINR19R20, C,_4 alkyl cycloalkyl, C 14 cyclohetalkyl, aryl, C.4 alkylaryl, hetaryl, C4 alkylhetaryl, or m ay be joined to form an optionally substituted 3-8 membered (saturated or unsaturated) rings optionally containing an atom selected fimom O, S, NR6; and RS is selected from H, C,4 alkyl, ary] or hetaryl; R6 is selected from H, C4 alkyl, CC 4alkyINR19R20, aryl, hertaryl,

Ci.4 alkyl aryl, C4 alkyl hetaryl; R19, R20 are each indepencdently selected from H, C;__4alkyl; RR1 is H, C4 alkyl, Ci cycloalkyl, or may form a 5-8 membered ring onto the ortho position of ring A; (Qs a bond, CH, C, 4 alkyl; AMENDED: 224 APRIL 2007

A is axyl, hetaryl optionally substituted with_ 0-3 substituents independently~ chosem from halogen, C4 alkyl, CF3;, OCF3,. CN, NR8RY, aryl, hetaryl, C,.=aryl,

Ci.she=taryl, C4 alkyINR8RI, OC, 4 alkyINFR8RY, nitro, NR10C,; 4NRERSY, NR8CZORY9, NR1I0OCONRERY, NR8SO,R9, @ ONR8RY9, CO,RS,; R8 and RY are each independently HF, C4 alkyl, aryl or together for—m an optionally substituted 4-8 membered ring which may contain a heteroatom selected from O, S, NRL I; R10 is selected from H, C;_4alkyl; R11 is selected from H, C,.4al kyl; W is selected from H, Cy.4alkyl, Cosalkenyl or may form a 5-8 membered r—ing onto the ortho position of ring A; where C;_4alkyl or C;.salkenyl may be optiorally substituted with C,.salkyl, OH, OC, salkyl, NR12R13; R12, and R13 are each independently H, C,_salkyl, or may be joineed to form an optionally substituted 3-8 membered ring optionally contai” ning an atom selected from O, S, NR14; R14 is selected from H, C,.4 alkyl; Y is O -2 substituents selected from H, C4 a_lkyl, NR15R16; R15 and R16 are independently sele=cted from H, C,4alkyl; or a compourd selected from the group consisting eof: AMENDED: 24 APRIL 2007

H — H — a we S ve woh, TY LL Jd \ me NI TN o a Ch id /=N H J=N NN M N NN 198 Ty 3 /=N UA /=N ~N x SN ord Mer Dr Dn LK Ne Na 10's TAR eas NH [0] Ne oe PI AN AMENDED: 24 APRIL 2007

= _N N N Lo = “1 = NY Nx xn Na J | pl HO N HN _N ~ ~

N No _N o) ES | XX Ho ni ou Ty i Xg—" = " pr” 0 The 0) ~~ J oJ _N aN Or N AMENDED: 24 AP=RIL 2007

F pO ni) ==N IAN Sy 51 0 | = N YY oH F F == H /=N [SN NN “rer wy o) So N x N L GN ] F =N Up Na ‘S H N VAR ON > y NT NY § NH AMZENDED: 24 APRI 12007

] F Uppy Ta /=N NN > 6} TY @ N= ©) = F =N /=N N Ny "a Us AN TY oJ NZ

~. _-NH N NN SIN F J=N a) N 7 : N H /=N N N N HO 1 bi = Ho N

F

F. N Nag a ’ /=N T I N N N _— 10h e Pp x UN Or AMENDEILD: 24 APRIL 2007

Ta Ue [Shel OH Cs @ TOL =) Nex N Nao N To [=p N N aaa - He NN Ths NN 3

OD . AMENDED: 24 AF>RIL 2007

- F /=N /=N N N N NN jo.

AN hay ops [ge y @ NNN F LL N a —=N = Uy ~ N or Qu 101 ~ Ke F F N Na N N Ne N _ Or TY H /=N H /=N N N N 1 NNA = NA & Nao | = x F F H /=N H /==N No _N_ _N N N_ _N he x = T = NN 2 Nao | PZ A AMENDED: 24 APRIL 2007

2. A compound according to formula (I) ©f claim 1, wherein the compound is select ed from compounds of the general formula (II): Ww PR A N ~~ D xX T J vy ~ II or pharmaceutically acceptable prodrugs, salts, Inydrates, solvates, crystal forms or diastereomers thereof, wherein: D is a h-eterocyclic ring selected from: Xq Xe A} 7 n> R17 R2 w “here X;, X3, Xa, X4 are optionally substituted carbon, or one of Xi, X;, X35, Xj is nitrogen and the rest optionally substituted carbon; R2 is se=lected from the group consisting of CN; NR18R19 wherein R18 and R19 are joimed to form an optionally substituted 3-8 membered (saturated or unsatur—ated) ring optionally containing aan atom selected fromm O, S, NR6; an optionaally substituted 3-8 membered (saturated or unsaturated) ring containing 2- nitrogzen atoms; an unsubstituted or op tionally substituted S-membered AMENDED: 24 APRIL 2€007 heterozaromatic ring containing one or more heteroatoms selected from O, N, S; an uns ubstituted or optionally substituted 6-memi>ered heteroaromatic ring contaiming two or more heteroatoms selected fromm O, N, S; R17 is. 0-2 substituents independently chosen frorm H, halogen, C, 4 alkyl, CF3, OCF3;, OCHF,, CN, aryl, hetaryl, C,4alkylOH, C ;.;alkyINR3R4,

C,.4allxylhetaryl, OC, 4 alkyl, OC, salkyINR3R4, COC, salkylhetaryl, OC,4 alkylOH, CO;R3, CONR3R4, NR3R4, nitro, NR 3COR4, NRSCONR3R4, NR3S=Q;R4, C,4alkyINR3COR4, C,4alkyINRSC ONR3R4, C,4alkyINR3SO,R4; R3, R4 are each independently H, C, 4 alk yl, C,.salkylOH, C;. salkyINR19R20, C,.4 alkyl cycloalkyl, C;. 4 cyclohetalkyl, aryl, C4 alkylaryl, hetaryl, C, 4 alkylhetaryl, or ma y be joined to form an optionally substituted 3-8 membered (satvarated or unsaturated) ring optionally containing an atom selected from O, S, NR6; and RS is selected from H, C4 alkyl, aryl or hetaryl; R6 is selected from H, C4 alkyl, C; _4,alkyINR19R20, aryl, hetaryl,

Ci.4 alkyl aryl, C,.4 alkyl hetaryl; R19, R20 are each independe=ntly selected from H, C,.salkyl; R1 is EH, C4 alkyl, Ci gcycloalkyl, or may form a_ 5-8 membered ring onto the ortho position of ring A; A is aryl, hetaryl optionally substituted with 0-3 substituents independently choser from halogen, C;.4 alkyl, CF3;, OCF;, CN, NRB8ROY, aryl, hetaryl, Caryl, AMENDED: 24 APRIEL 2007

Ci.shetamryl, C4 alkyINR8RY, OC; 4 alkyINR8RY, nitro, NR10C, 4sNR8RY, NR8CO_R9, NR1I0CONRSRY, NR8SCO,R9, CONRERY, CO,RS; MR8 and R9 are each independ ently H, C,.4 alkyl, aryl or together form an coptionally substituted 4-8 membered ring which may contain a Hheteroatom selected from O, S,NR11; TRI10 is selected from H, C; 4 alkyl; R11 is selected from H, C; alkyl; W is sel ected from H, C;_4alkyl, C,.¢alkenyl or may form a 5-8 membered ring onto thes ortho position of ring A; where C,.4alkyl or C,.¢alkenyl may be optionally substituted with C,_4alkyl, OH, OC;.4alkyl, NR12R13; “R12, and R13 are each indep endently H, C,.salkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, INR14; R14 is selected from H, C4 alkyl; Y is 0-2. substituents selected from H, C, 4 alkyl, NR15R16; R15 and R16 are independently selected from H, C,.4alkyl.

3. A comp~ound according to claim 1 or claim 2 wherein R2 is selected from the groupm consisting of CN; NR18R19 wherein R18 and R19 are joined to form an optiomnally substituted 3-8 membered (saturated or unsaturated) ring optionally conta ining an atom selected from QO, S, NR6; an unsubstituted or optionally substi tuted S-membered heteroaromatic ring containing one or more AMENDED: 24 APRIL 200)7 hete roatoms selected from O, N, S; an unsubstituted or optionaBR ly substituted 6- menmbered heteroaromatic ring containing two or more heteroat_oms selected from O, N, S;

4. A compound according to claim 3 wherein R2 is selected from CN and tetrazole.

5. A compound according to claim 1 selected from the group consissting of: ==N H /=N N N No @ N N Nd NT NT Il If N N 2 > yp N_ _N_ _N No _N_ Nd ) ry J 1o8 JTC XN AY AMENDED: 24 APRIL 2007

VWVO 2005/054230 PCT/~AU2004/001690 on A) SN ) T J N N N PP T x N © I Sy N = N | N N aa NN xn ZZ J LH x NZ Nx ry = Se F /=N Ri NN w anaes N ! S AMEND= ED: 24 APRIL 2007

H /=N N Na N 0 Apa F TC I i Sw H /=N N N N ANS 154 We > A TIL

P . Sy F —=N \ io Ne J A YY BD N F = Sy I AMNMMENDED: 24 APRIL 2007

F H /—==N F N N N LS YY ry v N Nn

F. " J=—=N H /=N c Nx N

F. N N > 0 F NZ I =, \ F N . N N N JL, X by ~ Sm == 7“

SN . N N N 0 AN ory 0 F F F N Il N AMEND ED: 24 APRIL 2007

H ~=N ” =N NY" oo AD N N= DAN Z Ee Su =N H J=N 9@ Na @ PN TY ir N Hoon NA =N SOPs Of ® “ ~ Sw bl H /=N H /=N N.

Na N tn 161 T s _ Sy I AMENDED: 24 APRIL 2007

IN o es N N N XY N =, | l =N Ne yo H = TY {nn s ory = AY NS _—N Dan By py

BON. ON T J = pf o ) Z N \ \ \ —N H ~ N N N XX es OY AS N A N AsMENDED: 24 APRIL 2007

_-N aN X py T J ol \ 4 _—N \ H ~ —N N.

N N ory TRG

J ‘ A Ne Sn \

—N = J Tr —0 H /~N Ur CL J Zz Sy AMENDED: 24 APRIL 20077

_N H ~ F No _N_ _N 4 FU = N W N H =—N oy NY AY —N g ’ B AD = AN N H /=N HTN J NY SN A= MENDED: 24 APRIL 2007

= =N Ren a N NS VC ry J Ne nN SUT a = XX ry AY H =N H f— rh one oN ry Tr nN vo 0=3=0 _/ NNN o Ph H (®] Ny H ==N QW H Mo _N So /=\ No _N N ® ) ) 8 AMENDED: 24 APRIL 2007

} /=na SN: /=N NN a LN OY YOY Ler? Geet UL TTTO No Ce ( JO Nn NZ =N AN _N ert “Aes ~ ) y RS RE NS Ne i Sas or

= oN S T NO xg” —N = A = NH 0 NN and N J OC —N H ~ N N N AN aul 8 N F H /=N Ls §! Ao N N = NG OT 0) CH A_MENDED: 24 APRIL 2007 pry, rrp N N N wh, TER N

L Q.

F. /=N i rey Ts nor b [eae NTS N N iP! oy E H /=N NNN Nd TJ Ta NN 3, SAG 0) N 0) AMENDED: 24 APRIL 200 7

F F =N /=—N NN ‘a Ths Nae Tr or p> N N Sa > AN F /=N N Ne N Tr - N H /=N N N N HO J C3

Ho. Nl F H =m F N Ny N y a T J O° P Ne > _N on F Can

N_. _N_ _N A Ty CL, oH AMEMNDED: 24 APRIL 2007

F F hs Ne 0) po Ne So) [ERs [=p F F Th NN) Ta nA 104 = Tr 0 ¢ O HO ~— F F N a N My . <r PS AMENDEND: 24 APRIL 2007

F /~=N K Na N F. T H /=N i Shel = N N il N = NH HN——N N= H /==N F No NM ~ TTT

H

N. Ne N NE NH 19] ped AMENDED: 24 APRIL 2007

F F H / H N= hts N Ths \ v® Pe TT PZ H /==N H /=N N N N N Ne N Oe TJ F F H /=N H /=N N N N N N T == = T = = SN

6. A compound according to claim 1 selected from the ggroup consisting of 6-(1H-Benzimid._azol-1-yl)-N-benzylpyrazin-2-amine , 6-(1H-Benzimid. azol-1-yl)-N-[(1R)-1-phenylethyl]py-razin-2-amine, 6-(1H-Benzimid azol-1-yl)-N-[(1S)-1-phenylethyl]pyrazin-2-amine, 1-(6-{[_ 1- (3-Fluorophenyl Dethyl]amino } pyrazin-2-yl)- 1H-benzimidazole-5-carboxanide, 1-(6-{[1-(3-Fluo-rophenyl)ethyl]Jamino } pyrazin-2-yl)— 1H-benzimidazole-6- carboxamide, 1-C 6-{[1-(3-Fluorophenyl)ethyl]amino} pyrazin-2-yl)-1H- benzimidazole-6—carbonitrile, 1-[{6-(3,4-Dihydroisoqueinolin-2(1H)-yl)pyraz=in- 2-yl]-1H-benzim. idazole-5-carbonitrile, 1-[6-(3,4-Dihydroisoquinolin-2(1H)- yl)pyrazin-2-yl]- 1H-benzimidazole-6-carbonitrile, 1- {6-[(1S)-1,2,3,4- TetrahydronaphtBhalen-1-ylamino]pyrazin-2-yl}-1H-b€enzimidazole-5- carbonitrile, 1-{6=~[(1S)-1,2,3,4-Tetrahydronaphthalen -1-ylamino]pyrazin-2— yl}-1H-benzimid azole-6-carbonitrile, AMENDED: 24 APRIL 2007

1-(6-{[(1S)-1-Phenylethyl]amino}pyrazin-2-yl)-1H-benz=imidazol-5-amine, 1-(6-{{(1S)-1-Phenylethyljamino}pyrazin-2-yl)-1H-benz=imidazol-6-amine, N-[1-(6-{[(1S)—1-Phenylethyl]amino } pyrazin-2-yl)-1H-b enzimidazol-6-yl]- 2,2-dimethylpropanamide, N-[1-(6-{[(1S)— 1-Phenylethyl]amino} pyrazin-2-yl)-1H-b enzimidazol-5-yl]acet amide, N-[1-(6-{[(1S)~- 1-Phenylethyl]amino } pyrazin-2-yl)-1H-beenzimidazol-5-yl] methanesulfonamide, 2-(S-a-Methylbenzylamino)-6-(5-(N-methylpiperazin-4-=yl-methyl)-benzimida zo-1-yl)-pyrazire, [1-(6-{[1-(4-Fluorophenyl)ethyljamino }pyrazin-2-yl)-1H- benzimidazol-5 —yl]methanol, and [1-(6-{[1-(4- Fluorophenyl)ethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl methanol and N-[1-(4-Fluorophenyl)ethyl]-6- {6-[(4-methylpiperazin-1- yl)methyl]-1H- benzimidazol-1-yl}pyrazin-2-amine.

7. The compound: F N = " r N N N bo T J FF N or a pharmaceutically acceptable prodrug, salt, hydrate, solvate, crystal form or diastereomer there of.

8. The compound: AMENDED: 24 APRIL 2007 r H N N N AA CTT N \! or a pharmaceutically acceptable prodrug, salt, hycdrate, solvate, crystal form or diastereomer thereof.

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

Use of a compoumd according to any one of clairms 1 to 8 or a composition according to clairm 9 in the preparation of a med cament for the treatment of a tyrosine kinase-asssociated disease state in a subjeect.

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

12. Use according to claim 10 or 11, wherein the diss ease state is sel ected from the group consisting of Atopy, Cell Mediated Hypersensitivity, Rhesumatic Diseases, Other autoimmune diseases, Viral disesases, Cancer, Neurodegenerati~ve Diseases, and Cardiovascular Diseases.

13. Use of a compound according to any one of claimms 1 to 8 or a ceomposition according to claiam 9 for use in the preparation o f medicaments for the treatment of JAKZ -associated disease states. AMENDED: 24 APRIL 2007

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

AMENDED: 24 APRIL 2007