AU2006201177B2 - Heterocyclic compounds - Google Patents

Abstract

Abstract. The present invention relates to compounds which are inhibitors of histone deacetylase. More particularly, the present invention relates to heterocyclic compounds and methods for their preparation. These compounds may be useful as medicaments 5 for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with enzymes having histone deacetylase (HDAC) activities. ruNKi NO DELETEWIBMS AU leeId NCdenaIl Wal as Fedc

Description

AUSTRALIA Patents Act COMPLETE SPECIFICATION (ORIGINAL) Class Int. Class Application Number: Lodged; Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: S*B10 Pte Ltd Actual Inventor(s): Pek Ling Lye, WelPing Deng, Ken Chi Lik Lee, Eric T. Sun, Dizhong Chen, Niefang Yu, Haishan Wang Address for Service and Correspondence: PHILLIPS ORMONDE & FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA 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 applicantss: -1- 2 HETEROCYCLIC COMPOUNDS 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 Incorporated herein by this reference. 5 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 10 as well as other diseases involving, relating to or associated with enzymes having histone deacetylase (HDAC) activities, BACKGROUND OF THE INVENTION [0002] Local chromatin architecture is generally recognized as an important factor in the regulation of gene expression. The architecture of chromatin, a protein-DNA 15 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 20 repression of gene expression [Wadem P.A. Hum. Mol. Genet. 10, 693-698 (2001), De Ruijter A.J.M. et al, Blochem. J., 370, 737-749 (2003)). In normal cells, histone deacetylases (HDACs) and histone acetyltransferase together control the level of acetylation of histories to maintain a balance. Inhibition of HDACs results in the accumulation of acetylated histones, which results in a variety of cell type dependent 25 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 30 differentiation and/or apoptosis In murine erythroleukemla, bladder, and myeloma cell lines [Richon V.M. at al, Proc. Nati. Acad. Sci. USA, 93: 5705-5708 (1996), Richon V.M. et al, Proc. Natil. 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 35 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, YqsmuYXY1 NO DELEM09.AUInd Pr al PIni qi qeM4X 3 due to the in vivo instability of these compounds they are less desirable as anti-cancer drugs. Recently, other small molecule HDAC inhibitors have become available for clinical evaluation [US6,552,065]. Additional HDAC inhibiting compounds have been reported in the literature [Bouchain 0. et al, J. Med. Chem., 46, 820-830 (2003)] and 5 patents [WO 03/066579A2]. The In vivo activity of such inhibitors can be directly 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 polyglutamine-dependent neurodegeneration [Nature, 413(6857): 739-43, 18 October, 2001]. In addition, HDAC 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. [J. Biol. Chem. 1990; 265(18): 10230-10237: Science, 1998; 281: 1001 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., 15 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 20 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 25 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 30 typically provide a longer duration of action due to the increased in vivo exposure (i.e., area under the curve, AUCO.bM) thereby yielding improved tumor growth inhibition profiles in the xenograft models. SUMMARY OF THE INVENTION 35 [0005] In one aspect the present invention provides a compound of the formula (I): WMm#NEINO DNJTEH1awMi. AU huiS RlensI PlpM N Friltl 4 R24/ 3 NC -R4 Y R1 Formula (1) wherein [0006] R' is an optionally substituted heteroaryl group, an optionally substituted 5 heterocycloalkyl group or a group of formula: -(CR R 1 )m(CR 2 R")n(CR1 4

R")-NR

2 R" [0007] R 2 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, 10 heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkoxyalkyl, RS(O)R"-, RRS(0)2R"-, R"C(O)N(R 12

)R'

3 -, R 1 S0 2

N(R

12

)R'

1 -, RN(R 1 2 )C(O)R-,

RUN(R

12

)SO

2

R'

3 -, R"N(R')C(O)N(R")R- and acyl, each of which may be optionally substituted; 15 [0008] R' is selected from the group consisting of H, C 1 -Ce 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 , -CFa, -OCF 3 , alkyl, alkenyl, alkynyl, 20 haloalkyl, haloalkenyl, haloalkyny, hetemalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalky, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, 25 arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, COOH -C(O)OR', -COR 5 , -SH, -SR', -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, 30 haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; Y:WIrfNKI NO DflTEM 09SM AUseud PeivialelFh Ti aflgi4g S [0011] each RI is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalky, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; 5 [0D12] each Re is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cydloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each of which may be optionally substituted; 10 [0013] 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; 15 [0014] each Rt" and R1 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 3 is a bond or is independently selected from the group consisting of: 20 alkyl, alkenyl, and alkynyl, each of which may be optionally substituted; [0016] each Ra R", R2, R", R 4 and R2 is independently selected from the group consisting of: H, halogen, -CN, -NO 2 , -CF3, -OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalky, cycloalkyl, cycloalkenyl, heterocycloalkyl, 25 heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkeny, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy heteroaryloxy, amino, 30 alkylamino, acylamino, aminoalkyl, arylamino, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, aminosulfonyl, arylsulfonyl, arylsulfinyl -COOH, -C(0)OR, COR', -SH, -SRO, -ORO 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 35 R" 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 =0 or =8; 6 [0017] each R2 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, 5 heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, io alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfiny, arylsulfonyl, arylsulfinyl, aminosulfonyl, SRG and acyl, each of which may be optionally substituted, or Ra and R 2 when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group; 15 [0018] Z is a bond or is selected from the group consisting of -CH2-, -CH 2 CH2-, -CH=CH-, C-C alkylene, CrCO alkenylene, CrC. alkynylene, CrC,$ cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of 01-C4 alkyl; 20 [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. 25 [0021] In one embodiment of the invention R 4 is H and the compounds are those of formula (Ia): R2 2 OH4hZ} R1 Formula (la) [0022] or a pharmaceutically acceptable salt or prodrug thereof 30 [0023] wherein R', R 2 , R 3 , X, Y and Z are as defined for compounds of formula (1), [0024] In another embodiment Ra and R 4 are H and the compounds are of formula (Ib); YNMWimAEINODELAThPLo90.s AU EmeudYi l e. P N lMWP , 7 x 0 R OH R1 Formula (Ib) [0025] or a pharmaceutically acceptable salt or prodrug thereof 5 [0026] wherein R", R 2 , R3, X, Y and Z are as defined for compounds of formula (1). (0027] As with any group of structurally related compounds which possess a particular utility, certain groups are preferred for the compounds of the Formula (1), (la) 10 and (Ib) in their end use application. [0028] In one embodiment the group RI is a group of formula -(CROR2),z(CRR"),(CR a)eNR2R 15 [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 20 compounds of formula (1c): R2 4 5 R4 R 24 I z 0> Y R Formula (Ic) wherein R' is a group of formula 25 -(CRaR CR R")r(CR"R ")NR2Rz [0031] and R 2 , R*, R 4 , X, Y, Z, R", R 21 , Re, R 2 3 , R, RI, R 2 , R 2 , m, n and o are as defined for compounds of formula (I).

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, 10, 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 5 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 is 10 selected from the group consisting of: -(CR'Re')2-NR2eR"21 -(CR"RDe)a-NR 2R;

-(CR

2

R

2 1

-)NR"R

27 ; -(CR4RD)-(CR2R1)-NR 2 R

-(CRR

2 )-(CR R")-NRfRl ; -(CR2R 2 3)-(CRSRas)-NR"R 2 ; (0034] In one form of this embodiment R 1 is the group: 20 -(CROR 2

)-(CR

22

R

2 )-NRR"; [0035] This provides compounds of the formula (11): R2 - R R2 Y R %>R22 N R 22 R276 Formula (I) 25 [0036] wherein X, Y, Z, R2, R', R 4 , R2, F 21 , R", R 23 , R and R" are as defined in formula (1). [0037] In a specific form of this embodiment R' is H which provides compounds of 30 formula (ila); YAMx tNO DMrUMnuw99 AD ~Sad lRmMaiI PL- M MW' 4K 9 R20x Y R2OrN\R 2 2 Formula (lla) [0C48] wherein X, Y, Z, R 2 , Re, R2, R 21 , RM, Ra, R 2 " and R 27 are as defined in 5 fortnula (I). [00 9] In another specific form R 3 is H leading to compounds of formula (lib): R2_4 N b-H N R 20 Y R22 R 21 I R23 R26eN"2 R2 Formula (lib) 10 [0040] wherein X, Y, Z, R, R, R, R R", R, R 2 and R 2 are as defined in formula (I). (0041] In an even more specific form of this embodiment R 2 , R 21 , R' 2 and R M are H 1 proIding compounds of formula (lc): x H R~R2N Formula (Ib) [0042] wherein X, Y, Z, R 2 , R 2 e and R2 are as defined in formula (I). M .ar Di~ f~i~iA e m 4 ia a. kh 10 [0043] In another embodiment the sum of m+n+o is 3. When this occurs R' is selected from the group consisting of:

-(CR

20

R

21 )rNRR 2 7; 5

-(CR

22 Ra-NR"R2; -(CR24Rt2)rNR 2R"7; -(CW'FmR2(CR~ea)-NR2'R2;

-(CR

2

R

21 )r(CR1 4 R )-NR2R"; -(CR20R 21)-(CR"2R"')rNR2R"7; 10 -(CR22R"Z)r(CRtR")-NRRT;

-(CR"R

21 )-(CR 24 R)rNR 2 e

R

27 ; -(CR"R)-(CR"R")rNRNR2;

-(CR

2 0

R

21 )-(CR R)-(CR2'R2)-NRrR 2 7; 15 [0044] In one form of this embodiment R 1 is a group of the formula:

')-R

2 2R 21 (RR)-(CR R )-NR2R2, [0045] This provides compounds of the formula (1II): N -N R2 Z O-R4 R20 y R21

R

22

R

2 4 R 2 3 20 R Formula (111) [0048] wherein X,Y, Z, R 2 , R', R 4 , R 2 , R 2 , R 2 , R",R 24 , R2 R 2 and R 2 7 are as defined in formula (1). 25 [0047] In a specific form of this embodiment R' is H which provides compounds of formula (Ilia). Y1h.fl&4KJ NO DPLflPPIUJ AU hecu hnidm;I PiuI a Ffldmw 11 R2-K(/ -Z O-H R2ONy R 21R2 R24 R 23 R25 ,N'R26 R 27 Formula (lila) [0048] wherein X,Y, Z, R, R 3 , R4, R 2 0, R 2 , R2, R 2

,R

2 , R 2 , R" and R 2 7 are as 5 defined in formula (1). [0049] In another specific form R3 is H leading to compounds of formula (lib): x H y R21 R0-H R22 R24 R23 R28 /N'R2 R27 Formula (illb) 10 [0050] wherein X,Y, Z, R 2 , R 5 , R 4 , R, R 2 1 , R", R",R 2 , R 1 , R" and R are as defined in formula (1). [0051] In an even more specific form of this embodiment R2, R, R 2 , RM are H, and

R

22 and R" am methyl providing compounds of formula (lil1). 5 YVMmWMO NO DELTWP1OSN4 AU9MdS N.iid.... flhdoe 12 N - .,\- Z 0 \ - H N--.'R26 R Formula (llic) [0052] wherein X,Y, Z, R 2 , R3, R 4 , R 20 , R 2 1 , R m, R",R 2 , R2, R 2 and R" are as 5 defined in formula (I). [00,53] In each of the above embodiments of the invention R and R 1 may represent a number of different variables. In one embodiment RI and R 2 ' are independently selected from the group consisting of H, alkyl, alkenyl and alkynyl. In another 10 embodiment Ra and R 2 1 are Independently selected from the group consisting of H and alkyl. In a specific embodiment R" and R 21 are both H. [0054] In each of the above embodiments of the invention R2 and R" may represent a number of different variables. In one embodiment R2 and R2 are independently 15 selected from the group consisting of H, alkyl, alkenyl and alkynyl, In another embodiment R22and R 23 are independently selected from the group consisting of H and alkyl. In a further embodiment R 2 2 and R"2 are independently selected from the group consisting of alkyl. In a most specific embodiment R2 and R" are both methyl. 20 [0055] In each of the above embodiments of the invention R and R 2 1 may represent a number of different variables, In one embodiment R24 and R are preferably independently selected from the group consisting of H, alkyl, alkenyl and alkynyl. In another embodiment R24and R" are independently selected from the group consisting of H and alkyl. In a specific embodiment R and R2 are both H. 25 [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 1 are Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, alkoxyalkyl, and acyl. In another embodiment R2 and R" are independently selected from the group consisting of: H, alkyl and acyl. Y;YMCL 2W DELBTUWPIISC$ AU SNOW PW.iUmd Metu Wr MUM~t 13 In a further embodiment R2 and R 2 7 are independently selected from the group consisting of H, methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, penty, pent-4-enyl, hexyl, heptyl, octyl, acetyl and 2-methoxy-ethyl. 5 10057] In another embodiment R 1 is a heterocycloalkyl group which may optionally be substituted. [0058] In one form of this embodiment the heterocycloalkyl group is selected from 10 the group consisting of: N R2N Rae RI R26 KR28R 2 [0059] wherein R2 is selected from the group consisting of H, halogen, alkyl, alkenyl, is alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryt, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, 20 arylalkyloxy, heteroaryloxy, amino, alkylamino, aminoelkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, arylacyl, sulfonyl, alkylsulfonyl, alkytsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR 6 and acyl, each of which may be optionally substituted. 25 [0060] In one embodiment R28 is selected from the group consisting of H, alkyl, alkenyl, arylalkyl and arylacyl. Specific values of R are H, 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; penten-4-yl, hexyl; heptyl, octyl, nonyl, 2 methoxy nonyl, benzyl, 2-phenyl-ethyl, 2-phenyl-acetyl, 3-pheny-propyl, 30 [00611 In another embodiment the heterocycloalkyl group is pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane. It is particularly YWNaIINO DUEiTNMIOOO.O AU Aeemd Pse'lin Fhia asFiltm 14 preferred that R' is selected from the group consisting of piperidine-3-yl, piperidine-4-yI and pyrollidin-3-y. [00621 In another embodiment R 1 is a heteroaryl group. 5 [0063] in another embodiment R 1 is a group selected from the group consisting of: H H NH2NN 10 H N N NN 15 THrHNNH NNH 0 Y.S6I 3 AN NO DULMWPIGW9S AU 604 hamWnrio Ra uflid- 15 VtNN *N N N 5 VNxN N 16 N NH N OH \ NH NH 5 [0064] In one specific embodiment R 1 is a group of formula: 10

NH

2 [0065] In another specific embodiment RI is a group of formula: H 15 Y~lAgfNK M ELETE\PPI09J4 AU 5send fProdsinal Final as FiI4Stc 17 [0066] In another specific embodiment R' is a group of formula: H 5 [0067] In yet another specific embodiment R' is a group of formula: H 10 [0068] In another specific embodiment R is a group of formula: N [0069] In another specific embodiment R 1 is a group of formula: 15 N [0070] In another specific embodiment R' is a group of formula: 20 [0071] In another specific embodiment R is a group of formula: V~q4.-AVwc4t nKTMffO9-OI AV UrnS No,4afl Maulm Muddop 18 NH [0072] In another specific embodiment R 1 is a group of formula' V~- N. 5 [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 10 Ci-Cia alkyl. In anotherform of this embodiment the alkyl is a CrC. 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-penty; hexyl; heptyl, octyl, nonyl, and 2-methoxy nonyl. 15 [0075] In one form of this embodiment R 2 is alkenyl. In one form of this embodiment the alkenyl is y a C-C 1 o alkeny. In another form of this embodiment the alkenyl is a C Ce alkenyl group, In another form of this embodiment R 2 is selected from the group consisting of: ethenyl, prop-1-enyl, prop-2-enyl, but-1-enyl, but-2-enyl but-3-enyl, pent 20 1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4 enyl and hex-5-enyl. [0076] In another embodiment R 2 is selected from the group consisting of R S(O)R 3 -, R 1 S(0) 2

R

3 -, R 1

C(O)N(R

12

)R

13 -, RSO 2

N(R

2 )R -. R1'N(R 12

)C(O)R

13 -, Y;UN#dOILSMTh*I9M AU SEW OrM dm FAnd m lfedn 19 RlN(Rl)SO 2 R--, and R"N(Rl 2 )C(O)N(R"2)R3-. In one form of this embodiment R 2 is a group of the formula R"C(O)N(R' 2 )R3-. In one form of this embodiment R" is a Cr Ce alkyl. In a specific form of this embodiment Ra is methyl or ethyl. In one form of thsi embodiment R 1 is H or C-Cealkyl. A specific value for R 1 is H. In one form of thsi 5 embodiment R" is C-CO alkyl group. Specific values for R include t-butyl and propyl. , Specific examples of groups of this type include: (CHs)sCCH 2

CONH(CH

2 )r; (CHs)sCCONH(CH2)r; (CH 3 )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; 10 ethoxymethyl; [Bicylco[2.2.1]2-ylmethyl; Adamantan-2-ylmethyl; 2-methansulfanyl ethyl; 2,2,2-triflouro-ethyl; propyl; 2-2-dimethyl-propyl; Isopropyi; 3,3,3.triouro-propyl; butyl; isobutyl; 3,3-dimethy-butyl; but-$-enyl; but-3-yny; pentyl; 2,4,4-trimethyl-pentyl; Bicyclo[2.2.1]hept-5-en-2yl; hexyl; hex-3-enyl; octyl; non-3-enyl; non-6-enyl; 2 meihoxy-nonyl, 2-phenyl-cyclopropyl; cyclohexyl; (CH 3

)

3

CCH

2

CONH(CH

2

)

2 -; 15 (CHs) 3 CCONH(CH2)2-; (CH 3

)CCONH(CH

2 )- and CHs(CH 2

)

2 CONH(CH2)-. [0078] In one embodiment X and Y may be the same or different and are selected from the group consisting of H, halogen, C-C 4 alkyl, -CF 3 , -NO 2 , -C(O)R, -OR 6 , -SR, CN and NR

T

R'. 20 10079] In one embodiment X is H; [0080] In one embodiment Y Is H; 25 [0081] In one embodiment X and Y (if present) are at the 4 and 7 positions of the aromatic ring. [00821 In one embodiment R 3 is H, C-Ce alkyl, or acyl. In another embodiment R 3 is H or C,-C 4 alkyl. A specific value for R 3 is H; 30 [0083] In one embodiment R4 is H or C-C 4 alkyl. A specific value for R4 is H; [0084] In one embodiment Re is Cl-C 4 alkyl, heteroalkyl, or acyl. A specific value for Re is methyl; 35 [0985] In one embodiment Re is C-C 4 alkyl, heteroalkyl or acyl. A specific value for R is C,-C 4 alkyl; WA~MJI1M DWSWIPS4I-0 AV 1M FmYI~ufu MiW a N8 d 20 [0086] In one embodimentR 7 and R8 are selected from the group consisting of H, C CB alkyl, C 4 -Cgcycloalkyl, C 4 -Coheteracycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl 5 [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, =0, =S, -CN, -NO 2 , -CF 3 , -OCF, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, 10 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylarnino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, 15 alkoxyalky, -COOH, -CR 5 , -C(O)OR', -SH, -SR 5 , -ORand acyl; [0088] In a further embodiment the optional substituents are selected from the group consisting of: halogen, =0, =S, -CN, -NO 2 , alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, 20 aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C(O)OR', 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 25 group of formula -CH=CH-. If the Z moiety is a group of this type it is preferably in the "E" configuration. [00901 In addition to compounds of Formula (I), the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, 30 and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites. $uch compounds, salts, prodrugs and metabolites are at times collectively referred to herein as "HDAC inhibiting agents" or "HDAC inhibitors". 35 [0091] The Invention also relates to pharmaceutical compositions including a compound of the invention with a pharmaceutically acceptable carrier, diluent or excipient. yWu)N 1?40 D!LETK IhP4OI5 AUSedfrtwakil iign, es ade 21 [00921 In yet a further aspect the present invention provides a method of treatment of a disorder caused by, associated with or accompanied by disruptions of call proliferation and/or angiogenesis Including administration of a therapeutically effective s amount of a compound of formula (1). The embodiments disclosed also relate to pharmaceutical compositions each comprising a therapeutically effective amount of a HDAC inhibiting agent of the embodiments described with a pharmaceutically acceptable carrier or diluent for treating cellular proliferative ailments, e.g., inhibition of proliferation of malignant cancer cells, benign tumor cells or other proliferative cells. 10 [0093] In one embodiment the method includes administration of a compound of formula (Ia) or (ib) as described herein. [0094] In one embodiment the disorder is selected from the group consisting of but 15 not limited to cancer (e.g. breast cancer, colon cancer, prostate cancer, pancreatic cancer, leukemias, lymphomas, ovarian cancers, neuroblastomas, melanoma, inflammatory diseases/immune system disorders, angiofibroma, cardiovascular diseases (e.g. restenosis, arteriosclerosis), fibrotic diseases (e.g. liver fibrosis), diabetes, autoimmune diseases, chronic and acute neurodegenerative disease like 20 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. 25 [00951 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 including a compound of formula (1) as disclosed herein, in one embodiment the agent is an anti-cancer agent. In another embodiment the agent Is an anti-angiogenesis agent. 30 (0096] In one embodiment the agent contains a compound of formula (la) or (lb). (0097 The invention also relates to the use of compounds of formula (1) in the preparation of a medicament for the treatment of a disorder caused by, associated with 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. YW~wtM NO BITSUOSAU IrNA ili" Od Fls UMAN 22 {0098] The compounds of the present Invention surprisingly show low toxicity, together with a potent anti-proliferative activity. 5 [00991 In yet a further embodiment the invention provides a method of treatment of a 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 (1). 10 [010] In one embodiment the method includes administration of a compound of formula (Ia) or (Ib) as described herein, [0101] In one embodiment the disorder is selected from the group consisting of but not limited to Proliferative disorders (e.g. cancer); Neurodegenerative diseases 15 Including Huntington's Disease, Polyglutamine diseases, Parkinson's Disease, Alzheimer's Disease, Seizures, Striatonigral degeneration, Progressive supranuclear palsy, Torsion dystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gilles de I2 'Tourette syndrome, Diffuse Lewy body disease, Pick's disease, Intracerebral haemorrhage Primary lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral 20 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, Peters 25 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 (RA), Osteoarthritis, 30 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 35 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 YN~ANK1WNO bMlTFFIN&WAtI-d AR~OI~MhIjflWfl 23 including liver fibrosis, lung fibrosis, cystic fibrosis and angiofibroma; Infectious diseases including Fungal infections, such as Candida Albicans, Bacterial infections, Virul infections, such as Herpes Simplex, Protozoal infections, such as Malaria, Leishmania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidiosis, 5 and Haematopoletic 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 (1) as disclosed herein. In one embodiment the agent is an anti 10 cancer agent. (0103] The invention also relates to the use of compounds of formula (1) In the preparation of a medicament for the treatment of a disorder, disease or condition that can be treated by the inhibition of histone deacetylase. 15 10104] The invention also provides a method for Inhibiting cell proliferation including administration of an effective amount of a compound according to formula (1). [015] In yet an even further aspect the invention provides a method of treatment of 20 a neurodegenerative disorder in a patient including administration of a therapeutically effective amount of a compound of formula (I). In one embodiment the method Includes administration of a compound of formula (Ia) or (Ib) as described herein. In one embodiment the neurodegenerative disorder is Huntington's Disease. 25 [0106] The invention also provides agents for the treatment of neurodegenerative disorder including a compound of formula (1) 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 (1) in the 30 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 on; Inflammatory disease and/or Immune system disorder in a patient including 35 administration of a therapeutically effective amount of a compound of formula (1). In onO embodiment the method includes administration of a compound of formula (Ia) or (Ib) as described herein. In one embodiment the inflammatory disease and/or immune NOM r Ei IC MLE 1PflflO All teed hwA*W P~s iPUAA 24 system disorder is rheumatoid arthritis. In another embodiment the inflammatory disease and/or immune system disorder is Systemic Lupus Erythematosus. [0109] The invention also provides agents for the treatment of inflammatory disease 5 and/or immune system disorder including a compound of formula (1) as disclosed herein. [0110] The invention also provides agents for the treatment of eye disease mediated by HDAC inhibition including a compound of formula (I) as disclosed herein. In one 10 embodiment, the eye disease is macular degeneration. In another embodiment, the eye disease Is glaucoma. In another embodiment, the eye disease is retinal degeneration. [0111] The invention also relates to the use of compounds of formula (1) in the 15 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. 20 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. 25 [0113] As used herein, the term unsubstituted means that there is no substituent or that the only eubstituents 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 30 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, 0, =S, -CN, -NO 2 , -CF 3 , -OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalylalkyl, 35 heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylaikenyl, cycloalkylheteroelkyl, heterocycloalkylheterOalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, T!.MWCNO DMEflBIopm US,, nuu iiulda 25 hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alkoxyheterocycloalky, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, arylalkyl, heteroarylalkyl, s cycloalkylalkyl, heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -COOH, COR 5 , -C(O)OR 5 , CONHR 5 , NHCOR, NHCOOR 5 , NHCONHR', C(=NOH)R, -SH, SR, -OR and acyl. 10 [0115] "Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a Cr-C 4 alkyl, more preferably C,-C 0 alkyl, most preferably C-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, t 15 butyl, hexyl, and the like. (0116] "Alkylamino" includes both monoalkylamino and dialkylamino, unless specified. "MonoalkylaminoN 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 20 or different and are each as defined herein for alkyl. The alkyl group is preferably a C Co alkyl group. [0117] "Alkylemino" includes both monoalkylamino and dialkylamino, unless specified. "Monoalkylamino" means a -NH-Alkyl group in which alkyl is as defined 25 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. 30 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 35 herein. Examples of acyl include acetyl and benzoyl. The alkyl group is preferably a C Ce alkyl group. Y.\MUrNK NO o=P"M ALImw misd NwdvsMrid 9R~ ,Ftsihu 26 [0120] "Alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain. The group may contain a 5 plurality of double bonds in the normal chain and the orientation about each is 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. 10 Preferably the alkoxy is a C 1 -Calkoxy. Examples include, but are not limited to, methoxy and ethoxy, [0122] "Alkenyloxy" refers to an -0- alkenyl group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C-Coalkenyloxy groups. 15 [0123] "Alkynyloxy" refers to an -0-alkynyl group in which alkynyl Is as defined herein. Preferred alkynyloxy groups are C-C alkynyloxy groups. [0124] "Alkoxycarbonyl" refers to an -C(O)-O-alkyl group in which alkyl is as defined 20 herein. The alkyl group is preferably a C-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 C-Ce alkyl group. Exemplary alkylsulfinyl groups 25 include, but not limited to, methylsulfinyl and ethylculfinyl. [0126] "Alkylsulfonylm refers to a -S(O)ralkyl group in which alkyl is as defined above. The alkyl group is preferably a C-Ce alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl. 30 [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 35 not limited to, ethynyl and propynyl. YAW=~~K N9 umsmflz49O AU jgpd rmAjma 7fliul .Pkdhd 27 [0128] "Alkylaminocarbonyl" refers to an alkylamino-carbonyl group in which alkylamino is as defined above. [0129] "Cycloalkyl" refers to a saturated or partially saturated, monocycle or fused or 5 spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, 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. 10 [0130] NcycloalkenylN means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl, The cycloalkenyl group may be substituted by one or more substituent groups, 15 [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 the like. 20 10132] "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocycloalkylalkyl groups include cyclopropyimethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. 25 [0133] "Halogen" represents chlorine, fluorine, bromine or iodine. [01341 NHeterocycloalkyl" refers to a saturated or partially saturated monocycli, bicyclic, or polycyclic 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 30 preferably from 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable heterocyclohlkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane.

35 [0135] "Heterocycloalkenyl" refers to a heterocycloalkyl as described above but containing at least one double bond.

VAE

1 YM'I10 DEMTIiWnSa AU SEd PlWbiinal P15t N FikdaM 28 [0136] "Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl group in which the heterocycloalkyl and alkyl moieties are as previously described. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl. 5 [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, 0, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, and the like. 10 [0138] "Aryl" as a group or part of a group denotes (I) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms 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 15 saturated bicyclic aromatic carbocyclic moiety In which a phenyl and a C,.7 cycloalkyl or Cr, cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indonyl or indanyl. [0139] "Arylaikenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are 20 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 C1.4 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthelenemethyl. 25 10141] "Arylacyl" means an aryl-acyl- group in which the aryl and acyl moletles 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 alkyl moiety in the acyl moiety. Exemplary 30 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 heterostoms as ring atoms in the aromatic ring with the remainder of the ring atoms 35 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, YVdanKINO EWLEWTPlsOM5 MiSed Fteinljminl F=ide NtdC 29 furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 11-1-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, 5 isooxazole, furazane, phenoxazine, 2-,3- or4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1-, 3-. 4-, or 5- isoquinollnyll-, 2-, or 3- indolyl, and 2-, 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 10 lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. [0144] "Lower alkyl" as a group means unless otherwise specified, an aliphatic 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 15 isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl). 10145] In Formula (1), as well as in Formulae (Ia) - (Ib) defining sub-sets of compounds within Formula (I), there is shown a benzimidazole ring system. Within this ring system, there are substitutable positions at the 4-,5-, 6-, and 7-ring positions. In 20 each of Formulae (1), (Ia), and (lb), 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 -CHr 25 or -CH 2 CHr, 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 (I) are isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical 30 isomers in "E" or '7" 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. 35 [0147] Some of the compounds of the disclosed embodiments may exist as single stereolsomers, racemates, and/or mixtures of enantlomers and /or diestereomers. All lrMNE NO DEMjTiMPLQOS a had fstladkl Pind a F is 30 such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter described and claimed, [0148] Additionally, Formula (1) is intended to cover, where applicable, solvated as 5 well as unsolvated forms of the compounds. Thus, each formula Includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms. [0149] In addition to compounds of the Formula (I), the HDAC inhibiting agents of the 10 various embodiments Include pharmaceutically acceptable salts, prodrugs, and active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites. [0160] The term "Pharmaceutically acceptable salts" refers to salts that retain the 15 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 (1) 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 20 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, fumeric, maleic, alkyl sulfonic, arylsulfonic, Suitable pharmaceutically acceptable base addition salts of compounds of Formula (1) include metallic salts made from lithium, sodium, potassium, magnesium, 25 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, 30 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. 35 [01511 "Prodrug" means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of formula (1). For example an ester prodrug of a compound of formula (I) containing a hydroxyl group YtM VtNKNO f3MELuJAJI9btS AVI casd ntrulai Main u P df 31 may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of formula (1) containing a hydroxyl group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-p-hydroxynaphthoStes, gestisates, isethionates, 5 di-p-toluoyltartrates, rnethanesulphonates, ethanesulphonates, benzenesulphonates, p toluenesulphonates, cyclohexylsulphamates and quinates. As another example an ester prodrug of a compound of formula (I) 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.,18:379, 1987). 10 10152] Preferred HDAC inhibiting agents include those having an ICSo value of 10 sM or less. (0153] Specific compounds of the invention include the following; 15 3-[l -(3-Dimethylamino-2,2-dimethyl-propyl)-2 (2,2-dimethyl-propy9-1 H-benzoimidazol-5-yl].N hydroxy-acrylamide 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2 isopropyl-1 H-benzoimidazol-5-yl}-N-hydroxy acrylamide 3-[2-Butyl-'i-(3-dimethylemino-2,2-dimethyl propyl)IH-bnzlmldazol-5-yl]-N-hydroxy acrylamide 3-[1-(3-Dimethylamino-2,2-dimethyl-propy)-2-(2 methylsulfanyl-ethyl)-1 H-benzoimidezol-6-yl]-N hydroxy-acrylamide 32 H 3-(1 -(3-Dimethylamina-2,2-dimethy-prOpyO-2 ethoxyrnothyl-1 H-benzoimidazol-5-y]-N hydroxy-arylamide CM 3.41-(3-Dimethylamino2,2-dimtl-PropyI)-2 / isabutyl-1 H-b~erzoimidazo--Y]-N-hYdroxy acrylamide / I 3-11 -(2-Diethylami no-othy)-2-isobUty-1 - KIMbenzolmidazol-5-yU-N-hydroxy-scrylmidS / ~ N A 4 3-12-Butyl.1 -(2-diethylamlno-ethyl)-1

H

- A benzoimidazol-5-yI]-N-hydroxy-lcrylmide - 3-[2-But-3-ynyl-1 -(3-cilmethylamino-2 1 2-dimethyl / propyl)-1 H-berizolmidazol-5-ylJ-N-hydrOxy acrylamide 3 -[2-But-3-enyl-1 -(3-climethylamino-2,2 A dimethyl-propyl)-1 H-benzoimidazol-5-yfl-N hydroxy-crylamide NIC 3-[2-But-3-eriyl-1 -(2-diethyllrfiro-Gthyl)-IH. / I benzolmidazcl.5-yl-N-bydroxy-acrylamide w'u3MNMr NO DU&KltfiU=d AU A-"mu. f ail FiS 33 N 3-[2-But-3-ynyl-1 -(2-diethylsmino-ethyl)-1

H

benzoimidazol-5-yl]-N-hydroxy-acrylamide 3-[ -(a-Dimethylamino-2,2-dimethyl-propyl)-2 (3,3,3-trifluoro-propyl)-1 H-benzoimidazol-5-yl]-N hydroxy-acrylemide 3-[1-(2-Diethylamino-ethyl)-2-(3,3,3-trifluoro propyl)-l H-benzolmidazol-5-yl-N-hydroxy acrylamide Hi Q 3-[l-(2-Diethylamino-ethyl)-2-thoxymethyl-1

H

benzoimidazol-5-yl]-N-hydroxy-acrylamide 3-[l-(3-Dimethylamino-2,2-dimethyl-propy)-2 methyl-I H-benzoimidazol-5-y]-N-hydroxy acrylamide 3-[1.(2-Diethylamino-ethyl)-2-(2,2-dimethyl e% propyl)-1 H-benzoimidazol-5-y]-N-hydroxy acrylamide * " N-Hydroxy-3-[I-(3-isopropylamino-propyl)-2 (3,3,3-trifluoro-propyl)-I H-benzoimidazol-5-y] \ /acrylamide Y.*MtKIW DEMRWIOtpoCS AU I..d hUmi~uisl a.4%s 34 3-(2-(2,2-Dimethyl-propyl)-1 -(2-isopropylamino ethyl )-1 H-benzoimldazol-5-y]-N-hydroxy I acrylamide /~NN 3-[1 -(2-Diieopropyamino-ethyl)-2-(Z,2-dimethyI. propyl)-l H-benzolmidazol-5-yl-N-hydroxy acrylamide / N 3-[1 -(2-Diisopropylamino-ethy-2-iSObUty-1 H. A benzoirnidazol-5-yJ-N-hydroxy-acrylamidG / ~ N 3-[1 .(3.Dimethylemino-2.2.drnethyl-propy)-2 hex-3-enyl-1 H-benzoimidazol-5-yI]-N-hydroxy acrylarnide 63-[l -(3-Dimethylamino-2,2-dimtthyl-propyl)-2" A (2,4,4-trimethyl-perityl)-1 H-benzoimidazol-5-yfl N-hydroxy-acrylamide 3-[2-Cyclohexyl-l -(3-dimethylamino-2,2 Idimethyl-propylyl)-l eziiaol5y] hydroxy-ecrylamide 3-[2-Blcydo[2.2. 1]hept-5-en-2-yl-1 -(3 /~ NNdimethylamnilno-2,2-d imethyl-propyl)-1 H benzoimidazol-6-yIJ-N-hydroxy-acrylamide 3-fl (2-Diethyl2lhifo-thyI>-2-hex-3Sflyl

H

benzoimidezo-5-yl-N-hydroxy-acrylanidG 35 3-fl -(2-Diisopropylamino-sthyl)-2-hex-3-enyt-l H / I benzomidazol-5-yIJ-N-hydroxy-Gcrylaride / N 3-[2-Hex-3-enyl-1 .(2-isopropylamno-ethyl)-1 H. A benzoimidazol-5-yl-N-hydroxy-GcryIamlde 3-[2-I-ix-3-enyl-1 -(3-isopropylmno-propyl)-1 H benzomidazol-5-yI]-N-hydroxy-Bcrylamide 3-[l -(2-Ethylamino-ethyl)-2-hox-3-eny-1 H bsnzoLmidazol-5-yU]-N-hydroxyacaylamide 3-fl -(2-Diethylamirio-othyl)-2-hexyl-1

H

/ A berizoimidszol-5-y].N-hydroxy-acrylamldQ N-Hydroxyf-3-[l -(3-isa propylamino-propyl)-2 / N < (2,4,4-trimothyl-pentyl)-l H-benzoimidazo-5-yl] A acrylamide 3-[2-(2,2-Dimsthyl-propyl)-1 -(3-isopropylamino N N propyl)-l H-benzomidazol-5-yI]-N-hydroxy.

acrylamide 3-fl -(2-Diieopropylamlno-ethyl)-2-(3,3,3-tifUOro propyl)-l H-benzoimidazol-5-yI]-N-hydroxy \ / acrlamide WIMs*W NO SLUNWIaRSf AU Zemi Yl*M n~ail M kdde 36 N-Hydroxy-3-[2-isobutyl-1 -(2-isopropylamino ethyl)-1 H-benzoimidazol-5-yI]-acrylamide 3-[2-(2,2-DImethyi-propyl)-l -(2-ethylamino ethyl)-1 H-benzolmidazol-5-yl]-N-hydroxy acrylamide 3-[1-(2-Ethylamino-ethyl)-2-isobutyl-1 H benzoimidazol-5-yl]-N-hydroxy-acrylamide 3-[l-(2-Diisopropylamino-ethyl)-2-(2,4,4 trimethyl-pentyl)-l H-benzoimidazol-5-yl]-N hydroxy-acrylamide N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2 (2,4,4-trimethyl-pentyl)-l H-benzoimidazol-5-yl] acrylamide 3-[1-(2-Ethylamino-ethyl)-2-(2,4,4-trimethyl pentyl)-1 H-benzoimidazol-5-yl]-N-hydroxy H acrylamide 3-[l-(2-Diethylamino-ethyl)-2-(2,4,4-trimethyl pentyl)-1 H-benzoimidazol-5-y]-N-hydroxy acrylamide 3-[l-(2-Diethylamino-ethyl)-2-propyl-1 H benzoimidazo-5-yl]-N-hydroxy-acrylamide WM*=~~~~~~ NOEEPM5ASW POL~ ia ,oo 37 3-[2-Butyl-1 -(2-diisopropylamino-ethyl)-1 H benzoimidazol-5-y]-N-hydroxy-acrylarmide NH 3-12-Buty-1 -(2-ethylamino-othyl)-1 H benzoimidazol-5-yl]-N-hydroxy-Orylamide 3-[1-(2-Diethylamino-ethyl)-2-(2-methylsulfanyl ethyl)-1 H-benzolmidazol-5-yl]-N-hydroxy acrylamide 3-[2-Butyl-1-(2-isopropylamIno-ethyl)-1

H

benzolmidazol-5-yl]-N-hydroxy-scrylamide 3-[2-Butyl-1 -(3-isopropylamino-propyl)-1 H benzoimidazol-5-yl)-N-hydroxy-acrylamide 3-[1 -(1 -Benzyl-pIperidin-4-yI)-2-butyl-1

H

benzoimidazol-5-yll-N-hydroxy-acrylamide 3-[2-But-3-enyl-1 -(2-ethylamino-ethyl)-1

H

benzoimidazol-5-y]-N-hydroxy-acrylamide Y\MitN'IW V WOKIMEWPISMS AU Smedi hNSuiSP Flu[ui rkdA 38 3-[2-Hexyl- 1 -(2-isopropylamlno-ethyl)-1

H

/ 1 benzoimidazol-5-yI)-N-hydroxy-Scf-ylamidS 3-[I -(2-Dimethylamino-ethyl)-2-(2,4,4-trimethyl pentyl)-1 H-benzoimidazol5y)-N-hydrOXY A aorylamide 3-[i -(2-Ethylamino-ethyl)-2-hexyl-I

H

*~ I benzoimidazol-6y]-N-hydroxy-BCryIamide N-Hydroxy-3-(1 -(2-isopropylamino-ethyl)-2 .- < .~ N(3,3,3-trifluoro-propyl)-1 I--benzoimidazol-5-yI] acrylamide N 3-El -(2-Dlmethylarnino-ethyl)-2-hex-3-ely-1

H

I beflzoimid8zoI-5i]Nhydrxyaylamide 3-(l -(2-Amino-ethyl)-2-%24,4-trimethyl-pentyl) N 1 H-benzomidazol-6.yl]-N-hydroxy-CrylamidC 3-[1 -(2-Amino-ethyl).2-(2-methoxy-nony)-1

H

/ A ~ benzolmldazol-5-yI]-N-hydroxy-acrylamide N 3-[2-Butyl-I -(2-dimethytamino-Qthyl)-i H. A benzoimidazol-5-y]-N-hydroxy-lrylamide WJAU*IXINO D=LTrIPIU0a AIIScd huvliiniIal F IciEW UOAC 39 V. 3-[l -(2.Dimethylamino-etlyl)-2-hexylI- H / Ibenzoimdazol-5-yO]-N-hydroxy-acyemidS 0) N-{2-(1 -(2-Diethylamino-ethyl)-5-(2 / N N < hydroxycarbamoy-viny)-1 H-benzoimidazol-2 yIJ-ethyl-3.3-dimethyl-butyramnide YJ~4 a3-{1 -(2-DIethylamino-ethyl)-2-[2-(2.2-dimethyl N propionylamirio)-ethyl]-i H-benzoimidazol-5-yI) ~ N-hydroxy-acrylamide 3-{1 -(2-Diethyleminc-ethy)2-R(2,2-dimthy / i propionylamino)-rlothyl-1 H-benzoimidazol-5 yI)-N-hydmxy-acrlde N41l .(2-Diethylemirio-ethyl)-5-(2 A tlhydroxycarbamoy-vinyl)-1 H-berizoimidazol-2 S ylmethyl]-butyramidle 341 .(2-ethylamino-ethyl) -2-(3,3-dimethyl-butyl) I I1 H-benzoimiciazol-5-ytUeN-hydroxy-acrylamide / N3E12(3,a-DimethylbuWI>1 I-(2-Dimethylamino ethyl)-I H-benzoImidazol-5-yQ.N-hydroxy acrylamide tASWNO MLEIUJ093- AU Zemi sy*lqu Fal m iIIafl 40 3-[I-(2-Dimethylamino-ethyl)-2-pentyl-1

H

benzoimidazol-5-yl]-N-hydroxy-acrylamide CH 3-[1-(2-Dimethylamino-ethyl)-2-(2,2,2-trifluoro ethyl)-1 H-benzoimidazol-5-yI]-N-hydroxy "' acrylamide - OH N-Hydroxy-3-[1 -(5-methyl-1 H-pyrazol-3-yl)-2 (2,4,4-trimethyl-pentyl)-i H-benzoimidazol-5-y] acrylamide 3-[1-(2-Ethylamino-ethyl)-2-pentyl-1 H. / benzoimidezol-5-y]-N-hydroxy-acrylamide 3-(2-Butyl-1 -pyrrolidin-3-yl-1 H-benzoimidazol-5 yl)-N-hydroxy-acryamide 3-(2-Butyl-1 -piperidin-4-yl-1 H-benzolmidazol-5 yl)-N-hydroxy-acrylamide N-Hydroxy-3-[I-(2-isopropylamino-ethyl)-2 pentyl-1 H-benzoimidazol-5-yl]-acrylamlde N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-non-3 / Nenyl-1H-benzoimidazol-5-yl]-acrylamide YfMaiAyqfNO DELMSW1904 M Sa PiMWOeI P)lM FikddiAm 41 N-Hydroxy-3-[11-(2-methylamino-ethyl)-2-non-6 enyI-1 H-benzoimidszol-5-yI-acrylamide N 3-[24'iexyl- 1 -(2.-methylamino-ethy)-1 H / I benzai mid azol-5-y]-N-hyd roxy-acryiamlide N N N-Hydroxy-3-EI -(2-methylemino-ethyl)-2-peltyl / I I H-benzoimidazol-5-yU]-aorylamicle N-Hydroxy-3-[1 -(2.rnethylamino-thyl)-2-oCty I H-benzoimidazol-5-yI]-mcrylumide / N 3-[1-(2.Amino-Othyl)-2-octy-1 I1-benzoimlazol $ 5-yt-N-hydroxy-acrylamide Oi 3-{2-ButyI-I -[2-(isopropyl-methyl-aminc)-ethyl] / ~ I H-benzomidazl5-y)-N-hydroxy-CryIamidB N ON 3-(I -t2.(EthyI-methyI-amIno)4thy1-2-PeflWI-I H 4 benzaimidazol-5-yI)-N-hydroxy-aCrytamidea rJviu5wi NO b=fT~f9O-I5 AU SUmd Rhow3 d uPia dSO0 42 3-(2-Hexyl-1 -pyrrolidin-3-yl-1 H-benzoimidazol-5 yi)-N-hydroxy-acrylamide 3-[2-Buty-1 -(1 -methyl-pyrrolidin-3-yl)-1 H benzolmidazol-5-y]-N-hydroxy-acrylamide 3-(2-Butyl-1-piperidin-3-yl-1 H-benzoimidazol-5 yl)-N-hydroxy-acrylamide 3-(2-Hexyl-1-piperidin-3-yl-1 H-benzoimidazol-5 yI)-N-hydroxy-acrylamide o 3-(1-{2-[Ethyl-(2-methoxy-ethyl)-amino]-ethyl}-2 N OH pentyl-I H-benzoimidazol-5-yl)-N-hydroxy H acrylamide o 3-{2-Butyl-1 .[2.(ethyl-methyl-amino)-ethyl]-1 H N N'OH benzoimidazol-5-yl}-N-hydroxy-acrylamide N 0 OH N-Hydroxy-3-[1 -(1 -methyl-piperidin-3-yI)-2 N H pentyl-1 H-benzoimidazol-5-yll-acrylamide Y~MAfNKINO bZLTlffPI9SU AUS*WcdMw*gIAnaliaaUila.

43 o 3.41 -[2-(Ethyl-hexyl-amino)-ethyll-1 H N N N ' NOH benzoimidazol-5-yI)-N-hydroxy-aCryflamidQ H N o 3-fl .[2.(Ethyl-pentyl-amino)-ethy)-1 H N ' WOH bnomdzlSA--ymysrlmd K'1H benzomidazol-5-y}-N-hydroxy-ecry~lidQ N (E)-3-(2-hexyl-1 -(1 -(2-hydroxyethyl)piperidin-3 hydroxyacrylamide o 3-(2-Butyl-1 -{2-[ethyl-(3-hydroxy-propyl)-amlno] N N / iH ethyl}-1 H-benzoimidazol-5-y)-N-hyclroxy ecrylamide 3-(1 -(2-(Ethyl-(3-hydroxy-propyD)-amino]-ethyl} 2-pentyl-1 I--benzoimidazol-5-yi)-N-hydroxy acrylamide 44 (E).N-hydroxy-3-(1 -(1 -phenethylpyrrolidin-3-y) 1 H-benzo[d]imidazol-5-yl)acrylamide (E)-N-hydroxy-3-(1 -(1 -pentylpiperidin-3-yI)-1 H benzo[dlimidazol-5-yl)acrylamide 3-{1.[2-(Butyl-ethyl-amino)-ethyl-1 H benzoimidazol-5-yl)-N-hydroxy-acrylamide (E)-N-hydroxy-3-(1 -(1 -phenethylpiperidin-3-y) 1 H-benzo[d]imidazol-5-yl)acrylamide (E)-N-hydroxy-3-(I-(1-(3-phenylpropy)piperldIn 3-yl)-1 H-benzo[dlimidazol-5-yl)acrytamide (E)-N-hydroxy-3-(I-(1-(3-phenylpropyl)pyrrolidin 3-yl)-1 H-benzo[d]imidazol-5-yl)acrylamide Y1t1 NoDEI? rBflp94!iAUseenamPovhidu Pli Fldit 45 3-{1(-[-(3,3-Dimethyl-buty-pyrrolidin-3-yl]-1 H <OH benzoimidazol-5-yl}-N-hydroxy-acrylamide (E)-3-(1-(2-(diethylamino)ethyl)-I H N "" benzo[d]imidazol-5-yl)-N-hydroxyacrylamide N 3-[2-(4-Cyano-butyl)-1 -(2-diethylamino-ethyl) / H H-benzoimidazol-5-yl]-N-hydroxy-acrylamide (E)-3-(1 -(1 -butylpiperidin-3-y)-1 H H benzo[d]imidazol-5-yl)-N-hydroxyacrylamide (E)-N-hydroxy-3-(1 -(1 -(pent-4-enyl)plperidin-3 NN NH yl)-1 H-bonzo[d]imidazol-5-yl)acrylamide -IIa H 46 (E)-3-(1 -(1 -(3,3-dimethylbutyl)piperidin.4y)-1 H IN oN < K ri benzo[d]Imidazol-5-yI)-N-hydroxyflcrlamide 3-[1 -(2-Dlethylamino-ethyi)-2-propylamino-1 H -4 berizoimidazoI-5-yi]-N-hydroxy-acrylamide CH (E)-N-hydroxy-3-(1 -(2

A

TM (isopropyi(propyl)amino)ethyl)-1 H ijN s q benzo(d]imidazol-5-yI)acrylamide IIN C 3-{1 -[2-(Butyl-ieopropyl-amino)-olhy]-1 - OH <ii? 'NbenzoimidazoI-5-yI)-N-hydroxy-aorylamide N-Hydroxy-3-{1 -[2-(Qsopropyl-pontyl-amin a). <OH ethyl]-1 H-benzoidazol-6-yI}-acrylamide IN 3-[2-(5-Cyano-pentyl)-1 -(2-diethylamino-ethyl) / 1 H-benzoidazol-5-yI]-N-hydraxy-acrylamlde 47 3-(lI-(2-[(3,3-Dimethyl-butyl)-ethyl-aminoj-ethyl) 3-{I -[2-(Ethyl-propyl-amino)-ethyl j-I H m benzoimidazol-5-yI)-N-hydroxy-aorlamide II N-Hydroxy-3-(1 -{2-[isopropyl-(2-methyl-pentyl) KH' amino]-ethy§)-1 -azliao-5y)arlm (E)-N-hydroxy-3-(1-(2-(isopropyl(4,4,4 N ir trifluorobutyl)amino)ethyi)-I H-benzo[d]imldazol 5-yI)acrylmicie 3-ji -(3-Dimethylaminc-2,2-dimethyl-propyl)-2 * N-it Npropylamino-1 H-benzoimidazo-3-yJ-N-hydroxy acrylamide 48 WH 3-{11-[2-(Ethyl-hexyl-amino)-ethyl]-2-methy-1

H

21 '.~ benzoidazoI-5-yi)-N-hydroxy-acrylamide N 3--2-(Butyi-ethyl-emino)-ethyll-2 NH trifluoromethy-1 H-benzoimidazol-5-yI}-N - 694 hydroxy-acrlamide rN 3-41 -[2-(Ethyl-hexyl-amino)-ethylj-2 C trifluoromethyl-1 H-benzoimidazol-5-y)-N hydroxy-acrylamide C (E)-3-(1 -(2-(dibutylemino)ethyl)-2-prapyl-1 H 'N h'~ ~ benza[d~imidazoi-5-yI)-N-hydroxyacrylamide 341 -(2-Dipropylamino-ethyl)-1 H-benzoimidazol ~N 5-yI]-N-hydroxy-acrylamide Y.fI4XflWN DSWERBIPQ- ALI SqmS 7ftiOm-i nWi P~c1doo 49 N-Hydroxy-3-(1 -{2-[isopropyl-(3-methyl-butyl) amino]-ethyl]-1 H-benzol mldazol-5-yi)-acrylamide 3.(l1 (2.[(3,3-Dinmethyl-butyl)-methyl-amino] N. N euhy}-1 H-benzomidazo--y)-N-hycdroxy acrylamide 3-(1 -{2-[(2-Ethyl-butyl)-methyl-amino]-ethyl-1 H OH benzoimldazol-5-yl)-N-hydroxy-acrylamide (E)-3-(1 -(2-(bIs(3,3-dimethylbutyt)amino)ehyl) (E)-3-(1 -(2-(diisobutylamino)ethyl).1 H A OH berizo[d]imidazol-5-yl)-N-hydroxyacrylamide 3-41 -[2-(3,3-Dimethyl-butylamino)-ethyl]-i H 7 N' benzoimidazo-5-yI}-N-hydrox(ybacrylamide 50 N-Hydroxy-3-{l -[2-(methyl-pent-4-enyI-amino) ethyl]-1 n-Denzolmluazol-o-ylp-acrylamlue 3-(l -{2-[(3,3-Dimethyl-butyl)-propyl-amino] N N H ethyilj- H-be nzoimidazol-5-yt)-N-hyd roxy- $7 acrylamide 3-fl -(3-Dimethylamino-2,2-dimethyl-propyfl-2 <N methylsulfanyl-1 H-benzoimidazo-5-yIj-N -~ hydroxy-acrylamide 3-{1 -(2-(3,3-Dimethyl-butylamino)-ethyl]-2 / j propyl-1 H-benzolmidazol-5-yI)-N-hydroxy acrylamide 3-fl -j2-(3,3-Dimethyl-butylamirio)-ethylj-2-(2,2 NN dimothyl-propyl)-l H-benzoidazol-5-yU-N hyciroxy-acrylamide v~qurAm NO fltstflMief4 AU hueod Pnill Final as MSAo 51 3-[1 -{2-[Bis-(3,3-dimethyl-butyl)-amino]-ethyl)-2 (2,2-dimethyl-propyl)-1 H-benzoimidazol-5-y]-N hydroxy-acrylamide N 3-(1-[2-(2,2-Dimethyl-propylamino)-ethyl-1

H

OH benzolmidazol-5-yl)-N-hydroxy-acrylamide N FIN 3-(1 -{2-[(2,2-Dimethyl-propyl)-propyl-amino] ethyl)-1 H-benzoimidazol-5-yl)-N-hydroxy acrylamide 3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl N'N~ ,OH 1 H-benzoimidazol-5-yl)-N-hydroxy-acrylamide [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 5 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. 10 [0155] Administration of compounds within Formula (I) 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 YarMx IJ NO DELTBND90-05 AV 5e eld n lm i dEU ilm-me 52 compound is typically Included in a pharmaceutically acceptable carrier or diluent and 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 rapidly proliferating cells, e.g. cancerous tumors, than to normal cells. 5 [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. 1o [0157] It is anticipated that the compounds of the invention will be useful in treating various cancers including but not limited to bone cancers including Ewing's sarcoma, osteosarcoma, chondrosarcoma and the like, brain and CNS tumours including acoustic neuroma, neuroblastomas, glioma and other brain tumours, spinal cord tumours, breast cancers, colorectal cancers, advanced colorectal adenocarcinomas, 15 colon cancers, endocrine cancers including adenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid 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 20 testicular cancer, penile cancer, prostate cancer, gynecological 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, 25 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 30 Macroglobulinemia, lung cancers including small cell lung cancer, non-small cell lung cancer, lymphomas including Hodgkin's disease, non-Hodgkin'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 35 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. YaMEar1 NO DELEMK FIlGS0 AU Amd PrMto iiudi wmlAuMd 53 [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 nedk cancer, renal cancer (e.g. renal cell carcinoma), gastric cancer, colon cancer, 5 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 (e.g. Burkitt's lymphoma), leukemias (e.g. acute promyelocytic leukemia), cutaneous T-cell lymphoma (CTCL) 10 and peripheral T-cell lymphoma. [0160] Exemplary cancers that may be treated by compounds of the present invention include solid tumors and hematologic malignancies. In another embodiment, preferred cancers that may be treated the compounds of the present invention are 15 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 deecetylase (HDAC). 20 [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 25 not limited to: Proliferative disorders (e.g. 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 dyskinesis, Familial tremor, Gilles de la Tourette syndrome, Diffuse Lewy body disease, Pick's disease, Intracerebral 30 hemorrhage 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 35 degeneration, Rubeotic glaucoma, interstitial keratitis, Diabetic retinopathy, Peter's anomaly, retinal degeneration, Cellophane Retinopathy; Cogan's Dystrophy; Comeal Dystrophy; Iris Neovascularization (Rubeosis); Neovascularization of the Cornea; YWSrM Wl DINQL.7WHPICO AU RMhstla flu, l uMhtdiU 54 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 (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, 5 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 10 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 anglofibroma; Infectious diseases including Fungal infections, such as Candida Albicans, Bacterial infections, Viral Infections, such as Herpes Simplex, Protozoal infections, such as Malaria, 15 Leishmania infection, Trypanosoma brucei infection. Toxoplasmosis and coccidiosis, and Haematopoletic 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 bloavailable. One skilled in the art of preparing 20 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. 25 [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 30 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. 35 As such in a further embodiment the present invention provides a pharmaceutical composition including a compound of Formula (1) and a pharmaceutically acceptable flajtfzT McalEMnhlm0i AU SUti1 be.M II.i FS.

55 carrier, diluent or exciplent. The compositions are prepared In manners well known in the art. [0166) The invention in other embodiments provides a pharmaceutical pack or kit 5 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 (a). The kits can include a composition comprising an effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the 10 concentration of use, where the vials may Include one or more dosages. Conveniently, in the kits, single dosages can be provided in sterile vials so that the physician can employ the 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. [0167] The compounds of the invention may be used or administered in combination 20 with one or more additional drug (s) that are chemotherapeutic drugs or HDAC inhibitor drugs and/or procedures (e.g. 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 25 the other drug (s). [0168] 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 30 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 35 (0169] Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, YdW NMi NO DELMW IM AU Smind vwfiFlIa@ SkdA.

56 dispersion, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), 5 and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic 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 the case of dispersions, and by the use of surfactants. 10 [0170] These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal 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 15 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 20 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 25 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 30 at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalclum 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 35 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 uMdg/NXJ NO DELBUM 1090M0 AU Simd PfmVisi hu FiJia 57 cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and 1) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. 5 [0174] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such exciplents as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. 10 [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 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. is 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, 20 liposomes, and microspheres. [0177] The active compounds can also be in mnicroencapsulated form, if appropriate, with one or more of the above-mentioned excipients. 25 [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, 30 benzyl alcohol, 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. 35 [0179] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. VMWimrK NO DELUIN-0 AU Snud inviml ul i nflti4o 58 [0180] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar 5 agar, 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 10 suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [0182] Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments and Inhalants. The active compound is 15 mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required, [0183] The term "therapeutically effective amount" or "effective amount" Is an amount sufficient to effect beneficial or desired results. An effective amount can be 20 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 25 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 bloavailability of the preparation administered, the dose regime selected, the use of other medications and other 30 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 35 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'ThmaINo DELETS\F19P-5 AU A1Se P Fl P pini EISL dm 59 [0186] As discussed above, the compounds of the embodiments disclosed inhibit histone deacetylases. The enzymatic activity of a histone deacetylase can be measured using known methodologies [Yoshida M. et al, J. Biol. Chem., 265, 17174 (1990). J. Taunton et al, Science 1996 272: 408]. In certain embodiments, the histone 5 deacetylase inhibitor interacts with and/or reduces the activity of more than one known 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 10 belongs to Class I HDAC enzymes [De Ruijter A.J.M. et al, Biochem. J., 370, 737-749 (2003)], HDACs can also target non-histone substrates to regulate a variety of biological functions implicated In disease pathogenesis. These non-histone substrates include Hsp9O, a-tubulin, p53, NFkb and HIFia [Drummond et al., Annu. Rev. Pharmacol. Toxicol. 45:495 (2004)]. Certain preferred histone deacetylase inhibitors 15 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 20 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 25 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 neoplasia, benign prostatic hyperplasia, papillomas of 30 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 and/or immune system disorders. 35 (0187] In one embodiment the disorder is selected from the group consisting of cancer, inflammatory diseases and/or immune system disorders (e.g. rheumatoid Y;YWJ4IUO 140 "M0 AmLreoo Am hsn tuWocliz IhuArAdi 60 arthritis, systemic lupus erythematosus), angiofibroma, cardiovascular diseases, fibrotic diseases, diabetes, autoimmune diseases, chronic and acute neurodegenerative disease like Huntington's disease, Parkinson's disease, disruptions of nerval tissue and Infectious diseases like fungal, bacterial and viral infections. In another embodiment 5 the disorder is a proliferative disorder. [0188] The histone deacetylase inhibitors of the invention have significant antiproliferative effects and promote differentiation, cell cycle arrest in the G1 or 02 phase, and induce apoptosis. 10 SYNTHESIS OF DEACETYLASE INHIBITORS [0189] The agents of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available, The preparation of 15 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 20 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 "d Edition, John Wiley & Sons, 1999. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for 25 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, 30 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 35 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 YA*Mr1 NO DILEtPIM.0 AU 6cew P .rhsie ial .fldE bottles and used as received. All solvents were purified by using standard methods In the art, unless otherwise indicated. [0193] The reactions set forth below were performed under a positive pressure of 5 nitrogen, argon or with a drying tube, at ambient temperature (unless otherwise stated), 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 10 (vlv). The reactions were assayed by TLC and terminated as judged by the consumption of starting material. [0194] The TLC plates were visualized by UV absorption or with a p-anisaldehyde spray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20wt% in ethanol) 15 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 20 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. 25 [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 CDCl 3 solutions (reported In ppm), using chloroform as the reference standard (7.26 ppm and 77.14 ppm) or CD 3 OD (3.3 and 49.3 ppm), or DMSO-da (2.50 30 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. 35 10196] Mass spectra were obtained using LC/MS either in ESI or APCI. All melting points are uncorrected. Y;WrMKINOD LETlO .SAUmd PmvisiaFinia MPiIS*4 62 [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 3.5 m 4.6 x 20mm IS column; 2.0 ml/min, gradient 5-65% B over 4 min, then 85-95%b 5 over 1 min and 95%B for additional 0.1 min; Solvent A: H 2 0 with 0.1% TFA; Solvent B: acetonitrile with 0.1% TFA. [0108] The following examples are intended to illustrate the embodiments disclosed and are not to be construed as being limitations thereto. Additional compounds, other 10 than those described below, may be prepared using the following described reaction scheme or appropriate variations or modifications thereof. SYNTHESIS [0199] Scheme I and il illustrates the procedure used for preparing compounds of 15 formula lb, 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 lb, such compound(s) can be synthesized by analogous method illustrated in Scheme I and I starting with a substituted cinnamic acid (e.g. trans-3-nitro-4-chloro 20 cinnamic acid), appropriate amine component (R'NH 2 ), carboxylic acid component

(R

2 CO2H, Scheme 1) or aldehyde (R'CHO, Scheme 1l), and appropriate hydroxylamine or N-alkyl hydroxylamine (NHR 3 OH where RI is defined as above in Formula la), [0200] Specifically, the hydroxamate compounds Formula lb can be synthesized by 25 the synthetic route shown in Scheme 1. The reaction of trans-4-chloro-3-nitrocinnamic acid (1) with an amine R 1

NH

2 in the present of a base (e.g. triethylamine) in an appropriate solvent (e.g. dioxane) gave (II), Treatment of (11) in methanol under acid catalysis (e.g. sulfuric acid) resulted in esterification providing (1i). Alternatively, the carboxylic acid (I) may be esterified to the methyl ester (Ia) and then the chloride was 30 replaced by the appropriate amine component R'NH 2 to give compound (111). The nitro group of (Ill) can be reduced by appropriate reducing agent (e.g. tin (li) chloride) and the resulting phenylenediamine (lV) was coupled with an acid R 2 C0 2 H to give amide (V) which was subsequently cyclized in an appropriate solvent (e.g. acetic acid) to give benzimidazole (VI) (J. Med. Chem. 2001, 44, 1516-1529). The hydroxamate 35 compounds (VI) were obtained from methyl ester (VI) by a known synthesis method (J. Med. Chem., 2002, 45, 753-757). Y;\MW NKNQVDCLEFJPIUU 5 AU mad Pid lludFlu l .filedsdoE 63 Scheme I 0N0

R

1

NH-

2 0 0 2 OH Base 0 2 N OH MeOHO 2 N N CII dioxane RN) H2~SR4 N II H ||H MeOM 0 2 N O 2 H+ Base la dioxine 0 SnC 2 , H2N O' R 2

CO

2 H AcOH/MeOH R'N coupling reagent H I o NH 2 0 R O and/or NO NH N N RO N 0 0 q- R 2 -N- NH 2 OH.HCI H2 NH N NaOCH 3 N VI R1 V1 [0201] Alternatively, as depicted in Scheme 11, compound (VI) was prepared by 5 reacting with an appropriate aldehyde component R 2 CHO in the presence of a reducing agent of nitro group (e.g. tin (11) 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. 10 Scheme 11

R

2 CHO 0 O SnC1 2 or Zn NR2 . 0- AcOH/MeOH N H Ill

HCO

2 H, SnC1 2 VI (R2 = H) MeOH [0202] In both Schemes I & II, the benzimidazole ring may be constructed by a cyclization step Invoiving either an aldehyde or a carboxylic acid. The following 15 reaction steps 1-4 refer to the use of carboxylic acid for the cyclization of (IV) via (V) to form benzlmldazole derivatives (VI), followed by the conversion of ester (VI) to the YMMWUM M DmslbVPNUM~o A fAt h..fr iinl f l id-f 64 hydroxamate (Vii). For one-pot cycylization of (I1) to (VI), see the procedures under Example 1. Step 1: Reduction of nitro group [0203] To a pre-stirred solution of starting material (111, 1.0 mmol) in 50 mL of co s solvent (glacial acetic acid: methanol= 2:8), Tin chloride was added (5.0 mmol). The resulting solution was heated to 550C 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 10 (15 mL) once and further dried over Na 2

SO

4 for 1 hour. It was filtered and concentrated; the diamino product (IV) was purified by flash chromatography. Step 2: Amide formation [0204] To a pre-stirred solution of carboxylic acid (1.1 mmol), diamino product (IV, 1.0 mmol) and PyBOP (1.1 mmol) in 10 mL of dried dichloromethane, was added DIEA 15 (3.0 mmol) via a syringe. The resulting mixture was stirred at room temperature for 4 hours. The amide product (V) was purified by silica gel column chromatography. Step 3: Cyclization [0205] The amide product (V), obtained in Step 2, was treated with 5 mL of glacial acetic acid, the resulting solution was heated to 75*C for 24 hours. After cooling down 20 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 NH20H9HCI (10 equiv.) in MeOH (0.5 M) was added NaOMe solution (20 equiv.) at - 78 *C, The reaction mixture was then allowed to warm up slowly to room temperature. The reaction was monitored by LC/MS 25 and was completed in around 15-60 min. 1N HCI was then added slowly into the reaction mixture at 0 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 40-70%). 30 [0207] Scheme Ill Illustrates another alternative procedure used for preparing compounds of formula lb, where X and Y are hydrogens and R 2 is selected from the group R"S(O)R 3 -, R 1 8(O) 2 R"-, R 1

C(O)N(R'

1

)R

8 -, R 1 S0 2

N(R

12

)R

13 -,

R"N(R

1

)C(O)R

1 -, R1'N(R"n)SO 2 Ra-, R"N(R 1 2

)C(O)N(R'

2 )R"- and heteroalkyl. For 35 example, in the case of Z Is -CH=CH- and attached to Crposition In Formula lb, such compound(s) (Xiii) can be synthesized by analogous method illustrated in Schemes I & NOWM MLDltP1W&C AU 5u147.withoSPA iJ& U 144 65 starting with appropriate (Ill), appropriate Fmoc protected amino acids, appropriate acid chlorides or aldehydes, and hydroxylamine. Scheme III 0 0 0Mm SnC02/C* H 2 N OMe Rt-N I-- MeOH HN H III

R

1 IV H Fmoo--HN 0 Fmoc--N O N N H2N OMe) PyBOP/DIEA/DCM Omt - H, Fmoc-HJn R'I

R

1 Vill MeOH/H 0

H

2 N OMe 20% Plperidine N OMe R1 2 -CHO NnBH(OAch R12COCI [or R' 2

-SO

2 CI] CHC00H Triethyl amine NN OMe / F R2

R

2 XIV

[R

1 2 -02-]

NH

2 OH.HCI NH2QH.HC NaOMe 0 N N NH NKN H N R n O R1 R1 XV [R1'SO 2 Sn=l, 2 n1, 2 [0208] More specifically, for example, the hydroxamate compounds Formula lb, where X and Y are hydrogens, R 2 is selected from the group R"S(O)R 13 -, R 1

S(O)

2 R"3

R"C(O)N(R

2

)R

3 -. R' 1 S0 2

N(R

12

)R

3 -, R"N(R')C(O)R"-, RN(R1 2

)SO

2

R

13 -, 10 R"N(R 12

)C(O)N(R

2

)R

13 . and heteroalkyl; and Z is attached to Cs-position, can be synthesized by the synthetic route shown in Scheme Ill. Appropriate Intermediate (Ill) was reduced with tin chloride to the corresponding diamines (IV). The coupling reaction with appropriate Fmoc protected amino acids in the presence of PyBOP gave coupling product(s) (Vill) and/or (IX). Without further separation, (VIII) and/or (IX) were 15 subjected to cyclization under acid conditions and yielded benzimdiazole (X). The key intermediate (XI) can be obtained by treating (X) with 20% piperidine. Treatment of (XI) 66 with an appropriate acid chloride or an appropriate sulfonyl chloride gave (XII) and the target compounds (Xlii) were obtained by using similar method described in Scheme I. [0209] When (XI) was reacted with an appropriate aldehyde under reduction 5 conditions (NaBH(OAc)s /CH 3

CO

2 H), (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' side chain. If the R' side chain contained a protecting group such as Boc in compound (Vial), it could be io removed before converting to the final hydroxamic acid (Vila). The intermediate (Vla) could be modified by acylation, reductive alkylation, alkylation or sulfonylation to form new analogs (ViIb, Vile, Vild and Vile) through new intermediates (Vib, Vic, Vid and Vie). The above described methods were also applied to R 1 = heterocycles, e.g., R= N-Boc-piperidin.3-yl, N-Boc-piperidin-4-yl and N-Boc-pyrrolidin-3-yl. 15 YWUA NOU l~flK9 IETW *0 AU 1e4allrnvjsiIa FUinS prieilli 67 Scheme IV N N0M 0 N0' R OMe - b R 2 -(' 0M8 NHZOH.HCI R N ~~ N R 2 -IIH vi51 NaOCH 3 IND- O BOdtRt H R11 HN 0 R1CO 2 H or R- I NH 2 OH.HCI ROH

RR

12 C0)0 N , H Vib NaOCH 3 5VIb R2 v1N111R HN'R R O2 R R2-<, O e NH2H.H-CI N2 OH K 12 Reductive Vie NaOCH 3 amintion R 1 2 Vil RRI- R NR1 0 NT N. A d i 0 N N N NOH RlZX NNH 2 OH.I-II N'I 5 VId NaC (X halide) Vild NN<0M N NNOH NR2 NH 2 OH.HCI RNI NN

R

1 2 50 2 01 53 VI. NeOCH, 0 V1111 R12-gNR1 I0~Nh 6 0 s [0211] Scheme V illustrates some alternative method to prepared (Via) and (Vic). The primary amine (111a2) was prepared either from (Ia) or via (111.1l). The derivertization of the amino group (e.g., reductive amination) could be performed either from (111a2) or (V1a2). The products, i.e., (111a2-1) and (VIa2-1), could be further derivertized (e~g., reductive amination of the secondary amine). YAUuYIMzNO D3LETS7PIDMO AULmW Pmuad huois wun PaikA# 68 Scheme V o H 2 N,.-- NBen O 2 N 02N 0 C~J IHCJH NHBoc H Ua2 NH2 H2N,. "NH2 02N R 0H R0 RCH H ma2 Va2 reductive aminatlon Vl2 H2N R12O HN reducve arination 2CHO or HC02 R12 02N 2 SC2 o r 2n 11h 2 ia2 -O RVial2.

R~

2 OI40 HN 12

R

12 VI2 R NH RlN 1 *2N ., 12 [0212] The following preparations and examples are given to enable those skilled in the 5 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 IlIl 10 [0213] Compound (1ll) was prepared either from (I) via (II) or from (1) via (la) (Scheme I and V). The following are examples of (1ll). Intermediate I 3-[4-(2-Dimethylamino-ethylamino).3.nitro-phenyl]-acrylic acid methyl ester iS [0214] A mixture of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (Ia, 0.658 g, 2.72 mmol), N,N-dimethylethylenedlamine (0.90 mL, 8.20 mmol) and triethylamine (1.2 ml., 8.6 mmol) In dioxane (20 mL) was heated at 80*C 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 20 red solid was filtered to give the titled compound (0.672 g, 84.2%). HPLC purity at 254 nm: 99.2%, tR = 1.59 min. LCMS (ESI) r/z: 294 ([M + H]'). 'H NMR (CDCl 3 + CD 3 OD) 8 8.21 (1H, d, J = 2.1 Hz), 7.55 (IH, dd, J = 9.0, 2.1 Hz), 7.48 (1H, d, J = 16.0 Hz), 6.81 (IH, d, J = 9.0 Hz), 6.20 (1H, d, J = 15.9 Hz), 3.70 (3H, s), 3.34 (2H, t, J = 6.5 Hz), 2.56 YnMdmytIdNO DmATEWOrD.M NJ ewd havtinuIlinaul as d.a 1 69 (21-, t, J 6.4 Hz), 2.23 (6H, s); "C NMR (CDC1 3 + CD3OD) 8 167.3, 145.4, 142.6, S 134.0, 1311, 127.1,121.3, 114.8, 114.0, 56.7, 51.1, 44.6, 40.1. Int Drmedi t. 2 3-[4I2-Di hylamino-ethylamino)3-nitro-phenyl]-acrylic acid methyl ester. [0215] Y fdow solid. LCMS (ESI) m/z: 322 ([M + H]'). 'H NMR (CDCla) 8 8.73 (1H, t lik4, J = 4.1 Hz), 8.32 (1H, d, J = 2.0 Hz), 7.62 (1H, dd, J = 9.2, 2.0 Hi), 7.58 (1H, d, J = 15.9 Hz) 6.85 (1H, d, J = 9.0 Hz), 6.29 (1H, d. J = 16.9 Hz), 3.80 (3H, s), 3.35 (2H, td, J = 5.4,!6.0 Hz), 2.77 (2H, t, J = 6.2 Hz), 2,59 (4H, q, J = 7.1 Hz), 1.07 (SH1, t, J = 7.1 10 Hzf. Int rmedite 3 3-[f-(2-Et ylamino-ethylamino).3-nitro-phenyl]-acrylic acid methyl ester [O16] R ed solid. LCMS (ESI) m/z: 294 ((M + H]*). 'H NMR (DMSO-de) 85.49 (IH, t, 15 J 6,1 H4, 8.35 (1H, d, J = 2.0 Hz), 7.96 (1H, dd, J = 9.1, 1.9 Hz), 7.62 (1H, d, J= 160 Hz), .20 (1H, d, J = 9.1 Hz), 6.52 (1H, d, J = 16.0 Hz), 3.75 (2H, td, J = 6.5, 6.2 Hz, 3.70 (H, s), 3.08 (2H, t, J 6.5 Hz), 2.93 (4H, q, J = 7.2 Hz), 1.17 (OH, t, J 7.2 Hz. . 20 I rmedlte 4 3-[i-(2-ls9oropylamino-ethylamino).3-nitro-phenyl]-acrylic acid methyl ester [0217] R d solid, LCMS (ESI) m/z: 308 ([M + H]). 1 H NMR (DMSO-d) 8 8.58 (IH, t, J 5.6 H4, 8.33 (1H, d, J =2.0 Hz). 7.94 (IH, dd, J =9.1, 1.9 Hz), 7.60 (IH, d, J = 16k Hz), t.14 (1H, d, J = 9.2 Hz), 6.49 (1H, d, J = 16.0 Hz), 3.70 (3H, s), 3.56 (2H, 25 masked b4 water peak, identified by COSY), 3.10 (1H, septet, J = 6.4 Hz), 2.94 (2H, t, J 4 6.2 Hz', 1.10 (6H, d, J = 6.4 Hz). Int rmd4te 5 3-f-(3-DirIsethylamino-2,2-dimethyl-propylamino)-3-nitro-phenyl] -acrylic acid 30 m hyl es er. [0T 8] R d solid. LCMS (ESI) m/z: 336 ([M + H]'). 'H NMR (CDClb) 8 9.73 (1 H, br s or), 8.33 1H, d, J = 2.0 Hz), 7.60 (1H, dd, J = 8.9, 2.0 Hz), 7.59 (1H, d, J = 16.1 Hz), 5.E8 (1H, , J = 9.1 Hz), 6.28 (1H, d, J = 15.9 Hz), 3.80 (3H, a), 3.21 (2H, d, J = 4.6 Hz , 2.36 (PH, s), 2.34 (OH, s), 1.04 (6H, s). 35 int rmediite 6 3-[ 1-(2-Dilsopropylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester Y "4W OPt..IS AV a9COU Pa4"M0 SUSI - rdU 70 (0219] Yellow solid. LCMS (ESI) m/z: 350 ([M + H]*). 1 H NMR (CDCs) 5 8.76 (iH, t 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 (1N, d, J = 15.9 Hz), 3.79 (3H, s), 3.31 (2H, 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, 5 J = 6.6 Hz). Intermediate 7 3 -[4-(2-Methylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester [0220] Red solid. LCMS (ESI) mlz: 280 ([M + H]*). 'H NMR (CDC 3 ) 8 8.54 (IH, t-lIke, 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, s). 3.45 (2H, td, J = 5.8, 5.6 Hz), 2.96 (2H, t, J = 6.2 Hz), 2.50 (3H, s). Intermediate 8 15 3.( 4

-(

2 -tert-Butoxycarbonylamino-ethylamino)-3-nitro-phenyl] -acrylic acid methyl ester (llal) Stop 1 [0221] A suspension of trans-4-chloro-3-nitrocinnamic acid (I, 5.057 g, 22.22 mmol) in MeOH (40 mL) and DCM (20 mL) was stirred and cooled in a dry-ice/acetone bath. 20 SOC1 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 *C till the reaction completed. The solution was evaporated to dryness to a pale yellow solid (5.364 g, 99.9%). HPLC purity at 254 nm: 99.5%; tp = 2.96 min. LCMS (ESI) m/z: 210 and 212 (very weak signal, [M+H-MeOH]*), 25 Step 2: (0222] A mixture of 3-(4-chloro-3-nitro-pheny)-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 0 C for about 80 h. The solution was 30 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 (Illal) 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: 368 ([M + H]'), 310 (M+H-56), 266 (M+H-Boc). 'H NMR (CDC) 8 8.41 (1H, br t like, NHAr), 8.31 (1H, 35 d, J = 1.8 Hz), 7.63 (1H, dd, J = 9.0,1.7 Hz), 7.57 (1, d, J = 16.0 Hz), 6.98 (IH, d, J = 8.9 Hz), 6.30 (1H, d, J = 15.9 Hz), 3.80 (3H, s), 3.52 (2H, m), 3,45 (2H, m), 1.45 (9H, V:%M NO PRZTEWIO id -W Ii PW .2 W idw c 71 S); ' 3 C NMN (CDC 3 ) 8 166.9, 155.7, 145.8, 142.3, 134.1, 131.5, 127.1, 121.8, 115.4, 113.9, 79.5, 512, 42.7,39.1, 27.9. Intermediate 9 5 3-[4-(2-Arrno-ethylamino)-3-nitro-pheny]-acrylic acid methyl ester (11a2) [0223] Method 1: Remove Bbc protecting group from (Illal) under acidic condition: 1) HCI/MeOH; 2) TFADCM. [0224] Method 2: 10 To the ester (la, 2.47 g, 10.2 mmol) in dioxane (102 mL, 0.1 M) was added ethylenediamine (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 lla2 tR = 1.6 min, starting material 1a tR = 3-1 min). Upon completion, 15 solvent was removed and the crude was dissolved in DCM. The solution was washed with water brine, dried over Na 2 SO4 and filtered. The filtrate after removal of the solvent gave the titled compound lla2. Yield = 98 %, LCMS m/z: 266 ([M+H]*). Example I 20 Preparatlan of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl).2.(2,2-dimethyl propyl)-1H-benzolmldazol-5-yl]-N-hydroxy-acrylamide (1) [0225] the titled compound (1) was prepared according to Scheme 1 and II, by using appropriate starting materials, Step 1: 25 [0226] To a pre-stirred solution of trans-4-chloro-3-nitrocinnamic acid (1, 11g, 48 mmol) in dioxane (200 mL) was added triethylamine (20 mL, 126 mmol), followed by 3 dirnethylantino-2,2-dimethyl-propylamine (20 mL, 143 mmol). The reaction mixture was allowed to stir at 100 "C for 1-2 days till all starting material was fully converted. Then, the solvent was removed under vacuum followed by the addition of H 2 0 (250 mL) to 30 dissolve the residue. Conc. HCI was added till pH m 1 with orange precipitation. The suspension was filtered and residue was washed with H 2 0 several times to obtain (II) as orange bolid (13 g, 84%). LCMS (ESI) m/z; 322 ([M+H]*). Step 2: [0227] Cbmpound (11,13 g, 40.5 mmol) was dissolved in MeOH (250 mL) followed by 35 the additioA of conc. H 2

SO

4 (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 residue. Na 2

CO

3 was added till pH o 8-9, subsequently, MeOH was added and Y yWUyKIUN DEEW ,.I0 AUSudinevi.i M a uihd 72 stirred for 1 hour. Then, the suspension was filtered under vacuo and the residue was washed with H2O several times to obtain ester (lli) as orange solid (10 g, 74%). LCMS (ESI) m/z: 336 ([M+H]*). Step 3: 5 [0228] To a stirred solution of ester (Ill, 1 equiv) and SnC 2 *2H 2 O (5 equiv) in AcOH and MeOH (0.2 M, 1:9 mixture) was added 3,3-dimethyl butyraldehyde (1.5 equiv). The resulting mixture was heated to 45 *C with stining. The progress of the reaction was monitor by LC/MS. When the reaction was completed, solvent was removed under reduced pressure at 30-350C. To the resulting residue, 20 mL of water and 20 mL of 10 ethyl acetate were added at room temperature, the pH value of the mixture was carefully adjusted to 9-10 by addition of conc. NI-lseH 2 0. The mixture was stirred for half an hour, followed by centrifuge if necessary to separate the organic layer. The organic layer was collected. The aqueous phase and residue (oily-solid precipitate) were extracted another 3 times more with ethyl acetate as described above. The 15 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 ([M+H]*). 20 Step 4: [0229] To a stirred solution of ester (VI) and NH 2 OH.HCI (10 equiv.) in MeOH (0.5M) was added NaOMe (20 equiv.) at - 78 *C. 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 25 0 0C. 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 - 70%). HPLC purity at 254 nm: 100%, tR Z 0.78 min. LCMS (ESI) m/z: 387 ([M+H]'). 'H NMR (DMSO-de) 8 0.99 (15H, s), 2,91 (6H, a), 2.92 (2H, s), 3.32 (2H, bs), 4.30 (2H, s), 6.49 (1H, d, J = 15.8 Hz), 7.56 (1H, d, J = 9.0 Hz), 30 7.61 (1H, d, J a 15.76 Hz), 7.83 (1H, d, J = 9.0 Hz), 7.85 (1H, e), 9.22 (1H, be), 10.72 (1H, bs); 13C NMR (DMSO-d 6 ) 8 162.6, 154.2, 138.0, 135.3 (br), 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. YsankINObLT Mb O4 AU lead fvieimauI uas Neds 73 Example 2 Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)2-isopropyl-1 H. benzolmidazol-5.yl]-N-hydroxy-acrylamide (2) [0230] The titled compound (2) was prepared according to the procedures described 5 in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100%, ta = 0.54 min. LCMS (ESI) m/z; 359 ([M+H]'). 'H NMR (DMSO-de) 5 1.05 (6H, s), 1.40 (6H, d, J = 6.36 Hz), 2.92 (6H, s), 3.36 (2H, s), 3.58 (1H, m, J = 6.4 Hz), 4.44 (2H, s), 6.56 (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, s), 9.71 (1H, bs), 10.80 (1H, bs). 10 Example 3 Preparation of 3-[2-Butyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H benzoimidazol-5-yl]-N-hydroxy-acrylamide (3) [0231] The titled compound (3) was prepared according to the procedures described 15 in Example 1, by using appropriate starting materials. YIeld: 74 mg as TFA salt. HPLC purity at 254 nm: 99.0%, tA = 0.89 min. LCMS (ESI) m/z: 373 ([M + H]*). 'H NMR (CD00D) 8 7.99 (1H, d, J = 8.8 Hz), 7.84 (1H, a), 7.72 (1H, d, J a 8,7 Hz), 7,55 (1H, d, J = 15.8 Hz), 6.53 (1H, d, J = 15.7 Hz), 4.55 (2H, s), 3.43 (211, s), 3.24 (2H, overlapped with CD2HOD), 3.00 (6H, s), 1.90 (2H, pentet, J = 7.2 Hz), 1.49 (2H, m), 1.21 (6H, s), 20 0.98 (3H, t, J = 7.3 Hz); '3C NMR (CD 3 0D) 8 165.5 (br), 158.2, 139.8, 135.3, 135.1, 132.4, 126.4, 120.6 (br), 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 25 Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2-methylsulfanyl Sthyl)-1 H-benzolmidazol-5-yl]-N-hydroxy-acrylamide (4) [0232] The titled compound (4) 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 ([M + H]*). 'H NMR 30 (C 3 0D) 8 8.02 (1H, d, J = 8.3 Hz), 7.92 (1H, s), 7.80 (1H, d, J = 8.7 Hz), 7.69 (1H, d, J = 16.8 Hz), 6.60 (1H, d, J = 15.8 Hz), 4.49 (2H, s), 3.50 (2H, t, J = 7.2 Hz), 3.37 (2H, s), 3.03 (2H, t, J = 7.2 Hz), 2.95 (611, a), 2.18 (3H, s), 1.25 (OH, s); " 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. 35 M%.,iKIU NO MM1P99.CS AD&=md ~ t Fh l'Ju -Ld 74 Ex mple4 Pr paratl4n of 3-1.(3-Dimethylamino-2,2-dlmethyl-propyl).2.isobutyl-1

H

be izoimi4azol-5-yl]-N-hydroxy-acrylamide (6) [0'l 33] the titled compound (6) was prepared according to the procedures described 5 in Ixamplg 1, by using appropriate starting materials. HPLC purity at 254 nm: 96.2%, tR = (.82 mini. LCMS (ESI) m/z; 373 ([M+H]*). 'H NMR (DMSO-de): 8 10.80 (1H, s), 9.47 (11 , s), 7.43 (1 H, s), 7.90 (1 H, d, J = 6.6 Hz), 7,64 (1 H, d, J = 7.4 Hz), 7.62 (1H, d, J , 15, > Hz), d.54 (IH, d, J= 15.8 Hz), 4,39 (2H, s), 3.33 (2H, s), 2.97 (2H, d, J= 7.26 Hz), 2.G (6H, 0), 2.35 (1H, qn), 1.09 (6H, s), 0.97 (6H, d, J = 6.6 Hz). 10 Ex ample Pr paratkon of 3-[1-(2-Diethylamino-ethyl)-2-Isobuty-1 H-benzolmidazol-5-yl]-N h roxy-arylamide (7) [0 4] the titled compound (7) was prepared according to the procedures described 15 in xampid 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.0%, tR S.56 mir, LCMS (ESI) m/z: 359 ([M+H]*). 'H NMR (DMSO-da): 8 10.81 (1H, s), 10.13 (1 ,s), 7.00 (1H, s), 7.81 (1H, d, J= 8.5 Hz), 7.66 (1H, d, J= 8.6 Hz), 7.61 (1H, d, J= 15, Hz), 0.53 (1H, d, J= 15,8 Hz), 4,72 (21-, t, J= 7.8 Hz), 3.30 (2H, d), 2.93 (2H, d, J .2 Hz), :2.27 (11-, in), 1.24 (6H, t, J = 7.2 Hz), 0.97 (OH, d, J = 6.6 Hz) '3C NMR 20 (DSO-de) & 162.7, 158.5, 158.2, 155.2, 138.4, 133.9, 131.0, 123.0, 118.6, 116.0, 11 .8, 48.4, 46.8, 34.1, 27.1, 22.2, 8.5. Ex mple" P paratlCn of 3-[2-Butyl-1-(2-dlethylamino-ethyl)-1 H.bnzoimidazol-5-y]-N 25 hy roxy-abrylamide (8) [0 5] The titled compound (8) was prepared according to the procedures described In xample 1, by using appropriate starting materials. Yield: 61 mg (20% in two steps) as FA sat. HPLC purity at 254 nm: 98.1%, tR = 0.59 min. LCMS (ESI) m/z: 359 ([M + H] -. 'H NOR (CDOD) 8 7.89 (1H, d, J = 8.6 Hz), 7.80 (1H, s), 7.71 (1H, d, J = 8.5 Hz), 30 7.45 (1H, 4, J = 15.7 Hz), 6.44 (1H, d, J = 15.7 Hz), 4.90 (2H, overlapped with DHO, Ide tified b' COSY), 3.64 (2H, t-llke, J,= 7.0 Hz), 3.39 (4H, q, J = 7.6 Hz), 3.21 (2H, t, J .9 Hz), -1.89 (2H, pentet, J = 7.5 Hz), 1.52 (2H, m), 1.35 (8N, t, J = 7.2 Hz), 1.00 (31 , t, J a 7.3 Hz); ' 3 C NMR (CD 3 OD) 6 163.6, 155.7, 138.1, 132.8, 132.1, 131,9, 12 .6, 1180, 113.2, 111.7,48.3, 46.8 (2C), 38.6, 27.5, 24.7, 21.4, 12.0, 7.0 (20) 35 YA~ 1KIN DEfltTf PPI00. AUSSu hemisinal Final as FUdf 75 Example 8 Preparation of 3-[2-But-3-ynyl-1 -(3-dimethylamino-2,2-dimethyl-propyl)-1

H

benzoimidazol-5-yI]-N-hydroxy-acrylamide (9) [0236] The titled compound (9) was prepared according to the procedures described 5 in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98.3 %: tR = 0.52 min; LCMS (ESI) m/z: 369 ([M +H]'). 'H NMR (DMSO-d) 5 9.49 (bra, 1H), 7.88 - 7.85 (m, 2H), 7.63 - 7.59 (m, 2H), 6.52 (d, J = 15.79 Hz, I H), 4.37 (s, I H), 3.33 (s, 2H), 3,26 (t, J = 7.24 Hz, 2H), 2.92 (e, 6H), 2.88 (t, J = 2,54 Hz, IH), 2.81 (dt, J = 2.40, 7.70 Hz, 2H), 1.09 (s, 6H); " NMR (DMSO-da) 6 162.8, 155.3, 138.4, 138.0, 10 138.9, 130.5, 122.3, 118.4, 117.8, 116.4, 114.9, 112.9, 111.9, 82.8, 72.3, 66.9, 50.9, 46.7, 25.8, 22.8, 16.2. Example 9 Preparation of 3-[2-But-3-enyl-1 -(3-dimethylamino-2,2-dimethyl-propyl)-1

H

15 benzoimidazol-5-yI]-N-hydroxy-acrylamide (10) [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 ([M + H]*). 'H NMR (CDsOD) 8 7.95 (d, J = 8.8 Hz, 1 H), 7.85 (s, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.63 (d, J = 15.8 Hz, I H), 6.54 20 (d, J : 15.8 Hz, I H), 5.94 - 5.84 (m, 1H), 5.10 (dd, J = 1.4, 17.1 Hz, IH), 5.03 (dd, J = 1.1, 10.2 Hz, IH), 4.51 (s, 2H), 3.40 (s, 2H), 3.32 (t, J= 7.6 Hz, 2H), 2.99 (s, 6H), 2.66 (q, J = 7.5 Hz, 2H), 1.19 (s, 6H): "C NMR (CD 3 OD) 8 165.7, 157.6, 140.2, 136.3, 135.9, 134.7, 134.5, 125.9, 120.2, 117.9, 116.2, 103.6, 68.8, 53.4, 39.6, 32.0, 27.2, 23.7. 25 Example 10 Preparation of 3-[2-But-3-enyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-y]N hydroxy-acrylamide (11) [0238] The titled compound (11) was prepared according to the procedures 30 described In Example 1, by using appropriate starting materials. HPLC: 99.4 %; tR = 0.52 min; LCMS (ESI) m/z: 357 ([M+H]*1). 'H NMR (CDD0 0 ) 8 7.94 (d, J = 8.7 Hz, 1H), 7.81 (s, 1H), 7.73 (d. J = 8.3 Hz, 1H), 7.50 (d, J = 15.87 Hz, 1H), 6.46 (d, J= 15,8 Hz, 1H), 5.96 - 5.86 (m, 1 H), 5.13 (dd, J = 1.4, 17,1 Hz, IH), 5.05 (dd, J = 1.1, 10.2 Hz, 1H). 4.93 (t, J = 7,9 Hz, 2H), 3,62 - 3.58 (m, 2H), 3.38 - 3.31 (m, 6H), 2.65 (q, J = 7.6 35 Hz, 2H), 1.35 - 1.32 (m, 6H); "C NMR (CDsOD) 5 165.8, 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. YtM 3 AMOWO DDIAWtWO' AU Suud PsticUl kMW MM1Sd4N 76 Example 11 Preparation of 3-[2-But-3-ynyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-y]-N hydroxy-acrylamide (12) [0239] The titled compound (12) was prepared according to the procedures 5 described in Example 1, by using appropriate starting materials. HPLC: 99.6 %; tR = 0.37 min; LOMS (ESI) m/z: 355 ([M+H]*). 1H NMR (CDaOD) 8 7.82 (d, J = 8.7 Hz, 1 H), 7.68 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.31 (d, J m 15.8 Hz, IH), 6.31 (d, J = 15.8 Hz, 1H), 4.87 - 4.79 (masked peaks), 3.54 - 3.50 (m, 2H), 3.37 (t, 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 (t, J = 2.5 Hz, 1 H), 1.21 (t, J = 7.2 10 Hz, 6H); "SC NMR (CD 3 OD) 6 165.9, 156.1, 140.9, 138.1, 135.2, 133.4, 125.6, 118.8, 117.0, 112.8, 82.4, 72.1, 50.6, 40.2, 26.7, 26.4, 17.3, 9.1, Example 12 Preparation of 3-[1 (3-Dimethylamino-2,2-dimethyl-propyl).2-(3,3,3-trifluoro 15 propyl)-1H-benzoinidazol-8-yi]-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 ([M+H]*). 20 Example 13 Preparation of 3-1 -(2-Diethylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1

H

benzoimidazol-5-yl]-N-hydroxy-acrylamide (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%; tf 25 = 1.37 min; LCMS (ESI) m/z: 399 ([M+H]*). "H NMR (DMSO-d 6 ) 8 1.25 (6H, t), 2.96 (2H, rn), 3.31 (OH. m), 3,44 (2H, m), 4.72 (2H, m), 6.51 (1H, in), 7.51 (2H, m), 7.65 (1H, in), 7.83 (1H, m), 10.45 (1H, bs). Example 14 30 Preparation of 3-1-(2-Diethylamino-ethyl)-2-ethoxymethyl-1H-benzolmidazol-5 yl-N-hydroxy-acrylamide (15) [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]*). 35 YflNK NO DEfLEtfllPD4S AV &=ud Nw~a,4 Fnd m FMA.

77 Example 15 Preparation of 3w[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-methyl1

H

behzoimidazol--yI]-N-hydroxy-acrylamide (16) [0243] The titled compound (16) was prepared according to the procedures 5 described in Example 1, by using appropriate starting materials, HPLC purity: 99.5%; tR = 0.30 min; LCMS (ESI) m/z: 331 ([M+Hr*). 'H NMR (DMSO-do) 8 1.13 (6H, a), 2.78 (2H, m), 2.89 (6H, s), 3.33 (2H, m), 4.42 (3H, s), 6.57 (1H, m), 7.57-7.69 (2H, m), 7.95 (2H, m), 9.68 (1H, bs), 10.81 (1H, bs) 10 Example 16 Preparation of 341-(2-Diethylamino-ethyl)-2-2,2-dimethyl-propy)-1

H

benzoimidazol-5-yIl]-N-hydroxy-acrylamide (17) [0244] The titled compound (17) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC purity at 254 15 nm: 99.9%, tR = 0.95 min. LCMS (ESI) m/z: 373 ([M+H]*). 'H NMR (CD3OD) 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 = 8.1 Hz), 3.54 (2H, t, J = 8.1 Hz), 3.31 (4H, qt, J = 7.3 Hz), 3.10 (2H, a), 1.27 (6H, t, J = 7.3 Hz), 1.06 (9H, s); 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. 20 Example 17 Preparation of N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-(3,3,3-trfluoro propyl)-1 H-benzoimidazol-5-yl]-acrylamide (18) [0245] The titled compound (18) was prepared according to the procedures 25 described in Example 1, by using appropriate starting materials. HPLC purity: 96.8%; tR = 0.72 min. LCMS (ESI) m/z: 399 ([M+H] 4 ). 'H NMR (DMSO-d) 5 1.18 (6H, d), 2.07 (2H, m), 2.95 (4H, m), 3.27 (3H, m), 4.43 (2H, rn), 6.52 (1H, m), 7.55 (2H, m), 7.61 (1H, m), 7.84 (1H, n), 8.65 (21-, bs). 30 Example 18 Preparation of 3-2-(2,2-Dimethyl-propyl)-i -(2-isopropylamino-ethyl)-1

H

benzolmldazol.5.yl].N-hydroxy-acrylamide (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 35 nm: 98.1%, tR = 0.86 min. LCMS (ESI) m/z: 359 ([M+H]'). 'H NMR (CD 5 OD) 8 7.86 (1H, d, J = 8.6 Hz), 7.78 (1H, s), 7.73 (1H, dJ = 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, YWJtNICWO DUZIEfWIOVO AU Sssd hwtimuui Pli NSfn 78 qt, J = 6,5 Hz), 3.13 (2H, s), 1.26 (6H, d, J = 6.2 Hz), 1.04 (91-, S); "C NMR (CD 3 OD) 8 161.2, 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. Example 19 5 Preparation of 3-[1-(2-Dilsopropylamino-ethyl)-2-(2,2-dimethyl-propyl)-1 H benzoimidazol-5-yl]-N-hydroxy-acrylamide (20) [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 ([M+H]*). 'H NMR (CD 3 OD) 8 7.86 10 (IH, s), 7.80 (1H, d. J = 8.7 Hz), 7.76 (1H, d, J = 8.6 Hz), 7.62 (1H, d, J = 15.8 Hz), 6.52 (1H, d, J = 16.0 Hz), 4.96 (2H, t, J = 5.2 Hz), 3.84 (2H, m), 3.53 (2H, t, J = 8.3 Hz), 3.06 (2H, s), 1.38 (12H, d, J = 6.5 Hz), 1.05 (9H, s); "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. 15 Example 20 Preparation of 3-[1-(2-Dilsopropylamino-ethyl)-2-Isobutyl-1H-benzoimidazol-5-yl] 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 20 nm: 95.3%, tR = 0.76 min. LCMS (ESI) m/z: 387 ([M+H]*). 'H NMR (CDaOD) 5 7.85 (1H, s), 7.71 (2H, a), 7.66 (1H, d, J= 15.8 Hz), 6.51 (1H, d, Jr 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). 25 Example 21 Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-hex-3-enyi- H benzoimidazol-5-yl]-N-hydroxy-acrylamide (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 30 nm: 99.9%; tf = 1.24 min; LCMS (ESI) m/z: 399 ([M+H]*). 'H NMR (CD 3 OD) 8 8.22 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 7.96 (d, J = 8.6 Hz, 1 H), 7.81 (d, J = 15.8 Hz, IH), 6,68 (d, J = 15.8 Hz, 1 H), 5.69 - 5.59 (m, 2H), 4.79 (s, 2H), 3.66 (s, 2H), 3.55 (t, J= 7.3 Hz, 2H), 3.24 (a, 6H), 2.91 (q, J = 6.8 Hz, 2H), 2.21 - 2.11 (m, 2H), 1.44 (s, 6H), 1.02 (t, J = 7.5 Hz, 3H); 1 3 C NMR (CD 3 OD) 8 185.7, 157.9, 140.2, 135.8, 134.6, 134.5, 126.1, 35 125.9, 120.1, 115.2, 114.6, 68.7, 533, 47.9, 39.6, 27.6, 25.9, 23.7, 21.4, 14.4. Y;WsiYSN PUNWUO omiwasm; Saw4 Nov~ami vhsmila~ 79 Example 22 Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,4,4-trimethyl pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide (23) [0250] The titled compound (23) was prepared according to the procedures 5 described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm" 98.6%; tR = 1.61 min; LCMS (ESI) m/z: 429 ([M+H]J). 'H NMR (CD 3 OD) 8 8.19 (d, J = 8.8 Hz, IH), 8.08 (s, IH), 7.90 (d, J r 8.8 Hz, 1H), 7.76 (d, J 15,7 Hz, 1H), 6.75 (d, J = 16.8 Hz, IH), 4.79 (s, 2H), 3.62 (s, 2H), 3.35 - 3.29 (m, 1H), 3.23 (s, OH), 2.52 (bra, 2H), 1.50 - 1.45 (m, 2H-), 1.38 (d, J= 3.8 Hz, SH), 1.12 (d, J = 5.5 Hz, 3H), 1.02 10 (s, 6H); '3C NMR (CDsOD) 8 165.6, 157.4, 139.9, 135.2, 135.1, 132.9, 126.4, 120.6, 115.7, 114.6, 68.6, 53.3, 51.4, 47.9, 39.7, 36.3, 31.9, 31.3, 30.2, 23.8, 22.3. Example 23 Preparation of 3-[2-Cyclohexyl-1 .(3-dimethylamino-2,2.dimethyl-propyl)-1H 15 benzoimidezol-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: 399([M+H]*). 'H NMR (CD 3 OD): 8 8.21 (d, J = 8.8 Hz, 1 H), 8.06 (s, I H), 7.95 (d, J= 8,8 Hz, I H), 7.83 (d, J= 15.8 Hz, I H), 6.76 20 (d, J = 15.8 Hz, 1 H), 4.79 (a, 2H), 3.65 (s, 2H), 3.60 - 3.51 (m, 1 H), 3.22 (s, 6H), 3.29 3.26 (m, 2H), 2.12 - 2.09 (m, 2H), 2.03 - 1.92 (m, 3H), 1.78 - 1.59 (m, 3H), 1.41 (s, 6H); 3 C NMR (CD 3 0D) 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.O, 32.4, 26.5, 26.3, 23.6. 25 Example 24 Preparation of 3-[2-Bicyclo[2.2.1]hept-5-en-2-yl-1-(3-dimethylamino-2,2-dimethyl propyl)-1 H-benzoimidazol-5-yl].N.hydroxy-acrylamide (25) [02521 The titled compound (25) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity at 254 30 nm: 99.9%; tR = 0.91 min; LCMS (ESI) m/z: 409 ([M+H]*). Example 25 Preparation of 3-[1-(2-Diethylamino-ethyl)-2-hex-3-nyl-1H-benzoimidazol-5-yl]-N hydroxy-acrylamide (26) 35 [0283] 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 ([M+H]*). 'H NMR (CD 3 OD) 8 7.95 (d, J= 8.6 Hz, 1H), YkflWQ O DELEEWPM-M5 AJThSemd NmI1 Pusd . at 80 77 (a, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 15.8 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H., 5.57 - 5.44 (m, 2H), 3.72 - 3.68 (m, 2H), 3.44 (q, J = 7.2 Hz, 41-), 3.35 - 3.30 (meked peaks), 2.73 (q, J = 7.1 Hz, 2H), 2.07 - 1.99 (m, 2H), 1.41 (t, J = 7.2 Hz, 8H), . (t, J= 7.5 Hz, 3H); 'C NMR (CDaOD) 8 165.6, 157.2, 140.2,135.9,134.8,134.6, 5 13 .2, 126.4, 126.1,119.8,115.6,113.5, 50.4,40.5, 26.9, 25.4, 21.4,14.4, 8.9. Ex, imple 26 Prepartion of 3-[1-(2-Diisopropylamino-thyl)-2-hex-3-enyl-1H-benzolmidazol-8 y,] N-hydroxy-acrylamide (27) 10 [0 4] The titled compound (27) was prepared according to the procedures d cribed in Example 1, by using appropriate starting materials. HPLC: 99.9%; t n = 1.22 min; LCMS (ESI) m/z 413 ([M+H]*). 1 H NMR (CD 2 OD) 5 7.94 - 7.89 (m, 2H), 7.7 3 (d. J = 8.7 Hz, 1H), 7.53 (d, J = 15.8 Hz, 1H), 6.50 (d. J = 15.8 Hz, 1), 5.63 5.41. (m, 2H), 3.99 - 3.91 (m, 2H), 3.59 - 3.64 (m, 2H), 3.36 - 3.26 (masked peaks), 15 2.72 (q, J = 7.2 Hz, 2H), 2.08 - 2.01 (m, 2H), 1.50 (d, J = 6.5 Hz, 12H), 0.89 (t, J = 7.5 Hz 3H): "C NMR (CD 3 0D) a 165.6, 157.0, 140.2, 135.9, 135.4, 134.5, 134.3, 126,6, 120.3, 126.2, 119.8, 115.8, 113.3, 56.9, 45.3, 41.9, 27.2, 25.5, 21.4, 18.2, 14.4. Ex mple 27 20 P paration of 3-[2-Hex-3-enyl-1-(2-Isopropylamino-ethyl)-1H-benzoimidazol-5 YU] -hydroxy-acrylamide (28) [0 5] The titled compound (28) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC purity at 254 nm 99,9 %; tR = 1.12 min; LCMS (ESI) mfz: 371 ([M+H]'). 'H NMR (CDaOD) 5 8.00 (d, INI 25 J5 9.1 Hz, IH), 7.77 - 7.75 (in, 2H), 7.17 (di, J = 15.7 Hz, IH), 6.34 (d, S = 15.7 Hz, 1H', 5.57 - 5.42 (m, 2H), 4.92 (t, J = 5.9 Hz, 2H), 3.72 (t, J = 5.7 Hz, 2H), 3.54 - 3.48 (m11 H), 3.39 (t, J = 7.5 Hz, 2H), 2.72 (q, J= 7.3 Hz, 2H), 2.06 - 1.99 (m, 2H), 1.39 (d, J = 6.5 Hz, 6Ff), 0.87 (t, J= 7.5 Hz, 3H). 30 Ex mple 28 Pr paratIon of 3-1.(2-Ethylamino-ethyl)-2-hex-3-enyl-1H-benzolmidazol-5-y]-N hy roxy-acrylamide (29) [02 6] The titled compound (29) was prepared according to the procedures do cribed in Example 1, by using appropriate starting materials. HPLC purity at 254 35 nm 99.9%; tRa= 1.23 min; LCMS (ESI) m/z: 385 ([M+H]*). 1 H NMR (CDOD) 8 7.94 (d, J= 8.6 Hz, 1H), 7.89 (s, IH), 7.77 (d, J m8.4 Hz, IH), 7.56 (d, J = 15.8 Hz, 1 H), 6.55 (d, =15.7 Hz, IH), 5.57-5.42 (m, 2H), 4.62 (t, J= 7.5 Hz, 2H), 3.42- 3.33 (m, IH), 'e NO OEL&ThWI004 AV Bupq P'VCI*IQ.I 1 asRI aaiisM 81 3.32 - 3.30 (masked peaks), 3.28 - 3.24 (m, 2H), 2.71 (q, J = 7.2 Hz, 2H), 2.33 (brs, 2H), 2.03 - 1.94 (m, 2H), 1.36 (d, J = 6.5 Hz, 6H}, 0.84 (t, J = 7.5 Hz, 3H); "C NMR (C0 3 00) 8 165.6, 156.3, 139.9, 136.8, 136.2, 135.2, 133.8, 132.8, 126.7, 125.8, 120.4, 114.6, 114.1, 52.2, 43.5, 42.9, 27.2, 26.5, 25.5, 21.4, 19.2, 14.4. 5 Example 29 Preparation of 3-[2-Hex-3-enyl-1-(3-isopropylamino-propyl)-1H-benzolmidazol-5 yl].N-hydroxy-aorylamide (30) [0257] The titled compound (30) was prepared according to the procedures 10 described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.9%; ta = 1.04 min: LCMS (ESI) m/z: 357([M+H]*). 'H NMR (CDsOD) 8 7.93 (d, J = 8.4 Hz, I H), 7.77 - 7.73 (m, 2H), 7.23 (d, J = 15.7 Hz, 1H), 6.34 (d, J= 15.7 Hz, 1 H), 5.57 - 5.42 (m, 2H), 4.87 (masked peaks), 3.68 (brs, 2H), 3.35 - 3.30 (masked peaks), 3.22 - 3.17 (m, 2H), 2.72 (q, J = 7.1 Hz, 21-), 1.35 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7,6 15 Hz, 3H); "3C NMR (CD 3 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 30 Preparation of 3-[1-(2-Diethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N 20 hydroxy-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%, ta = 1.31 min. LC-MS m/z: 387 ([M+H]r). 'H NMR (DMSO-de) 8 0.88 (3H, t, J = 7.0 Hz), 1.26 (6H, t, J = 7.2 Hz), 1.34 (4H, m), 1.44 (2H, m), 1.85 (2H, m), 3.12 25 (2H, t, J = 7.7 Hz), 3.31 (4H, m), 3.52 (2H, t, J = 7.7 Hz), 4.81 (2H, t, J = 7.7 Hz), 6.59 (IH, d, J 15.8 Hz), 7.63 (1H, d, J = 16.8 Hz), 7.73 (1H, d, J = 8.8 Hz), 7.93 (1H, d, J = 8.8 Hz), 7.94 (1H, s) Example 31 30 Preparation of 3-[1-(3-isopropylamino-propyl)-2-(2,4,4-trimethyl-pentyl)-1 H benzoimidazol-5-yli]-N-hydroxy-acrylamide (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 rim: HPLC; 97.5%, tR = 1.68 min. LC-MS m/z: 416 ([M+H]'). 1H NMR (DMSO-de) 8 0.89 35 (9H, s), 0.98 (3H, d, J = 6.6 Hz), 1.23 (61-, d, J z 6,5 Hz), 2.08-2.29 (4H, m), 2.27 (1H-, m), 2.98-3.12 (4H, n), 3.29 (1 H, m), 4.53 (2H, t, J = 7.4 Hz), 6.60 (1H, d, J = 15,8 Hz), Y lfNK NO DELRTWM 0.0 AU kEmed PN skadl Fai u Mkd"a.

82 7.65 (1H, d, J = 15.8 Hz), 7.75 (1H, d, J = 9.0 Hz), 7.96 (1H, d, J = 9.0 Hz), 7.98 (1H, s), 8.75 (2H, bs). Example 32 5 Preparation of 3-[2-(2,2-Dimethyi-propy)-1 -(3-isopropylamino-propyl)-1H benzolmldazol-5-y]-N-hydroxy-acrylamide (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 nm; 99%, tR W 1.01 min. LC-MS m/z: 375 ([M+HI). 1 H NMR (DMSO-de) 8 0.98 (9H, s). 10 1.24 (6H, bs), 2.17 (2H, bs), 3.14 (4H, m), 3.28 (1H, be), 4.53 (2H, bs), 6.65 (1H, d, J = 15.5 Hz), 7.65 (1H, d, J = 15.5 Hz), 7.81 (1H, d, J = 7.4 Hz), 8.02 (1H, s), 8.03 (1H, d, J = 7.4 Hz), 8.85 (2H, bs). Example 33 15 Preparation of 3-[1 (2-Diisopropylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1 H benzoimidazol-5-yl]-N-hydroxy.acrylamide (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 ([M+H]'). 'H NMR (DMSO-de) 81.35 (12H, m), 2.94 20 (2H, m), 3.24 (2H, in), 3.45 (2H, t), 3.80 (2H, m), 4.68 (2H. t), 6.48 (1H, m), 7,55 (3H, m), 7.85 (1H, m), 9.48 (1H, bs). Example 34 Preparation of N-Hydroxy-3-[2-isobutyl-1-(2-isopropylamino-ethyl)-1 H 25 benzolmidazol-5,-y]-acrylamide (35) [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 ([M+H]'). ''H NMR (CD 3 OD) 8 7.78 (1H, d, J = 8.7 Hz), 7.76 (1H, s), 7.68 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J= 15.8 Hz), 30 6.42 (1 H, d, J = 15,9 Hz), 4.70 (2H, t, J = 7.4 Hz), 3.48 (211, t, J = 6.9 Hz), 3.37 (1H, m), 3.01 (2H, d, J= 7A Hz), 2.21 (1H, m), 1.27 (6K, d, J= 6.5 Hz), 1.00 (6H, d, J= 6.6 Hz); 30 NMR (CD 3 OD) 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. 35 Y.twiU ND DELBTMhPIMQ4F AV Iecw~ Fu] iiu fbdn 83 Example 35 Preparation of 3-[2-(2,2-Dimethyl-propyl)-1 -(2-ethylamino-ethyl)-1 H benzolmidazol-5.yl].N-hydroxy-acrylamide (36) [0263] The titled compound (36) was prepared according to the procedures 5 described in Example 1, by using appropriate starting materials. Yield: 74%. HPLC purity at 254 nm: 99.9%, tR = 0.71 min. LCMS (ESI) m/z: 345 ([M+H]f). 1 H NMR

(CD

3 OD) 8 7.81 (1H, d, J = 8.8 Hz), 7.75 (1H, s), 7.69 (1 H, d, J = 8.5 Hz), 7.36 (1 H, d, J = 15.7 Hz), 6.40 (1H, d, J = 15.3 Hz), 4.81 (2H, t, J= 6.4 Hz), 3.51 (21, t, J = 6.3 Hz), 3.10 (2H, s), 3.06 (2H, qt, J a 7.3 Hz), 1.23 (3H, t, J = 7.2 Hz), 1.04 (9H, s); "C NMR 10 (CO 3 OD) 5 161.0, 153.3, 138.5, 132.7, 132.2, 124.2, 117.5, 113.9, 111.9, 44.2, 43.0, 41.0, 37.4. 33.0, 27.9, 9.5. Example 36 Preparation of 3-[1-(2-Ethylamino-sthyl)-2-isobutyl-1H-benzoimidazol-5-y]-N 15 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 254 nm: 99.9%, ta = 0.40 min. LCMS (ESI) m/z: 331 ([M+H]*). 'H NMR (CD 3 OD) 8 7.81 (IH. d, J = 8.6 Hz), 7.73 (1H, s), 7.67 (1H, d, J = 8.2 Hz), 7,34 (1H, d, J = 15.7 Hz), 20 6.36 (1 H, d, J a 15.7 Hz), 4.74 (21-, t, J = 6.7 Hz). 3.54 (2H, t, J= 8.5 Hz), 3,10 (2H, d, J 7.4 Hz), 3.06 (2H, d, J = 9.5 Hz), 2.21 (1 H, m), 1.23 (3H, t, J= 7.3 Hz), 1.04 (6H, d, J = 6.6 Hz): "C NMR (CD 2 OD) 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, 9.5, 25 Example 37 Preparation of 3-[1-(2-Diisopropylamino-ethyl).2-(2,4,4-trlmethyl-pentyl)-1 H benzoimidazol-5-yl]-N-hydroxy-acrylamide (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 = 30 1.62 min; LCMS (ESI) m/z: 443 ([M+H]*). 'H NMR (CD 3 0D) 5 7.96 - 7.94 (m, 2H), 7.82 (d, J = 8.7 Hz, IH), 7.55 (d, J = 15.8 Hz, 1H), 6.54 (d, J = 15.8 Hz, 1H), 5.13 5.06 (masked peaks), 4.01 - 3.92 (m, 2H), 3.71 - 3.67 (m, 21-), 3.33 - 3.24 (masked peaks), 3.18 - 3.12 (m, 1H), 2.38 - 2.36 (m, I H), 1.52 (s, SH), 1.51 (s, 6H), 1.41 - 1.40 (m, 2H), 1.09 (d, J = 6.6 Hz. 3H), 0.94 (s, 9K); '3C NMR (CDOOD) 8 165.5, 156.5, 35 140.1, 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 ulMEh NO DELTgMMwa.os AU amd fmviSm Fm u iem- 84 Example 38 Preparation of N-Hydroxy-3[1-(2-Isopropylmmino-ethyl)-2-(2,4,4-trimethyl-pentyl) 1H-benzoimidazol-5-yl]-acrylamide (39) [0266] The titled compound (39) was prepared according to the procedures 5 described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 97.9 %; ta = 1.49 min; LCMS (ESI) m/z; 401 ([M+H]'). 'H NMR (CDaOD) 5 7.98 (d, J = 8.7 Hz, 1 H), 7.79 - 7.76 (m, 2H), 7.24 (d, J = 15.7 Hz, IH), 8.39 (d, J = 15.7 Hz, 1 H), 4.97 - 4.89 (masked peaks), 3.70 - 3.66 (m, 2H), 3.53 - 3.47 (m, 1 H), 3.34 - 3.28 (masked peaks), 3.22 - 3.15 (m, I H), 2.31 - 2.29 (m, 1 H). 1.39 - 1.38 (m, 9H), 1.07 (d. 1o J = 6.6 Hz, 3H), 0.9 (s, 9H); "C NMR (CDaOD) 8 165,5, 156.9, 140.5, 134.7, 134.4, 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, 18.8. Example 39 15 Preparation of 3-(1-(2-Ethylamino-ethyl)-2-(2,4,4-trlmethyl-pentyl)-1 H benzolmidazol-5-yi]-N-hydroxy-acrylamide (40) [02671 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 ([M+H]*). "H NMR (CDaOD) 8 7.96 (d, 20 J = 8.6 Hz, 1 H), 7.79 (s, 1 H), 7.78 - 7.75 (d, J = 8.7 Hz. 1 H), 7.23 (d, J = 15.7 Hz, 1 H), 6.37 (d, J= 15.7 Hz, 1 H), 4.95 - 4.89 (masked peaks), 3.70 - 3,68 (m, 2H), 3.36 - 3.28 (masked peaks), 3.26 - 3.14 (m, 3H), 2.31 - 2.30 (m, 1 H), 1.40 - 1.32 (m, 5H), 1.07 (d, J = 6.6 Hz, 3H), 0.92 (8, 9H); 130 NMR (CDaOD) 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, 25 11,4. Example 40 Preparation of 3-[1-(2-Diethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1 H benzolmidazol-5-yl]-N-hydroxy-acrylamlde (41) 30 [0288] The titled compound (41) was prepared according to the procedures described in Example 1, by using appropriate starting materials, HPLO purity at 254 nm: 85.6%, tR = 1.55 min. LC-MS m/z: 415 ([M+H]*), -1 NMR (CD 3 OD) 8 7.91 (d, 2H, J = 6.0 Hz), 7.80 (br, d, 1H, J = 8.9 Hz), 7.68 (d, 2H, J = 15.8 Hz), 6.58 (d, 1H, J = 15.8 Hz), 4.96 (br, q, 2H), 3.64 (br, q, 2H), 3.43 (q, 4H, J = 7.3 Hz), 1.40 (t, 8H), 1.09 (br, d, 35 4H, J = 6.6 Hz), 0.94 (br, s, 10H); "C NMR (CD0D) 8 156.8, 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, 9.0. Y NM P IZLHTrWPIUCE, AU Bind hkiufal Hnu dmdn 85 Example 41 Preparation of 3-[1-(2-DiethylImino-ethyl)-2-propyl-1H-benzolmidazol-5-yl]-N hydroxy-acrylamide (42) [0269] The titled compound (42) was prepared according to the procedures 5 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 ([M+H]'). 'H NMR (CDaOD) 8 8.15 (d, 2H, J= 8,7 Hz). 7.68 (d, 1H, J = 15.8 Hz), 6.83 (d, 1H, J = 15.8 Hz), 5.08 (br, t, 2H), 3.70 (br, t, 2H), 3.44 (br, m, 4H), 3.35 (t, 2H), 2.03 (br, m, 2H), 1.44 (t, 6H, J = 7.2 Hz), 1.20 (t, 3H); ' 3 C NMR (CD 3 OD) 8 165.5, 157.4, 139.8, 135.5, 133.5, 132.3, 120.7, 120.7, 10 114.5,114.3, 40.8, 28.5, 21.0.13.9, 9.1. Example 42 Preparation of 3-[1-(2-Diethylamino-ethyl)-2-(2-methylsulfany-ethyl)-1 H benzolmidazol-5-y]-N-hydroxy-acrylamide (45) iS [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 284 nm: 80%, tR = 0.50 min. LCMS (ESI) m/z: 377 ([M + H]J). 'H NMR (CD 3 0D) 8 7.79 (1H, s), 7.77 (1H. d). 7.66 (11H, d, J = 8.8 Hz), 7.54 (11H, d, J = 15,8 Hz), 6.44 (1H, d, J = 15.8 Hz), 4.83 (2H, masked by DHO, identified by 20 COSY), 3.57 (2H, m), 3.41 (211, t, J x 7.1 Hz), 3.32 (4H), 3.01 (2H, t, J = 7.1 Hz), 2.89 (3H, s), 1.30 -1.26 (9H, overlapped t), Example 43 Preparation of 3-[2-Butyl-1-(2-isopropylamino-ethyl).1H-benzolmldzol-5-yl]-N 25 hydroxy-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 ([M+H]*). 'H NMR (DMSO-da) 8 0.95 (3H, t), 1.22 (BH, m), 1.42 (2H, m), 1.80 (2H, m), 3.13 (2H, m), 3.41 (311, t), 4.69 (2H, t), 6.58 30 (1H, m), 7.56 (1H, m), 7.73 (1H, m), 7.90 (2H, m), 9.14 (2H, be). Preapration of the freebase of the titled compound: [0272] To a pre-stirred solution of the methyl eater (1 eq) in dried methanol,

NH

2 OH,HCI (12 eq.) was added. The mixture was stirred in ice-water bath for about 10 35 min, followed by adding sodium methoxide solution (20 eq.). HPLC showed the reaction completed after 20 mln, less than 1% of the acid was observed. Y;MiYKJ No DILI=WP0S Mi kAi Mna aili as m ldes 86 [0273] The above crude was treated with 1 M of HCI until all the precipitate was dissolved (pH around 1-2). 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 solid was washed with water once. The above solid was suspended in methanol and 5 water again and was treated with ON HCI until all dissolved, the pH value was carefully adjusted to around 7-8 using NaOH and NaHCO, 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%. 10 Preapration of the hydrochloric acid salt of the titled compound: [0274] The above freebase compound was suspended in methanol and water and was treated with ON HCI (2.8 eq.). The solution became dear. After removing the methanol on a Rotary Evaporator, the hydrochloric acid salt was obtained by freeze drying. It was further recrystallized from methanol (HPLC purity at 254 nm: > 99%). 15 Example 44 Preparation of 3.[2-Butyl-1-(3-isopropylamino-propyl)-1H-banzoimidazol-5-yl].N hy4roxy-acrylamide (47) [0275] The titled compound (47) was prepared according to the procedures 20 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 ([MH]*). 'H NMR (DMSO-de) 8 0.95 (3H, t), 1.22 (611, m), 1.45 (211, m), 1.82 (2H, m), 2.14 (211, m), 3.17 (4H1-, m), 3.28 (11-1, m), 4.52 (211, t), 6.62 (1H, m), 7.57 (1H, m), 7.72 (1H, m), 7.89 (2H, m), 8.80 (2H, bs). 25 Example 45 Preparation of 3.[1-(1-Benzyl-pipsridin.4.y)-2-butyl-1H-benzoimidazol-5.yi]-N hydroxy-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 30 nm: 96,7%, tR = 1.35 min. LC-MS m/z: 433 ([M+H]*). 'H NMR (DMSO-de) 8 0.94 (31-, s), 1.41 (2H, m), 1.77 (2H, m), 2.19 (2H, m), 2.99-3.10 (211, m), 3.24 (4H, m), 3.68 (21-, m), 4.38 (2H, s), 5.01 (1H, m), 6.65 (1H, d, J = 15.8 Hz), 7.47-7.49 (3H, m), 7.61 (1H, d, J = 15.8 Hz), 7.69 (311, m), 7.97 (1H, s), 8.60 (111, d, J = 8.8 Hz), 10.35 (211, s), 11.95 (1H, s). 35 YAM.JXNO WDIEWPIMfl4 AUS-aSPbtihnItUS VMIadoc 87 Example 46 Preparation of 3-[2-Butyl-1-(2-thylamino-ethyl)-1 H-benzoimidazol-5-y]-N hydroxy-acrylamide (44) [0277] The titled compound (44) was prepared according to the procedures described 5 in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98%; LC-MS m/z: 331 ([M+H]'). 1 H NMR (DMSO-dl) 8 10.88 (br a, 1H), 9.12 (br s, 2H), 7.93 (s, 1H), 7.87 (d, 1H, J = 8.4 Hz), 7.71 (d, 1H, J = 8.3 Hz), 7.62 (d, 1H, J = 15.7 Hz). 6.59 (d. IH, J = 15.6 Hz), 4.67 (t-like, 2H), 3.42 (br s, 2H), 3.08 (q, 2H, J W 7.7 Hz, Pr

CH

2 ), 3.05 (br s, 21-), 1.81 (m, 2H), 1.45 (m, 2H), 1.18 (t, 3H, J = 7.1 Hz), 0.95 (t, 3H, J 10 = 7.0 Hz); " 1 C NMR (DMSO-de) 8 162.6, 156,2, 138.0, 135.0, 133.5, 131.6, 123.5, 119.2, 114.8, 112.1, 44.5, 42.4, 40.6, 28.2, 25.2, 21.7, 13.5, 10.8. Example 47 Preparation of 3-[2-But-3-enyl-1-(2-ethylamlno-ethyl)-1H-benzoimidazol-5-yl]-N 15 hydroxy-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 ([M+H]*). 'H NMR (CD 3 OD) 8 7.85 (d, J = 8.5 Hz, 1 H), 7.78 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 15.7 Hz, 1H), 6.40 (d, J = 15.5 Hz, 1H), 20 6.02 - 5.92 (m, 1H), 5.19 (dd, J = 17.1, 1.3 Hz, 1H), 5.12 (dd, J = 10.2, 0.9 Hz, 1H), 4.80 (t, J = 6.4 Hz, 2H), 3.62 (t, J = 6.2 Hz, 2H), 3.22 - 3.16 (m, 2H), 2.71 (q, j = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H); "C NMR (CD 3 0D) 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. 25 Example 48 Preparation of 3-[2-Hexyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N hydroxy-acrylamide (50) [0279] The titled compound (50) was prepared according to the procedures 30 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 ([M+H]'), 'H NMR (CD 3 OD) 5 7.80 (1H, d, J = 8.5 Hz), 7.74 (1H, s), 7.64 (1H, d, J = 9.0 Hz), 7.50 (1H, d, J = 13. 6 Hz), 6.42 (11-, d, J = 15.8 Hz), 4.65 (2H, d, J = 6.6 Hz), 3.48 (2H, d, J = 6.6 Hz), 3.38 (IH, 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) 35 1.29 (7H, m) 0.84 (OH, d, J = 7.0 Hz). Y;Mhr j NO DEUTMJD90-! AU Late mvWU AFi alilledme 88 Example 49 Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1 H benzoimidazol4.yl]-N.hydroxy-acrylamide (51) [0280] The titled compound (51) was prepared according to the procedures 5 described In Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100%, tR = 1.49 min. LC-MS m/z: 331 ([M+HJ'). H NMR (DMSO-de) 8 0.85 (9H, a), 1.03 (2H, d, J = 6.4 Hz), 1.34 (2H, m), 2.27 (1H, m), 3.00 (6H, s), 3.24-3.27 (4H, m), 4.79 (3H, m), 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, s), 7.87 (1H, d, J = 8.4 Hz). 10 Example 50 Preparation of 3-[1.(2-Ethylamino-ethyl)-2-hexyl.1H-benzoimidazol-5-yi]-N hydroxy-acrylamide (52) [0281] The titled compound (52) was prepared according to the procedures 15 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 20 eq) in AcOH and MeOH (1:9 v/v, 300mL) was added SnCl 2 2H 2 0 (31.45 g, 139.4 mmol, 5 eq) in portions. The resulting mixture was heated to 40 *C 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 25 with dichloromethane (x3). 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 65 mm, solvent MeOH/DCM gradient from 0 to 10%). 3-[1-(2-ethylamino-ethyl)-2-hexyl 30 1 H-benzoimidazol-5-yl]-acrylic acid methyl ester was obtained as yellow solid (4.445 g, 44.6%). HPLC purity at 254 nm: 98.8%, tR = 1.71 min. LCMS (ESI) m/z: 358 ([M + H]*). 'H NMR (CDCI 3 ) 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 = 6.6 Hz), 3.80 (3H, s), 3.01 (2H, t, J = 6.6 Hz), 2.89 (2H. t, J = 7.9 Hz), 2.65 (2H, q, J = 7.1 Hz), 35 1.91 (2H, pentet, J = 7.8 Hz), 1.46 (2H, m), 1.35 (4H, m), 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:W1NKIKO OELEEP9,0.0 AL aAemu4 hma Fui a a t Md 89 [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% yield (1.753 g). 5 Step 4: [0284] To a solution of 3-[1-(2-ethylamino-ethyl)-2-hexyl-1lH-benzoimidazol-5-y] 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 10 NaOMe solution in MeOH (25%, 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 (usually reaction completed within 30-90 min) and quenched by adding 6N HCI (40 mL). The mixture (HPLC purity at 254 nm = 94.6%) was added Milll-Q water, adjusted pH ~8 by IN NeOH and evaporated to remove the organic solvent. The resultant 15 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 (x2). The free base of the titled compound was obtained (HPLC purity at 284 nm = 98%). The free base could be recrystallized from MeOH-Ethyl acetate to give a white 20 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, co 25 evaporated with PhMe (x1l) and EtOAc (x2). The solid was recrystallized from MeOH EtOAc to give a white or pale yellow solid (3.298 g, 61.7%). HPLC purity at 254 nm: 98.4-99.6%, tR = 1.23 min. LCMS (ESI) m/z: 359 ([M + HJ*). 'H NMR (CD 2 0D) 8 9.33 (residual NH), 8.03 (1H, d, J m 8.3 Hz), 7.77 (1H, s), 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 30 COSY), 3.63 (2H, br t like), 3.32 (2H, d, J = 7.9 Hz), 3.15 (2H, q, J = 7.1), 1.94 (2H, pentet, J = 7.1), 1.53 (21-, pentet, J = 6.7 Hz), 1.42-1.31 (4H, m), 1.33 (3H, t, J = 7.1 Hz), 0.88 (3H, t, J = 7.0 Hz): ' 3 C NMR (CDOD) 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. 35 YM*r4KK10 DEL~tfIPPMT1,0S AU Send PnlaaIlliaLm Nedur 90 Example 51 Preparation of N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(3,3,3-trifluoro-propyl) '1H-benzolmidazol-5-yl]-acrylamide (53) [0286] The titled compound (53) was prepared according to the procedures 5 described in Example 1. by using appropriate starting materials. HPLC: 98.1%; tf = 0.63 min. LC-MS m/z: 385 ([M+H]'). Example 52 Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-hmx-3-enyl-1H-benzoimidazol-5-y] 10 N-hydroxy-acrylamide (54) [0287] The titled compound (54) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.9%, ta = 0.96 min. LCMS (ESI) m/z: 357 ([M+H]r). '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 (1H, d, J = 15.8 Hz), 5.44 (1H, m), 5.38 (1H, m), 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. s), 2.61 (4H, qt, J = 7.1 Hz), 1.93 (2H, qn, J = 7.7 Hz), 0.78 (3H, t, J = 7.5 Hz); 18C NMR (CD 3 OD) 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. 20 Example 53 Preparation of 3-[-(2-Amino-thyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5 yl]-N-hydroxy-acrylamide (55) 0 0 0 2 N N c SnC12-2H 2 0 N N ,r 2 00H 3 N0 HOAc-MeOH (1:9) \ HN B iHNi BOC Vial .1 0 HCI/MeOH

NH

2 OH/NaOMe N NHOH

H

2 N Via-1 H 2 N 25 Step 1: [0288] To a stirred solution of 3-[4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro phenyl]-acrylic acid methyl ester (lllal, 65.2 mg. 0.178 mmol) and 3,5,5-trimetylhexanal YMla-l41I NDDELEIEFPI9Q0 AUS o flo~iaS Pil 111wFileA (44 yL, 0.2k mmol) In a mixed solvent of AcOH-MeOH (1:9 v/v, 2 ml) and DCM (1 ml) wal added SnCI 2 2H 2 0 (184 mg, 0.815 mmol). The resulting mixture was heated to 40 C with stirring overnight. The solvent was removed under reduced pressure and the res Atant residue was added saturated aqueous Na 2

CO

3 and extracted with EtOAc 5 (x . The eOtracts gave the crude (Vial-1, 91 mg) with HPLC purity at 254 nm: 49.3%, tR 3.02 tin and 7.9%, tR = 1.97 min (de-Boc product). LCMS (ESI) m/z; 458 ([M + H] and 348 ([M + H]*, de-Boc product). Ste p 2: 10 [02 9] The above crude (Vlsi-1) was dissolved in MeOH (4 mL) and 6N HCI (1 mL) an( heated at 70"C for 30 min. The solution was evaporated to dryness and co e prote dwith PhMe (x2) and MeOH (xl). The residue (crude Via-1, 81.9 mg) was spi to two! parts (43.4 mg, equal to 0.0945 mmol of Illal, and 38.5 mg equal to 0.0839 mrol of 1Il01). Sta p 3: [02 O] The titled compound (55) was prepared according to the Step 4 described in Ex mple 1, by using crude (VIa-1, 38.6 mg). VIla-I was obtained as TFA salt (2.3 mg, 4.$ fromillal). HPLC purity at 254 nm: 92.7%, tR = 1.46 min. LCMS (ESI) m/z: 359 + H]*). H NMR (CD30D) 5 7,81 (1H, s), 7.70 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 8A 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), 3. (2H, t J = 6.5 Hz), 3.02 (1H, dd, J = 15.5, 6.5 Hz), 2.90 (1H, dd, J = 15.3, 8.6 Hz), 2. (1H, }r s or m), 1.33 (1H, dd, J = 14.1, 3.4 Hz), 1.25 (1H, dd, J 14.0, 6.6 Hz), 0.E3 (3H, , J = 6.2 Hz), 0.83 (9H, s). 25 Ex 1mple 4 Prtparat4n of 3-[1-(2-Amino-ethyl)-2-(2-methoxy-nonyl)-1H-benzoimidazol-5-yl] N4 ydrox*acrylamide (56) [021] The titled compound (56) was prepared according to the procedures 30 de cribed In Example 53, by using appropriate starting materials. HPLC purity at 254 n 91.8%, tR = 1.93 min- LCMS (ESI) m/z: 403 ([M + H]*). 'H NMR (CD3OD) 8 some ide itified ieaks: 7.81 (1H, s), 7.70 - 7.58 (3H, m), 6.46 (1H, br d, J = 14.4 Hz), 4.62 (2 , m), 3169 (1H, br s or m), 3.38 (2H, t, J = 7.3 Hz), 1.67 (1H, m), 1.58 (1H, m), 1.5 3-1.20 (1OH, m), 0.82 (3H, t, J = 6.2 Hz). 35 't '#4 NO 1PW Ik OO1Q-S Al] HUN MAS fr.~F#INI&I rkd.fl 92 Example 55 Preparation of 3-[2-Butyl-1-(2-dimethylamino-ethyl)-1H-benzoimidazol-5-y]-N hydroxy-acrylamide (57) [0292] The titled compound (57) was prepared according to the procedures 5 described In Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100%, tR = 0.42 min. LC-MS m/z: 331 ([M + H]*), 'H NMR (DMSO-de) 6 0.97 (31, t, J = 7.3 Hz), 1.49 (31, m), 1.83 (2H, m), 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 = 8.6 Hz), 7.93 (1H, d, J = 8.6 Hz), 7.97 (1H, s), 10.68 (2H, bs). 10 Example 56 Preparation of 3-[2-Hexyl-1-(2-dimethylamino-ethyl)-1H-benzolmidazol-5-y]-N hydroxy-acrylamide (58) [0293] The titled compound (58) was prepared according to the procedures 15 described In Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100%, tR = 0.42 min. LC-MS m/z: 359 ([M + H]'). 1 H NMR (DMSO-d) 8 0.89 (3H, t, J = 6.9 Hz), 1.28-1.54 (6H, m), 1.85 (2H, m), 2.92 (OH, s), 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, s), 10.68 (2H, bs). 20 Example 57 Preparation of 3-(1-(2-Diethylamino-ethyl)-2-[2-(2,2-dimethyl-proplonylamino) ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-serylamide (61) [0294] The titled compound (61) was prepared according to the procedures 25 described below, Steps I & 2 were performed as in Scheme I: Step 3: 0 0 0 N 8nC1 2 2H 2 0, H 2 N N ," AcOH, MeOH, N 45"DC [0295] To a pre-stirred solution of 3-[4-(2-diethylemino-ethylamino).3.nitro-phenyl] 30 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 YMiaNXJ NO DELETEMF5I5 AJ $Smand Fnh&sionalPal as Fillee 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)-pheny-acrylic acid methyl ester was obtained in 54.9% yield (207.6 mg). LOMS m/z: 292 ([M+K]'). 5 Step 4 HNoo NN '- /0m 4 PEDcOB ,H 20 C + DiEA, 0CM y OH room temp. HN [0296] To a pre-stirred solution of 3-[3-amino-4-(2-diethylamino-ethylamino)-phenyl] 10 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)-N'-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 15 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-diethylamino ethylamino)-phenyl]-acrylic acid methyl ester was obtained In 67.3% yield (2.54 g). 20 LCMS m/z; 571 ([M+H]*). Step 5 Fmm,' o HNO 'C0O 2 MO Fmoc-NH N CO2Me HI AcOH,70 0 C N rN~ ceti acd (89 mL wa [0297] Glacial acetic acid (8.9 ml) was added into 3-[3-amino-4-(2-diethylamino 25 ethylamino)-phenyl]-acrylic acid methyl ester (61-4, 2.54 g, 4.46 mmol) and the reaction mixture was stirred at 70 "C 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 VVIAyNO =ETrniOSQSQ AU) 8.i PawWMal F&aili 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-9 ylmethoxycarbonylamino)-methyl]-1 H-benzoimidazol-5-yl}-acrylic acid methyl ester (61 5) was obtained in 66.1 % (1.02 g). LCMS mlz 553 ([M+H]'). 5 Sep Step S Fmoo-NH N CO 2 M. H 2 N N - CN 0 2 Me N piporidine, DCM, rm trp [0298] To a pre-stirred solution of 3-(1-(2-dethylamino-ethyl)-2-[(QH-fluoren-9 10 ylmethoxycarbonylamino)-methy]-IH-benzolmdazol-5-yl}-acrylic acid methyl ester (61. 5, 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 Un 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)-1H 15 benzoimidazol-5-yI]-acrylic acid methyl ester was obtained as powder. LCMS mfz: 331 ([M+H]*). Step 7 HaN N coM NH N cOMe DEA, DoCM 20 [0299] To a pre-stirred solution of 3-[2-aminomethyl-1-(2-diethylamino-ethyl)-1H benzoimidazol-5-y]-acrylic acid methyl ester (61-6. 0.10 g, 0.23 mmol), N,N diisopropylethylamine (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 25 was stirred at room temperature for ih. When the reaction has completed, ethyl acetate (20 nL) 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-propionylamino)-methyl]-1H-benzolmidazol YVM K NI NO DELEl'WPIOM AUStead PWisPliul Uilide- 95 5-yl)-acrylic acid methyl ester (61-7) was obtained in 76.6 % (74.1 mg), L.CMS m/z: 415 ([M+H]*). Step 8

NH

2 OHNHHCI, "KO N NCon eN20H .C N NH NaOMe, MeOH 5K 215.-78C [0300] To a stirred solution of 3-{1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl propionylamino)-methyl]-1H-benzoimidazol-5-y)-acrylic acid methyl ester (61-7, 73.8 mg, 0.18 mmol) and hydroxylamine hydrochloride (124 mg, 1.78 mmol) in MeOH (0.3 10 mL) was added sodium methoxide (30% in methanol) (0.8 mL, 3.6 mmol) at - 78 "C. 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. IN HCI was then added slowly into the reaction mixture at 0 0C. The desired product was separated by reverse phase preparative HPLC. After lyopholyzation, 22.2 mg (24.3 %) of 3-{1-(2 15 diethylamino-ethyl)-2-[(2,2-dimethyl-proponylamino)-methyl]-1 H-benzoimidazol-5-yl) N-hydroxy-acrylamide was obtained as powder. HPLC purity: 99.5%, tR = 0.94min. LCMS m/z: 416 ([M+H]'). tH NMR (CD 3 OD) 8 7.89 (a, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.4 Hz, IH), 7.55 (d, J= 15.8 Hz, 1H), 6.53 (d, J 15.8 Hz, 1iH), 4.98 (t, J= 7.3 Hz, 21-), 4.73 (s, 2H), 3.75 (t, J = 7.5 Hz, 2H), 3.42 (q, J= 7.2 Hz, 411), 1.37 (t, J = 20 7.3 Hz, OH), 1.22 (s, 9H); "C NMR (CDaOD) a 182.5, 168.9, 162.2, 181.9, 154.8, 140.8,137,9,135.0,133.9,126.0,119.3, 117.1,112.9, 50.9, 40.5, 39.7, 36.7,27.6, 9.1. Example 58 Preparation of N-(2..1-(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoy-vinyl)-1H 25 benzoimidazol-2-yI]-othyl).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-M$ m/z: 444 ([M+ H]+). 30 YM fhOrI HMDETI'L WH4SAU gindPtcrtlnd Phiil. fsid 96 Example 59 Preparation of N-[1- 2-Diethylamino-ethyl)-5-(2-hydroxycarbamoy-vinyl)-1 H benzoimidazol-2-ylmethyl).butyramide (62) [03021 The titled compound (62) was prepared according to the procedures 5 described in Example 57, by using appropriate starting materials. HPLC purity at 254 nm: 88.1 %; tR = 0.58 min; LCMS m/z: 402 ([M + H]*). 'H NMR (CD 3 OD) 8 7.88 - 7.56 (m, 2H), 7.73 (s, IH), 7.60 (d, J = 15.8 Hz, IH), 6.51 (d, J = 15.8 Hz, 1H), 4.99 - 4.79 (m, masked peaks), 4.81 (s, 2H), 3.74 (t, J = 7.8 Hz, 2H), 3,46 - 3.41 (m, 4H), 2.31 (t, J 7.4 Hz, 2H), 1.39 (t, J = 7.2 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H); 3 C NMR (CD 3 OD) a 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, 9.0. Example 60 Preparation of 3-[2-(3,3-Dimethyl-butyl)-1 -(2-ethylamino-ethyl)-1 H-benzoimidazol 15 5-yIj-N-hydroxy-acrylamide (63) (0303] The titled compound (63) was prepared according to the procedures described in Example 1, by using appropriate starting materials, HPLO: 99.0 %; tR = 0.93 min; LCMS m/z: 359 ([M + H]'). 'H NMR (CD 3 OD) a 7.5 (d, J = 8.4 Hz, 1H), 7.75 - 7.74 (m, 2H), 7.16 (d, J = 15.7 Hz, 1H), 6.31 (d, J = 15.7 Hz, 1H), 4.89 (brs, 2H), 3.72 20 (bra, 2H), 3.29 - 3,18 (m, 4H), 1.90 - 1.86 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.09 (s, 911); 130 NMR (CD 3 OD) 8 165.7, 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 25 Preparation of 3-[1-2-Dimethylamino-ethyl)-2-(3,3-dimethyl-butyl)-1H benzoimidazol-5-yl]-N-hydroxy-acrylamide (64) [0304] The titled compound (64) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC: 99.0 %; tt = 0.83 min; LCMS m/z: 359 ([M + H]'), IH NMR (CD 3 0D) 5 7.94 (d, J = 7.8 Hz, IH), 7,81 30 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 15.7 Hz, 1H), 6.64 (d, J = 15.7 Hz, 1H), 4.93 (bra, 2H), 3.76 (brs, 2H), 3.22 (t, J = 7.7 Hz, 2H), 3.09 (s, 6H), 1.91 - 1.87 (m, 2H), 1.08 (s, 9K); "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. 35 Example 62 Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-N hydroxy-acrylamide (65) YMurKIt3O DSZSI OPm9 S Au Mod yEmd nl ni PIe-dw 97 (0308] The titled compound (65) was prepared according to the procedures 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]'). 'H NMR (DMSO-d 6 ) 8 0.89 (3H, m), 1.38 (41H, m), 1.83 (2H, rn), 2.93 (6H, s), 3.04 (2H, n), 3.50 (21-, t), 4.70 (2H, m), 5 6.55 (1H, d), 7.57 (1H, d), 7.81 (1H, m), 7.81 (2H, m), 10.42 (1H, bs). Example 63 Preparation of 3-[1-(2-Dimethylamino-sthyl)-2-(2,2,2-trifluoro-ethyl)-1H benzolmidazol-5-y]-N-hydroxy-acrylamide (64) 10 [0306] The titled compound (64) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 91.1%; tR = 0.68 min. LOMS m/z: 357 ([M+H]'). Example 64 15 Preparation of 3-[1-(2-Ethylamino-sthyl)-2-pentyl-1 H-benzoimidazol-6-y]-N hydroxy-acrylamide (68) [0307] The titled compound (88) 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: 345([M+H]*). 20 Example 65 Preparation of N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-penty-1H benzolmidazol-5-yl].acrylamide (71) [0308] The titled compound (71) was prepared according to the procedures 25 described in Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 97.4%; tR = 0.95 min. LCMS m/z: 359 ([M + H]'). 1 H NMR (DMSO-ds) 8 0.89 (3H, m), 1.22 (6H, d), 1.38 (4H, m), 1.82 (2H, m), 2.99 (3H, m), 4.56 (2H, m), 6.51 (11, d), 7.59 (2H, d), 7.64 (1H, m), 7.88 (11H, m), 8.74 (21, bs). 30 Example 66 Preparation of 3-[2-Hexyl-1-(2-methylamino-ethyl)-4H-benzoimidazol-5-yl]-N hydroxy-acrylamide (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 35 nm: 96.0%, tR = 1.12 min. LCMS m/z: 345 ([M+H]'). 'H NMR (CD 3 OD) 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 (21-, d, J = 5.7 Hz), 3.49 (2H, be), 3.15 (2H, dt, J = 4.8 Hz), 2.71 (3H, s), 1.85 (2H, qn, J = Y:*4"Ky NO PELETIFPIO-4i AU kSO PMV4iWiu Fonai ist ng 4el 98 5.1 Hz), 1,46 (2H, m), 1.33 (41-, m), 0.85 (3H, t, J = 7.1 Hz); 1 C NMR (CDaOD) a 163.7, 157.8, 138.5, 132.7, 124.2, 117.0, 113.7, 111.2, 40.2, 32.2, 30.5, 28.0, 25.6, 25.1, 21.6, 12.3. 5 Example 67 Preparation of N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-pentyl-1H-benzoimidazol. 5-ylj-acrylamide (75) [03101 The titled compound (75) was prepared according to the procedures described In Example 1, by using appropriate starting materials. HPLC purity at 254 10 nm: 97.8%; tR = 0.80 min. LCMS m/z: 331 ([M + H]'). 1 H NMR (DMSO-d) 8 0.89 (3H, m), 1.38 (4H, m), 1.84 (2H, m), 2.51 (3H, s), 3.14 (2H, m), 3.38 (2H, t), 4.70 (2H, m), 6.57 (1H, d), 7.62 (1H, d), 7.73 (1H, m), 7.96 (2H, m), 9.13 (2H, a). Example 68 15 Preparation of 3-(2-Butyl-1-pyrrolidin-3-yl-1H-benzolmidazol-5-yl)-N-hydroxy acrylamide (69) 0N N O O HN ' cE EN c 50a, MeO/ AcOH i N Heat boo boo 04 4 0 N N NN NHOH sos HCIIMeOH NH2OH NIHO Step1 (0311] To a solution of methyl trans-4-Chloro-3-nitrocinnamate (la, 4.8 g, 20 mmol) in 20 triethyl amine (5.5 mL, 40 mmol) was added 3-Amino-pyrrolidine-1-carboxylic acid tert butyl 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-Chlcro-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 "C, then reaction was quenched by adding 200 mL of DCM and 80 25 ML of 1M HCI solution. After separation of DCM layer, the aqueous solution was extracted 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 (2:1) until the orange Y; Hn44KNO DM&XfWI.OQjS $@O R W fto OLau AO U tiI ..

99 color band was completely rinsed down. After removal of solvent under reduced pressure, the residue 69-2 was obtained (around 80% of yield in most of cases) as orange solid, which is pure enough (95% purity from HPLC) for next step. LC-MS m/z: 292 ([M-Boc +H]*). 5 Step 2 [0312] To a solution of compound 69-2 (7.84 g, 20.0 mmol) in 100 mL of MeOH and AcOH mixture (1;9) 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 0C for 24 hrs. Then 10 the mixture was diluted using ethyl acetate (300 mL) at room temperature, and was then quenched with sat. sodium carbonate (30 mL). The resulting mixture was stirred for additional 1 hour, then organic layer was decanted to another conic flask. Solid left 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 15 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, 44%). LC-MS m/z: 456 ([M + H]'). 20 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 ([M + 25 H]*). Step 4 [0314] To a solution of above crude 69-4 (around 0.16 mmol) product in MeOH (0.5 mL) was added a pre-prepared NH 2 OH stock solution (2.0 M, 2 mL). The resulting 30 mixture was stirred at room temperature for 2 hr. 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 rn/z: 329 ([M + H]*), 'H NMR (CO 3 QD) 8 0.95 (3H, t, J = 7.2 Hz), 1.46 (2H, m), 1.77 (2H, m), 2.52-2.82 (21-, m), 3.10-3.17 (2H, m), 3.48 (1H, m), 3.80 (2H, m), 5.55 (1H, 35 m), 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). v.y Kno DELETB\PPIWQQS AU ZOd ftvkinal Fllrs U FlIAe 100 Example 69 Preparation of 342-Butyl-1 -piperidin-4-y-1 H-benzoimidazol-5-y)-N-hydroxy acrylamide (70) [0315] The titled compound (70) was prepared according to the procedures 5 described In Example 78, by using appropriate starting materials. HPLC purity: 98%; LCMS m/z: 343 ([M + H]*). 'H NMR (CD3OD) 5 0.96 (3H, t, J = 7.2 Hz), 1.46 (2H, in), 1.79 (2H, rn), 2.21 (2H, in), 2.82 (2H, m), 3.10-3.17 (2H, in), 3.26 (1H, m), 3.60 (2H, in), 4.96 (1H, m), 6.49 (11-1, d, J = 15.8 Hz), 7.60 (1H, d, J = 15.8 Hz), 7.66 (1H, d, J 8.0 Hz), 7.82 (1 H, s) (1 H, d, J= 8.0 Hz). 10 Example 70 Preparation of 3-2-Hexyl-1-pyrrolidin-3-yl-1H-benzolmidazol-5.yl)-N-hydroxy acrylamide (80) [0316] The titled compound (80) was prepared according to the procedures described 15 in Example 68, by using appropriate starting materials. HPLC purity: 98%; LCMS m/z: 357 ([M + H]*). 1 H NMR (CDaOD) 8 0.84 (3H, t, J = 7.2 Hz), 1.22-1.38 (41, in), 1.44 (2H, in), 1.81 (2H, m), 2.52-2.82 (21-, m), 3.10-3.17 (2H 1 , m), 3.48 (1H, n), 3.80 (2H, m), 5.56 (1H, m), 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, s), 7.90 (1 H, d, J = 9.2 Hz). 20 Example 71 Preparation of 3-[2-Butyl-1-(1-methyl-pyrroidin-3-y)-1H-benzoimidazol-5-yl]-N hydroxy-acrylamilde (81) [0317] The titled compound (81) was prepared according to the procedures described 25 in Example 68, by using 69-4 via reductive amination to introduce a methyl group. HPLC purity: 98%; LCMS m/z: 343 ([M + H]*). 'H NMR (CDaOD) 8 0.99 (3H, t, J = 7.2 Hz), 1.52 (2H, m), 1.83 (2H, m), 2.65-2.92 (2H, m), 3.09 (3H, s), 3.15-3.25 (2H, m), 3.58 (1H, br.), 3.90 (2H, m), 5.73 (1H, in), 6.51 (1H, d, J = 16.0 Hz), 7.58 (iH, d, J = 16.0 Hz), 7.69 (1H, d, J= 8.0 Hz). 7.88 (1H, s), 8.00 (1 H, d, J= 9.2 Hz). 30 Example 72 Preparation of 3-(2-Hexyl-1-piperldin-3-yl-1H-benzolmidazol-5-yl)-N-hydroxy acrylamide (82) [0318] The titled compound (82) was prepared according to the procedures described 35 in Example 68, by using appropriate starting materials. HPLC purity; 97%; LCMS m/z: 343 ([M + H]*). 1 H NMR (CDsOD) 8 0.99 (3H, t, J = 7.2 Hz), 1.52 (2H, m), 1.84 (21-, m), 2.04 (1H, m), 2.20 (2H, m), 2.81 (1H, m), 3.12-3.22 (2H, m), 3.49 (1H, n), 3.67 (1H, VfIi U NO DELEIFVFiO,-5 A, Igd .Fnignaal sd .IblLd 101 n), 3.78 (1H, t, J = 12.0 Hz), 4,98 (1H, m), 6.53 (1H, d, J = 15.8 Hz), 7.63 (1H, d, J = 15,8 Hz), 7.70 (1H, d, J= 9.2 Hz), 7.86 (1H, s), 8.06 (1H, d, J= 8.8 Hz). Example 73 5 Preparation of 3-(2-Butyl-1-piperidin-3-yl-1H-benzoimidazol.5-yl).N.hydroxy acrylamide (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 ((M + H]*). 1 H NMR (CD3OD) 8 0.88 (3H, t, J = 7.2 Hz), 1.22-1.42 (4H, m), 1.47 10 (2H, m), 1.84 (2H, m), 2.04 (1H, m), 2.20 (2H, m), 2.62 (1H, m), 3.12-3.22 (2H, m), 3,48 (1H, m), 3.68 (1H, m), 3.78 (1H, t, J= 12.0 Hz), 5.01 (1H, m), 6.53 (1H, d, J= 15.8 Hz), 7.62 (1H, d, J 15.8 Hz), 7.70 (1H, d, J = 9.2 Hz), 7.86 (1H, s), 8.06 (1H, d, J = 8.8 Hz). 15 Example 74 Preparation of (E)-N-hydroxy4-(1-(1-methylpiperidin4-3yl)-2-pentyl.-1 H benold]imidazol-5-yl)acrylamide (86) [0320] The titled compound (88) was prepared according to the procedures described in Example 71, by using appropriate starting materials.HPLC purity: 99.3 %, tR =1.06 20 min; LCMS m/z: 371 ([M + H]). 'H NMR (CD 9 0D) 8 8.18 (d, J = 7.9 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J= 8.1 Hz, IH), 7.61 (d, J= 15.7 Hz, IH), 6.58 (d, J= 15.7 Hz, 1H), 5.21 (brs, 1H), 3.89 (brs, 2H), 3.69 - 3.66 (m, 1H), 3.37 - 3.27 (masked peaks), 3.03 (a, 3H), 2.68 (bra, 1H), 2.29 -- 2.22 (m, 3H), 1.94 - 1.90 (m, 2H), 1.54 - 0,94 (m, 4H), 0.96 (t, J = 7.1 Hz, 3M); 13C NMR (CD 3 OD) 8165.6, 157.6, 139.9, 134.6, 134.1, 132.5, 126.3, 25 120.4, 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 75 Preparation of (E)-3-(2-hexyl-1-(1-42-hydroxyethyl)piperIdin4-y)-1H benzo[d]imidazol,5-yl)-N-hydroxyacrylamide (90) 30 [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 ([M + H]*). 35 102 Example 76 Preparation of N-Hydroxy-3.[1-(1-pentyl-piperidin-3yl)-1H-benzolmidazol-5-yl] acrylamide (94) [0322] The titled compound (94) was prepared according to the procedures described 5 in Example 8, by using appropriate starting materials (formic acid for benzimdiazoel ring formation and reductive amination of the piperidine with pentanal). HPLC purity: 95%; LC-MS mlz: 357 ([M+H]*). 1 H NMR (CDaOD) 6 9.04 (s, IH),.7.94 (brs, 2H), 7.78 (d, 1H, J= 8.2 Hz), 7.70 (d, IH, J - 16.7 Hz), 6.57 (d, IH, Jm 15.9 Hz), 5.14 - 5.10 (m, 1H), 3.85(dd, 2H, J = 88.0, 9.0 Hz), 3.48 - 3.13 (m, 4H), 2.43 - 2.12 (m, 4H), 1.94 10 1.80 (m, 2H), 1.39 - 1.29 (m, 4H), 0.94 (t, 3H, J= 6.8 Hz). Example 77 Preparation of N-Hydroxy-3*[1-(1-phenethyl-piperidin-3-y)-1H-benzoimidazol-5 yl]-acrylamide (96) 15 [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: 391([M+H]*). 'H NMR (CD 3 OD) 8 8.93 (s, IH), 7.95 (s, 1H), 7.91 (d, 1H, J - 8.5 Hz), 7.76 (d, IH, J = 8.5 Hz), 7.70 (d, 1H, J = 15.8 Hz), 7.35 - 7.24 (m, 6H), 6.56 (d, 1H, J = 15,7 Hz), 5.10 (t, 1H, J = 11.4 Hz), 3.91 (dd, 2H), 3.55 - 3.46 (m, 2H), 3.15 20 3.11 (m, 2H), 2.46 - 2.13 (m, 6H). Example 78 Preparation of N-Hydroxy.3-(1-[1-(3-phenyI-propyl)-piperidin4-y]-1 H benzoimidazol-5-yl)-acrylamlde (97) 25 [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 ([M+Hl') 1 H NMR (CDsOD) 8 8.68 (s, 1H), 7.94 (s, 1H), 7.80 (d, 1H, J M 8.4 Hz), 7.71 (d, 1H, J= 15.7 Hz), 7.69 (d, IH, J= 8.2 Hz), 7.31 - 7.17 (m, SH), 6.54 (d, 1H, J= 15.6 Hz), 3.71 (dd, 2H, J = 66 Hz, 10.9 Hz), 3.48 - 3.40 (m, 1H), 3.13 - 3.05 (m, 2H), 30 2.73 (t, 2H, J = 7.4 Hz), 2.38 - 2.04 (m, 8H); Example 79 Preparation of 3-(1-[1-(3,3-Dimethyl-butyl)-pyrrolldln.3yl]-1H-benzolmidazol-5 yl).N-hydroxy-acrylamide (99) 35 (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 ([MH]*). 'H NMR (DMSO-de) 8 0.91 (SH, s), 1.52 (4H, m), 3.09 f.*Mt2i2C NO DELETWFlI0U. AUh ea mmmlu nI uMldm 103 (1H, M), 3.29 (6H, m), 8.52 (1H, d), 7.43 (2H, M), 7.62 (1H, m), 7.80 (1H, m), 8.82 (1 H, s), 10.25 (1H, bS). Example 80 5 Preparation of 3-(1-[2-Ethyl-methyl-amino)-ethyl]-2.pentyl-1H-benzolmidazol-5 yl-N-hydroxy-acrylamide (79) [0326] The titled compound (79) was prepared according to the procedures described in Example 1, by using appropriate starting materials. HPLC purity: 99%; tft = 0.68 min, LC-MS m/z: 359 ([M+H]'). IH NMR (DMSO-ds) 5 0.89 (3H, m), 1.23 (3H, m), 1.38 (4H1, 10 m), 1.84 (2H, m), 2.92 (3H, a), 3.10 (211, m), 3.28 (2H, m), 3.52 (211, m), 4.77 (2H, m), 6.58 (1H, d), 7.61 (11H. d), 7.71 (1H, m), 7.92 (2H, m), 10.48 (1H, bs), Example 81 Preparation of 3-{2-Butyl-1 -[2-(ethyl-methyl-amino)-ethyl]-1 H-benzoimidazol-5-yl) is N-hydroxy-acrylamide (85) [0327] The titled compound (85) was prepared according to the procedures described in Example 1, by using appropriate starting materials, HPLC purity: 95.8%; t =1.04 min. LC-MS m/z: 345 ([M+H]r). 'H NMR (DMSO-dg) 5 0.95 (3H, m), 1.25 (3H-, m), 1.46 (2H,r m), 1.81 (2H, m), 2.92 (311, s), 3.13 (211, m), 3.27 (211, m), 3.54 (211, m), 4.80 (2H, 20 m), 6.60 (1 H, d), 7.62 (1H, d), 7.75 (1 H, m), 7.92 (2H, m), 10.59 (1H, bs). Example 82 Preparation of 3-(2-Butyl-1- 2.[ethyl.(3-hydroxy-propyl)-amino]-ethyl)-1 H benzolmidazol-5-yl)-N-hydroxy-acrylamide (91) 25 [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 (m/z): 389 ([MH]'). 'H NMR (DMSO-dg) 8 0.94 (3H, m), 1.25 (311, m), 1.46 (2H, m), 1.83 (4H, m), 3.04 (211, m), 3.31 (411, m), 3.50 (4H, m), 4.72 (211, m), 6.54 (1H, d), 7.61 (11H, m), 7.69 (1H, m), 7.80 (1H, m), 7.90 (11H, m), 10.20 (1H, bs). 30 Example 83 Preparation of 3-(1 -[2.[Ethyl-(3-hydroxy-propyl)-amino]-ethyl}-2-pentyl-1 H benzolmldazol-5-y)-N-hydroxy-acrylamide (92) [0329] The titled compound (92) was prepared according to the procedures described 35 in Example 1, by using appropriate starting materials. HPLC purity: 93.5%; tR = 0.50 min. LC-MS (m/z): 389 ([M+H]') 'H NMR (DMSO-d) 8 0.94 (3H, m), 1.25 (311, m), 1.46 Y!'MMX M~ DELNIPIICM AUl beRA ks961f 9 nUL AmnsaJM 104 (2H, m), 1.83 (4H, m), 3.04 (2H, m), 3.31 (4H, m), 3.50 (4H, m), 4.72 (211, m), 6.54 (1H, d), 7.61 (1 H, m), 7.69 (1 H, m), 7.80 (1 H, m), 7.90 (1 H, m), 10.20 (1 H, bs). Example 84 5 Preparation of 3-{1-[2-(Butyl-ethyl-amino)-ethyl]-1H-benzolmidazol-5-yl-N hydroxy-acrylamide (95) [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 m/z: 331 ([M+H]*). 'H NMR (CD 3 OD) 8 9.29 (s, IH), 7.99 - 7.95 (m, 21-), 7.82 (d, 1H, J 10 = 8.5 Hz), 7.56 (d. 1H, J = 15.6 Hz), 6.53 (d, 1H, J = 15.5 Hz), 5,0 - 4.95 (m, 2H), 3.86 -3.78 (m, 2H), 3.42 (dd, 2H, J A 13.3, 7.1 Hz), 3.28 - 3.28 (m, 2H), 1.74 - 1.71 (m, 21-), 1.43 (qt, 2H, J = 7.4, 3.8 Hz), 1.38 (t, 3H, J = 7.2 Hz), 1.00 (t, 3H, J = 7.3 Hz). Example 85 15 PreparatIon of 3-[2-(4-Cyano-butyl)-1-(2-dlethylamino-ethyl)-1H-benzolmidazol-5 yl]-N.hydroxy-aorylamide (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 ([M+H]'). 'H NMR (CD 3 OD) 5 7.78 (1H, s) 7.76 (1 H, d, J = 8.5 20 Hz), 7.83 (1H, d, J = 16.9 Hz), 7.58 (1H, d. J = 5.1 Hz), 6.44 (1 H, d, J= 15.3 Hz), 4.70 (211, in water peak), 3.50 (2H, t, J = 7.6 Hz), 3.32 (411, qt, J = 7,3 Hz), 3.07 (211, t, J= 8.0 Hz), 2.50 (211, 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). 25 Example 86 Preparation of 3-11-[2-(Butyl-isopropyl-amino)-ethyl]-1H-benzolmidazol-5-yl)-N hydroxy-acrylamide (103) [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= 133 30 min. LC-MS m/z: 345 ([M+H]*). 'H NMR (DMSO-de) 5 0.90 (311, m), 1.25 (611, d), 1.35 (2H, m), 1.64 (2H, in), 3.09 (2H, in), 3.51 (1-1, rn), 3.73 (2H, m), 4.74 (21-, m), 6.52 (1H, d), 7.53 (21-, m), 7.64 (1H, m), 7.80 (1 H. m), 8.62 (11H, m), 9.40 (11H, bs), 10.72 (11H, bs). 35 V'%ITMSE NO DELZTZOPVIQM0 AV a~d ftwP~M.AS $aM 00 FldCU 105 Example 87 Preparation of N-Hydroxy-3-(1-[2-(Isopropyl-pentyl-amino)-thyl]-1 H benzaimidazol-5-yI)-acrylamide (109) [0333] The titled compound (109) was prepared according to the procedures described 5 in Example 76, by using appropriate starting materials. LC-MS mfz: 359 ([M+H]*). 1 H NMR (DMSO-de) 8 0.88 (3H, t), 1.25 (10H, m), 1.64 (2H, m), 3.12 (2H, m), 3.51 (1H, b), 3.60 (1H, b), 3.73 (1H, b), 4.74 (2H, t), 6.51 (1H, d), 7.59 (1H, s), 7.63 (1H, d), 7.80 (1H, d), 7.93 (1H, a), 8.65 (1H, a), 9.46 (IH, b) 10 Example 88 Preparation of 3-[2-(5-Cyano-pentyl)-1-(2-diethylamino-ethyl)-1H-benzoimidazol 5-yikN-hydroxy-acrylam ide (110) [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%, is LC-MS (ESI) n/z: 347 ([M+H]'). 1-1 NMR (CD 3 OD) 8 7.96 (1H, d, J= 8.5 Hz), 7.90(1 H, 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), 3.69 (21-1, t, j a 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, m), 1.78 (2H, m, J = 7.4 Hz), 1.70 (2H, m, J = 6.4 Hz), 1.41(3H, t, J = 7.2 Hz); 20 Example 89 Preparation of 3-(1-{2-[(3,3-Dimethyl-butyl)-ethyl-aminob-ethyl)-1H-benzoimidazol 5-yl)-N-hydroxy-acrylamide (111) [0335] The titled compound (111) was prepared according to the procedures described 25 in Example 76, by using appropriate starting materials. TFA salt. HPLC purity: 97.7%; LC-MS m/z: 359 ([M+H]'). 1 H NMR (CD 3 OD) 8 9.10 (s, 1H), 7.89 (d, 1H, J = 8.9 Hz), 7.88 (s, 1H), 7.74 (d, 1H, J = 8.6 Hz), 7.51 (d, IH, J = 15.7 Hz), 6.46 (d, 1H, J = 15.7 Hz), 4.98 - 4,93 (m, 2H), 3.77 - 3.75 (m, 2H), 3.38 (dd, 2H, Jw 13.3, 7.2 Hz), 3.22 3.18 (m, 2H), 1.60 - 1.59 (m, 2H), 1.33 (t, 3H, J= 7.1 Hz), 0.91 (a, 9H); 30 [0336] HCI salt. 1 H NMR (DMSO-de) 8 9.90 (bs, I H), 8.65 (s, I H), 7.93 (s, 1 H), 7.82 (d, 1H, J = 8.5 Hz), 7.64 (d, 1H, J = 8.1 Hz), 7.61 (d, 1H, J = 15.6 Hz), 7.52 (d, IH, J = 15.8 Hz), 4.76 - 4.72 (t, 2H, J = 7.0), 3.65 - 3.60 (m, 2H), 3.32 - 3.24 (m, 2H), 3.17 3.08 (m, 2H), 1.52 - 1,47 (m, 2H), 1.22 (t, 3H, J = 7.2 Hz), 0.87 (s, 9Hz). 35 Y.UtrN NO DfLETLW1f90 AU sMi ftniieMI Fij A, Me A 106 Example 90 Preparation of 3.1-[2-(Ethyl-propyl-amino)-ethylk11 H-bnzoimidazol-5-y}-N hydroxy-acrylamide (112) [0337] The titled compound (112) was prepared according to the procedures described 5 in Example 76, by using appropriate starting materials. HPLC purity: 98.1%; LC-MS mlz: 315 ([M+H]'). 1 H NMR (CD 3 OD) 6 9.43 (s, 1IH), 7.99 (d, 1H, J = 8.5 Hz), 7.93 (s, 1H), 7.82 (d, IH, J= 8.5 Hz), 7.53 (d, 1H, J = 15.7 Hz), 6.50 (d, 1H, J= 15.5 Hz), 5.00 - 4.96 (m, 2H), 3.78 (t, 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 (t, 3H, J = 7.2 Hz), 0.99 (t, 3H, J = 7.3 Hz). 10 Example 91 Preparation of N-Hydroxy-3-(1-(2-[isopropyl-(2-methyl-pentyl)-amino]-ethyl}-1H benzoimidazol-5-yl)-acrylamide (113) [0338] The titled compound (113) was prepared according to the procedures described 15 in Example 76, by using appropriate starting materials. LC-MS m/z: 373[(M+H)']. 'H NMR (DMSO-d)56 0.86 -0.97 (7H, m), 1.14-1.28 (12H, m), 4.70 (2H, b), 6.49 (1H, d), 7.58 -7.62 (2H, m), 7.73 (1H, d), 7.91 (1H, s), 8.48 (1H, s) Example 92 20 Preparation of 3-(1-[2-(Ethyl-hexyl-amino)-ethylb.2-methyl-1H-benzoimidazol-5 yl)-N-hydroxy-acrylamide (116) [0339] The titled compound (118) was prepared according to the procedures described in Example 57, by using appropriate starting materials. HPLC purity at 254 nm: 98.2%, t = 1.27 min. LC-MS (ESI) m/z: 373 ([M+H]*). 'H NMR (CD 8 OD) 8 7.85 (1H, s), 7.78 25 (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 (2H), 3.63 (2H, t, J= 7.7 Hz), 3.41 (2H, qt, J = 7.2 Hz), 3.29 (2H), 2.82 (3H, s), 1.74 (2H, m), 1.37 (11 H, m), 0.93 (3H, t, J = 6.9 Hz). Example 93 30 Preparation of 3-(1 -[2-(Butyl-ethyl-amino)-ethyl]2-trifluoromethyl-1 H benzoimidazol-5-yl)-N-hydroxy-acrylamide (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 ([M+H]'). 'H NMR (CDaOD) 6 7.95 (1-1, a). 7.70 35 (2H, s), 7.62 (1H, d, J= 15.9 Hz), 8.46 (1H, d, J = 15.8 Hz), 5.24 (2H), 3.50 (2H, t, J = 8.8 Hz), 3.31 (2H, qt, J = 7.2 Hz), 3.17 (2H), 1.63 (2H, m), 1.35 (2H, qt, J = 7.5 Hz), 1.29 (3H, t, J = 7.2 Hz), 0.92 (3H, t, J = 7.4 Hz). YV'WUKNODlBETFPl05AUS4mdyroisiadiP Ml d 107 Example 94 Preparation of 3-(1-[2-(Ethyl-hexyl-amino)-ethyl]-2-trifluoromethy-1H benzolmidazol-5-y}-N-hydroxy-acrylamide (118) 5 [0341] The titled compound (118) was prepared according to the procedures described 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 ([M+H]'). 'H NMR (CD 3 00) 5 8.04 (1H, s), 7.80 (21-1, s), 7,72 (1H, d, J = 15.8 Hz), 6.58 (1H, d, J = 15.6 Hz), 4.85 (2H). 3.61 (2H, t, J 8.5 Hz), 3.42 (2H, qt, J = 7.2 Hz), 3.26 (2H), 1.75 (2H-1, m), 1.39 (91-, m, J = 7.5 Hz), 10 0.93 (3H, t, J = 7.0 Hz). Example 95 Preparation of 3-[1-(2-Dipropylamino-ethyl)-1H-benzolmldazol-5-yl]-N-hydroxy acrylamide (120) 15 [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 ([M+H]'). 'H NMR (DMSO-d) 8 0.86 (6H, d), 1.64 (4H, m), 3,09 (4H, m), 3.60 (2H, m), 4.76 (21-, m), 6.53 (1 H, d), 7.55 (2H, m), 7.65 (1 H, m), 7.88 (1 H, m), 8.75 (1 H, m), 9.93 (1H, bs). 20 Example 96 Preparation of N-Hydroxy-3-(1-(2-[isopropyl-(3-methyl-butyl)-amino]-ethyl)-1 H benzolmidazol-5-y)-acrylamide (121) [0343] The titled compound (121) was prepared according to the procedures described 25 in Example 76, by using appropriate starting materials. HPLC purity: 98.7%; tR = 1.02 min. LC-MS (mlz): 358 ([M+H]*). 1H NMR (DM30-de) 8 0.88 (6H, d), 1.28 (6H, m), 1.59 (3H, m), 3.10 (3H, m), 3.68 (2H, m), 4.71 (2H, m), 6.50 (1H, d), 7.50 (2H, m), 7.59 (1H, m), 7.63 (1H, m), 8.52 (1H, m), 9.50 (1 H, bs), 10.70 (1H, bs). 30 Example 97 Preparation of 3-(1-(2-[(3,3-Dlmethyl-butyl)-methyl-aminol-ethyl)-1 H benzolmidazol-5-yI)-N-hydroxy-acrylamide (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%; 35 ta= 0.93 min. LC-MS m/z: 345 ([M+H]J). 'H NMR (DMSO-d 6 ) 8 0.84 (9H, s), 1.52 (2H, m), 2.90 (3H, s), 3.17 (2H, m), 3.68 (2H, m), 4.80 (2H, m), 6,58 (1H, d), 7.59 (2H, m), 7.86 (1H, m), 7.90 (1H, m), 8.82 (1H. m), 10.10 (1H. bs). YtEAM l M DELUflLC90.0AU Sswd Prklnd PiaL u Misdo.

108 Example 98 Preparation of 3.(1-{2-[(2-Ethyl-butyl)-methyl-amino]-ethyl)-lH-benzoimidazol4 yl).N-hydroxy-acrylamide (123) 5 [0345] The titled compound (123) was prepared according to the procedures described in Example 76, by using appropriate starting materials. HPLO purity at 254 nm: 97.7%; tR= 0.87 min. LC-MS m/z: 345 ([M*H]*). 'H NMR (DMSO-d.) 8 0.81 (OH, m), 1.29 (4H, m), 1.89 (1H, m), 2.89 (3H, s), 3.08 (2H, m), 3.59 (2H, m), 4.77 (21-, m), 6.53 (1H, d), 7.52 (2H, m), 7.86 (1H, m), 7.94 (1H, m), 5.80 (1 H, m), 9.54 (1H, bs). 10 Example 99 Preparation of 3-(1-[2-(3,3-Dimethyl-butylamino)-ethyl]-1H-benzoimidazol-5-y)-N hydroxy-acrylamide (126) [0346] The titled compound (126) was prepared according to the procedures described 15 in Example 76, by using appropriate starting materials. HPLC purity; 100%; tR = 1.01 min. LC-MS m/z: 331 ([M+H]*). 'H NMR (DMSO-ds) a 0.88 (9H, s), 1.44 (2H, m), 2.92 (2H, m), 3.50 (2H, m), 4.66 (21-1, m), 6.54 (1H, d), 7.68 (2H, m), 7.82 (1H, m), 7.90 (1H, m), 8.74 (1H, m). 20 Example 100 Preparation of N-Hydroxy-3-(1-[2-(methyl-pent-4-enyl-amino)-ethyl]-1H benzoimidazol-5-yl)-acrylamide (127) [0347] The titled compound (127) was prepared according to the procedures described in Example 78, by using appropriate starting materials. HPLC purity: 100%; tR = 0.92 25 min. LC-MS m/z: 329 ([M+H] 4 ). 'H NMR (DMSO-de) 8 1.17 (21-, m), 2.06 (2H, m), 2.90 (3H, s), 3.10 (2H, m), 3.65 (2H, m), 4.80 (2H, m), 5.03 (2H, m), 5.75 (1H, m), 8.57 (1 H, d), 7.60 (1H, d), 7.69 (1H, m), 7.90 (1H, m), 7.97 (1H, m), 8.92 (1H, m), 10.29 (1 H, bs). Example 101 30 Preparation of 3-(1-{2-[(3,3-DImethyl-butyl)-propyl-amlno]-ethyl)-1 H benzoimidazol-5-yI)-N-hydroxy-acrylamide (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=1.1 8 min. LC-MS m/z: 373 ([M+HJ*). 'H NMR (DMSO-de) & 0.88 (12H, m), 1.51 (2H, m), 1.64 35 (2H, m), 3.10 (4H, m), 3.63 (2H, m), 4.76 (2H, m), 6.54 (1H, d), 7.65 (21-, m), 7.80 (1H, m), 7.94 (1H, m), 8.83 (1H, m), 9.93 (1H, bs). r uNi Nt DO DUE fl9iO0.0 AU Sumd hvmial Fi = PlUids 109 Example 102 Preparation of 3-(1-[2-(3,3-Dimethyl-butylamino)-ethyll-2-propyl-1H benzoimidazol-5-yI)-N-hydroxy-acrylamide (130) (0349 Step 1: Cyclization 0 0 0 2 N-K, N OMe N OM Zn, MeOH/AcOH 50"IC 5 NH 2 50CH 2 N [0350] To the starting material (lla2, 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 (4.12 9, 63 mmol). The resulting mixture was heat up to 50 *C and stirred at this 10 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 15 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 = 25 %, LC-MS m/z: 288 ([M+HJ*. [0351] Step 2: Reductive-amination 20 0 N N o ONN e OM. H No NaCNsH 8 , ACOW MeH NH HzN [0352] To 3-[1-(2-Amino-ethyl)-2-propy-1 H-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 25 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 v'M uitfI b1L1Tb"fl0f0-05AU lqnand rMistabmltalsIuEUSe 110 bicarbonate, water and brine. The combined organic layer, after workup, was purfied by flash chromatography (silica, 4% MeOH In DCM). LC-MS mlz: 372 ([M+H]J), [0353] Step 3: hydroxamic acid formation. 5 The titled compound (130) was prepared according to the procedures described In Example 1 (Step 4), by using appropriate starting materials. TFA salt of 130; HPLC purity: 99.9%: LC-MS mfz: 373 ([M+H]*), 'H NMR (CD 2 OD) 8 7.89 (d, IH, J = 8.6 Hz), 7.81 (s, IH), 7.76 (d, 1H, J = 8.6 Hz), 7.44 (d, 1H, J = 15.7 Hz), 6.44 (d, 1H, J = 15.7 Hz), 4.81 (t, 2H, J = 7.0 Hz), 3.65 (t, 2H, J= 6.4 Hz), 3.23 10 3.19 (M, 2H), 3.16 - 3.12 (m, 2H), 2.01 - 1.94 (m, 2H), 1.65 - 1.61 (m, 2H), 1.16 (t, 3H, 7.3 Hz), 0.96 (s, 9H). HCI salt of 130: HPLC purity; 98,1 %; LC-MS m/z: 373 ([M+H]). 'H NMR (CDOD) 8 8.06 (d, 1H, J = 8.3 Hz), 7.90 (s, 1H), 7.88 (d, 1 H, J r 8.4 Hz), 7.59 (d, 1H, J = 15.8 Hz), 6.56 (d, IH, J = 15.8 Hz), 4.91 - 4.81 (m, 2Hz), 3.60 - 3.66 (m, 2H), 3.31 - 3.35 15 (m, 2H), 3.17 - 3.13 (m, 2H), 2.05 - 1.97 (m, 2H), 1.70 - 1.66 (m, 2H), 1.20 (t, 3H, J= 7.3 Hz), 0.98 (s, 9 H). Example 103 Preparation of 3-[1-[243,3-Dimethyl-butylamino)-ethyl]-2-(2,2.dimethyl-propyl) 20 1 H-benzolmldazol-5-yI]-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: 401 ([M+H]r). 'H NMR (CD 3 OD) 8 7.89 (a, 1H), 7.85 (d, IH, J = 8.5 Hz), 7.77 (d, 1H, J = 8.7 Hz), 7.63 (d, I H, J = 15.8 Hz), 6.55 (d, IH, J = 15.7 Hz), 4.91-4.81 (m, 2H), 25 3.58 (t, 2H, J =6.5 Hz), 3.13-3.08 (m, 4H), 1.63-1.58 (m, 2H), 1.13 (s, 9H), 0.96 (s, 9H). Example 104 Preparation of 3-[1-(2.[Bis-(3,3-dimethyl-butyl)-aminol-ethyl)-2-(2,2-dImethyl 3o propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide (132) f0355] 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: 485([M+H]*). 'H NMR (CDaOD) 6 7.93 (s, 1H), 7.88 (d, 1H, J = 8.5 Hz), 7.80 (d, IH, J = 8.7 Hz), 7.72 (d, 1H, J = 15.8 Hz), 6.59 (d, 1 H, J = 15.8 Hz), 5.00 (t, 2H, J = 6.5 35 Hz), 3.67 (t, 2H, J = 7.5 Hz), 3.13 - 3.08 (m, 2H), 1.68 - 1.64 (m, 4H), 1.14 (s, 9H), 0.96 (s, 18H), Y, NIWJSNWDELETPmIm,. AUIdnPiOtdlavaLinDaUAm idw 111 Example 105 Preparation of 3-(1.[2-(2,2-Dimethyl-propylamino)-ethyl]-iH-benzoimidazol-5-yl) N-hydroxy-acrylamide (133) [0356] The titled compound (133) was prepared according to the procedures described 5 in Example 76, by using appropriate starting materials. HPLC purity: 99.9%; LC-MS m/z: 317([M+H]'). 1 H NMR (CDsOD) 8 8.82 (s, 1H), 7.94 (s, 1H), 7.83 (d, 1H, J = 8.5 Hz), 7.75 (d, I H, J = 8.7 Hz), 7.66 (d, 1H, J = 15.8 Hz), 6.53 (d, 1H, J = 15.8 Hz), 4.92 - 4.78 (m, 2H), 3.64 (t, 2H, J = 7.0 Hz), 2.98 (s, 2H), 1.09 (s, 9H), 10 Example 106 Preparation of 3-(1-(2-[(2,2-Dimethyl-propyl)-propyl-amino]-thyl}-1 H benzoimidazol-5-yI)-N-hydroxy-acrylamide (134) [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 15 m/z: 359 ([M+H]r). 1H NMR (CD 3 0D) 8 9.07 (s, 1H), 7.95 (s, 1H), 7.92 (d, 1H, J = 8.7 Hz), 7.78 (d, 1H, J = 8.4 Hz), 7.66 (d, 1H, J= 15.8 Hz), 6.56 (d, 1H, J= 15.8 Hz), 4.99 - 4.97 (m, 2H), 3.74 (t, 2H = 7.0 Hz), 3.32 - 3.20 (m, 4H), 1.85 - 1.82 (m, 2H), 1.03 (a, 9H), 0.92 (t, 3H, J = 7.1 Hz). 20 Example 107 Preparation of 3-(1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl.1H-benzoimidazol 5-y)-N-hydroxy-acrylamide (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 25 m/z: 359 ([M+H]*). 'H NMR (CD 3 OD) 5 7.69 (d, 1 H, J= 8.0 Hz), 7.54 (s, 1 H), 7.53 (d, IH, J = 9.8 Hz), 6.89 (d, IH, J = 16.1 Hz), 6.08 (d, 1H, J = 15.7 Hz), 4.80 - 4.70 (m, 2H), 3.55 - 3.45 (m, 2H), 3.20 - 3.19 (m, 2H), 2.95 - 2.90 (m, 2H), 1.56 -1.52 (m, 2H), 1.42 (t, 3H, 7.4 Hz). 0.81 (s. 9H). 30 Example 108 Preparation of 3-[1-(2-Diethylaminoethyl)-2-propylamino-1H-benzolmidazol--yl] N-hydroxy-acrylamide (105) [0359] The titled compound (105) was made according to the following synthetic scheme. Yt&6'tmrno DELRprliu04 Au spp4 Fwvowsra an uhiledh 112 0

H

3 N 0~ H)F N HH2N HN '0 and /oNN H f t N DCC N Gndo HN-%occN : NHaOH N NOH NN H /-N) /N [0360] HPLC purity: 100%. 'H-NMR (DMSO-d,) 8 0.97 (3H, t, J = 7.32 Hz), 1.22 (61, m), 1.68 (2H, m), 3.09-3.60 (1OH, in), 6.47 (1H, d, J = 15.80 Hz), 7.52-7.64 (4H, m), 903 (2H, bs), 10.10 (1H, a), 10.81 (1-1, s) 5 Example 109 Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-propylamino-1H benzolmIdazol-5-ylb-N-hydroxy-acrylamide (115) [03611 The titled compound (115) was made by using method analogous to compound 10 (105).HPLC purity: 97%. H-NMR (DMSO-de) 8 0.97 (3H, t, J = 7.28), 1.15 (6H, s), 1.69 (2H, m, J = 7.28 Hz), 2.89 (6H, s), 3.28 (2H, s), 3.42 (2H, m), 4.15 (2H, s), 6.47 (2H, d, J = 15.80), 7.49-7.75 (4H, m), 8.94 (1H, bs), 9.42 (1H, bs), 10.81 (1H, bs), 13.44 (1H, bs). 15 [0362] The following compounds are representative examples prepared by methods disclosed or analogous to those disclosed in above Examples 1-109: Cmpd mla Structure NAME No [M+H] 3-[1-(3-Dimethylamino 2,2-dimethyl-propyl)-2 N (2,2-dlmethyl-propyl) S1H-bsnzoimidazol-5 yl]-N-hydroxy acrylamide Y'WM.NO D&TfIMIWI AW O SMMUPO ftAIN II U FUCUM 113 Cmpd Structure M+H NAME No [M+H]* 3-[1-(3-Dimethylamino 2,2-dimethyl-propyl)-2 2 359 isopropyl-iH benzoimidszol-5-yl]-N hydroxy-acrylamide 3-[2-Butyl-1-(3 N N dimethylamino-2,2 3 373 dimethyl-propyl)-1H benzoimidazol-5-y]-N hydroxy-acrylamide 3-[i-(3-Dimethylamino N N2,2-dimethyl-propyl)-2 4 391 (2-methylsulfanyl ethyl)-1 H benzoimidazol-5-yl]-N hydroxy-acrylamide 3-[1-(3-Dimethylamino 2,2-dimethyl-propyl)-2 5 375 ethoxymethyl-1IH benzoimidazol-5-yl]-N hydroxy-acrylamide 3-[1-(3-Dimethylamino N P~t~bH2,2-dimethyl-propyl)-2 6 373 isobutyl-IH benzolmidazol-5-y]-N hydroxy-acrylamide 3-[1-(2-Diethylamino ethyl)-2-isobutyl-1 IH 7 359 benzoimidazol-5-y)-N hydroxy-acrylamide YMmfl NO DBLETEWPlW AU -0 M d freviioU a u l w iedw 114 Cmpd Structure m/z NAME No [M+H] 3-[2-Butyl-1-(2 Sdiethylemino-ethyl)-1 H 359 benzoimidazol-5-yl]-N hydroxy-acrylamide 3-[2-But-3-ynyl-1 -(3 dimethylamlno-2,2 9 369 dimethyl-propyl)-1 H benzoimidazol-5-yl]-N hydroxy-acrylamide 3-[2-But-3-enyl-1 -(3 dimethylamino-2,2 10 371 dimethyl-propyl)-IH benzoimidazol-5-y]-N hydroxy-acrylamide 3-[2-But-3-enyl-1-(2 diethylamino-ethyl)-1H 11 357 benzoimidazol-5-yl]-N hydroxy-acrylamide NH 3-[2-But-3-ynyl-1-(2 diethylamino-ethyl-1 H 12 355 benzoimidazol-6-y]-N hydroxy-acrylamide OH 3-[l-(3-Dimethylamino F2,2-dimethyl-propyl)-2 13 413 (3,3,3-trifluoro-propyl) 1 H-benzoimidezol-5 yl]-N-hydroxy acrylamide YblA'ifINODKErNiT09Q AU Sfld PMlAiVa1tN HAsJ AcmtfLd 115 Cmpd Structure m/Z NAME No [M+H] 3-[1-(2-Diethylamino N-eethyl)-2-(3,3,3-trifluoro 14 399 propyl)-1 H benzoimidazol-5-yl]-N hydroxy-acrylamide H a-[l-(2-Diethylamino ethyl)-2-ethoxymethyl 15 351 1 H-benzoimidazol-5 yll-N-hydroxy acrylamide 3-[1-(3-Dimethylamino 2,2-dimethyl-propyl)-2 16 331 methyl-IH benzoimidazol-5-y]-N if hydroxy-acrylamide 3-[1-(2-Diethylamino ethyl)-2-(2,2-dimethyl 17 373 propyl)-1 H benzoimidazol-5-y]-N hydroxy-acrylamide N-Hydroxy-3-[1-(3 isopropylamino-propyl) 2-(3,3,3-trifluoro 18 399 propyl)-1H benzoimidazol-5-yl] acrylamide 3-[2-(2,2-Dimethyl propyl)-1-(2 \35 lsopropylamino-ethyl) 19 359 1H-benzolmidazol-5 yl]-N-hydroxy acrylamide yMsMNO DELlPIO- AU ESmd Prmad Maml as Fig|Li 116 Cmpd Structure + NAME No (MIIII 3-1 -(2 Diisopropylamino 20 401 ethyl)-2-(2,2-dimethyl propyl)-1

H

benzoimidazol-5-y]-N hydroxy-acrylamide Diisopropylamino 21 387 ethyl)-2-isobutyl-1 H benzomidazol-5-y]-N hydroxy-acrylamide 3-[l-(3-Dimethylamino 2,2-dimethyl-propyl)-2 399 hex-3-nyl-1 H 22 benzoimidazol-5-yl]-N hydroxy-acrylamide 3-[1-(3-Dimethylamino 2,2-dimethyl-propyl)-2 23 /429 (2,4,4-trimethyl-pentyl) 2 H-benzoimidazo-5 yL]-N-hydroxy acrylamide 3-{2-Cyclohexyl-1 -(3 dimethylamino-2,2 24 399 dimethyl-propyl)-1

H

benzoimidazol-5-yl]-N hydroxy-acrylamide 3-12-Bicyclo[2.2.l]hept - 'N- 5-eii-2-yl-1 (3 25 409 diethylamino-2,2 dimethyl-propyl)-1 H benzoimidazol-5-yl]-N hydroxy-acrylamide V, aIUK ELODMZTVJI0&5 AU seSa nidma lPinll FidAet 117 Cmpd mx NM Structure [M+H) NAM No [~l 3-[l-(2-Diethylamino ethyl).2-hex-3-enyl-1

H

26 385 benzoimidazol-5-yl}-N A hydroxy-acrylamide 3-1 -(2 Dilsopropylamino 27 / 413 ethyl)-2-hex-3-eny-1

H

benzoimidazol-5-yl]-N hydroxy-acrylamide 3-[2-Hex-3-enyl-1,-(2 isopropylamino-ethyl) 28 371 1H-benzolmidazol-5 / yl].N-hydroxy scrylamide 3-[2-HQx-3-eny-1-(3 isopropylamino-propyl) 29 385 1 H-benzoimidazol-5 t yl]-N-hydroxy acrylamide 3-[1-(2-Ethylamino 30 357 ethyl)-2-hex-3-enyl-1

H

benzoimidazol-5-yl]-N hydroxy-acrylamide 3-[1-(2-Diethylamino ethyl)-2-hexyl-l

H

31 387 benzolmidazol-5-y]-N hydroxy-acrylamide Y4M&iVt NO DELgISCPI. Ay geAeU lowild PF- l. M r Ft 118 N-Hydroxy-3-[1-(3 Isopropylamino-propyl) 415 2-(2,4,4-trimethyl pentyl)-1 H benzoimidalol-5-yU acrylamide 3-[2-(2,2-Dimethyl isopropylamino-propyl) 3 H-benzoimidazol-5 yl]-N-hydroxy acrylamide Dilsopropylamino 4 /7 ethyl)-2-(3,3,3-trifluoro propyl)-l

H

benzoimidazol-5-yl]-N hydroxy-acryiamide N-Hydroxy-3-[2 isobutyl-1-(2 35 345 isopropylamino-ethyl) 1 H-benzoimidazol-5 yl]-acrylamide 3-[2-(2,2-Dimethyl propyl)-1-(2 36 345 ethylemino-ethyl)-iH benzoimidazol-5-yQl-N hydroxy-acrylamide 3-[1-(2-Ethylamino ethyl)-2-isobutyl-1

H

37 331 benzoimidazol-5-yl]-N hydroxy-acrylamide TAMUtK0 NO DELNTIOIDH.8 AU lamd Nnisi I i" a anlidae 119 3-[1-(2 Diisopropylamino ethyl)-2-(2,4,4 38 trimethyi-pentyl)-1 H benzoimidazol-5-y]-N hydroxy-acrylamide N-Hydroxy-3-1i-(2 isopropylamino-ethyl) 9 /2-(2,4,4-trimethyl 39 401 pentyl)-1 H benzoimidazol-5-yl] acrylamide 3-[1-(2-Ethylamino ethyl)-2-(2,4,4 40 387 trimethyl-pentyl-1 H benzomidazol-5-yl]-N hydroxy-acrylamide 3-[1 -(2-Diethylamino ethyl)-2-(2,4,4 41 415 trimethyl-pentyl)-l H benzoimidazol-5-yll-N hydroxy-acrylamide 3-[1-(2-Diethylamino / \ MS ethyl)-2-propyl-1

H

-H 35 benzolmidazol-5-yl]-N hydroxy-acrylamide 3-[2-Butyl-1-(2 dilsopropylamino 43 387 ethyl)-1H benzoimidazol-5-yl]-N hydroxy-acrylamide

-

3-[2-ButyI-l-(2 ethylamino-ethyl)-l H 331 benzoimidazol-5-yl]-N hydroxy-acryamide YMVWSINO M DEL~rnPFuDU-d AU lusnd WpfeSinisu Fnil Pedet 120 3-[1 -(2-Diethylamino N ~ etriyl)-z-(2 45 377 mothylsufanyl-thyl) I H-benzolmidazol-5 yl]-N-hydroxy acrylamide 3-[2-Butyl-1-(2 isopropylamino-ethyl) 46 '345 1 H-benzoimidazol-5 yl]-N-hydroxy acrylamide 3-[2-Butyl-1-(3 isopropylamino-propyl) 47 359 1 H-benzoimidazol-5 yl]-N-hydroxy acrylamide 3-[1 -(1 -Benzyl piperidin-4-yi)-2-butyl 48 433 1 H-benzolmldazol-5 yl]-N-hydroxy aCrylamIde 3-[2-But-3-enyl-1 -(2 ethylamino-ethyl)-I

H

49 329 benzolmidazol-5-y]-N hydroxy-acrylamide 3-[2-Hexyl-1-(2 isopropylamlno-ethy) so 373 1H-benzoimidazol-5 yl]-N-hydroxy acrylamide 3-[1-(2-Dimethylamino ethyl)-2-(2,4,4 51 387 trimethyl-pentyl)-i H benzoimidazol-5-yl]-N hydroxy-acrylamide Y:2bMyfKIUIQ DELNUI M*O5 AVSWd fA...I iuali Of PilIeAme 121 3-[i-(2-Ethylamino ethyl)-2-hexyl-1

H

52 359 benzoimidazol-5-y]-N hydroxy-acrylamide N-Hydroxy-3-[1-(2 /1 N Nisopropylamino-ethyl) 2-(3,3,3-trifluoro 53 385 propyl)-1 H H benzoimidazol-5-y] acrylamide 3-[1-(2-Dimethylamino ethyl)-2-hex-3-enyl-1

H

64 357 benzolmidazol-5-yI]-N hydroxy-acrylamide 3-[1-(2-Amino-ethyl)-2 (2,4,4-trimethyl-pentyl) 55 359 1 H-benzomidazol-5 yl]-N-hydroxy acrylamide 3-[i-(2-Amino-ethyl)-2 (2-methoxy-nonyl)-1H 56 403 benzoimidazol-5-yl]-N hydroxy-acrylamide 3-[2-Butyl-1-(2 / OH dimethylamino-ethyl) 57 331 1 H-benzoimidazol-5 yl]-N-hydroxy acrylamide \_ 3-[i-(2-Dimethylamino ethyl)-2-hexyl-1H 58 359 benzoimidazol-5-y]-N hydroxy-acrylamide YUaofAKINO UDLE'P 1o AU eSad rftvisoil Finals Sdos 122 N-{2-[1-(2 Diethylamino-ethyl)-5 (2-hydroxycarbamoyl 59 444 vinyl)-1 H benzoimidazol-2-yll ethyl}-3,3-dimethyl butyramide 3-(1-(2-Diethylamino ethyl)-2-[2-(2,2 dimethyl 60 430 propionylamino)-ethyl] 1 H-benzoimidazol-5 yl)-N-hydroxy ecrylamide 3-{1-(2-Diethylamino ethyl)-2-[2,2-dimethyl 61 416 proplonylamino) methyl]-1 H benzoimidazol-5-yl}-N hydroxy-acrylamide N-[I -(2-Diethylamino ethyl)-5-(2 82 402 hydroxycarb'amoyl vinyl)-1 H benzoimidezol-2 ylmethyll-butyramide 3-[i-(2-ethylamino ethyl) -2-(3,3-dimethyl 83 359 butyl)-I1H benzoimidazol-5-yt]-N hydroxy-acrylamide 3-[2-(3,3-Dimethyl butyQ)-1-(2 S3 Dimethylamino-ethyl) 4 H-benzoimidazol-5 yl]-N-hydroxy acrylamide Y.MutiNOm pEZJIITWio04 AU s3wrd h ii FiL Y4 fmLda 123 3-[i -(2-Dimethylamino ethyl)-2-pentyl-I

H

65 345 benzoimidazol-5-yl]-N hydroxy-acrylamide 3-[I-(2-Dimethylamino ethyl)-2-(2,2,2-trifluoro 66 357 ethyl)-1H benzoimidazol-5-yll-N hydroxy-acrylamide N-Hydroxy-3-[1-(5 methyl-IH-pyrazol-3 yl)-2-(2,4,4-trimethyl 67 395 pentyl)-1H benzoimidazol-5-yl acrylamide 3-[1-(2-Ethylamino N. OH ethyl)-2-pentyl-1

H

68 345 benzoimidazol-5-yl]-N hydroxy-acrylamide 3-(2-Butyl-1-pyrroldin 3-yl-i H-benzoimidazol 69 329 5-yl)-N-hydroxy acrylamide H 3-(2-Butyl-1 -piperidin

-

34H 4-yl-1 H-benzolmidazol 70 343 5-yl)-N-hydroxy acrylamide N-Hydroxy-3-[1-(2 isopropylamino-ethyi) 11 359 2-pentyl-1 H benzoimidazol-5-yll scrylamide YWMarNKINO DBLETBKEFOOO49AU Icadraavisiad rSinPltdP 124 N-Hydroxy-3-[1-(2 methylemino-ethyl)-2 2 385 non-3-enyl-1 H benzomidazol-5-yl] acrylamide N-Hydroxy-3-[1-(2 methylamino-ethyl)-2 non-6-enyl-1 H 73 385 benzoimidazol-5-yl] acrylamide 3-[2-Hexyl-i -(2 1cw N.methylamino-ethyl)-1 H 74 345 benzoimidazol-5-y]-N hydroxy-acrylamide N-Hydroxy-3-[1-(2 * methylamino-ethyl)-2 75 331 pentyl-i H benzolmldazol-5-yll acrylamide N-Hydroxy-3-[1-(2 methylamino-ethyl)-2 76 373 octyl-1 H benzoimidazol-5-yl] N acrylamide 3-(1-(2-Amino-ethyl)-2 octyl-1

H

77 359 benzolmidazol-5-yl)-N hydroxy-acrylamide 3-{2-Butyl-1-[2 (isopropyl-methyl 78 359 amino)-ethyl-1 H benzoimidazol-5-yi}-N hydroxy-acrylamide Y\MWNKI ND DILETEFPI0l4 AU bmd rvkihiml MpI sfiedd- 125 3.41 -[2-(Ethyl-methyl amino)-ethyl]-2-pentyl 359 1 H-benzoimidazol-6 yl}.N-hydroxy acrylamide 3-(2-Hexyl-1-pyrrolidin 0N7 3-yl-1 H-benzoimidazol 80 35-yi)-N-hydroxy ecrylamide 3-[2-Butyl-1 -(1-methyl pyrrolidin-3-yi)-1 H 1 343 benzoimidazol-5-y]-N hydroxy-acrylamide 3-(2-Hexyl-1 -piperidin 3-yl-1 H-benzoimidazol 5-yl)-N-hydroxy acrylamIde 3-(2-Butyl-1-piperidin 3-yI-1 H-benzoimidazol 83 343 5-yI)-N-hydroxy acrylamide 0 3-(1-(2-[Ethyl-(2 N N'OH methoxy-ethyl-amino] 'I H N H ethyl)-2-pentyl-1 H benzolmidazol-5-yl)-N 4 N hydroxy-acrylamide 3.{2-Butyl-1 -[2-(ethyl N N' OH methyl-amino)-ethyl] 85 N 345 1 H-benzolmidezol-5 S5 yl}.N-hydroxy N acrylamide Y.4r,*4JKNO DELENIFWIDSO-S AU umand rffev i l lm FilFios 126 N-Hydroxy-3-[1-(1 N NOH methyl-piperidin-3-y) H 371 2-pentyl- H 861 benzoimidazol-5-yl} N acrylamide 0 3-{1-[2-(Ethyl-hexyl K' N OH amino)-ethyl]-1 H N benzoimidazol-5-yl}-N 87 359 hydroxy-acrylamide N 1 3-{-[2-(Ethyl-pentyl N' -OH amino)-ethyl]-1 H K'I H N benzoimidazol-5-yl}-N 88 345 hydroxy-acrylamide N 0 3-{1-[2.(Ethyl-heptyl H N ~ N OH amino)-ethyl]-1H N Abenzoimidazol-5-y}-Nb 9 hydroxy-acrylamide 89 N7 0 3-{2-Hexyl-1-[1-(2 N H hydroxy-ethyl) /: r

-

I N OH piperidin-3-y]-1

H

90 415 benzoimidazol-5-y)-N N hydroxy-acrylamide OH YN~ufNK ND DULETWFIC9O-s Au semed hvisiea|m Fina in Pld.dm 127 0 3-(2-Butyl-1 -2-[ethyl N NH (3-hydroxy-propyl) N DO- OH amino]-ethyl}-IH 91 389 benzolmidazol-5-y)-N N hydroxy-acrylamide HO 3-(1 -{2-[Ethyl-(3 hydroxy-propyl) amino]-ethyl-2-pentyl 92 403 1H-benzoimidezol-5 yl)-N-hydroxy acrylamide (E)-N-hydroxy-3-(1 -(I phenethylpyrrolidin-3 93 377 yl)-1H benzo[dlimidazol-5 yl)acrylamide (E)-N-hydroxy-3-(l-(1 pentylplperidin-3-y) 94 357 1H-benzo[d]imldazol-5 yN)acrylamide 3-{I-[2-(Butyl-ethyl amino)-ethyl]-1 H 95 331 benzoimidazol-5-yl}-N hydroxy-acrylamide yhl)A24gflO =DRAT 3flOSS AuSeci Pr.-ioM .ui.T f 128 N AH (E).N-hydroxy-3-(1-(1 phenethylpiperidin-3 96 391 yl)-1H bentozd]imidazol-5 yl)acrylamide (E).N-hydroxy-3-(1 -(1 phenylpropyl)piperidin 97 405 3-yl)-1H 98 391$-yI)-1H benzo[dlimidazol-5 yl)acrylamide N NA7z 11 (E)-N-hydroxy-3-(-(l A (3 phylpropyl)pyInoidif 98 391 3-yl)-1 H benzo[d]Imdazo-5 yi)acrylamide m 'N N A

T

3-(1-[1-(3,3-Dinethyl A butyl)-pyrrolidln-3-yJ 99 357 1 H-benzolimidazol-5 yl)-N-hydroxy acrytamide H (diethylamino)Qthyl). 10303 1 H-benzo[dlirnidazol-5 yI)-N hydroxyacrylamide Y:qAr NoDE N LTB\MPt 10n.A ausimod Prvaimo Idmia Filsds 129 3-[2-(4-Cyano-butyl)-1 H (2-diethylamino-ethyl) 101 N384 1H-benzoimidazol-5 yl]-N-hydroxy acrylamide NNH (E)-3-(1 -(1 butylpiperidin-3-y)-1

H

102 343 benzold]imidazol-5-yl) N-hydroxyacrylamide (E)-N-hydroxy-3.(1-(1 (pent-4-enyl)piperidin 103 355 3-yI)-IH benzo[djimidazol-5. 6 N yI)acrylamide / N (E)-3-(1-(1-(3,3. dimethylbutyl)piperidin 104 371 4-yl)-l H benzo[d]imidazol-5-yl) N-hydroxyacrylamide 3-[1-(2-Diethylamino ethyl)-2-propylamino 105 360 H-benzoimidazol-5 yl]-N-hydroxy acrylamide HN (E)-N-hydroxy-3-(1-(2 %I~. H(isopropyl(propyl)amiflo 107 331 )ethyl)-1 H benzo[d]imidazol-5 yY)acrylrmiKve Y;%ItiulC~ mSSSPPLU**5 AU Usc= PMv4diuIo Pi.a llt 130 3-{1-[2-(Butyl isopropyl-amino)-ethyl] 108 345 1 H-benzoimidazol-5 yl}-N-hydroxy acrylamide N-Hydroxy-3-{1-12 (isopropyl-pentyl 109 359 amino)-ethyl]-1 H benzoimidazol-5-yl} -crylamide 3[2-(5-Cyano-pentyl) 1-(2-diethylamino 110 398 ethyl)-IH benzoimidazol-5-yl].N hydroxy-acrylamide N N NA3-(1 -{2-[(3,3-Dimothyl N butyl)ethyl-amino] 359 ethyl}-1

H

benzoimidazol-5-y)-N hydrOxy-acrylmide 3-(1-[2-(Ethyl-propyl amino)-ethyl-1H 112 317 benzolmidazol-5-y}-N hydroxy-acrylamide N-Hydroxy-3-(1-(2 [isopropyl-(2-methyl 373 pentyl)-amino]-ethyl} 1 H-bonzoimidazol-5 yI)-acrylamide fl mAHIo ammlofl. AV I-W. P-W- Phi) a ftdd 131 (E)-N-hydroxy-3-(1-(2 / N(isopropyl(4,4,4 trifluorobutyl)amino)eth 114 399 yl)-1H. benzo[d]imidazol-5 yl)acrylamide 3-[1-(3-Dimethylamina 2,2-dimethyl-propyl)-2 115 314 propylamino-1

H

benzoimidazol-5-yl]-N hydroxy-acrylamide 3-fl-[2-(Ethyl-hexyl amino)-ethyl]-2-methyl 116 373 1 H-benzoimidazol-5 yl)-N-hydroxy acrylamide NH 3-(1-(2-(Butyl-ethyl amino)-ethyl]-2 117 399 trifluoromethyl-1 H benzoimidazol-5-yl)-N hydroxy-acrylamide 3j41 -[2-(Ethyl-hexyt emino)-ethylJ-2 118 427 trfluoromethyl-1

H

benzoimidazol-5-yl}-N hydroxy-acrylamide Y~Mjq4J NO DhV3WLDPOCS AllScu BMWiS VlSIW~ Iifs.*hC & 132 DH (E)-3-(1 -(2 (dibutylamino)ethyl)-2 11e 401 propyl-1H benzo[d]imidazol-5-yl) N-hydmxyacrylamide 3LI (2-Dipropylamino ethyl)-1 H 120 331 benzoimidazol-5-yll-N hydroxy-acrylamide N-Hydroxy-3-(1-{2 [isopropyl-(3-methyl 121 359 butyl)-amino]-ethyl} 1 H-benzoimidazol-5 yI)-acrylamide 3-(1-{2-[(3,3-Dimethyl butyl)-methyl-amino] 122 341 ethyl}- 1H benzoimidazol-5-y)-N hydroxy-acrylamide 3-(1-{2-[(2-Ethyl-butyl) K N methyl-aminc)-ethyl) 123 345 1 H-benzoimidazol-5 yl)-N-hydroxy acrylamide (E)-3-(1-(2-(bis(3,3 dimethylbutyl)amino)et 124 415 hyl)-1H benzo[d]imidazol-5-yl) N-hydroxyacrylamide yaMlyNGSjM DILEBjSWPI0S-S5AU~UdPreviIML NES ufIlSIdDa 133 (E)-3-(1-(2 (diisobutylamino)ethyl) 125 359 1 H-benzo[d]imidazol-5 yl)-N hydroxyacrylamide N OH 3-(1-[2-(3,3-Dimethyl - butylamino)-ethyl]-1 H 126 331 benzoimidazol-5-yl)-N hydroxy-acrylamide N-Hydroxy-3-{1-(2 No (methyl-penta4-enyl 127 329 amino)-ethyll-1 H benzoimidazol-5-yl) acrylamide 3-(1-(2-[(3,3-Dimethyl butyl)-propyl-amino] 128 373 ethyl)-1 H benzoimidazol-5-y)-N hydroxy-acrylamide 3-{1-(3-Dimethylamino 2,2-dimethyl-propyl)-2 129 363 methyl5ulfanyl-1 H benzoimidazol-5-yl]-N hydroxy-acrylamide 3-{1-[2-(3,3-Dimethyl butylamino)-ethyl]-2 130 373 propyl-1 H benzomidazol-5-yl}-N hydroxy-acrylamide Y;\M&sAMJ NDO DEIzTErnhnC AU ISeie fltijigIIl FtDu Flkfl 134 3-[l-[2-(3,3-Dimethyl butylamino)-ethyl]-2 (2,2-dimethyl-propyl) 131 401 1 H-benzoimidazol-5 yl}-N-hydroxy acrylamide 0 ~3-fl1-{2-[Bis-(3,3 / Ndimethyl-butyl)-amino] ethyl}-2-(2,2-dimethyl 132 485 propyl)-1H benzoimidazol-5-y]-N hydroxy-acrylamide H 3-{i-[2-(2,2-Dimethyl propylamino)-athyl]-l

H

133 317 benzoimidazol-5-y)-N hydroxy-acrylamide 3-(1 -{2-[(2,2-Dimethyl propyl)-propyl-amino] 134 359 ethyl}-1 H benzomidezol-5-y)-N hydroxy-acrylamide 3-{1.[2.(3,3-Dimethyl butylamino)-ethyl]-2 135 359 ethyl-1 H NH benzoimidazol-5-yl}-N _ r~llhydroxy-acrylamide BIOLOGICAL TESTING AND ENZYME ASSAYS Recombinant GST-HDAC1 Protein expression and purification 5 [0363] Human cDNA library was prepared using cultured SWS20 cells. Amplification of human HDACI coding region from this cDNA library was cloned separately into the baculovirus expression pDEST20 vector (GATEWAY Cloning Technology, Invitrogen Vnmy41 T0 DELETNFla 3 -as AU emtf d ftvkimW uaL 8 itidc 135 Pte Ltd). The pDEST20-HDAC1 construct was confirmed by DNA sequencing. 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. 5 [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-equilibrated Glutathione Sepharose 4B beads (Amersham) at 4"C for 2 h. The beads were washed with PBS buffer for 3 times. The GST-HDAC1 protein 10 was eluted by elution buffer containing 50 mM Tris, pH8.0, 150mM NaCl, 1% Triton X 100 and 10mM or 20mM reduced Glutathione. The purified GST-HDACI protein was dialyzed with HDAC storage buffer containing 10mM Tris, pH7.5, 100mM NaCI and 3mM MgC 2 . 20% Glycerol was added to purified GST-HDACI protein before storage at -80*C. 15 in yitro HDAC aesay 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 NaCl, 2.7 mM KCI, 1 mM MgCl 2 , 1 20 mg/mI 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 25 light and the emitted light (460 nm) Is detected on a fluorometric plate reader (Tecan Ultra Microplate detection system, Tecan Group Ltd.). [0366] The analytical software, Prism 3.0 (GraphPad Software Inc) has been used to generate IC50 from a series of data. 30 [0367] The HDAC enzyme inhibition results of representative compounds are shown in Table 1 (unit is micromolar). vWlM"tMNO DEZTrwtM-a AVJ M~w hoviimdA ASrn aPA.M 136 [0368] Table 1. HDACI enzyme activity IC6 (unit Is micromolar). Compound ICw (pM) Compound ICM (PM) Compound ICS (PM) No 15(M) No 15(M) No IC 0 () 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 5 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 10 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 15 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 20 0.26 6 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 68 0.034 113 0.016 25 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 30 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 0.086 35 0.082 80 0.040 125 0.16 Y:12tWi f 30DhL9flPIC04M AV R M4f FlavluudMFU) S~bfkU 137 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 40 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 45 0.063 90 0.51 Cell-based proliferation assay for determlnxtion of GL 0 VEInWS (0369] Human colon cancer cell lines (Colo205, HCT116), Ovarian cancer cell line 5 (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/mI 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 10 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 L glutamine, 5%FBS, 1% non essential amino acid, 1mM Na Pyruvate, I U/m of penicillin and 1 pg of streptomycin. PC3 cells worn cultivated in F12K, 2 mM L glutamine, 5%FBS, I U/mi of penicillin and 1 gg of streptomycin. PC3, Colo205, and 15 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% C02, for 24 h. Cells were treated with compounds at various concentrations for 96 h. Cell growth was then monitored using CyQUANTO cell proliferation assay (Invitrogen Pte Ltd). Dose response 20 curves were plotted to determine G15o 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 25 inhibition of tumour cell growth. YAONNO DUPIlOfld AU Aa i wing~ w(U mFMAs 138 [0371] Table 2. Cellular or Growth Inhibition Activity in Colo205 cells (unit Is micromolar) Compound Compound Compound Glso (p) Gi50 (pM) Glso (PM) 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 5 2.58 50 0.17 95 0.57 a 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 10 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 15 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 20 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 25 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 30 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;Ia.ji4a No DELTIM~lt~4S AV SW M~s Ai.d mh*. idh.

139 34 4.4 79 0.45 125 0.68 35 0.68 80 1.37 126 0,42 36 0.86 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 40 0.16 85 1.52 131 0.33 41 0,92 86 2.08 133 0.56 42 0.98 87 1.07 134 2.30 43 1.86 88 0.55 135 0.26 44 0.87 89 0.87 45 0.54 90 8.1 10372] Table 3. Cellular or Growth Inhibition Activity in Various Cancer Cell Lines Cell lines Compound HCT116 A2780 PC3 HEP3B I++ +9 + + 7 + ++ Not tested 8 ++ ++ + + 22 + .+* +4+ Not tested 23 ++ +++ ++ Not tested 30 ++ +++ .+ Not tested 40 +++ +++ Not tested 44 + 4+ + Not tested 46 +++ +++ +++ + 50 ++++ ++ Not tested 52 +++ +++ +++ Not tested 58 +++ ++ +++ +++ 71 +++ +++ +++ Not tested 111 Not testedlNot tested Not tested +++ 130 +++ I++ +++ Not tested ("+++" for Gi < 0.5 pM, "++" for G1m between 0.5 and 1.0 pM," +" for Giso 5 between 1.0 pM to 5.0 pM) Yrtbni NO DEIZTIPD"~ AU Sm tA &M M qss PliWA fld 140 Histone H3 acetylation assay [0373] A hallmark of histone deacetylase (HDAC) inhibition is the increase in the acetylation level of histones. Histone acetylation, including H3, H4 and H2A can be detected by immuno-blotting (western-blot). Colo205 cells, approximately 5 x10 cells, s were seeded in the previously described medium, cultivated for 24 h and subsequently 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 10 (Invitrogen Pte Ltd) and was transferred onto PVDF membrane (BioRad Pte Ltd). The membrane was probed using primary antibody specific for acetylated histone H3 (Upstate Pte Ltd). The detection antibody, goat anti rabbit antibody conjugated with HRP was used according to the manufacturing instruction (Pierce Pte Ltd). After removing the detection antibody from the membrane, an enhanced chemiluminescent 15 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 min. 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 20 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. 25 Y!W*Mf~ MO bZEWIDPD.43 AU IKESI Palsucal FiN iu Fd e 141 [0375] Table 4 _____ lHistone Histone Histone Acetylation Acetylation Acetylation activities activities activities Compound (Histone-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 [03761 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 10377] 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. 10 [0378] Pooled human liver microsome (HLM was purchased from BD Gentest (80 BidSciences). The incubations consisted of test compound (5 pM) or control compound (Verapamil), NADPH-generating system solution A (25 mM NADP*, 66 mM glucose-6 phosphate, 66 mM MgCi2 in H 2 0), NADPH-generating system solution B (40 U/mi 15 glucose-S-phosphate dehydrogenase in 5 mM sodium citrate) and 1.0 mg/mi 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 80% acetonitrile and 20% DMSO. Samples are subsequently centrifuged at 4 0 C for 15 min at 2,000 rpm. 100 pL of the supernatant Is transferred to the LC-MS Plate for 20 analysis. Before quantitative analysis, the compound is tuned in LC/MS machine to get Y-MOM NO nBUrAIMO.O AU katd 7tiak.. Fha . Flk wi 142 the optimized MS condition. Liquid chromatography Is performed on a Luna C18 column (Phenomenex U.S.A, Torrance, CA) (2x50mm, 5 pM). % remaining of compound (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 5 the t 1 /, These are demonstrated in table 5. [0379] Table 5. Compound No T112 (min) Compound No T1/2 (min) 1 >30 52 >30 2 >30 58 >30 8 30 63 >30 - 11 >30 68 >30 12 >30 71 >30 14 >30 74 ,30 19 >30 78 >30 35 >30 80 >30 40 >30 88 >30 44 >30 108 >30 46 >30 130 >30 [0380] The measured in vitro T>, 2 '30 mins for the above compounds signifies that the 10 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 (1) were 15 metabolically stable In human liver microsme assay. Together with the appropriate physioochemical properties, e.g., 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. 20 in vivo Pharmacokinetic (PK) studies [0382] Compound is dissolved in appropriate solution (saline or DMA and Cremaphor in saline) at 1 mg/mi 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 25 IV dose (10 mglkg) via tail vein, or single oral dose (50 mg/kg) via gavage. At pre defined time points (predose, 5 or 10, 30min, 1, 2, 4, 8, and 24h), one group of mice is sacrificed by overdose C02 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 Y:WaslJKi NdDELEBEPL09043 AU eKmilrviend W idag M WN 143 analysis, the method is developed for LC/MS/MS assay. The method is validated for signal-response of the calibration standards, auto-sampler stability for -15 hours Intra day and inter-day calibration curve using eight calibration standards excluding the blank plasma. QC samples at three different concentrations in triplicates were prepared 5 to determine the accuracy and precision, The extracted QC samples were compared to unextracted samples to determine the extraction efficiency of the analyte. LLOO 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, 10 Mountain View, CA, USA). The mean values for the plasma compound concentration time profiles are used in mouse PK study. [0383] The PK parameter AUC 4,t 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 15 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 5 were shown in Table 6 below. [03841 Table 6. Representative pharmacokinetic data [compounds were in 20 hydrochloric acid salt form (2HC), dosed at 50 mg/kg, p.o.] Compound AUC.

1 (ng.h/mI) 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, e.g., molecular weight, logP, and high 25 solubility, were able to yield adequate pharmacological exposure and effect in the animal when administrated orally. In vivo antineoplastic (or anti-4umor) effect of HDAC Inhibiting agents: [0386] The efficacy of the compounds of the invention can then be determined using 30 in vivo animal xenograft studies, The animal xenograft model is one of the most commonly used in vivo cancer models. YMu|lU No DaLmnI 03045 AUta Irad onal Flna w Miled.

144 [0387] In these studies Female athymic nude mice (Harlan), 12-14 weeks of age would be implanted subcutaneously in the flank with 5 x 10 cells of HCT116 human colon tumor cells, or with 5 x 100 cells of A2780 human ovarian tumor cells, or with 5 x 108 cells of PC3 prostate cancer cells. When the tumor reaches the size 100 mm 3 , the s xenograft nude mice would be paired-match into various treatment groups. The 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 10 will be 0.01 mi/g body weight. Tumor volume will be calculated every second day or twice-a-week of post injection using the formula: Volume (mm 3 ) = (w 2 x )/2, where w = 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 15 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 20 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. YW4M1 M~ DELErFFPION.SAM tWi ft*ci Phul ai Plt

Claims (20)

1. A compound of the formula (1): 0 N N O H R2/ N H 5 R1 wherein R 1 is a group of formula: 10 -(CR 20 R 2 1 )m-(CR 22 R 23 )n(CR 24 R 2 5 )o-NR 26 R 27 ; R 2 is selected from the group consisting of: alkyl and heteroalkyl, each of which may be optionally substituted with one or more optional substituents wherein each optional 15 substituent is selected from the group consisting of halogen, =0, -CN, alkenyl, alkynyl and alkoxy; each R 20 , R 21 , R 2 2 , R 23 , R 24 and R 25 is independently selected from the group consisting of: H, halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, 20 haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, 25 arylalkyloxy, phenoxy, benzyloxy heteroaryloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, aminosulfonyl, arylsulfonyl, arylsulfinyl -COOH, -C(O)OR 5 , -COR', -SH, -SR6, -OR 6 and acyl, each of which may be optionally substituted; or R 2 0 and R 21 when taken together may form a group of formula =0 or =S, and/or 30 R 22 and R 23 when taken together may form a group of formula =0 or =S, and/or R 24 and R 2 5 when taken together may form a group of formula =0 or =S; each R 5 is alkyl; <flaname8 146 each R 6 is alkyl; each R 26 and R 27 is independently selected from the group consisting of is selected 5 from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, 10 heterocycloalkyloxy, aryloxy, arylalkyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR 5 , and acyl, each of which may be optionally substituted, or R 2 6 and R 2 7 when taken together with the nitrogen atom to which they are attached form an 15 optionally substituted heterocycloalkyl group; m, n and o are integers independently selected from the group consisting of 0, 1, 2, 3 and 4; 20 or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein the sum of m+n+o is 2 or 3.

3. A compound according to any one of claims 1 to 2 wherein R 1 is selected from the 25 group consisting of: -(CR 20 R 2 1 ) 2 -NR 2 6 R 2 7 ; -(CR 22 R23)2-NR 26R27. -(CR 24 R 2 5 ) 2 -N R 26 R 27 ; -(CR 20 R 2 1 )-(CR 22 R 23 )-N R 26 R 27 ; 30 -(CR 20 R 2 1 )(CR 24 R 2 5 )-NR 2 6 R 27 ; and -(CR 2 2 R 2 3 )-(CR 24 R 2 5 )-NR 26 R 2 7 ; -(C R 20 R 21 ) 3 -NR 26 R 2 7 ; -(CR 22 R 23 ) 3 -NR 26 R 2 7 ; -(CR 2 4 R 2 5 ) 3 -NR 26 R 27 ; 35 -(CR 20 R 2 1 ) 2 -(CR 22 R 2 3 )-NR 2 6 R 27 ; -(CR 20 R 21 ) 2 -(CR 24 R 25 )-NR 26 R 27 ; -(CR 20 R 21 )-(CR 2 2 R 23 ) 2 -NR 26 R 27 ; Cfilname 147 -(CR 22 R 23 ) 2 -(CR 24 R 25 )-NR 2 6 R 27 ; -(CR 20 R21 )-(CR 24 R 2 5 ) 2 -NR 2 6 R 27 ; -(CR 22 R 23 )-(CR 24 R 2 5 ) 2 -NR 2 6 R 27 ; and -(CR 20 R 21 )-(CR 22 R 23 )-(CR 24 R 2 5 )-NR 2 6 R 27 . 5

4. A compound according to any one of claims 1 to 3 wherein the compound is selected from the group consisting of: 0 N R 2 317 R 2 2 N R23 R 27 10 and 0 N N H R2 </2 3 4 H N H R 2 o R 21 R 22 R 24 R 23 R 25 /,'R 26 R 27

5. A compound according to any one of claims 1 to 4 wherein R 2 o, R 2 R 22 , R 2 3 , R 24 and R 2 5 are independently selected from the group consisting of H, alkyl, alkenyl and alkynyl. 15

6. A compound according to any one of claims 1 to 4 wherein R 20 , R 2 R 22 , R 23 , R 24 and R 2 5 are independently selected from the group consisting of H and alkyl.

7. A compound according to any one of claims 1 to 6 wherein R 20 and R 21 are H. 20

8. A compound according to any one of claims 1 to 7 wherein R 22 and R 2 3 are methyl.

9. A compound according to any one of claims 1 to 8 wherein R 24 and R 2 5 are H. <fienamO> 148

10. A compound according to any one of claims 1 to 9 wherein R 26 and R 27 are independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, alkoxyalkyl, and acyl. 5

11. A compound according to any one of claims 1 to 10 wherein R 2 6 and R 27 are independently selected from the group consisting of H, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, acetyl and 2-methoxy-ethyl. 10 12. A compound according to any one of claims 1 to 4 wherein R' is a group of formula: H H NH2 H N H 15 N 15 0 <tiicnam,> 149 <flN N N N N V~xN N N < N N N~ <filename> 150 N NN HNoH NH SN N N

13. A compound according to any one of claims 1 to 12 wherein R 2 is alkyl. 5

14. A compound according to any one of claims 1 to 12 wherein R 2 is selected from the group consisting of: methyl; ethoxymethyl; 2-methansulfanyl-ethyl; 2,2,2-triflouro-ethyl; propyl; 2-2-dimethyl-propyl; isopropyl; 3,3,3-triflouro-propyl; butyl; isobutyl; 3,3-dimethyl-butyl; but-3 enyl; but-3-yny; pentyl; 2,4,4-trimethyl-pentyl; hexyl; hex-3-enyl; octyl; non-3-enyl; non-6-enyl; 10 2-methoxy-nonyl, (CH 3 ) 3 CCH 2 CONH(CH 2 ) 2 -; (CH 3 ) 3 CCONH(CH 2 ) 2 -; (CH 3 ) 3 CCONH(CH 2 )- and CH 3 (CH 2 ) 2 CONH(CH 2 )-

15. A compound according to any one of claims 1 to 14 wherein the optional substituent is selected from the group consisting of: halogen, =0, =S, -CN, -NO 2 , -CF 3 , -OCF 3 , alkyl, 15 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, 20 alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR 5 , -C(O)OR', SH, -SR 5 , -OR 6 and acyl. <flename, 151

16. The compound of claim 1 wherein the compound is selected from compounds, and their pharmaceutically acceptable salts, selected from the group consisting of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,2 H dimethyl-propyl)-1 H-benzoimidazol-5-yl]-N-hydroxy acrylamide 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2 ' N ',OH OH isopropyl-1 H-benzoimidazol-5-yl]-N-hydroxy acrylamide 3-(2-Butyl-1 -(3-dimethylamino-2,2-dimethyl-propyl) H 1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide oi 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2 / "N methylsulfanyl-ethyl)-1 H-benzoimidazol-5-yl]-N hydroxy-acrylamide HN 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2 N o ethoxymethyl-1 H-benzoimidazol-5-yl]-N-hydroxy acrylamide 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2 isobutyl-1 H-benzoimidazol-5-yl]-N-hydroxy acrylamide / 3-[1-(2-Diethylamino-ethyl)-2-isobutyl-1 H N benzoimidazol-5-yl]-N-hydroxy-acrylamide c Na COname> 152 3-[2-Butyl-1 -(2-diethylamino-ethyl)- 1 H 0 benzoimidazol-5-yI]-N-hydroxy-acrylamide 0 3-[2-But-3-ynyl-1 -(3-dimethylamino-2, 2-dimethyl - N propyl)-1 H-benzoimidazol-5-y]-N-hydroxy acrylamide N ~ l0 O 3-[2-But-3-enyl-1 -(3-dimethylamino-2,2-dimethyl / A propyl)-1 H-benzoimidazol-5-y]-N-hydroxy acrylamide 0 3-[2-But-3-enyl-1 -(2-diethylamino-ethyl)-1 H 0 benzoimidazol-5-yI]-N-hydroxy-acrylamide H benzoimidazol-5-yI]-N-hydroxy-acrylamide HN~~ 3-[1 -(3-Dimethylamino-2,2-dimethyl-propyl)-2-(3, 3,3 I trifluoro-propyl)-1 H-benzoimidazol-5-yI]-N-hydroxy A acrylamide H '10 3-[1 -(2-Diethylamino-ethyl)-2-(3, 3, 3-trifluoro-propyl) N A H-benzoimidazol-5-yI]-N-hydroxy-acrylamide 153 HN ,O 3-[1 -(2-Diethylamino-ethyl)-2-ethoxymethyl-1 H N0 benzoimidazol-5-yI]-N-hydroxy-acrylamide 3N HN OH ~3-[l -(3-Di methyla min o-2,2-d imethyl-pro pyl) -2-m ethyl N o 1 H-benzoimidazol-5-yI]-N-hydroxy-acrylamide / 3-[1 -(2-Diethylamino-ethyl)-2-(2, 2-dimethyl-propyl) 1 H-benzoimidazol-5-yI]-N-hydroxy-acrylamide 0 / 0.N-Hydroxy-3-[1 -(3-isopropylamino-propyl)-2-(3, 3,3 trifluoro-propyl)-1 H-benzoimidazol-5-yI]-acrylamide N 3 03-[2-(2, 2-Dimethyl-propyl)-1 -(2-isopropylamino N ethyl)-1 H-benzoimidazol-5-yI]-N-hydroxy-acrylamide 0 3-[ -(2-Diisopropylamino-ethyl)-2-(2,2-dimethyl N / propyl)-1 H-benzoimidazol-5-yJ-N-hydroxy acrylamide 0 3-[1 -(2-Diisopropylamino-ethyl)-2-isobutyl-1 H / K N benzoimidazol-5-yI]-N-hydroxy-acrylamide <filename, 154 0 3-[1 -(3-Dimethylamino-2,2-dimethyl-propyl)-2-hex-3 11' enyl-1 H-benzoimidazol-5-yI]-N-hydroxy-acrylamide 0" 0 3-[1 -(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,4,4 I" trimethyl-pentyl)-1 H-benzoimidazol-5-yJ-N-hydroxy acrylamide N 3-[1-(2-Diethylamino-ethyl)-2-hex-3-enyl-1 H / benzoimidazol-5-yI]-N-hydroxy-acrylamide N3-[1l-(2- Di iso pro pyla m ino-ethyl)-2-hex-3-enyl- 1 H / benzoimidazol-5-yI]-N-hydroxy-acrylamide o 3-[2-Hex-3-enyl-1 -(2-isopropylamino-ethyl)-1 H N benzoimidazol-5-yI]-N-hydroxy-acrylamide 0. N 3-[2-Hex-3-enyl-1 -(3-isopropylamino-propyl)-1 H benzoimidazol-5-yI]-N-hydroxy-acrylamide /O 0 3-[1 -(2-Ethylamino-ethyl)-2-hex-3-enyl-1 H ccl: , Ibenzoimidazol-5-yI]-N-hydroxy-acrylamide o 3-ti -(2-Diethylamino-ethyl)-2-hexyl-1 H ,GH4 benzoimidazol-5-yI]-N-hydroxy-acrylamide -filename> 155 N-Hydroxy-3-[1 -(3-isopropylamino-propyl)-2-(2,4,4 2 OH trimethyl-pentyl)-1 H-benzoimidazol-5-yI]-acrylamide 3-[2-(2, 2-Dimethyl-propyl)-1 -(3-isopropylamino / H propyl)-1 H-benzoimidazol-5-y]-N-hydroxy acrylamide NH 3-ji -(2-Diisopropylamino-ethyl)-2-(3, 3, 3-trifluoro propyl)-1 H-benzoimidazol-5-y]-N-hydroxy \ / acrylamide 0 N N ~ NHN-Hydroxy-3-[2-isobutyl-1 -(2-isopropylamino-ethyl) N L 1 H-benzoimidazol-5-yI]-acrylamide N NH 3-[2-(2,2-Dimethyl-propyl)-1 -(2-ethylamino-ethyl)-1 H benzoimidazol-5-yI]-N-hydroxy-acrylamide / N 3-[1 -(2-Ethylamino-ethyl)-2-isobutyl-1 H N benzoimidazol-5-yI]-N-hydroxy-acrylamide N 0 N 0 3-[1 -(2-Diisopropylamino-ethyl)-2-(2,4,4-trimethyl I"N pentyl)-1 H-benzoimidazol-5-y]-N-hydroxy acrylamide cfdename, 156 0 N-Hydroxy-3-(1 -(2-isopropylamino-ethyl)-2-(2,4,4 OHI"r trimethyl-pentyl)-1 H-benzoimidazol-5-yI]-acrylamide

23-[l -(2- Ethyl am ino-ethyl)-2-(2,4,4-tri methyl-pe nty) - \0 1 H-benzoimidazol-5-yI]-N-hydroxy-acrylamide NH NM NN 2 3-[1 -(2-Diethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl) N - ~ 01 H-benzoimidazol-5-yI]-N-hydroxy-acrylamide N0 3-[1 -(2-Diethylamino-ethyl)-2-propyl-1 H - benzoimidazol-5-yI]-N-hydroxy-acrylamide 3-[2-Butyl-1 -(2-diisopropylamino-ethyl)-1 H ) benzoimidazol-5-yI]-N-hydroxy-acrylamide M0 3-[2-Butyl-1 -(2-ethylamino-ethyl)-1 H-benzoimidazol 5-yI]-N-hydroxy-acrylamide 0 0. 3-[1 -(2-Diethylamino-ethyl)-2-(2-methylsulfanyl rjND ethyl)-1 H-benzoimidazol-5-y]-N-hydroxy-acrylamide 0 3-[2-Butyl-1 -(2-isopropylamino-ethyl)-1 H benzoimidazol-5-yI]-N-hydroxy-acrylamide Nfiens-e 157 0O 3-[2-Butyl-1 -(3-isopropylamino-propyl)-1 H H benzoimidazol-5-yI]-N-hydroxy-acrylamide HN0 N o ,H3-[2-But-3-enyl-1 -(2-ethylamino-ethyl)-1 H / I benzoimidazol-5-yI]-N-hydroxy-acrylamide 3-[2-Hexyl-1 -(2-isopropylamirio-ethyl)- 1 H benzoimidazol-5-yI]-N-hydroxy-acrylamide 3-[ 1 -(2- Dim ethyl am ino-ethyl)-2-(2,4,4-trim ethyl 7 I ~"N rpentyl)-1 H-benzoimidazol-5-yI]-N-hydroxy N acrylamide o 3-[1 -(2-Ethylamino-ethyl)-2-hexyl-1 H-benzoimidazol 5-yI]-N-hydroxy-acrylamide N-Hydroxy-3-[1 -(2-isopropylamino-ethyl)-2-(3, 3,3 / I trifluoro-propyl)-1 H-benzoimidazol-5-yI]-acrylamide 3- [1I-(2- Dim ethyl am ino-ethyl)-2-hex-3-en yl- 1 H / I benzoimidazol-5-yI]-N-hydroxy-acrylamide crdensme, 158 0 N ,OH3-[1 -(2-Amino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1 H benzoimidazol-5-yI]-N-hydroxy-acrylamide H2N 3-[1 -(2-Amino-ethyl)-2-(2-methoxy-nonyl)-1 H benzoimidazol-5-yI]-N-hydroxy-acrylamide 0 N N N 3-[2-Butyl-1 -(2-dimethylamino-ethyl)-1 H / benzoimidazol-5-yI]-N-hydroxy-acrylamide 3-[1 -(2-Di methyl am ino-ethyl)-2-hexy1- 1 H / OW benzoimidazol-5-yI]-N-hydroxy-acrylamide N-{2-[1 -(2-Diethylamino-ethyl)-5-(2 - hydroxycarbamoyl-vinyl)-1 H-benzoimidazol-2-y] ethyl}-3,3-dimethyl-butyramide 0 3-{1 -(2- Diethyl am ino-ethyl)-2-[2-(2, 2-d im ethyl N N . / I propionylamino)-ethyl]-1 H-benzoimidazol-5-y}-N N hydroxy-acrylamide 0 0 N0 3-{1 -(2-Diethylamino-ethyl)-2-[(2,2-dimethyl N propionylamino)-methyll H-benzoimidazol-5-yl-N hydroxy-acrylamide cmeno mc'. 159 0 N-[1 -(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoyl N / vinyl)-1 H-benzoimidazol-2-ylmethyl]-butyramide 3-[1 -(2-ethylamino-ethyl) -2-(3,3-dimethyl-butyl)-1 H I H benzoimidazol-5-yi]-N-hydroxy-acrylamide NDO 0N 3-[2-(3, 3-Dimethyl-butyl)-1 -(2-Dimethylamino-ethyl) N L 1 H-benzoimidazol-5-yI]-N-hydroxy-acrylamide 3-[1 -(2-Dimethylamino-ethyl)-2-pentyl-1 H 0 benzoimidazol-5-yl]-N-hydroxy-acrylamide N NOM F 3-[1 -(2-Dimethylamino-ethyl)-2-(2,2,2-trifluoro-ethyl) N 1 H-benzoimidazol-5-yI]-N-hydroxy-acrylamide UN-ON 0 3-ji -(2-Ethylamino-ethyl)-2-pentyl-1 H 'I benzoimidazol-5-yI]-N-hydroxy-acrylamide N0 .NN 2N H1 H-benzoimidazol-5-yI]-acrylamide crdeneme> 160 N-Hydroxy-3-[1 -(2-methylamino-ethyl)-2-non-3-enyl 0 1 H-benzoimidazol-5-yI]-acrylamide N _NHH N -Hyd roxy-3-[1 -(2-m ethyl am ino-ethyl)-2-non-6-e nyl 1 H-benzoimidazol-5-yI]-acrylamide 0 N OH 0 3-[2-Hexyl- 1 -(2-methylamino-ethyl)-1 H p OH benzoimidazol-5-yI]-N-hydroxy-acrylamide 0 OHN-Hydroxy-3-[1 -(2-methylamino-ethyl)-2-pentyl- 1 H / I benzoimidazol-5-yI]-acrylamide HN N N-Hyd roxy-3-[1 -(2-m ethyl am ino-ethyl) -2-octyl- 1 H I 'N rbenzoimidazol-5-yI]-acrylamide N 3-[1 -(2-Amino-ethyl)-2-octyl-1 H-benzoimidazol-5-y] / K"''N rN-hydroxy-acrylamide 'N ~.3-{2-Butyl-1 -[2-(isopropyl-methyl-amino)-ethyl]-1 H H benzoimidazol-5-yI}-N-hydroxy-acrylamide 161 0 3-(1-[2-(Ethyl-methyl-amino)-ethyl]-2-pentyl-1 H N benzoimidazol-5-yI}-N-hydroxy-acrylamide /N\ N 0N OH 3-(1 -{2-[Ethyl-(2-methoxy-ethyl)-amino]-ethyl)-2 H pentyl-1 H-benzoimidazol-5-yI)-N-hydroxy-acrylamide N 0 OH 3-{2-Butyl-1 -[2-(ethyI-methyI-amino)-ethy]-1 H N benzoimidazol-5-yl)-N-hydroxy-acrylamide 0 3-(2-Butyl- I -{2-[ethyl-(3-hydroxy-propyl)-amino] N N~ - NH ethyl)l H-benzoimidazol-5-yI)-N-hydroxy-acrylamide N 6 HO 3-(l1 -{2-[Ethyl-(3-hydroxy-propyl)-amino]-ethyl}-2 'I penty-1 H-benzoimidazol-5-yI)-N-hydroxy-acrylamide cOlans me 162 0 3-[2-(4-Cyano-butyl)-1 -(2-diethylamino-ethyl)-1 H / ~ 'On benzoimidazol-5-yI]-N-hydroxy-acrylamide N' 0 3-[1 -(2-Diethylamino-ethyl)-2-propylamino-1 H N "OH HN / benzoimidazol-5-yI)-N-hydroxy-acrylamide N' 3-[2-(5-Cyano-pentyl)-1 -(2-diethylamino-ethyl)-1 H N benzoimidazol-5-yIJ-N-hydroxy-acrylamide 3-[1 -(3-Dimethylamino-2,2-dimethyl-propyl)-2 N O HN- / ~ ~~~~propylamino-1 Hbnomdzl5y]Nhdoy N acrylamide 163 0 ~3-{l -[2-(Ethyl-hexyl-a min o)-ethyl]-2-m ethyl- 1 H N benzoimidazol-5-yI}-N-hydroxy-acrylamide rN 0 3-{l -[2-(B utyl-ethyl-a m ino)-ethyl]-2-trifl uorom ethyl F NNHIH 1 H-benzoimidazol-5-yI}-N-hydroxy-acrylamide rN 0 3-(1 -[2-(Ethyl-hexyl-amino)-ethyl]-2-trifluoromethyl F H 1 -benzoimidazol-5-yI}-N-hydroxy-acrylamide rN (E)-3-(1 -(2-(dibutylamino)ethyl)-2-propyl-1 H NN OH benzo[d]imidazol-5-yI)-N-hydroxyacrylamide 164 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2 \ N methylsulfanyl-1H-benzoimidazol-5-yl]-N-hydroxy / H N -acrylamide 0 3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-propyl-1 H N N benzoimidazol-5-yl}-N-hydroxy-acrylamide IN 3-[1-[2-(3,3-Dimethyl-butylamino)-ethyl)-2-(2,2 N N ,,/ dimethyl-propyl)-1 H-benzoimidazol-5-yl]-N-hydroxy acrylamide 0 3-[l-{2-[Bis-(3,3-dimethyl-butyl)-amino]-ethyl}-2-(2,2 dimethyl-propyl)-1 H-benzoimidazol-5-yl]-N-hydroxy acrylamide N 0 3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl-1 H N benzoimidazol-5-yl}-N-hydroxy-acrylamide. NH 17. A pharmaceutical composition including a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable diluent, excipient or carrier. NfdenameN 165 18. 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 5 claims 1 to 16 to the patient. 19. A method according to claim 18 wherein the disorder is a proliferative disorder. 20. A method according to claim 19 wherein the disorder is cancer. 10 21. A method according to claim 20 wherein the cancer is selected from the group consisting of colon cancer, prostate cancer, hepatoma and ovarian cancer. 22. A method of treatment of a disorder that can be treated by the inhibition of histone 15 deacetylase in a patient including administration of a therapeutically effective amount of a compound according to any one of claims 1 to 16 to the patient. 23. A method according to claim 22 wherein the disorder is selected from the group consisting of Proliferative disorders (e.g. cancer); Neurodegenerative diseases including 20 Huntington's Disease, Polyglutamine diseases, Parkinson's Disease, Alzheimer'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 25 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 30 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 (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, 35 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 <flwnama> 166 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 5 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. 10 24. A method of treatment of cancer in patient including administration of a therapeutically effective amount of a compound according to any one of claims 1 to 16 to the patient.

25. A method according to claim 24 wherein the cancer is a hematologic malignancy or a solid tumour. 15

26. A method according to claim 25 wherein the hematologic malignancy is selected from the group consisting of B-cell lymphoma, T-cell lymphoma and leukemia.

27. A method according to claim 25 wherein the solid tumor is selected from the group 20 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.

28. A method according to claim 27 wherein the cancer is selected from the group consisting of colon cancer, prostate cancer, hepatoma and ovarian cancer. 25