AU2006201177A1 - Heterocyclic compounds - Google Patents

Description

21-MAR-2006 17:01 PHILLIPS ORMONDE FITZPATRICK NO. 3858-P.

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged; Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: S*BIO Pte Ltd Actual Inventor(s): Pek Ling Lye, WelPing Deng, Ken Chi Lik Haishan Wang Address for Service and Correspondence: Lee, Eric T. Sun, Dizhong Chen, Niefang Yu, PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Oa A9 fr t 4t Invention Title: HETEROCYCLIC COMPOUNDS Our Ref 768903 POF Code: 469642/469642 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:01 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 6 2 o HETEROCYCLIC COMPOUNDS 0 This application claims priority from United States of America Patent Application No. 60/714,827 on 8 Septembe 2005, the contents of which are to be taken as SIncorporated herein by this reference.

FIELD OF THE INVENTION [0001] The present invention relates to hydroxamate compounds that are inhibitors of histone deacetylase (HDAC). More particularly, the present invention relates to benzimidazole containing compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders o 10 as well as other diseases involving, relating to or associated with enzymes having \hislone deacetylase (HDAC) activities, o BACKGROUND OF THE INVENTION C [0002] Local chromatin architecture is generally recognized as an important factor in the regulation of gene expression. The architecture of chromatin, a protein-DNA complex, is strongly influenced by post-translational modifications of the histones which are the protein components. Reversible acetylation of histones is a key component in the regulation of gene expression by altering the accessibility of transcription factors to DNA. In general, increased levels of histone acetylation are associated with increased transcriptional activity, whereas decreased levels of acetylation are associated with repression of gene expression [Wadem P.A. Hum. Mol. Genet. 10, 693-698 (2001), De Ruijter A.J.M. et al, Biochem. 370, 737-749 (2003)], In normal cells, histone deacetylases (HDACs) and histone acetyltransferase together control the level of acetylatlon of histones to maintain a balance. inhibition of HDACs results in the accumulation of acetylated histones, which results in a variety of cell type dependent cellular responses, such as apoptosis, necrosis, differentiation, cell survival, inhibition of proliferation and cytostasis.

[0003] Inhibitors of HDAC have been studied for their therapeutic effects on cancer cells. For example, suberoylanilide hydroxamic acid (SAHA) Is a potent inducer of differentiation and/or apoptosis In murine erythroleukemia, bladder, and myeloma cell lines [Richon V.M. et al, Proc. Natl, Acad. Sci. USA, 93: 5705-5708 (1996), Richon V,M. et al, Proc. Natl. Acad, Sci. USA, 95: 3003-3007 (1998)]. SAHA has been shown to suppress the growth of prostate cancer cells in vitro and in vivo [Butler L.M. et al, Cancer Res, 60, 5165-5170 (2000)]. Other inhibitors of HDAC that have been widely studied for their anti-cancer activities are trichostatin A (TSA) and trapoxin B [Yoshida M. et al, J. Biol, Chem., 265, 17174 (1990), Kijima M. et al, J. Biol. Chem., 268, 22429 (1993)]. Trichostatin A is a reversible inhibitor of mammalian HDAC. Trapoxin B is a cyclic tetrapeptide, which is an irreversible inhibitor of mammalian HDAC. However, Y;I~wsmlU NO DILrIuEMR

D

5l AU Imd Pmiuaaal Ploal FIT~a COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:02 PHILLIPS ORMONDE FITZPATRICK NO. 3858--P. 7 3

O

O due to the in vivo instability of these compounds they are less desirable as anti-cancer 0 drugs. Recently, other small molecule HDAC inhibitors have become available for clinical evaluation [US6,552,065]. Additional HDAC inhibiting compounds have been Sreported in the literature [Bouchain G. et al, J. Med. Chem., 46, 820-830 (2003)] and patents [WO 03/066579A2]. The in vivo activity of such inhibitors can be directly

C

monitored by their ability to increase the amount of acetylated histones in the biological sample. HDAC inhibitors have been reported to interfere with neurodegenerative processes, for instance, HDAC inhibitors arrest polyglutamlne-dependent neurodegeneration [Nature, 413(6857): 739-43, 18 October, 2001]. In addition, HDAC O 10 inhibitors have also been known to inhibit production of cytokines such as TNF, IFN, IL- 1 which are known to be implicated in inflammatory diseases and/or immune system disorders. Biol. Chem. 1990; 265(18): 10230-10237; Science, 1998; 281: 1001c 1005; Dinarello C.A. and Moldawer L.L. Proinflammatory and anti-inflammatory cytokines in rheumatoid arthritis, A primer for clinicians, 2 nd Edition, Amergen Inc., 2000].

[0004] Nevertheless, there is still a need to provide further HDAC inhibitors that would be expected to have useful, improved pharmaceutical properties in the treatment of diseases such as cancer, neurodegenerative diseases, disorders involving angiogenesis and inflammatory and/or immune system disorders. With a view to meeting this need a number of small organic moiety scaffolds have been investigated including a number of heterocyclic systems, especially bicyclic heterocyclic ring systems. One heterocyclic system that has been investigated has been the benzimidazole ring system, We have now found that judicious selection of the substituents on the 5 membered ring of the benzimidazole ring system leads to the production of a family of compounds with improved pharmacokinetic properties when compared with the compounds of the prior art. The compounds within the family exhibit microsomal stability and thereby demonstrate improved half lives in the plasma when compared to the compounds of the prior art. The compounds within the family typically provide a longer duration of action due to the increased in vivo exposure area under the curve, AUCo.bM) thereby yielding improved tumor growth inhibition profiles in the xenograft models.

SUMMARY OF THE INVENTION [0005] In one aspect the present invention provides a compound of the formula VWMU I NO DBLJTWlaSol AU Srhid ldnpi PlpM N riltdAd COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:02 PHILLIPS ORMONDE FITZPATRICK NO. 3858---P. 8 00 N A 4 R2 N O-R4 I Y R1 Formula (1) wherein [0006] R' is an optionally substituted heteroaryl group, an optionally substituted heterocycloalkyl group or a group of formula: 0 INO -(CR 'R 1 )m(CR 22

R

3 )n(CR 4

R"),-NRMR";

[0007] R 2 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkoxyalkyl, R"S(0)2R-, R 1

"C(O)N(R

12

)R'

3

R

1 SO0 2

N(R

12

R"

1

N(R

1 2

)C(O)R

3

R"N(R

12

)SO

2

R'

3 R"N(R)12C(O)N(R')R 1 and acyl, each of which may be optionally substituted; [0008] R3 is selected from the group consisting of H, C 1 alkyl, and acyl, each of which may be optionally substituted; [0009] X and Y are the same or different and are independently selected from the group consisting of; H, halogen, -CN, -NO 2 -CF3, -OCF 3 alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylarnino, sulfonyl, alkyisulfonyl, arylulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, COOH -COR 5 -SH, -SRI, -ORO acyl and -NR 7

R

8 each of which may be optionally substituted; [0010] each R 4 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; Y:IWINK NO DELlMRWISM AU dl l htaolul Find as fL4 COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:02 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 9

INO

o [0011] each RI is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; [0012] each Re is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyf, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cydloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each of which may be optionally substituted; o cio NO [0013] each R' and Re is independently selected from the group consisting of: H, 0 alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; [0014] each R" and R' 2 Is independently selected from the group consisting of H, alkyl, alkenyl, and alkynyl, each of which may be optionally substituted; [0015] each R" 1 is a bond or is independently selected from the group consisting of: alkyl, alkenyl, and alkynyl, each of which may be optionally substituted; [0016] each Ra 21 R, R23, R24 and R2 is independently selected from the group consisting of: H, halogen, -CN, -NO 2 -CF, -OCF 3 alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyr, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalky, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy heteroaryloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, aminosulfonyl, aryisulfonyl, arylsulfinyl -COOH, -C(0)OR COR', -S8, -SRO, -OR' and acyl, each of which may be optionally substituted; or R" and R 2 1 when taken together may form a group of formula =0 or =S, and/or R2 and R 2 3 When taken together may form a group of formula =0 or =S, and/or R" and R2 when taken together may form a group of formula Q=0 or =8; W1r UIINO DETCHPIO4b AU Vi%4Mlldau nul N P UM A ld.dpa

V!

COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:03 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 6

\O

0 [0017] each R28 and R 27 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, aryiheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, O io alkylaminocarbony], sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, O aminosulfonyl, SR' and acyl, each of which may be optionally substituted, or Ra and R 27 when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group; [0018] Z is a bond or is selected from the group consisting of -CH2-, -CH2CH-, -CH=CH-, %-C 6 alkylene, CrCs alkenylene, CarC alkynylene, Cr-C, cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of 01-C4 alkyl: [0019] m, n and o are integers independently selected from the group consisting of 0, 1, 2, 3 and 4; [0020] or a pharmaceutically acceptable salt or prodrug thereof.

[0021] In one embodiment of the invention R 4 is H and the compounds are those of formula (la) R2 23 1 9H N, y R3,R ,O R1 Formula (la) [0022] or a pharmaceutically acceptable salt or prodrug thereof [0023] wherein R 2

R

3 X, Y and Z are as defined for compounds of formula [0024] In another embodiment R 3 and R 4 are H and the compounds are of formula (Ib): YMuiA NDDEBLI o efPa iAU EIi n Pid lPMIk S Fild MI COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21,MAR, 2006 17:03 PHILLIPS ORMONDE FITZPATRICK NO. 3858~ P. 11 7 0 x 0 N

OH

N R' Y

H

c Formula (Ib) [0025] or a pharmaceutically acceptable salt or prodrug thereof S[0026] wherein R 1

R

2

R

3 X, Y and Z are as defined for compounds of formula

(O

o [0027] As with any group of structurally related compounds which possess a C particular utility, certain groups are preferred for the compounds of the Formula (ia) and (Ib) in their end use application.

[0028] In one embodiment the group R 1 is a group of formula -(CRR2 ),,-(CR"R2)n-(CR"Ra).NR 2

R";

[0029] in which m, n and o are Integers independently selected from the group consisting of 0, 1, 2, 3 and 4; [0030] Accordingly in one embodiment the compounds of the invention are compounds of formula (Ic): R2 <Qz

'O-R

4 N Y

R

1 Formula (Ic) wherein R 1 is a group of formula -(CR2R 2

R

1 )(CRR2)n-( R )-N4RR2a7 [0031] and R 2

R

4 X, Y, Z, R 2 RR, R R 2 RI, R 2

R

27 m, n and o are as defined for compounds of formula YulatWJ N4 Di lBTPLf FIO R I AU Sedwl Pidmla Panlun l ild.g COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:03 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 12 8 [0032] As the values of m, n and o are integers ranging from 0 to 4 the sum of m+n+o is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, and 12. In one embodiment the sum of m+n+o is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8. In another embodiment the sum of m+n+o is an integer selected from the group consisting of 0, 1, 2, 3 and 4. In another embodiment that the sum of m+n+o is an integer selected from the group consisting of 2 and 3.

[0033] In one specific embodiment the sum of m+n+o is 2. When this occurs R 1 is to selected from the group consisting of:

-(CR

2 0

R

21

)-NR

2

R

2 7 -(CRR)a-NRR 27

R"R

2 -(CR4R=')-(CRR')-NR2"R 7 -(CRR2'1)-(CRR25)-NR21R2 7 -(CR2R 2 3)-(CR4R )-NR2R27; [0034] In one form of this embodiment R 1 is the group:

.(CRR

2 1

)-(CR

22

R

2 s

-NR

e

R

2 [0035] This provides compounds of the formula (II): Formula (II) [0036] wherein X, Y, Z, R, R 4

R

20

R

2 1 R2, R 2 3 R and R 2 are as defined in formula [0037] In a specific form of this embodiment R is H which provides compounds of formula (lla); Y;AMtN lNO Mbr lt uo Au seemd aidmua i u Pal de COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:03 PHILLIPS ORMONDE FITZPATRICK NO. 3858~-P. 13 Formula (Ila) [008] wherein X, Y, Z, R 2 R, R 1

R

2

R

2 R, R 2 and R 27 are as defined in forrnula [0O39] In another specific form R 3 is H leading to compounds of formula (lib): Formula (lib) [0040] wherein X, Y, Z, R 2

R

2 0 R21, R 22 Rv, R 2 and R 2 7 are as defined in formula [0041] In an even more specific form of this embodiment R 2 R, R 2 1 and R 2 are H proidding compounds of formula (lic): [0042]

I

Formula (lIc) wherein X, Y, Z, R2, R 2 6 and R 7 are as defined in formula IWaMeA NO MIUrLIOe.S AU Mee PmmiiU1 al.. KalA COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 121. MAR. 2006 17:04 PHILLIPS ORMONDE FITZPATRICK -NO. 385K' P. 14 [0043] In another embodiment the sum of m+n+o is 3. When this occurs R 1 is selected from the group consisting of:

-(CR

2 0

R

2 1 )s-NRaR 2 7;

-(CR

22 Ra-NRR2;

-(CR

2 4F 2 1 )3-NRR 2 2RRR; R2a)-NR 2R27 -(CR2R 2 )ra(CR 1

R

2 6 ")-NR2R 7

-(CR

2

OR"

21

)-CR

2 2 R2)-NRR 27 -(CR"Ru1)C-(CR"R")-NReRr; -(CRR21)-(CR 2R21)2-NR2eR27; -(CR222 _(CR2 4Ra)2-NR R 27;

-(CR

2 0

R

2 1 )-(CR2R2)-(CR 24 R25)-N RrR 2 7; [0044] In one form of this embodiment R' is a group of the formula: ')-RRaR )-(CRR)-(CR2R25)-NR2R2.

[0045] This provides compounds of the formula (III): x R2 Z O-R4

R

2 0 Y C4 R R22 R22' .24 R23 R27 Formula (III) [0046] wherein X,Y, Z, R 2 R, R 4

R

2

R

21

R

2

R",R

2 4 R2, R 2 and R27 are as defined In formula [0047] In a specific form of this embodiment R4 is H which provides compounds of formula (Ilia).

YAhdeMKI NOD DPLETaMPWP95 AU faud nvidmI1l Pinul a ldea COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:04 PHILLIPS ORMONDE FITZPATRICK NO. 385B-P. Formula (Ilia) [0048] wherein X,Y, Z, R 2 R R 4 R4, R2 R 21 R"3,R 2 R25, R and R 2 7 are as defined in formula [0049] In another specific form R 3 is H leading to compounds of formula (Illb): Formula (Illb) [0050] wherein X,Y, Z, R 2 R, R 4

R

2

R

2 1

R

2

R,R

2 4 R R 2 and R 27 are as defined in formula [0051] In an even more specific form of this embodiment R 2 0

R

21

R

24

R

2 are H, and

R

22 and R 3 am methyl providing compounds of formula (Illc).

YVMWmWA NO DELBTWP1OSN AU SOWNPi.* lntu ~Lhdoe COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21, MAR, 2006 17:04 PHILLIPS ORMONDE FITZPATRICK NO, 385B- P. 16 12 §X 0s\ ,H x /H VaV 0N ^4 s

Y

N--.R26

R

27 Formula (lilc) 0 [0052] wherein X,Y, Z, R 2 R, R 4 R R R, R 3

,R

2

R

2 and R 27 are as defined in formula [0053] In each of the above embodiments of the invention Rn and R 1 may represent a number of different variables. In one embodiment R4 and R 21 are independently selected from the group consisting of H, alkyl, alkenyl and alkynyl. In another embodiment R 2 and R 2 1 are independently selected from the group consisting of H and aikyl. In a specific embodiment R1 and R 21 are both H.

[0054] In each of the above embodiments of the invention R 22 and R' may represent a number of different variables. In one embodiment R 22 and R 23 are independently selected from the group consisting of H, alkyl, alkenyl and alkynyl, In another embodiment R and R 2 3 are independently selected from the group consisting of H and alkyl. In a further embodiment R 22 and R' 0 are independently selected from the group consisting of alkyl. In a most specific embodiment R 2 2 and R" are both methyl.

[0055] In each of the above embodiments of the invention R 4 and R 2 1 may represent a number of different variables. In one embodiment R 2 4 and R 25 are preferably independently selected from the group consisting of H, alkyl, alkenyl and alkynyt. In another embodiment R 2 4 and R 25 are independently selected from the group consisting of H and alkyl. In a specific embodiment R 4 and R 25 are both H.

[0056] In each of the above embodiments there are a number of values for Rm and

R

2 7 In one embodiment R and R 2 7 are independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, alkoxyalkyl, and acyl. In another embodiment

R

2 and R2 are independently selected from the group consisting of: H, alkyl and acyl.

Y;'MYuMlKI 2O DELEBTIIM. AU SeOl Pn.iUd siL rn P l ite COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:04 PHILLIPS ORMONDE FITZPATRICK- NO. 3858---P. 17-

I

13

NO

o In a further embodiment R2' and R 2 7 are independently selected from the group consisting of H, methyl, ethyl, isopropyl, propyl, 2-ethyl-propyt, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, Z-ethyl-butyl, pentyl, 2-methyl, pentyl, pent-4-enyl, hexyl, heptyl, octyl, acetyl and 2-methoxy-ethyl.

10057] In another embodiment R 1 is a heterocycloalkyl group which may optionally be substituted.

4 [0058] In one form of this embodiment the heterocycloalkyl group is selected from the group consisting of: cI IN, R 2 R28 R2 [0059] wherein R2B is selected from the group consisting of H, halogen, alkyl, alkenyl, is alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cyclolkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, hateroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, haterarylalkyl, 2rylalkenyl, cycloalkylhoteroalkyl, hetercycloalkylhetealkyl, heterorylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aloxyary, alkenyloxy, alkyn yloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, hateroaryloxy, amino, alkylamin, aminolkyl, 2cyISMino, arlamino, phenxy, benzIyloxy, COOK, alkoxycarbonyl, alkylaminoaErbonyl, arylacyl, sulfnyl, alkylsulfonyl, alkylsulfinyl, aryisulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be optionally substituted.

[0060] In one embodiment R28 is selected from the group conssting of H, alkyl, ~alkenyl, aryilkyl and aryl2Cyl. Specific values of e" ame H, methyl: ethyl; propyl; 2mthyl-propyl, 2-2-dimethylpropyl: ieopropyl; 3,3,3-triflouro-prpyl; butyl: isbutyl; 3,3dimethyl-butyl; pentyl: 2,4,4-trimethyl-pentyl; penten-4-yl, hexyl; heptyl, octyl, nnyl, 2methoxy nonyl, benzyl, 2-phenyl-ethy, 2-phenyl-acetyl, 3-phenyi-propyl, [00611 In another embodiment the heterocycloalkyl glroup is pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piparidyl, piperayl, tetrahydropyranyl, morphilino, 1,3diazapane, 1,4-dizapane, 1,-oxazpane, and 1,-oxathapane. It is particularly Va COMS ID No: SBMI-03086169 Received by 1P Australia: Time 18:02 Date 2006-03-21 1: 21.MAR.2006 17:04 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 18 14 preferred that R' is selected from the group consisting of piperidine-3-yl, piperidine-4-yl and pyrollidin-3-y.

[00621 In another embodiment R' is a heteroaryl group.

[0063] in another embodiment R 1 is a group selected from the group consisting of: V -NH 2

H

N

N

N ?4~/N

N

YhraNEI NO DELPwrI0945 AU I64 Prvmionl ai FledUA COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:05 PHILLIPS ORMONDE FITZPATRICK NO. 3358 P. 19

I

Y:IWIW4UnD NLoCDfLMO4 AU laced AwIdsnI Phi a PSoitk COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 1I Va 21. MAR. 2006 17:05 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P.

N\N/N

"17 N oH

~Z~N~N

C

~z~JI

N

[0064] In one specific embodiment R' is a group of formula;

NH

2 [0065] In another specific embodiment R is a group of formula;

H

I

y-xuNK NO bLTB\PI09S AU Seed PRodiald uil as Filel.doc COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21

O

O

V-a 0N 21, MAR. 2006 17:05 PHILLIPS ORMONDE FITZPATRICK N0. 3858 P. 21 17 [0066] In another specific embodiment R' is a group of formula:

H

[0067] In yet another specific embodiment R' is a group of formula:

H

[0068] In another specific embodiment R 1 is a group of formula:

N

[0069] In another specific embodiment R 1 is a group of formula: [0070] In another specific embodiment R" is a group of formula: ox1N [0071] In another specific embodiment R' is a group of formula: v*.-HAiw tiO DntLLIMl090-l AU SM &Mleoafli MWul Hied.do COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 S21. MAR. 2006 17:05

O

0 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 22 ~2~2/ [0072] In another specific embodiment R' is a group of formula: [0073] In one embodiment R 2 is selected from the group consisting of H, alkyl, cycloalkyl, heteroalkyl, alkenyl, alkynyl, alkoxyalkyl and cycloalkylalkyl.

[00741 In one form of this embodiment R 2 is alkyl. In one embodiment the alkyl is a Ci-Calo alkyl. In anotherform of this embodiment the alkyl Is a Cr-Cs alkyl group. In another form of this embodiment R 2 Is selected from the group consisting of: methyl; ethyl; propyl; 2-methyl-propyl, 2-2-dimethyl-propyl; isopropyl; 3,3,3-triflouro-propyl butyl; isobutyl; 3,3-dimethyl-butyl; pentyl; 2,4,4-trimethyl-pentyl; hexyl; heptyl, octyl.

nonyl, and 2-methoxy nonyl.

(0075] In one form of this embodiment R' is alkenyl. In one form of this embodiment the alkenyl is y a C 1 -Clo alkeny. In another form of this embodiment the alkenyl is a Cj- Ce alkenyl group. In another form of this embodiment R 2 is selected from the group consisting of: ethenyl, prop-i-enyl, prop-2-enyl, but-1-enyl, but-2-enyl but-3-enyl, pent- 1-enyl, pent-2-eny, pent-3-enyl, pent-4-enyl, hex-I-enyl, hex-2-enyl, hex-3-enyl, hex4enyl and [0076] in another embodiment R 2 is selected from the group consisting of

R

1 1

S(O)R

1 RS(0)2R 1 3

R

11

"C(Q)N(R

2

)R

1 3

R"SO

2 N(R)R R" 1

N(R

1

)C(O)R

1

Y;

3 AZXI N wODmLSTIQO1S AU Sws oMM ial FAnd m Plled COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:05 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 23 19 \o 1R"N(R")SO 2 and In one form of this embodiment R 2 is 0~ a group of the formula R"'C(O)N(RI 2 In one form of this embodiment R 1 3 is a CG.

Co alkyl. In a specific form of this embodiment R" Is methyl or ethyl. In one form of thsi embodiment R 1 is H or C 1 -Cealkyl. A specific value for R 2 is H. In one form of thsi embodiment R" is Cl-Co alkyl group. Specific values for R" 1 Include t-butyl and propyl.

Specific examples of groups of this type include: (CHs)sCCH 2

CONH(CH

2 )r (CHs)sCCONH(CH2)-; (CH3)3CCONH(CH 2 and CH 3

(CH

2 2 CONH(CH2)-.

[0077] Specific values of R 2 are selected from the group consisting of: H: methyl; lo ethoxymethyl; [Bicylco[2.2.1]2-ylmethyl; Adamantan-2-ylmethyl; 2-methansulfanylethyl; 2,2,2-triflouro-ethyl; propyl; 2-2-dimethyl-propyl; Isopropy; 3,3,3-trlflouro-propyl; butyl; isobutyl; 3,3-dimethyl-butyl; but-$-enyl; but-3-yny; pentyl; 2,4,4-trimethyl-pentyl; C Bicyclo[2.2.1]hept-5-en-2y; hexyl; hex-3-enyl; octyl; non-3-enyl; non-6-enyl; 2methoxy-nonyl, 2-phenyl-cyclopropyl; cyclohexyl; (CH 3 3

CCH

2

CONH(CH

2 2 (CHs)aCCONH(CH,),-; (CH 3 3

CCONH(CH

2 and CHa(CHa)sCONH(CH)-,.

[0078] In one embodiment X and Y may be the same or different and are selected from the group consisting of H, halogen, CI-C 4 alkyl, -CF 3

-NO

2 -OR, -SRO, CN and NR'R'.

10079] In one embodiment X is H; [0080] In one embodiment Y Is H; [0081] In one embodiment X and Y (if present) are at the 4 and 7 positions of the aromatic ring.

[0082] In one embodiment R 3 is H, CI-Ce alkyl, or acyl, In another embodiment R 3 is H or C,-C 4 alkyl, A specific value for R 3 is H; [0083] In one embodiment R4 is H or C 1 -0 4 alkyl. A specific value for R' is H; [0084] In one embodiment Re is Cl-C 4 alkyl, heteroalkyl, or acyl. A specific value for R' is methyl; [0085] In one embodiment Re is C-C 4 alkyl, heteroalkyl or acyi. A specific value for R'is C 1

-C

4 alkyl; YMatrJNJl DaERTFPIP p5MI AV M PMaIonalMlW Ina Nd'd COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:06 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 24

O

0 0 [0086] In one embodimentR 7 and R8 are selected from the group consisting of H, C,-

C

6 alkyl, C 4 -Cgcycloalkyl, C 4 -Coheterocycloalkyl, aryl, heteroaryl, arylalkyl, and Sheteroarylalkyl

C

[0087] Many if not all of the variables discussed above may be optionally substituted.

If the variable is optionally substituted then in one embodiment the optional substituent is selected from the group consisting of: halogen, -CN, -NO 2

-CF

3

-OCFS,

alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, 3 hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, o cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, -COOH, -COR 5

-C(O)OR

s -SH, -SR

S

-ORand acyl; [0088] In a further embodiment the optional substituents are selected from the group consisting of: halogen, -CN, -NO 2 alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoaikyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C(O)OR5, COOH, SH, and acyl.

[0089] In one embodiment the Z moiety is at the 5 or 6 position. In a specific embodiment the Z moiety is at the 5 position, In one embodiment the Z moiety is a group of formula -CH=CH-. If the Z moiety is a group of this type it is preferably in the configuration.

[00901 In addition to compounds of Formula the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites. Such compounds, salts, prodrugs and metabolites are at times collectively referred to herein as "HDAC inhibiting agents" or "HDAC inhibitors".

[0091] The Invention also relates to pharmaceutical compositions including a compound of the invention with a pharmaceutically acceptable carrier, diluent or excipient.

Y!UWlNIHaO DBLUDITlFWP4SO AUsdPraieuasil aiLS e COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21, MAR. 2006 17:06 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 21 Va 0 0 [0092] In yet a further aspect the present invention provides a method of treatment of Sa disorder caused by, associated with or accompanied by disruptions of cell Sproliferation and/or angiogenesis including administration of a therapeutically effective amount of a compound of formula The embodiments disclosed also relate to

C

pharmaceutical compositions each comprising a therapeutically effective amount of a HDAC inhibiting agent of the embodiments described with a pharmaceutically acceptable carrer or diluent for treating cellular proliferative ailments, inhibition of proliferation of malignant cancer cells, benign tumor cells or other proliferative cells.

o O [0093] In one embodiment the method includes administration of a compound of Sformula (la) or (Ib) as described herein.

[0094] In one embodiment the disorder is selected from the group consisting of but not limited to cancer breast cancer, colon cancer, prostate cancer, pancreatic cancer, leukemias, lymphomas, ovarian cancers, neuroblastomas, melanoma, inflammatory diseases/immune system disorders, angiofibroma, cardiovascular diseases restenosis, arteriosclerosis), fibrotic diseases liver fibrosis), diabetes, autoimmune diseases, chronic and acute neurodegenerative disease like disruptions of nerval tissue, Huntington's disease and infectious diseases like fungal, bacterial and viral infections. In another embodiment the disorder is a proliferative disorder. In one embodiment the proliferative disorder is cancer. The cancer can include solid tumors or hematologic malignancies.

[0095] The invention also provides agents for the treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis I including a compound of formula as disclosed herein. In one embodiment the agent is an anti-cancer agent. In another embodiment the agent is an anti-angiogenesis agent.

[0096] In one embodiment the agent contains a compound of formula (la) or (Ib).

[0097] The invention also relates to the use of compounds of formula in the preparation of a medicament for the treatment of a disorder caused by, associated with J 35 or accompanied by disruptions of cell proliferation and/or angiogenesis. In one embodiment the disorder is a proliferative disorder. In a specific embodiment the disorder is a cancer.

lWlawlM NO pDlBFPrmoJS AU Imd hPisitii Od ds lPUMadN COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21, MAR. 2006 17:06 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 26 22

O

0 C [0098] The compounds of the present invention surprisingly show low toxicity, together with a potent anti-proliferative activity.

[0099] In yet a further embodiment the invention provides a method of treatment of a ClI disorder, disease or condition that can be treated by the inhibition of histone deacetylase Including administration of a therapeutically effective amount of a compound of formula oo [0100] In one embodiment the method includes administration of a compound of \0 formula (la) or (Ib) as described herein, 0 C [0101] In one embodiment the disorder is selected from the group consisting of but not limited to Proliferative disorders cancer); Neurodegenerative diseases including Huntington's Disease, Polyglutamine diseases, Parkinson's Disease, Alzheimer's Disease, Seizures, Strlatonigral degeneration, Progressive supranuclear palsy, Torsion dystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gilles de la Tourette syndrome, Diffuse Lewy body disease, Pick's disease, Intracerebral haemorrhage Primary lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia, Progressive ataxia and Shy-Drager syndrome: Metabolic diseases including Type 2 diabetes; Degenerative Diseases of the Eye Including Glaucoma, Age-related macular degeneration, macular myopic degeneration, Rubeotic glaucoma, Interstitial keratitis, Diabetic retinopathy, Peter's anomaly retinal degeneration, Cellophane Retinopathy; Cogan's Dystrophy; Corneal Dystrophy; Iris Neovascularization (Rubeosis); Neovascularization of the Cornea; Retinopathy of Prematurity; Macular Edema; Macular Hole; Macular Pucker; Marginal Blepharitis, Myopia, nonmalignant growth of the conjunctiva; Inflammatory diseases and/or Immune system disorders including Rheumatoid Arthritis Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease, Colitis Ulcerosa, Alcoholic hepatitis, Diabetes, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain, Systemic Lupus Erythematosus, allergic contact dermatitis; Disease involving angiogenesis including cancer, psoriasis, rheumatoid arthritis; Psychological disorders including bipolar disease, schizophrenia, depression and dementia; Cardiovascular Diseases including Heart failure, restenosis, cardiac hypertrophy and arteriosclerosis; Fibrotic diseases Y!WUtPNKO BS TlBTIB fPIU AUS d haaamiil Fill Iilesfl COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR 2006 17:07 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 27 23

INO

O including liver fibrosis, lung fibrosis, cystic fibrosis and angiofibroma; Infectious 0 diseases including Fungal infections, such as Candida Albicans, Bacterial infections, Viral infections, such as Herpes Simplex, Protozoal infections, such as Malaria, SLeighmania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidiosis, and Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.

[0162] The invention also provides agents for the treatment of a disorder, disease or condition that can be treated by the inhibition of histone deacetylase Including a compound of formula as disclosed herein. In one embodiment the agent is an antio 10 cancer agent.

o[0103] The invention also relates to the use of compounds of formula in the Cl preparation of a medicament for the treatment of a disorder, disease or condition that can be treated by the inhibition of histone deacetylase.

10104] The invention also provides a method for Inhibiting cell proliferation including administration of an effective amount of a compound according to formula [0105] In yet an even further aspect the invention provides a method of treatment of a neurodegenerative disorder in a patient including administration of a therapeutically effective amount of a compound of formula In one embodiment the method Includes administration of a compound of formula (la) or (Ib) as described herein. In one embodiment the neurodegenerative disorder is Huntington's Disease.

[0106] The invention also provides agents for the treatment of neurodegenerative disorder including a compound of formula as disclosed herein. In one embodiment the agent is preferably anti-Huntington's disease agent.

[01.07] The invention also relates to the use of compounds of formula in the preparation of a medicament for the treatment of a neurodegenerative disorder. In one embodiment the neurodegenerative disorder is Huntington's Disease.

[0108] In yet an even further aspect the invention provides a method of treatment of an; Inflammatory disease and/or immune system disorder in a patient including administration of a therapeutically effective amount of a compound of formula In oni embodiment the method includes administration of a compound of formula (la) or (Ib) as described herein. In one embodiment the inflammatory disease and/or immune rng*IC NO DLEWuPIlOl-OSM AU tod sial M PMs iPUas COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21 MAR. 2006 17:07 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 28 24 o system disorder is rheumatoid arthritis. In another embodiment the inflammatory 0 disease and/or immune system disorder is Systemic Lupus Erythematosus.

[0109] The invention also provides agents for the treatment of inflammatory disease and/or immune system disorder including a compound of formula as disclosed herein.

[0110] The invention also provides agents for the treatment of eye disease mediated by HDAC inhibition including a compound of formula as disclosed herein. in one o 10 embodiment, the eye disease is macular degeneration. In another embodiment, the Seye disease is glaucoma. In another embodiment, the eye disease is retinal o degeneration.

[0111] The invention also relates to the use of compounds of formula in the preparation of a medicament for the treatment of inflammatory disease and/or immune system disorder. In one embodiment the inflammatory disease and/or immune system disorder is rheumatoid arthritis. In another embodiment the inflammatory disease and/or immune system disorder is Systemic Lupus Erythematosus.

DETAILED DESCRIPTION OF THE INVENTION [0112] In this specification a number of terms are used which are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined.

[0113] As used herein, the term unsubstituted means that there is no substituent or that the only substituents are hydrogen.

[0114] The term "optionally substituted" as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more substituent groups. Preferably the substituent groups are one or more groups independently selected from the group consisting of halogen, -CN, -NO 2

-CF

3

-OCF

3 alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, T!ivrN lNO DLL BfIE O m AU I. Sed hnirril Fipi mP Sald COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:07 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 29

O

o hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloelkyl, alkoxyheterocycloalkyl, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, arylalkyl, heteroarylalkyl, s cycloalkylalkyl, heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino, N aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -COOH, COR", -C(0)OR 5

CONHR

5

NHCOR

5

NHCOOR

5 NHCONHR', C(=NOH)R, SH,

SR

5 -OR and acyl.

cio [0115] "Alkyl" as a group or part of a group refers to a straight or branched aliphatic o hydrocarbon group, preferably a C 1 -C14 alkyl, more preferably C,-C 10 alkyl, most N preferably Cl-Ca unless otherwise noted. Examples of suitable straight and branched

C

1 -Ce alkyl substituents Include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tbutyl, hexyl, and the like.

(0116] "Alkylamnino" includes both monoalkylamino and dialkylamino, unless specified. "Monoalkylamino" means a -NH-Alkyl group, in which alkyl is as defined above. "Dialkylamino" means a -N(alkyl)2 group, in which each alkyl may be the same or different and are each as defined herein for alkyl. The alkyl group is preferably a C 1 Co alkyl group.

[0117] "Alkylamino" includes both ronoalkylamino and dialkylamino, unless specified, "Monoalkylamino" means a -NH-Alkyl group in which alkyl is as defined above. "Dialkylamino" means a -N(alkyl) 2 group in which each alkyl may be the same or different and are each as defined herein for alkyl. The alkyl group is preferably a C- Ce alkyl group.

(0118] "Arylamino" includes both mono-arylamino and di-arylamino unless specified.

Mono-arylamino means a group of formula aryl NH-, in which aryl is as defined herein.

di-arylamino means a group of formula (aryl 2 N- where each aryl may be the same or different and are each as defined herein for aryl, [0119] "Acyl" means an alkyl-CO- group in which the alkyl group is as described herein. Examples of acyl include acetyl and benzoyl. The alkyl group Is preferably a C,- Ce alkyl group.

Ywune4K so o N Dmz .05wO ALu Samd ravisSai 9Nm A7lidi e COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:07 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 26 o [0120] "Alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon 0 group containing at least one carbon-carbon double bond and which may be straight or Sbranched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms, Smost preferably 2-6 carbon atoms, in the normal chain. The group may contain a plurality of double bonds in the normal chain and the orientation about each is C independently E or Z. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.

[0121] "Alkoxy" refers to an -0-alkyl group in which alkyl is defined herein.

Preferably the alkoxy is a C 1 -C6alkoxy. Examples include, but are not limited to, I methoxy and ethoxy.

0 CN [0122] "Alkenyloxy" refers to an alkenyl group in which alkenyl is as defined herein. Preferred alkenyloxy groups are Ci-Coalkenyloxy groups.

[0123] "Alkynyloxy" refers to an -0-alkynyl group in which alkynyl is as defined herein. Preferred alkynyloxy groups are Ci-C alkynyloxy groups.

[0124] "Alkoxycarbonyl" refers to an -C(O)-O-alkyl group in which alkyl is as defined herein. The alkyl group is preferably a Ci-Cs alkyl group. Examples include, but not limited to, methoxycarbonyl and ethoxycarbonyl.

[0125] "Akylsulfinyl" means a -S(O)-alkyl group in which alkyl is as defined above.

The alkyl group is preferably a C1-C 6 alkyl group. Exemplary alkylsuifinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl.

[0126] "Alkylsulfonyl" refers to a -S(O)ralkyl group in which alkyl is as defined above. The alkyl group is preferably a C1-Ce alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl.

[0127] "Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-14 carbon atoms, more preferably 2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl.

Y;thWKI Nw umBLETrFl9M AU jd Prai l hi as ildAk COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21,MAR2006 17:08 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 31 I 27 O [0128] "Alkylaminocarbonyl" refers to an alkylamino-carbonyl group in which 0 alkylamino is as defined above.

S[0129] "Cycloalkyl" refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as Scyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified.

It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane.

[0130] "Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system N containing at least one carbon-carbon double bond and preferably having from 5-10 Scarbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, C cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituent groups.

[0131] The above discussion of alkyl and cycloalkyl substituents also applies to the alkyl portions of other substituents, such as without limitation, alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and Sthe like.

10132] "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

[0133] "Halogen" represents chlorine, fluorine, bromine or iodine.

[0134 "Heterocycloalkyi" refers to a saturated or partially saturated monocycli, bicyclic, or polycydic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane.- [0135] "Heterocycloalkenyl" refers to a heterocycloalkyl as described above but containing at least one double bond.

YmfNI 10 NC lrW nmpIU A u 8Bmm htiwPia si in Fililda COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:08 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 32 28

O

O [0136] "Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl group in which the 0 heterocycloalkyl and alkyl moieties are as previously described. Exemplary heterocycloalkylalKyl groups include (2-tetrahydrofuryl)methyl, C (2-tetrahydrothlofuranyl)methyl.

[0137] "Heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having from 2 to 14 atoms, more preferably 2 to 10 atoms In the chain, one or more of which is a heteroatom selected from S, O, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, and the like.

o O [0138] "Aryl" as a group or part of a group denotes an optionally substituted o monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms

C

that are all carbon) preferably having from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety In which a phenyl and a C,.7 cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.

[0139] "Arylalkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Exemplary arylalkenyl groups include phenylallyl.

[0140] "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C-5 alkyl moiety.

Exemplary arylalkyl groups include benzyl, phenethyl and naphthelenemethyl.

[0141] "Arylacyl" means an aryl-acyl- group in which the aryl and acyl moieties are as previously described, In general the aryl moiety is attached to the alkyl portion of the acyl moiety, typically to the terminal carbon of the alkyl portion of the acyl moiety.

Preferred arylacyl groups contain a C1.6 alkyl moiety in the acyl moiety. Exemplary arylacyl groups include 2-phenyl-acetyl.

[0142] "Heteroaryl" either alone or part of a group refers to groups containing an aomatic ring (preferably a 5 or 6 membererd aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.

Examples of hetreoaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, Y NfanA«KwI NO PWLBIEW109041 AUlSsd ftninlfminldl E RNiC COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:08 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 33 29 Va O furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, 0 pyrazine, pyrimidine, pyridazine, indole, isoindole, 1-1-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, Sphenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, or4- pyridyl, or 8- quinolyl, 3-,

C

or 5- isoquinolinyll-, or 3- indolyl, and or 3-thienyl.

[0143] "Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a o 10 lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.

O

S[0144] "Lower alkyl" as a group means unless otherwise specified, an aliphatic Cl hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).

10145] In Formula as well as in Formulae (la) (Ib) defining sub-sets of compounds within Formula there is shown a benzimidazole ring system. Within this ring system, there are substitutable positions at the and 7-ring positions. In each of Formulae and there is a requirement for attachment of an acidic moiety at one of the ring positions. This acidic moiety may be provided by but is not limited to groups containing, a hydroxamic acid or salt derivatives of such acid which when hydrolyzed would provide the acidic moiety. In some embodiments the acidic moiety may be attached to the ring position through an alkylene group such as -CHor -CH 2 CH2-, or an alkenylene group such as -CH=CH-. Preferred positions for attachment of the acidic moiety are the 5- and 6-ring positions.

[0146] It is understood that included in the family of compounds of Formula are isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in or configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantlomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art.

[0147] Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All TMrem NO DWBLET %lPtOCS AU Iasld frllll Pilad PFilstU COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21 MAR. 2006 17:09 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 34 Ssuch single stereoisomers, racemates and mixtures thereof are intended to be within Sthe scope of the subject matter described and claimed.

[0148] Additionally, Formula is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, each formula includes compounds

C

having the indicated structure, including the hydrated as well as the non-hydrated forms.

r"- [01491 In addition to compounds of the Formula the HDAC inhibiting agents of the various embodiments include pharmaceutically acceptable salts, prodrugs, and active N metabolites of such compounds, and pharmaceutically acceptable salts of such o metabolites.

[0150] The term "Pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic, Suitable pharmaceutically acceptable base addition salts of compounds of Formula include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine. Other examples of organic salts are: ammonium salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arginine. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.

[0151] "Prodrug" means a compound which is convertible in vivo by metabolic means by hydrolysis, reduction or oxidation) to a compound of formula For example an ester prodrug of a compound of formula containing a hydroxyl group VYMletnJ NO DBIAEW 9BS An r*U scd ils.woDluI ilN Pled COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:09 21. AR. 6C6 ]:U9PHILLIPS ORMONDE FITZPATRICK N.35 ,3 NO. 3858 P, may be convertible by hydrolysis in viva to the parent molecule. Suitable esters of compounds of formula containing a hydroxyl group, are for example acetates, citratos, lactates, tartrates, malonhtes, oxalates, saiiyAates, propionates, BsicciflateB, flumarates, rnaleates, methylene-bi-p-hydrOKyflhPhthOatBs, gestisates, isethionates, di-p-toiuoyltsrtrfltes, meothanesuiphonates, ethanesuiphonates, benzenesulphOrlatel, p.

toluenesuiphonates, cyclohexylsulphamates and quinates. As another example an ester prodrug of a compound of formula containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. (Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res.,1 8:379, 1987).

10152] or less.

Preferred HOAC inhibiting agents include those having an MCo value of 10 pM (0153] Specific compounds of the invention include the following; 3-fl .(3-Dimethylamino-2,2-dImethyl-prOPYl)-2- (2,2-dlmethyl-propy9- hydroxy-acrylamide 3-fl .<3-Dimethylamino-2,2-dimethyl-propyfl2isopropyl-1 acrylamide 3-{2-Butyl-1 -(3-dimethylemino.2,2-dimnethylpropyl)-l acrylamide 3-fl -(3-Dimethylamino-2,2-dimethy-propyU-2-(2methylsulfanyl-ethyl)-1 H-benzoirnidezol-6-yl]-Nhydroxy-acrylamido

NN

'IA

r

'IA

y;%U~'WiU 102LBflI[U-OSAUA- ko d dni Find F1Ied4M COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:09 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 36

H

N.

-r N CM

F-.

N 'N

'I

3-(1 -(3-Dimethylamina-2,2-dimethy-prOpyO-2ethoxyrriothyl-1 hydroxy-arylamide 3.41 -(3-Dimethylamino2,2-dimtl-PropyI)-2isabutyl-1 H-b~erzoimidazo--Y]-N-hYdroxyacrylamide 3-1-(2-Diethyami no-,thyl)-2-isobuty-1 3-12-Butyl.1 -(2-diethylamlno-ethyl)-1

H-

3-[2-But-3-ynyl-1 -(3-cilmethylamino-2 1 2-dimethylpropyl)-1 acrylamide 8-[2-But-3-enyl-1 -(3-climethylamino-2,2dimeothyl-propyl)-1 hydroxy-crylamide 3-[2-But-3-erlyl-1 -(2-diethylamirio-ethyl)-1 Hbenzolmidazcl5-y1-N-hydroxy-acrylamide N 'N

H

I

rfdU 3 Arm NO D~tffli.@4j AU hvvk. Mi-I-- Fdtin COMB ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21, MAR. 2006 17:09 PHILLIPS ORMONDE FITZPATRICK NO. 3856 P. 37 N N V

S

6)

NN

M1 3-[2-But-3-ynyl-l -(2-diethylsmino-ethyl)-1 H- 3-[l-(a-Dimethylamino-2,2-dimethyl-propyl)-2- (3,3,3-trifluoro-propyl)-l hydroxy-acrylemide 3-[l -(2-Dlethylamino-eothyI)-2-(3,3,3-trifluoropropyl)-l acrylamide 3-El -(2-Diethylamino-thy-2-thOXYmethYl-l H- 3-El -(3-Dlmethylamino-2,2-dimethyl-propyt)-2methyl-I H-benzoimidezol--yI]-N-hydroxyacrylanhide 341 .(2-Diethylamino-ethyl)-2-(2,2-dimathylpropyl)-l acrylamide N-Hydroxy-3-[I -(3-iaopropylamino-propyl)-2- (3,3 1 3-trifluoro-propyI)-I acrylarnide Y.*A*tNKIWI DELMRWIOPOCS AU PaiSuiPiul ii mtt~ COMB ID No: SBMI-03086169 Received by P1 Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:10 21. MA. 2%6l7:1U PHILLIPS ORMONDE FITZPATRICK N.35 .3 NO. 3858 P. 38

S

3-(2-(2,2-Dimethyl-propy)-1 -(2-isopropylaminoethyl acrylmide 3-fl -(2-Diieopropylamino)-ethyl)-2-(2,2-dimethy.

propyl)-l acrylamide 3-[l -(2-Diisopropylamino-ethy-2-iSObUty-1

H-

3-[l .(3.Dimethylemino-2.2.drnethyl-propy)-2hex-3-enyl-l acrylarnide 3-fl -(3-Dimethylamino-2,2-dimtthyl-propyl)-2" (2,4,4-trmethyl-peityl)-1 N-hydroxy-acrylalmide 3-[2-Cyolohexyl-l -(3-dimethylamino-2,2dimethyl-propyl)-l hydroxy-ecrylamide 3-f 2-Blcydo[2.2. 1]hept-5-en-2-yl-1 dimethylamnino-2,2-dimethyl-propyl)-l Hbenzoimidazol-6-yIJ-N-hydroxy-acrylaimide 3-fl -(2-Diethylamino-ethyt)-2-hex-3-enyI1

H-

Ki-KC

V

C

K-

F->

Y-,UltNC NOQD!111WF1104 AUkcud fCO~SC8 I hi w hs COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:10 21. AR. 006 7:10PHILLIPS ORMONDE FITZPATRICK N.35 .3 NO. 3358 P. 39 N~ N.

A

3-fl -(2-Diisopropylamino-sthyl)-2-hex-3-enyt-l H- 3-[2-Hex-3-enyl-1 .(2-isopropylamlno-ethyl)-1 H- 3-[2-I-ex-3-enyl-1 -(3-isopropylamino-prapyl)-1 H- 3-[l -(2-Ethylamino-ethyl)-2-hox-3-enyl-l H- 3-fl -(2-Diethylamirio-othyl)-2-hexyl-1 H- N-Hydroxyf-3-[l -(3-isa propylamino-propyl)-2- (2,4,4-trimothyl-pentyl)-l acrylamide 3-[2-(2,2-Dimsthyl-propy)-1 -(3-isopropylaminopropyl)-l acryamide 3-fl .(2-Diieopropylamno-ethyl)-2-(3,3,3-tifUOropropyl)-l acryamide N N

K-

yW.r*jW No =flLTW1aMM AU Esati Pl*m nail M Mkdti COMS ID No: SSMI-03086169 Received by P1 Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:10 21. AR. QC6 7:1~ PHILLIPS ORMONDE FITZPATRICK N.35 .4 NO. 3858 P. a

N

K.-

6

N

'1

N.

N-Hydroxy-3-(2-Isobutyl-1 -(2-isopropylaminoethyl)-l 3-[2-(2 1 2-D~methyi-propyl)-l -(2-ethylaminoe-thyl)-1 acrylarnide 3[l -(2-Ethylamino-ethyl)-2-ieobutyl-l H- 3-El -(2.Diisopropylamino-ethyl)-2-(2,4,4trimethyl-pentyl)-l hydroxy-acrylamide N-Hydroxy-341 .(2.isopropylamino-ethyl)-2- (2,4,4-trimethyl-pentyl)-l acrylamide 341 .(2-Ethylaniino-ethy)-2-C2,4,4strImethyI.

pentyl)-l acrylamide 3-[l -(2-Diethylamino-ethyl)-2-(2,4,4-trimethylpentyI)-l acrylamide 3-fl -(2-Diethylamlno-ethyl)-2-propyl-l H- Y1.4= NOVaILrEPIH45 AUmu.4PrWLnaMa UP'I hi 4Co COMB ID No: SBMI-03086169 Received by P1 Australia: Time 18:02 Date 2006-03-21 Va 0 0 ci ci 21-MAR-2006 17: 10 21. AR. 006 1:10PHILLIPS ORMONDE FITZPATRICKMa35 P.4 NO. 385B P. 41 3-[2-ButyI-1 -(2-d1isopropylamino-ethvl)-1 H- 3-12-ButW-1 -(2-ethylarrino-othyl)-1 H- 3-ji -(2-Diethylamino-ethyl)-2-(2-methyIsulfanyethyl)-1 aarylamide 3-[2-ButylI -(2-isopropylamlno-ethyl)-1 H- 3-[2-Butyl-1 I.(3-isopropylamlno-propyl)-1

A

T M N rH 1< 3-(1 -Benzy-plperdin-4-yI)-2-buty-1 H- -aorylamide 3-[2-But-3-enyl-1 -(2-ethylamino-ethyl)-1 H- NN 9tW s/i

A

H

%ThWtNyM' wD sISEwPISMS AU Siceid ?fSwuIMIL Flu[. ru Md COMS ID No: SBMI-03086169 Received by 113 Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:10 2PMAR.2C6 17:1UPHILLIPS ORMONDE FITZPATRICK N.35 .4 NO. 3858 P. 42 3-[2-Hexyl- 1 -(2-isopropylamlno-ethyl)-1 H- 3-[I -(2-Dimethylamino-ethyl)-2-(2,4,4-trimethylpentyl)-1 aorylamide 3-[i -(2-Ethylamino-ethyl)-2-hexyl-I Hbenzoimidazol-6y]-N-hydroxy-BCryIamide N-Hydroxy-3-(1 -(2-isopropylamino-ethyl)-2- (3,3,3-trifluoro-propyl)-1 acrylamide 3-El -(2-Dlmethylarnino-ethyl)-2-hex-3-eny-1

H-

3-(l -(2-Amino-ethyl)-2-%24,4-trimethyl-pentyl)- 1 H-benzoimidazol-6.yl]-N-hydroxy-SCrylamide 3-[1 -(2-Amino-ethyfr2-(2-methoxy-nonyI).I

H-

3-[2-Butyl-I -(2-dimethytamino-Qthyl)-i Ha NN ~tWl p r~

S

-4' YWAU*IXNO OULTrIPIUS AIIkccd Phun Il fiIFC4.f COMB ID No: SBMI-03086169 Received by IP Australia: Time (I-tm) 18:02 Date 2006-03-21 21-MAR-2006 17:11 2PMAR.26 17:11 PHILLIPS ORMONDE FITZPATRICK N.35 .4 NO. 3358 P. 43 39 3-[l -(2.Dimethylamino-ethyl)-2-heXylI- H- -(2-Diethylamino-ethyl)-5-(2hydroxycarbamoy-viny)-1 H-benzoimidazol-2yIJ-ethyl)-3.3-dimethyl-butyramnide 3-{1 -(2-DIethylamino-ethyl)-2-[2-(2.2-dimethylpropionylamirio)-ethyl]-i N-hydroxy-acrylamide 3-{1 -(2-Diethyleminc-ethy)2-R(2,2-dimthypropionylamino)-mothyQl-1 yI)-N-hydmoxy-acrylamide N4[1 -{2-Diethylemirio-ethyl)-5-(2tiydroxycarbamoyl-vinyl)-1 H-berizoimidazol-2ylmethyl]-butyramide 34[1 (2-ethylamino-ethy) -2-(3,3-dimethyl-butyl)- 1 3-E2-(3,a-DimetMy-buWIl)-I -(2-Dimethylaminoethyl)-I acrylamide VtAM9WI=NO MLEWDPIUGJ3AU Seems Ymmueleuu Fwl MNPIWA COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 200% 17:11 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 44 3-LI -(2-Dimethylamlno-ethyl)-2-pentyl-1 H- 3-[1 -(2-Dimethylamino-ethyl)-2-(2,2,2-triflucrcethyl)-1 acrylamide N-Hydroxy-3-[1 -(5-methyl-1 H-pyrazol-3-yI)-2- (2,4,4-trimethyl-pentyt)-I acrylamide 341 -(2-Ethylamino-ethyl)-2-penty-1 H.

3-(2-Butyl*1 -pyrrolidin-3-y-1 yI)-N-hydroxy-acryamide 3-(2-Butyl-1 -piperidin-4-yl yI)-N-hydroxy-acrylamide N-Hydroxy-3-[I -(2-lsopropylamlno-ethy)"2pentyl-1 H-berizoimidazol-6-yIJ-acrylamlde N-Hydroxy-3-(1 -(2-methylamino)-ethyl)-2-non-3enyi-1

A"

A

HN

7- YWflm 1 Aqfl DLM?1U04 "I aa MWAO" PWMl FMediA.

COMS ID No: SBMI-03086169 Received by IP Australia: lime 18:02 Date 2006-03-21 21-MAR. 2006 17:11 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 41 N-Hydroxy-3-[11-(2-methylamino-ethyl)-2-non-6enyI-1 I N m 3-[24'iexyl- 1 -(2.-methylamino-ety)-1 Hbenzai mid azol-5-y]-N-hyd roxy-acryiamide N-Hydroxy-3-EI -(2-methylemino-ethyl)-2-peltyl- I N-Hydroxy-3-[1 -(2.rnethylamnino-thyl)2oCty- I 3-[1 -(2.Amino-othy)-2-octy-1 H-benzoimiclazol- 3-{2-ButyI-I -[2-(isopropyl-methyl-aminc)-ethyl]- I 3-(I -t2.(EthyI-methyI-amIno)4thy1-2-PeflWI-I

H-

N

<SN

(77 N N

C)

C

no mzgMOqo-es AU SUmd RovhiOcaid uPiadSQ0 COMS ID No: SBMI-03086169 Received by P1 Australia: Time 18:02 Date 2008-03-21 21-MAR-2006 17:11 21. AR. 11PHILLIPS ORMONDE FITZPATRICK N.35 .4 NO, 3858 P. 46 N <eN

C-.

N rAN eN

N

-r 6 3-(2-I-exyl-1 -pyrrolidin-3-y-1 yl)-N-hydroxy-acrylamide 3-[2-ButyI-1 -methyl-pyrrolidin-3-y)-1 H- 3-(2-Butyl1 -piperidin-3-yI-1 H-benzoimidazol-SyI)-N-hydroxy-acrylamide 3-(2-Hexyl-1 -piperidin-3-y-1 yI)-N-hydroxy-acrylamide 3-(1 -{2-(Ezthyl-(2-methoxy-ethyl)-amino-ethyl}-2perityl-I acrylamide 3-{2-Butyt-1 .[2.(ethyI-methy-aminosthyL*1 H- 0 N N N' NOH

H

N

0 OHN-Hydroxy-3-[1 .methyl-piperidin-3-yI)-2- N~ Ne O /H pentyl-1 Y,.%flHqmNO bZLulffPIOS AUS*W Wi?*gCIAnaaauia.

COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:11 21. MA. 2%617:11PHILLIPS ORMONDE FITZPATRICK N.35 .4 NO. 3858 P, 47 0 N N' 'N NOH

H

N

3.41 -[2-(Ethyl-hexyl-amino)-ethyll-1 H- 0 3-fl .[2.(Ethyl-pentyl-amino)-ethy)-1 H- K' NH

ZN

N

O

S-{1 -12-(EthyI-heptyl-amino)-ethyl-1 H- (E)-3-(2-hexy-1 -(2-hydroxyethyl)piperidin-3yI)-l hydroxyacrylamide 3-(2-Butyl-1 -{2-[ethyl-(3-hydroxy-propyl)-amlno]ethyl}-1 ecrylamide 3-(1 -(2-(Ethyl-(3-hydroxy-propyD)-amino]-ethyl}- 2-pentyl-1 acrylamide N N vmoknyaxlO DBLEThWAiI9O Mflnpd Pt*A4lin Thini UrU~dteN COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2066 17:12 PHILLIPS ORMONDE FITZPATRICK N.35 .4 NO.3B58 P. 48 44 (E).N-hydrcxy-3-(1 -phoethylpyrrolidin-3-yI)- 1 H-benzo[d]imidazol-5-yI)acryam ide (E)-N-hydroxy-3-(1 -pentylpiperidin-3-yI)-I H- 3-{1 .[2-(Butyl-ethyl-amino)-ethyfl-l H- (E)-N-hydroxy-3-(1 .phenethylpiperidin-3-yI)- 1 H-benzo~dlimiciazol-S-yI)acrylamlde (E)-N-hydraxy-3-(I -(3-phenylpropyl)plperldln- 3-yI)-1 (E)-N-hydroxy-3-(I -(1-(3-phenylpmopyl)pyrrolidin- 3-yI)-1 rtwaaW NO DELI? 1fl1990AU tMi en MVhMuS Plod N Mflt COMS IDNa: SBMI-03086169 Received by P1 Australia: Time 18:02 Date 200"-3-21 21-MAR-2006 17:12 21.MAR 200611:12PHILLIPS ORMONDE FITZPATRICK N.35 .4 NO.3858 P. 49 3-{1 -(1-(3,3-Dimethyl-buty9-pyrrlidin-3-yl]-1 H- -(2-(diethylamlno)etiyl)-1 H- 3-[2-(4-Cyano-buty)-1 -(2-diethylamino-ethyl)- 1 H-benzoimidazol-S-yU.-N-hydroxy-acrylamicie -butylpiperidin-3-y)-1 H- (E)-N-hydroxy-3-(1 -(pent-4-ny)plperidin-3yI)-1 N. *N NM 4

T~)

YSq~lIKJ N40 LKUTIIO-KO AT) 2d PmnidunInal a PUS.x COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2008-03-21 21-MAR-2006 17:12 21. AR. 6C6 7:12PHILLIPS ORMONDE FITZPATRICK N.35 .5 NO. 3858 P. q N -(3,3-dimethylbutyl)piperidin.4y)-1 H- 3-[1 -(2-Dlethylamino-ethyi)-2-propylamino-1 H- (E)-N-hydroxy-3-(1 (isopropyi(propyl)amino)ethyl)-1 H- 3-{1 -[2-(Butyl-ieopropyl-amino)-olhy]-1 H- N-Hydroxy-3-{1 -[2-(Qsopropyl-pontyl-amin a).

ethyl]-1 H-benzoidazol-6-yI}-acrylamide 3-[2-(5-Cyano-penty)-1 -(2-diethylamino-ethyl)- 1

OH

r yWS~v~tNWOUTOifl.ts AUS.S PrnI jdtSRO N PF11@I COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:12 21. MA. 26%17:12 PHILLIPS ORMONDE FITZPATRICK N.35 .5 NO. 3858 P. 51

N

'I

3-(lI-(2-[(3,3-Dimethyl-butyl)-ethyl-aminoj-ethyl)- I 3-{I -[2-(Ethyl-propyl-amino)-ethyl j-I H- N-Hydroxy-3-(1 -{2-[isopropyl-(2-methyl-pentyl)amino]-ethy§-1 (E)-N-hydroxy-3-(1 -(2-(isopropyl(4,4,4trifluorobutyl)amino)ethyi)-I H-benzo[d]imldazol- 3-ji -(3-Dimethylaminc-2,2-dimsthyl-propyl)-2propylamino-1 H-be nzoimidazol-3-yJ-N-hyd roxyacrylamide Y!wflYtUNO btL11TV~MflU. Ukmi tiM lis'a UI COMB ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:12 21. AR. @Q6 7:12PHILLIPS ORMONDE FITZPATRICK N.35 .5 NO. 3858 P. 52 3-{11-[2-(Ethyl-hexyl-amino)-ethyl]-2-methy-1 H- 3--2-(Butyi-ethyl-emino)-ethyll-2trifluoromethyl-1 hydroxy-acrlamide 3-41 -[2-(Ethyl-hexyl-amino)-ethylj-2trifluoromethyl-1 hydroxy-acrylamide -(2-(dibutylemino)ethyl)-2-prapyl-1 H- 3[1 -(2-Dipropylamirio-ethy)-1 H-benzoimidazol- Y.AboMNOW DMf~WIOR-M ALI 3mWt 7~ftwOm-d flm P~ic.dcg COMS ID No: SBMI-03086169 Received by IP Australia: lime 18:02 Date 2006-03-21 21-MAR-2006 17:12 21. MA. 20%17:12PHILLIPS ORMONDE FITZPATRICKNR38 P.5 NO. 3858 P. 53 49 N-Hydroxy-3-(1 -{2-[isopropyl-(3-methyl-butyl)amino]-ethyl]-i H-benzol 3.(l1 (2.[(3,3-Dinmethyl-butyl)-methyl-amino]euhyI}-1 H-benzomidazo--y)-N-hycdroxyacrylamide 3-(1 -{2-[(2-Ethyl-butyl)-methyl-amino]-ethyl-1 H- -(2-(bIs(3,3-dimethylbutyt)amino)ehyl)- 1 -(2-(diisobutylamino)ethyl).1 H- 3-41 -[2-(3,3-Dimethyl-butylamino)-ethyl]-i H- Yt~wM NO DMTMWLCPO.AUZaPrMaiN3a"lFMrNd COMS ID No: SBMI-03086169 Received by 1P Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:13 21. AR. CQ6 7:13PHILLIPS ORMONDE FITZPATRICK N.35 .5 NO. 3858 P. 54 N-Hydroxy-3-{l -[2-(methyl-pent-4-onyI-amino)ethyl]-1 3-(l -{2-[(3,3-Dimethyl-butyl)-propyl-amino]ethyilj- acrylamide 3-fl -(3-Dimethylamino-2,2-dimethyl-propyfl-2methylsulfanyl-1 H-benzoimidazo-5-y1j-Nhydroxy-acrylamide 3-{1 -(2-(3,3-Dimethyl-butylamino)-ethyl]-2propyl-1 acrylamide 3-fl -j2-(3,3-Dimethyl-butylamirio)-ethylj-2-(2,2dimothyl-propyl)-l hyciroxy-acrylamide v~qurflm o fltstfPiefl4 AU hueod Pnill Final w MSAoc COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21, MAR,2006 17:13 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 51 I J 3-[1 -{2-[Bis-(3,3-dimethyl-butyl)-amino]-ethyl)-2o Y (2,2-dimethyl-propyl)-1 N hydroxy-acrylamide 3-{1-[2-(2,2-Dimethyl-propylamino)-ethyl-1 H- -OH

NO

3-(1 -{2-[(2,2-Dimethyl-propyl)-propyl-amino]ethyl)-1 Sacrylamide 3-{1 -[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl- [0154] The compounds disclosed are hydroxamate compounds containing a hydroxamic acid type moiety in one of the substituents that may be inhibitors of deacetylases, Including but not limited to inhibitors of histone deacetylases. The hydroxamate compounds may be suitable for prevention or treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis when used either alone or together with a pharmaceutically acceptable carrier, diluent or excipient. An example of such a disorder Is cancer.

[0155] Administration of compounds within Formula to humans can be by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion. The active YIM0rjU NO DeLBSilis-O G r A tio5 nos f m piu ndEsa se ae COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:13 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 56 52 O compound is typically included in a pharmaceutically acceptable carrier or diluent and o in an amount sufficient to deliver to the patient a therapeutically effective dose. In various embodiments the inhibitor compound may be selectively toxic or more toxic to Srapidly proliferating cells, e.g. cancerous tumors, than to normal cells.

C [0156] As used herein the term 'cancer' is a general term intended to encompass the vast number of conditions that are characterised by uncontrolled abnormal growth of cells.

[0157] It is anticipated that the compounds of the invention will be useful in treating c various cancers including but not limited to bone cancers including Ewing's sarcoma, o osteosarcoma, chondrosarcoma and the like, brain and CNS tumours including C acoustic neuroma, neuroblastomas, glioma and other brain tumours, spinal cord tumours, breast cancers, colorectal cancers, advanced colorectal adenocarcinomas, colon cancers, endocrine cancers including adenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyrold cancer, thymus cancer, multiple endocrine neoplasma. gastrointestinal cancers including stomach cancer, esophageal cancer, small intestine cancer, Liver cancer, extra hepatic bile duct cancer, gastrointestinal carcinoid tumour, gall bladder cancer, genitourinary cancers including testicular cancer, penile cancer, prostate cancer, gynaecological cancers including cervical cancer, ovarian cancer, vaginal cancer, uterus/endometrium cancer, vulva cancer, gestational trophoblastic cancer, fallopian tube cancer, uterine sarcoma, head and neck cancers including oral cavity cancer, lip cancer, salivary gland cancer, larynx cancer, hypopharynx cancer, orthopharynx cancer, nasal cancer, paranasal cancer, nasopharynx cancer, leukemias including childhood leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia, myelomas, haematological disorders including myelodysplastic syndromes, myeloproliferative disorders, aplastic anemia, Fanconi anemia, Waldenstroms Macroglobulinemia, lung cancers including small cell lung cancer, non-small cell lung cancer, lymphomas including Hodgkin's disease, non-Hodgkln's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, AIDS related Lymphoma, B-cell lymphoma, Burkitt's lymphoma, eye cancers including retinoblastoma, intraocular melanoma, skin cancers including melanoma, non-melanoma skin cancer, merkel cell cancer, soft tissue sarcomas such as childhood soft tissue sarcoma, adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancers including kidney cancer, Wilms tumour, bladder cancer, urethral cancer, and transitional cell cancer.

VY maarI1U o DELl esrIsIWGOS AU Imd PrMsioal Flu s hl COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:13 PHILLIPS ORMONDE FITZPATRICK NO. 3856 P. 57 53 O 0 0 [0158] Exemplary cancers that may be treated by the compounds of the present invention are breast cancer, lung cancer, ovarian cancer, prostate cancer, head and Sneck cancer, renal cancer renal cell carcinoma), gastric cancer, colon cancer, colon cancer, colorectal cancer and brain cancer.

[0159] Exemplary cancers that may be treated by compounds of the present inventions include but are not limited to B-cell lymphoma Burkitt's lymphoma), leukemias acute promyelocytic leukemia), cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma.

IN

S[0160] Exemplary cancers that may be treated by compounds of the present C invention include solid tumors and hematologic malignancies. In another embodiment, preferred cancers that may be treated the compounds of the present invention are colon cancer, prostate cancer, hepatoma and ovarian cancer.

[0161] The compounds may also be used in the treatment of a disorder involving, relating to or, associated with dysregulation of histone deacetylase (HDAC).

[0162] There are a number of disorders that have been Implicated by or known to be mediated at least in part by HDAC activity, where HDAC activity is known to play a role in triggering disease onset, or whose symptoms are known or have been shown to be alleviated by HDAC inhibitors. Disorders of this type that would be expected to be amenable to treatment with the compounds of the invention include the following but not limited to: Proliferative disorders cancer); Neurodegenerative diseases including Huntington's Disease, Polyglutamine diseases, Parkinson's Disease, Alzheimer's Disease, Seizures, Striatonigral degeneration, Progressive supranuclear palsy, Torsion dystonia, Spasmodic torticollis and dysklnesis, Familial tremor, Gilles de la Tourette syndrome, Diffuse Lewy body disease, Pick's disease, Intracerebral haemorrhage Primary lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia, Progressive ataxia and Shy-Drager syndrome; Metabolic diseases including Type 2 diabetes; Degenerative Diseases of the Eye including Glaucoma, Age-related macular degeneration, macular myopic degeneration, Rubeotic glaucoma, Interstitial keratitis, Diabetic retinopathy, Peter's anomaly, retinal degeneration, Cellophane Retinopathy; Cogan's Dystrophy; Corneal Dystrophy; Iris Neovascularization (Rubeosis); Neovascularization of the Cornea; YWMalKII NO DLffB PIOlMS AU aesma Pulro S l ua l Fs nIiUdo COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR.2006 17:14 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 58 54 O Retinopathy of Prematurity; Macular Edema; Macular Hole; Macular Pucker; Marginal 0 Blepharitis, Myopia, nonmalignant growth of the conjunctiva; Inflammatory diseases and/or Immune system disorders including Rheumatoid Arthritis Osteoarthritis, SJuvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease, Colitis Ulcerosa, LC Alcoholic hepatitis, Diabetes, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain, Systemic Lupus Erythematosus, allergic contact dermatitis; Disease involving angiogenesis including cancer, psoriasis, rheumatoid arthritis; Psychological disorders including bipolar 1to disease, schizophrenia, depression and dementia; Cardiovascular Diseases including Heart failure, restenosis, cardiac hypertrophy and arteriosclerosis; Fibrotic diseases Sincluding liver fibrosis, lung fibrosis, cystic fibrosis and angiofibroma; Infectious CN diseases including Fungal infections, such as Candida Albicans, Bacterial infections, Viral infections, such as Herpes Simplex, Protozoal infections, such as Malaria, Leishmania infection, Trypanosoma brucei infection. Toxoplasmosis and coccidiosis, and Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.

[0163] In using the compounds of the invention they can be administered in any form or mode which makes the compound bioavailable. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19' edition, Mack Publishing Co. (1995) for further information.

[0164] The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. The compounds of the invention, while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.

[0165]The compounds are, however, typically used in the form of pharmaceutical compositions which are formulated depending on the desired mode of administration.

As such in a further embodiment the present invention provides a pharmaceutical composition including a compound of Formula and a pharmaceutically acceptable wYartm nfo amLEMnl0mi AU Sa brrwa .iWl I WnnFa.

COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:14 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 59 o carrier, diluent or exciplent. The compositions are prepared In manners well known in o the art.

[0168) The invention in other embodiments provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the Invention. In such a pack or kit can be found a container having a unit dosage of the agent The kits can include a composition comprising en effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the ol1 concentration of use, where the vials may Include one or more dosages. Conveniently, INO in the kits, single dosages can be provided in sterile vials so that the physician can o employ tie vials directly, where the vials will have the desired amount and concentration of agent(s). Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a is governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0187] The compounds of the invention may be used or administered in combination with one or more additional drug that are chemotherapeutic drugs or HDAC inhibitor drugs and/or procedures surgery, radiotherapy) for the treatment of the disorder/diseases mentioned. The components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug (0188] In addition to being able to be administered in combination with one or more additional drugs that include chemotherapeutic drugs or HDAC inhibitor drugs the compounds of the invention may be used In a combination therapy. When this is done the compounds are typically administered in combination with each other, Thus one or more of the compounds of the invention may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result (0169] Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nanaqusous solutions, Y'Wt.9M NO IDMlLWIOM AV mindP"M A lnuffa@ SSdA.

COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:14 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 56 Va o dispersions, suspensions or emulsions as well as sterile powders for reconstitution into Ssterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, Sethanol, polyois (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic l esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in 7- the case of dispersions, and by the use of surfactants.

t"- [0170] These compositions may also contain adjuvants such as preservative, wetting c agents, emulsifying agents, and dispersing agents. Prevention of the action of Smicroorganisms may be ensured by the inclusion of various antibacterial and antifungal Cl agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.

[0171] If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

[0172] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[0173] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, Y:dtM3J NO IELEBFM 1090 AU SUImd PtvO allt a on FI Jad COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:15 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 61 57 O cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite O clay, and 1) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of Scapsules, tablets and pills, the dosage form may also comprise buffering agents.

CLl [0174] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0175] The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying Cl agents and can also be of a composition that they release the active Ingredient(s) only, or preferentially, in a certain part of the Intestinal tract, optionally, in a delayed manner.

Examples of embedding compositions which can be used include polymeric substances and waxes.

[0176] If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

[0177] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0178] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl aloohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0179] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Y:1Mw.a I NO DEUII 4 -0 AU Swtad TvisimF l u RKlet COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:15 PHILLIPS ORMONDE FITZPATRICK NO- 3858 P. 62 58

O

0 0 [0180] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and Ssorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agaragar, and tragacanth, and mixtures thereof.

[0181] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non.

irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature O and therefore melt in the rectum or vaginal cavity and release the active compound.

0 S[0182] Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required, [01.83] The term "therapeutically effective amount" or "effective amount" Is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state. A therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.

[0184] A preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day. A more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day.

Y!'MTaKI NO DBLEBTSIP9Oi4 AU Sc PreWlml Flui E=hi.dAC COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:15 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 63 59 \o O [0185] As discussed above, the compounds of the embodiments disclosed inhibit 0 histone deacetylases. The enzymatic activity of a histone deacetylase can be measured using known methodologies [Yoshida M. et al, J. Biol. Chem., 265, 17174 S(1990), J. Taunton et al, Science 1996 272: 408]. In certain embodiments, the histone deacetylase inhibitor interacts with and/or reduces the activity of more than one known

C

histone deacetylase in the cell, which can either be from the same class of histone deacetylase or different class of histone deacetylase. In some other embodiments, the histone deacetylase inhibitor interacts and reduces the activity of predominantly one histone deacetylase, for example HDAC-1, HDAC-2, HDAC-3 or HDAC-8 which belongs to Class I HDAC enzymes [De Ruijter A.J.M. et al, Biochem. 370, 737-749 S(2003)]. HDACs can also target non-histone substrates to regulate a variety of o biological functions implicated in disease pathogenesis. These non-histone substrates C include Hsp90, a-tubulin, p53, NFkb and HIFIa [Drummond et al., Annu. Rev.

Pharmacol. Toxicol. 45:495 (2004)]. Certain preferred histone deacetylase inhibitors are those that interact with, and/or reduce the activity of a histone deacetylase which is involved in tumorigenesis, and these compounds may be useful for treating proliferative diseases, Examples of such cell proliferative diseases or conditions include cancer (include any metastases), psoriasis, and smooth muscle cell proliferative disorders such as restenosis. The inventive compounds may be particularly useful for treating tumors such as breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, head and/or neck cancer, or renal, gastric, pancreatic cancer and brain cancer as well as hematologic malignancies such as lymphomas and leukemias. In addition, the inventive compounds may be useful for treating a proliferative disease that Is refractory to the treatment with other chemotherapeutics; and for treating hyperproliferative condition such as leukemias, psoriasis and restenosis. In other embodiments, compounds of this invention can be used to treat pro-cancer conditions or hyperplasia including familial adenomatous polyposis, colonic adenomatous polyps, myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia with atypia, cervical dysplasia, vaginal intraepithelial neoplasla, benign prostatic hyperplasia, papillomas of the larynx, actinic and solar keratosis, seborrheic keratosis and keratoacanthoma.

[0186] Additionally compounds of the various embodiments disclosed herein may be useful for treating neurodegenerative diseases, and inflammatory diseases andlor immune system disorders.

[0187] In one embodiment the disorder is selected from the group consisting of cancer, inflammatory diseases and/or immune system disorders rheumatoid YIWM;Y I NO DBL IMtmrneo A Alm l hswavl iul Fin MFilAddK COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21,MAR2006 17:16 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 64 o arthritis, systemic lupus erythematosus), angiofibroma, cardiovascular diseases, fibrotic 0 diseases, diabetes, autoimmune diseases, chronic and acute neurodegenerative disease like Huntington's disease, Parkinson's disease, disruptions of nerval tissue and Sinfectious diseases like fungal, bacterial and viral infections. In another embodiment the disorder is a proliferative disorder.

[0188] The histone deacetylase inhibitors of the invention have significant 17- antiproliferative effects and promote differentiation, cell cycle arrest in the G1 or G2 phase, and induce apoptosis.

c SYNTHESIS OF DEACETYLASE INHIBITORS S[0189] The agents of the various embodiments may be prepared using the reaction Cl routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available, The preparation of particular compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. A list of suitable protecting groups in organic synthesis can be found in T.W. Greene's Protective Groups in Organic Synthesis, 3 r d Edition, John Wiley Sons, 1999. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the various embodiments.

[01901 Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.

10191] In the examples described below, unless otherwise indicated, all temperatures in the following description are in degrees Celsius and all parts and percentages are by weight, unless indicated otherwise.

[0192] Various starting materials and other reagents were purchased from commercial suppliers, such as Aldrich Chemical Company or Lancaster Synthesis Ltd., and used without further purification, unless otherwise indicated. Tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) were purchased from Aldrich in SureSeal VAlmr'NI NO DILEMBPIMMS AU Sted nPi.i.i Fal u luida COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:16 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 61 0 bottles and used as received. All solvents were purified by using standard methods in 0 the art, unless otherwise indicated, S[0193] The reactions set forth below were performed under a positive pressure of nitrogen, argon or with a drying tube, at ambient temperature (unless otherwise stated), C in anhydrous solvents, and the reaction flasks are fitted with rubber septa for the Introduction of substrates and reagents via syringe. Glassware was oven-dried and/or heat-dried. Analytical thin-layer chromatography was performed on glass-backed silica gel 60 F 254 plates (E Merck (0.25 mm)) and eluted with the appropriate solvent ratios l (vlv). The reactions were assayed by TLC and terminated as judged by the Sconsumption of starting material.

0 Cl [0194] The TLC plates were visualized by UV absorption or with a p-anisadehyde spray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20wt% in ethanol) which was activated with heat, or by staining in iodine chamber. Work-ups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume (unless otherwise indicated), Product solutions were dried over anhydrous sodium sulfate prior to filtration, and evaporation of the solvents was under reduced pressure on a rotary evaporator and noted as solvents removed in vacuo.

Flash column chromatography [Still et al, J. Org. Chem., 43, 2923 (1978)] was conducted using Silica gel 60 (Merck KGaA, 0.040-0,063 mm, 230-400 mesh ASTM) and a silica gel:crude material ratio of about 20:1 to 50:1, unless otherwise stated.

Hydrogenolysis was done at the pressure indicated or at ambient pressure.

[0195] NMR spectra were recorded on a Bruker AVANCE 400 spectrometer operating at 400 MHz for 1H NMR and 100 MHz for 13 C-NMR. NMR spectra are obtained as CDC13 solutions (reported in ppm), using chloroform as the reference standard (7.28 ppm and 77.14 ppm) or CDaOD (3.3 and 49.3 ppm), or DMSO-de (2.50 and 39.5 ppm) or an internal tetramethylsilane standard (0,00 ppm) when appropriate.

Other NMR solvents were used as needed, When peak multiplicities are reported, the following abbreviations are used; s singlet, d doublet, t triplet, q quartet, m multiplet, br broadened, dd doublet of doublets, dt doublet of triplets. Coupling constants, when given, are reported in Hertz.

(0196] Mass spectra were obtained using LC/MS either in ESI or APCI. All melting points are uncorrected.

NO DTELT OMBT 0 SOS AU Sgnd Pisil i a nil MilNS i COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:16 PHILLIPS ORMONDE FITZPATRICK NO. 385B P. 66 62

NO

0 0 [0197] All final products had greater than 90% purity (by HPLC at wavelengths of 254 nm and/or 220 nm). Analytical HPLC conditions for purity check: Xterra@ RP18 SiLm 4.6 x 20mm IS column; 2.0 ml/min, gradient 5-65% B over 4 min, then 65-95%b over 1 min and 95%B for additional 0.1 min; Solvent A: HgO with 0.1% TFA; Solvent B: C acetonitrile with 0.1% TFA.

[0198] The following examples are intended to illustrate the embodiments disclosed and are not to be construed as being limitations thereto. Additional compounds, other 0 10 than those described below, may be prepared using the following described reaction O scheme or appropriate variations or modifications thereof.

0 CN SYNTHESIS [0199] Scheme I and II illustrates the procedure used for preparing compounds of formula Ib, wherein X and Y are hydrogens, compounds (VII) of formula la can be prepared by analogous procedure, for example, by the choice of appropriate starting material. For example, in the case of Z is -CH=CH- and attached to Cr-position in Formula Ib, such compound(s) can be synthesized by analogous method illustrated in Scheme I and II starting with a substituted cinnamic acid trans-3-nitro-4-chlorocinnamic acid), appropriate amine component (R 1

NH

2 carboxylic acid component

(R

2 COgH, Scheme I) or aldehyde (R'CHO, Scheme II), and appropriate hydroxylamine or N-alkyl hydroxylamine (NHR 3 OH where R' is defined as above in Formula la), [0200] Specifically, the hydroxamate compounds Formula Ib can be synthesized by the synthetic route shown in Scheme I. The reaction of trans-4-chloro-3-nitrocinnamic acid with an amine R 1

NH

2 in the present of a base triethylamine) in an appropriate solvent dioxane) gave Treatment of (II) in methanol under acid catalysis sulfuric acid) resulted in esterification providing Alternatively, the carboxylic acid may be esterified to the methyl ester (la) and then the chloride was replaced by the appropriate amine component R'NH 2 to give compound (III). The nitro group of (III) can be reduced by appropriate reducing agent tin (II) chloride) and the resulting phenylenediamine (IV) was coupled with an acid R 2

CO

2 H to give amide which was subsequently cyclized in an appropriate solvent acetic acid) to give benzimidazole (VI) Med. Chem. 2001, 44, 1516-1529). The hydroxamate compounds (VI) were obtained from methyl ester (VI) by a known synthesis method (J.

Mad. Chem,, 2002, 45, 753-757).

YWWl NQ PVIUEW PlUOSM AU Smd Prakoduim Phil asFilrtdE COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-~AR-2006 17:17 PHILLIPS ORMONDE FITZPATRICK NO. 385B P. 67 Scheme I 0 0 2 N N

OH

cl-A.

R

1

NH

2 Base dioxane 0 2 N 1 OH H II C II la 0 MeOH O 2 N o.

H204

R'N-

H III =iRNH2 Base dioxane MeOM

H

0 SnCI 2

MH

2 N Co- AcOH/MeOH RNJ' H IV NH N 0

R'

u

R

2

CO

2

H

coupling reagent 0

'N

N

R

Al VI1 NHaOH.HCI NaOCH N N.OH R1

VII

[0201] Alternatively, as depicted in Scheme II, compound (VI) was prepared by reacting with an appropriate aldehyde component R 2 CHO in the presence of a reducing agent of nitro group tin (II) chloride or zinc powder) in one-pot (Tetrahedron Letters, 2000, 41, 9871-9874). Formic acid was used to prepare compound (VI) when R 2

H.

Scheme II 0 NOZN II

R

1 I 'N 1 Hl II

R'CHO

SnCl 2 or Zn AcOH/MeOH

HCO

2 H, SnC1 2 MeOH 0 R2-

O

R VI VI (R 2

H)

[0202] In both Schemes I II, the benzimidazole ring may be constructed by a cyclization step Involving either an aldehyde or a carboxylic acid. The following reaction steps 1-4 refer to the use of carboxylic acid for the cyclization of (IV) via to form benzlmldazole derivatives followed by the conversion of ester (VI) to the YAMYwiu MI DmsEflFImw AV ud h.fm ri n ficim l uip Pdae COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:17 PHILLIPS ORMONDE FITZPATRICK NO, 3858 P. 68 64 o hydroxamate (VII). For one-pot cycylization of (III) to see the procedures under SExample 1.

Step 1: Reduction of nitro group S[0203] To a pre-stirred solution of starting material (III, 1.0 mmol) in 50 mL of cosolvent (glacial acetic acid: methanol= Tin chloride was added (5.0 mmol). The Cl resulting solution was heated to 55°C overnight and then cooled to room temperature.

The solvent was removed and the mixture was neutralized with sodium bicarbonate to pH 8. The crude product was extracted with dichloromethane (20 mL) for three times.

The organic extracts were combined and washed with water (15 mL) twice and brine (15 mL) once and further dried over NazSO 4 for 1 hour. It was filtered and Sconcentrated; the diamino product (IV) was purified by flash chromatography.

SStep 2: Amide formation NC [0204] To a pre-stirred solution of carboxylic acid (1.1 mmol), diamino product (IV, mmol) and PyBOP (1.1 mmol) in 10 mL of dried dichloromethane, was added DIEA (3.0 mmol) via a syringe. The resulting mixture was stirred at room temperature for 4 hours. The amide product was purified by silica gel column chromatography.

Step 3: Cyclization [0205] The amide product obtained in Step 2, was treated with 5 mL of glacial acetic acid, the resulting solution was heated to 75 0 C for 24 hours. After cooling down to rt, the solvent was removed under vacuum to give product (VI) near quantitatively.

Step 4: Hydroxamic acid formation [0206] To a stirred solution of ester (VI) and NH2OH.HCI (10 equiv.) in MeOH M) was added NaOMe solution (20 equiv.) at 78 OC. The reaction mixture was then allowed to warm up slowly to room temperature, The reaction was monitored by LC/MS and was completed in around 15-60 min. 1N HCI was then added slowly into the reaction mixture at 0°C. The desired product was separated by reverse-phase preparative HPLC and the fractions containing the desired product were freeze-dried.

The hydroxamate product (VI) was obtained as TFA salt (isolated yield varies between [0207] Scheme III illustrates another alternative procedure used for preparing compounds of formula Ib, where X and Y are hydrogens and R 2 is selected from the group R 1

S(O)R

1 3 R"S(0) 2

R"

1

C(O)N(R'

1

R

11 0 2

N(R

1 2

)R

13

R"

1

N(R

12

)C(O)R

1

R

1 N(Run)SO 2 aR 1

R"N(R

1 2

)C(O)N(RI')R

3 and heteroalkyl. For example, in the case of Z is -CH=CH- and attached to Cs-posltlon in Formula Ib, such compound(s) (XIII) can be synthesized by analogous method illustrated in Schemes I Y~mWrw N DSLrtfiPlb IW AU I5ud 1 iihoi FiA U FIN04Ki COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR.2006 17:17 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 69 starting with appropriate (III), appropriate Fmoc protected amino acids, appropriate acid chlorides or aldehydes, and hydroxylamine.

Scheme III

O

0 2 N SnCI 2

/H,

2w OMe SO

RIN-

MeOH H III H F 4 Fmo-HN 1 Fmo-N OH

O

BO P DI A DC

HN

PyBOPNDIEANDCM

T

0

H

2 N- N OMe

R

1

IV

MeOH/H

RI

2

-CHO

NaBH(OAc)

CHWCOOH

NH2OH.HCJ NaOMe

O

OH rNI n

OH

R

1 2

R

1

XV

n=l, 2 [R2-SO 2

XIII

n=1, 2 [0208] More specifically, for example, the hydroxamate compounds Formula Ib, where X and Y are hydrogens, R 2 is selected from the group R"S(O)R 1 3

R"S(O)

2

R

13

R"C(O)N(R

1 2

)R

3

R

1

SO

2

N(R

12

)R

1 3

R

1 1N(R'1)C(O)R 1 RN(R12)SO 2

R

1 3

R"N(R

1 2 )C(O)N(R )R 1 3 and heteroalkyl; and Z is attached to Cs-position, can be synthesized by the synthetic route shown in Scheme III. Appropriate intermediate (III) was reduced with tin chloride to the corresponding diamines The coupling reaction with appropriate Fmoc protected amino acids in the presence of PyBOP gave coupling product(s) (VIII) and/or Without further separation, (VIII) and/or (IX) were subjected to cyclization under acid conditions and yielded benzimdiazole The key intermediate (XI) can be obtained by treating with 20% piperidine. Treatment of (XI) Ywtnlamm DELTBPlAIS AU Snl heovisiost ffll iato COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21, MAR. 2006 17:17 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 66 with an appropriate acid chloride or an appropriate sulfonyl chloride gave (XII) and the target compounds (XIII) were obtained by using similar method described in Scheme I.

[0209] When (XI) was reacted with an appropriate aldehyde under reduction conditions (NaBH(OAc) 3 /CH3CO 2 (XIV) was obtained and can be transformed to corresponding hydroxamate derivatives (XV) by the same methods described above, [0210] Scheme IV illustrates some reactions to further modify R 1 side chain. If the R' side chain contained a protecting group such as Boc in compound (Vial), it could be to removed before converting to the final hydroxamic acid (VIla). The intermediate (Via) could be modified by acylation, reductive alkylation, alkylation or sulfonylation to form new analogs (VIIb, Vile, Vld and Vile) through new intermediates (VIb, Vic, VId and Vie). The above described methods were also applied to R 1 heterocycles, R' N-Boc-piperidin-3-yl, N-Boc-piperidin-4-yl and N-Boc-pyrrolidin-3-y.

YWIUPINC NDO DUELT FIO AU MBet PrOHfi l kal pgo uMA COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR.2006 17:18 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 71 Scheme IV 0 0 N kN OMe N NNO Me NHBOH.HC I b R 2

IHOHH

N' N Vio via NaOCH 3 BOCN, R" HW R1

N

R HNRI

W

V12VI HW R1 Rl 2

CO

2 H or

{R

2 C0) 2 0

R

12 CH0 Reductive aminetion RlZX (Xz =halide)

R

12 50 2

CI

0

N

0 0 N zS NWOe

N'

Vie RIt. N1

'A

11 0 N2( N. N MS RI-ct N i

NH

2

OH.H(

NaOCH 3

NH

3

OH.HC

NaOCH 3

NH

2 0H.I 01 NaOCH% 1 2 0H.HCI aOCH3 0 N OH V113 HN,5 Ri it! N1OH N H

VIM

0 0 RN N'J N 0OH N

H

,i R11 0 N

OH

H

N R R12.§ N-R1 0

I

N

s [0211] Scheme V illustrates some alternative method to prepared (Via) and (Vic).

The primary amine (111a2) was prepared either from (Ia) or via (ll1.1). The derivertization of the amino group reductive amination) could be performed either from (111a2) or (V1a2). The products, (111a2-1) and (VIa2-1), could be further derivertized reductive amination of the secondary amine).

YUAPuI4 NoBEETS7ID9D A IAUd Iioudml hiul wuPikdig COMS ID No: SBMI-03086169 Received by IP Australia: lime 18:02 Date 2006-03-21 21. MAR. 2006 17:18 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 72 Scheme V o2NyoX H1N NHBac 0

HN

A' S lUaU NH2 'a ON 0 O2NtrAor' sf NH2 R1 2 ri40 reductive nmnn.

NH

2 CHO or HC02H C12 or Zn Va

R

1 CH0 a reductive aminatlon

R

2 CHO or HC0H SnCl 2 or Zn N 'N 0

N

N:

HN

R1 0 0 R2

R

12 Via.2 0 0 0 2 N 1 e 0 2

N

HN 1 HN Ft12 R lu 1 2 11* Nl-l IR12 [0212] The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the subject matter hereof. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

Preparation of intermediates III [0213] Compound (III) was prepared either from via (11) or from via (Ia) (Scheme I and The following are examples of (III).

Intermediate I 3-[4(2eDimethylamino-ethylamino).3.nitro-phenyl]-acrylic acid methyl ester [0214] A mixture of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (la, 0.658 g, 2.72 mmol), N,N-dimethylethylenediamlne (0.90 mL, 8.20 mmol) and triethylamine (1.2 ml, 8.8 mmcl) in dioxane (20 mL) was heated at 801C for Sh, The solution was evaporated and the residue was added DCM and aqueous Na 2 CO3. The DCM (x3) extracts were concentrated and the residue was added EtOAc-hexane. The resulting red solid was filtered to give the titled compound (0.872 g, HPLC purity at 254 nm: 99.2%, tR 1.59 min. LCMS (ESI) m/z: 294 (M 1 H NMR (CDC 3 CD3OD) 8 8.21 H, d, J 2.1 Hz), 7.55 (1H, dd, J 9.0, 2.1 Hz), 7.48 (1H, c, J 16.0 Hz), 6.81 (1H, d, J a 9.0 Hz), 6.20 (1H, d, J 15.9 Hz), 3.70 (3H, 3.34 (2H, t, J m 6.5 Hz), 2.56 YTMfArUmI o DSETEIDO.GM AJ Stmid MrnauIl slint! ldAs COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 I 21.MAR..2006 17:18 PHILLIPS ORMONDE FITZPATRICK NO.3858 P. 13 vi 0 0 ci ci j i 5 *1

I

10k4 tdl G9 ItJ 6.4 Hz), 2.23 (61H, l"C NMR (ODC1 3 OD3OD) 8 187.3, 145.4, 142.6, 13101, 127.1,121.3, 114.8.,114.0, 50.7,51.1, 44.5, 40.1.

Drmedi to 2 112-Di 4hylaanino-ethylamlno),-.nltro-phenylj-acrylic acid methyl ester.

15] 'lillow solid. LOMB (ESI) mlz: 322 'H NMR (COC13) 8 8.73 (I1H, t- J 4t Hz), 8.32 (1IH, d, J 2.0 Hz), 7.62 (I H, dd, J 9.2, 2.0 Hi), 7.58 (iNH, d, J 5.9 Hz4j 6.85 (IN, d, J 9.0 Hz), 6.29 (1H, d. J 16.9 Hz), 3.80 (31H, 3.35 (2H.

5.4,!6.0 Hz), 2.77 t, J 6.2 Hz), 2.59 (4H, q, J 7.1 Hz), 1.07 (15HI, t, J 7.1 Hz) lnt rmedi te3 3-[H 2.EtL amno-thYmIno).3-ntrophenyli-cwllc acid methyl ester [Ot 5] F;sd solid. LCMS (ESI) m/z: 294 (fM 1 H NMR (DMSO-d.)8 5.49 (1H. t, 6.1H4, 8.3 (I H, d, J 2.0 Hz), 7.96 (11H, dd, J 9.1, 1.9 Hz), 7.52 d, J I6 Hz), 1.20 (INH, d, J a 9.1 Hz), 6.52 (INH, d, J 16.0 Hz), 3.75 (2H, td, J 6.5, 6.2 Hz 1 3.70 (OH, 3.08 t, J 6.5 Hz), 2.93 (4H, q, J 7.2 Hz), 1.17 (OH, t, JG 7.2 I rmmd4te 4 3-,-(2-lsaoropylamlnoethylamlno)-3.nitro-phenyl].,cryllc acid methyl ester [0 17] Fd solid, LOMS (ESI)rmlz: 308 1 H NMR (DMSO-d 8 88.58 (IH,t, J 5.6 H4, 8.33 (1iH, d, J =2.0 Hz). 7.94 (I H, tdd, J 1.9 Hz), 7.60 (IH, dE, J= i6 1 k Hz), t14 (I H, d, J 9.2 Hz), 6.49 (I1-H, d, J 16.0 Hz), 3.70 3.56 (2H, malked b 4 water peak, identified by COSY), 3.10 (i H, septet, J 6.4 Hz), 2.94 (2H1, t, j 4 6.2 Hz), 1. 10 (6H. dE, J 6.4Hz).

Intirmd4te 3-f-(3-DlIthylamlno-2,2dlmethyl-propylarnino)4-nitro-phnyl].acrylic acid M hyl es r.

[0T 8] ~d solid. LCMS (ESI) m/z: 336 Hfl). 1 H NMR (ODC~b) 8 9.73 (1 H, br s or) 8.33 1~l M, J =2.0 Hz), 7.60 (IN H. d, J r- 8.9, 2.0 Hz). 7.59 (INH, d. J 16. 1 Hz), t(IH, 9.1 Hz), 6.28 (11H, d, J 15.9 Hz), 3.80 (3H, 3.21 (2H1, di, Jm 4.6 Hz,2.36 (PH, 2.34 (15H. 1.04 (6H, s).

lnt -rmedte 6 3.[1t-(2-Dllopropylamlno-ethylamino).a-nitro-phenyl].acrylic acid methyl esar IM4NU OPt IS AV3U a VMine US M FUMNi-l e COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:18 PHILLIPS ORMONDE FITZPATRICK NO- 3858 P. 74 O (0219] Yellow solid. LCMS m/z: 350 1 H NMR (CDCIl) 8 8.76 (1I, t- O like, J 4.3 Hz), 8.32 (1H, d, J 2.0 Hz), 7.61 (1H, dd, J 8.3, 2.7 Hz), 7.58 (1H, d, J 15.8 Hz), 6.85 (1H, d, J 9.0 Hz), 6.29 (1H, d, J 15.9 Hz), 3.79 (3H, 3.31 (2H, C td, J 5.3, 6.1 Hz), 3.08 (2H, septet, J 6.6 Hz), 2.84 (2H, t, J 6.2 Hz), 1.07 (12H, d, J 86.6 Hz).

Intermediate 7 3 -[4-(2-Methylamino-ethylamino)-3-nitro-phenyl]-acryllc acid methyl ester [0220] Red solid. LCMS (ESI) m/z; 280 1 H NMR (CDCI 3 8 8.54 (1H, t-like, o 10 J 4.2 Hz), 8.33 (1H, d, J 2,1 Hz), 7.63 (1H, dd, J 9.0, 2.2 Hz). 7.59 (1H, d, J= 16.0 Hz), 6.90 (1H, d, J= 9.0 Hz), 6.31 (1H, d, J= 15.9 Hz), 3.80 (3H, 3.45 (2H, td, J 5.8, 5.6 Hz), 2.96 (2H, t, J 6.2 Hz), 2.50 (3H, s).

Intermediate 8 3-[ 4 2 -tert-Butoxycarbonylamino-ethylamlno)-3-nitro-phenyl]-acrylic acid methyl ester (Illal) Step 1: [0221] A suspension of trans-4-chloro3-nitrocinnamic acid 5.057 g, 22.22 mmol) in MeOH (40 mL) and DCM (20 mL) was stirred and cooled in a dry-ice/acetone bath.

SOCI

2 (1.0 mL, 13.8 mmol) was added to the above mixture. Dry-ice bath was removed, then the mixture was warmed to room temperature and stirred at 40 OC till the reaction completed. The solution was evaporated to dryness to a pale yellow solid (5.364 g, HPLC purity at 254 nm: 99.5%; tp 2.96 min. LCMS (ESI) m/z: 210 and 212 (very weak signal, [M+H-MeOH]*).

Step 2: [0222] A mixture of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (la, 0.243 g, 1.00 mmol), N-Boc-ethylenediamine (0.316 mL, 2.0 mmol) and triethylamine (0.50 mL, 3.59 mmoL) in dioxane (7 mL) was heated at 80"C for about 80 h. The solution was evaporated and the residue was added MeOH. The resulting solid was filtered and washed with MeOH. 3 4 2 -tert-Butoxycarbonylamino-ethylamino)-3-nitro-phenyl]acrylic acid methyl ester (Ilial) was obtained as bright yellow solid (0,193 g, 52,6%), HPLC purity at 254 nm: 96.0-98.1%; tR 3.27 min, LCMS (ESI) m/z: 366 310 266 (M+H-Boc). 1H NMR (CDCis) 8 8.41 (1H, br t like, NHAr), 8.31 (1H, d, J 1.8 Hz), 7.63 (1H, dd, J 9.0,1.7 Hz), 7.57 (1H, d, J 16.0 Hz), 6.98 (1H, d, J 8.9 Hz), 6.30 (1H, d, J 15.9 Hz), 3.80 (3H, 3.52 (2H, 3,45 (2H, 1.45 (9H, VY;\%EOW MN PBIITEllRBOS AU Bus iidall PUnhl a 7id*dc COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:19 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 71 o 13 C NMR (CDC13) 8 166.9, 155.7, 145,8, 142.3, 134.1, 131.5, 127.1, 121.8, 115.4, 0 113.9, 79.5, 512, 42.7, 39.1, 27.9, Intermedi4te 9 3-[4-(2-Arrino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester (11a2) C( [0223] Method 1: Remove Bbc protecting group from (Illal) under acidic condition: 1) HCI/MeOH; 2)

TFA/DCM.

[0224] Method 2: To the ester (la, 2.47 g, 10.2 mmol) in dioxane (102 mL, 0.1 M) was added Sethylenediamine (Merck. Product no. 8.00947, 2.04 mL, 30.6 mmol) followed by triethylamirte (2.8 mL, 20.47 mmol). The resulting mixture was heated to 90 °C and stirred for 20 hours. The completion of reaction was confirmed by using HPLC (where the product llla2 tR 1.6 min, starting material la tR 3.1 min). Upon completion, solvent was removed and the crude was dissolved in DCM. The solution was washed with water, brine, dried over Na 2 SO, and filtered. The filtrate after removal of the solvent gave the titled compound llia2. Yield 98 LCMS m/z: 266 4 Example 1 Preparatlan of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl).2-(2,2-dimethylpropyl)-1 H-benzolmldazol-5-yl]-N-hydroxy-acrylamide (1) [0225] the titled compound was prepared according to Scheme 1 and II, by using appropriate starting materials, Step 1: [0226] To a pre-stirred solution of trans-4-chloro-3-nitrocinnamic acid 11g, 48 mmol) in dloxane (200 mL) was added triethylamine (20 mL, 126 mmol), followed by 3dimethylantino-2,2-dimethyl-propylamine (20 mL, 143 mmol). The reaction mixture was allowed to stir at 100 OC for 1-2 days till all starting material was fully converted. Then, the solvent was removed under vacuum followed by the addition of H0O (250 mL) to dissolve the residue. Cone. HCI was added till pH 1 with orange precipitation, The suspension was filtered and residue was washed with H 2 0 several times to obtain (II) as orange solid (13 g, LCMS (ESI) m/z; 322 Step 2: [0227] Cbmpound (11,13 g, 40.5 mmol) was dissolved in MeOH (250 mL) followed by the additiot of cone. HzSO, (5 mL). The reaction mixture was allowed to stir at 80 °C for 18 h. Solvent was removed under vacuum and H 2 0 (250 mL) was added to dissolve the residu). Na 2

CO

3 was added till pH 8-9, subsequently, MeOH was added and YV UyQ4IUN DE*EL F1M.IQ AUSl nd Pniiail Mid as rlad.

COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 !21-.MAR. 2006 17:19 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 76 72 o stirred for 1 hour. Then, the suspension was filtered under vacuo and the residue was 0 washed with H20 several times to obtain ester (III) as orange solid (10 g, LCMS (ESI) m/z: 336 SStep 3: [0228] To a stirred solution of ester (III, 1 equiv) and SnCl 2 2HaO (5 equiv) in AcOH Cand MeOH (0.2 M, 1:9 mixture) was added 3,3-dimethyl butyraldehyde (1.5 equiv). The resulting mixture was heated to 45 OC with stirring. The progress of the reaction was monitor by LC/MS. When the reaction was completed, solvent was removed under reduced pressure at 30-35°C. To the resulting residue, 20 mL of water and 20 mL of ethyl acetate were added at room temperature, the pH value of the mixture was O carefully adjusted to 9-10 by addition of cone. NHslH 2 0. The mixture was stirred for half an hour, followed by centrifuge if necessary to separate the organic layer. The Sorganic layer was collected. The aqueous phase and residue (oily-solid precipitate) were extracted another 3 times more with ethyl acetate as described above. The combined organic contents were dried over sodium sulphate, filtered and evaporated to dryness. The resulting oily residue was purified by flash column chromatography (isolated yield of cyclized product (VI) varies between 50-90%). LCMS (ESI) m/z: 386 Step 4: [0229] To a stirred solution of ester (VI) and NH 2 OHHCI (10 equiv,) in MeOH was added NaOMe (20 equiv.) at 78 OC. The reaction mixture was then allowed to warm up slowly to room temperature. The reaction was monitored by LC/MS and was completed in around 15 min. 1N HCI was then added slowly Into the reaction mixture at 0 oC. The desired product was separated by prep-HPLC and the fractions containing the desired product were freeze-dried, Product (VII) was obtained as di-TFA salt (isolated yield varies between 40 HPLC purity at 254 nm: 100%, tR 0.78 min.

LCMS (ESI) m/z: 387 'H NMR (DMSO-de) 8 0.99 (15H, 2,91 (6H, 2,92 (2H, 3.32 (2H, bs), 4.30 (2H, 6.49 (1H, d, J 15.8 Hz), 7.56 (1H, d, J 9,0 Hz), 7.61 (1H, d, J a 15.76 Hz), 7.83 (1H, d, J 9.0 Hz), 7.85 (1H, 9.22 (1H, be), 10.72 (1H, bs); 13C NMR (DMSO-de) 8 162.6, 154.2, 138.0, 135.3 134.7, 131.5, 122.8, 119.2, 115.2, 114.0, 66.5, 51.1, 46.7, 38,4, 38.3, 33.6, 29.1, 22.8.

Y.Mr«nH Ol 0 MLEfMO0 AU lamd havieoua Nl as NRd,s COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:19 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 77 73 O Example 2 SPreparation of 3-[1 (3-Dlmethylamlno-2,2-dlmethyl-propyl)-2-isopropyl-1H.

(2) S[0230] The titled compound was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100%, tR S= 0.54 min. LCMS (ESI) m/z; 359 1 H NMR (DMSO-de) 5 1.05 (6H, 1.40 (6H, d, J 6.36 Hz), 2,92 (6H, 3.36 (2H, 3.58 (1H, m, J 6.4 Hz), 4.44 (2H, s), 6.65 (1H, d, J 15.8 Hz), 7.63 (1H, d, J 15.8 Hz), 7.66 (1H, d, J 8.7 Hz), 7.95 (1H, d, J 8.7 Hz), 7.90 (1H, 9.71 (1H, bs), 10.80 (1H, bs).

o SExample 3 Preparation of 3-[2-Butyl-l-(3-dlmethylamlno-2,2-dimethyl-propyl).1H- N benzoimidazol-5-yl]-N-hydroxy-acrylamide (3) [0231] The titled compound was prepared according to the procedures described in Example 1, by using appropriate starting materials. Yield: 74 mg as TFA salt. HPLC purity at 254 nm: 99.0%, tR 0.89 min. LCMS (ESI) m/z: 373 'H NMR (CDO0D) 8 7.99 (1H, d, J 8.8 Hz), 7.84 (1H, 7.72 (1H, d, J 8.7 Hz), 7,55 (1H, d, J 15.8 Hz), 6.53 (1H, d, J 15.7 Hz), 4.55 (2H, 3.43 (2H, 3.24 (2H, overlapped with CD2HOD), 3.00 (6H, 1.90 (2H, pentet, J 7.2 Hz), 1.49 (2H, 1,21 (6H, s), 0.98 (3H, t, J 7.3 Hz); '3C NMR (CDsOD) 8 165.5 158.2, 139.8, 135.3, 135.1, 132.4, 126.4, 120.6 115.6, 114.3, 68.7, 53.5, 47,8 (Mex2), 39.5, 29.9, 27.2, 23.6 (Mex2), 23.3, 13.9.

Example 4 Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2-methylsulfanylethyl)1 H-benzolmldazol-5-yl]-N-hydroxy.acrylamide (4) [0232] The titled compound was prepared according to the procedures described in Example 1, by using appropriate starting materials, Yield; 17 mg as TFA salt. HPLC purity at 254 nm: 96.2%, tR 0,75 min. LCMS (ESI) m/z: 391 'H NMR

(CDO

3 D) 8 8.02 (1H, d, J 8.3 Hz), 7.92 (1H, 7.80 (1H, d, J 8.7 Hz), 7.69 (1H, d, J 15.8 Hz), 6.60 (1H, d, J 15.8 Hz), 4.49 (2H, 3.50 (2H, t, J 7.2 Hz), 3.37 (2H, s), 3.03 (2H, t, J 7.2 Hz), 2,95 (6H, 2.18 (3H, 1.25 (6H, 3 C NMR (CD 3 OD) 8 163.7, 154.0, 138.2, 133.9, 132.8, 132,5, 124,1, 118.2, 113.3, 113.2, 66.7, 51.5, 45,9 (Mex2), 37.6, 29.9, 26.2, 21.7 (Mex2), 13.7.

YfirI H NODELTP IC.CAUSrndmrtalu AlFhlul al COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 Va 0 0 ci ci 0 ci Va 0 0 ci 121. MAR. 2006 1 Pr be [old Ex Pri hy il

(DI

Ex~

P

hy~ In as 7.4 Ida (3 121 1: 19 PHILLIPS ORMONDE FITZPATRICK NO. 3856 P. 78 ample 0 hparatl4n of 341 .(3-Dlmethylmmlno-2,2..dlmethyl-propyl).2.isobutyl1

H-

lzoimi4azols-yI]-N-hydroxy-acrylamide (6) 33] the titled compound waB prepared according to the procedures described xamplg 1, by using appropriate starting materials. HPLC purity .t 254 nm: 96.2%, tR .82 mini. LCMS (E81) m/z; 373 ([M+l-lfl. 'H NMR (DMSO-de): 8 10.80 (i H, sn), 9.47 7.03 (1 H, 7.90 (1 H, d, J a 6.6 Hz), 7,64 (1I-H, d, J a 7.4 Hz), 7.62 (1IH, d, J'M Hz),0.54 (IN, d,J= 15.8 Hz), 4.39(2H, 3.33(2H, s).2.97 (2H, d,J= 726Hz), 2(6H, 2.35 (1 H, qn), 1.09 (OH, 0.97 (OH, d, J =6.6 Hz).

Imple

I

ipnrtcn of 341 -(2-Dlethylamnlno-ethyl)-2-Isobutyl-1 lroxy-4larylamide (7) 41 the titled compound was prepared according to the procedures described xampldl 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.0%, tR .,56 min, LOMB (ESI) m/z: 359 (jM+I-Ifl. 'H NMR (DMWIS-da): 8 io.ai (IN, sn), 10.13 in), 7.00 (INH, sn), 7.81 (INH, d, J =8.5 Hz), 7.68 (1iH, d, J1=8.68Hz), 7.81 (INH, d, Hz), 0.53 (IN di, J =15.8Hz), 4.72 t, J5=7.8 Hz), 3.30 (2H, 2.93 (2H, d, J .2 Hz), :2.27 in), 1.24 (OH, t, J 7.2 Hz), 0.97 (OH, d, J 6.6 Hz) '3 C NMR SO0-d.) 162.7, 158.5, 158.2, 155.2, 138.4, 133.9, 131.0, 123.0, 118.6, 116.0, 48.$,46.8, 84.1, 27.1, 22.2, mple p aratl n of 3 Butyl lethylam ino-thyl) H.b mnzoim id uzol-5 y pNroxy-abrylaimde (8) 5] IThe tidled compound was prepared according to the procedures described xampIo 1, by using appropriate starting materials. Yield: 61 mg (20% in two steps) r PA sat. H PLO purity at 254 nm: 98.1 tR 0. 59 min. LCMS (ESI1) m/z: 359 1'H NO~R (00 3 0D) 8 7.89 (1iH, d, J 8.6 Hz), 7.80 (11H, 7.71 (11H, d, J 8.5 Hz), 5 (114 H, J 15.7 Hz), 6.44 (1IH, d, J 15.7 Hz), 4.90 (2H4, overlapped with DHO, htlfied bWCOSY), 3.64 (2H, t-llke, J -a7.0 Hz), 3.39 (4H, q, J 7.0 Hz), 3.21 (2N, t, J .9 Hz),-1.89 (2H, pentet, J 7.5 Hz), 1.52 (2H4, mn), 1.35 (8H, t, J 7.2 Hz), 1.00 bt, J a7.3 Hz); 3 C NMR (CD 3 OD) 8 163.6, 155.7, 11, 132.8, 132.1, 131.9, 118j0, 113.2, 111.7,48.3, 46.8 38.5, 27.5, 24.7, 21.4, 12.0, 7.0 %IJX NO MLtTIFUM3AUSa Itmisoal fid. Fflm COMS ID No: SBMI-03086189 Received by IP Australia: Time 18:02 Date 2008-03-21 21-MAR2006 17:20 PHILLIPS ORMONDE FITZPATRICK NO, 3858 P. 79 o Example 8 o Preparation of 3-[2-But-3-ynyl-1-(3-dimethylamlno-2,2-dlmethyl-propyl)-1H- (9) S[0236] The titled compound was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98.3 C tR 0.52 min; LCMS (ESI) m/z: 369 'H NMR (DMSO-de) 8 9.49 (bra, 1H), 7.88 7.85 2H), 7.63 7.59 2H), 6.52 J 15.79 Hz, IH), 4.37 1H), 3.33 2H), 3,26 J 7.24 Hz, 2M), 2.92 6H), 2.88 J 2.54 Hz, 1H), 2.81 (dt, J 2.48, 7.70 Hz, 2H), 1.09 6H); 3C NMR (DMSO-do) 6 162.8, 155.3, 138.4, 138.0, 138.9, 130.5, 122.3, 118,4, 117.8, 116.4, 114.9, 112.9, 111.9, 82.8, 72.3, 66.9, 50.9, S45.7, 25.8, 22.8, 16.2.

0 Ci Example 9 Preparation of 3-[2-But-3-enyl-1 (3-dimethylamino-2,2-dlmethyl-propyl)-1 Hbenzoimidazol-5-yl]-N-hydroxy-acrylamide [0237] The titled compound (10) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm; 99 tR 0.80 min; LCMS (ESI) m/z: 371 'H NMR (CDsOD) 8 7.95 (d, J 8.8 Hz, 1 7.85 1H), 7.73 J 8.8 Hz, 1H), 7.63 J= 15.8 Hz, 1H), 6.54 J 15.8 Hz, 1 5.94 5.84 1H), 5.10 (dd, J= 1.4,17.1 Hz, IH), 5.03 (dd, J= 1.1, 10.2 Hz, 1H), 4.51 2H), 3,40 2H), 3,32 J= 7.6 Hz, 2H), 2,99 6H), 2,66 J 7.5 Hz, 2H), 1.19 6H); "C NMR (CDaOD) 8 165.7, 157.6, 140.2, 136.3, 135.9, 134.7, 134.5, 125.9, 120,2, 117.9, 115.2, 103.6, 88.8, 53.4, 39.6, 32.0, 27.2, 23.7, Example Preparation of 3-[2-But-3-enyl-1-(2-diethylamlno-ethyl)-1 hydroxy-acrylamide (11) [0238] The titled compound (11) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC: 99,4 tR 0.52 min; LCMS (ESI) m/z: 357 'H NMR (CD0D) 8 7.94 J 8.7 Hz, 1H), 7.81 1H), 7.73 J= 8.3 Hz, 1H), 7.50 J 15.87 Hz, 1H), 6,46 J= 15,8 Hz, 1H), 5,96 -5,86 1H), 5.13 (dd, J 1.4, 17,1 Hz, 1H), 5.05 (dd, J= 1.1, 10.2 Hz, 1H), 4.93 J 7,9 Hz, 2H), 3,62 3.58 2H), 3.38 3.31 6H), 2,65 J 7.6 Hz, 2H), 1.35 1.32 6H); "C NMR (CDsOD) 8 165.8, 157.0, 140.5, 136.6, 135.9, 134.6, 134.2, 126,1, 119.5, 117.7, 116.0, 113.3, 50.4, 40.4, 31.7, 26.7, 9.1.

YtaM WnoO DDEaTWlWluOr AU sWrd PMriuOl AFin WIIe el4 COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21.MAR. 2006 17:20 PHILLIPS ORMONDE FITZPATRICK NO, 3858 P. 76 o Example 11 o Preparation of 3-[2-But-3-ynyl-1-(2-diethylamlno-ethyl)-1H-benzoimidazol-5-yl]-N- Shydroxy-acrylamide (12) [0239] The titled compound (12) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC: 99.6 tR Cl 0.37 min; LCMS (ESI) m/z: 355 1H NMR (CD.OD) 8 7.82 J 8.7 Hz, 1H), 7.68 1H), 7,58 J 8.5 Hz, 1H), 7.31 J m 15.8 Hz, IH), 6.31 J 15.8 Hz, 1H), 4,87 -4.79 (masked peaks), 3.54 3.50 2H), 3.37 J 7.1 Hz, 2H), 3.24 (q, J 7.2 Hz, 4H), 2.73 (dt, J 2.4, 6.9 Hz, 2H), 2.30 J 2.5 Hz, 1H), 1.21 J 7.2 o 10 Hz, 6H); 1"C NMR (CD 3 OD) 5 165.9, 156.1, 140.9, 138.1, 135.2, 133.4, 125.6, 118.8, S117.0, 112.8, 82.4, 72.1, 50.6, 40.2, 26.7, 26.4, 17.3, 9.1.

0 CN Example 12 Preparation of 3*[1 (3-Dimethylamino-2,2-dlmethyl-propyl).2-(3,3,3-trifluoropropyl)-1H-benzoinidazol-5-yl]-N-hydroxy-acrylamide (13) [0240] The titled compound (13) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 96.5 tR 0.80 min; LCMS (ESI) m/z: 413 Example 13 Preparation of 3-1 -(2-Dlethylamlno.ethyl)-2-(3,3,3-trifluoro-propyl)

.H-

(14) [0241] The titled compound (14) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity: 96.4%; tR 1.37 min; LCMS (ESI) m/z: 399 "H NMR (DMSO-de) 5 1.25 (6H, 2.96 (2H, 3.31 (6H, 3,44 (2H, 4.72 (2H, 6.51 (1H, 7.51 (2H, 7.65 (1H, 7.83 (1H, 10.45 (1H, bs).

Example 14 Preparation of 3-[1-(2-Diethylamino-ethyl)-2-ethoxymethyl-1H-benzolmidazol-5yl]-N-hydroxywacrylamide [0242] The titled compound (15) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity: 98.1%; tR 0.48 min; LCMS (ESI) m/z: 361([M+H] VMlAUu Nm DELEf W L omgS tml ha inn l nPIum h Fi idepA COMS ID No: SBM1-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21,MAR2006 17:20 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 81 77 O Example 0 Preparation of 3,[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-methyl1 H- (16) [0243] The titled compound (16) was prepared according to the procedures s described in Example 1, by using appropriate starting materials. HPLC purity: 99.5%; tR 0.30 min; LCMS (ESI) m/z: 331 'H NMR (DMSO-d) 5 1.13 (6H, 2.78 (2H, 2,89 (6H, 3.33 (2H, 4.42 (3H, 6.57 (1H, 7.57-7.69 (2H, 7.95 (2H, 9.68 (1H, bs), 10.81 (1H, bs) Example 16 c Preparation of 3-[1 (2-Diethylamino-ethyl)-2-(2,2-dlmethyl.propyl)1 H- O benzoimldazol-5-yl]-N-hydroxy-acrylamlde (17) C [0244] The titled compound (17) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 s1 nm: 99.9%, tR 0.95 min. LCMS (ESI) m/z; 373 1 H NMR (CDsOD) 8 7.85 (2H, t, J= 8.3 Hz), 7.75 (1H, d, J= 8.8 Hz), 7,61 (1H, d, J= 15.8 Hz), 6.51 (1H, d, J= 15.8 Hz), 4,93 (2H, t, J 6.1 Hz), 3.54 (2H, t, J 8.1 Hz), 3.31 (4H, qt, J 7.3 Hz), 3.10 (2H, 1.27 (6H, t, J 7.3 Hz), 1.06 (9H, 13 C NMR (CD 3 OD) 8 163.7, 153.3, 138.3, 133.1, 131.9, 124.5, 118.3, 117.1, 113.5, 111.8, 48.1, 39.1, 37.5, 32.9, 27.8, 7.1.

Example 17 Preparation of N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-(3,3,3-trlfluoropropyl)-1 H-benzoimidazol-5-yl]-acrylamide (18) [0245] The titled compound (18) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity: 96.8%; tR 0,72 min. LCMS (ESI) m/z: 399 4 'H NMR (DMSO-ds) 5 1.18 (6H, 2.07 (2H, 2.95 (4H, 3.27 (3H, 4.43 (2H, 6.52 (1H, 7,55 (2H, 7.61 (1H, 7.84 (1H, 8,65 (2H, bs).

Example 18 Preparation of 3-2-(2,2-Dimethyl-propyl)-1 -(2-isopropylamino-ethyl)-1 H- (19) [0246] The titled compound (19) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98.1%, tR 0.86 min. LCMS (ESI) m/z: 359 'H NMR (CDaOD) 8 7,86 (1H, d, J 8.6 Hz), 7.78 (1H, 7.73 (1H, d, J 8.5 Hz), 7.44 (1H, d, J 15.8 Hz), 6.45 (1H, d, J 15.4 Hz), 4.83 (2H, t, J 6.42 Hz), 3.52 (2H, t, J= 6.6 Hz), 3.36 (1H, Y.WtNW WO LuIE'WEOu-Oj AU Seam PwtviiMaui Full RIme d COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:21 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 82 78 Va O qt, J= 6,5 Hz), 3.13 (2H, 1.26 (6H, d, J 6.2 Hz), 1.04 (9H, 3C NMR (CDsOD) 8 0 161.2, 153.4, 138.3,133.0,124.4, 113,6,112.0, 51.1,41.8,41.1,37.3, 33.1,27.8, 17.2.

SExample 19 Preparation of 3-[1-(2-Dllsopropylamlno-ethyl)-2-(2,2-dimethyl-propyl)1 H- [0247] The titled compound (20) was prepared according to the procedures described in Example 1. by using appropriate starting materials. HPLC purity at 254 nm: 96.8%, tA 0.94 min. LCMS (ESI) m/z: 400 'H NMR (CD 3 OD) 5 7.86 o 10 (1H, 7.80 (1H, d. J 8.7 Hz), 7.76 (1H, d, J 8.6 Hz), 7.62 (1H, d, J 15.8 Hz), O 6.52 (1H, d, J 16.0 Hz), 4.96 (2H, t, J 5.2 Hz), 3.84 (2H, 3.53 (2H, t, J 8,3 Hz), o 3.06 (2H, 1.38 (12H, d, J 6.5 Hz), 1.05 (gH, "C NMR (CD 3 OD) 5 160.2, 153.1, 138.2, 133.2, 131.9, 124.6, 113.5, 111.8, 54,9,423.0, 40.5, 37.7, 33.0, 27.8, 16.3.

Example Preparation of 3-[1-(2-Dllsopropylamlno-ethyl)-2-isobutyl- N-hydroxy-acrylamide (21) [0248] The titled compound (21) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 95.3%, tR 0.76 min. LCMS (ESI) m/z: 387 1 H NMR (CDaOD) 5 7.85 (1H, 7.71 (2H, 7.66 (1H, d, J= 15.8 Hz), 6.51 (1H, d, J= 15,8 Hz), 4.75 (2H, t, J 7.2 Hz), 3.86 (2H, t, J 6.5 Hz), 3.50 (2H, t, J 8.6 Hz), 2.98 (2H, d, J 7.4 Hz), 2.26 (1H, m) 1.41 (12H, d, J 6.3 Hz), 1.06 (6H, d, J 6.6 Hz), Example 21 Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-hex-3-enyl-1 H- (22) [0249] The titled compound (22) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99,9%; tR 1.24 min; LCMS (EI1) m/z: 399 'H NMR (CD 3 OD) 8 8.22 (d, J 8.7 Hz, 1H), 8.11 1H), 7.96 J= 8,6 Hz, 1H), 7.81 J= 15.8 Hz, 1H), 6.68 J 15.8 Hz, 1H), 5.69 5.59 2H), 4.79 2H), 3.66 2H), 3.55 J 7.3 Hz, 2H), 3.24 6H), 2.91 J 6.8 Hz, 2H), 2.21 2.11 2H), 1.44 6H), 1.02 J Hz, 3H); NMR (CD 3 OD) 6 165.7, 157.9, 140.2, 135.8, 134.6, 134.5, 126.1, 125,9, 120.1, 115.2,114.6, 68.7, 533, 47.9, 39.6, 27.6, 25.9, 23.7, 21.4,14.4.

YWMiaYNO DoITEWImos MIam uwd PaWa' I N F lau sA COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21, MAR. 2006 17:21 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 83 79 o Example 22 o Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,4,4-trimethylpentyl) 1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide (23) S[0250] The titled compound (23) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 Cl nm: 98.6%; tR 1.61 min; LCMS (ESI) m/z: 429 'H NMR (CD 3 OD) 88.19 (d, J 8.8 Hz, 1H), 8.08 1H), 7.90 J= 8.8 Hz, 1H), 7.76 J m 15.7 Hz, 1H), 6.75 J 15.8 Hz, 1H), 4.79 2H), 3.62 2H), 3.35 3.29 1H), 3.23 6H), 2.52 (bre, 2H), 1,50 1.45 2H), 1.36 J= 3.8 Hz, 6H), 1.12 J= 5.5 Hz, 3H), 1,02 o 10 6H); '3C NMR (CDsOD) 8 165.6, 157.4, 139.9, 135.2, 135.1, 132.9, 126.4, 120.6, S115.7, 114.6, 68.6, 53.3, 51.4, 47.9, 39.7, 36.3, 31.9, 31.3, 30.2, 23.8, 22.3.

0 Cl Example 23 Preparation of 3-[2-Cyclohexyl-1 -(3-dimethylamino-2,2-dimethyl-propyl)-1Hbenzoimidezol-5-yl]-N-hydroxy-acrylamide (24) [0251] The titled compound (24) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.9%; tR 0.96 min; LCMS (ESI) mlz: 'H NMR (CDO3D): 8 8.21 (d, J 8.8 Hz, 1H), 8.06 1H), 7.95 J= 8,8 Hz, 1H), 7.83 J= 15.8 Hz, 1H), 6.76 J 15.8 Hz, 1H), 4.79 2H), 3.65 2H), 3.60 3.51 1 3.22 6H), 3.29 3.26 2H), 2.12 2.09 2H), 2,03 1.92 3H), 1.78 1.59 3H), 1.41 (s, 6H); 1 "C NMR (CD 3 OD) 8 165.7. 161.3, 140.1, 135.4, 134.8, 134.0, 126.1, 120.3, 119.6, 116.7, 115.5, 114.9, 68,7, 53.1,47.9, 39.2, 37.0, 32.4, 26.5, 26.3, 23.6.

Example 24 Preparation of 3-[2-Bicyclo[2.2.1]hept-5-en-2-yl- -(3-dimethylamino-2,2-dimethyl- [02521 The titled compound (25) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.9%; tR 0.91 min; LCMS (ESI) m/z: 409 Example Preparation of 3-[1-(2-Diethylamino-ethyl)-2-hex-3-enyl-1H-benzolmidazol-5-yl]-Nhydroxy-acrylamide (26) [0253] The titled compound (26) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC: 99.9%; tR 1.14 min; LCMS (ESI) m/z: 385 H NMR (CDO3D) 6 7.95 J 8,6 Hz, 1H), vWuNI DELETBwPg o IIM 45AVAUmndm ls riu Pua Fad COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 Va 0 0 ci ci 0 ci Va 0 0 ci J21, MAR. 2006 17 Ex 10 l[0e :21 .21 ~PHILLIPS ORMONDE FITZPATRICK N.35 .8 NO, 3858 P. 84 Ex Pr [02 de4 nm J M 1IH (m, Exi Pre hyc [02 des nm is (di, 7 1 7.77 (di, J 8.5 Hz, 1 7.52 (di, J 15. 8 Hz, 1 6.50 i 15.8 H~z, ,5.57 5.44 21-1), 3.72 3.68 (in, 3.44 J 7.2 Hz, 41-1). 3.35 3.30 isked peaks), 2.73 J 7.1 Hz, 21-1), 2.07 1.99 (in, 1.41 J 7.2 Hz, 81H), B Ct S= 7.5 Hz, 3H); 'aC NMR (CD 3 OD) 8165.6, 157.2, 140.2,135.9,134.8,134,, 126A4, 126.1, 119.8, 115.8. 113.5, 50.4, 40.5, 28.9, 25.4, 21 14.4, 6.9.

imple 26 paration of 341 -(2-Diisopropylamino-ethyl)-2-hex-3-enyl-1 H-benzolmldazol-8- N-hydroxy-acrylamlde (27) 54] The titled compound (27) was prepared according to the procedures cribeci in Example 1, by using appropriate starting materials. HPLC: 99.9%; tn 2 min; LCMVS (ESI) m/r 413 1 H-1 NMR (CD 2 OD1) 5 7.94 7.89 (in, 21-), 3 J 8.7 Hz, IH-1), 7.53 (di, J 15.8 Hz, I 6.50 (di, JS 15.8 Hz, i1-1), 5.63 3.99 3.91 (in, 21-1), 3M9 3.64 (in, 2H-1), 3.36 3.28 (masked peaks), 2 J 7.2 Hz. 2.08 2.01 (in, 1.50 J =6.5 Hz, 12H), 0.89 j l2C NMR (0ID 3 00) a 165.6, 157.0, 140.2, 135.9, 135.4, 134.5, 134.3, 1286, 126.2, 119.8, 115.8, 113.3, 56.9, 45.3, 41.9, 27.2, 25.5, 21.4, 18.2, 14.4.

imple 27 paration of 3-[2-Mex-3-enyl-1 -(2-Isopropylamino-.thyl)-1 bnzliazla N-hydroxy-acrylamide (28) 55] The titled compound (28) was prepared according to the procedures cribed In Example 1, by using appropriate starting materials. H-PLC purity at 254 99.9 tR 1.12 min; LCMVS (ESI) mfz: 371 'H NMR (CD 8 OD) 5 8.00 (d, 9. 1 Hz, 1 7.77 7.75 (in, 2H), 7.17 (di, J 15.7 Hz, 11H), 6.34 i 15.7 Hz.

,5.57 5.42 (mn, 21-1), 4.92 J 5.9 Hz, 3.72 J 5.7 Hz, 3.54 3.48 1 HI), 3.39 J 7.5 Hz. 21-1), 2.72 i 7.3 Hz, 21-1), 2.06 -1.99 (in, 1.39 (di, 6.5 Hz, 6Ff), 0.87 5 7.5 Hz, 3H-1).

imple 28 paratlon of 341 .(2-Ethylamino-ethyl)-2-hex-3-enyl-1 Iroxyaorylamide (29) 58] The titled compound (29) was prepared according to the procedures cribed in Example 1, by using appropriate starting materials. HPLO purity at 254 99.9%; tR a 1.23 min; LOMBI mlz: 385 1 H NMR (00 5 0D) 8 7.94 (di, 8.6 Hz, 1I-H), 7.89 I 7.77 (di, J m 8.4 Hz, I 7. 56 (di, J1 15.8 Hz, 11H), 6.55 1 15.7 Hz, 1 5.57 5.42 (mn, 2H-1), 4.62 J 7.5 Hz, 2H), 3.42 3.33 (mn, I H), VAMU4MKZNO DEL&ThWI004 AV up PqU1p4 ftrAI1a sFfise COMB ID No: SBMI-03086169 Received by IP Australia: lime 18:02 Date 2006-03-21 21. MAR. 2006 17:22 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 81 3.32 3.30 (masked peaks), 3.28 3.24 2H), 2.71 J 7,2 Hz, 2H), 2.33 (brs, o 2H), 2.03 1.94 2H), 1.36 J 6.5 Hz, 6H), 0,84 J 7.5 Hz, 3H); "C NMR

(CDO

3 D) 8 165.6, 156.3, 139.9,136.8,136.2,135.2,133.8, 132.8, 126.7, 125.8,120.4, S114.6, 114.1, 52.2, 43.5, 42.9, 27.2, 26.5, 25.5, 21.4, 19.2, 14.4.

C Example 29 Preparation of 3-[2-Hex-3-enyl-1-(3-isopropylamino-propyl)-lH-benzolmidazol-5- Syl]*N-hydroxy-acrylamide [0257] The titled compound (30) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.9%; ta 1.04 min; LCMS (ESI) m/z: 1H NMR (CDsOD) 8 7.93 J O 8.4 Hz, 1H), 7.77 7.73 2H), 7.23 J= 15.7 Hz, 1H), 6.34 J 15.7 Hz, 1H), CN 5.57 5.42 2H), 4,87 (masked peaks), 3.68 (brs, 2H), 3.35 3.30 (masked peaks), 3.22 3.17 2H), 2.72 J 7.1 Hz, 2H), 1.35 J 7.2 Hz, 3H), 0.88 J 7,6 Hz, 3H); 9C NMR (CD s OD) 8 165.6, 157.3, 140.5, 135.8, 134.9, 134.6, 134.2, 126.2, 126.1, 118,7, 115,9, 113.7, 113.6, 46.5, 45.0, 42.7, 26.4, 25.4, 21.4, 14,4, 11.4, Example Preparation of 3-[1-(2-Diethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-Nhydroxy-acrylamide (31) [0258] The titled compound (31) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100%, tR 1.31 min. LC-MS m/z: 387 H NMR (DMSO-de) 8 0.88 (3H, t, J 7.0 Hz), 1.26 (6H, t, J 7.2 Hz), 1.34 (4H, 1.44 (2H, 1.85 (2H, 3.12 (2H, t, J 7.7 Hz), 3.31 (4H, 3,52 (2H, t, J 7.7 Hz), 4.81 (2H, t, J 7.7 Hz), 6.59 (1H, d, J 15.8 Hz), 7.63 (1H, d, J 15.8 Hz), 7.73 (1H, d, J 8.8 Hz), 7.93 (1H, d, J 8.8 Hz), 7.94 (1H, s) Example 31 Preparation of 3-[1-(3-isopropylamino-propyl)-2-(2,4,4-trlmethyl-pentyl)-1H- (32) [0259] The titled compound (32) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: HPLC: 97,5%, tR 1.68 min. LC-MS m/z: 415 'H NMR (DMSO-de) 6 0,89 (9H, 0.98 (3H, d, J 6.6 Hz), 1.23 (6H, d, J 6.5 Hz), 2.08-2.29 (4H, 2.27 (1H, 2.98-3.12 (4H, 3.29 (1H, 4.53 (2H, t, J 7.4 Hz), 6.60 (1H, d, J 15.8 Hz), YWMrfI NO DELEl TPII IM AU ISamd Pwhisdl Flial u ldd COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:22 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 86 82 o 7.65 (1 H, d, J 15.8 Hz), 7.75 (1 H, d, J 9.0 Hz), 7.96 (1 H, d, J 9.0 Hz), 7.98 (1H, 0 8.75 (2H, bs).

SExample 32 Preparation of 3-[2-(2,2-Dlmethyl-propyl)-1-(3-isopropylamino-propyl)-1H- Cl benzolmldazol-5-yl]-N-hydroxy-arylamide (33) [0260] The titled compound (33) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 Snm: 99%, tR 1.01 min. LC-MS m/z: 375 1 H NMR (DMSO-de) 6 0.98 (9H, s), o 10 1.24 (6H, bs), 2.17 (2H, bs), 3.14 (4H, 3.28 (1H, be), 4.53 (2H, bs), 6.65 (1H, d, J 3 15.5 Hz), 7,65 (1H, d, J 15.5 Hz), 7.81 (1H, d, J 7.4 Hz), 8.02 (1H, 8.03 (1H, d, J o= 7.4 Hz), 8.85 (2H, bs).

Example 33 Preparation of 3-[1-(2-Diisopropylamino-ethyl)-2-(3,3,3-trlfluoro-propyl)-1H- (34) [0261] The titled compound (34) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC: 97.5%; tR 0.93 min. LCMS (ES1) m/z: 427 'H NMR (DMSO-de) 81.35 (12H, 2.94 (2H, 3.24 (2H, 3.45 (2H, 3.80 (2H, 4.68 (2H. 6.48 (1H, 7,55 (3H, 7.85 (1H, 9.48 (1H, bs).

Example 34 Preparation of N-Hydroxy3-[2-isobutyl-1-(2-isopropylamino-ethyl)-1Hbenzolmldazol-5-yl]-acrylamide [0262] The titled compound (35) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98.3%, tR 0,51 min, LCMS (ESI) m/z: 345 1H NMR (CDsOD) 8 7.78 (1H, d, J 8.7 Hz), 7,76 (1H, 7.68 (1H, d, J 8.6 Hz), 7.46 (1H, d, J= 15.8 Hz), 6.42 (1 H, d, J 15,9 Hz), 4.70 (2H, t, J 7.4 Hz), 3,48 (2H, t, J 69 Hz), 3.37 (1H, m), 3,01 (2H, d, J= 7.4 Hz), 2.21 (1H, 1.27 (6H, d, J= 6.5 Hz), 1,00 (6H, d, J= 6.6 Hz); '3C NMR (CDaOD)8 160,3, 155,3, 138.5, 134.1, 131.5, 124.2, 113.9, 111.4, 51.1, 42,0, 40.3, 33.4, 27.3, 20.6, 17.2.

YA.MiU f NO DELBE RPIOQ4F AU ItCllPr' ulm Filul uH IMdde COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:22 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 87 83 o Example SPreparation of 3-[2-(2,2-Dimethyl-propyl)-1 -(2-ethylamino-ethyl)-1H- (36) S[0263] The titled compound (36) was prepared according to the procedures described in Example 1, by using appropriate starting materials. Yield: 74%. HPLC Cl purity at 254 nm: 99.9%, tR 0.71 min. LCMS (ESI) m/z: 345 1 H NMR (CDsOD) 8 7.81 (1 H, d, J 8.8 Hz), 7.75 (1 H, 7.69 (1 H, d, J 8.5 Hz), 7.36 (1H, d, J 15.7 Hz), 6.40 (1H, d, J 15.3 Hz), 4.81 (2H, t, J= 6,4 Hz), 3.51 (2H, t, J= 6.3 Hz), 3.10 (2H, 3.06 (2H, qt, J 7.3 Hz), 1.23 (3H, t, J 7.2 Hz), 1.04 (9H, 1"C NMR O 10 (CD3OD) 5 161.0, 153.3, 138.5, 132.7, 132.2, 124.2, 117.5, 113.9, 111.9, 44.2, 43.0, S41.0, 37.4, 33.0, 27.9, 0 C Example 36 Preparation of 3-[1-(2-Ethylamino-ethyl)-2-isobutyl- hydroxy-acrylamide (37) [0264] The titled compound (37) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 264 nm: 99.9%, t 0.40 min. LCMS (ESI) m/z: 331 1 H NMR (CDaOD) 8 7.81 (1H, d, J 8.6 Hz), 7.73 (1H, 7.67 (1H, d, J 8.2 Hz), 7,34 (1H, d, J 15.7 Hz), 6.36 (1H, d, J a 15.7 Hz), 4.74 (2H, t, J= 6.7 Hz), 3,54 (2H, t, J= 6.5 Hz), 3,10 (2H, d, J 7.4 Hz), 3.06 (2H, d, J 9.5 Hz), 2.21 (1 H, 1.23 (3H, t, J 7.3 Hz), 1.04 (6H, d, J 6.6 Hz); NMR (CDsOD) 8 163.7, 161.1, 154.8, 138.6, 133.2, 132.6, 132.4, 124.2, 117.2, 113.9, 111.6, 44.4, 43.0, 40.5, 33.4, 27.3, 20.6, Example 37 Preparation of 3-[1-(2-Diisopropylamlno-ethyl)-2-(2,4,4-trlmethyl-pentyl)-1 H- (38) [0265] The titled compound (38) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC: 99.0 tR 1.62 min; LCMS (ESI) m/z: 443 1 H NMR (CD 3 0D) 8 7.96 7.94 2H), 7,82 J 8.7 Hz, 1H), 7.55 J 15.8 Hz, 1H), 6.54 J 15.8 Hz, 1H), 5.13 5.06 (masked peaks), 4.01 3.92 2H), 3.71 3.67 2H), 3.33 3.24 (masked peaks), 3.18 3.12 1H), 2.38 2.36 1H), 1.52 BH), 1.51 6H), 1.41 1.40 2H), 1.09 J 6.6 Hz, 3H), 0.94 9H); 13C NMR (CDsOD) 8 165.5, 156.5, 140.1, 134,8, 134.7, 134.0, 126.5, 120.0, 114.6, 113.6, 56.9, 51.7, 45.2, 42.0, 35.9, 31.9, 30.6, 30.2, 22.6, 18.3.

Y;Waul NO MMIlB OIPoM1W.S AU sma N miPm iM mul FI P RlML.d COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 I, 21-MAR2006 17:22 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P, 88 84 o Example 38 o Preparation of N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)- (39) S[0266] The titled compound (39) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 Cl nm: 97.9%; tR 1.49 min; LCMS (ESI) m/z; 401 1H NMR (CDsOD) 5 7.98 (d, J 8.7 Hz, 1H), 7,79 -7.76 2H), 7.24 J 15.7 Hz, 1H), 6.39 J 15.7 Hz, 1 4.97 4.89 (masked peaks), 3.70 3.66 2H), 3.53 3.47 1H), 3.34 3.28 (masked peaks), 3.22 -3.15 1H), 2.31 -2.29 1H), 1.39 1.38 9H), 1.07 (d, o 10 J 6.6 Hz, 3H), 0.9 9H); 1"C NMR (CD 3 0D) 8 165.5, 156,9, 140.5, 134.7, 134.4, NO 126.3, 118.9, 115.9, 113.8, 53.2, 51.5, 44.2, 42.8, 35.7, 31.9, 30.9, 30.2, 29.6, 19.1, S18.8.

Example 39 Preparation of 3-[1 -(2-Ethylamino-ethyl)-2-(2,4,4-trlmethyl-pentyl)- H- [0267] The titled compound (40) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100,0%; tR 1.57 min; LCMS (ESI) m/z: 387 'H NMR (CDaOD) 8 7.96 (d, J 8.6 Hz, 1H), 7.79 1H), 7.78 7.75 J 8.7 Hz, 1H), 7.23 J 15.7 Hz, 1 H), 6.37 J= 15.7 Hz, 1H), 4.96 4.89 (masked peaks), 3.70 -3,68 2H), 3.36 -3.28 (masked peaks), 3.26 3.14 3H), 2.31 2.30 1H), 1.40- 1.32 5H), 1.07 (d, J 6.6 Hz, 3H), 0.92 9H); 1C NMR (CD 1 OD) 8 165.6, 156.9, 140.6, 134.9, 134.5, 134,2, 126.2, 118.7, 116.0, 113.7, 51.6, 46.5, 45.0, 42,7, 35.8, 31.9, 30.8, 30.2, 22.6, 11,4.

Example Preparation of 3-[1-(2-Diethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)- H- (41) [0268] The titled compound (41) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm; 85.6%, tR 1.55 min. LC-MS m/z: 415 'H NMR (CD 3 OD) 8 7.91 2H, J 6.0 Hz), 7.80 (br, d, 1H, J 8.9 Hz), 7.68 2H, J 15.8 Hz), 6.58 1H, J 15,8 Hz), 4.96 (br, q, 2H), 3.64 (br, q, 2H), 3,43 4H, J 7.3 Hz), 1.40 8H), 1.09 (br, d, 4H, J 6.6 Hz), 0.94 (br, s, 10H); '0C NMR (CDaOD) 6 156.8, 140.4, 135.8, 134.4, 134.3, 126,1, 115.8, 113.2, 119.7, 119.2, 51.6. 50.3, 40.3, 35.8, 31.9, 22.6, YMUlyWi P CLEBlMPIVm AUII SBEad ihwki fial F =lul d R COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:23 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 89 VaD 0 Example 41 SPreparation of 3-[1-(2-Diethylamlno-ethyl)-2-propyl-1H-benzoimldazol-5-yl]-Nhydroxy-acrylamide (42) S[0269] The titled compound (42) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254nm: 99.0%, tR 0.68 min. LC-MS (ESI) m/z: 345 'H NMR (CDaOD) 8 8.15 2H, J= 8.7 Hz), 7.68 1H, J 15.8 Hz), 6.63 1H, J 15.8 Hz), 5.08 (br, t, 2H), 3,70 (br, t, 2H), 3.44 (br, m, 4H), 3.35 2H), 2.03 (br, m, 2H), 1.44 6H, J 7.2 Hz), 1.20 3H); 3 C NMR (CD 3 0D) 8 165.5, 157.4, 139.8, 135.5, 133.5, 132.3, 120.7, 120.7, 114.5,114.3, 40.8, 285, 21.0, 13.9, 9.1.

cN SExample 42 Preparation of 3-[1-(2-Diethylamino-ethyl)-2-(2-methylsulfanyl-ethyl)-1 H- [0270] The titled compound (45) was prepared according to the procedures described in Example 1, by using appropriate starting materials. Yield:17 mg (in two steps) as TFA salt. HPLC purity at 264 nm: 80%, tR 0.50 min. LCMS (ESI) m/z: 377 'H NMR (CD3OD) 5 7.79 (1H, 7.77 (1H, 7.66 (1H, d, J 8.6 Hz), 7.54 (1H, d, J 15.8 Hz), 6.44 (1H, d, J 15.8 Hz), 4.83 (2H, masked by DHO, identified by COSY), 3.57 (2H, 3.41 (2M, t, J 7.1 Hz), 3.32 3.01 (2H, t, J 7.1 Hz), 2.89 (3H, 1.30 -1.25 (9H, overlapped t), Example 43 Preparation of 3.[2-Butyl-l-(2-isopropylamino-ethyl)-1H-benzolmidazol-5-yl]-Nhydroxy-acrylamide (46) [0271] The titled compound (46) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98.4%; tR 1.56 min. LCMS m/z: 345 'H NMR (DMSO-da) 5 0.95 (3H, t), 1.22 (6H, 1.42 (2H, 1.80 (2H, 3.13 (2H, 3.41 (3H, 4.69 (2H, 6.58 (1H, 7.56 (1H, 7.73 (1H, 7.90 (2H, 9.14 (2H, be).

Preapration of the freebase of the titled compound: [0272] To a pre-stirred solution of the methyl ester (1 eq) in dried methanol, NHaOH,HCI (12 eq.) was added. The mixture was stirred in ice-water bath for about min, followed by adding sodium methoxide solution (20 HPLC showed the reaction completed after 20 min, less than 1% of the acid was observed.

Y;Mi l I NO1 Dlo, Ie WPL UP 05 AM ,l nsam l m Pl Il na l l.d COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:23 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 86 o [0273] The above crude was treated with 1M of HCI until all the precipitate was o dissolved (pH around The pH value was carefully adjusted to around 7-8 using NaOH or NaHCO 3 the precipitate which was formed was collected by filtration. The Ssolid was washed with water once. The above solid was suspended in methanol and water again and was treated with 6N HCI until all dissolved, the pH value was carefully l adjusted to around 7-8 using NaOH and NaHCOa, The precipitate, which was formed, was again collected by filtration; the freebase compound was obtained by drying in vacuo, the yield was around 80%-85%.

Preapration of the hydrochloric acid salt of the titled compound: C [0274] The above freebase compound was suspended in methanol and water and o was treated with 6N HCI (2.8 The solution became dear. After removing the Cl methanol on a Rotary Evaporator, the hydrochloric acid salt was obtained by freezedrying. It was further recrystallized from methanol (HPLC purity at 254 nm: 99%).

Example 44 Preparation of 3-[2-Butyl-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl].Nhydroxy-acrylamide (47) [0275] The titled compound (47) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98.2%; tR 1.72 min. LCMS (ESI) m/z: 359 'H NMR (DMSO-de) 8 0.95 (3H, 1.22 (6H, 1.45 (2H, 1.82 (2H, 2.14 (2H, 3.17 (4H, 3.28 (1H, 4.52 (2H, 6.62 (1H, 7.57 (1H, 7.72 (1H, 7.89 (2H, 8.80 (2H, bs).

Example Preparation of 3[1 (1 -Benzyl-piperidin.4-yl)-2-butyl. hy(roxy-acrylamide (48) [0276] The titled compound (48) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 96,7%, tR 1.35 min. LC-MS m/z: 433 'H NMR (DMSO-de) 8 0.94 (3H, 1.41 (2H, 1.77 (2H, 2.19 (2H, 2.99-3.10 (2H, 3.24 (4H, 3.68 (2H, 4.38 (2H, 5.01 (1H, 6.65 (1H, d, J 15.8 Hz), 7.47-7.49 (3H, 7.61 (1H, d, J 15.8 Hz), 7.69 (3H, 7.97 (1H, 8.60 (1H, d, J 8.8 Hz), 10.35 (2H, s), 11.95 (1 H, s).

Y.nrNIMto NIrO D IIOmiBlwmI AUS.SlahbrifiAmVla Flu ramdo COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:23 ,PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 91 87

INO

0 Example 46 0 Preparation of 3-[2-Butyl-1-(2-ethylamino-ethyl)-1 hydroxy-acrylamide (44) S[0277] The titled compound (44) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98%; SLC-MS m/z: 331 1 H NMR (DMSO-d 6 8 10.88 (br s, 1H), 9.12 (br s, 2H), 7.93 1H), 7.87 1H, J 8.4 Hz), 7.71 1H, J 8.3 Hz), 7.62 1H, J 15.7 Hz), 6.59 1H, J 15.6 Hz), 4.67 (t-like, 2H), 3,42 (br s, 2H), 3.08 2H, J W 7.7 Hz, Pr-

CH

2 3.05 (br s, 2H), 1.81 2H), 1.45 2H), 1.18 3H, J 7.1 Hz), 0.95 3H, J 7.0 Hz); 1 C NMR (DMSO-de) 8 162.6, 156,2, 138.0, 135.0, 133.5, 131.6, 123.5, O 119.2, 114.8, 112.1, 44.5, 42.4, 40.6, 28.2, 25.2, 21.7, 13.5, 10.8.

0 C Example 47 Preparation of 3-[2-But-3-enyl-1-(2-ethylamlno-ethyl)-1H-benzoimidazol-5-yl]-Nhydroxy-acrylamide (49) [0278] The titled compound (49) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC: 99.0 tR 1.61 min; LCMS mlz: 329 'H NMR (CDsOD) 8 7.85 J 8.5 Hz, 1H), 7.78 1H), 7.72 J r 8.5 Hz, 1H), 7.38 J 15.7 Hz, 1H), 6.40 J 15.5 Hz, 1H), 6.02- 5.92 1H), 5.19 (dd, J 17.1, 1.3 Hz, 1H), 5.12 (dd, J 10.2, 0.9 Hz, 1H), 4.80 J 6.4 Hz, 2H), 3.62 J 6.2 Hz, 2H), 3.22 3.16 2H), 2.71 J 7.2 Hz, 2H), 1.35 J 7.2 Hz, 3H); "C NMR (CDsOD) 8 178.3, 157.1, 140.7, 136.5, 133.9, 125.9, 118.8,117.6,116.2,113.2, 101.5, 67.6, 46.4, 44.9, 42.4,31.6,26.7,20.7, 11.4.

Example 48 Preparation of 3-[2-Hexyl- -(2-isopropylamlno-ethyl)- hydroxy-acrylamide [0279] The titled compound (50) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 94.4%, tR 1.32 min. LCMS (ESI) m/z: 373 'H NMR (CD 3 OD) 5 7.80 (1H, d, J 8.5 Hz), 7.74 (1H, 7.64 (1H, d, J 9.0 Hz), 7.50 (1H, d, J 13. 8 Hz), 6.42 (1H, d, J 15.8 Hz), 4.65 (2H, d, J 6.6 Hz), 3.48 (2H, d, J 6.6 Hz), 3.38 (1H, qt, J 6.5 Hz), 3.13 (2H, t, J 5.9 Hz) 1.82 (2H, t. J 6.7 Hz), 1.44 (2H, t, J 7.0 Hz) 1.29 (7H, m) 0.84 (6H, d, J 7.0 Hz).

Y;IMWa51 J NO DGUTWrDlo i tnal Lmanm l f invW a MsiledAm COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:24 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 92 88 o Example 49 o Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1 H- (51) S[0280] The titled compound (51) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 Cl nm: 100%, tR 1.49 min. LC-MS m/z; 331 'H NMR (DMSO-de) 8 0,85 (9H, a), 1.03 (2H, d, J 6.4 Hz), 1.34 (2H, 2.27 (1H, 3.00 (6H, 3.24-3.27 (4H, m), 4.79 (3H, 6.53 (1H, d, J 15,72 Hz), 7,62 (1H, d, J 15.7 Hz), 7.75 (1H, d, J 8.4 Hz), 7.86 (1H, 7.87 (1 H, d, J 8.4 Hz).

C Example P0reparation of 3-[1-(2-Ethylamlno-ethyl)-2-hexyl*1H-benzoimidazol-5-yl]-N- NC\ hydroxy-acrylamide (52) [0281] The titled compound (52) was prepared according to the procedures described in Example 1, by using appropriate starting materials. The modified or detailed procedures were described as below, Step 3: [0282] To a stirred solution of 3-[4-(2-ethylamino-ethylamino)-3-nitro-phenyl-acrylic acid methyl ester (8.174 g, 27,87 mmol) and heptaldehyde (4.85 g, 42.47 mmol, 1.52 eq) in AcOH and MeOH (1:9 v/v. 300mL) was added SnCa2H 2 0 (31.45 g, 139,4 mmol, eq) in portions. The resulting mixture was heated to 40 oC with stirring. The progress of the reaction was monitor by LC/MS. When the reaction was completed, solvent was removed under reduced pressure below 40°C. The resultant residue was diluted with EtOAc (50 mL) then basified (pH >10) with saturated aqueous Na 2 CO and extracted with dichloromethane Filtration may be needed to remove the white precipitates or suspension derived from Tin in order to get clearly separated layers. The organic extracts were combined, dried (Na 2 S0 4 filtered, and evaporated to dryness. The resulting oily residue was purified by flash column chromatography (silica, 467 x mm, solvent MeOH/DCM gradient from 0 to 3-[1-(2-ethylamino-ethyl)-2-hexyl- 1 H-benzoimidazol-5-yl]-acrylic acid methyl ester was obtained as yellow solid (4.445 g, HPLC purity at 254 nm: 98.8%, tR 1.71 min. LCMS (ESI) m/z: 358 'H NMR (CDCIs) 8 7,88 (1H, d, J 1.2 Hz), 7.83 (1H, d, J 16.0 Hz), 7.43 (1H, dd, J 8.4, 1.4 Hz), 7.33 (1H, d, J 8.4 Hz), 6.43 (1H, d, J 15.9 Hz), 4.22 (1H, t, J a 6.6 Hz), 3.80 (3H, 3.01 (2H, t, J 6.6 Hz), 2.89 (2H, t, J 7.9 Hz), 2.65 (2H, q, J 7.1 Hz), 1.91 (2H, pentet, J 7.8 Hz), 1.46 (2H, 1.35 (4H, 1.07 (3H, t, J 7.1 Hz), 0,90 (3H, t, J 7.0 Hz), The solid could be recrystallized from Hexanes-ether to give a white or pale yellow solid with HPLC purity at 254 nm: 99.2%.

Y:lMrr'NKN1C OILEUB P1P9043 AULIecumd Pholdial Hiua a rtd COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:24 PHILLIPS ORMONDE FITZPATRICK NO, 3858 P. 93 89

O

S[0283] In another experiment starting with 2.725 g of 3-[4-(2-ethylamino-ethylamino)- 3-nitro-phenyl]-acrylic acid methyl ester, the titled compound was obtained in 52.8% Syield (1.753 g), Step 4: [0284] To a solution of 3-[1-(2-ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]acrylic acid methyl ester (4.428 g, 12.39 mmol) and NH 2 OH'HCI (8.66 g, 124.7 mmol) in dry MeOH (50 mL) which was stirred and cooled in a dry-ice acetone bath, added Sto NaOMe solution in MeOH 4.37 M, 55 mL, 240 mmol). The reaction mixture was then stirred at room temperature. The progress of reaction was monitored by LC/MS 0 (usually reaction completed within 30-90 min) and quenched by adding 6N HCI C mL), The mixture (HPLC purity at 254 nm 94.6%) was added Milll-Q water, adjusted pH -8 by 1N NaOH and evaporated to remove the organic solvent. The resultant is residue was washed with Milli-Q water (x3) and re-dissolved in MeOH-DCM, the solution was filtered and diluted with Milli-Q water. The suspension was evaporated to remove the organic solvent and the resultant residue was washed with Milli-Q water The free base of the titled compound was obtained (HPLC purity at 254 nm The free base could be recrystallized from MeOH-Ethyl acetate to give a white or pale yellow solid, Step 5: hydrochloric acid salt formation.

[0285] The above freebase was dissolved in MeOH and excess 6N HCI (final pH <2) and the clear solution was evaporated to dryness and then diluted with MeOH, coevaporated with PhMe (xl) and EtOAc The solid was recrystallized from MeOH- EtOAc to give a white or pale yellow solid (3.298 g, HPLC purity at 254 nm: 98.4-99.6%, tR 1.23 min. LCMS (ESI) m/z: 359 1 H NMR (CDaOD) 8 9.33 (residual NH), 8.03 (1H, d, J 8.3 Hz), 7.77 (1H, 7.73 (1H, d, J 8.2 Hz), 7.16 (1H, d, J 15,7 Hz), 6.34 (1H, d, J 15.7 Hz), 4,88 (2H, overlapped with DHO, identified by COSY), 3.63 (2H, br t like), 3.32 (2H, d, J 7.9 Hz), 3.15 (2H, q, J 1.94 (2H, pentet, J 1.53 (2H, pentet, J 6.7 Hz), 1.42-1.31 (4H, 1.33 (3H, t, J 7.1 Hz), 0.88 (3H, t, J 7.0 Hz); 3 C NMR (CDsOD) 8 163.4, 155.8, 138.1, 133.0, 132.0, 130.3, 125.1, 117.4, 112,8, 112.5, 44.5, 43.2, 41.1, 30.5, 28.0, 25.3, 25.2, 21.6. 12.4, 9.6.

YMayL KO1100 DEEB TtlD04 ll5 l enmd l ,,,ionl Fuil x PINdW COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21.MAR.2006 17:24 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 94 Va Example 51 SPreparation of N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(3,3,3-trifluoro-propy)- IH benzolmdazol-5-yl]-acrylamde (53) [0286] The titled compound (53) was prepared according to the procedures described in Example 1. by using appropriate starting materials. HPLC: 98.1%; tf C 0.63 min. LC-MS m/z: 385 Example 52 Preparation of 3-[1 -(2-Dimethylamino-ethyl)-2-hex-3-enyl-1 N-hydroxy-acrylamide (54) [0287] The titled compound (54) was prepared according to the procedures o descrlbed in Example 1, by using appropriate starting materials. HPLC purity at 254 0 C nm: 99.9%, tz 0.96 min. LCMS (ESI) m/z: 357 1 H NMR (CD 3 OD) 6 7.87 (1H, d, J 8.6 Hz), 7.80 (1H, d, J 8.8 Hz), 7.72 (1H, d, J 8.3 Hz), 7.49 (1H, d, J w Is 15.8 Hz), 6.44 (1IH, d, J 15.8 Hz), 5.44 (1H, 5.38 (1H, 4.84 (2H, t, J 6.1 Hz), 3.61 (2H, t, J 7.7 Hz), 3,20 (2H, t, J 4.2 Hz) 2.97 (6H. 2.61 (4H, qt, J 2 7.1 Hz), 1,93 (2H, qn, J 7.7 Hz), 0.78 (3H, t, J 7.5 Hz); 18C NMR (CDaOD) 5 163.6, 160.0, 155,1, 138,1, 134.1, 133,1, 131.9, 131.6, 124.7, 123.9, 118.2, 117.2, 114.3, 113.1, 111.8, 53.2, 42.1, 38.8, 24.8, 23.3, 19.4, 12.4.

Example 53 Preparation of 3-[1 -(2-Amino-thyl)-2(2,4,4-trimethyl-pentyl)- yl]*Nhydroxy-acrylamide

OO

0 0 0 N SnC1 2

H

2 0 N N 2 OCH 3 0 HN' N i HOAc-MeOH (1:9) HN 1111 BNoc Vial .1 0 HCIJMeOH

NH

2 OH/N.OM N NHOH HN Via-1 H 2 N VII.-1 Step 1: [0288] To a stirred solution of 3-[4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitrophenyl]-acrylic acid methyl ester (IIlal, 65.2 mg, 0.178 mmol) and 3,5,5-trimetylhexanal YMlyl4Z NPLDDEI1FPLO9SQ0 AUSl Bo loiin iII M 1 Fwil.doA COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21 MAR. 2006 17 i wa oc res (x3 ttR

H]F

Ste [02 an< ev spi mn I St sta [02

EX

4.7 ([1 8.4 3.1 2.1 T 0.9

EX,

Pn N-1 [02 d n ide (2t 24 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 91 :pL, 0.2B mmol) In a mixed solvent of AcOH-MeOH (1:9 v/v, 2 mL) and DCM (1 mL) Sadded SnCIl2H 2 0 (184 mg, 0,815 mmol). The resulting mixture was heated to with stirring overnight. The solvent was removed under reduced pressure and the iltant r sidue was added saturated aqueous Na 2 CO and extracted with EtOAc The uextracts gave the crude (VIal-1, 91 mg) with HPLC purity at 254 nm: 49.3%, 3.02 rin and tR 1.97 min (de-Boc product). LCMS (ESI) m/z; 458 and 348 de-Boc product), p 2: 9] The above crude (Vial-1) was dissolved in MeOH (4 mL) and 6N HCI (1 mL) heateo at 70°C for 30 min. The solution was evaporated to dryness and coprote dwith PhMe (x2) and MeOH The residue (crude Via-1, 81.9 mg) was Sto two parts (43.4 mg, equal to 0.0945 mmol of Illal, and 38.5 mg equal to 0.0839 iol of II$1).

p3: D0] The titled compound (55) was prepared according to the Step 4 described in imple 1, by using crude (Via-1, 38.5 mg). Vlla-I was obtained as TFA salt (2.3 mg, A fromillial). HPLC purity at 254 nm: 92.7%, tR 1.46 min. LCMS (ESI) m/z: 359 NMR (CDsOD) 8 7.81 (1H, 7.70 (1H, d, J 8.6 Hz), 7.65 (1H, d, J Hz), 7.$9 (1H, d, J 15.8 Hz); 6,47 (1H, br d, J 14.6 Hz), 4.63 (2H,t, J 5.4 Hz), S(2H, ti J 6.5 Hz), 3.02 (1H, dd, J 15.5, 6.5 Hz), 2.90 (1H, dd, J 15.3, 8.6 Hz), S(1H, )r s or 1.33 (1H, dd, J 14.1, 3.4 Hz), 1.25 (1H, dd, J 14.0, 6.6 Hz), S(3H, 4, J 6.2 Hz), 0.83 (9H, s).

lmple *4 paratl4n of 3-[1 -2-Amino-ethyl)-2-(2-methoxy-nonyl)-1H-benzoimidazol-5-yl]iydrox*acrylamide (56) 91] The titled compound (56) was prepared according to the procedures icribed In Example 53, by using appropriate starting materials. HPLC purity at 254 S91.8%, tR 1.93 mln. LCMS (ESI) m/z: 403 'H NMR (CDsOD) 8 some tifled 0eaks: 7.81 (1H, 7.70 7.58 (3H, 6.46 (1H, br d, J 14.4 Hz), 4.62 I, 369 (1H, br a or 3.38 (2H, t, J 7.3 Hz), 1.67 (1H, 1.58 (1H, m), 0-1.20 (10H, 0.82 (3H, t, J 6.2 Hz).

MW No PlB OIKOos A1 sal P*M il Flii r ldlL COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-AR-2006 17:25 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 96 92 o Example O Preparation of 3-[2-Butyl-1-(2-dimethylamino-ethyl)-1H-benzoimidazol-5-yl]-Nhydroxy-acrylamide (57) S[0292] The titled compound (57) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC purity at 254 Cl nm: 100%, tR 0.42 min, LC-MS m/z: 331 'H NMR (DMSO-ds) 6 0.97 (3H, t, J 7.3 Hz), 1.49 (3H, 1.83 (2H, 3.09 (2H, t, J 7.72 Hz), 3.54 (2H, t, J 7.6 Hz), 4.74 (2H, t, J 7.6 Hz), 6.57 (1H, d, J 15.7 Hz), 7.62 (1H, d, J 15.7 Hz), 7.71 (1H, d, J z 8.6 Hz), 7.93 (1H, d, J 8.6 Hz), 7.97 (1H, 10.68 (2H, bs).

SExample 56 O Preparation of 3-[2-Hexyl-1-(2-dlmethylamlno-ethyl).1H-benzolmldazol-5-yl]-N- C hydroxy-acrylamde (58) [0293] The titled compound (58) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100%, tR 0.42 min. LC-MS m/z: 359 'H NMR (DMSO-ds) 8 0.89 (3H, t, J 6.9 Hz), 1.28-1.54 (6H, 1.85 (2H, 2.92 (6H, 3.09 (2H, t, J 7.6 Hz), 3.51 (2H, t, J 7.8 Hz), 4.76 (2H, t, J 7.8 Hz), 6.57 (1H, d, J 15.8 Hz), 7.63 (1H, d, J 15.8 Hz), 7.70 (1H, d, J 8.6 Hz), 7.90 (1H, d, J 8.6 Hz), 7.91 (1H, 10.68 (2H, bs).

Example 57 Preparation of 3-{1-(2-Dlethylamlno-ethyl)-2-[2-(2,2-dlmethyl-proplonylamino)- (61) [0294] The titled compound (61) was prepared according to the procedures described below, Steps 1 2 were performed as in Scheme I: Step 3; 0 o 04'OhNf

A,

N 8J SnCl 2 .2H4 HON HN

HN

AcOH, MeOH, [0295] To a pre-stirred solution of 3-[4-(2-diethylamino-ethylamlno)-3-nitro-phenyl]acrylic acid methyl ester (61-1, 280 mg, 1.0 mmol) in glacial acetic acid (5 mL), tin chloride was added (1.18 g, 10.0 mmol). The resulting solution was heated to 45°C for 17 hours and then cooled to room temperature. The solvent was removed under vacuum. Water (20 mL) and dichloromethane (20 mL) was added to the residue and YTMaqXJ D DNLETFO IDF MI AU Seam na l PhiionA lRJ a FlRklM COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:25 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 97 93 stirred for 30 minutes. The organic layer was dried (MgSO4), filtered and concentrated to an oily residue. 100 mL diethyl ether was added and stirred for 4 hours. The product 3-[3-amino-4-(2-diethylamino-ethylamino)phenyl]-acrylic acid methyl ester was obtained in 54,9% yield (207.6 mg), LCMS m/z: 292 Step 4 o

HN

Fmoc N _Y0 EDO, HO H2, H HN C02M DIEA, DCM HN OH room temp.

[0296] To a pre-stirred solution of 3-[3-amino-4-(2-diethylamino-ethylamino)-phenyl]acrylic acid methyl ester (61-2, 1.93 g, 6.65 mmol) and dichloromethane (13.3 mL) was added a cocktail solution of N-(3-dimethylaminopropyl)-MN-ethylcarbodiimide hydrochloride (2.55 g, 13.31 mmol), 1-hydroxybenzotriazole hydrate (2.04 g, 13.31 mmol), N,N-dilsopropylethylamine (2.20 mL, 13.31 mmol) and dichloromethane (26.6 mL). After stirring for 0.5h, Fmoc-Gly-OH (61-3, 2.97 g, 9.98 mmol) was added. When the starting material has fully reacted, ethyl acetate (100 mL) was added to dilute the mixture. The organic contents were washed with saturated sodium hydrogencarbonate (2 x 25 mL) and brine (2 x 25 mL), before drying in sodium sulphate. The mixture was then filtered and concentrated in vacuo. The product 3-[3-amino-4-(2-diethylaminoethylamino)-phenyl]-acrylic acid methyl ester was obtained in 67.3% yield (2.54 g).

LCMS m/z; 571 Step Fmon, oNO H HN N~CO 2 Me H 4. AcOH,70°C ,r HIr 1 6 Fmoc-NH N N COaMe N I i b [0297] Glacial acetic acid (8.9 mL) was added into 3-[3-amino-4-(2-diethylaminoethylamino)-phenyl]-acrylic acid methyl ester (61-4, 2,54 g, 4.46 mmol) and the reaction mixture was stirred at 70 OC for 14h. When the reaction has completed, the mixture was concentrated in vacuo. Saturated sodium hydrogencarbonate (20 mL) was added and dicholoromethane (3 x 20 mL) was used to extract the aqueous layer. The VYMSAIIIU NO TrEiEODQTE AU m d PwMI SMal a n MAPildi COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:25 PHILLIPS ORMONDE FITZPATRICK NO- 3858 P. 98 94 combined organic contents were dried in sodium sulphate before being filtered and concentrated in vacuo, The product 3-1-(2-dethylamino-ethyl)-2-[(9H-fluoren-9ylmethoxycarbonylamino)-rnmethyl]-1 H-benzoimidazol-5-yl}-acrylic acid methyl ester (81was obtained in 66.1 (1.02 LCMS m/z 553 Step 6 Fmoo-NH N 'N CO 2

M

N pi0

DOM,I

nridine, rm tarrip

H

2 N N NN 00-Me [0298] To a pre-stirred solution of 3-(1 -(2-dethylamino-ethyl)-2-[(9H-fluoren-9ylmethoxycarbonylamino)-methyl]-IH-benzolmldazol-5-yl)-acrylic acid methyl ester (61.

1.62 g, 2.94 mmol) and dichloromethane (8.90 mL) was added piperidine (1.45 mL, 14.69 mmol). When the reaction has completed, the mixture was concentrated iin vacuo. The desired product was separated by reverse phase preparative HPLC. After lyopholyzation, 0.52 g (53.6 of 3-[2-aminomethyl-1-(2-diethylamino-ethyl)-1

H-

benzoimidazol-5-yl]-acrylc acid methyl ester was obtained as powder. LCMS m/z: 331

([M+HJ

t Step 7 H N N NCOMe cool N DJEA DCM N COaMe NH N k N 02MG rj [0299] To a pre-stirred solution of 3-[2-aminomethyl-1 -(2-diethylamino-ethyli)-1Hacid methyl ester (61-6, 0.10 g, 0.23 mmol), N,Ndiisopropylethylamine (97 pL, 0.58 mmol) and dichloromethane (1,17 mL) was added 2,2-dimethyl-propionyl chloride (34.6 pL, 0.28 mmol) and the resulting reaction mixture was stirred at room temperature for 1h. When the reaction has completed, ethyl acetate (20 mL) was added to dilute the mixture. The organic contents were washed with saturated sodium hydrogencarbonate (2 x 20 mL) and brine (2 x 20 ml), before drying in Na 2

SO

4 The mixture was filtered and concentrated in vacuo. The product 3- {1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl-proponylamino)-methyl1 H-benzolmidazol- VMWvNKZI DELENO FP IOMS AU Stad fN&4inu lul nFisde COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:26 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 99 Va o 5-yl)-acrylic acid methyl ester (61-7) was obtained in 76.6 (74.1 mg), LCMS m/z: 415 o Step 8 00 0 NH N N -02MeNHN N H

N,

iN C NHOH.HCI,

I

N0 N OH r NaOMe, MuCH C [0300] To a stirred solution of 3-{1 -(2-diethylaminoethyl)-2-[(2,2dimethylpropionylamino)-methyl]-1 H-benzolmdazol-5-yi)-acrylic acid methyl ester (61-7, 73.8 0 mg, 0.18 mmol) and hydroxylamine hydrochloride (124 mg, 1.78 mmol) in MeOH (0.3 mL) was added sodium methoxide (30% in methanol) (0.8 mL, 3.6 mmol) at 78 1C.

The reaction mixture was then allowed to warm up slowly to room temperature. The reaction was monitored by LC/MS and was completed in around 15 min, 1N HCI was then added slowly into the reaction mixture at 0 OC. The desired product was separated by reverse phase preparative HPLC. After lyopholyzation, 22.2 mg (24.3 of diethylamino-ethyl)-2-[(2,2-dimethyl-proplonylamino)-methyl]-1 H-benzoimidazol--yl)- N-hydroxy-acrylamlde was obtained as powder. HPLC purity: 99.5%, tR 0.94min.

LCMS m/z; 416 1H NMR (CD 3 OD) 8 7.89 1H), 7.84 J 8.5 Hz, 1H), 7.73 J= 8.4 Hz, 1H), 7.55 J= 15.8 Hz, 1H), 6.53 J 15.8 Hz, 1H), 4.98 J= 7,3 Hz, 21-H), 4.73 2H), 3.75 J 7.5 Hz, 2H), 3.42 J= 7.2 Hz, 4H11), 1.37 J 7.3 Hz, OH), 1.22 91); "C NMR (CDaOD) 5 182.5, 168.9, 162.2, 161.9, 154.8, 140.8,137,9,135.0, 133.9, 128.0,119.3,117.1,112.9, 50.9, 40,5, 39,7, 36.7,27.6, 9.1.

Example 58 Preparation of N-(2-1 -(2-Diethylamlno-ethyl)-5-(2-hydroxycarbamoy-vinyl)-1

H-

benzoimidazol-2-yI]-thyl).3,3.dimethyl-butyramide (59) [0301] The titled compound (59) was prepared according to the procedures described in Example 57, by using appropriate starting materials, HPLC purity at 254 nm: 94.0%; tA 0.99 min. LC-MS m/z; 444 YIfNOIDD ITBPLLWOSAU kndPrthisd Phlba iFlhdo COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:26 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 100 96 O Example 59 o Preparation of N-[1-(2-Dlethylamino-ethyl)-5-(2-hydroxycarbamoyl-vinyl)-1 Hbenzoimidazol-2-ymtylmethybutyramlde (62) S[0302] The titled compound (62) was prepared according to the procedures described in Example 57, by using appropriate starting materials. HPLC purity at 254 N nm: 85.1 tR 0.58 min; LCMS m/z: 402 H] 'H NMR (CD 3 OD) 8 7.88 7,56 2H), 7.73 1H), 7.60 J 15.8 Hz, 1H), 6.51 J 15.8 Hz, 1H), 4.99 4.79 masked peaks), 4,81 2H), 3.74 J 7.8 Hz, 2H), 3,46 3.41 4H), 2,31 J 7.4 Hz, 2H), 1.39 J 7.2 Hz, 6H), 0.95 J 7.4 Hz, 3H); "C NMR (CD 3 OD) 6 0 10 117,1, 165.9, 154.6, 140.9, 129.6, 128.4, 127.3, 125.9, 118.6, 112.8, 111.5, 50.7, 40.4, 38.4, 36.4,19.9,14.0, 0 CN Example Preparation of 3-[2"(3,3-Dimethyl-butyl)-1 -(2-ethylamino-ethyl)-1 H-benzoimidazol- 5-yl]-N-hydroxy-acrylamide (63) [0303] The titled compound (63) was prepared according to the procedures described in Example 1, by using appropriate starting materials, HPLC: 99.0 tR 0,93 min; LCMS m/z: 359 1H NMR (CD 3 OD) 6 7.5 J 8.4 Hz, 1H), 7.75 7.74 2H), 7.16 J 15.7 Hz, 1H), 6.31 J 15.7 Hz, 1H), 4.89 (brs, 2H), 3.72 (brs, 2H), 3.29 3,18 4H), 1.90 1.86 2H), 1.35 J 7.1 Hz, 3H), 1.09 (s, 9H); 13C NMR (CD 3 OD) 6 165.7, 158.4, 140.4, 134.9, 134.5, 134.2, 126.2, 122.5, 119.2, 115.6, 113.4, 55.3, 44.0, 40.8, 40,7, 31.3, 29,3, 22,9.

Example 61 Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-(3,3-dimethyl-butyl)-1H- (64) [0304] The titled compound (64) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC: 99.0 tR 0.83 min; LCMS m/z: 359 'H NMR (CDO 3 D) 5 7.94 J 7.8 Hz, 1H), 7,81 1H), 7.73 J 7.9 Hz, 1H), 7,42 J 15,7 Hz, 1H), 6,64 J 15.7 Hz, 1 4.93 (bra, 2H), 3.76 (brs, 2H), 3.22 J 7.7 Hz, 2H), 3.09 6H), 1.91 1.87 (m, 2H), 1.08 9H); "C NMR (CDaOD) 8 165.4, 158.4,140.2, 134.5, 134.2,133.2, 126.5, 118.8, 115.3, 113.9, 46.4, 45.1,42.9, 40.6, 31.3, 29.2, 22.9, 11.4.

Example 62 Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-Nhydroxy-acrylamlde Y:vM-NMXA m DIwIPlaOim4S AU lEMd wm.i.ll R1 PIkddLd COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:26 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 101 97 (0305] The titled compound (65) was prepared according to the procedures o described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98,5%; tR 0.78 min, LCMS m/z: 345([M 'H NMR (DMSO-d 6 8 0.89 (3H, Sm), 1.38 (4H, 1.83 (2H, 2.93 (6H, 3.04 (2H, 3.50 (2H, 4,70 (2H, m), 6.55 (1H, 7.57 (1H, 7.61 (1H, 7.81 (2H, 10.42 (1H, bs).

Example 63 Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-(2,2,2-trifluoro-ethyl)-I H- (64) [0306] The titled compound (64) was prepared according to the procedures C described In Example 1, by using appropriate starting materials. HPLC purity at 254 Snm: 91.1%; tR 0.68 min. LOMS m/z: 357 Example 64 s1 Preparation of 3-[1-(2-Ethylamino-ethyl)-2-pentyl-1 hydroxy-acrylamide (68) [0307] The titled compound (68) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98.4%; tR 0.87 min. LCMS m/z: Example Preparation of N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-pentyl-1H- (71) [0308] The titled compound (71) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 97.4%; tR 0.95 min. LCMS m/z: 359 1 H NMR (DMSO-d.) 8 0.89 (3H, 1.22 (6H, 1.38 (4H, 1.82 (2H, 2.99 (3H, 4.56 (2H, 8.51 (1H, d), 7.59 (2H, 7.64 (1H, 7.88 (1H, 8,74 (2H, bs).

Example 66 Preparation of 3-[2-Hexy-1 -(2-methylamino-ethyl)-1H-benzoimidazol-5-yl]-Nhydroxy-acrylamlde (74) [0309] The titled compound (74) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 96.0%, tR 1.12 min. LCMS m/z: 345 'H NMR (CDsOD) 6 7.76 (2H, s), 7.70 (1H, d, J 8.6 Hz). 7.50 (1H, d, J 15.7 Hz), 6.43 (1H, d, J 15.7 Hz), 4.81 (21H, d, J 5.7 Hz), 3,49 (2H, be), 3.15 (2H, dt, J 4.8 Hz), 2.71 (3H, 1.85 (2H, qn, J YVWIWKA NO PaeLETiPIM4l AU g PVrlv4 u Fl FtU i 7il ge COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:26 PHILLIPS ORMONDE FITZPATRICK NO, 3858 P. 102 98

VO

O 5.1 Hz), 1,46 (2H, 1.33 (4H, 0.85 (3H, t, J 7.1 Hz); 3C NMR (CD 3 OD) a S163.7, 157.8, 138.5, 132.7, 124.2, 117.6, 113.7, 111.2, 40.2, 32,2, 30.5, 28.0, 25.6, 25.1, 21.6, 12.3.

Example 67 Ci Preparation of N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-pentyl-1H-benzoimidazol- [03101 The titled compound (75) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 97.8%; tR 0.80 min. LCMS m/z: 331 1 H NMR (DMSO-de) 8 0.89 (3H, Sm), 1.38 (4H, 1.84 (2H, 2.51 (3H, 3.14 (2H, 3.38 (2H, 4.70 (2H, m), §6.57 (1 H, 7.62 (1H, 7,73 (1H, 7.96 (2H, 9.13 (2H, s).

Example 68 Preparation of 3-(2-Butyl-1-pyrrolidin-3-yl-1H-benzolmldazol-5-yl)-N-hydroxyacrylamide (69) I We

-^^^CHO

oN 'o m N N M H NN u Cl" EtN SInCl, MeO0WAcOH Ia N Heat boc Boo HCIIOH ^^XNH20H I 69-4 mB Step1 [0311] To a solution of methyl trans-4-Chloro-3-nitrocinnamate (la, 4,8 g, 20 mmol) in triethyl amine (5.5 mL, 40 mmol) was added 3-Amino-pyrrolidine-1-carboxylic acid tertbutyl ester (11.2 g, 60 mmol), the resulting mixture was then heated to 100 "C for 8 hours, then another portion of methyl trans-4-Chloro-3-nitrocinnamate (4.8 g, 20 mmol) and triethyl amine (5.5 mL, 40 mmol) was added, the resulting mixture was allowed to stir overnight at 100 then reaction was quenched by adding 200 mL of DCM and mL of 1M HCI solution. After separation of DCM layer, the aqueous solution was extiacted with DCM one more time, and combined with previous DCM solution, which was then washed with brine, dried over sodium sulfate, then filtered through silica gel short column, and rinsed with ethyl acetate and hexanes mixture until the orange Y;,,MWlKNO nDartspEW-ais AU Sted faO u,l Prlu at~ W 4l COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR, 2006 17:27 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 103 99 O color band was completely rinsed down. After removal of solvent under reduced 0 pressure, the residue 69-2 was obtained (around 80% of yield in most of cases) as Sorange solid, which is pure enough (95% purity from HPLC) for next step. LC-MS m/z: 292 ([M-Boc (C Step 2 [0312] To a solution of compound 09-2 (7.84 g, 20.0 mmol) in 100 mL of MeOH and AcOH mixture was added corresponding aldehyde (3.0 mL, 30.0 mmol) and tin chloride (22.6 g, 100 mmol), the resulting mixture was stirred at 42 °C for 24 hrs. Then the mixture was diluted using ethyl acetate (300 mL) at room temperature, and was c then quenched with sat. sodium carbonate (30 mL). The resulting mixture was stirred 0 for additional 1 hour, then organic layer was decanted to another conic flask. Solid left CN in reaction flask was suspension with another portion of ethyl acetate (300 mL), which was then decanted and combined with previous portion of ethyl acetate and was then filtered through silica gel short column and rinsed with ethyl acetate, after removal of filtrate under reduced pressure, the residue was pure enough for next step and also could be purified on column (hexanes:EtOAc 1:2) to give a pale-yellow solid 69-3 (3.8 g, LC-MS m/z: 456 Step 3 [0313] To a flask charged with compound 69-3 (456 mg, Immol) was added 1.25 M HCI in MeOH (4 mL), the resulting mixture was then heated to reflux for 2 hours, which was then evaporated to dryness under reduced pressure to give compound 4 as HCI salt, which is pure enough for next step without any purification. LC-MS m/z: 356 Step 4 [0314] To a solution of above crude 69-4 (around 0.16 mmol) product in MeOH mL) was added a pre-prepared NH 2 OH stock solution (2.0 M, 2 mL). The resulting mixture was stirred at room temperature for 2 hrs. After quenching with TFA (0.4 mL), the resulting mixture was subjected to HPLC purification to afford 25 mg of 3-(2-Butyl- 1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide. HPLC purity: 98%; LC- MS m/z: 329 'H NMR (CDO 3 D) 8 0.95 (3H, t, J 7.2 Hz), 1.46 (2H, 1.77 (2H, 2.52-2.82 (2H, 3.10-3.17 (2H, 3.48 (1H, 3.80 5.55 (1H, 6.48 (1H, d, J= 16.0 Hz), 7.58 (1H, d, J= 16.0 Hz), 7.67 (1H, d, J= 8.0 Hz), 7.78- 7.92 (2H, m).

YaMtyHrI IO. DELETBSPI090QS AU aaNd Pftliion l FIs U PllFadAe COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:27 PHILLIPS ORMONDE FITZPATRICK NO. 385B P. 104 100 SExample 69 SPreparation of 3-(2-Butyl-1-piperidin-4-yl-1H-benzoimidazol-5-yl)-N-hydroxyacrylamlde [0315] The titled compound (70) was prepared according to the procedures described In Example 78, by using appropriate starting materials. HPLC purity: 98%; Cl LCMS m/z: 343 1 H NMR (CDOD) 5 0.96 (3H, t, J 7.2 Hz), 1.46 (2H, m), 1,79 (2H, 2.21 (2H, 2.82 (2H, 3.10-3.17 (2H, 3.26 (1H, 3.60 (2H, Sm), 4.96 (IH, 6.49 (1H, d, J= 15,8 Hz), 7.60 (1H, d, J= 15.8 Hz), 7.66 (1H, d, J= Hz), 7.82 (1H, s) (1H, d, J= 8.0 Hz), C Example o Preparation of 3-(2-Hexyl-1-pyrrolidin-3-yl-1H-benzolmldazol-5.yl)-N-hydroxy- C acrylamide [0316] The titled compound (80) was prepared according to the procedures described in Example 68, by using appropriate starting materials. HPLC purity: 98%; LCMS m/z: 357 H NMR (CDaOD) 8 0.84 (3H, t, J 7.2 Hz), 1.22-1.38 (4H, 1.44 (2H, 1,81 (2H, 2.52-2.82 (2H, 3.10-3.17 (2H, 3.48 (1H, 3.80 (2H, 5.56 (1H, 6.48 (1H, d, J= 15.8 Hz), 7.56 (1H, d, J= 15.8 Hz), 7.65 (1H, d, J= 9,2 Hz), 7.84 (1 H, 7.90 (1 H, d, J 9.2 Hz).

Example 71 Preparation of 3-[2-Butyl-1-(1-methyl-pyrrolidin-3-yl)-1H-benzoimidazol-5-yl]-Nhydroxy-acrylamlde (81) [0317] The titled compound (81) was prepared according to the procedures described in Example 68, by using 69-4 via reductive amination to introduce a methyl group.

HPLC purity; 98%; LCMS m/z; 343 'H NMR (CD3OD) 8 0.99 (3H, t, J 7.2 Hz), 1.52 (2H, 1.83 (2H, 2.65-2.92 (2H, 3.09 (3H, 3.15-3.25 (2H, m), 3.58 (1H, 3.90 (2H, 5.73 (1H, 6,51 (1H, d, J 16.0 Hz), 7.58 (1H, d, J 16,0 Hz), 7.69 (1H, d, J= 8.0 Hz), 7.88 (1H, 8.00 (1H, d, J= 9.2 Hz).

Example 72 Preparation of 3-(2-Hexyl-1-plperldin-3-yl-lH-benzolmldazol-5-yl)-N-hydroxyacrylamide (82) [0318] The titled compound (82) was prepared according to the procedures described in Example 68, by using appropriate starting materials. HPLC purity: 97%; LCMS m/z: 343 1 H NMR (CDsOD) 8 0.99 (3H, t, J 7.2 Hz), 1.52 (2H, 1.84 (2H, m), 2.04 (1H, 2.20 (2H, 2.61 (1H, 3.12-3.22 (2H, 3.49 (1H, 3.67 (1H, V:lMu NO DBLEIWMO l-MIS1 AU WSdionilh l i lld .1 tdae COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:27 PHILLIPS ORMONDE FITZPATRICK NO.3858 P. 105 101 o 3.78 (1H, t, J 12,0 Hz), 4,98 (1H, 6.53 (IH, d, J 15.8 Hz), 7.63 (1H, d, J o 15,8 Hz), 7.70 (1H, d, J= 9.2 Hz), 7.86 (1H, 8.06 (1H, d, J= 8.8 Hz).

SExample 73 Preparation of 3-(2-Butyl. -piperidin-3-yl-1H-benzoimidazol.5-yl).N.hydroxy- Cl acrylamlde (83) [0319] The titled compound (83) was prepared according to the procedures described in Example 68, by using appropriate starting materials. HPLC purity; 97%; LCMS m/z: 371 1 H NMR (CDsOD) 8 0.88 (3H, t, J= 7.2 Hz), 1.22-1.42 (4H, 1.47 (2H, 1.84 (2H, 2.04 (1H, 2.20 (2H, 2.62 (1H, 3.12-3.22 (2H, m), l 3.48 (1H, 3.68 (1H, 3.78 (1H, t, J= 12.0 Hz), 5.01 (1H, 6.53 (1H, d, J= 15.8 SHz), 7.62 (1H, d, J= 15.8 Hz), 7.70 (1H, d, J 9.2 Hz), 7.86 (1H, 8.06 (1H, d, J 'N 8.8 Hz).

Example 74 Preparation of (E)-N-hydroxy-3-(1-(1-methylpiperidin-3-yl)-2-pentyl-1H- (86) [0320] The titled compound (86) was prepared according to the procedures described in Example 71, by using appropriate starting materials.HPLC purity: 99.3 tR =1.06 min; LCMS m/z: 371 1H NMR (CDaOD) 8 8.18 J 7.9 Hz, 1H), 7.92 (s, 1H), 7,77 J= 8.1 Hz, 1H), 7.61 J= 15.7 Hz, 1H), 6.58 J= 15.7 Hz, 1H), 5.21 (brs, 1H), 3.69 (brs, 2H), 3.69 3.66 1H), 3.37 3.27 (masked peaks), 3.03 (s, 3H), 2.66 (brs, 1H), 2.29 2.22 3H), 1.94 1.90 2H), 1.54 0,94 4H), 0.96 J= 7.1 Hz, 3H); 3"C NMR (CDsOD) 8165.6, 157.6, 139.9, 134.6, 134.1, 132,5, 126.3, 120.4, 115.5, 115.2, 54,9, 54,4, 53.3, 44.1, 32.4, 27.5, 27.3, 26.8, 23.2, 23.1, 14,2.

Example Preparation of (E)-3-(2-hexyl-1-(1-(2-hydroxyethyl)piperidln-3-yl)-1H- [0321] The titled compound (90) was prepared according to the procedures described in Example 68, by using appropriate starting materials and alkylation of the piperidine with 2-bromoethanol. LCMS m/z: 415 H]i).

vlkpTsi NQ oDlirTerlm.wsV AUUBclHwnimUfW a Pi fuid COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:27 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 106 102 O Example 76 o Preparation of N-Hydroxy-3-[1-(1-pentyl-plperdln-3-yl)-1H-benzolmldazol-5-yl]acrylamide (94) S[0322] The titled compound (94) was prepared according to the procedures described in Example 68, by using appropriate starting materials (formic acid for benzimdiazoel C ring formation and reductive aminatlon of the piperidine with pentanal). HPLC purity: LC-MS m/z: 357 'H NMR (CDaOD) 8 9.04 1H),.7.94 (brs, 2H), 7.78 1H, J= 8.2 Hz), 7,70 1, J= 15.7 Hz), 6.57 1H, J= 15.9 Hz), 5.14-5.10 (m, 1H), 3.85(dd, 2M, J 88.0, 9.0 Hz), 3.48 3.13 4H), 2.43 2.12 4H), 1.94 1.80 2H), 1,39 1.29 4H), 0.94 3H, J 68 Hz).

SExample 77 C1 Preparation of N-Hydroxy-3-[1-(1-phenethyl-piperidin-3-yl)-1H-benzoimidazol-5yl]-acrylamide (96) [0323] The titled compound (96) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity: 98.6%; LC-MS m/z: 'H NMR (CD 3 OD) 8 8.93 1H), 7.95 s 1H), 7.91 1H, J Hz), 7.76 1H, J 8.5 Hz), 7.70 1H, J 15.8 Hz), 7.35 7.24 6H), 6.56 (d, 1H, J 15.7 Hz), 5.10 1H, J 11.4 Hz), 3,91 (dd, 2H), 3.55 3.45 2H), 3.15 3.11 2H), 2.46 2.13 6H).

Example 78 Preparation of N-Hydroxy-3-{1-[1-(3-phenyl-propyl)-piperidin-3-yl]-1H- (97) [0324] The titled compound (97) was prepared according to the procedures described in Example 76, by using appropriate starting materials, HPLC purity: 94.5%; LC-MS: 405 'H NMR (CDsOD) 8 8.68 1H), 7.94 1H), 7.80 1H, J 8,4 Hz), 7.71 1H, J= 15.7 Hz), 7.69 1H, J= 8.2 Hz), 7.31 7.17 6H), 6,54 1H, J= 15.6 Hz), 3.71 (dd, 2H, J 66 Hz, 10.9 Hz), 3.48 3.40 1H), 3.13 3.05 2H), 2.73 2H, J 7,4 Hz), 2.38 2.04 8H); Example 79 Preparation of 3-{1-[1-(3,3-Dimethyl-butyl)-pyrrolldln-3.yl].1H.benzolmidazol-5yl})N-hydroxy-acrylamide (99) [0325] The titled compound (99) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity: 91.9%; tR 1.10 min. LC-MS m/z: 357 'H NMR (DMSO-de) 6 0.91 (9H, 1,52 (4H, 3.09 YMlutfi2 NO DELKZTBFMll4 AUea ,mi mihm Fil n Flldi COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:28 PHILLIPS ORMONDE FITZPATRICK'"'N;8 NO, 3858 P. 107 103 O (1H, 3.29 (6H, 6.52 (1H, 7.43 (2H, 7.62 (1H, 7.80 (1H, 8.82 (1H, Ss), 10.25 (1H, bs).

SExample Preparation of 3{(1 [2-(Ethyl-methyl-amino)ethyl].2.pentyl.1H-benzolmidazol-5- Cl yl})N-hydroxy-acrylamide (79) [0326] The titled compound (79) was prepared according to the procedures described 7- in Example 1, by using appropriate starting materials. HPLC purity: 99%: tt 0.68 min, LC-MS m/z: 359 'H NMR (DMSO-ds) 6 0.89 (3H, 1.23 (3H, 1.38 (4H, 1.84 (2H, 2.92 (3H, 3.10 (2H, 3.28 (2H, 3.52 (2H, 4.77 (2H, m), C 6.58 (1H, 7.61 (1H, 7.71 (1H, 7.92 (2H, 10.48 (1H, bs), 0 Cl Example 81 Preparation of 3{2-Butyl-1 -[2-(ethyl-methyl-amlno)-ethyl]-1 N-hydroxy-acrylamide [0327] The titled compound (85) was prepared according to the procedures described in Example 1, by using appropriate starting materials, HPLC purity: 95.8%; tR =1.04 min. LC-MS m/z: 345 1H NMR (DMSO-d) 5 0.95 (3H, 1.25 (3H, 1.46 (2H, 1.81 (2H, 2.92 (3H, 3.13 (2H, 3.27 (2H, 3.54 (2H, 4.80 (2H, 6.60 (1H, 7.62 (1H, 7.75 (1H, 7.92 (2H, 10.59 (1H, bs).

Example 82 Preparation of 3-(2-Butyl-1-(2.[ethyl.(3-hydroxy-propyl)-amino]-ethyl)-1 H- (91) [0328] The titled compound (91) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity: 93.5%; tR= 0.50 min. LC-MS 389 IH NMR (DMSO-de) 8 0.94 (3H, 1.25 (3H, 1.46 (2H, 1.83 (4H, 3.04 (2H, 3.31 (4H, 3.50 (4H, 4.72 (2H, 6,54 (1H, 7.61 (1H, 7.69 (1H, 7.80 (1H, 7.90 (1H, 10.20 (1H, bs).

Example 83 Preparation of 3-(1 -[2-[Ethyl-(3-hydroxy-propyl)-amino]-ethyl}-2-pentyl-1 H- (92) [0329] The titled compound (92) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity: 93.5%; tR 0.50 min. LC-MS 389 'H NMR (DMSO-de) 8 0.94 (3H, 1.25 (3H, 1.46 Y.NMMH XI IO DELBWIICMM0E AU SeRd PksfInU F atU1 ar P COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:28 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 108 104 O (2H, 1.83 (4H, 3.04 (2H, 3.31 (4H, 3.50 (4H, 4.72 (2H, 6.54 (1H, O 7.61 (1H, 7.69 (1H, 7.80 (1 H, 7.90 (1 H, 10.20 (1 H, bs).

SExample 84 Preparation of 3-{1-[2-(Butyl-ethyl-amlno)-ethyl]-1H-benzolmidazol-5-yl}-N- C hydroxy-acrylamlde [0330] The titled compound (95) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity: 99.9%; LC-MS Sm/z: 1 H NMR (CDsOD) 8 9,29 1H), 7.99 7.95 2H), 7.82 1H, J 8,5 Hz), 7.56 1H, J= 15.6 Hz), 6.53 1H, J 15,5 Hz), 5.0 4.95 2H), 3.86 C 3.78 2H), 3.42 (dd, 2H, J r 13.3, 7.1 Hz), 3.28 3.28 2H), 1.74 1.71 (m, S2H), 1.43 (qt, 2H, J 7.4, 3.8 Hz), 1.38 3H, J 7.2 Hz), 1.00 3H, J 7.3 Hz).

Example Preparation of 3-[2-(4-Cyano-butyl)-1-(2-dlethylamlno-ethyl)-1H-benzolmldazol-5yl]-N.hydroxy-acrylamide (101) [0331] The titled compound (101) was prepared according to the procedures described in Example 57, by using appropriate starting materials. HPLC purity at 254 nm: 99.9%.

LC-MS (ESI) m/z: 384 'H NMR (CDsOD) 5 7.78 (1H, s) 7.76 (1H, d, J Hz), 7.63 (1H, d, J 16.9 Hz), 7.58 (1H, d. J 5.1 Hz), 6.44 (1H, d, J 15,3 Hz), 4.70 (2H, in water peak), 3.50 (2H, t, J 7.6 Hz), 3.32 (4H, qt, J 7.3 Hz), 3,07 (2H, t, J= Hz), 2,50 (2H, t, J= 7.0 Hz), 1.99 (2H, q, J= 7.5 Hz), 1.78 (2H, q, J; 7.3 Hz), 1,29 (6H, t, J= 7.3 Hz).

Example 86 Preparation of 3-{1-[2-(Butyl-isopropyl-amino).ethyl]-1H-benzolmldazol-5-yl)-Nhydroxy-acrylamide (108) [0332] The titled compound (108) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity: 98.8%; tR 1,33 min. LC-MS m/z: 345 'H NMR (DMSO-d) 8 0.90 (3H, 1.25 (6H, 1.35 (2H, 1.64 (2H, 3.09 (2H, 3.51 (1H, 3.73 (2H, 4.74 (2H, 6.52 (1H, 7.53 (2H, 7,64 (1H. 7,80 (1H, 8.62 (1H, 9.40 (1H, bs), 10.72 (1H, bs), Yvufplu NO DELZBT)FPII.0) AU eand PMWlfiaSl Filu 0 FUClUAC COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:28 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 109 105 o Example 87 o Preparation of N-Hydroxy-3-{1-[2-(Isopropyl-pentyl-amino)-ethyl]-1 H- (109) S[0333] The titled compound (109) was prepared according to the procedures described in Example 76, by using appropriate starting materials. LC-MS m/z: 359 'H CN NMR (DMSO-de) 8 0.88 (3H, 1.25 (10H, 1,64 (2H, 3.12 (2H, 3.51 (1H, b), 3.60 (1H, 3.73 (1H, 4.74 (2H, 6.51 (1H, 7.59 (1H, 7.63 (1H, 7.80 l- (1H, 7.93 (1H, 8.65 (1H, 9.46 (1H, b) Example 88 Cl Preparation of 3-[2-(5-Cyano-pentyl)-1-(2-dlethylamlno-ethyl)-1H-benzoimidazol- (110) Ci [0334] The titled compound (110) was prepared according to the procedures described in Example 57, by using appropriate starting materials. HPLC purity at 254 nm: 95.4%, LC-MS (ESI) m/z: 347 'H NMR (CDsOD) 8 7.96 (1H, d, J= 8.5 Hz), 7.90(1H, s) 7.81 (1H, d, J 8.5 Hz), 7.59 (1H, d, J 15,6 Hz), 6.55 (1H, d, J 15.5 Hz), 4.96 (2H, t, J 7.3 Hz), 3.89 (2H, t, J 7,1 Hz), 3.44 (4H, qt, J 7.2 Hz), 3.31 (2H, embedded in MeOD peak), 2.51 (2H, t, J 6.9Hz), 2.05-1.98 (2H, 1.78 (2H, m, J 7.4 Hz), 1.70 (2H, m, J 6.4 Hz), 1.41(3H, t, J= 7.2 Hz); Example 89 Preparation of 3-(1-{2-[(3,3-Dimethyl-butyl)-ethyl.amino]-ethyl}-1H-benzoimidazol- (111) [0335] The titled compound (111) was prepared according to the procedures described in Example 76, by using appropriate starting materials. TFA salt. HPLC purity: 97.7%; LC-MS m/z: 359 1 H NMR (CD 3 OD) 8 9.10 1H), 7.89 1H, J 8.9 Hz), 7.88 1H), 7.74 1H, J 8.6 Hz), 7.51 IH, J 15.7 Hz), 6.46 1H, J 15.7 Hz), 4.98 4,93 2H), 3.77 3,75 2H), 3.38 (dd, 2H, J 13.3, 7.2 Hz), 3,22 3.18 2H), 1.60 1.59 2H), 1.33 3H, J= 7.1 Hz), 0.91 9H); [0336] HCI salt. 1 NMR (DMSO-de) 8 9.90 (bs, 1H), 8.65 IH), 7.93 1H), 7.82 (d, 1H, J 8.5 Hz), 7.64 1H, J 8.1 Hz), 7.61 1H, J 15.6 Hz), 7.52 1H, J 15.8 Hz), 4.76 4.72 2H, J 3.65 3.60 2H), 3.32 3.24 2H), 3.17 3.08 2H), 1.52 1.47 2H), 1.22 3H, J 7.2 Hz), 0.87 9Hz).

YMYUl NOBL DETERlG090n- AU SMU Fiial FId MPild COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:29 PHILLIPS ORMONDE FITZPATRICK NO, 3B58 P. 110 106 o Example o Preparation of 3-{1-[2-(Ethyl-propyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-Nhydroxy-acrylamide (112) i[0337] The titled compound (112) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity; 98.1%; LC-MS C m/z: 315 1 H NMR (CDsOD) 6 9.43 1H), 7,99 1H, J= 8.5 Hz), 7.93 (s, 1H), 7.82 1H, J= 8.5 Hz), 7.53 1H, J 15.7 Hz), 6.50 1H, J= 15.5 Hz), 5.00 4.96 2H), 3.78 2H, J 6.1 Hz), 3.37 (dd, 2H, J 14.2, 7.2 Hz), 3.22 3.19 (m.

2H), 1.75 (qt, 2H, J= 7.5 Hz), 1.33 3H, J 7.2 Hz), 0.99 3H, J 7.3 Hz).

o SExample 91 o Preparation of N-Hydroxy-3-(1-{2-[lsopropyl-(2-methyl-pentyl)-amino]-ethyl}-lH- C benzoimidazolf5-yl).acrylamide (113) [0338] The titled compound (113) was prepared according to the procedures described in Example 76, by using appropriate starting materials. LC-MS m/z: 373[(M+H)l]. 'H NMR (DMSO-de) 0.86 -0.97 (7H, 1.14-1.28 (12H, 4.70 (2H, 6.49 (1H, d), 7.58 -7.62 (2H, 7,73 (1H, 7.91 (1H, 8.48 (1H, s) Example 92 Preparation of 3-(1-[2-(Ethyl.hexyl-amlno)-ethyl]-2-methyl-1H-benzoimidazol-5yl}-N-hydroxy-acrylamide (116) [0339] The titled compound (116) was prepared according to the procedures described in Example 57, by using appropriate starting materials, HPLC purity at 254 nm: 98.2%, tR 1.27 min. LC-MS (ESI) m/z: 373 'H NMR (CD3OD) 8 7.85 (1H, 7.78 (1H, d, J= 8.4 Hz), 7.70 (1H, d, J= 8.7 Hz), 7.15 (1H, d. J= 15.9 Hz), 6.53 (1H, d, J= 15.9 Hz), 4.81 3.63 (2H, t, J= 7.7 Hz), 3.41 (2H, qt, J 7.2 Hz), 3.29 2.82 (3H, 1.74 (2H, 1.37 (11 H, 0.93 (3H, t, J 6.9 Hz).

Example 93 Preparation of 3-{1-[2-(Butyl-ethyl-amino)-ethyl]-2-trfluoromethyl-1H- (117) [0340] The titled compound (117) was prepared according to the procedures described in Example 57, by using appropriate starting materials. HPLC purity at 254 nm: 97.3%, tR 1.50 min. LC-MS (ESI) m/z: 399 'H NMR (CDsOD) 5 7.95 (1H, 7.70 (2H, 7.62 (1H, d, J= 15.9 Hz), 6.46 (1H, d, J= 15.8 Hz), 5.24 3.50 (2H, t, J= 8.8 Hz), 3.31 (2H, qt, J 7.2 Hz), 3,17 1.63 (2H, 1.35 (2H, qt, J 7,5 Hz), 1.29 (3H, t, J 7,2 Hz), 0,92 (3H, t, J 7.4 Hz).

Y:Mht)III NO DELBTWPFIQ05AUScmidat Prhi i hd dA COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:29 PHILLIPS ORMONDE FITZPATRICK NO. 385B P. 111 107 O 0 0 Example 94 Preparation of 3-{1-[2-(Ethylhexyl-amlno)-ethyl]-2-trifluoromethyl-1H- (118) [0341] The titled compound (118) was prepared according to the procedures described c in Example 57, by using appropriate starting materials, HPLC purity at 254 nm: 94.6%, tR 2.07 min. LC-MS (ESI) m/z: 427 'H NMR (CDaOD) 5 8,04 (1H, 7.80 (2H, 7,72 (1H, d, J 15.8 Hz), 6.58 (1H, d, J= 15.6 Hz), 4.85 3.61 (2H, t, J= Hz), 3.42 (2H, qt, J 7.2 Hz), 3.26 1.75 (2H, 1.39 (9H, m, J 7.5 Hz), o 10 0.93 (3H, t, J 7.0 Hz).

cN SExample 0 C Preparation of 3-[1-(2-Dipropylamino-ethyl)-1H-benzolmldazol-5-yl]-N-hydroxyacrylamide (120) [0342] The titled compound (120) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity; 100%. LC-MS m/z: 331 'H NMR (DMSO-da) 8 0.86 (6H, 1.64 (4H, 3.09 (4H. 3.60 (2H, 4.76 (2H, 6.53 (1H, 7.55 (2H, 7.65 (1H, 7.88 (1 H, 8.75 (1H, 9.93 (1H, bs).

Example 96 Preparation of N-Hydroxy3.(1 (2-[Isopropyl-(3-methyl-butyl)-amino]-ethyl).1 H- (121) (0343] The titled compound (121) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity: 98.7%; tR 1.02 min. LC-MS 358 'H NMR (DMSO-de) 8 0.88 (6H, 1.28 (OH, 1.59 (3H, 3.10 (3H, 3.68 (2H, 4.71 (2H, 6,50 (1M, 7.50 (2H, 7.59 (1H, 7.63 (1H, 8.52 (1H, 9 .50 (1H, bs), 10.70 (1H, bs).

Example 97 Preparation of 3-(1-{2-[(3,3.Dlmethyl-butyl)-methyl-amino]-ethyl}-lH- (122) [0344] The titled compound (122) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity at 254 nm: 97.8%; tR 0.93 min. LC-MS m/z; 345 'H NMR (DMSO-d 6 8 0.84 (9H, 1.52 (2H, 2.90 (3H, 3.17 (2H, 3.68 (2H, 4.80 (2H, 6.58 (1H, 7.59 (2H, m), 7.86 (1H, 7.90 (1H, 8.82 (1H, 10.10 (1H, bs).

Y.WMzU NI DELUTBP1MM04IAU SamWd Prkwds Phal u MesUdo COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR, 2006 17:29 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 112 108

O

o Example 98 Preparation of 3-(-{(2-[(2-Ethyl-butyl)-methyl-amino]-thyl}-lH-benzoimidazol-5- Syl).N-hydroxy-acrylamide (123) [0345] The titled compound (123) was prepared according to the procedures described l in Example 76, by using appropriate starting materials. HPLC purity at 254 nm: 97.7%; tR= 0.87 min. LC-MS rn/z: 345 'H NMR (DMSO-de) 5 0.81 (OH, 1.29 (4H, 1.69 (1H, 2.89 (3H, 3.08 (2H, 3.59 (2H, 4,77 (2H, 6.53 (1H, d), 7.52 (2H, 7.86 (1H, 7.94 (1H, 8.80 (1H, 9.54 (1H, bs).

o-i SExample 99 0 Preparation of 3-{1-[2-(3,3-Dlmethyl-butylamino)-ethyl]-lH-benzoimidazol-5-yl)-N- CN hydroxy-acrylamide (126) [0346] The titled compound (126) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity: 100%; tR 1.01 min. LC-MS m/z: 331 'H NMR (DMSO-ds) a 0.88 (9H, 1.44 (2H, 2.92 (2H, 3.50 (2H, 4.66 (2H, 8.54 (1H, 7.58 (2H, 7.82 (1H, 7.90 (1H, 8.74 (1H, m).

Example 100 Preparation of N-Hydroxy-3-{1-[2-(methyl-pent-4-enyl-amlno)-ethyl]-1H- (127) [0347] The titled compound (127) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity: 100%; tR 0.92 min. LC-MS m/z: 329 'H NMR (DMSO-de) 8 1.17 (2H, 2.06 (2H, 2.90 (3H, 3,10 (2H, 3.65 (2H, 4.80 (2H, 5.03 (2H, 5.75 (1H, 6.57 (1H, 7.60 (1H, 7.69 (1H, 7.90 (1H, 7.97 (1H, 8.92 (1H, 10.29 (1H, bs).

Example 101 Preparation of 3-(1-(2-[(3,3-Dlmethyl-butyl)-propyl-amlno].ethyl-1 H- (128) [0348] The titled compound (128) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity: 99.0%; tR=1.18 min. LC-MS m/z: 373 'H NMR (DMSO-de) 8 0.88 (12H, 1.51 (2H, 1.64 (2H, 3.10 (4H, 3.63 (2H, 4,76 (2H, 6.54 (1H, 7.65 (2H, 7.80 (1H, 7.94 (1H, 8.83 (1H, 9.93 (1H, bs).

rrUPQlt NiO BLUMBZ PIOG0@4 AU Smd hmviimaall Fil etis COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:29 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 113 109

VO

o Example 102 SPreparation of 3-{1-[2-(3,3-Dimethyl-butylamino)-ethyll-2-propyl-lH- (130) [0349] Step 1: Cyclization i0 0 HN 0 ON OMe N h OMe JZn, MeOH/AcOH NH2 HgN O [0350] To the starting material (Illa2, 3.34 g, 12.6 mmol) in 20% AcOH in MeOH (33 mL, 0,2 M) was added butyraldehyde (1.7 mL, 18.9 mmol) followed by zinc powder l (4.12 g, 63 mmol). The resulting mixture was heat up to 50 OC and stirred at this temperature for 30 minutes. The completion of reaction was monitored by HPLC and LCMS. The solvent was then evaporated to dryness and the crude was dissolved with ethyl acetate, subsequently saturated aqueous sodium carbonate was added till pH 9 and the mixture was centrifuged spin at 9000 rpm for 10 min. The liquid was decanted and solid was rinsed with ethyl acetate (sonicated). The liquid was extracted with ethyl acetate and then purifed by flash chromatography (silica, 3% MeOH in DCM) to give 3- [1-(2-Amino-ethyl)-2-propyl-1 H-benzoimidazol-5-yl]-acrylic acid methyl ester. Yield LC-MS m/z: 288 [0351] Step 2: Reductive-amination o OMe H ON NaCNBH 8

N

ACOH/ MeOH NH

HN

[0352] To 3-[1-(2-Amino-ethyl)-2-propyl-1H-benzoimidazol-5-yl]-acrylic acid methyl ester (1,2 g, 4.2 mmol) in MeOH (40 mL) was added 3,3-Dimethyl-butyraldehyde (0.524 mL, 4.2 mmol), The resulting mixture was stirred at rt for 2 hours prior to the addition of acetic acid (2 mL) and sodium cyanoborohydride (0.395 g, 6.3 mmol) and the reaction was stirred at rt for another 30 minutes. Solvent was removed and the residual was dissolved in DCM upon which was washed with aqueous sodium W INKI Mit bhM KLBbPIO4 AU lsaKd P i ii l PlUl 4 alll COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:30 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 114 110 O bicarbonate, water and brine. The combined organic layer, after workup, was purfied by Sflash chromatography (silica, 4% MeOH in DCM). LC-MS m/z: 372 S[0353] Step 3: hydroxamic acid formation.

The titled compound (130) was prepared according to the procedures described in C Example 1 (Step by using appropriate starting materials.

TFA salt of 130: HPLC purity: 99.9%; LC-MS m/z: 373 1 H NMR (CD 2 OD) 8 7.89 1H, J 8.6 Hz), 7.81 1H), 7.76 1H, J 8,6 Hz), 7.44 1H, J 15,7 Hz), 6.44 1H, J= 15.7 Hz), 4.81 2H, J 7.0 Hz), 3.65 2H, J= 6.4 Hz), 3.23 3.19 2H), 3.16 3.12 2H), 2.01 1.94 2H), 1.65- 1.61 2H), 1.16 3H, N 7.3 Hz), 0.96 9H).

SHCI salt of 130: HPLC purity; 98,1 LC-MS m/z: 373 'H NMR (CDaOD) 8 (N 8.06 1H, J 8.3 Hz), 7.90 1H), 7.88 1H, J 8.4 Hz), 7.59 1H, J 15.8 Hz), 6.56 1H, J 15.8 Hz), 4.91 4.81 2Hz), 3.60 3.66 2H), 3.31 3.35 2H), 3.17 3.13 2H), 2.05 1.97 2H), 1.70 1.66 2H), 1.20 3H, J= 7.3 Hz), 0.98 9 H).

Example 103 Preparation of 3-[1-[2-(3,3-Dimethyl*butylamino)-ethyl]-2-(2,2-dimethyl-propyl)- 1H-benzolmldazol-5-yl]-N-hydroxy-acrylamide (131) [0354] The titled compound (131) was prepared according to the procedures described In Example 102, by using appropriate starting materials. HPLC purity; 92%; LC-MS m/z: 'H NMR (CDsOD) 8 7,89 1H), 7.85 1H, J 8.5 Hz), 7.77 (d, 1H, J= 8.7 Hz), 7.63 1H, J= 15.8 Hz), 6.55 1H, J 15.7 Hz), 4.91-4.81 2H), 3.58 2H, J 6.5 Hz), 3.13-3.08 4H), 1.63-1.58 2H), 1.13 9H), 0.96 (s, 9H).

Example 104 Preparation of 3-[1-{(2[Bis-(3,3-dimethyl-butyl)-amino].ethyl}-2-(2,2-dlmethylpropyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide (132) 10355] The titled compound (132) was prepared according to the procedures described in Example 102, by using appropriate starting materials. HPLC purity; 96%; LC-MS m/z: 'H NMR (CDaOD) 8 7.93 1H), 7.88 1H, J= 8.5 Hz), 7.80 (d, 1H, J= 8,7 Hz), 7.72 1H, J= 15.8 Hz), 6.59 1H, J 15.8 Hz), 5.00 2H, J= Hz), 3,67 2H, J 7.5 Hz), 3.13 3.08 2H), 1.68 1.64 4H), 1.14 9H), 0.96 18H).

Y:IIWKJmX DELETEFmIgSDPI AU SMcId Phaidla iaL a Plida COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:30 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 115 111 o Example 105 o Preparation of 3-{1.[2-(2,2-Dimethyl-propylamlno)-ethyl]-iH-benzoimidazol-5-yl}- N-hydroxy-acrylamlde (133) S[0356] The titled compound (133) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity: 99.9%; LC-MS C m/z: 1 H NMR (CDsOD) 5 8.82 1H), 7.94 1H), 7.83 1H, J Hz), 7.75 1H, J 8.7 Hz), 7.66 1H, J 15,8 Hz), 6.53 1H, J 15.8 Hz), 4.92 -4.78 2H), 3.64 2H, J 7.0 Hz), 2.98 2H), 1.09 9H).

o 10 Example 106 Preparation of 3-(1-{2-[(2,2-Dimethyl-propyl)-propyl-amino]-ethyl}-1H- 0 benzoimidazol-5-yl)-N-hydroxy-acrylamide (134) CN [0357] The titled compound (134) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLC purity: 99.9%; LCMS m/z: 359 H NMR (CDO 3 D) 5 9.07 1H), 7.95 1H), 7.92 1H, J 8.7 Hz), 7.78 1 H, J 8.4 Hz), 7.66 1 H, J 15.8 Hz), 6.56 1H, J= 15.8 Hz), 4.99 4.97 2H), 3.74 2H 7.0 Hz), 3.32 3.20 4H), 1.85 1.82 2H), 1.03 (a, 9H), 0.92 3H, J 7.1 Hz).

Example 107 Preparation of 3-(1-[2-(3,3.Dimethyl-butylamino)-ethyl]-2-ethyl-1H-benzoimidazol- (135) [0358] The titled compound (135) was prepared according to the procedures described in Example 102, by using appropriate starting materials. HPLC purity: 94.3%; LCMS m/z: 359 'H NMR (CD 3 OD) 5 7.69 1H, J 8.0 Hz), 7.54 7.53 (d, 1H, J 9.8 Hz), 6.89 1H, J 16.1 Hz), 6.08 1H, J 15.7 Hz), 4.80 4.70 (m, 2H), 3,55 3.45 2H), 3.20 3.19 2H), 2.95 2.90 2H), 1.56 -1.52 2H), 1.42 3H, 7.4 Hz). 0,81 9H).

Example 108 Preparation of 3-[1 (2-Dlethylaminoethyl)-2-propylamino-1H-benzoimidazol-5-yl]- N-hydroxy-acrylamlde (105) [0359] The titled compound (105) was made according to the following synthetic scheme.

Y*tym tN O DELErWl10o0w AU sgoa Fwvrs PwlAll a il edld COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:30 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 116 0

H

3

N

HN~a

(-N

DCG

NCS

H

2 N 0

NH

Sf-- 0 N NHaOH NN N'H

N

I 0360] HPLC purity: 100%. 'H-NMR (DMSO-d,) 8 0.97 (3H, t, J 7.32 Hz), 1.22 (61, 1.68 (2H, 3.09-3.80 (10H, 6.47 (1H, d, J 15.80 Hz), 7.52-7.64 (4H, m), 9.03 (2H, bs), 10.10 (1H, 10.81 s) Example 109 Preparation of 3-[1 -(3-Dimethylamino-2,2-dimethyl-propyl)-2-propylamino-1 H- (115) [03611 The titled compound (115) was made by using method analogous to compound to (105)HPLC purity: 97%. 1 H-NMR (DMSO-de) 8 0.97 (SH, t, J 7.28), 1.15 (1H, 1.69 (2H, m, J 7.28 Hz), 2.89 (6H, 3.28 (2H, 3.42 (2H, 4.15 (2H, 6.47 (2H, d, J 15.80), 7.49-7,75 (4H, 8.94 (IH, bs), 9.42 (1H, bs), 10,81 (1H, bs), 13.44 (1H, bs).

[0362] The following compounds are representative examples prepared by methods disclosed or analogous to those disclosed in above Examples 1-109; Cmpd miz Structure NAME No 3-[1-(3-Dimethylamino- 2,2-dimethyl-propyl)-2- N (2,2-dlimethyl-propyl)- 1 387 1 yl]-N-hydroxyacrylamide YtAMnXL .NO DElIWMI095 AU SOW Fraspp Pil m Vaand COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21.MAR.2006 17:30 21.MAR 200617:30PHILLIPS ORMONDE FITZPATRICK N.88 P F NO. 3853 P. 117 Gmpd Structure [M+HJ AM 31-(3-Dimethyamino- N 2,2-dlmethyl-propyl)-2- 2 A359 isopropyl-iMhydroxy-acrylamide 3-(2-Butyl-1 N N A dimethylamino-2,2- 3 373 dimethyl-propyl)-1 H- C hydroxy-acrylemide 3-ti -(3-Dimethylamino- N N .2,2-dimethyl-propyl)-2- A 391 (2-methylsulfanylethyl)-1 Hhydroxy-acrylamide 3-[1 -(3-Dimethylaminoa 2,2-dimethyl-propyl)-2- \A375 *thoxyrnethyl-1Ihydroxy-acrylamide 34[1-(3-Dimethyamino- N Ytb 2,2-dimethyl-propyl)-2- 6 373 isobutyl-IHhydroxy-acrylamide N 3-[1 -(2-Diethylamino- I ethyl)-2-isobutyl- I-- 7 359 hydroXY-a1crylamide YlMI NO DBLTWflWH AU kucd frfrvkUu riuu uw P14A COMS ID No: SBMI-03086169 Received by IP Australia: lime 18:02 Date 2006-03-21 21-MAR-2006 17:31 21. MA. 26%17:31 PHILLIPS ORMONDE FITZPATRICK N.88 P 1 NO. 3858 P. 118 CmdStructure 12 NAME 3-[2-Butyl-1 diethylemino-sthyl)-1 Hbenzoimidszo-e-y]-Nhydroxy-acrylamide 3-[2-But-3-ynyl-I N dimethylamlino-2,2- 9 369 dirnethyl-propy)-1 Hhydroxy-acrylamide 3-[2-But-3-enyl-I 1 NN <OHdimethylarnino-2,2- A371 dimethyl-propyl)-IHhydroxy-acrylamide 3-[2-But-3-enyl-l-(2diethylamino-othyi)-I H- 11357 hydroxy-acrylamide CH 3-[2-But-3-yny-1 diethylamino-etiyly1 H- 12 355 hydroxy-acrylamide OH 3-LI -(3-Dimethylamino- /1 N N2,2-dimethyl-propyl)-2- 13 413 (3,3,3-trifluoro-propyl)- 1 H-be yI]-N-hydroxyacrylamide YA&4MIAYiNO DK~fhi0*9I AU 5101d PMVA1SNN1 FWuJ APUc~tf COMB ID Na:SBMI-03086169 Received by I13 Australia: Time (I-tm) 18:02 Date 2006-03-21 21-MAR-2006 17:31 21. MA. 20% 17:31PHILLIPS ORMONDE FITZPATRICKNC388 P 19 NO, 3858 P. 119 Cmpd Structurew

NAME

No

MH

H 3-(1 -(2-Diethylamino- N e ethyl)-2-(3,3,3-trfluoro- 14 A399 propyl)-1 Hhydroxy-acrylamide H a-[1-(2-Diethyaminoa ethyl)-2-ethoxymethyl- 15A3511 1 yll-N-hydroxyacrylamide me 3-[1 -(3-Dimethylamino- N 2,2.dimethyl-propyl)-2- 16331 methyl-I Hif hydroxy-acrylamide 3-[1 -(2-Diethylamirio- A Nethyl)-2-(2,2-dimethyl- 17 373 propyfl-I H- C) hydroy-acrylamide PB N-Hydroxy-3-[1 isopropylamino-propyl)- 18 N /2-(3,3,3-trifluorola 399 propyl)-I Haorleamide 3-[2-(2 4 2-Dimethylpropyl)-1-(2- 19 359 sopropylamino-ethyl)- 19 359 I ylj-N-hydroxy- I I Iacrylamide ytWstMUNO wMlTNWUo AU 3md ftwdd Muas FIIASw COMS ID No: SBMI-03086169 Received by iP3 Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:31 21.MAR 200617:31PHILLIPS ORMONDE FITZPATRICK N.88 P 2 NO-3856 P. 120 CmdStructure

NAME

No

(MIIII

341 Diisopropylamino- 401 ethyl)2-(2,2-dimethylpropyl)-1 Hbydroxy-acrylamido Diisopropylamino- 21 387 ethyl)-2-isobutyl-1 Hhydroxy-acrylamide 3-El -(3-Dimethyamino- N. Z,2-dlnmethyl-propyl)-2- 3L hex-34ny-1 H- 22 1< hydroxy-acrylamide 3-ti -(3-Dimethylamino- E 2,2-dimethyl-propyl)-2- 23 /429 (2,4,4-trimethyl-pentyl)- 1 7 yL-N-hydroxyacrylamide 3-(2-Cyclohexyl-I N Ndimethylamino-2,2- 24 IN 399 dlmethyl-propyl)-1 Hhydroxy-acrylamide 3-j2-Bicyclo(2.2. ljhept- 5-eii-2-yl-1 (3- 409 dinmethylamino-2,2- 409 dimethyl-propyl)-1 H- 7 hydroxy-acrylamide Y~w,WwfINIoDZLZTwflIM At; NeSS Fm~dI.S Phig a FAe COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:31 21. AR. CQ6 7:31PHILLIPS ORMONDE FITZPATRICK .333 P 12 NO. 3858 P. 121 Struoture (M+H3 AM No (+j 3-fl -(2-Diethylamninoethyl).2-hex-3-elyl-1 H- 28 385 A hydroxy-crylamide 341 I EDllsopropylamino- 27 /413 ethyl)-2-hex-3-eriyl-1 Hhydroxy-acrylamide 3-(2-Hex-3-enyl-i N Nisopropylamino-ethyl)- 28 I371 1 yI].N-hydroxyscrylamide 3-[2-HQX-34fly-1 ~'-isopropylamino-propyl)- 29 A385 1 yI]-N-hydroxyacjr4Iorn;de /0 35N ethyl)-2-hex-3-enyl-1

H-

hydroxy-acrylamide 3-fl -(2-Diethylamino- -t ethyl)-2-hexyl-lI H- 31 387 hydroxy-acryiamide Y14utCUW NOD naWMtlSC'AU OJgce-t lFM*Joa Mlil -dMAW COMB ID No: SBMI-03086169 Received by IP Australia: lime 18:02 Date 2006-03-21 2MA20617:31 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 122 I 118 N-Hydroxy-3-[11-(3- 32 N sopropylamino-propyl)- 32 415 2-(2,4,4-trimethylperityl)-l Hacrylam'idet 3-[2-(2,2-Dimethyl- 33 373 isopropylamino-propyl)- 1 yI)-N-hydroxyacrylemide Diisoprapylamino- \4 /42 ethyl)-2-(3,3,3-trifluorapropyl)-l H- (3 hydroxy-acryismide N-Hydroxy-3-12q N isobutyl-14-2- A% 345 iscpropylamino-ethyl)- 1 yI]-acrylamide 3-[2-(2,2-Dimnethyl- N N propyl)-1-(2- 368 345 ethytemino-ethyl)-I H- S hydroxy-acrylamnide 3-fl -(2-Ethytaminor ethyl)-2-iobutyl-1 H- 37 331 hydroxy-acryamidQ V!TAUtR4KI NO ILNTIIDH.8 AU 1"ad Nni iOI IF"a aM Illod.

COMS ID No: SBMi-03086169 Received by P1 Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 11:32 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 123 119 3-[1 0 N Diisopropylamino- Cl /ethyl)-2-(2,4,4- 38 43 trimethylpentyl)-i H-- Cl hydroxy-acrylamide N-Hydroxy-3-1i N isopropylamino-ethyl)- 39 401 2-(2,4,4-trimethyl.

00 pentyl)-1 Ho acryAsmlde Cl 3-il -(2-Ethylarino- -t ethyl)-2-(2,4,4- /0 1387 trimethyl-penty9)-1 H- W hydroxy-acrylamide 3.[1 -(2-Diethylaminoethyl)-2-(2,4,4- 41 415 trimethyl-pentyl)-1 H- 2 hydroxy-acrylamido 3-El -(2-Diethyaomino- /2 \345 ethyl)2-pmpyll

H-

bertzoimidazo-S-yJ-N- K hydroxy-acrylamide 3-(2-Butyl-1 clisoprcpylamino- 43 387 ethyi)-I H- 'B,,.hydroxy-acrylamide 3-[2-ButyI-l-(2ethylamino-ethyl)-1 H- I331 benzoimidazol-6-y]-Nwrl, Ihyciroxy-acrylamilde vrnugWsINo DZL*WFIID.OAU lundWpftda Ain FMfleh COMB ID No: SBMI-03086169 Received by IF Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:32 21. MA. 2%617:32PHILLIPS ORMONDE FITZPATRICKNO338 P 12 NO.3858 P. 124 3-(1 -(2-Diethyamina- N N N etriyl)-z-(2- II377 mothylsufanyl-Qthyl)- I yI]-N-hydroxy.acrylamide aS isopropylamino-ethyl)- 46 '345 1 yI]-N-hydroxyacrylamide 3-f2-Butyl-1 NN wA ~isopropylamino-propyl)- 47 359 1 U yI]-N-hydroxy- -K acrylamide 3-[1 -Benzyli piperdiln-4-yI)-2-butyl- 48 433 1 yI]-N-hydroxy- Waylami1de C" 3-[2-But-3-enyl-1 I ethylsmino-ethyl)-1 H- 49 /329 hydroxy-acrylamide 3-[2-Hexyl-I N isopropylamino-ethyiso 373 1 '7 yI]-N-hydroxyacrylamide 3-[1 -(2-D1imethylamino- N ethyl)-2-(2,4,4- 51 -387 trimethyl-pentyl)-i Hhydroxy-acrylarnide yA1WbyaKU'Q DZMLnT&%IO45 AVUWd ftcA.iu...I ?kAuO Piki So COMS ID No: SBMI-03086169 Received by IP Australia: Time (H:rn) 18:02 Date 2006-03-21 21-MAR-2006 17:32 21. MA. 2%617:32PHILLIPS ORMONDE FITZPATRICKNO353 P 12 NO. 3858 P. 125 3-(l -2-Ethymaminoethyl)-2-hexyl-1

H-

52 39 hydroxy-acrylaniide N-Hydroxy-3-[1 N N isopropylamino-ethyl)- 53 I385 2-(3,3,3-trifluoropropyl)-1 H- H acrylamide 3-(11-(2-Dimethyaomino- N ethyl)-2-hex-3-enyl-1 H- 6435 enoliazl--S]N hydroxy-acrylamide 3-El -(2-Amina-ethyl)-2- 'N ~OM(2,4,4-trimethyl-pentyl)- 359 1 H-benzomiclazol yI]-N-hydroxyacrylamide 3-[i -(2-Amino-ethyfl-2- 56 N 403 (2-methoxy-nonyl)-IHhydroy-acrylamicie 3-[2-Butyl-1 N OH dimethylamino-ethyD)- 57331 1 H-benzoimidazol yI]-N-hydroxyacrylamide N- 3-[1 -(2-Dimethyamino- N 'N ethyl)-2-hexyl-1H- 58 1359 hydroxy-acrylamida YIkAOKJNO DILPE'P11041 AU Samd rf~iohI Fils w ikdo.

COMS ID No: SBMI-03086169 Received by P1 Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:32 PHILLIPS ORMONDE FITZPATRICK NO. 3658 P. 126 122

NO

0 N(2-[14-2o N (2-hydroxycerbamoyl- 59 444 vinyl Hvs benzoilmidazol-2-yUlc-I .thyl}.3,3-dimethylbutyramirie 3-(1 -(2-Diethyisminoethyl)-2-[2-(2,2- Ndimethyl- 430 propionylarnino)-ethyl]- VaO o 1 o yI)-N-hydroxyecrylamide 3-{1 -(2-Diethylaminoethyfl-2-R2,2-dimethyl- 61 416 proplonylamiric)methyl-1 Hhydroxy-acrylamide N-[1 -(2-Diethylamino- 82 402 hydroxycarbamoyllviriyl)-1 Hbenzoimidezo-2ylmethylj-butyramide 3-ji -(2-ethylaminoethyl) -2-Q3.3-dimethyl- 83 359 butyl)-1 benzomidazol-5-Y11-N- \~NH hydroxy-acrylamide 3-[2-(3,3-Dimethyi- 64 36 D -m Lthylem2,thl) 1 yI]-N-hydroxcyacrylamide y.qh~tmiUN pEZjIWioNp4E Au 3owrd N4F-AiI FLU Y4 fldda COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2008-03-21 I 21. MAR. 2006 17:32 PHILLIPS ORMONDE FITZPATRICK NO. 3658 P. 127 3-[i -(2-Dimethyaminoethyl)-2.pentyl-1 H- OH 345 hydroxy-acrlarne ethyl)-2.(2,2 1 2-trlfluoro- 66 0357 ethyl)-I Hhydroxy-acrylamide N-Hydroxy-3-[1 methyl-I H-pyrazol-3- 57 398 yI)-2-(2,4,4-trimethyi- 67 395penty l)-1 H acrylamide 3-ri -(2-Ethyamino- N. OH ethyl)-2-pentyl-1 H- 68 345 berizoimidazo-S-yII-N' hydroxy-acrylamicle 3-(2-Butyl-pyrroildiri- I 3.yl-i H-benzoimidazol- 89 329 U acrylamide LVH 3-(2-Buty-1 -piperid in- 343 4-y-1 H-benzolmidczolacrylamide N-Hydroxy-3-[1 I isopropylamino-ethyl)- 11 S359 2-pentyl-1 H- II sorylamide y,.atNEy NO DBLETKWIOOO4NJ Icd IxyisiadrSI lic~hdo COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:33 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 128 Y;WVNWK N oBLETMf PIOfl AU MCad ?hvhsi~ul MIi aFUldcd COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 I 21. MAR. 2006 17:33 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 129 3.41 -[2-(Ethyl-methylamino)-ethylj-2-pertyl- 359 1 H-benzoimidazo-6yI}.N-hydroxyacrylamide 3-(2-I-Ixyl-1 -pyrrolidin- N N. 3-yI-1 H-benzoimidazol- 37 ecrylamide 3-E2-ButYI-1I -methyl- Npyrrolidin-3-yI)-1

H-

$1 34 hydroxy-acrylamide 3-(2-Hexyl-1 -piperidin- 3-yI-1 H-bonzoimidazol- 62 371 cjz acrylamIde 3-(2-Butyl-1 -piperidin- V 3-yI-1 H-benzoimidazo- 83 343 acrylamide 0 3-(1 -(2-[Ethyl-(2- N N'OH methoxy-thyl-aminoJ-

H

ethyl)-2-pentyl-1 H- '84 403 rN hydroxy-acrylamide 3.{2-Butyl-1 -[2-(ethyl- N N' OH methyl-amino)-ethyl]- "I 34 1 yI.N-hydroxy- I-N acrylamide Y~ Kaz4J No DELxpiTwETISO Au w humidmt1 Y1o..m Filui COMS ID No: SBMI-03086169 Received by P1 Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:33 21.MAR 200617:33PHILLIPS ORMOND[ FITZPATRICK N.88 P 3 NO. 3858 P. 130 0 OH.-ydroxy-3-[1-(1- N N N'O methyl-piperinc3-yi)-

H

N: A1371 2-penty-1 H- 86 benzoimidazol-5-y3- N acrylamide 3-{1 -[2-(Ethyl-hexyl- .0N H amino)ethyl]-1 H- N' 87 359 hydroxy-acrylamide

N

?J7 311 (Ethyl-pG ntyl- N N N ,ONH amino)-ethyl]-1 H- K'I H N 88 S4 hydroxy-acrylamide 0 3-{1-[2.(E-thyl-heptyl- 0 WH amino)-ethyQl-IH- K'I

H

N A 5937 hydroxy-acrylamlde a 34(2-Nexyl1 1 N NH hydroxy-ethyl)r

I

N N OH piperidin-3-y]-1 415 N hydroxy-scrylamide ItIOH yW.%&,MKI mO OgUIfl1090 Au Lst Pniiiu. FWW mr 912-.dm COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:33 21~ MA. 2%617:33 PHILLIPS ORMONDE FITZPATRICK N.86 P 3 NO. 3858 P, 131 0 3-(2-Butyl-1 4-{zG(thyl- N A N NH (3-hydroxy-propyl)- N OHamiflo]4thyl}-IH- 91 389 N hydroxy-acryiamide

HO

3-(1 f{2-[EthyA-(3- N hydroxy-propyl)amino]-ethyl)-2-pefltyl- 92 403 I yl)-N-hydroxyacrylamide z:I& 9H(E)-N-hydroxy-3-(1 phenethylpyrrolidin-3- 93377 y)lHbenzo[d~imidazol-8yl)acrylamide (E)-N-hydroxy-3-(l -(I1.

pentylplperidir-3-yl)- 94 357 I H-ben yI)acryloamide 3-{I (Butyl-ethylsmlno)-ethyl]-1 H- 331 hydroxy-acrylamide yhl)A24gflO =&nT~flIOSO AuSkeat.rniioo Pkd Vb1db COMS ID No: SBMI-03086189 Received by IP Australia: lime 18:02 Date 2006-03-21 21-MAR-2006 17:33 21. MA. 20%17:33 PHILLIPS ORMONDE FITZPATRICK O333P12 NO. 335B P. 132 (E).N-hydroxy"3-(1 phenethylpiperidin-3yl)-l HyI)acrylamide g~r(E'Nhydmoxy3-(1 -01- N phenylpropyl)piperidifl- 07405 IKyI)acrylamide 'N N (E)-N-hydroxy-3-(1 A (3pheriylpropyl)pyrrolidifl- 98 391 3-yl)-1 HyI)acrylamide I M 3-{1-[1-(3,3-Dinmethylp butyl)-pyrrolidln-3-yJ- 99 357 1 yI}-N-hydroxyacrytamide H(diethylamino)Qthyl)- 100 303 1 yI)-Nhydroxyacrylamide Y:.MqANE NO DLMLKTB 10CSO AU Sood Pruvbk4ld PrbuI ilsio COMS ID No: SBMI-03086169 Received by P1 Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:33 21. AR. QQ6 7:33PHILLIPS ORMONDE FITZPATRICKNO383 P 13 NO-3858 P. 133 3-[2-(4-Oyano-buty)-1 NWN OQH (2-diothylamino-ethyl)- 101 NI8 384 yiJ-N-hydroxy- 6) ___acrylame butylplperidin-3-y)-1 H-

N

102 343 N-hydroxyacrylamlde (E)-N-hydroxy-3.(1 rM (pent-4-.riyl)piperidin- 103 355 3-yI)-IH- 6 N yI)acrylamide T dimethylbutyl)piperidin- 104 371 4-yI)-l H- N-hydroxyacrylemide 3-ji -(2-Diethyaminoethyl).2-propylamino- 105 360 1 yI]-N-hydroxyacrylamide OHN (E)-N-hydroxy-3-(1-(2- H (sopropyl(propyl)amiflo 107 331 )ethyl)-1 II- N yI)acrylamide Y;W%W M~UI DSMLU**5M AU IOWA n.~4duui MhI a M.44 COMS ID No: SBMI-03086169 Received by P1 Australia: Time (I-tm) 18:02 Date 2006-03-21 21-MAR-2006 17:34 22. AR. 006 7:34PHILLIPS ORMONDE FITZPATRICKNO333 P 14 NO. 385B P. 134 3-41 -[2-(Butyl- N N isopropyI-amino)-ethy]- 108 35 1 yI}-N-hydroxyacrylamide N-Hydroxy-3-{1 -12- (isopropyl-pentyl- 109 359 amino)-ethyl]-1 Hecrylamide 342-(5-Cyano-pentyl)- N I -(2-diethylamino- 110 /L 398 ethyl)-IHrh hydroxy -acrylemide N 'N NA3-(1 -{2-[(3,3-Dimothylbutyl~ethyl-amino]- 359 Cthyll-I hydroxy-acryismide 3-(1 -[2-(Ethyl- pro pylamnino)-ethyqllH- 112 317 hydroxy-acryAmoide

AN

II

N.Hydroxy-3-(I [isopropyl-(2-methylpenty)-amino-ethy}- 1 yI)-aorylamide .1 J fl~A4CNO nELMrrn 0on0c AV) Iw.. P-W~mNl Pb-9im IWk.

COMS IDNo: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:34 21. MA. 2%617:34PHILLIPS ORMONDE FITZPATRICK N 33 P 3 NO. 3858 P. 135 (E)-N-hydroxy-3-(l N (isopropyl(4,4 1 4trifluorobutyl~amino)eth 114 39 yI)-I Hyi)acrylamide S34[1 -(3-Dimethya9mina- 2,2-dlmethyl-propyI)-2- 115314 propylamino-1 Hhydroxy-acrylamide N NH

NON

373 3-fl -j2-(Ethyl-hexylamino)-ethyl]-2-methyl- I yI}-N-hydroxyacrylamide -L 4 117 3-{1 -(2-(Butyl-ethylamino)-ethyl]-2trifluoromethyl-1 Hhydroxy-acrylamkte N QH 3j{ 1-[2-(Ethyl-hexytemino)-ethylJ-2triluoromethyl-1 Hhydroxy-acrylamide .1 YdMN)M4IU NO DS.ML.4S All SecuW PMuiinI Wl ii48Fls.*c0 COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21,MAR-2006 17:34 21.MAR 200617:34PHILLIPS ORMONDE FITZPATRICKNQ88 P 13 NO.3858 P. 136 N (dibutylamino)ethyl)-2- 11e 401 propyl-I Hbenzo[d]irrldazol-a-yI)- N-hydmxyacrylamlde 3-LI -(2-Dipropylaminoethyl).1 H- 10331 hydroxy-acrylamide N-I-ydroxy-3-(1-(2- [isopropyl-(3-methyl- 121 359 butyl).aminoJ-ethyl}- 1 yI)-acrlarnide 3-(1 -{2-((3,3-Dlmethyl- 122 A T M butyl)-methyl-emino]- 122 341 ethyl}-I H-, benzoimidazol-6-yi)-Nhydroxy-acrylamide 3-(I -{2-[(2-Ethy-b~tyI)- CH methyl-aminc)-ethyl)- 123 7 -345q 1 yI)-N-hydroxyacrylamide A" dimethylbutyl)amino)et 124 415 Ihyl)-1 H- N> N-hydroxyacrylarnide YeIZVNKXMO DUAX"lOOCS Alfl.UdPVifML XUS u EWAN COMS ID Na:SBMI-03088169 Received by 113 Australia: Time 18:02 Date 2008-03-21 21. MAR. 2006 17:34 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 137 133 0 H 0 I (diisobutylamino)ethyl)- 125 359 1 yI)-Nhyciroxyacrylamide Nl-OH 3-(1 -(2-(3,3-Dimethyl- 4 butylamino)-ethyl]-1 H- 126 331 Cl hydroxy-acrylamide N A~ N-Hydroxy-3-{1 I (methyl-pent-4-enyl- 127 4)329 amino)-ethyll-1 Haorylamide 3-(1 -(2-[3,3-Dimethylbutyi)-propyl-emino]- 128 33 ethyl)-1 Hhydroxy-acrylamide 3-ti -(3-Dimethyamlna- 2,2-dlmethyl-propyl)-2- 129 363 methylisulfanyl-1 Hhydroxy-acrylamide N NA 4 1-(2-(3,3-Dimethylbutyiamino)-thyl]-2- 130 33 propyl-1 Hhydroxy-acrylamide COMS ID Na:SBMI-03086169 Received by I13 Australia: Time (I-tm) 18:02 Date 2006-03-21 21-MAR-2006 17:34 21. AR. 0C6 7:34PHILLIPS ORMONDE FITZPATRICKNO388 P 18 NO. 3858 P. 138 3-El -[2-(3,3-Dimethyl- N N 7Kbutylamino)-ethyl]-2- (2,2-dimethyl-propyl)- 131 401 1 yl-N-hydroxy acrylarnice dimethyl-butyl)-amino]ethyl}-2-(2 1 2-dimethyl- 132 8485 poy)lH hydroxy-acrylemide H 3-{i -[2-(2,2-Dimethylpropylamirio)-ethyl]-l H- 1133 317 hydroxy-acrylamide N sui3-(1 -{2-[(2,2-Dimethyl- I propyl)-propyl-aminoJ- 134 359 ethyl}-1 Hhydroxy-acrylamicle 3-f41.[2.(3,3-Dimethyibutylamino)-ethylj-2- 135 359 ethyl-i H- NH r~llhydroxy-acrylamide BIOLOGICAL TESTING AND ENZYME ASSAYS Recombinant OST-HOACI PrOtein expression and purification 10383] Human eDNA library was prepared using cultured SWS2O cells, Amplification of human HDACI coding region from this cDNA library was cloned separately into the baculovirus expression pDEST2O vectior (GATEWAY Cloning Technology, Invitrogen V!~WU Y4I10 DELMWt? 3800 AU Bmt-d ftpvkimWi MuLa 8Vitdc COMS ID No: SBMI-03086169 Received by P1 Australia: lime (I-tm) 18:02 Date 2006-03-21 21. MAR. 2006 17:35 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 139 135 IO Pte Ltd). The pDEST20-HDAC1 construct was confirmed by DNA sequencing.

o Recombinant baculovirus was prepared using the Bac-To-Bac method following the manufacturer's instruction (Invitrogen Pte Ltd). Baculovirus titer was determined by plaque assay to be about 10 PFU/ml.

[0364] Expression of GST-HDAC1 was done by infecting SF9 cells (Invitrogen Pte Ltd) with pDEST20-HDAC1 baculovirus at MOI=1 for 48 h. Soluble cell lysate was incubated with pre-equllibrated Glutathione Sepharose 4B beads (Amersham) at for 2 h. The beads were washed with PBS buffer for 3 times. The GST-HDAC1 protein was eluted by elution buffer containing 50 mM Tris, pH8,0, 150mM NaCI, 1% Triton X- LC- 100 and 10mM or 20mM reduced Glutathione. The purified GST-HDAC1 protein was O dialyzed with HDAC storage buffer containing 10mM Trls, pH7.5, 100mM NaCI and S3mM MgCI 2 20% Glycerol was added to purified GST-HDACI protein before storage at -800C.

In vitro HDAC assay for determination of IC50 values [0365] The assay has been carded out in 96 well format and the BIOMOL fluorescent-based HDAC activity assay has been applied. The reaction composed of assay buffer, containing 25 mM Tris pH 7.5, 137 mM NaCI, 2.7 mM KCI, 1 mM MgCIl, 1 mg/ml BSA, tested compounds, an appropriate concentration of HDAC1 enzyme, 500 uM Flur de lys generic substrate for HDAC1 enzyme and subsequently was incubated at room temperature for 2 h. Flur de lys Developer was added and the reaction was incubated for 10 min. Briefly, deacetylation of the substrate sensitizes it to the developer, which then generates a fluorophore. The fluorophore is excited with 360 nm light and the emitted light (460 nm) is detected on a fluorometric plate reader (Tecan Ultra Microplate detection system, Tecan Group Ltd.).

[0386] The analytical software, Prism 3.0 (GraphPad Software Inc) has been used to generate ICso from a series of data.

[0367] The HDAC enzyme inhibition results of representative compounds are shown in Table 1 (unit is micromolar).

VMUsW NO DImIZTrm1IM-A AsV um Prhoviimd Ihl aPMikPg COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21, MAR. 2006 17:35 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 140 136 [0368] Table 1. HDACI enzyme activity IC6 (unit is micromolar).

Compound Compound Compound Compound ICw (pM) ComICO (pM) pound IC (pM) 1 0.042 46 0,049 91 0,060 2 0.38 47 0.21 92 0,050 3 0.15 48 0.43 93 0.23 4 0.12 49 0.11 94 0.064 0.17 50 0.036 95 0.052 6 0.18 51 0.066 96 0.080 7 0.091 52 0.025 97 0.10 8 0.052 53 0.10 98 0.32 9 0.21 54 0.048 99 0.12 0.14 55 0.037 100 0.19 11 0.070 56 0.029 101 0.08 12 0.064 57 0.090 102 0.54 13 0.42 58 0.030 103 0.10 14 0.077 59 0.077 104 0.41 0.085 60 0.10 105 0.13 17 0.13 61 0.070 107 0.074 19 0.064 62 0.054 108 0.043 0.26 63 0.051 109 0.048 21 0.38 64 0.10 110 0.044 22 0.064 65 0.078 111 0.029 23 0,045 66 0.34 112 0.12 24 0.51 88 0.034 113 0.016 0.23 70 0.068 114 0.063 26 0.040 71 0.040 116 0.10 27 0.23 72 0.017 117 0.19 28 0.021 73 0.026 118 0.48 29 0.13 74 0.028 119 0.18 0.021 75 0.050 120 0.11 31 0.045 76 0.018 121 0.079 32 0,060 77 0,026 122 0,037 33 0.23 78 0.044 123 0.027 34 0.88 79 0.040 124 0.085 0.082 80 0.040 125 0.16 Y;:UWii JIO DELEB PIC0OI0 AU 8c PfavimiaUd MIl Filtt e COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:35 PHILLIPS ORMONDE FITZPATRICK NO. 3856 P. 141 36 0.096 81 0.12 126 0.042 37 0.091 82 0.10 127 0.078 38 0.56 83 0,19 128 0.031 39 0.024 84 0.063 129 0,77 0.027 85 0.11 130 0.036 41 0.062 86 0.16 131 0,066 42 0.15 87 0.10 133 0.072 43 0.33 88 0.047 134 0.22 44 0.054 89 0.080 135 0.074 0.063 90 0.51 Cell-based proliferation assay for determination of Gl values [0369] Human colon cancer cell lines (Colo205, HCT116), Ovarian cancer cell line (A2780), Hepatoma cell line (HEP3B), Prostate cancer cell line (PC3) were obtained from ATCC or ECACC. Colo205 cells were cultivated in RPMI 1640 containing 2 mM L- Glutamine, 5%FBS, 1.0 mM Na Pyruvate, 1 U/ml of penicillin and 1 pg of streptomycin.

HCT116 cells were cultivated in McCoy's containing RPMI 1640 containing 2 mM L- Glutamine, 5% FBS, 1 U/ml of penicillin and 1 pg of streptomycin. A2780 cells were cultivated in RPMI 1640 containing 2 mM L-Glutamlne, 5% FBS, 1 U/ml of penicillin and 1 pg of streptomycin. HEP3B cells were cultivated in EMEM containing 2 mM Lglutamine, 5%FBS, 1% non essential amino acid, 1mM Na Pyruvate, 1 U/ml of penicillin and 1 pg of streptomycin. PC3 cells were cultivated in F12K, 2 mM Lglutamine, 5%FBS, 1 U/ml of penicillin and 1 gg of streptomycin. PC3, Colo205, and HCT116 cells were seeded in 96-wells plate at 1000, 5000 and 6000 cells per well respectively, A2780 and HEP3B cells were seeded in 96-wells plate at 4000 cells per well respectively. The plates were incubated at 37°C, 5% CO, for 24 h. Cells were treated with compounds at various concentrations for 96 h. Cell growth was then monitored using CyQUANTe cell proliferation assay (Invitrogen Pte Ltd). Dose response curves were plotted to determine Glao values for the compounds using XL-fit (ID Business Solution, Emeryville, CA).

[0370] The cell activity results of representative compounds are shown in Table 2 and 3, The data indicated that the compounds of this invention are active in the inhibition of tumour cell growth.

vWAOAi NO DaTTIONO Mar U hSand ni.hInt alin mP IMdA COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:35 |0 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 142 138 [0371] Table 2. Cellular or Growth Inhibition Activity in Colo205 cells (unit Is micromolar) Compound Compound G, Compound GIso Glo (iM) GIso (IM) No No No 1 0.50 46 0.48 91 2.40 2 2.12 47 3.6 92 1.82 3 2.22 48 0.78 93 2.14 4 2.62 49 1.75 94 0.60 2.58 50 0.17 95 0.57 6 2.69 51 0.26 96 0.70 7 0.81 52 0.21 97 0.67 8 0.56 53 1.05 99 1.89 9 1.87 54 0.46 100 2.25 1.77 55 0.91 101 2.44 11 0,48 56 0.90 102 2.08 12 0.51 57 0.65 103 0.48 13 5.5 58 0.38 104 1.99 14 0.63 59 2.28 105 1.77 1.50 60 2.48 107 0.63 17 1.19 61 1.32 108 0.44 19 0.53 62 2.60 109 0.49 2.66 63 0.54 110 1.74 21 2.51 64 0.73 111 0.21 22 0.75 65 0.56 112 0.88 23 0.19 66 8.8 113 0.61 24 2.99 68 0.52 114 0.72 2.38 70 7.0 116 0.70 26 0.37 71 0.24 117 1.80 27 1.42 72 0.16 118 1.88 28 0.18 73 0.23 119 0.77 29 1.92 74 0.55 120 0.49 0.31 75 1.20 121 0.49 31 0.42 76 0.29 122 0.15 32 0.74 77 0.67 123 0.15 33 2.11 78 0.54 124 0.54 Y;uyaMKI NO DhLVTrEtIBO4S AU Stad fwI.ad Fand m FilAmi COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21

IN

Va 0 21. MAR. 2006 17:36 PHILLIPS ORMONDE FITZPATRICK NO. 3856 P. 143 uoo 34 0.45 U0e 0.68 80 1.37 126 0,42 36 0.85 81 1.00 127 0.34 37 1.09 82 1.23 128 0.14 38 1.94 83 4.9 129 3.9 39 0.23 84 1.03 130 0.15 0.16 85 1.52 131 0.33 41 0.92 86 2.08 133 0.58 42 0.98 87 1.07 134 2.30 43 1.86 88 0.55 135 0.26 44 0.87 89 0.87 0.54 90 8.1 10372] Table 3. Cellular or Growth Inhibition Activity in Various Cancer Cell Lines Cell lines Compound HCTII6 A2780 PC3 HEP3B I 7 Not tested 8 22 Not tested 23 Not tested Not tested Not tested 44 Not tested 46 Not tested 52 Not tested 58 71 Not tested Mi Not tested Not tested Not tested 4++ Not tested between 0.5 and 1.0 for Giso L I for Gls 0.5 pM, for G1 between 1.0 pM to 5.0 pM) YnA3I NO DELETIYID" 1 AU tisd hsialm PhisAl s flkdA COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:36 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 144 140 S Histone H3 acetylation assay S[0373] A hallmark of histone deacetylase (HDAC) inhibition is the increase in the Sacetylation level of histones. Histone acetylation, including H3, H4 and H2A can be detected by immuno-blotting (western-blot). Colo205 cells, approximately 5 x10 5 cells, were seeded in the previously described medium, cultivated for 24 h and subsequently C-l treated with HDAC inhibitory agents and a positive control at 10 pM final concentration.

After 24 h, cells were harvested and lysed according to the instruction from Sigma Mammalian Cell Lysis Kit. The protein concentration was quantified using BCA method (Sigma Pte Ltd). The protein lysate was separated using 4-12% bis-tris SDS-PAGE gel (Invitrogen Pte Ltd) and was transferred onto PVDF membrane (BioRad Pte Ltd). The Lc membrane was probed using primary antibody specific for acetylated histone H3 o (Upstate Pte Ltd). The detection antibody, goat anti rabbit antibody conjugated with 0' HRP was used according to the manufacturing instruction (Pierce Pte Ltd). After removing the detection antibody from the membrane, an enhanced chemiluminescent substrate for detection of HRP (Pierce Pte Ltd) was added onto the membrane. After removing the substrate, the membrane was exposed to an X-ray film (Kodak) for 1 sec 20 mine. The X-ray film was developed using the X-ray film processor. The density of each band observed on the developed film could be qualitatively analyzed using UVP Bidimaging software (UVP, Inc, Upland, CA). The values were then normalized against the density of actin in the corresponding samples to obtain the expression of the protein.

[0374] The results of immuno-blotting assay using acetylated histone H3 antibody are shown in Table 4 for representative compounds of this invention.

Y:PtfKI NO bCLUFWFIDPD41 AU eid PalsiDnal Fibllu fadicde COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:36 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 145 [0375] Table 4 Histone Histone Histone Acetylation Acetylation Acetylation activities activities activities Compound (Hlstone-3) Compound (Histone-3) Compound (Histone-3) I Active 30 Active 49 Active 2 Active 32 Active 50 Active 3 Active 35 Active 52 Active 7 Active 36 Active 55 Active 8 Active 37 Active 58 Active 11 Active 39 Active 63 Active 12 Active 40 Active 65 Active 14 Active 41 Active 68 Active 17 Active 42 Active 71 Active 19 Active 44 Active 74 Active 22 Active 45 Active 130 Active 26 Active 46 Active 28 Active 48 Active [0376] These data demonstrate that compounds of this invention Inhibit histone deacetylases, thereby resulting in the accumulation of acetylated histones such as H3.

Measurement of Microsomal stability [0377] Metabolic stability measurements in the in vitro using liver microsomes aids in the prediction of the in vivo hepatic clearance and the compound stability towards phase I biotransformation reactions mediated by P450 isozymes.

[0378] Pooled human liver microsome (HLM was purchased from BD Gentest (BD BioSciences). The incubations consisted of test compound (5 pM) or control compound (Verapamil), NADPH-generating system solution A (25 mM NADP', 66 mM glucose-6phosphate, 66 mM MgCIa in H 2 NADPH-generating system solution B (40 U/ml glucose-6-phosphate dehydrogenase in 5 mM sodium citrate) and 1.0 mg/ml microsomal protein, respectively, in 100 mM potassium phosphate buffer (pH 7.4).

Samples are incubated for 0, 5, 15, 30, 45, 60min. Reaction is terminated with ice-cold acetonitrile and 20% DMSO. Samples are subsequently centrifuged at 4 0 C for min at 2,000 rpm. 100 L of the supernatant is transferred to the LC-MS Plate for analysis. Before quantitative analysis, the compound is tuned in LC/MS machine to get YNMryO NO1 DEBLTIPIi 6M0U AU SlMt Mrw7 ad FIlI u FlkLi.

COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 S 21, MAR. 2006 17:36 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 146 142 o the optimized MS condition. Liquid chromatography Is performed on a Luna C18 o column (Phenomenex U.S.A, Torrance, CA) (2x50mm, 5 pM). remaining of Scompound (by area) of each time point is calculated with respect to time 0. Plot %remaining against time (min) to obtain the curve and use the Prism software to obtain the ti., These are demonstrated in table [0379] Table SCompound No T1/2 (mln) Compound No T1l2 (min) S1 >30 52 2 >30 58 o 8 >30 63 C 11 >30 68 S12 >30 71 0 14 >30 74 019 >30 78 >30 80 >30 88_ 44 >30 108 46 >30 130 [0380] The measured in vitro >30 mins for the above compounds signifies that the contribution towards the clearance of the compound due to metabolism is expected to be low in the in vivo situation and thus help in yielding longer half-life and increased exposure of the compounds.

[0381] The above results demonstrated the compounds of formula were metabolically stable In human liver microsme assay. Together with the appropriate physicochemical properties, molecular weight, logP and high solubility, the above compounds could exhibit adequate pharmacological exposure and effect to the body when administrated intravenously or especially orally.

In vivo Pharmacoklnetic (PK) studies [0382] Compound is dissolved in appropriate solution (saline or DMA and Cremaphor in saline) at 1 mg/ml for intravenous (IV) administration, or in 0.5% methyl cellulose, 0.1% Tween 80 in water at 5 mg/ml for oral administration. Mice are randomized according to body weight, grouped three per time point. Mice are administered single IV dose (10 mg/kg) via tail vein, or single oral dose (50 mg/kg) via gavage. At predefined time points (predose, 5 or 10, 30min, 1, 2, 4, 8, and 24h), one group of mice is sacrificed by overdose CO2 and blood samples are collected by cardiac puncture. The blood samples are centrifuged immediately for 10 min at 3000 rpm to separate plasma, and plasma is kept frozen at -80 'C until analysis by LC/MS/MS. Before sample Yi;:Ml I NO DELEI PLr~F00n AU svind fit w iR A M iWe COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:37 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 147 143 O analysis, the method is developed for LC/MS/MS assay. The method is validated for 0 signal-response of the calibration standards, auto-sampler stability for -15 hours intraday and inter-day calibration curve using eight calibration standards excluding the Sblank plasma. QC samples at three different concentrations in triplicates were prepared to determine the accuracy and precision, The extracted QC samples were compared to Cl unextracted samples to determine the extraction efficiency of the analyte. LLOQ was determined by using triplicate samples of 1ng/mL and 2ng/mL to obtain accuracy and precision at the low end. Samples are analysed using the validated method. Data are analyzed by the non-compartmental model using WinNolin 4,0 software (Pharsight, Mountain View, CA, USA). The mean values for the plasma compound concentration- C time profiles are used in mouse PK study.

O

0 [0383] The PK parameter AUC providing the information on the overall exposure of the drug in vivo is one of the key PK/PD parameters that helps in predicting the efficacy of a anticancer compound. The higher the AUC value, the better will be the efficacy of the compound, Pharmacokinetic data of selected compounds in Table were shown in Table 6 below.

[0384] Table 6. Representative pharmacokinetic data [compounds were in hydrochloric acid salt form (2HCI), dosed at 50 mg/kg, p.o.] Compound AUCo.

1 t (ng.hlml) 1 1868 8 1836 130 1050 [0385] The data in Table 6 further demonstrated that compounds with high metabolic stability as shown by representative compounds in Table 5 together with the appropriate physicochemical properties, molecular weight, logP, and high solubility, were able to yield adequate pharmacological exposure and effect in the animal when administrated orally.

In vivo antineoplastic (or antl-tumor) effect of HDAC Inhibiting agents: [0386] The efficacy of the compounds of the invention can then be determined using in vivo animal xenograft studies. The animal xenograft model is one of the most commonly used in vivo cancer models.

YM rwyKINO D LETI I 0'P04 AU AUem Prmilonal Fial m Nrlld COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:37 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P, 148 144

O

O [0387] In these studies Female athymic nude mice (Harlan), 12-14 weeks of age Swould be implanted subcutaneously in the flank with 5 x 10 cells of HCT116 human Scolon tumor cells, or with 5 x 100 cells of A2780 human ovarian tumor cells, or with 5 x cells of PC3 prostate cancer cells. When the tumor reaches the size 100 mm 3 the xenograft nude mice would be paired-match into various treatment groups. The C-i selected HDAC inhibitors would be dissolved in appropriate vehicles and administered to xenograft nude mice intraperitoneally or orally daily for 21 days. The dosing volume will be 0.01ml/g body weight. Paclitaxol, used as positive control, will be prepared for intravenous administration in an appropriate vehicle. The dosing volume for Paclitaxol will be 0.01 ml/g body weight. Tumor volume will be calculated every second day or Stwice-a-week of post injection using the formula: Volume (mm 3 (w x where w O width and I length in mm of an HCT116, or A2780, or PC3 tumor. Compounds of this invention that are tested would show significant reduction in tumor volume relative to controls treated with vehicle only. Acetylated histone relative to vehicle treated control group when measured shall be accumulated. The result will therefore indicate that compounds of this invention are efficacious in treating a proliferative disease such as cancer.

[0388] The details of specific embodiments described in this invention are not to be construed as limitations. Various equivalents and modifications may be made without departing from the essence and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Y.W mr~ M DELEBFP100 BAU NwA nftbCI Pihl u Pktld COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21

Claims (14)

1. A compound of the formula Formula I wherein R' is an optionally substituted heteroaryl group, an optionally substituted heterocycloalky group or a group of formula: (CRR 2 R )(CRR 3 )n(CR4Rz5o.NR2R2 R 2 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkoxyalkyl, R" 1 R"C(0)N(R2)R3-, R1SO2N(R12)R3-, R"N(Ri2)C(0)R13-, R"N(R 12 )SO 2 R 3 R 1 "N(R' 2 )C(O)N(R" 12 and acyl, each of which may be optionally substituted; R 3 is selected from the group consisting of H, C, -Cs alkyl, and acyl, each of which may be optionally substituted; X and Y are the same or different and are independently selected from the group consisting of: H-i, halogen, -CN, -NO 8 -CF 3 -OCF 3 alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylaulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, COOH -COR 5 -SH, -SR, -ORO acyl and each of which may be optionally substituted; V!Wwr)flVTD DELfBfSPLP b1. *1U besoad NvidouaIsiI a Ted.ta COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21

21-MAR. 2006 17:37 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 150 146 NO each R' is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, Cl haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be C optionally substituted; cl I'each R5 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; 511 1 ieach R is independently selected from the group consisting of: alkyl, alkenyl, o alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Cl cycloalkylalkyl, heterocycloalkylalkyl, arylarkyl, heteroarylalkyl and acyl; each of which may be optionally substituted: each R 7 and Re is Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted each R" 1 and R 1 is independently selected from the group consisting of H, alkyl, alkenyl, and alkynyl, each of which may be optionally substituted; each R 1 s is a bond or Is independently selected from the group consisting of: alkyl, alkenyl, and alkynyl, each of which may be optionally substituted; each R 2 1 R2, Ra, R2 and R' is independently selected from the group T!consisting of: H, halogen, -CN, -NO 2 -CF 3 -OCF 3 alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, S 30 heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroarkyl, reteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy heteroaryloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, aminosulfonyl, arylsulfonyl, arylsulfinyl -COOH, C(0)OR 5 COR 5 -SH, -SRe, -OR 6 and acyl, each of which may be optionally substituted; or fld*YNI PC9 DIL~R WPUN4 AD~e~ Pnvim Pint, Mkdifae~ COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21.MAR. 2006 17:38 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 151 147 N RZ and R 21 when taken together may form a group of formula =0 or and/or SR' 2 and R 2 when taken together may form a group of formula =0 or and/or SR 2 4 and R 25 when taken together may form a group of formula =0 or =S: each R 2 and R 27 is independently selected from the group consisting of is Ci selected from the group consisting of: H, halogen, alkyl, alkenyl. alkynyl, haloalkyl, haloalkenyl, heteroalky, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylarkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, ci alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, heteroaryloxy, 0 amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, 0 alkoxycarbonyl, alkylaminocarbanyl, sulfonyl, alkylsulfonyl, alkyfsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR 5 and acy[, each of which may be optionally substituted, or R and R 2 7 when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group; Z is a bond or is selected from the group consisting of -CHr, -CH2CH2-, -CH=CH-, Cs-Cs alkylene, C 3 -Ce alkenylene, Cs-Ce alkynylene, Cs-Ce cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C 4 alkyl; m, n and o are integers independently selected from the group consisting of 0, 1, 2, 3 and 4; or a pharmaceutically acceptable salt or prodrug thereof, 2. A compound of claim 1 wherein Z is attached at ring position 5 or 6. 3. A compound according to claim 1 or 2 wherein Z is -CH=CH-, and is attached at ring position 4. A compound of any one of claims 1 to 3 wherein R 3 H. 5. A compound of any one of claims 1 to 4 wherein X and Y H. 6. A compound according to any one of claims 1 to 5 wherein R 4 H. Yr\iuyNU NO bDULsElOtW9 AU emed RoWieAal NaJ fla ia COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:38 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 152 148 O 7. A compound according to any one of claims 1 to 6 wherein the sum of m+n+o is an Integer selected from the group consisting of 0, 1, 2, 3 and 4. s 8. A compound according to any one of claims 1 to 7 wherein the sum of m+n+o is 2 or 3, 9. A compound according to any one of claims 1 to 8 wherein R' is selected from the group consisting of: -(CRaoR21-NR8R"; 0 .i(CRIR 5 )r-NR M R?; -(CRR2s)2-NR"WR' NO -(CRa4R25)zNR"R 27; -(CR"Rl)-(CR2R ).NR2R; -(OR2RaR)(R2'R2)-NR2R"; and -(CR 22 R')-(CR4Rm-NR6R .27 A compound according to any one of claims 1 to 8 wherein R 1 is selected from the group consisting of: -(CR m R')rNRR; -(CRR23)-NR" W7; -(CR4R25)3NRR 27; -(C"R 2 '')r(CR 2 2 Ras)-NRR7; -(CR"R)r2-(CR2 4 R2)-NR28R7: -(CRoR 2 )-(CR 2 Rl)rNR2SR27; _(CR 22 R)2-(CRR25)-NR2R 27. -(CR 2 "R 2 a)(CR 1 R W)-NR2R"; -(CR22R2)-(CR R 2 )2-NRR27; and -(CRfOR 2 )-(CR2R2)-(CR"R .)-NRR27, 11 A compound according to any one of claims 1 to 9 wherein the compound has the formula; \M&NtIMO ODasrgIPPu.gI AU and uidiml Pnlu i iQW COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:38 PHILLIPS ORMONDE FITZPATRICK NO. 3858-P. 153 R2Ve 12. A compound according to any one of claims 1 to 8 or 10 wherein the compound has the formula: 13, A compound according to any one of claims 1 to 12 wherein R 2 0 and R 21 are independently selected from the group consisting of H, alkyl, alkenyl and alkynyl. 14. A compound according to any one of claims 1 to 13 wherein R2 and R 21 are independently selected from the group consisting of H and alkyl. A compound according to any one of claims 1 to 14 wherein R 2 and R 2 1 are H, 16. A compound according to any one of claims 1 to 15 wherein R 2 2 and Rs 2 are independently selected from the group consisting of H, alkyl, alkenyl and alkynyl. 17. A compound according to any one of claims 1 to 16 wherein R"and R 2 are independently selected from the group consisting of H and alkyl. 18. methyl. A compound according to any one of claims 1 to 17 wherein R 2 2 and Ra 2 are YOMq'A NO D2nnLrZW0 MAU Smp4 F!WiIdnZ mpiedia COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:38 PHILLIPS ORMONDE FITZPATRICK NO. 3858-P. 154--- 150 VO 0 o 19. A compound according to any one of claims 1 to 18 wherein R 2 and R 2 are independently selected from the group consisting of H, alkyl, alkenyl and alkynyl. 20. A compound according to any one of claims 1 to 19 wherein R 2 and R 25 are C- independently selected from the group consisting of H and alkyl. 21. A compound according to any one of claims 1 to 20 wherein R 24 and R 2 5 are H.

22. A compound according to any one of claims 1 to 21 wherein R 2 and R 2 are independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, alkoxyalkyl, and acyf.

23. A compound according to any one of claims 1 to 22 wherein R 2 and R 27 are independently selected from the group consisting of: H, alkyl and acyl. 24, A compound according to any one of claims 1 to 23 wherein R 2 and R 27 are independently selected from the group consisting of H, methyl, ethyl, isopropyf, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, acetyl and 2-methoxy-ethyl. A compound according to any one of claims heterocycloalkyl group which may optionally be substituted. 1 to 8 wherein R 1 Is a

26. formula: A compound according to any one of claims 1 to 8 wherein R 1 is a group of <N NH 2 H N H N YVMMyr*I NO DBLETEPIfMl AU Smla fotviinl Phil 1 Filed. COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 I 21. MAR. 2006 17:39 PHILLIPS ORMONDE FITZPATRICK NO. 3858-P. 155 4 -N L 'NH C1~Z~t\ll N \00 N c~" YA&4tNWU b Vt Ir.LMWPIMIS- AU Skmd Pnlska pi"i as COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2QC6 17:39 Va 0 0\ PHILLIPS ORMONDE FITZPATRICK NO. 3858-P. 156 t <%NX N -OH Nr" Y:WVANPi NOQ MLflWFIUOJI AU See ITS(JiP=uI Fh gg Pggdn COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2008-03-21 Va 0 0O 21. MAR. 2006 17 Z, fr( :39 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 157 153 A compound according to any one of claims 1 to 8 wherein R' is selected im the group consisting of: Vi1t NH 2 S

28. fornr

29. form H I H Ii N H N N, A compound according to any one of claims 1 to 8 wherein R' is a group of IN. NH 2 A compound according to any one of claims 1 to 8 wherein R' is a group of H QNO DEATrlIf4 AUC fitd PlWaaIl FuHl Fld. COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21.MAR, 2006 17:39 PHILLIPS ORMONDE FITZPATRICK NO.3858-P. 158 154 formula; A compound according to any one of claims 1 to 8 wherein R 1 is a group of H N

31. formula: A compound according to any one of claims 1 to 8 wherein R 1 is a group of H 32, formula: A compound according to any one of claims 1 to 8 wherein R 1 is a group of N

33. formula:

34. formula: A compound according to any one of claims 1 to 8 wherein R 1 is a group of N A compound according to any one of claims 1 to 8 wherein R 1 is a group of A compound according to any one of claims 1 to 8 wherein R 1 is a group of formula: YWMflEl NO DBLRTWPluHoj AL sS jha j final z Fb.m4 COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21,MAR-2006 17:39 21.MAR 266 1:39PHILLIPS ORMONDE FITZPATRICK NO. 3853-P. 159 ci NH

36. A compound according to any one of claims I to 8 wherein R 1 is a group of o formula: N

37. A compound according to any one of claims 1 to 36 wherein R 2 is selected from the group consisting of alkyl, cycloalkyl, heteroalky, alkenyl, alkynyl, alkoxylkyf end cycloalkylalkyl each of which may be unsubstituted or substituted. 38, A compound according to any one of claims 1 to 37 wherein R 2 is selected from the group consisting of: H: miethyl; ethoxymethyl; [Bicylco[2.2.I]2-yimethyl; Adanmantan-2ylmethy; 2 -methansulfanyl.ethyl; 2 ,2,2-triflouro-etriyl; propyl; 2-2- dimethyl-propyl; isopropyl; 3.3,3-triflouro-propy; butyl; isobutyl; 3 .3-dimethyl-butyl; but- IS 3-enyf; but-3.yny; pentyl; 2 3 4 4 -trimethyl-pentyl; Bicyclo(2.2.1I]hept-5-en-2y; hexyl; hex- 3-ertyl; octyl; non-3-enyf; non-6-enyl; 2-methoxy-nonyl, 2 -phenyl-cyclopropy: cyclohexyl; (CHS)SCCHZCONHCCHZ)r-; (CH3)aCCONH(C- 2 (CHZ) 8 CCONK(CH 2 and CHBCCHz)ZCONH(CH 2

39. A compound according to any one of claims I to 34 wherein the optional substituent is selected from the group consisting of: halogen, -CN, -NO 2 -CF 2 -0CF 8 alkyl, alkenyl, alkynyl, hasloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycoalkenyl, aryf, heteroaryl, hydroxy, hydroxyalkyf, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroeryI, alkenyloxy, alkyriyloxy, COMS ID No: SBMI-03086169 Received by IP Australia: lime 18:02 Date 2006-03-21 21-MAR-2006 17:39 21.MAR 206 1:39PHILLIPS ORMONDE FITZPATRICK NO. 3853-P. 160 156 c~ycloalkyloxy, cyoloalkenyloxy, heterocycfoalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryoxy, aryalkyf, heteroarylalkyl, arylaikyloxy, -amino, alkylamiria, acyiamirio, aminoalkyl, arylamino, sulfonyl, alkyisulfonyl, aryleulfonyl, aminosufonyl, aminoalkyl, alkoxyalky, -COOK, -CORO, -C(O)0R 8 -SH, -8R 5 -ORWand acyl. The compound of claim 1 wherein the compound Is selected from compounds, and their pharmaceutically acceptable salts, selected from the group consisting of r N 'N I 341 3 -Dimethylamino22,dimethyl-propyr)-2 (2,2-dimethy-propyl)-1 hydroxy-acrylamide 3-[i 3 sDImethylamino.2,2..hjmethyf-prpyl 2- isopropy-1 acrylamide 3-[2-Butyl-1 -(3-dimethyiamino-2,2-dimethyl- propyl)-1 acrylamide 3-ti .(S-Dimethylamino-2,2dimethyl.pmpyl).2.c2. methylsulfanyl-ethyty-i H-benzoimIdaZol-5.yQ N- hydr-oxy-acrylarnide 3-[1 -(3-Dimethylamino-2,2-dimethyi..pmpyl)z2 ethcxymethyl-1 hydraxy-ecrylamide 3-[1 -(3-Dimethylamino-2,2-dimnethyl-propyiy.2 isobutyl-1 H-benzolmidazol-s-yl]-N-hydroxy- acrylamide N -t r Y:;Mq t NOQ DMEWIU90435o AU &-ad P-*ks Fi..i aqI*,o COMB ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 1;21. MAR. 2006 17:40 i i Ij 0i.MAR 206 1:40 PHILLIPS ORMONDE FITZPATRICK -NO. 3856-P. 161 N e~ 'I' F- 157 3-[I .(2-Diethyiamino-thy)o2isobuty,-1 H- 3 A1 2 -ButyI-i-(2-diethylamino-ethy)-1 H- 3-12-But.3-yrnyI. 1 3 -dimethyfamino-2,2.wmethy- propyilI Scrylamide 3-[2-But-3-enyl-i -(3-dimethylamino-2,2- dimethyi-propyl).1 hydroxy-acrylamide 3-12-But-3-enyl- I -(2-dlethylamino-ethyl).1 H- 3-j2-But-3-ynyl-I -(2-dlethylamino-ethy)-1 H- 3-[I -(S-Dimethylamino-z,2-dlmethy..propyjy2- (3 1 3,3-trifluoro-propyl)-1 H-benzoimidazol-s-y]-N- hydraxy-ecryhamide Nsr r) '1rg'etMtJO nswruwewaAU lkmd PT~O*J MsAt alibaf COMS ID No: SBMI-03088189 Received by 113 Australia: Time 18:02 Date 2006-03-21 21-MAR-2006 17:40 22. MA. 2%617:4UPHILLIPS ORMONDE FITZPATRICKNO358 P 16 NO. 3858 P. 162 044 t JN N S A 158 3-ji -(2-Diethylamino-ethyl)-2-(3,3,3-trifluora- propyl)-1 acrylamide 341 -(2-Diethylamino-ethyl)-2-ethoxymethyl.1 H- 3-ji -(8-Dimethylemino-2,2-dimethyl-propyl)-2- methyl-I acrylamide 3-[i -(2-Diethylamnino-ethyl)-2-(2,2-dimethyl. propyl)-l acrylemnide N-Hydroxy-3-[I -(3-isopropylarnino-propyl)-2- (3,3,3-trlfluoro-propyl)-I acr$'Iamide 3-[2-(2,2-Dimethy-propy)-1 -(2-isopropylamino- ethyl)-I ecrylamide N A) 3-fl -(2-Diisopropylamino-ethyl)-2-(2,2.dimethyl- propyl)-1 acrylamide YPbrMmNO DLBfnWIQPM AUSw"wW~m Andl Plod xu COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR.2006 17:40 21. AR. 006 7:40PHILLIPS ORMONDE FITZPATRICKN.358 P 16 NO. 3858 P. 163 N F- N 4 159 3-[1 -(2-Diisopropylamirio-ethy)-2-isobutyl-1 H- 3-El -(3-Dimsthylamino-2 1 2-dimethyl-propy)-2- hex-3-enyl-1 acrylamide 341 .(3..Dimethyiamlno..2,2-4imethyf..propyl).2. (2,4 1 4-trimethyi-pentyl)-1 N-hydroxy-acrylamide 3-[2-Cyclohoxyl-1 -G3-dimethylamino-2,2- dimethyl-propyl)-1 hydroxy-acrylamide 3-[2-Bic~yolo[2.2.1I]hept-5-en-2-y-1 dlmethylamno-2,2-ilmethyl-propyl)-1 M- 3-(1 -(2-Diethylamino-ethyl)-2-hex-3-enyl-i H- benzoimidazo-6-yIJ-N-hydroxy-acrylamlde 341 -(2-Diisoprapylamirio-ethyl)-2-hex-3-enyl-l H- 3-(2-I-ex-3-enyl-1 -(2-isopropylamirio-ethyl)-1 H- yfmmlsmy1J OUWWQ&O5 AV Baud flovidM i ul Emli~ COMS ID No: SBMI-03086169 Received by P1 Australia: Time 18:02 Date 2006-03-21 '21. MAR. 2886 17:40 PHILLIPS ORMONDE FITZPATRICK NO. 3856 P. 164 I l- r 'N Op p A a (z 'N' 3-[2-Hex-3-enyl-1 -(3-isopropylamina-propyl-1 H- 3-[1 -(2-Ethylamirio-ethyl)-2-hex-3-enyl-1 H- 3-(1 -(2-Diethylamino-ethyl)-2-hexy -1 H- N-Hydroxy-3-[1 -(3-isopropylamino-propyl)-2- (2.4,4-trimethyl-peityl)-1 acrylamide 3-(2-(2,2-Dimethy-propy)-1 -(3-isopropylamino- propyl)-1 acrylamide 3-[1 -(2-Diisopropylamlno-ethyf)-2-(3,3,3-trifluora- propy)-1 acrylamide N-Hydroxy-3-[2-isobutyl-1 -(2-isopropylamirto- ethyl)-1 3-[2-(2,2-Dimethy-propy)-1 -(2-ethylernino- ethyl)-1 acrylarnide YWtMU$CW1O DEUST5EFplQU4 AU Soad Ftnvdna Find n IiISAu COMB ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 I 21. MAR. 2006 17:40 PHILLIPS ORMONDE FITZPATRICK NC. 3853P. 165 N N r >KYY/ a K 161 3-[1 -C2-Ethylamino-ethyl)-2-isobuty-1 H- 3-[l -(2-Diisopropylamino-ethy)-2-C2,4,4- trimethyl-pentyl)-l hydroxy-acrylmide N-Hydroxy-3.[1 s(2..isopropylamino.ethy).2. (2 1 4,4-trmsthyl-pentyl)-l acrylamide 3-El -(2-Ethylamino-ethyl)-2-(2,4,4-trimethyl- pentyl)-1 acrylamide 3-El -(2-Diethylamlno-ethyl)-2.(2,4,4-trimethyl- pentyl)-1 acrylamide 3-[l -(2-Diethylamino-ethyl)-2-propy-1 H- 3-[2-Butyl-1 -(2-dllsopropylamino-ethyl)-l H- 3-(2-Butyl-l -(2-ethylamlno-ethyl)-1 H- benzoimldaZOl-S-yI]-N-hydroxy-acrylamide Y:'&Ms#K NO DELI? Wfl9woasAUBMMAftIVA11M &W asi fe. COMB ID No: SBMi-03086169 Received by 113 Australia: Time 18:02 Date 2006-03-21 I 22. MAR. 2Q06 17:41 PHILLIPS ORMONDE FITZPATRICK NO. 3858-P. 166 SM N H H Ki7 oJ N N 'I -t 1,12 3-[1 -(2-Diethylamnino-ethyQ)-2-(2-methylsulfanyl- ethyl)-i acrylamide 3-(2-Butyl-1-(2-isopmopylamirio-ethyl)-l H- 3-[2-Butyl-1 -(3-isopropylamino-propy)-1 benzoimidazol-S-ylj-N-hydroxy-acrylamide 3-[1 -BenzyI-piperldin-4-yl)-2-butyl-1 H- benzoidazol-S-yIJ-N-hydroxy-acrylamide 3-[2-But-3-eiyl-1 -(2-othylamino-othyl)-l H- benzoimidazol-S-yI]-N-hydroxy..acrylamide 3-[2-Hoxy-1 -(2-sopropylamino-ethyl)-1 H- benzoimidazo-6-yI-N-hydroxy-acry~amkge 3-fl -(2-Dimethyiamino-ethyl).2-(2.4,4-trimethyl- pentyl)-l acryiamide 7i1.J.iM. COMS ID No: SBMI-03086189 Received by P1 Australia: Time (I-tm) 18:02 Date 2006-03-21 P21.MAR. 2006 17:41 PHILLIPS ORMONDE FITZPATRICK- NO.358-P. 167 F- N F-K' 163 3-ji -(2-Ethylamino-ethyl)-2-hexyl-1 H- N-iydroxy-3.{1 -(2-isopropylamino-ethyl)-2- (3,3,3-trifluoro-propy)-1 acrylamide 3-fl -(2-Dlmethylamino-othyQ-2-hex-3-enyl.1 H- 3-[l -(2-Amino-ethyl)-2-(2,4,4.trimothy-pentyl). 1 3-(l -(2-Amino-ethyl).2-(2-mnethoxy-nonyl).1 H- benzolmidazol-5-yIJ-N-hydroxy-2crylamlde, 3-[2-Butyl-1 -(2-dimethylamino-ethyf H- 3-fl -(2-Dimethylamlno-etiyl)-2hexy-1 H- N-{2-f I-(2-Diethylamirio-ethyI)-s-(z- hydroxycarbamoy-vinyl).I H-benzoimidezol-2- yIJ-ethyl-3,3-dmethyl-butyramide Y:WtMlUO bEUMflW1iOP4 AU Bend PrM~.m Fnil MoNtd COMS ID No: SBMI-03088169 Received by IP Australia: lime 18:02 Date 2006-03-21 21. MAR. 206 17:41 PHILLIPS ORMONDE FITZPATRICK -N0. 3856-P. 168 164 Va 6 a 3-fl -(2-Diethylamino-ethyl)-2-[2-(2,2-dimethy- propioriylamino)-ethyi]-l N-hydroxy-acrylamide Cl 3-fl .(2-Diethylamino-ethy)-2-(22-dlmethyl- 'I propionyfamino)-methyq]-l yl}-N-hydroxy-acrylamide Cl N N-[l -(2-Diethy~amino-ethyI)-5-(2- hydroxycarbamoyl-vinyl).l H-benzomiciazol-2- Cl ylmethyl]-butyrmmide NN N 6k 3-(l -(2-ethylamino-ethyl) -2-(3,3-dimethyl-butyly. 1 3-E2-(3,3-Dimethyl-butyl)-l -(2-Dimethylamina- ethyl acrylamide 3-Li -(2-Dimethylamino-ethyl)-2-pentyl-1 H- 3-[1 -(2-Dimethylamino-ethyl)-2-(2,2,2-tifiuomo ethyl)-l acrytamide N-Hydroxy-3-[1 -(5-methyl-I H-pyrazol-3-yl)-2- (2,4,4-trlmethyl-pentyl)-1 acrylamide V'%UMMWNQ UNLIMIQ 45 AUSUctd Pumvldmcl Mns wI4k COMS ID No: SSMI-03088169 Received by IP Australia: lime 18:02 Date 2008-03-21 I 21-MAR. 2006 17:41 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 169 .21 I" 165 3-[1 -(2-Ezthylamino-ethyl)-2-pentyl-1 H- 3-(2-Butyl-1 -pyrrolidin-3-yiI1 yI)-N-hydroxy-acrylamide 3-(2-Buty-1 -piperldin-4-y-1 yt)-N-hydroxy-acrylamide N-Hydroxy-3-[1 -(2-iuopropylamirio-ethyl)-2- pentyl-1 N-Hydroxy-3-(1 -(2-methylamino-ethyl)-2-non-3- enyl-1 N-Hydroxy-3-[1 -(2-methylamino-ethyl)-2-non-6- enyl-1 3-[2-Hexyl-1 -(2-methylamirio-ethyl)-1 H- N A j YW =MI NO DtLEMIUO AUJ Sond har*cg flfs 31 FhhdW COMS ID No: SBMI-03086169 Received by IP Australia: Time (I-tm) 18:02 Date 2006-03-21 21. MAR. 2666 17:41 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 170 o N-Hydroxy-3-f 1-(2-methylamino.elhyl)-2-pentyl- 1 N-Hydroxy-3-[1 -2-methylamino-ethyl)-2-octyl- I 1 Cl3-[14-2-Amino-ethyl)-2-ootyl-I H-benzaimidazcl- VaO o i a N A A C N~ N A K 3.{2-Butyl-1 -[2-(isopropyl-methyl-nmino)-ethyl]. 1 H-benzoimidezol-8-yI}-N-hydroxy-aarylamide 3.{1 -(2-(Ethyl-methyl-amino)-ethyl]-2-pentyl.1 H- 3-(2-Hexyl-1 -pyrrolidin-3-yI-I 1 yI)-N-hydroxy-mcrylemicde 3-[2-Butyl-1 -methyl-pyrrolidin-3-yI)-l H- YAMwM fNO OILEMWPIUO AU kao hcrow11as 9I 1dtfl COMS ID No: SBMI-03086169 Received by IP Australia: Time (H:rn) 18:02 Date 2006-03-21 21. MAR. 2006 17:42 PHILLIPS ORMONDE FITZPATRICK NO. 3856 P. 171 a N II .6 0 W-I r NO 0 NN OH /-N N N'o 0 N N N N A 0 C KO:H N 167 3-(2-Buty-1 -piperdin-3-y-1 yI)-N-hydroxy-acrylamide 3-(2-Hexyl-1 -piperidin-3-y-1 yI)-N-hydroxy-aorylamlde 3-(1 -(2-[EthyI-(2-methoxy-ethyl).amino]-ethyl}.2. penty-1 acrylamide 3-{2-Butyl-1 -C2-(ethyl-methyl-amino)-ethyl-1 H- benzoimidazol-yl}4)-N-hyclroxy -acrytamide N-Hydroxy-3-[1 -(1-methyl-piperidin-3-yI)-2- pentyl-1 3-{1 -[2-(Ethyl-hexyl-amino)-ethy]-1 H- 3.411-[2-(Ethyl-perityl-amino)-ethyl]-1 H- YWaySELO blsTeioMSw AfUJ hwIoWFjPkdEU COMB ID No: SBMI-03086169 Received by P1 Australia: lime 18:02 Date 2006-03-21 I tI 21.MAR. 2006 11:42 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 112 N .H N 0 N N 61 168 3-{1 -[2-(Ethyl-heptyl-amino)-ethyl]-1 H- 3-{2-HexyI-1 -11 -(2-hydroxy-ethy)-pperdin-3-yJ- 1 3-(2-Butyl- -2-[ethyl-(3-hydraxy-propyl)-emino]-, ethyi)-1 acrylamide 3-(I -{2-[Ethyl-(3-hydroxy-propyl)-amino].sthyl). 2-pentyl-I acrylamide (E)-N-hydroxy-3-(I -phenethylpyrrolidin-3y)- 1 (E)-N-bydroxy-3-( 1 -pentylpiperdin-3-yI)-I H- benzo[d]Imidazol-6-yI)acrylamide C; C Y' NuWC NO DSETE4MLSIS All 9d ftuvldeuml pus. eSss COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:42 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 173 169 3-(1 -[2-(Sutyl-ethyls-amina)-ethyl]-1 H. ON~ H N benzoimidazol-5-yI1-N-hydroxy-acryamide (E)-N-hyciroxy-3-(1 -phenethylpiperidii-3-y)- N GH 1 (E)-N-hydroxy-3-(1 <1 -(3-pheriprpyl)piperidin- N 3-yI)-1 (E)-N-hydroxy-3-(1 -(3-phenylpropy)pyrralidin- 9 3-yI)-1 3-{I I -(8,3-Dimethyl-butyl)-pyrroludin-3-y]-1 M, N Y',M~U)lKI NO OMMWrrinUMM AU 869.d~ hwill M. rUsh. COMS ID No: SBMI-03086169 Received by I13 Australia: Time 18:02 Date 2006-03-21 I 21.MAR. 2006 17:42 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 174 OM Ntiiu r\ 170 .(2-(dlethylamino)ethyl)-1 H- 3.[2-(4-Cyano-bUty)-1 -(2-diethylamno-ethYI)- I H-benzomidazo-5-yI]-N-hyrOXY4aCIYImide .butylpiperidln-3-y)-1 H- (E)-N-hydroxy-3-(1 -(pent-4-enyl)pipeidifl-3- yI)-1 (3,3-dimethylbuty)piperidil-4-y)-1 H- 3-El -(2-Diethylamino-QthYI)-2-PropyIlamiflol H- KG "N ,AN yfl*u~u1 NW DI~atrFOiNCS AU SoU1 NRovlnd Fagil uFlutiu COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006T17: 42- PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 115 171 (E=)-N-hydraxy-3-(1 (Isopropyl(propyl)milO)OtYI)-l H- benzo[d]i 3-(1 -[2-(Butyl-isopropyl-amInO)-ethyl)-l H.. N-Hydroxy-3-(1 -f2-(isopropyl-pelty-alifla)- ethyl]-1 H-benzoimidazo-5-y}-BCrYlamid6 3-[2-(5-Cyano-pentYO-1 -(2-diethylamino-ethyl)- 1 I I-benzoimidBZO-55.YN-hYdrOKY-BcrYIamid8 3-{1 -(2-(Ethyl-propyl-amino)4thYI-1 H- benzolmidazo-5yI)-N-hydroxy4acrylamid8 0 N. wMutflCNO OKEfM7iDOOM AU Swrd Nt*iami FioAl faMAN COMB ID No: SBMI-03086169 Received by I13 Australia: Time 18:02 Date 2006-03-21 7 21MAR. 2006 17:42 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 176 OAH N H NN N 172 N-Hydroxy-3-(1 -{2-ifopropyI-(2-methY-Pel) amino]-ethyl}-1 (E)-N-hydroxy-3-(1 -(2-(isopropyl(4,4,4- trifluarcbutyl)amiflO)OthylP- H-benzo[dimidSzoI- 341 -(3-Dimethylamino-2,2-dimthYt-PrOPYD- 2 propytamiflo-1 acrytamidio 341 -(2-CEthy-heXyI-amiflQ)-ethYI1-2-methYl-l H- benzoimidzo5y)-Nhydroxy-9Orylamide trifluoromethyl-1 H-benzolidazol--YI1-N- hydroxyf-acryiamido NiH rIX N YAMIt NO DgUTSIPIQOU AU Smd NOraM AM 99 rW COMS ID No: SBMI-03086169 Received by I13 Australia: Time 18:02 Date 2006-03-21 I -21, MAR. 2006 17:43 PHILLIPS ORMONDE FITZPATRICK NO. 3853 P. 17? 173 trifluoromethyl-1 H-benzoimidazol-5-YI1'- hydroxy-acrylamide

341-C2-(dibutyIamiflo)6tbyI)-2-pOPYlIl H- benzo[d]imidazo5y)-N-hydroxy9cryIamidS 34[1 (2-Dipropy~aminO-ethy)-1 H-benzoimnidazol- N-Hydroxy-3-(1 J{2-[sopropy-(3-methyI-butyI)- aminoj-ethyl}-1 H-benzolmidazo-5-y)-8CryIamidS ethyl)-1 acrylemide 3-Cl -(--ty-uy)-ehlain]ehl- H- Z- OH Y,*MVHKI No DELTWJtUoJs AUhkwd tGwi*Ii Ai cliSAN COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR-2006-17:43 21. MA. 20017:43PHILLIPS ORMONDE FITZPATRICK N 88 P 1 NO. 3358 P. 178 I -(2.(diisobutylarnino)ethyl)-1 H- 3-(1 -t2-(3,3.Dimethy-butylamino)-ethYll-1 H- N-Hydroxy-3-{% -(2-(methyl-pont4-eny-afilO)- ethyfl-1 3.(-({2-[(3,3.Dimethy-buty)-PrOPYI-amiflol- ethyl}-I ecryismide Y;NWAri NO 3D8 WTBfPPIU4dAU I.MdP1*wGW nhd usSfl COMS ID No: SBMI-03086169 Received by 113 Australia: Time 18:02 Date 2006-03-21 21. MAR. 2006 17:43 PHILLIPS ORMOND[ FITZPATRICK NO. 3858 P. 119 175 INO 3-[l -(3sDimethylamTiflo-2,2-dimethyWPTOPYI)- 2 NzzmethiylsulfanyI-i H-benzoidazo--Y]-W hydroxy-mCrYIlidS 3-{1 -f2-(3,3.DirrIthyI-bUty1BmiflO)6thYWl2- N propyl-l scrylariide 0-l[-33Dmty-uyaio-ty--22 3-[1 -f2-[i(3,3-DImethy-butyl)iflQ}-eth-2- ~2Ndirethyl-propy)- H -benzomdoz1-5-yN hydroxy-acrlamdS II 1 2-imeth-pmptyl-H-benzomido--y- A N YMIV? NO DZLI'EL09O4S AU Brad NtviMS lta Me MWA COMS ID No: SBMI-03086169 Received by P1 Australia: Time 18:02 Date 2006-03-21 21, MAR. 2006 17:43 PHILLIPS ORMONDE FITZPATRICK NO. 3858 P. 180 176 No^ 3-(1-{2-[(2,2-Dimethyl-propyl)-propyl-aminol- 'NA acrylamide 3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl- t 41. claims A pharmaceutical composition including a compound according to any one of 1 to 40 and a pharmaceutically acceptable diluent, excipient or carrier. 42, Use of a compound according to any one of claims I to 40 in the preparation of a medicament for the treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation andlor angiogenesis. 43. A use according to claim 42 wherein the disorder is a proliferative disorder. 44. A use according to claim 43 wherein the proliferative disorder is cancer. A use according to claim 44 wherein the cancer is colon cancer, prostate cancer, hepatoma and ovarian cancer. 46. A method of treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis in a patient the method including administration of a therapeutically effective amount of a compound according to any one of claims 1 to 40 to the patient. 47. A method according to claim 46 wherein the disorder is a proliferative disorder. 48. A method according to claim 46 wherein the disorder is cancer. yWMmMC NO BM*sJ?(SMS AC MAlh SecoW mhi Md a TiSiAN COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21-MAR2006 17:43 PHILLIPS ORMONDE FITZPATRICK NVO. 3858 P. 181 177 O 49. A method according to claim 48 wherein the cancer is selected from the group o consisting of colon cancer, prostate cancer, hepatoma and ovarian cancer. Use of a compound according to any one of claims 1 to 40 or a pharmaceutical composition according to claim 41 to modify deacetylase activity. 51. A use according to claim 50 wherein the deacetylase activity is histone deacetylase activity. 52. A use according to claim 50 wherein the deacetylase activity is class 1 histone c deacetylase activity. l 53. A use according to claim 51 or 52 wherein the histone deacetylase is HDAC1. s1 54. A method of treatment of a disorder that can be treated by the inhibition of histone deacetylase in a patient including administration of a therapeutically effective amount of a compound according to any one of claims 1 to 40 to the patient. A method according to claim 54 wherein the disorder is selected from the group consisting of Proliferative disorders cancer); Neurodegenerative diseases including Huntington's Disease, Polyglutamine diseases, Parkinson's Disease, Alzhelmer's Disease, Seizures, Striatonigral degeneration, Progressive supranuclear palsy, Torsion dystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gilles de la Tourette syndrome, Diffuse Lewy body disease, Pick's disease, Intracerebral haemorrhage Primary lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia, Progressive ataxia and Shy-Drager syndrome: Metabolic diseases including Type 2 diabetes; Degenerative Diseases of the Eye Including Glaucoma, Age-related macular degeneration, macular myopic degeneration, Rubeotic glaucoma, Interstitial keratitis, Diabetic retinopathy, Peter's anomaly, retinal degeneration, Cellophane Retinopathy; Cogan's Dystrophy; Corneal Dystrophy; Iris Neovascularization (Rubeosis); Neovascularization of the Cornea; Retinopathy of Prematurity; Macular Edema; Macular Hole; Macular Pucker; Marginal Blepharitis, Myopia, nonmalignant growth of the conjunctiva; Inflammatory diseases and/or Immune system disorders including Rheumatoid Arthritis Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, ,Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease, Colitis Ulcerosa, YutNK O usErP ILoa i AU SaWad wiinl Adl af Ped=e COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 1:21-MNAR- 2006 17:44 PHILLIPS ORMONDE FITZPATRICK NVO. 3858 P. 182 u Alcoholic hepatitis, Diabetes, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis. Membranous glomerulopathy, Discogenic pain, Systemic Lupus Erythematosus, allergic contact dermatitis; Disease involving angiogenesis including cancer, psoriasis, rheumatoid arthritis; Psychological disorders including bipolar disease, schizophrenia, depression and dementia: Cardiovascular Diseases including Heart failure, restenosis, cardiac hypertrophy and arteriosclerosis; Fibrotic diseases including liver fibrosis, lung fibrosis, cystic fibrosis and angiofibroma; Infectious diseases including Fungal infections, such as Candida Albicans, Bacterial infections, Viral infections, such as Herpes Simplex, Protozoal infections, such as Malaria, Leishmania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidiosis and Haematopoietic disorders including thalassemia, anemia and sickle cell anemia. 56, A method for inhibiting cell proliferation including administration of an effective amount of a compound according to any one of claims 1 to 57. A method of treatment of a neurodegenerative disorder in a patient including administration of a therapeutically effective amount of a compound according to any one of claims 1 to 40 to the patient. 58, A method according to claim 57 wherein the neurodegenerative disorder is Huntington's Disease. 59. A method of treatment of an inflammatory disease andlor immune system disorder in a patient including administration of a therapeutically effective amount of a compound according to any one of claims 1 to 40 to the patient. A method according to claim 59 wherein the inflammatory disease and/or immune system disorder is rheumatoid arthritis. 30 61. A method according to claim 59 wherein the inflammatory disease and/or immune system disorder is systemic lupus erythematosus. 62. A method of treatment of a degenerative eye disease in a patient including administration of a therapeutically effective amount of a compound according to any one of claims 1 to 40 to the patient. Y~WMmW TO DUELETPII 0 AU Bld PI b i n l l ll Filtis II i I, COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21 21.MAR. 2006 17:44 PHILLIPS ORMONDE FITZPATRICK NO.3858 P. 183 179 o 63. A method according to claim 62 wherein the degenerative eye disease is selected o from the group consisting of macular degeneration, retinal degeneration and glaucoma. 64. The use of a compound according to any one Of claims 1 to 40 in the manufacture of a medicament for the treatment of cancer. s codn oci 4weenth acri eaooi ainny A use according to claim 64 wherein the cne s hematologic malignanc y. slce from a group consisting of B-cell lymphoma, T-cell lymphoma and leukemia. 01 IN 67. A use according to claim 64 wherein the cancer is a solid tumor. 68. A use according to claim 67 wherein the solid tumor is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, renal cancer, gastric cancer, colon cancer, pancreatic cancer and brain Cancer. 69. A use according to claim 54 wherein the cancer is selected from the group consisting of colon cancer, prostate cancer, hepatoma and ovarian cancer. 2o 70. A method of treatment of a proliferative disorder in patient including administration of a therapeutically effective amount of a compound according to any one of claims 1 to 40 to the patient. 71. Use of a compound according to any one of claims I to 40 in the preparation of a medicament for the treatment of a proliferative disorder. 72. A method of treatment of cancer in patient including administration of a therapeutically effective amount of a compound according to any one of claims I to to the patient. 73. A method according to claim 72 wherein the cancer is a hematologic malignancy. 74. A method according to claim 79 wherein the 'hematologic malignancy is selected fromn the group consisting of B-cell lymphoma, T-cell lymphoma and leukemia. A method according to claim 72 wherein the cancer is a solid tumor. t'AWYN44jNO DLS2V.WISUJ AU Semd FWmlaiv Phul z Mdiw COMB ID Na:SBMI-03086169 Received by IP Australia: lime 18:02 Date 2006-03-21 ,21, MAR, 2006 17:44 PHILLIPS ORMONDE FITZPATRICK NO., 3858 P. 184 76. A method according to claim 75 wherein the solid tumor is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, renal cancer, gastric cancer, colon cancer, pancreatic cancer and brain cancer. 77. A method according to claim 72 wherein the cancer is selected from the group consisting of colon cancer, prostate cancer, hepatoma and ovarian cancer, DATED: 21 March 2006 PHILLIPS ORMONDE FITZPATRICK Attorneys for: 8*BIO Pte Ltd. YfIUM KINO DNLTWIOmO- A flead Prta nl avi RiDl I m COMS ID No: SBMI-03086169 Received by IP Australia: Time 18:02 Date 2006-03-21