Indian Patents
Title of Invention

BENZIMIDAZOLE DERIVATIVES
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 for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with enzymes having histone deacetylase (HDAC) activities.
Full Text WO 2007/030080

PCT/SG2006/000217

HETEROCYCLIC COMPOUNDS
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
heterocyclic compounds and methods for their preparation. These compounds may be
useful as medicaments for the treatment of proliferative disorders 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 complex, is
strongly influenced by post-translational modifications of the histones Which are the
protein components. Reversible acetylation of histones is a key component in the
regulation of gene expression by altering the accessibility of transcription factors to DNA.
In general, increased levels of histone acetylation are associated with increased
transcriptional activity, whereas decreased levels of acetylation are associated with
repression of gene expression [Wadem P.A. Hum. Mol. Genet. 10, 693-698 (2001), De
Ruijter A.J.M. et al, Biochem. J., 370, 737-749 (2003)]. In normal celis, histone
deacetylases (HDACs) and histone acetyltransferase together control the level of
acetylation of histones to maintain a balance. Inhibition of HDACs results in the
accumulation of acetylated histones, which results in a variety of cell type dependent
cellular responses, such as apoptosis, necrosis, differentiation, cell survival, inhibition of
proliferation and cytostasis.
[0003] Inhibitors of HDAC have been studied for their therapeutic effects on cancer
cells. For example, suberoylanilide hydroxamic acid (SAHA) is a potent inducer of
differentiation and/or apoptosis in murine erythroleukemia, bladder, and myeloma cell
lines [Richon V.M. et al, Proc. Natl. Acad. Sci. USA, 93: 5705-5708 (1996), Richon V.M. et
al, Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998)]. SAHA has been shown to
suppress the growth of prostate cancer cells in vitro and in vivo [Butler L.M. et al, Cancer
Res. 60, 5165-5170 (2000)]. Other inhibitors of HDAC that have been widely studied for
their anti-cancer activities are trichostatin A (TSA) and trapoxin B [Yoshida M. et al, J.
Biol. Chem., 265, 17174 (1990), Kijima M. et al, J. Biol. Chem., 268, 22429 (1993)].
Trichostatin A is a reversible inhibitor of mammalian HDAC. Trapoxin B is a cyclic
tetrapeptide, which is an irreversible inhibitor of mammalian HDAC. However, due to the

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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 G. et al, J. Med. Chem., 46, 820-830 (2003)] and patents [WO
03/066579A2]. The in vivo activity of such inhibitors can be directly 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 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):
10232-10237; Science, 1998; 281: 1001-1005; Dinarello C.A. and Moldawer L.L.
Proinflammatory and anti-inflammatory cytokines in rheumatoid arthritis, A primer for
clinicians, 3rd Edition, Amgen Inc., 2002].
[0004] Nevertheless, there is still a need to provide further HDAC inhibitors that would
be expected to have useful, improved pharmaceutical properties in the treatment of
diseases such as cancer, neurodegenerative diseases, disorders involving angiogenesis
and inflammatory and/or immune system disorders. With a view to meeting this need a
number of small organic moiety scaffolds have been investigated including a number of
heterocyclic systems, especially bicyclic heterocyclic ring systems. One heterocyclic
system that has been investigated has been the benzimidazole ring system. We have
now found that judicious selection of the substituents on the 5 membered ring of the
benzimidazole ring system leads to the production of a family of compounds with
improved pharmacokinetic properties when compared with the compounds of the prior art.
The compounds within the family exhibit microsomal stability and thereby demonstrate
improved half lives in the plasma when compared to the compounds of the prior art. The
compounds within the family typically provide a longer duration of action due to the
increased in vivo exposure (i.e., area under the curve, AUC0.iast) thereby yielding improved
tumor growth inhibition profiles in the xenograft models.
SUMMARY OF THE INVENTION
[0005] In one aspect the present invention provides a compound of the formula (I):


WO 2007/030080 PCT/SG2006/000217
wherein
[0006] R1 is an optionally substituted heteroaryl group, an optionally substituted
heterocycloalkyl group or a group of formula:
-(CR20R21)m-{CR22R23)n-(CR24R25)o-NR26R27;
[0007] R2 is selected from the group consisting of: H, alky!, alkenyl, alkynyl, heteroalkyl,
cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkoxyalkyl, R11S(0)R13-, R11S(0)2R13-,
R11C(0)N(R12)R13-, R11S02N(R12)R13-, R11N(R12)C(0)R13-, R11N(R12)S02R13-,
R11N(R12)C(0)N(R12)R13- and acyl, each of which may be optionally substituted;
[0008] R3 is selected from the group consisting of H, C, -C6 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, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl,
alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy,
heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl,
heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino,
sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, aikoxyalky, -COOH
-C(0)OR5, -COR5, -SH, -SR6, -OR6 acyl and -NR7R8, each of which may be optionally
substituted;
[0010] R4 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl,
heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally
substituted;

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[0011] each R5 is independently selected from the group consisting of: H, alkyl, alkenyl,
alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyi, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally
substituted;
[0012] each R6 is independently selected from the group consisting of: H, alkyl, alkenyl,
alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyi, arylalkyl, heteroarylalkyl and acyl; each of which may be optionally
substituted;
[0013] each R7 and R8 is independently selected from the group consisting of: H, alkyl,
alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyi, arylalkyl, heteroarylalkyl and acyl, each of which
may be optionally substituted;
[0014] each R11 and R12 is independently selected from the group consisting of H, alkyl,
alkenyl, and alkynyl, each of which may be optionally substituted;
[0015] each R13 is a bond or is independently selected from the group consisting of:
alkyl, alkenyl, and alkynyl, each of which may be optionally substituted;
[0016] each R20, R21, R22, R23, R24 and R25 is independently selected from the group
consisting of: H, halogen, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyi, arylalkyl,
heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,
heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,
alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy,
aryloxy, arylalkyloxy, phenoxy, benzyloxy heteroaryloxy, amino, alkylamino, acylamino,
aminoalkyl, arylamino, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl,
aminosulfonyl, arylsulfonyl, arylsulfinyl -COOH, -C(0)OR5, -COR5, -SH, -SR6, -OR6 and
acyl, each of which may be optionally substituted; or
R20 and R21 when taken together may form a group of formula =0 or =S, and/or
R2Z and R23 when taken together may form a group of formula =0 or =S, and/or
R24 and R25 when taken together may form a group of formula =0 or =S;

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[0017] each R26 and R27 is independently selected 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, heterocycloalkyloxy, aryloxy,
arylalkyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino,
phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl,
alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR5 and acyl, each of which may be
optionally substituted,
or R26 and R27 when taken together with the nitrogen atom to which they are attached form
an optionally substituted heterocycloalkyl group;
[0018] Z is selected from the group consisting of -CH2-, -CH2CH2-, -CH=CH-, C3-C6
alkylene, C3-C6 alkenylene, C3-C6 alkynylene, C3-C6 cycloalkyl, unsubstituted or
substituted with one or more substituents independently selected from the group
consisting of C1-C4 alkyl;
[0019] m, n and 0 are integers independently selected from the group consisting of 0, 1,
2, 3 and 4;
[0020] or a pharmaceutical^ acceptable salt or prodrug thereof.
[0021] In one embodiment of the invention R4 is H and the compounds are those of
formula (la):

[0022] or a pharmaceutically acceptable salt or prodrug thereof
[0023] wherein R1, R2, R3, X, Y and Z are as defined for compounds of formula (I).
[0024] In another embodiment R3 and R4 are H and the compounds are of formula (lb):


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[0025] or a pharmaceutical^ acceptable salt or prodrug thereof
[0026] wherein R1, R2, X, Y and Z are as defined for compounds of formula (I).
[0027] As with any group of structurally related compounds which possess a particular
utility, certain groups are preferred for the compounds of the Formula (I), (la) and (lb) in
their end use application.
[0028] In one embodiment the group R1 is a group of formula
-(CR20R21)m-(CR22R23)n-(CR24R25)o-NR26R27;
[0029] in which m, n and o are integers independently selected from the group
consisting of 0, 1, 2, 3 and 4.
[0030] Accordingly, in one embodiment the compounds of the invention are compounds
of formula (Ic):

wherein R1 is a group of formula
-(CR20R21)m-(CR22R23)n-(CR24R25)o-NR26R27
[0031] and R2, R3, R\ X, Y, Z, R20, R2\ R22, R23, R24, R25, R26, R27, m, n and o are as
defined for compounds of formula (I).

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[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 m+n+o is an integer
selected from the group consisting of 0,1, 2, 3 and 4. In another embodiment 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 R1 is
selected from the group consisting of:
-(CR20R21)2-NR26R27;
-(CR22R23)2-NR26R27;
-(CR24R25)2-NR23R27;
-(CR20R21MCR22R23)-NR26R27;
-(CR20R21 )-(CR24R25)-NR26R27;
-(CR22R23MCR24R25)-NR26R27;
[0034] In one form of this embodiment R1 is the group:
-(CR20R21)-(CR22R23)-NR26R27;
[0035] This provides compounds of the formula (II):

[0036] wherein X, Y, Z, R2, R3, R4, R20, R21, R22, R23, R26 and R27 are as defined in
formula (I).
[0037] In a specific form of this embodiment R4 is H which provides compounds of
formula (lla):

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PCT/SG2006/000217


8
[0038] wherein X, Y, Z, R2, R3, R20, R21, R22, R23, R26 and R27 are as defined in formula
(I).
[0039] In another specific form R3 is H leading to compounds of formula (lib):

[0040] wherein X, Y, Z, R2, R20, R21, R22, R23, R26 and R27 are as defined in formula (I).

[0042] wherein X, Y, Z, R2, R26 and R27 are as defined in formula (I).
[0041] In an even more specific form of this embodiment R20, R21, R22 and R23 are H
providing compounds of formula (lie):

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[C043] In another embodiment the sum of m+n+o is 3. When this occurs R1 is selected
from the group consisting of:
-(CR20R21)3-NR26R27;
-(CR22R23)3-NR26R27;
-(CR24R25)3-NR26R27;
-(CR20R21)2-(CR22R23)-NR26R27;
-(CR20R21 )2-(CR24R25)-NR26R27;
-(CR20R21 HCR^R^^-NR^R27;
-(CR22R23)2-(CR24R25)-NR26R27;
-(CR20R21 )-(CR24R25)2-NR26R27;
-(CR22R23)-(CR24R25)2-NR26R27;
-(CR20R21)-(CR22R23)-(CR24R25)-NR2eR27;
[0044] In one form of this embodiment R1 is a group of the formula:
-(CR20R21)-(CR22R23)-(CR24R25)-NR26R27.
[0045] This provides compounds of the formula (III):

[0046] wherein X, Y, Z, R2, R3, R4, R20, R21, R22, R23,R24, R25, R26 and R27 are as defined
in formula (l).
[0047] In a specific form of this embodiment R4 is H which provides compounds of
formula (Ilia).

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[0048] wherein X, Y, Z, R2, R3, R20, R21, R22, R23, R24, R25, R26 and R27 are as defined in
formula (I).
[0049] In another specific form R3 is H leading to compounds of formula (lilb):

[0050] wherein X, Y, Z, R2, R20, R21, R22, R23,R24, R25, R26 and R27 are as defined in
formula (I).
[0051] In an even more specific form of this embodiment R20, R21, R24 and R25 are H,
and R22 and R23 are methyl providing compounds of formula (lllc).


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PCT/SG2006/000217

Formula (lllc)
[0052] wherein X, Y, Z, R2, R26 and R27 are as defined in formula (I).
[0053] In each of the above embodiments of the invention R20 and R21 may represent a
number of different variables. In one embodiment R2Dand R21 are independently selected
from the group consisting of H, alkyl, alkenyl and alkynyl. In another embodiment R20 and
R21 are independently selected from the group consisting of H and alkyl. In yet another
embodiment R20 and R21 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, pentyl, pent-4-enyl, hexyl, heptyl and octyl.
In a specific embodiment R20 and R21 are both H.
[0054] In each of the above embodiments of the invention R22 and R23 may represent a
number of different variables. In one embodiment R22 and R23 are independently selected
from the group consisting of H, alkyl, alkenyl and alkynyl. In another embodiment R22 and
R23 are independently selected from the group consisting of H and alkyl. In yet another
embodiment R22 and R23 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, pentyl, pent-4-enyl, hexyl, heptyl and octyl.
in a further embodiment R22 and R23 are independently selected from the group consisting
of alkyl. In a most specific embodiment R22 and R23 are both methyl.
[0055] In each of the above embodiments of the invention R24 and R25 may represent a
number of different variables. In one embodiment R24 and R25 are preferably
independently selected from the group consisting of H, alkyl, alkenyl and alkynyl. In
another embodiment R24and R26 are independently selected from the group consisting of
H and alkyl. In yet another embodiment R24 and R25 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, pentyl, pent-4-enyl,
hexyl, heptyl and octyl. In a specific embodiment R24 and R25 are both H.
[0056] In each of the above embodiments there are a number of values for R26 and R27.
In one embodiment R26 and R27 are independently selected from the group consisting of:
H, alkyl, alkenyl, alkynyl, alkoxyalkyl, and acyl. In another embodiment R26 and R27 are
independently selected from the group consisting of: H, alkyl and acyl. In a further
embodiment R26 and R27 are independently selected from the group consisting of H,
methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-

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dimethyl-butyl, 2-ethy!-butyl, pentyl, 2-methyl, pentyl, pent-4-enyl, hexyl, heptyl, octyl,
acetyl and 2-methoxy-ethyl.
[0057] In another embodiment R1 is a heterocycloalkyl group which may optionally be
substituted.
[0058] In one form of this embodiment the heterocycloalkyl group is selected from the
group consisting of:

[0059] wherein R2B is selected from the group consisting of H, halogen, alky!, alkenyl,
alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,
heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,
heteroaryiheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,
alkoxyaryi, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy,
arylalkyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino,
phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, arylacyl, sulfonyl,
alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsurfinyl, aminosulfonyl, SR5 and acyl, each of
which may be optionally substituted.
[0060] In one embodiment R28 is selected from the group consisting of H, alkyl, alkenyl,
arylalkyl and arylacyl. Specific values of R28 are H, methyl; ethyl; propyl; 2-methyl-propyl,
2-2-dimethyl-propyl; isopropyl; 3,3,3-tr'rflouro-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-phenyl-propyl,
[0061] 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. In one specific embodiment R1 is
selected from the group consisting of piperidine-3-yl, piperidine-4-yl and pyrollidin-3-y.

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[0062] In another embodiment R1 is a heteroaryl group.
[0063] In another embodiment R1 is a group selected from the group consisting of:


WO 2007/030080 PCT/SG2006/000217
1


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[0064] In one specific embodiment R1 is a group of formula:

[0065] In another specific embodiment R1 is a group of formula:

[0066] In another specific embodiment R1 is a group of formula:

[0067] In yet another specific embodiment R1 is a group of formula:

[0068] In another specific embodiment R1 is a group of formula:

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[0069] In another specific embodiment R1 is a group of formula:

[0070] In another specific embodiment R1 is a group of formula:

[0071] In another specific embodiment R1 is a group of formula:

[0072] In another specific embodiment R1 is a group of formula:


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[0073] In one embodiment Rz is selected from the group consisting of H, alkyl,
cycloalkyl, heteroalkyl, alkenyl, alkynyl, alkoxyalkyl and cycloalkylalkyl, each of which may
be optionally substituted.
[0074] In one form of this embodiment R2 is alkyl. In one embodiment the alkyl is a Cr
C10 alkyl. In another form of this embodiment the alkyl is a CrC6 alkyl group. In another
form of this embodiment R2 is selected from the group consisting of: methyl; ethyl; propyl;
2-methyl-propyl, 2-2-dimethyl-propyl; isopropyl; 3,3,3-triflouro-propyl; butyl; isobutyl; 3,3-
dimethyl-butyl; pentyl; 2,4,4-trimethyl-pentyl; hexyl; heptyl, octyl, nonyl, and 2-methoxy
nonyl.
[0075] In one form of this embodiment R2 is alkenyl. In one form of this embodiment the
alkenyl is a C1-C10 alkenyl. In another form of this embodiment the alkenyl is a Ci-C6
alkenyl group. In another form of this embodiment R2 is selected from the group
consisting of: ethenyl, prop-1-enyl, prop-2-enyl, but-1-enyl, but-2-enyl but-3-enyl, pent-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 R2 is selected from the group consisting of R11S(0)R13-,
R^StO^R13-, R11C(0)N(R12)R13-, R11S02N(R12)R13-, R11N(R12)C(0)R13-,
R11N(R12)S02R13-, and R11N(R12)C(0)N(R12)R13-. In one form of this embodiment R2 is a
group of the formula R11C(0)N(R12)R13-. In one form of this embodiment R13 is a d-C6
alkyl. In a specific form of this embodiment R13 is methyl or ethyl. In one form of this
embodiment R12 is H or CrC6alkyl. A specific value for R12 is H. In one form of this
embodiment R11 is CrC6 alkyl group. Specific values for R11 include t-butyl and propyl. .
Specific examples of groups of this type include: (CH3)3CCH2CONH(CH2)2-;
(CH3)3CCONH(CH2)2-; (CH3)3CCONH(CH2)- and Ch^CI-yaCONhKCr^)-.
[0077] Specific values of R2 are selected from the group consisting of: H; methyl;
ethoxymethyl; [Bicylco[2.2.1]2-ylmethyl; Adamantan-2-ylmethyl; 2-methansuifanyl-ethyl;
2,2,2-triflouro-ethyl; propyl; 2-2-dimethyl-propyl; isopropyl; 3,3,3-triflouro-propyl; butyl;
isobutyl; 3,3-dim ethyl-butyl; but-3-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-methoxy-
nonyl, 2-phenyl-cyclopropyl; cyclohexyl; (CH3)3CCH2CONH(CH2)2-; (CH3)3CCONH(CH2)2-;
(CH3)3CCONH(CH2)- and CH3(CH2)2CONH(CH2)-.

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[0078] In one embodiment X and Y may be the same or different and are selected from
the group consisting of H, halogen, CrC4 alkyl, -CF3, -N02> -C(0)R5, -OR6, -SR6, -CN and
NR7R8.
[0079] In one embodiment X is H;
[0080] In one embodiment Y is H;
[0081] In one embodiment X and Y (if present) are at the 4 and 7 positions of the
aromatic ring.
[0082] In one embodiment R3 is H, Ci-C6 alkyl, or acyl. In another embodiment R3 is H
or CrC4 alkyl. A specific value for R3 is H;
[0083] In one embodiment R4 is H or C-i-C4 alkyl. A specific value for R4 is H;
[0084] In one embodiment R5 is C1-C4 alkyl, heteroalkyl, or acyl. A specific value for R5
is methyl;
[0085] In one embodiment R6 is CrC4 alkyl, heteroalkyl or acyl. A specific value for R6
is CrC4 alkyl;
[0086] In one embodiment R7 and R8 are selected from the group consisting of H, CrC6
alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl
[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, -N02, -CF3, -OCF3, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy,
alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy,
cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy,
arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl,
arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, -
COOH, -COR5, -C(0)OR5, -SH, -SR5, -OR6and acyl.

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[0088] In a further embodiment the optional substituents are selected from the group
consisting of: halogen, =0, =S, -CN, -N02l alkyl, alkenyl, heteroalkyl, haloalky!, alkynyl,
aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino,
aminoalkyl, acylamino, phenoxy, alkoxyalky!, benzyloxy, alkylsulfonyl, arylsulfonyl,
aminosulfonyl, -C(0)OR5, COOH, SH, and acyl.
[0089] In one embodiment the Z moiety is at the 5 or 6 position. In a specific
embodiment the Z moiety is at the 5 position. In one embodiment the Z moiety is a group
of formula -CH=CH-. If the Z moiety is a group of this type it is preferably in the "E"
configuration.
[0090] In addition to compounds of Formula (I), the embodiments disclosed are also
directed to pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and
pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable
salts of such metabolites. Such compounds, salts, prodrugs and metabolites are at times
collectively referred to herein as "HDAC inhibiting agents" or "HDAC inhibitors".
[0091] The invention also relates to pharmaceutical compositions including a compound
of the invention with a pharmaceutically acceptable carrier, diluent or excipient.
[0092] 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 cell proliferation
and/or angiogenesis including administration of a therapeutically effective amount of a
compound of formula (I). 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.
[0093] In one embodiment the method includes administration of a compound of
formula (la) or (lb) as described herein.
[0094] In one embodiment the disorder is selected from the group consisting of but 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

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diseases, chronic and acute neurodegenerative disease like disruptions of nerval tissue,
Huntington's disease and infectious diseases like fungal, bacterial and viral infections. In
another embodiment the disorder is a proliferative disorder. In one embodiment the
proliferative disorder is cancer. The cancer can include solid tumors or hematologic
malignancies.
[0095] The invention also provides agents for the treatment of a disorder caused by,
associated with or accompanied by disruptions of cell proliferation and/or angiogenesis
including a compound of formula (I) as disclosed herein. In one embodiment the agent is
an anti-cancer agent. In another embodiment the agent is an anti-angiogenesis agent.
[0096] In one embodiment the agent contains a compound of formula (la) or (lb).
[0097] The invention also relates to the use of compounds of formula (I) in the
preparation of a medicament for the treatment of a disorder caused by, associated with 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.
[0098] The compounds of the present invention surprisingly show low toxicity, together
with a potent anti-proliferative activity.
[0099] In yet a further embodiment the invention provides a method of treatment of a
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 (I).
[0100] In one embodiment the method includes administration of a compound of
formula (la) or (lb) 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 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 haemorrhage Primary
lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic
interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary
spastic paraplegia, Progressive ataxia and Shy-Drager syndrome; Metabolic diseases

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including Type 2 diabetes; Degenerative Diseases of the Eye including Glaucoma, Age-
related macular degeneration, macular myopic degeneration, Rubeotic glaucoma,
Interstitial keratitis, Diabetic retinopathy, Peter's anomaly retinal degeneration, Cellophane
Retinopathy; Cogan's Dystrophy; Corneal Dystrophy; Iris Neovascularization (Rubeosis);
Neovascularization of the Cornea; Retinopathy of Prematurity; Macular Edema; Macular
Hole; Macular Pucker; Marginal Blepharitis, Myopia, nonmalignant growth of the
conjunctiva; Inflammatory diseases and/or Immune system disorders including
Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host
disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowei
disease, Colitis Ulcerosa, Alcoholic hepatitis, Diabetes, Sjoegrens's syndrome, Multiple
Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain,
Systemic Lupus Erythematosus, allergic contact dermatitis; Disease involving
angiogenesis including cancer, psoriasis, rheumatoid arthritis; Psychological disorders
including bipolar disease, schizophrenia, depression and dementia; Cardiovascular
Diseases including Heart failure, restenosis, cardiac hypertrophy and arteriosclerosis;
Fibrotic diseases including liver fibrosis, lung fibrosis, cystic fibrosis and angiofibroma;
Infectious diseases including Fungal infections, such as Candida Albicans, Bacterial
infections, Viral infections, such as Herpes Simplex, Protozoal infections, such as Malaria,
Leishmania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidiosis, and
Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.
[0102] 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 (I) as disclosed herein. In one embodiment the agent is an anti-
cancer agent.
[0103] The invention also relates to the use of compounds of formula (I) 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.
[0104] The invention also provides a method for inhibiting cell proliferation including
administration of an effective amount of a compound according to formula (I).
[0105] In yet an even further aspect the invention provides a method of treatment of a
neurodegenerative disorder in a patient including administration of a therapeutically
effective amount of a compound of formula (I). In one embodiment the method includes

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administration of a compound of formula (la) or (lb) as described herein. In one
embodiment the neurodegenerative disorder is Huntington's Disease.
[0106] The invention also provides agents for the treatment of neurodegenerative
disorder including a compound of formula (I) as disclosed herein. In one embodiment the
agent is preferably anti-Huntington's disease agent.
[0107] The invention also relates to the use of compounds of formula (I) in the
preparation of a medicament for the treatment of a neurodegenerative disorder. In one
embodiment the neurodegenerative disorder is Huntington's Disease.
[0108] In yet an even further aspect the invention provides a method of treatment of an
inflammatory disease and/or immune system disorder in a patient including administration
of a therapeutically effective amount of a compound of formula (I). In one embodiment the
method includes administration of a compound of formula (la) or (lb) as described herein.
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.
[0109] The invention also provides agents for the treatment of inflammatory disease
and/or immune system disorder including a compound of formula (I) 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
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 (I) in the
preparation of a medicament for the treatment of inflammatory disease and/or immune
system disorder. In one embodiment the inflammatory disease and/or immune system
disorder is rheumatoid arthritis. In another embodiment the inflammatory disease and/or
immune system disorder is Systemic Lupus Erythematosus.
[0112] The invention also provides methods of preparation of the compounds of the
invention. In one embodiment the invention provides a method of synthesis of
compounds of formula I as defined above the method including:

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[0113] (a) providing a compound of the formula (A1):



[0114] wherein X, Y and Z are as defined above and L is a leaving group;
[0115] (b) protecting the carboxyl group to produce a compound of the formula (A2):

[0116] wherein X, Y and Z are as defined above L is a leaving group and Pc is a carboxyl
protecting group;
[0117] (c) displacing the leaving group with an amine of formula R1NH2 to produce a
compound of the formula (A3):

[0118] wherein X, Y, Z are as defined above, R1 is as defined above or a protected form
thereof, and Pc is a carboxyl protecting group;
[0119] (d) optionally reacting the compound to further functionalise R1;
[0120] (e) reducing the nitro group;

WO 2007/030080 PCT/SG2006/000217
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[0121] (f) reacting the reduced product with a compound of formula R2C02H or a
compound of formula R2CHO and cyclising the product thus produced to produce a
compound of the formula (A4)

[0122] wherein X, Y, Z are as defined above, R1 and R2 are as defined above or
protected forms thereof, and Pc is a carboxyl protecting group;
[0123] (g) converting the compound to a compound of formula I;
[0124] wherein (d) can be carried out after any one of (c) (e) or (f) and further wherein (e)
and (f) can be carried out sequentially or simultaneously.
[0125] In yet an even further aspect the invention provides a method of synthesis of
compounds of formula I as defined above

[0126] wherein R1, R2, R3, R4, X, Y and Z are as defined above, the method including:
[0127] (a) providing an aldehyde of the formula (B1)

[0128] wherein R1, R2, X, and Y are as defined above;

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[0129] (b) subjecting the aldehyde to reaction with an appropriately substituted
olefination agent to produce a compound of formula (B2)

[0130] wherein R1, R2, X, Y, and Z are as defined above, and Pc is H or a carboxyl
protecting group;
[0131] (c) converting the compound to a compound of formula I.
[0132] In one embodiment of this method (a) includes:
[0133] (a1) providing a compound of the formula (B3):

[0134] wherein X and Y are as defined above, L is a leaving group and P° is a carboxyl
protecting group;
[0135] (a2) displacing the leaving group with an amine of formula R1NH2 to produce a
compound of the formula (B4):

[0136] wherein X, and Y are as defined above, R1 is as defined above or a protected form
thereof, and Pc is a carboxyl protecting group

WO 2007/030080 PCT/SG2006/000217
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[0137] (a3) optionally reacting the compound to further functionalise R1
[0138] (a4) reducing the nitro group;
[0139] (a5) reacting the reduced product with a compound of formula R2C02H or a
compound of formula R2CHO and cyclising the product thus produced to produce a
compound of the formula (B5):

[0140] wherein X, and Y are as defined above, R1 and R2 are as defined above or
protected forms thereof, and Pc is a carboxyl protecting group
[0141] (a6) converting the compound of formula (B5) to the corresponding aldehyde
[0142] wherein (a3) can be carried out after any one of (a2), (a4), (a5) or (a6) and further
wherein (a4) and (a5) may be carried out sequentially or simultaneously.
[0143] In yet an even further aspect the invention provides a method of synthesis of
compounds of formula I as defined above

[0144] wherein R1, R2, R3, R4, X, Y and Z are as defined above, the method including:
[0145] (a) providing a compound of the formula (C1)


WO 2007/030080 PCT/SG2006/000217
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[0146] wherein X, and Y are as defined above, R1 and R2 are as defined above or
protected forms thereof, and L1 is a leaving group
[0147] (b) converting the compound (C1) to a compound of formula (C2);

[0148] wherein X, Y and Z are as defined above, R1 and R2 are as defined above or
protected forms thereof, and Pc is H or a carboxyl protecting group
[0149] (c) converting the compound to a compound of formula I.
[0150] In one form of this embodiment (a) includes:
[0151] (a1) providing a compound of the formula (C3):

[0152] wherein X and Y are as defined above and L and L1 are leaving groups;
[0153] (a2) displacing the leaving group (L) with an amine of formula R1NH2 to produce a
compound of the formula (C4):

WO 2007/030080 PCT/SG2006/000217
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[0154] wherein X and Y, are as defined above, R1 is as defined above or a protected form
thereof, and L1 is a leaving group;
[0155] (a3) optionally reacting the compound to further functionalise R1;
[0156] (a4) reducing the nitro group;
[0157] (a5) reacting the reduced product with a compound of formula R2C02H or a
compound of formula R2CHO and cyclising the product thus produced to produce a
compound of the formula (C1):

[0158] wherein (a3) can be carried out after any one of (a2), (a4) or (a5) and further
wherein (a4) and (a5) may be earned out sequentially or simultaneously.
DETAILED DESCRIPTION OF THE INVENTION
[0159] 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.
[0160] As used herein, the term unsubstituted means that there is no substituent or that
the only substituents are hydrogen.
[0161] The term "optionally substituted" as used throughout the specification denotes
that the group may or may not be further substituted or fused (so as to form a condensed
polycyclic system), with one or more substituent groups. Preferably the substituent
groups are one or more groups independently selected from the group consisting of

WO 2007/030080 PCT/SG2006/000217
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halogen, =0, =S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
haloalkyny!, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,
aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl,
cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl,
cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl,
hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl,
alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy,
cycloalkyioxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy,
phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino,
sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl,
alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -COOH, -COR5, -C(0)OR5, CONHR5,
NHCOR5, NHCOOR5, NHCONHR5, C(=NOH)R5 -SH, -SR5, -OR5 and acyl.
[0162] "Alkyl" as a group or part of a group refers to a straight or branched aliphatic
hydrocarbon group, preferably a C1-C14 alkyl, more preferably C1-C10 alkyl, most
preferably Ci-C6 unless otherwise noted. Examples of suitable straight and branched (V
C6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl,
hexyl, and the like. The group may be a terminal group or a bridging group.
[0163] "Alkylamino" includes both monoalkylamino and dialkylamino, unless specified.
"Monoalkylamino" means a -NH-Alkyl group, in which alkyl is as defined above.
"Dialkylamino" means a -N(alkyl)2 group, in which each alkyl may be the same or different
and are each as defined herein for alkyl. The alkyl group is preferably a CrCe alkyl group.
The group may be a terminal group or a bridging group.
[0164] "Arylamino" includes both mono-arylamino and di-arylamino unless specified.
Mono-arylamino means a group of formula aryl NH-, in which aryl is as defined herein,
di-arylamino means a group of formula (aryl2) N- where each aryl may be the same or
different and are each as defined herein for aryl. The group may be a terminal group or a
bridging group.
[0165] "Acyl" means an alkyl-CO- group in which the alkyl group is as described herein.
Examples of acyl include acetyl and benzoyl. The alkyl group is preferably a Ci-C6 alkyl
group. The group may be a terminal group or a bridging group.

WO 2007/030080 PCT/SG2006/000217
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[0166] "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 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. The group may be a terminal group or
a bridging group.
[0167] "Alkoxy" refers to an -O-alkyl group in which alkyl is defined herein. Preferably
the alkoxy is a CrC6alkoxy. Examples include, but are not limited to, methoxy and
ethoxy. The group may be a terminal group or a bridging group.
[0168] "Alkenyloxy" refers to an -O- alkenyl group in which alkenyl is as defined herein.
Preferred alkenyloxy groups are C1-C6 alkenyloxy groups. The group may be a terminal
group or a bridging group.
[0169] "Alkynyloxy" refers to an -O-alkynyl group in which alkynyl is as defined herein.
Preferred alkynyloxy groups are CrC6 alkynyloxy groups. The group may be a terminal
group or a bridging group.
[0170] "Alkoxycarbonyl" refers to an -C(0)-0-alkyl group in which alkyl is as defined
herein. The alkyl group is preferably a CrC6 alkyl group. Examples include, but not
limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a
bridging group.
[0171] "Akylsulfinyl" means a -S(0)-alkyl group in which alkyl is as defined above. The
alkyl group is preferably a C-i-C6 alkyl group. Exemplary alkylsulfinyl groups include, but
not limited to, methylsulfinyl and ethylsulfinyl. The group may be a terminal group or a
bridging group.
[0172] "Alkylsulfonyl" refers to a -S(0)2-alkyl group in which alkyl is as defined above.
The alkyl group is preferably a CrC6 alkyl group. Examples include, but not limited to
methylsulfonyl and ethylsulfonyl. The group may be a terminal group or a bridging group.
[0173] "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

WO 2007/030080 PCT/SG2006/000217
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having from 2-14 carbon atoms, more preferably 2-12 carbon atoms, more preferably 2-6
carbon atoms in the normal chain. Exemplary structures include, but are not limited to,
ethynyl and propynyl. The group may be a terminal group or a bridging group.
[0174] "Alkylaminocarbonyl" refers to an alkylamino-carbonyl group in which alkylamino
is as defined above. The group may be a terminal group or a bridging group.
[0175] "Cycloalkyl" refers to a saturated or partially saturated, monocyclic or fused or
spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as
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. The group may be a terminal
group or a bridging group.
[0176] "Cycloalkenyl" 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. The group may be a terminal group or a bridging group.
[0177] 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.
[0178] "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl
moieties are as previously described. Exemplary monocycloalkylalkyl groups include
cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The
group may be a terminal group or a bridging group.
[0179] "Halogen" represents chlorine, fluorine, bromine or iodine.
[0180] "Heterocycloalkyl" refers to a saturated or partially saturated monocyclic, 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 preferably
from 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable
heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl,
piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-

WO 2007/030080 PCT/SG2006/000217
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oxazepane, and 1,4-oxathiapane. The group may be a terminal group or a bridging
group.
[0181] "Heterocycloalkenyl" refers to a heterocycloalkyi as described above but
containing at least one double bond. The group may be a terminal group or a bridging
group.
[0182] "Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl group in which the
heterocycloalkyi and alkyl moieties are as previously described. Exemplary
heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl,
(2-tetrahydrothiofuranyl)methyl. The group may be a terminal group or a bridging group.
[0183] "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
heter'oatom selected from S, O, and N. Exemplary heteroalkyls include alkyl ethers,
secondary and tertiary alkyl amines, alkyl sulfides, and the like. The group may be a
terminal group or a bridging group.
[0184] "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 saturated
bicyclic aromatic carbocyclic moiety in which a phenyl and a C5.7 cycloalkyl or C5.7
cycloalkenyl group are fused together to form a cyclic structure, such as
tetrahydronaphthyl, indenyl or indanyl. The group may be a terminal group or a bridging
group.
[0185] "Arylalkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as
previously described. Exemplary arylalkenyl groups include phenylallyl. The group may
be a terminal group or a bridging group.
[0186] "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as
previously described. Preferred arylalkyl groups contain a Ci^ alkyl moiety. Exemplary
arylalkyl groups include benzyl, phenethyl and naphthelenemethyl. The group may be a
terminal group or a bridging group.

WO 2007/030080 PCT/SG2006/000217
33
[0187] "Arylacyl" means an aryl-acyl- group in which the aryl and acyl moieties are as
previously described. In general the aryl moiety is attached to the alkyl portion of the acyl
moiety, typically to the terminal carbon of the alkyl portion of the acyl moiety. Preferred
arylacyl groups contain a C^s alkyl moiety in the acyl moiety. Exemplary arylacyl groups
include 2-phenyl-acetyl. The group may be a terminal group or a bridging group.
[0188] "Heteroaryl" either alone or part of a group refers to groups containing an
aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more
heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being
carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur. Examples of
heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole,
benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene,
phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,
indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine,
quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole,
isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-,3- or4- pyridyl,
2-, 3-, 4-, 5-, or 8- quinolyl, 1-, 3-, 4-, or 5- isoquinolinyh-, 2-, or 3- indolyl, and 2-, or
3-thienyl. The group may be a terminal group or a bridging group.
[0189] "Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl
moieties are as previously described. Preferred heteroarylalkyl groups contain a lower
alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be
a terminal group or a bridging group.
[0190] "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 isopropyl)
or butyl (n-butyl, isobutyl or tertiary-butyl). The group may be a terminal group or a
bridging group.
[0191] In Formula (I), as well as in Formulae (la) - (lb) 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 each of Formulae
(I), (la), 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 hydrolysed
would provide the acidic moiety. In some embodiments the acidic moiety may be

WO 2007/030080 PCT/SG2006/000217
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attached to the ring position through an alkylene group such as -CH2- or-CH2CH2-, or an
aikenylene group such as -CH=CH-. Preferred positions for attachment of the acidic
moiety are the 5- and 6-ring positions.
[0192] It is understood that included in the family of compounds of Formula (I) are
isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical
isomers in "E" or "Z" configurations! isomer or a mixture of E and Z isomers. It is also
understood that some isomeric forms such as diastereomers, enantiomers, and
geometrical isomers can be separated by physical and/or chemical methods and by those
skilled in the art.
[0193] Some of the compounds of the disclosed embodiments may exist as single
stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All
such single stereoisomers, racemates and mixtures thereof are intended to be within the
scope of the subject matter described and claimed.
[0194] Additionally, Formula (I) is intended to cover, where applicable, solvated as 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.
[0195] In addition to compounds of the Formula (I), the HDAC inhibiting agents of the
various embodiments include pharmaceutically acceptable salts, prodrugs, and active
metabolites of such compounds, and pharmaceutically acceptable salts of such
metabolites.
[0196] The term "Pharmaceutically acceptable salts" refers to salts that retain the
desired biological activity of the above-identified compounds, and include
pharmaceutically acceptable acid addition salts and base addition salts. Suitable
pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be
prepared from an inorganic acid or from an organic acid. Examples of such inorganic
acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be
selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic
classes of organic acids, examples of which are formic, acetic, propionic, succinic,
glyeolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic.
Suitable pharmaceutically acceptable base addition salts of compounds of Formula (I)
include metallic salts made from lithium, sodium, potassium, magnesium, calcium,
aluminium, and zinc, and organic salts made from organic bases such as choline,

WO 2007/030080 PCT/SG2006/000217
35
diethanolamine, morpholine. Other examples of organic salts are: ammonium salts,
quaternary salts such as tetramethylammonium salt; amino acid addition salts such as
salts with glycine and arginine. Additional information on pharmaceutically acceptable
salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack
Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by
those skilled in the art that the inventive compounds, agents and salts may exist in
different crystalline or polymorphic forms, all of which are intended to be within the scope
of the present invention and specified formulae.
[0197] "Prodrug" means a compound which is convertible in vivo by metabolic means
(e.g. by hydrolysis, reduction or oxidation) to a compound of formula (I). For example an
ester prodrug of a compound of formula (I) containing a hydroxyl group may be
convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of
formula (I) containing a hydroxy! group, are for example acetates, citrates, lactates,
tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates,
methylene-bis-p-hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates,
methanesulphonates, ethanesulphonates, benzenesulphonates, p-toiuenesulphonates,
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).
[0198] Preferred HDAC inhibiting agents include those having an iC50 value of 10 |j.M or
less.
[0199] Specific compounds of the invention include the following:



3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylam ide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
isopropyl-1H-benzoimidazol-5-yrj-N-hydroxy-
acrylamide

WO 2007/030080 PCT/SG2006/000217
36

3-[2-Butyl-1-(3-dimethylamino-2,2-dimethyl-
propyl)-1 H-benzoim idazol-5-yl]-N-hydroxy-
acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2-
methylsulfanyl-ethyl)-1H-benzoimidazol-5-yl]-N-

hydroxy-acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
ethoxymethyl-1H-benzoimidazol-5-yl]-N-

hydroxy-acrylamide
3-[1-(3-Dimethytamino-2,2-dimethyl-propyl)-2-
isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-

acrylamide

3-[1-(2-Diethylamino-ethyl)-2-isobutyl-1H-
benzoim idazol-5-yl]-N-hydroxy-acrylam ide

3-[2-Butyl-1 -(2-diethylamino-ethyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-But-3-ynyl-1-(3-dimethylamino-2,2-dimethy!-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-

acrylamide
3-[2-But-3-enyl-1-(3-dimethylamino-2,2-
dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide

WO 2007/030080 PCT/SG2006/000217

37

3-[2-But-3-enyl-1 -(2-diethylamino-ethyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acry!amide

3-t2-But-3-ynyl-1-(2-diethylamino-ethyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2~
(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylam ide

3-[1-(2-Diethylamino-ethyI)-2-(3,3,3-trifluoro-
propy l)-1 H-benzoim idazol-5-yl]-N-hydroxy-
acrylamide

3-[1 -(2-Diethylamino-ethyl)-2-ethoxymethyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
methyl-1H-benzoimidazol-5-yl]-N-hydroxy-

acrylamide
3-[1-(2-Diethylamino-ethyl)-2-(2,2-dimethyl-
propyl)-1 H-benzoim idazol-5-yl]-N-hydroxy-
acrylamide

WO 2007/030080 PCT/SG2006/000217
38








N-Hydroxy-3-[1-{3-isopropy1amino-propyl)-2-
(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-
acrylamide
3-[2-(2,2-Dimethyl-propyl)-1-(2-isopropylamino-
ethyl)-1 H-benzoim idazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Diisopropylamino-ethyl)-2-(2,2-dimethyl-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1 -(2-Diisopropylamino-ethyl)-2-isobutyl-1 H-
benzoimidazol-5-yI]-N-hydroxy-acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]"
N-hydroxy-acrylam ide
3-[2-Cyclohexyl-1-(3-dimethylamino-2,2-
dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylam ide

WO 2007/030080 PCT/SG2006/000217

39
3-[2-Bicyclo[2.2.1]hept-5-en-2-yl-1-(3-
dimethylamino-2,2-dimethyl-propyl)-1H-

benzoimidazo!-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diethylamino-ethyl)-2-hex-3-enyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diisopropylamino-ethyl)-2-hex-3-enyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Hex-3-eny!-1 -(2-isopropylamino-ethyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Hex-3-enyl-1-(3-isopropylamino-propyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1 -(2-Ethylamino-ethyl)-2-hex-3-enyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diethylamino-ethyl)-2-hexyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-
(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-
acrylamide

WO 2007/030080 PCT/SG2006/000217
40









3-[2-(2,2-Dimethyl-propyl)-1-(3-isopropylamino-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Diisopropylamino-ethyl)-2-(3,3,3-trifiuoro-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
N-Hydroxy-3-[2-isobutyl-1-(2-isopropylamino-
ethyl)-1H-benzoimidazol-5-yl]-acrylamide
3-[2-(2,2-Dimethyl-propy!)-1-(2-ethylamino-
ethyl)-1 H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1 -(2-Ethylamino-ethyl)-2-isobutyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1-(2-Diisopropylamino-ethyl)-2-(2,4,4-
trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylam ide
N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-
(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-
acrylamide
3-[1-(2-Ethylamino-ethyl)-2-(2,4,4-trimethyl-
pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide

WO 2007/030080 PCT/SG2006/000217
41









3-[1-(2-Diethylamino-ethyl)-2-(2,4,4-trimethyl-
pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Diethylamino-ethyl)-2-propyl-1H-
benzoimidazo!-5-yl]-N-hydroxy-acrylamide
3-[2-Buty I-1 -(2-diisopropylam i no-ethyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-Butyl-1-(2-ethylamino-ethyl)-1H-
benzoim idazo!-5-yl]-N-hydroxy-acrylam ide
3-[1-(2-Diethylamino-ethyl)-2-(2-methylsulfanyl-
ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[2-Butyl-1-(2-isopropylamino-ethyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-Butyl-1 -(3-isopropylamino-propyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acryIamide
3-[1 -(1 -Benzyl-piperidin-4-yl)-2-butyl-1 H-
benzoim idazol-5-yl]-N-hydroxy-acrylam ide

WO 2007/030080 PCT/SG2006/000217

42
3-[2-But-3-enyl-1 -(2-ethylam ino-ethyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide








3-[2-Hexyl-1-(2-isopropylamino-ethyl)-1H-
benzoimidazol-5-yQ-N-hydroxy-acrylamide
3-[1-(2-Dimethylamino-ethyl)-2-(2,4,4-trimethyl-
pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Ethylamino-ethyl)-2-hexyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-
(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-
acrylamide
3-[1 -(2-Dimethylamino-ethyl)-2-hex-3-enyl-1 H-
benzoim idazol-5-yl]-N-hydroxy-acrylam ide
3-[1-(2-Amino-ethyl)-2-(2,4,4-trimethyl-pentyl)-
1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1 -(2-Amino-ethyl)-2-(2-methoxy-nonyl)~1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide

WO 2007/030080 PCT/SG2006/000217
43


3-[2-Butyl-1-(2-dimethylamino-ethyl)-1H-
benzoimidazol-5-y!]-N-hydroxy-acrylamide






3-[1-(2-Dimethylamino-ethyl)-2-hexyl-1H-
benzoim idazol-5-yl]-N-hydroxy-acrylam ide
N-{2-[1-(2-Diethylamino-ethyl)-5-(2-
hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2-
yl]-ethyl}-3,3-dimethyl-butyramide
3-{1-(2-Diethylamino-ethyl)-2-[2-(2,2-dimethy!-
propionylamino)-ethyl]-1H-benzoimidazol-5-yl}-
N-hydroxy-acrylam ide
3-{1-(2-Diethylamino-ethyl)-2-[(2,2-dimethyl-
propionylamino)-methyl]-1H-benzoimidazol-5-
yl}-N-hydroxy-acrylamide
N-[1-(2-Diethylamino-ethyl)-5-(2-
hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2-
ylmethyl]-butyramide


3-[1 -(2-ethylamino-ethyl) -2-(3,3-dimethyl-butyl)-
1H-benzoimidazo!-5-yl]-N-hydroxy-acrylamide

WO 2007/030080 PCT/SG2006/000217
44









3-[2-(3,3-Dimethyl-butyl)-1-(2-Dimethylamino-
ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Dimethylamino-ethyl)-2-pentyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1-(2-Dimethylamino-ethyl)-2-(2,2,2-trffluoro-
ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
N-Hydroxy-3-[1 -(5-methyl-1 H-pyrazol-3-yl)-2-
(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-
acrylamide
3-[1 -(2-Ethylam ino-ethyl)-2-pentyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-(2-Butyl-1 -pyrrolidin-3-yl-1 H-benzoimidazol-5-
yl)-N-hydroxy-acrylam ide
3-(2-Butyl-1-piperidin-4-yl-1H-benzoimidazol-5-
yl)- N-hydroxy-acrylam ide
N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-
pentyl-1 H-benzoim idazol-5-yl]-acrylamide

WO 2007/030080 PCT/SG2006/000217
45








N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-non-3-
enyl-1H-benzoimidazol-5-yl]-acrylamide
N-Hydroxy-3-[1-(2-methylamino-ethy!)-2-non-6-
enyl-1H-benzoimidazol-5-yl]-acrylamide
3-[2-Hexyl-1-(2-methylamino-ethyl)-1H-
benzoim idazol-5-yl]-N-hydroxy-acrylam ide
N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-pentyl-
1H-benzoimidazol-5-yl]-acrylamide
N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-octyl-
1 H-benzoimidazol-5-yl]-acrylamide
3-[1 -(2-Aminoethyl)-2-octyl-1 H-benzoim idazol-
5~yl]-N-hydroxy-acrylamide
3-{2-Butyl-1-f2-(isopropyl-methyl-amino)-ethyl]-
1 H-benzoimidazol-5-yl}-N-hydroxy-acrylam ide

WO 2007/030080 PCT/SG2006/000217
46







3-{1-[2-(Ethyl-methyl-amino)-ethyl]-2-pentyl-1H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-(2-Hexyl-1 -pyrrolidin-3-yl-1 H-benzoimidazol-5-
yl)-N-hydroxy-acrylam ide
3-[2-Buty!-1-(1-methyl-pyrrolidin-3-yl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-(2-Butyl-1-piperidin-3-yl-1H-benzoimidazol-5-
yl)-N-hydroxy-acrylamide
3-(2-Hexyl-1 -piperidin-3-yl-1 H-benzoim idazol-5-
yl)-N-hydroxy-acrylamide
3-(1-{2-[Ethyl-(2-methoxy-ethyl)-amino]-ethyl}-2-
pentyl-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide


3-{2-Butyl-1 -[2-(ethy!-methyl-amino)-ethyl]-1 H-
benzoim idazol-5-yl}-N-hydroxy-acrylam ide

WO 2007/030080 PCT/SG2006/000217
47


N-Hydroxy-3-[1 -(1 -methyl-piperidin-3-yl)-2-
pentyl-1H-benzoimidazol-5-yl]-acrylamide


3-{1 -[2-{Ethyl-hexyl-amino)-ethyl]-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide


3-{1 -[2-(Ethyl-pentyl-am ino)-ethyl]-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide


3-{1 -[2-(Ethy!-heptyl-amino)-ethyl]-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide


(£)-3-(2-hexyl-1 -(1 -(2-hydroxyethyl)piperidin-3-
yl)-1 H-benzo[d]imidazol-5-yl)-N-
hydroxyacrylamide


3-(2-Butyl-1-{2-[ethyl-(3-hydroxy-propyl)-amino]-
ethyl}-1 H-benzoimidazol- 5~yl)-N-hydroxy-
acrylamide

WO 2007/030080 PCT/SG2006/000217
48







3-( 1 -{2-[Ethyl-(3-hydroxy-propyl)-am ino]-ethyl}-
2-pentyl-1 H-benzoim idazol-5-yl)-N-hydroxy-
acrylamide
(E)-N-hydroxy-3-(1-(1-phenethylpyrrolidin-3-yl)-
1H-benzo[d]imidazol-5-yl)acrylamide
(E)-N-hydroxy-3»(1-(1-pentylpiperidin-3-yl)-1H-
benzo[d] im idazol-5-yl)acrylam ide
3-{1-[2-(Butyl-ethyl-amino)-ethyl]-1H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
(E)-N-hydroxy-3-(1-(1-phenethylpiperidin-3-yl)-
1 H-benzo[d]im idazol-5-yl)acrylam ide
(E)-N-hydroxy-3-(1-(1-(3-phenylpropyl)piperidin-
3-yl)-1H-benzo[d]imidazol-5-yI)acrylamide

WO 2007/030080 PCT/SG2006/000217
49






(E)-N-hydroxy-3-(1~(1-(3-phenylpropyl)pyrrolidin-
3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide
3-{1-[1-(3,3-Dimethyl-butyl)-pyrrolrdin-3-yl]-1H-
benzoim idazol-5-yl}-N-hydroxy-acrylam ide
(E)-3-(1 -(2- benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
3-[2-(4-Cyano-butyl)-1-(2-diethylamino-ethyl)-
1H- benzo im idazol-5-yl]-N-hydroxy-acry la m ide
(E)-3-(1-(1-butylpiperidin-3-yl)-1H-
benzo[d]imidazol-5-yl)-N-hydroxyacrylamide

WO 2007/030080 PCT/SG2006/000217
50







(E)-N-hydroxy-3-(1-(1-{pent-4-enyl)piperidin-3-
yl)-1 H-benzo[d]i m idazol-5-yl)acrylam ide
(E)-3-(1-(1-(3,3-dimethylbutyl)piperidin-4-yl)-1H-
benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
3-[1-(2-Diethylamino-ethyl)-2-propylamino-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
(E)-N-hydroxy-3-(1-(2-
(isopropyl(propyl)amino)ethyl)-1H-
benzo[d] im idazol-5-yl)acrylam ide
3-{1 -[2-(Butyl-isopropyl-amino)-ethyl]-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
N-Hydroxy-3-{1-[2-(isopropyl-pentyl-amino)-
ethyl]-1H-benzoimidazol-5-yl}-acrylamide

WO 2007/030080 PCT/SG2006/000217
51







3-[2-{5-Cyano-pentyl)-1-(2-diethylamino-ethyl)-
1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-(1-{2-[(3,3-Dimethyl-butyl)-ethyl-amino]-ethyl}-
1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide
3-{1-[2-{Ethyl-propyl-amino)-ethyl]-1H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
N-Hydroxy-3-(1-{2-flsopropyl-(2-methyl-pentyl)-
amino]-ethyI}-1H-benzoimidazol-5-yl)-acrylamide
(E)-N-hydroxy-3-(1-(2-0'sopropyl(4,4,4-
trifluorobutyl)amino)ethyl)-1H-benzo[d]imidazol-
5-yl)acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
propylamino-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide

WO 2007/030080 PCT/SG2006/000217
52






3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-methyl-1H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-{1-[2-(Butyl-ethyl-amino)-ethyl]-2-
trifluoromethyl-1H-benzoimidazol-5-yl}-N-
hydroxy-acrylamide
3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-
trifluoromethyl-1H-benzoimidazol-5-yl}-N-
hydroxy-acrylamide
(E)-3-(1-(2-(dibutylamino)ethyl)-2-propyl-1H-
benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
3-[1-(2-Dipropylamino-ethyl)-1H-benzoimidazol-
5-yl]-N-hydroxy-acrylamide

WO 2007/030080 PCT/SG2006/000217
53







N-Hydroxy-3-(1-{2-[isopropyl-(3-methyl-butyl)-
amino]-ethyl}-1H-benzoimidazol-5-yl)-acrylamide
3-(1-{2-[(3,3-Dimethyl-butyl)-methyl-amino]-
ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide
3-(1-{2-[(2-Ethyl-butyl)-methyl-amino]-ethyl}-1H-
benzoimidazol-5-yI)-N-hydroxy-acrylamide
(E)-3-(1-(2-(bis(3,3-dimethylbutyl)amino)ethyl)-
1 H-benzo[d]imidazol-5-yl)-N-hydroxyacrylam ide
(E)-3-(1-(2-(diisobutylamino)ethyl)-1H-
benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
3-{1-[2-(3,3-Dimethyl-butylamino)-ethyri-1 H-
benzoim idazol-5-yl}-N-hydroxy-acrylam ide

WO 2007/030080 PCT/SG2006/000217
54
N-Hydroxy-3-{1 -[2-(methyl-pent-4-enyl-am ino)-
ethyl]-1H-benzoimidazol-5-yl}-acrylamicle
3-(1 -{2-[(3,3-Dimethyl-butyl)-propyl-am ino]-
ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
methylsulfanyl-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide
3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-
propyl-1H-benzoimidazol-5-yl}-N-hydroxy-
acrylamide
3-[1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-(2,2-
dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylam ide

WO 2007/030080 PCT/SG2006/000217
55







3-[1-{2-[Bis-(3.3-dimethyl-butyl)-amino]-ethyl}-2-
(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylam ide
3-{1 -[2-(2,2-Dimethyl-propylamino)-ethyl]-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-(1-{2-[(2,2-Dimethyl-propyl)-propyl-amino]-
ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide
3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl-
1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-(1-{2-[(3,3-Dimethyl-butyl)-methyl-amino]-
ethy l}-2-propyl-1 H-benzoim idazol-5-y l)-N-
hydroxy-acrylamide
S-O-^-KS.S-Dimethyl-butylJ-^^rifluoro-
ethyl)-amino]-ethyl}-1 H-benzoim idazol-5-yl)-N-
hydroxy-acrylam ide

WO 2007/030080 PCT/SG2006/000217
56


3-(1-{2-[Butyl-(2,2,2-trifluoro-ethyl)-amino]-
ethyl}-1H-benzoimidazol-5-yI)-N-hydroxy-
acrylamide

[0200] The compounds disclosed are hydroxamate compounds containing a
hydroxamic acid type moiety in one of the substituents that may be inhibitors of
deacetylases, including but not limited to inhibitors of histone deacetylases. The
hydroxamate compounds may be suitable for prevention or treatment of a disorder caused
by, associated with or accompanied by disruptions of cell proliferation and/or
angiogenesis when used either alone or together with a pharmaceutically acceptable
carrier, diluent or excipient. An example of such a disorder is cancer.
[0201] 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 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.
[0202] 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.
[0203] 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 including ductal adenocarcinoma, metastatic ductal breast carcinoma, colorectal
cancers, advanced colorectal adenocarcinomas, 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

WO 2007/030080 PCT/SG2006/000217
57
cancer, extra hepatic bile duct cancer, gastrointestinal carcinoid tumour, gall bladder*
cancer, genitourinary cancers including testicular cancer, penile cancer, prostate cancer,
gynaecological cancers including cervical cancer, ovarian cancer, vaginal cancer,
uterus/endometrium cancer, vulva cancer, gestational trophoblastic cancer, fallopian tube
cancer, uterine sarcoma, head and neck cancers including oral cavity cancer, lip cancer,
salivary gland cancer, larynx cancer, hypopharynx cancer, orthopharynx cancer, nasal
cancer, paranasal cancer, nasopharynx cancer, leukemias including childhood leukemia,
acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia,
chronic myeloid leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell
leukemia, erythroleukemia.myelomas, haematological disorders including myelodysplastic
syndromes, myeloproliferative disorders, aplastic anemia, Fanconi anemia, Waldenstroms
Macroglobulinemia, lung cancers including small cell lung cancer, non-small cell lung
cancer, mesothelioma, lymphomas including Hodgkin's disease, non-Hodgkin's
lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, AIDS related
Lymphoma, B-cell lymphoma, Burk'rtt's lymphoma,, eye cancers including retinoblastoma,
intraocular melanoma, skin cancers including melanoma, non-melanoma skin cancer,
squamous cell carcinoma, merkel cell cancer, soft tissue sarcomas such as childhood soft
tissue sarcoma, adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancers
including kidney cancer, Wilms tumour, bladder cancer, urethral cancer, and transitional
cell cancer.
[0204] Exemplary cancers that may be treated by the compounds of the present invention
are breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer,
renal cancer (e.g. renal cell carcinoma), gastric cancer, colon cancer, colorectal cancer
and brain cancer.
[0205] Exemplary cancers that may be treated by compounds of the present invention
include but are not limited to leukemias such as erythroleukemia, acute promyelocytic
leukemia, acute myeloid leukemia, acute lymophocytic leukemia, acute T-cell leukemia
and lymphoma such as B-cell lymphoma (e.g. Burkitt's lymphoma), cutaneous T-cell
lymphoma (CTCL), and peripheral T-cell lymphoma.
[0206] 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 with the compounds of the present invention are colon
cancer, prostate cancer, hepatoma and ovarian cancer.

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[0207] In another embodiment, exemplary cancers that may be treated with the
compounds of the present invention are non small cell lung cancer, small cell lung cancer
and mesothelioma.
[0208] In another embodiment, exemplary cancers that may be treated with the
compounds of the present invention are clear cell carcinoma/mesonephroma, intestinal
cancer and pancreatic cancer.
[0209] The compounds may also be used in the treatment of a disorder involving,
relating to or, associated with dysregulation of histone deacetylase (HDAC).
[0210] There are a number of disorders that have been implicated by or known to be
mediated at least in part by HDAC activity, where HDAC activity is known to play a role in
triggering disease onset, or whose symptoms are known or have been shown to be
alleviated by HDAC inhibitors. Disorders of this type that would be expected to be
amenable to treatment with the compounds of the invention include the following but not
limited to: Proliferative disorders (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 haemorrhage Primary
lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic
interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary
spastic paraplegia, Progressive ataxia and Shy-Drager syndrome; Metabolic diseases
including Type 2 diabetes; Degenerative Diseases of the Eye including Glaucoma, Age-
related macular degeneration, macular myopic degeneration, Rubeotic glaucoma,
Interstitial keratitis, Diabetic retinopathy, Peter's anomaly, retinal degeneration,
Cellophane Retinopathy; Cogan's Dystrophy; Corneal Dystrophy; Iris Neovascularization
(Rubeosis); Neovascularization of the Cornea; Retinopathy of Prematurity; Macular
Edema; Macular Hole; Macular Pucker; Marginal Blepharitis, Myopia, nonmalignant
growth of the conjunctiva; Inflammatory diseases and/or Immune system disorders
including Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus
Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory
bowel disease, Colitis Ulcerosa, Alcoholic hepatitis, Diabetes, Sjoegrens's syndrome,
Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain,
Systemic Lupus Erythematosus, allergic contact dermatitis; Disease involving
angiogenesis including cancer, psoriasis, rheumatoid arthritis; Psychological disorders

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including bipolar disease, schizophrenia, depression and dementia; Cardiovascular
Diseases including Heart failure, restenosis, cardiac hypertrophy and arteriosclerosis;
Fibrotic diseases including liver fibrosis, lung fibrosis, cystic fibrosis and angiofibroma;
Infectious diseases including Fungal infections, such as Candida Albicans, Bacterial
infections, Viral infections, such as Herpes Simplex, Protozoal infections, such as Malaria,
Leishmania infection, Trypanosoma brucei infection, Toxoplasmosis arid coccidiosis, and
Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.
[0211] In using the compounds of the invention they can be administered in any form or
mode which makes the compound bioavailable. One skilled in the art of preparing
formulations can readily select the proper form and mode of administration depending
upon the particular characteristics of the compound selected, the condition to be treated,
the stage of the condition to be treated and other relevant circumstances. We refer the
reader to Remingtons Pharmaceutical Sciences, 19th edition, Mack Publishing Co. (1995)
for further information.
[0212] The compounds of the present invention can be administered alone or in the
form of a pharmaceutical composition in combination with a pharmaceutically acceptable
carrier, diluent or excipient. The compounds of the invention, while effective themselves,
are typically formulated and administered in the form of their pharmaceutically acceptable
salts as these forms are typically more stable, more easily crystallised and have increased
solubility.
[0213] The compounds are, however, typically used in the form of pharmaceutical
compositions which are formulated depending on the desired mode of administration. As
such in a further embodiment the present invention provides a pharmaceutical
composition including a compound of Formula (I) and a pharmaceutically acceptable
carrier, diluent or excipient. The compositions are prepared in manners well known in the
art.
[0214] The invention in other embodiments provides a pharmaceutical pack or kit
comprising one or more containers filled with one or more of the ingredients of the
pharmaceutical compositions of the invention. In such a pack or kit can be found a
container having a unit dosage of the agent (s). 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 concentration of
use, where the vials may include one or more dosages. Conveniently, in the kits, single

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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 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.
[0215] The compounds of the invention may be used or administered in combination
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 the
other drug(s).
[0216] In addition to being able to be administered in combination with one or more
additional drugs that include chemotherapeutic drugs or HDAC inhibitor drugs the
compounds of the invention may be used in a combination therapy. When this is done the
compounds are typically administered in combination with each other. Thus one or more
of the compounds of the invention may be administered either simultaneously (as a
combined preparation) or sequentially in order to achieve a desired effect. This is
especially desirable where the therapeutic profile of each compound is different such that
the combined effect of the two drugs provides an improved therapeutic result.
[0217] Pharmaceutical compositions of this invention for parenteral injection comprise
pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions,
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), 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.
[0218] These compositions may also contain adjuvants such as preservative, wetting
agents, emulsifying agents, and dispersing agents. Prevention of the action of

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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 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.
[0219] If desired, and for more effective distribution, the compounds can be
incorporated into slow release or targeted delivery systems such as polymer matrices,
liposomes, and microspheres.
[0220] The injectable formulations can be sterilized, for example, by filtration through a
bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid
compositions that can be dissolved or dispersed in sterile water or other sterile injectable
medium just prior to use.
[0221] Solid dosage forms for oral administration include capsules, tablets, pills,
powders, and granules. In such solid dosage forms, the active compound is mixed with at
least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose,
glucose, mannitol, and silicic acid, b) binders such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c)
humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate,
e) solution retarding agents such as paraffin, f) absorption accelerators such as
quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i)
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.
[0222] Solid compositions of a similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high
molecular weight polyethylene glycols and the like.
[0223] 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

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can also be of a composition that they release the active ingredients) only, or
preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions which can be used include polymeric substances
and waxes.
[0224] If desired, and for more effective distribution, the compounds can be
incorporated into slow release or targeted delivery systems such as polymer matrices,
liposomes, and microspheres.
[0225] The active compounds can also be in microencapsulated form, if appropriate,
with one or more of the above-mentioned excipients.
[0226] Liquid dosage forms for oral administration include pharmaceutically acceptable
emulsions, solutions, suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents and emulsifiers such as
ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl 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.
[0227] Besides inert diluents, the oral compositions can also include adjuvants such as
wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming
agents.
[0228] 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-
agar, and tragacanth, and mixtures thereof.
[0229] Compositions for rectal or vaginal administration are preferably suppositories
which can be prepared by mixing the compounds of this invention with suitable non-
irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository
wax which are solid at room temperature but liquid at body temperature and therefore melt
in the rectum or vaginal cavity and release the active compound.

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[0230] Dosage forms for topical administration of a compound of this invention include
powders, patches, sprays, ointments and inhalants. The active compound is mixed under
sterile conditions with a pharmaceutically acceptable carrier and any needed
preservatives, buffers, or propellants which may be required.
[0231] The term "therapeutically effective amount" or "effective amount" is an amount
sufficient to effect beneficial or desired results. An effective amount can be administered
in one or more administrations. An effective amount is typically sufficient to palliate,
ameliorate, stabilize, reverse, slow or delay the progression of the disease state. A
therapeutically effective amount can be readily determined by an attending diagnostician
by the use of conventional techniques and by observing results obtained under analogous
circumstances. In determining the therapeutically effective amount a number of factors
are to be considered including but not limited to, the species of animal, its size, age and
general health, the specific condition involved, the severity of the condition, the response
of the patient to treatment, the particular compound administered, the mode of
administration, the bioavailability of the preparation administered, the dose regime
selected, the use of other medications and other relevant circumstances.
[0232] A preferred dosage will be a range from about 0.01 to 300 mg per kilogram of
body weight per day. A more preferred dosage will be in the range from 0.1 to 100 mg per
kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body
weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day.
A suitable dose can be administered in multiple sub-doses per day.
[0233] 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 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 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 Hsp90, a-tubulin, p53, NFkb and
HIF1a [Drummond et al., Annu. Rev. Pharmacol. Toxicol. 45:495 (2004)]. Certain

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preferred histone deacetylase inhibitors are those that interact with, and/or reduce the
activity of a histone deacetylase which is involved in tumorigenesis, and these compounds
may be useful for treating proliferative diseases. Examples of such cell proliferative
diseases or conditions include cancer (include any metastases), psoriasis, and smooth
muscle cell proliferative disorders such as restenosis. The inventive compounds may be
particularly useful for treating tumors such as breast cancer, colon cancer, lung cancer,
ovarian cancer, prostate cancer, head and/or neck cancer, or renal, gastric, pancreatic
cancer and brain cancer as well as hematologic malignancies such as lymphomas and
leukemias. In addition, the inventive compounds may be useful for treating a proliferative
disease that is refractory to the treatment with other chemotherapeutics; and for treating
hyperproiiferative condition such as leukemias, psoriasis and restenosis. In other
embodiments, compounds of this invention can be used to treat pre-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 the
larynx, actinic and solar keratosis, seborrheic keratosis and keratoacanthoma. In a
preferred embodiment, exemplary pre-cancer conditions or hyperplasia that can be
treated by compounds of this invention are familial adenomatous polyposis, colonic
adenomatous polyps and myeloid dysplasia.
[0234] Additionally compounds of the various embodiments disclosed herein may be
useful for treating neurodegenerative diseases, and inflammatory diseases and/or
immune system disorders.
[0235] In one embodiment the disorder is selected from the group consisting of cancer,
inflammatory diseases and/or immune system disorders (e.g. rheumatoid 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 the disorder is
a proliferative disorder. In yet another embodiment, the proliferative disorder is cancer.
[0236] The histone deacetylase inhibitors of the invention have significant anti-
proliferative effects and promote differentiation, cell cycle arrest in the G1 or G2 phase,
and induce apoptosis.

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SYNTHESIS OF DEACETYLASE INHIBITORS
[0237] The present invention also provides a number of synthetic routes to synthesize the
compounds of the invention.
[0238] In one embodiment the method of synthesis of compounds of formula I as defined
above



[0239] includes: (a) providing a compound of the formula (A1):



[0240] (b) protecting the carboxyl group to produce a compound of the formula (A2):

[0241] (c) displacing the leaving group with an amine of formula R1NH2 to produce a
compound of the formula (A3):

[0242] (d) optionally reacting the compound to further functionalise R1

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[0243] (e) reducing the nitro group;
[0244] (f) reacting the reduced product with a compound of formula R2C02H or a
compound of formula R2CHO and cyclising the product thus produced to produce a
compound of the formula (A4):

[0245] (g) converting the compound to a compound of formula I;
[0246] wherein (d) can be carried out after any one of (c) (e) or (f) and further wherein (e)
and (f) can be carried out sequentially or simultaneously.
[0247] The reaction sequence employed above typically utilises a carboxyl protecting
group. The term "protecting group" refers to a chemical group that exhibits the following
characteristics: 1) reacts selectively with the desired functionality in good yield to give a
protected substrate that is stable to the projected reactions for which protection is desired;
2) is selectively removable from the protected substrate to yield the desired functionality;
and 3) is removable in good yield by reagents compatible with the other functional
group(s) present or generated in such projected reactions. Examples of suitable
protecting groups can be found in Greene et al. (1991) Protective Groups in Organic
Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York). A number of well known
carboxyl protecting groups may be used and the methodology chosen to attach the
protecting group will depend upon the choice of protecting group to be used as would be
well understood by a skilled addressee in the art. In one embodiment the protecting group
is an alkyl protecting group to form the ether. These may be produced in a number of
ways however it is typically found that they can be readily accessed via reaction of the
free acid with an alcohol under acidic conditions. An example of a suitable alcohol for this
purpose is methanol however other alcohols such as ethanol, propanol, butanol and the
like may also be used.
[0248] The reaction sequence detailed above also takes advantage of a suitably located
leaving group on the starting material to facilitate reaction with the amine in (b). A leaving

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group is a chemical group that is readily displaced by the desired incoming chemical
moiety. Accordingly in any situation the choice of leaving group will depend upon the
ability of the particular group to be displaced by the incoming chemical moiety. Suitable
leaving groups are well known in the art, see for example "Advanced Organic Chemistry"
Jerry March 4th Edn. pp 351-357, Oak Wick and Sons NY (1997). Examples of suitable
leaving groups include, but are not limited to, halogen, alkoxy (such as ethoxy, methoxy),
sulphonyloxy, optionally substituted arylsulfonyl and the like. Specific examples include
chloro, iodo, bromo, fluoro, ethoxy, methoxy, methonsulphonyl, triflate and the like. It is
preferred that the leaving group is either chloro or bromo. The displacement of the
leaving group typically is carried out by reaction of the compound containing the leaving
group with a nucleophile such as an amine which undergoes nucleophilic aromatic
substitution to displace the leaving group. This typically involves reaction of the
compound containing the leaving group in a non-interfering solvent with an excess of
amine, The amine may vary and is typically chosen to provide the appropriate substitution
pattern after displacement of the leaving group. The substitution reaction may also be
catalysed by any of a number of catalysts well known in the art such as palladium, copper
and the like.
[0249] In some embodiments it may be desired to then further functionalise the R1 group
introduced in the displacement either at this stage or at a later stage in the synthesis.
This may be achieved in a number of ways depending upon the exact functionality of the
R1 group introduced. For example if the R1 group contains an NH group then it may be
further reacted with other agents to add additional functionality. For example it may be
reacted with an acid, an acid chloride or an acid anhydride under standard conditions to
introduce an amide linkage. Alternatively it may be reacted with an aldehyde under
reducing conditions (reductive amination) to form an alkyl amine (via the imine).
Alternatively it may be reacted with an alkylating agent such as an alkyl halide to produce
the corresponding alkylated amine. The amine may also be reacted with an aryl or alkyl
sulphonyl chloride to introduce an aryl or alkyl sulphonyl group onto the amine. It may
also be that the amine introduced is in a protected form in which case the amine
protecting group may need to be removed under standard conditions prior to the
modifications discussed above being carried out. If this is done the protecting group is
typically removed under standard conditions (depending upon the exact nature of the
protecting group) and then reacted as discussed above.
[0250] The reaction sequence also involves a reduction of the nitro group. Reduction of
the nitro group may be carried out using any technique well known in the art. For example

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it may be reduced using strong reducing agents such as LiAIH4 or NaBH4 (typically in an
alcoholic solvent). It may also be achieved by reaction with triphenyl phosphine in water
or by reaction with SnCI2 or Zn (typically in an alcoholic solvent or acetic acid or a
combination thereof). The reduction may be conducted in any suitable solvent although it
is typically conducted in a hydroxylic solvent such as methanol or ethanol in the presence
of acetic acid.
[0251] The process then typically involves reaction of the reduced nitro moiety with a
carboxyl group or an aldehyde to produce a product which is then cyclised to produce the
cyclised product. This typically involves addition of a stoichiometric amount of the
carboxyl group or the aldehyde to a solution of the di-amine under suitable reaction
conditions. These conditions typically induce dehydration of the reaction product such as
Dean-and-Stark apparatus or the presence of a coupling agent such as DCC.
[0252] The reduction of the nitro moiety to produce a reduced product and the reaction of
the reduced product with a carbonyl moiety (acid or aldehyde) followed by intramolecular
cyclisation may be carried out in a sequential fashion or they may be carried out
simultaneously in a one-pot operation.
[0253] The synthesis involves conversion of the compounds thus formed into the
compounds of the invention. This may be carried out in a number of ways but is most
conveniently achieved by reaction with hydroxylamine hydrochloride to produce the free
hydroxamic acid. Entry to other hydroxamic acid species within the scope of the invention
may be readily achieved through the use of different hydroxylamine derivatives.

[0255] includes: (a) providing an aldehyde of the formula (B1)
[0254] In another embodiment the method of synthesis of compounds of formula I as
defined above

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[0256] (b) subjecting the aldehyde to reaction with an appropriately substituted
olefination agent to produce a compound of formula (B2)

[0257] (c) converting the compound to a compound of formula I.
[0258] This sequence employs an olefination to introduce the desired functionality to the
six membered ring. The olefination agent used may be any olefination agent well known
in the art. In one embodiment the olefination agent is a Wittig reagent (a phosphorous
ylide or phosphorane). Reagents of this type are readily accessible by reaction of a
phosphonium salt with a base. In another embodiment the olefination agent is a Horner
Emmons or Wadsworth Emmons reagent which is a phosphonate ylide (RO)2P(0)-CH2R
which can readily be accessed via the Arbuzov reaction. In each of these instances the
reaction is carried out under standard conditions. Judicious selection of the reagent
allows for a wide variety of products to be accessed.
[0259] As with the earlier sequence the product is then converted to the compounds of
the invention using the techniques described above.
[0260] The aldehyde used as the starting material in the sequence described above may
be provided using any methodology well known in the art. In one embodiment the
aldehyde is produced by
[0261] (1) providing a compound of the formula (B3) as described above

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PCT/SG2006/000217


[0262] (2) converting the compound to the aldehyde.
[0263] The compound (B5) may be converted to the aldehyde via a variety of techniques
well known in the art. In one embodiment the conversion includes first reducing the
protected carboxyl group to the alcohol followed by oxidation of the alcohol. The
reduction of the carboxyl group may be carried out using any technique well known in the
art. For example it may include treatment of the protected carboxyl group with a strong
reducing agent such as DIBAL, LiAIH4, LiBH4, lithium trimethyl borohydride, BH3-SMe2 (in
refluxing THF) and triethoxysilane in a non-interfering solvent. Alternatively, rather than
reducing the protected carboxyl group all the way to the alcohol it may be selectively
reduced directly to the aldehyde using standard conditions.
[0264] Once the alcohol has been obtained it may be oxidised to the aldehyde using a
number of techniques well known in the art. This may involve reaction of the alcohol with
oxidants such as acid dichromate, KMn04, Br2, Mn02, ruthenium tetroxide and the like.
The reaction may also be carried out by the use of Jones reagent. The conversion may
also be carried out by catalytic dehydrogenation or by reaction with agents such as N-
bromosuccinimide or related compounds. These oxidation conditions are typically carried
out under standard conditions.
[0266] (2) reducing the nitro group;
[0265] The compound of formula (B5) may be provided in any way well known in the art.
In one embodiment providing the compound of formula (B5) includes (1) providing a
compound of formula (B4)


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[0267] (3) reacting the reduced product with a compound of formula R2C02H or a
compound of formula R2CHO and cyclising the product thus produced to produce (B5).
[0268] The reduction of the nitro compound and the reaction of the reduced product thus
produced followed by cyclisation are typically carried out using the methodologies as
discussed above.
[0269] Providing a compound of formula (B4) generally includes (1) providing a
compound of the formula (B3):

[0270] (2) displacing the leaving group with an amine of formula R1NH2 to produce a
compound of the formula (B4): The reaction of the amine to displace the leaving group
typically occurs in the presence of a base. Any suitable base may be used with examples
of suitable bases including hindered tertiary amines, alkali earth metal carbonates and
and any inorganic base, which is compatible with protected carboxylic group by way of
example. Specific bases include sodium carbonate, sodium bicarbonate, potassium
carbonate and potassium bicarbonate.
[0272] (a) providing a compound of the formula (C1)
[0271] In another embodiment the invention provides a method of synthesis of
compounds of formula I as defined above



WO 2007/030080 PCT/SG2006/000217
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[0273] (b) converting the compound of formula (C1) to a compound of formula (C2);

[0274] (c) converting the compound to a compound of formula I.
[0275] Conversion of the compound of formula (C1) to a compound of formula (C2) may
be carried out using any of a wide range of conditions well known in the art. In general
any electrophilic aromatic substitution reaction may be used to introduce the desired
functionality. An example of a suitable reaction is a Heck reaction.
[0276] The compound of formula (C1) may be provided by (1) providing a compound of
formula (C4) and converting a compound of formula (C4) to a compound of formula (C1).
This typically involves (a4) reducing the nitro group to produce a reduced product and
reacting the reduced product with a compound of formula R2C02H or a compound of
formula R2CHO followed by intramolecular cyclisation of the product thus produced to
produce a compound of the formula (C1). These processes are typically carried out using
the methodology as discussed above.
[0277] The compound of formula (C4) is typically provided by providing a compound of
the formula (C3):


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[0278] and displacing the leaving group (L) with an amine of formula R1NH2 to produce a
compound of the formula (C4):

[0279] The displacement reaction is typically carried out using the methodology as
discussed above.
[0280] 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 particular
compounds of the embodiments is described in detail in the following examples, but the
artisan will recognize that the chemical reactions described may be readily adapted to
prepare a number of other agents of the various embodiments. For example, the
synthesis of non-exemplified compounds may be successfully performed by modifications
apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by
changing to other suitable reagents known in the art, or by making routine modifications of
reaction conditions. A list of suitable protecting groups in organic synthesis can be found
in T.W. Greene's Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons,
1991. Alternatively, other reactions disclosed herein or known in the art will be recognized
as having applicabil ity for preparing other compounds of the various embodiments.
[0281] Reagents useful for synthesizing compounds may be obtained or prepared
according to techniques known in the art.
[0282] 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.
[0283] Various starting materials and other reagents were purchased from commercial
suppliers, such as Aldrich Chemical Company or Lancaster Synthesis Ltd., and used
without further purification, unless otherwise indicated. Tetrahydrofuran (THF) and N,N-
dimethylformamide (DMF) were purchased from Aldrich in SureSeal bottles and used as

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received. All solvents were purified by using standard methods in the art, unless
otherwise indicated.
[0284] The reactions set forth below were performed under a positive pressure of
nitrogen, argon or with a drying tube, at ambient temperature (unless otherwise stated), 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 (v/v). The
reactions were assayed by TLC and terminated as judged by the consumption of starting
material.
[0285] 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) which
was activated with heat, or by staining in iodine chamber. Work-ups were typically done
by doubling the reaction volume with the reaction solvent or extraction solvent and then
washing with the indicated aqueous solutions using 25% by volume of the extraction
volume (unless otherwise indicated). Product solutions were dried over anhydrous
sodium sulfate prior to filtration, and evaporation of the solvents was under reduced
pressure on a rotary evaporator and noted as solvents removed in vacuo. Flash column
chromatography [Still et al, J. Org. Chem., 43, 2923 (1978)] was conducted using Silica
gel 60 (Merck KGaA, 0.040-0.063 mm, 230-400 mesh ASTM) and a silica gel:crude
material ratio of about 20:1 to 50:1, unless otherwise stated. Hydrogenolysis was done at
the pressure indicated or at ambient pressure.
[0286] NMR spectra were recorded on a Bruker AVANCE 400 spectrometer operating
at 400 MHz for 1H NMR and 100 MHz for 13C-NMR. NMR spectra are obtained as CDCI3
solutions (reported in ppm), using chloroform as the reference standard (7.26 ppm and
77.14 ppm) or CD3OD (3.3 and 49.3 ppm), or DMSO-cfe (2.50 and 39.5 ppm) or an internal
tetramethylsilane standard (0.00 ppm) when appropriate. Other NMR solvents were used
as needed. When peak multiplicities are reported, the following abbreviations are used:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet
of doublets, dt = doublet of triplets. Coupling constants, when given, are reported in Hertz.
[0287] Mass spectra were obtained using LC/MS either in ESI or APCI. All melting
points are uncorrected.

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[0288] 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 urn 4.6
x 20mm IS column; 2.0 ml/min, gradient 5-65% B over 4 min, then 65-95%b over 1 min
and 95%B for additional 0.1 min; Solvent A: H20 with 0.1% trifluoroacetic acid (TFA);
Solvent B: acetonitrile with 0.1% TFA.
[0289] The following examples are intended to illustrate the embodiments disclosed and
are not to be construed as being limitations thereto. Additional compounds, other than
those described below, may be prepared using the following described reaction scheme
or appropriate variations or modifications thereof.
SYNTHESIS
[0290] Schemes I and II illustrate the procedures used for preparing compounds of
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 C5-position in
Formula lb, such compound(s) can be synthesized by analogous method illustrated in
Scheme I and II starting with a substituted cinnamic acid (e.g. frans-3-nitro-4-chloro-
cinnamic acid), appropriate amine component (R1NH2), carboxylic acid component
(R2C02H, Scheme I) or aldehyde (R2CHO, Scheme II), and appropriate hydroxylamine or
N-alkyl hydroxylamine (NHR3OH where R3 is defined as above in Formula la).
[0291] Specifically, the hydroxamate compounds Formula lb can be synthesized by the
synthetic route shown in Scheme I. The reaction of frans-4-chloro-3-nitrocinnamic acid (I)
with an amine R1NH2 in the presence of a base (e.g. triethylamine) in an appropriate
solvent (e.g. dioxane) gave (II). Treatment of (II) in methanol under acid catalysis (e.g.
sulfuric acid) resulted in esterification providing (III). Alternatively.Jhe,carboxylic acid (I)
may be esterified to the methyl ester (la) and then the chloride was replaced by the
appropriate amine component R1NH2 to give compound (III). The nitro group of (III) can be
reduced by appropriate reducing agent (e.g. tin (II) chloride) and the resulting
phenylenediamine (IV) was coupled with an acid R2C02H 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 compounds (VI) were
obtained from methyl ester (VI) by a known synthesis method (J. Med. Chem., 2002, 45,
753-757).

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Scheme I

[0292] Alternatively, as depicted in Scheme II, compound (VI) was prepared by reacting
with an appropriate aldehyde component R2CHO in the presence of a reducing agent of
nitro group (e.g. tin (II) chloride, or zinc powder) in one-pot (Tetrahedron Letters, 2000, 41,
9871-9874). Formic acid was used to prepare compound (VI) when R2 = H.
Scheme II

[0293] In both Schemes I & II, the benzimidazole ring may be constructed by a
cyclization step involving either an aldehyde or a carboxylic acid. The following reaction
steps 1-4 refer to the use of carboxylic acid for the cyclization of (IV) via (V) to form
benzimidazole derivatives (VI), followed by the conversion of ester (VI) to the

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hydroxamate (VII). For one-pot cycylization of (III) to (VI), see the procedures under
Example 1.
Step 1: Reduction of nitro group
[0294] To a pre-stirred solution of starting material (III, 1.0 mmol) in 50 mL of co-solvent
(glacial acetic acid: methanol 2:8), Tin chloride was added (5.0 mmol). The resulting
solution was heated to 55°C overnight and then cooled to room temperature. The solvent
was removed and the mixture was neutralized with sodium bicarbonate to pH 8. The
crude product was extracted with dichloromethane (20 mL) for three times. The organic
extracts were combined and washed with water (15 mL) twice and brine (15 mL) once and
further dried over Na2S04 for 1 hour. It was filtered and concentrated; the diamino
product (IV) was purified by flash chromatography.
Step 2: Amide formation
[0295] 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 (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
[0296] 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 to
rt, the solvent was removed under vacuum to give product (VI) near quantitatively.
Step 4: Hydroxamic acid formation
[0297] To a stirred solution of ester (VI) and NH2OH«HCI (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 and was
completed in around 15-60 min. 1/V HCI was then added slowly into the reaction mixture
at 0°C. The desired product was separated by reverse-phase preparative HPLC and the
fractions containing the desired product were freeze-dried. The hydroxamate product (VI)
was obtained as TFA salt (isolated yield varies between 40 - 70%).
[0298] Scheme III illustrates another alternative procedure used for preparing
compounds of formula lb, where X and Y are hydrogens and R2 is selected from the group
R11S(0)R13-, R11S(0)2R13-, R11C(0)N(R12)R13-. R11S02N(R12)R13-, R11N(R12)C(0)R13-,
R11N(R12)S02R13-, R11N(R12)C(0)N(R12)R13- and heteroalkyl. For example, in the case of Z

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is -CH=CH- and attached to (^-position in Formula lb, such compound(s) (XIII) can be
synthesized by analogous method illustrated in Schemes I & starting with appropriate
(III), appropriate Fmoc protected amino acids, appropriate acid chlorides or aldehydes,
and hydroxylamine.
Scheme III

[0299] More specifically, for example, the hydroxamate compounds Formula lb, where
X and Y are hydrogens, R2 is selected from the group R11S(0)R13-, R11S(0)2R13-,
R11C(0)N(R12)R13-, R11S02N(R12)R13-, R11N(R12)C(0)R13-, R11N(R12)S02R13-.
R11N(R12)C(0)N(R12)R13- and heteroalkyl; and Z is attached to exposition, can be
synthesized by the synthetic route shown in Scheme III. Appropriate intermediate (III) was
reduced with tin chloride to the corresponding diamines (IV). The coupling reaction with

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appropriate Fmoc protected amino acids in the presence of PyBOP gave coupling
produces) (VIII) and/or (IX). Without further separation, (VIII) and/or (IX) were 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) with an appropriate
acid chloride or an appropriate sulfonyl chloride gave (XII) and the target compounds (XIII)
were obtained by using similar method described in Scheme I.
[0300] When (XI) was reacted with an appropriate aldehyde under reduction conditions
(NaBH(OAc)3 /CH3C02H), (XIV) was obtained and can be transformed to corresponding
hydroxamate derivatives (XV) by the same methods described above.
[0301] Scheme IV illustrates some reactions to further modify R1 side chain. If the R1
side chain contained a protecting group such as Boc in compound (Vla1), it could be
removed before converting to the final hydroxamic acid (Vila). The intermediate (Via)
could be modified by acylation, reductive alkylation, alkylation or sulfonylation to form new
analogs (Vllb, Vile, Vlld and Vile) through new intermediates (Vlb, Vic, Vld and Vie). The
above described methods were also applied to R1 = heterocycles, e.g., R1 = N-Boc-
piperidin-3-yl, /V-Boc-piperidin-4-yl and /V-Boc-pyrrolidin-3-yl.

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Scheme IV
[0302] Scheme V illustrates some alternative method to prepare (Via) and (Vic). The
primary amine (IHa2) was prepared either from (la) or via (Ills'!). The derivertization of the
amino group (e.g., reductive amination) could be performed either from (Illa2) or (Vla2).
The products, i.e., (Illa2-1) and (Vla2-1), could be further derivertized (e.g., reductive
amination of the secondary amine).

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Scheme V
[0303] Scheme VI and VII illustrate some alternative methods to prepare (VI) by forming
the benzimidazole ring first and introducing the double bond later.
[0304] In Scheme VI, compound (XVI) was reacted with an amine R1NH2 in the
presence of a base (e.g. triethylamine) in an appropriate solvent (e.g. dioxane) to give
(XVII). Benzimidazole (XVIII) ring was formed by reacting compound (XVII) with aldehyde
R2CHO in the presence of a reducing agent of nitro group (e.g. tin (II) chloride, zinc
powder or other appropriate reducing agent) in one-pot. The ester (XVIII) was converted
to the aldehyde (XX) via a reduction and oxidation process. Finally, (VI) was obtained by
reacting aldehyde (XX) with a Wittig or Wittig-Horner reagent.

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82
Scheme VI
[0305] In Scheme VII, compound (XXI) was reacted with an amine R1NH2 in the
presence of a base (e.g. triethylamine) in an appropriate solvent (e.g. dioxane) to give
(XXII). Benzimidazole (XXIII) ring was formed by reacting compound (XXII) with aldehyde
R2CHO in the presence of a reducing agent of nitro group (e.g. tin (II) chloride, zinc
powder or other appropriate reducing agent) in one-pot. Finally, the bromide (XXIII) was
converted to (VI) under Heck reaction condition.
Scheme VII

[0306] The following preparations and examples are given to enable those skilled in the
art to more clearly understand and to practice the subject matter hereof. They should not
be considered as limiting the scope of the disclosure, but merely as being illustrative and
representative thereof.

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Preparation of intermediates III
[0307] Compound (III) was prepared either from (I) via (II) or from (I) via (la) (Scheme I
and V). The following are examples of (111).
Intermediate 1
3-[4-(2-Dimethylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester
[0308] A mixture of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (la, 0.658 g,
2.72 mmol), N,N-dimethylethylenediamine (0.90 ml_, 8.20 mmol) and triethylamine (1.2
mL, 8.6 mmol) in dioxane (20 mL) was heated at 80°C for 5h. The solution was
evaporated and the residue was added DCM and aqueous NazC03. The DCM (x3)
extracts were concentrated and the residue was added EtOAc-hexane. The resulting red
solid was filtered to give the titled compound (0.672 g, 84.2%). HPLC purity at 254 nm:
99.2%, tR = 1.59 min. LCMS (ESI) m/z: 294 ([M + H]+). 1H NMR (CDCI3 + CD3OD) 5 8.21
(1H, d, J = 2.1 Hz), 7.56 (1H, dd, J = 9.0, 2.1 Hz), 7.48 (1H, d, J = 16.0 Hz), 6.81 (1H, 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 (2H, t, J =
6.4 Hz), 2.23 (6H, s); 13C NMR (CDCI3 + CD3OD) 8 167.3, 145.4, 142.6, 134.0, 131.1,
127.1, 121.3, 114.8, 114.0, 56.7, 51.1, 44.6, 40.1.
Intermediate 2
3-[4-(2-Diethylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester.
[0309] Yellow solid. LCMS (ESI) m/z: 322 ([M + H]+). 1H NMR (CDCI3) 8 8.73 (1H, t-like,
J = 4.3 Hz), 8.32 (1H, d, J = 2.0 Hz), 7.62 (1H, dd, J = 9.2, 2.0 Hz), 7.58 (1H, d, J = 15.9
Hz), 6.85 (1H, d, J = 9.0 Hz), 6.29 (1H, d, J = 15.9 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 (6H, t, J = 7.1 Hz).
Intermediate 3
3-[4-(2-Ethy!ammo-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester
[0310] Red solid. LCMS (ESI) m/z: 294 ([M + Hf). 1H NMR (DMSO-cfe) 8 8.49 (1H, t, J =
6.1 Hz), 8.35 (1H, d, J = 2.0 Hz), 7.96 (1H, dd, J = 9.1,1.9 Hz), 7.62 (1H, d, J = 16.0 Hz),
7.20 (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 (3H,
s), 3.08 (2H, t, J = 6.5 Hz), 2.93 (4H, q, J = 7.2 Hz), 1.17 (6H, t, J = 7.2 Hz).
Intermediate 4
3-[4-(2-lsopropylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester
[0311] Red solid. LCMS (ESI) m/z: 308 ([M + H]+). 1H NMR (DMSO-cfe) 8 8.58 (1H, t, J =
5.6 Hz), 8.33 (1H, d, J =2.0 Hz), 7.94 (1H, dd, J = 9.1, 1.9 Hz), 7.60 (1H, d, J = 16.0 Hz),
7.14 (1H, d, J = 9.2 Hz), 6.49 (1H, d, J = 16.0 Hz), 3.70 (3H, s), 3.56 (2H, masked by

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water peak, identified by COSY), 3.10 (1H, septet, J = 6.4 Hz), 2.94 (2H, t, J = 6.2 Hz),
1.10 (6H, d, J =6.4 Hz).
Intermediate 5
3-[4-(3-Dimethy!amino-2,2-dimethyl-propylamino)-3-nitro-phenyl]-acryli<: acid> methyl ester.
[0312] Red solid. LCMS (ESI) m/z: 336 ([M + H]+). 1H NMR (CDCI3) 5 9.73 (1H, br s or
t), 8.33 (1H, d, J = 2.0 Hz), 7.60 (1H, dd, J = 8.9, 2.0 Hz), 7.59 (1H, d, J = (1H, d, J = 9.1 Hz), 6.28 (1H, d, J = 15.9 Hz), 3.80 (3H, s), 3.21 (2H, d, J = 4.6 Hz), 2.36
(2H, s), 2.34 (6H, s), 1,04 (6H, s).
Intermediate 6
3-[4-(2-Diisopropylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester
[0313] Yellow solid. LCMS (ESI) m/z: 350 ([M + H]+). 1H NMR (CDCI3) 5 8.76 (1H, 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 (1H, 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, J = 6.6 Hz).
Intermediate 7
3-[4-(2-Methylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester
[0314] Red solid. LCMS (ESI) m/z: 280 ([M + H]+). 1H NMR (CDCI3) 8 8.54 (1H, t-like, 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, 6, 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
3-[4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl
ester (II Ia1)
Stepl:
[0315] A suspension of frans-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/acetons bath. SOCI2
(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 CC till the reaction completed.
The solution was evaporated to dryness to a pale yellow solid (5.364 g, £0.9%). HPLC
purity at 254 nm: 99.5%; tR = 2.96 min. LCMS (ESI) m/z: 210 and 212 (very weak signal,
[M+H-MeOH]+).

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Step 2:
[0316] A mixture of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (la, 0.243 g,
1.00 mmol), N-Boc-ethylenediamine (0.316 mL, 2.0 mmol) and triethylamine (0.50 mL,
3.59 mmoL) in dioxane (7 mL) was heated at 80°C for about 80 h. The solution was
evaporated and the residue was added MeOH. The resulting solid was filtered and
washed with MeOH. 3-[4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-phenyl]-acrylic
acid methyl ester (lllal) was obtained as bright yellow solid (0.193 g, 52.6%). HPLC purity
at 254 nm: 96.0-98.1%; tR = 3.27 min. LCMS (ESI) m/z: 366 ([M + H]*), 310 (M+H-56),
266 (M+H-Boc). 1H NMR (CDCI3) 8 8.41 (1H, br t like, NHAr), 8.31 (1H, d, J = 1.8 Hz),
7.63 (1H, dd, J = 9.0,1.7 Hz), 7.57 (1H, d, J = 16.0 Hz), 6.98 (1H, d, J = 8.9 Hz), 6.30 (1H,
d, J = 15.9 Hz), 3.80 (3H, s), 3.52 (2H, m), 3.45 (2H, m), 1.45 (9H, s); 13C NMR (CDCI3) 5
166.9, 155.7, 145,8, 142.3, 134.1, 131.5, 127.1, 121.8, 115.4, 113.9, 79.5, 51.2, 42.7,
39.1,27.9.
Intermediate 9
3-[4-(2-Amino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester (Illa2)
[0317] Method 1:
Remove Boc protecting group from (lllal) under acidic condition: 1) HCI/MeOH; 2)
TFA/DCM.
[0318] Method 2:
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
triethylamine (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 Illa2 fa = 1.6 min, starting material la fa = 3.1 min). Upon completion, solvent was
removed and the crude was dissolved in DCM. The solution was washed with water,
brine, dried over Na2S04 arid filtered. The filtrate after removal of the solvent gave the
titled compound Illa2. Yield = 98 %, LCMS m/z: 266 ([M+H]+).
Example 1
Preparation of 3-[1 -(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,2-dimethyl-propyl)-
1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide (1)
[0319] The titled compound (1) was prepared according to Scheme 1 and II, by using
appropriate starting materials.
Stepl:
[0320] To a pre-stirred solution of frans-4-chloro-3-nitrocinnamic acid (1,11g, 48 mmol)
in dioxane (200 mL) was added triethylamine (20 mL, 126 mmol), followed by 3-

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dimethylamino-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 H20 (250 mL) to dissolve
the residue. Cone. HCI was added till pH ~ 1 with orange precipitation. The suspension
was filtered and residue was washed with H20 several times to obtain (II) as orange solid
(13 g, 84%). LCMS (ESI) m/z: 322 ([M+H]+).
Step 2:
[0321] Compound (11,13 g, 40.5 mmol) was dissolved in MeOH (250 mL) followed by the
addition of cone. H2SO4 (5 mL). The reaction mixture was allowed to stir at 80 °C for 18 h.
Solvent was removed under vacuum and H20 (250 mL) was added to dissolve the
residue. Na2C03 was added till pH * 8-9, subsequently, MeOH was added and stirred for
1 hour. Then, the suspension was-filtered under vacuo and the residue was washed with
H20 several times to obtain ester (III) as orange solid (10 g, 74%). LCMS (ESI) m/z: 336
«M+H]+).
Step 3:
[0322] To a stirred solution of ester (III, 1 equiv) and SnCI2»2H20 (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 stirring. The progress of the reaction was
monitor by LC/MS. When the reaction was completed, solvent was removed under
reduced pressure at 30-35°C. To the resulting residue, 20 mL of water and 20 mL of ethyl
acetate were added at room temperature, the pH value of the mixture was carefully
adjusted to 9-10 by addition of cone. NH3»H20. 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 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]+).
Step 4:
[0323] To a stirred solution of ester (VI) and NH2OH.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. 1A/ HCI was then added slowly into the reaction mixture at 0 °C. The
desired product was separated by prep-HPLC and the fractions containing the desired
product were freeze-dried. Product (VII) was obtained as TFA salt (isolated yield varies
between 40 - 70%). HPLC purity at 254 nm: 100%, tR = 0.78 min. LCMS (ESI) m/z: 387

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([M+Hf). 1H NMR (DMSO-cfe) 5 1.05 (15H, s), 2.91 (6H, s), 2.92 (2H, s), 3.32 (2H, bs),
4.35 (2H, s), 6.49 (1H, d, J = 15.8 Hz), 7.56 (1H, d, J = 9.0 Hz), 7.61 (1H, d, J = 15.76 Hz),
7.83 (1H, d, J = 9.0 Hz), 7.85 (1H, s), 9.22 (1H, bs), 10.72 (1H, bs); 13C NMR (DMSO-cfe) 6
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.
Example 2
Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-lsopropyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide(2)
[0324] The titled compound (2) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100%, tR =
0.54 min.lCMS (ESI) m/z: 359 ({M+H]+). 1H NMR (DMSO-d6) 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), 6.55 (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).
Example 3
Preparation of 3-[2-Butyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (3)
[0325] The titled compound (3) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. Yield: 74 mg as TFA salt. HPLC purity
at 254 nm: 99.0%, ^ = 0.89 min. LCMS (ESI) m/z: 373 ([M + H]+). 1H NMR (CD3OD) 8
7.99 (1H, d, J = 8.8 Hz), 7.84 (1H, s), 7.72 (1H, d, J = 8.7 Hz), 7.55 (1H, d, J = 15.8 Hz),
6.53 (1H, d, J = 15.7 Hz), 4.55 (2H, s), 3.43 (2H, 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), 0.98 (3H, t, J = 7.3
Hz); 13C NMR (CD3OD) 5 165.5 (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
Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2-methylsulfanyl-
ethyl)-1 H-benzoimidazol-5-yl]-N-hydroxy-acrylamide (4)
[0326] 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]+). 1H NMR (CD3OD) 5
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 = 15.8 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 (6H, s), 2.18 (3H, s), 1.25 (6H, s); 13C NMR (CD3OD) 5 163.7, 154.6,

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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.
Example 5
Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-isobutyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (6)
[0327] The titled compound (6) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 96.2%, tR =
0.82 min. LCMS (ESI) m/z: 373 ([M+H]*). 1H NMR (DMSO-cfe): 8 10.80 (1H, s), 9.47 (1H,
s), 7.93 (1H, s), 7.90 (1H, d, J= 6.6 Hz), 7.64 (1H, d, J = 7.4 Hz), 7.62 (1H, d, J= 15.5
Hz), 6.54 (1H, d, J = 15.8 Hz), 4.39 (2H, s), 3.33 (2H, s), 2.97 (2H, d, J = 7.26 Hz), 2.92
(6H, s), 2.35 (1H, qn), 1.09 (6H,s), 0.97 (6H,d,J= 6.6 Hz). ........
Example 6
Preparation of 3-[1-(2-Diethylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (7)
[0328] The titled compound (7) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.0%, tR =
0.56 min. LCMS (ESI) m/z: 359 ([M+H]+). 1H NMR (DMSO-ofe): 8 10.81 (1H, s), 10.13 (1H,
s), 7.90 (1H, s), 7.81 (1H, d, J = 8.5 Hz), 7.66 (1H, d, J = 8.6 Hz), 7.61 (1H, d, J = 15.8
Hz), 6.53 (1H, d, J = 15.8 Hz), 4.72 (2H, t, J = 7.8 Hz), 3.30 (2H, d), 2.93 (2H, d, J = 7.2
Hz), 2.27 (1H, m), 1.24 (6H, t, J = 7.2 Hz), 0.97 (6H, d, J = 6.6 Hz) 13C NMR (DMSO-d6) 8
162.7, 158.5, 158.2, 155.2, 138.4, 133.9, 131.0, 123.0, 118.6, 116.0, 111.6, 48.8, 46.8,
34.1,27.1,22.2,8.5.
Example 7
Preparation of 3-[2-Butyl-1-(2-diethylamino-ethyl)-"W-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (8)
[0329] The titled compound (8) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. Yield: 61 mg (20% in two steps) as
TFA salt. HPLC purity at 254 nm: 98.1%, tR = 0.59 min. LCMS (ESI) m/z: 359 ([M + H]+).
1H NMR (CD3OD) 8 7.94 (1H, d, J = 8.6 Hz), 7.85 (1H, s), 7.76 (1H, d, J = 8.5 Hz), 7.50
(1H, d, J = 15.7 Hz), 6.49 (1H, d, J = 15.7 Hz), 4.96 (2H, overlapped with DHO, identified
by COSY), 3.69 (2H, t-like, J = 7.6 Hz), 3.44 (4H, q, J = 7.6 Hz), 3.26 (2H, t, J = 7.9 Hz),
1.94 (2H, pentet, J = 7.5 Hz), 1.57 (2H, m), 1.40 (6H, t, J = 7.2 Hz), 1.05 (3H, t, J = 7.3
Hz); 13C NMR (CD3OD) S 165.5, 157.7, 140.0, 134.8, 134.0, 133.8, 126.5, 119.9, 115.1,

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113.6, 50.2, 48.7 (2C), 40.5, 29.4, 26.6, 23.3, 13.9, 8.9 (2C). (TFA peak 163.4. 163.0,
162.6, 162.3; 122.3, 119.5, 116.6).
Dihydrochloride salt of 8 was prepared according to the procedures described in Example
50, Step 4 and 5, by using appropriate starting materials. 1H NMR (DMSO-d6) 8 11.79
(brs, 1H), 10.92 (very brs, 1H), 8.18 (1H, d, J = 8.6 Hz), 7.97 (1H, s), 7.79 (1H, d, J = 8.6
Hz), 7.64 (1H, d, J = 15.8 Hz), 6.65 (1H, d, J = 15.8 Hz), 5.01 (2H, t-like, J = 7.7 Hz), 3.48
(2H, m), 3.30-3.19 (6H, m), 1.87 (2H, pentet, J = 7.8 Hz), 1.47 (2H, sextet, J = 7.5 Hz),
1.29 (6H, t, J = 7.2 Hz), 0.97(3H, t, J = 7.3 Hz); 13C NMR (DMSO-cfe) 6 162.3, 156.0, 137.3
(CH), 132.8,132.3, 132.0 (br, identified by HMBC), 124.7 (CH), 120.2 (CH), 113.1 (2xCH),
48.2, 46.3, 39.0, 28.1, 25.0, 21.7, 13.6, 8.3.
Example 8
Preparation of 3-[2-But-3-ynyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (9)
[0330] The titled compound (9) was prepared according to the procedures described 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]+). 1H NMR (DMSO-cfe) 6 9.49 (brs, 1H), 7.88 -
7.85 (m, 2H), 7.63 - 7.59 (m, 2H), 6.52 (d, J = 15.79 Hz, 1H), 4.37 (s, 1H), 3.33 (s, 2H),
3.26 (t, J = 7.24 Hz, 2H), 2.92 (s, 6H), 2.88 (t, J = 2.54 Hz, 1H), 2.81 (dt, J = 2.48, 7.70
Hz, 2H), 1.09 (s, 6H); 13C NMR (DMSO-d6) 8 162.8, 155.3, 138.4, 138.0, 135.9, 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-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (10)
[0331] 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]+). 1H NMR (CD3OD) 8 7.95 (d, J = 8.8 Hz, 1H),
7.85 (s, 1H), 7.73(d, J= 8.8 Hz, 1H), 7.63 (d, J= 15.8 Hz, 1H), 6.54 (d, J= 15.8 Hz, 1H),
5.94- 5.84 (m, 1H), 5.10 (dd, J= 1.4, 17.1 Hz, 1H), 5.03 (dd, J= 1.1, 10.2 Hz, 1H), 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); 13C NMR (CD3OD) 8 165.7, 157.6, 140.2, 136.3, 135.9, 134.7, 134.5, 125.9,
120.2, 117.9, 115.2, 103.6, 68.8, 53.4, 39.6, 32.0, 27.2, 23.7.

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Example 10
Preparation of 3-[2-But-3-enyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (11)
[0332] The titled compound (11) was prepared according to the procedures described
in Example 1, by using appropriate starting materials. HPLC: 99.4 %; fe = 0.52 min; LCMS
(ESI) m/z: 357 ([M+H]+1). 1H NMR (CD3OD) 3 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,
1H), 5.13 (dd, J = 1.4, 17.1 Hz, 1H), 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 Hz, 2H), 1.35 - 1.32 (m,
6H); 13C NMR (CD3OD) 8 165.8, 157.0, 140.5, 136.6, 135.9, 134.6, 134.2, 126.1, 119.5,
117.7, 116.0, 113.3, 50.4, 40.4, 31.7, 26.7, 9.1.
Example 11
Preparation of 3-[2-But-3-ynyl-1 -(2-diethylamino-ethyl)-1 H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (12)
[0333] The titled compound (12) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC: 99.6 %; tR = 0.37 min; LCMS
(ESI) m/z: 355 ([M+Hf). 1H NMR (CD3OD) 5 7.82 (d, J = 8.7 Hz, 1H), 7.68 (s, 1H), 7.58
(d, J = 8.5 Hz, 1H), 7.31 (d, J = 15.8 Hz, 1H), 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, 1H), 1.21 (t, J = 7.2 Hz, 6H); 13C NMR
(CD3OD) 5 165.9, 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-propyl)-
1H-benzoimidazol-5-yl]-N-hydroxy-acry!amide(13)
[0334] 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 %; tfj =
0.80 min; LCMS (ESI) m/z: 413 ([M+H]+).
Example 13
Preparation of 3-[1-(2-Diethylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide(14)
[0335] The titled compound (14) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity: 96.4%; fe = 1.37 min;
LCMS (ESI) m/z: 399 ([M+H]+). 1H NMR (DMSO-d6) 5 1.25 (6H, t), 2.96 (2H, m), 3.31 (6H,

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m), 3.44 (2H, m), 4.72 (2H, m), 6.51 (1H, m), 7.51 (2H, m), 7.65 (1H, m). 7.83 (1H, m),
10.45 (1H,bs).
Example 14
Preparation of 3-[1-{2-Diethylamino-ethyl)-2-ethoxymethyl-1H-benzoimidazol-5-yl]-
N-hydroxy-acrylamide (15)
[0336] 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]+).
Example 15
Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-methyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide(16)
[0337] The titled compound (16) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity: 99.5%; tR = 0.30 min;
LCMS (ESI) m/z: 331 ([M+H]+). 1H NMR (DMSO-d6) 5 1.13 (6H, s), 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).
Example 16
Preparation of 3-[1-(2-Diethylamino-ethyl)-2-(2,2-dimethyl-propyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (17)
[0338] The titled compound (17) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.9%, tR =
0.95 min. LCMS (ESI) m/z: 373 ([M+H]+). 1H NMR (CD3OD) 5 7.85 (2H, t, J = 8.3 Hz), 7.75
(1H, d, J= 8.8 Hz), 7.61 (1H, d, J= 15.8 Hz), 6.51 (1H, d, J = 15.8 Hz), 4.93 (2H, t, J = 6.1
Hz), 3.54 (2H, t, J = 8.1 Hz), 3.31 (4H, qt, J = 7.3 Hz), 3.10.(2H, s), 1,27 (6H, t, J = 7.3
Hz), 1.06 (9H, s); 13C NMR (CD3OD) 8 163.7, 153.3, 138.3, 133.1, 131.9, 124.5, 118.3,
117.1, 113.5, 111.8, 48.1, 39.1, 37.5, 32.9, 27.8, 7.1.
Example 17
Preparation of N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-(3,3,3-trifluoro-propyl)-
1H-benzoimidazol-5-yl]-acrylamlde(18)
[0339] The titled compound (18) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity: 96.8%; tR = 0.72 min.
LCMS (ESI) m/z: 399 ([M+H]+). *H NMR (DMSO-af6) 8 1.18 (6H, d), 2.07 (2H, m), 2.95

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(4H, m), 3.27 (3H, m), 4.43 (2H, m), 6.52 (1H, m), 7.55 (2H, m), 7.61 (1H, m), 7.84 (1H,
m), 8.65 (2H, bs).
Example 18
Preparation of 3-[2-(2,2-Dimethyl-propyl)-1-(2-isopropylamino-ethyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (19)
[0340] The titled compound (19) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98.1%, fo =
0.86 min. LCMS (ESI) m/z: 359 ([M+Hf). 'H NMR (CD3OD) 5 7.86 (1H, 6, J = 8.6 Hz),
7.78 (1H, s), 7.73 (1H, d, J= 8.5 Hz), 7.44 (1H, d, J = 15.8 Hz), 6.45 (1H, d, J= 15.4 Hz),
4.83 (2H, t, J = 6.42 Hz), 3.52 (2H, t, J = 6.6 Hz), 3.36 (1H, qt, J = 6.5 Hz), 3.13 (2H, s),
1.26 (6H, d, J = 6.2 Hz), 1.04 (9H, s); 13C NMR (CD3OD) 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
Preparation of 3-[1-(2-Diisopropylamino-ethyl)-2-(2,2-dimethyl-propyl)-1 H-
benzoimidazo!-5-yl]-N-hydroxy-acrylamide (20)
[0341] 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%, tR =
0.94 min. LCMS (ESI) m/z: 400 ([M+Hf). 1H NMR (CD3OD) 8 7.86 (1H, 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); 13C NMR (CD3OD) 8 160.2, 153.1, 138.2, 133.2, 131.9, 124.6,
113.5, 111.8, 54.9, 423.0, 40.5, 37.7, 33.0, 27.8, 16.3.
Example 20
Preparation of 3-[1-(2-Diisopropylamino-ethyl)-2-isobutyl-1H'benzoimidazol-5-yl]-N-
hydroxy-acrylamide (21)
[0342] The titled compound (21) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 95.3%, tR =
0.76 min. LCMS (ESI) m/z: 387 ([M+H]+). 1H NMR (CD3OD) 5 7.85 (1H, s), 7.71 (2H, s),
7.66 (1H, d, J= 15.8 Hz), 6.51 (1H, d, J= 15.8 Hz), 4.75 (2H, t,J = 7.2 Hz), 3.86 (2H, t, J
= 6.5 Hz), 3.50 (2H, t, J = 8.6 Hz), 2.98 (2H, d, J= 7.4 Hz), 2.26 (1H, m) 1.41 (12H, d, J =
6.3 Hz), 1.06 (6H, d, J = 6.6 Hz).

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Example 21
Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-hex-3-enyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (22)
[0343] The titled compound (22) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.9%; tR =
1.24 min; LCMS (ESI) m/z: 399 ([M+H]+). 1H NMR (CD3OD) 5 8.22 (d, J = 8.7 Hz, 1H),
8.11 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 15.8 Hz, 1H), 6.68 (d, J = 15.8 Hz, 1H),
5.69 - 5.59 (m, 2H), 4.79 (s, 2H), 3.66 (s, 2H), 3.55 (t, J = 7.3 Hz, 2H), 3.24 (s, 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); 13C NMR
(CD3OD) 5 165.7, 157.9, 140.2, 135.8, 134.6, 134.5, 126.1, 125.9, 120.1, 115.2, 114.6,
68.7, 533, 47.9, 39.6, 27.6, 25.9, 23.7, 21.4, 14.4.
Example 22
Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,4,4-trimethyl-pentyl)-
1 H-benzoimidazol-5-yl]-N-hydroxy-acrylamide (23)
[0344] The titled compound (23) was prepared according to the procedures 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]+). *H NMR (CD3OD) 5 8.19 (d, J = 8.8 Hz, 1H),
8.08 (s, 1H), 7.90 (d, J= 8.8 Hz, 1H), 7.76 (d, J= 15.7 Hz, 1H), 6.75 (d, J= 15.8 Hz, 1H),
4.79 (s, 2H), 3.62 (s, 2H), 3.35 - 3.29 (m, 1H), 3.23 (s, 6H), 2.52 (brs, 2H), 1.50- 1.45 (m,
2H), 1.36 (d, J = 3.8 Hz, 6H), 1.12 (d, J= 5.5 Hz, 3H), 1.02 (s, 6H); 13C NMR (CD3OD) 5
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-
benzoimidazol-5-yl]-N-hydroxy-acrylarnide (24)
[0345] 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) m/z: 399([M+H]+). 1H NMR (CD3OD): 5 8.21 (d, J = 8.8 Hz, 1H),
8.06 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.83 (d, J= 15.8 Hz, 1H), 6.76 (d, J= 15.8 Hz, 1H),
4.79 (s, 2H), 3.65 (s, 2H), 3.60 - 3.51 (m, 1H), 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); 13C NMR (CD3OD) 8
165.7, 161.3, 140.1, 135.4, 134.8, 134.0, 126.1, 120.3, 119.6, 116.7, 115.5, 114.9, 68.7,
53.1, 47.9, 39.2, 37.0, 32.4, 26.5, 26.3, 23.6.

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Example 24
Preparation of 3-[2-Bicyclo[2.2.1]hept-5-en-2-yl-1-(3-dimethylamino-2,2-dimethyl-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide (25)
[0346] The titled compound (25) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.9%; fo =
0.91 min; LCMS (ESI) m/z: 409 ([M+Hf).
Example 25
Preparation of 3-[1-(2-Diethylamino-ethyl)-2-hex-3-enyl-1 H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (26)
[0347] 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]+). 1H NMR (CD3OD) 8 7.95 (d, J = 8.6 Hz, 1H), 7.87 (s, 1H), 7.77
(d, J a 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, 4H), 3.35 - 3.30 (masked peaks), 2.73 (q, J
= 7.1 Hz, 2H), 2.07 - 1.99 (m, 2H), 1.41 (t, J = 7.2 Hz, 6H), 0.88 (t, J = 7.5 Hz, 3H); 13C
NMR (CD3OD) 5 165.6, 157.2, 140.2, 135.9, 134.8, 134.6, 134.2, 126.4, 126.1, 119.8,
115.6, 113.5, 50.4, 40.5, 26.9, 25.4, 21.4, 14.4, 8.9.
Example 26
Preparation of 3-[1-(2-Diisopropylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-
N-hydroxy-acrylamide (27)
[0348] The titled compound (27) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC: 99.9%; fe = 1.22 min; LCMS
(ESI) m/z: 413 ([M+H]+). 1H NMR (CD3OD) S 7.94 - 7.89 (m, 2H), 7.78 (d, J= 8.7 Hz, 1H),
7.53 (d, J = 15.8 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H), 5.63 - 5.44 (m, 2H), 3.99 - 3.91 (m,
2H), 3.69 - 3.64 (m, 2H), 3.36 - 3.26 (masked peaks), 2.72 2.01 (m, 2H), 1.50 (d, J = 6.5 Hz, 12H), 0.89 (t, J = 7.5 Hz, 3H); 13C NMR (CD3OD) 8
165.6, 157.0, 140.2, 135.9, 135.4, 134.5, 134.3, 126.6, 126.3, 126.2, 119.8, 115.8, 113.3,
56.9, 45.3, 41.9, 27.2, 25.5, 21.4, 18.2, 14.4.
Example 27
Preparation of 3-[2-Hex-3-enyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (28)
[0349] 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) m/z: 371 ([M+H]+). 1H NMR (CD3OD) 8 8.00 (d, J = 9.1 Hz, 1H),

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7.77 - 7.75 (m, 2H), 7.17 (d, J = 15.7 Hz, 1H), 6.34 (d, J = 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 (m, 1H), 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, 6H), 0.87 (t, J =
7.5 Hz, 3H).
Example 28
Preparation of 3-[1-(2-Ethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (29)
[0350] The titled compound (29) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.9%; fo =
1.23 min; LCMS (ESI) m/z: 385 ([M+Hf). 1H NMR (CD3OD) 5 7.94 (d, J = 8.6 Hz, 1H),
7.89 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.56 (d, J= 15.8 Hz, 1H), 6.55 (d, J= 15.7 Hz, 1H),
5.57 - 5.42 (m, 2H), 4.62 (t, J = 7.5 Hz, 2H), 3.42 - 3.33 (m, 1H), 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); 13C NMR(CD3OD) 6 165.6, 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.
Example 29
Preparation of 3-[2-Hex-3-enyl-1-(3-isopropylamino-propyl)-1 H-benzoimidazol-5-yl]-
N-hydroxy-acrylamide (30)
[0351] The titled compound (30) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 99.9%; tR =
1.04 min; LCMS (ESI) m/z: 357([M+H]+). 1H NMR (CD3OD) 5 7.93 (d, J = 8.4 Hz, 1H), 7.77
- 7.73 (m, 2H), 7.23 (d, J = 15.7 Hz, 1H), 6.34 (d, J = 15.7 Hz, 1H), 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, 2H), 1.35 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H); 13C NMR
(CD3OD)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-1 H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (31)
[0352] The titled compound (31) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100%, tR =
1.31 min. LC-MS m/z: 387 ([M+H]+). 1H NMR (DMSO-Qe) 5 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 (2H, t, J = 7.7 Hz), 3.31

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(4H, m), 3.52 (2H, t, J = 7.7 Hz), 4.81 (2H, t, J = 7.7 Hz), 6.59 (1H, d, J = 15.8 Hz), 7.63
(1H, d, J = 15.8 Hz), 7.73 (1H, d, J = 8.8 Hz), 7.93 (1H, d, J = 8.8 Hz), 7.94 (1H, s).
Example 31
Preparation of 3-[1-(3-isopropylamino-propyl)-2-(2,4,4-trimethyl-pentyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (32)
[0353] The titled compound (32) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: HPLC: 97.5%,
tR = 1.68 min. LC-MS m/z: 415 ([M+Hf). 1H NMR (DMSO-d6) 8 0.89 (9H, s), 0.98 (3H, d, J
= 6.6 Hz), 1.23 (6H, d, J = 6.5 Hz), 2.08-2.29 (4H, m), 2.27 (1H, m), 2.98-3.12 (4H, m),
3.29 (1H, m), 4.53 (2H, t, J = 7.4 Hz), 6.60 (1H, d, J = 15.8 Hz), 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
Preparation of 3-[2-(2,2-Dimethyl-propyl)-1-(3-isopropylamino-propyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (33)
[0354] 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 = 1.01
min. LC-MS m/z: 375 ([M+Hf). 1H NMR (DMSO-cfe) 5 0.98 (9H, s), 1.24 (6H, bs), 2.17
(2H, bs), 3.14 (4H, m), 3.28 (1H, bs), 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
Preparation of 3-[1-(2-Diisopropylamino-ethyI)-2-(3,3,3-trifluoro-propyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (34)
[0355] 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
(ESI) m/z: 427 ([M+H]+). 1H NMR (DMSO-d6) 81.35 (12H, m), 2.94 (2H, m), 3.24 (2H, m),
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)-1H-
benzoimidazol-5-yl]-acrylamide(35)
[0356] 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]+). 1H NMR (CD3OD) 5 7.78 (1H, d, J = 8.7 Hz),

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7.76 (1H, s), 7.68 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J= 15.8 Hz), 6.42 (1H, d, J= 15.9 Hz),
4.70 (2H, t, J = 7.4 Hz), 3.48 (2H, t, J = 6.9 Hz), 3.37 (1H, m), 3.01 (2H, d, J = 7.4 Hz),
2.21 (1H, m), 1.27 (6H, d, J = 6.5 Hz), 1.00 (6H, d, J = 6.6 Hz); 13C NMR (CD3OD) 5
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.
Example 35
Preparation of 3-[2-(2,2-Dimethyl-propyl)-1-(2-ethylamino-ethyl)-1 H-benzoimidazol-
5-yl]-N-hydroxy-acrylamide (36)
[0357] The titled compound (36) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. Yield: 74%. HPLC purity at 254 nm:
99.9%, fe = 0.71 min. LCMS (ESI) m/z: 345 ([M+H]+). 1H NMR (CD3OD) 8 7.81 (1H, d, J =
8.6 Hz), 7.75 (1H, s), 7.69 (1H, d, J= 8.5 Hz), 7.36 (1H, d, J= 15.7 Hz), 6.40 (1H, d, J =
15.3 Hz), 4.81 (2H, t, J = 6.4 Hz), 3.51 (2H, t, J = 6.3 Hz), 3.10 (2H, s), 3.06 (2H, qt, J =
7.3 Hz), 1.23 (3H, t, J = 7.2 Hz), 1.04 (9H, s); 13C NMR (CD3OD) 8 161.0, 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-ethyl)-2-isobutyl-1 H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (37)
[0358] 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%, tR =
0.40 min. LCMS (ESI) m/z: 331 ([M+Hf). 1H NMR (CD3OD) 5 7.81 (1H, 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), 6.36 (1H, d, J= 15.7 Hz),
4.73 (2H, t, J = 6.7 Hz), 3.54 (2H, t, J = 6.5 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.06 (2H, d, J =
9.5 Hz), 2.21 (1H, m), 1.23 (3H, t, J= 7.3 Hz), 1.04 (6H, d, J = 6.6 Hz); 13C NMR (CD3OD)
5 163.7, 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.
Example 37
Preparation of 3-[1-(2-Diisopropylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide(38)
[0359] The titled compound (38) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC: 99.0 %; tR = 1.62 min; LCMS
(ESI) m/z: 443 ([M+H]+). 1H NMR (CD3OD) 8 7.96 - 7.94 (m, 2H), 7.82 (d, J = 8.7 Hz,
1H), 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, 2H), 3.33 - 3.24 (masked peaks), 3.18 - 3.12 (m,

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1H), 2.38 - 2.36 (m, 1H), 1.52 (s, 6H), 1.51 (s, 6H), 1.41 - 1.40 (m, 2H), 1.09 (d, J = 6.6
Hz, 3H), 0.94 (s, 9H); 13C NMR (CD3OD) S 165.5, 156.5, 140.1, 134.8, 134.7, 134.0,
126.5, 120.0,114.6, 113.6, 56.9, 51.7, 45.2, 42.0, 35.9, 31.9, 30.6, 30.2, 22.6, 18.3.
Example 38
Preparation of N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-
1H-benzoimidazol-5-yl]-acrylamide (39)
[0360] The titled compound (39) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 97.9 %; tR =
1.49 min; LCMS (ESI) m/z: 401 ([M+H]+). 1H NMR (CD3OD) 8 7.98 (d, J = 8.7 Hz, 1H),
7.79 - 7.76 (m, 2H), 7.24 (d, J = 15.7 Hz, 1H), 6.39 (d, J = 15.7 Hz, 1H), 4.97 - 4.89
(masked peaks), 3.70 - 3.66 (m, 2H), 3.53 - 3.47 (m, 1H), 3.34 - 3.28 (masked peaks),
3.22 - 3.15 (m, 1H), 2.31 - 2.29 (m, 1H), 1.39 - 1.38 (m, 9H), 1.07 (d, J = 6.6 Hz, 3H), 0.9
(s, 9H); 13C NMR (CD3OD) 6 165.5, 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
Preparation of 3-[1-(2-Ethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-
5-yl]-N-hydroxy-acrylamide (40)
[0361] Thetitled compound (40) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100.0%; fe =
1.57 min; LCMS (ESI) m/z: 387 ([M+Hf). 1H NMR (CD3OD) 8 7.96 (d, J= 8.6 Hz, 1H),
7.79 (s, 1H), 7.78 - 7.75 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 15.7 Hz, 1H), 6.37 (d, J = 15.7
Hz, 1H), 4.96 - 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, 1H), 1.40 - 1.32 (m, 5H), 1.07 (d, J = 6.6 Hz, 3H),
0.92 (s, 9H); 13C NMR (CD3OD) 8 165.6, 156.9, 140.6, 134.9, 134.5, 134.2, 126.2, 118.7,
116.0, 113.7, 51.6, 46.5, 45.0,42.7,-35.8, 31.9, 30.8, 30.2, 22.6, 11.4.
Example 40
Preparation of 3-[1-(2-Diethylamino-ethyI)-2-(2,4,4-trimethyl-pentyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide(41)
[0362] The titled compound (41) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 85.6%, tR =
1.55 min. LC-MS m/z: 415 ([M+H]+). 1H NMR (CD3OD) 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, 4H, J = 6.6 Hz), 0.94 (br,

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s, 10H); 13C NMR (CD3OD) 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.
Example 41
Preparation of 3-[1-(2-Diethylamino-ethyl}-2-propyl-1 H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (42)
[0363] The titled compound (42) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254nm: 99.0%, fe =
0.68 min. LC-MS (ESI) m/z: 345 ([M+H]+). 1H NMR (CD3OD) 5 8.15 (d, 2H, J= 8.7 Hz),
7.68 (d, 1H, J = 15.8 Hz), 6.63 (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); 13C NMR
(CD3OD) 5 165.5, 157.4, 139.8, 135.5, 133.5, 132.3, 120.7, 120.7, 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-methylsulfanyl-ethyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (45)
[0364] 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 254 nm: 80%, tR = 0.50 min. LCMS (ESI) m/z: 377 ([M + H]+). 1H NMR
(CD3OD) 5 7.79 (1H, s), 7.77 (1H, d), 7.66 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 15.8 Hz),
6.44 (1H, d, J = 15.8 Hz), 4.83 (2H, masked by DHO, identified by COSY), 3.57 (2H, m),
3.41 (2H, t, J = 7.1 Hz), 3.32 (4H), 3.01 (2H, t, J = 7.1 Hz), 2.89 (3H, s), 1.30 -1.25 (9H,
overlapped t).
Example 43
Preparation of 3-[2-Butyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (46)
[0365] 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+Hf). 1H NMR(DMSO-d6) 8 0.95 (3H, t), 1.22 (6H, m), 1.42
(2H, m), 1.80 (2H, m), 3.13 (2H, m), 3.41 (3H, t), 4.69 (2H, t), 6.58 (1H, m), 7.56 (1H, m),
7.73 (1H, m), 7.90 (2H, m), 9.14 (2H, bs).
Preapration of the freebase of the titled compound:
[0366] To a pre-stirred solution of the methyl ester (1 eq) in dried methanol, NH2OH.HCI
(12 eq.) was added. The mixture was stirred in ice-water bath for about 10 min, followed

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by adding sodium methoxide solution (20 eq.). HPLC showed the reaction completed after
20 min, less than 1% of the acid was observed.
[0367] The above crude was treated with 1M 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 NaHC03, the precipitate which was formed was collected by filtration. The solid
was washed with water once. The above solid was suspended in methanol and water
again and was treated with 6N HCI until all dissolved, the pH value was carefully adjusted
to around 7-8 using NaOH and NaHC03. The precipitate, which was formed, was again
collected by filtration; the freebase compound was obtained by drying in vacuo, the yield
was around 80%-85%.
Preapration of the hydrochloric acid salt of the titled compound:
[0368] The above freebase compound was suspended in methanol and water and was
treated with 6N HCI (2.8 eq.). The solution became clear. 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%).
Example 44
Preparation of 3-[2-Butyl-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (47)
[0369] The titled compound (47) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98.2%; tR =
1.72 min. LCMS (ESI) m/z: 359 ([MH]+). 1H NMR (DMSO-d6) 8 0.95 (3H, t), 1.22 (6H, m),
1.45 (2H, m), 1.82 (2H, m), 2.14 (2H, m), 3.17 (4H, m), 3.28 (1H, m), 4.52 (2H, t), 6.62
(1H, m), 7.57 (1H, m), 7.72 (1H, m), 7.89 (2H, m), 8.80 (2H, bs).
Example 45
Preparation of 3-[1-(1-Benzyl-piperidin-4-yl)-2-butyl-1H-benzoimidazol-5-y!]-N-
hydroxy-acrylamide (48)
[0370] The titled compound (48) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 96.7%, tR =
1.35 min. LC-MS m/z: 433 ([M+Hf). 1H NMR (DMSO-cfe) 5 0.94 (3H, s), 1.41 (2H, m), 1.77
(2H, m), 2.19 (2H, m), 2.99-3.10 (2H, m), 3.24 (4H, m), 3.68 (2H, 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 (3H,
m), 7.97 (1H, s), 8.60 (1H, d, J = 8.8 Hz), 10.35 (2H, s), 11.95 (1H, s).

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Example 46
Preparation of 3-[2-Butyl-1-{2-ethylamino-ethyl)-1 H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide (44)
[0371] The titled compound (44) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98%; LC-MS
m/z: 331 ([M+H]+). 1H NMR (DMSO-cfe) 5 10.88 (br s, 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, 1H, J
= 15.6 Hz), 4.67 (t-like, 2H), 3.42 (br s, 2H), 3.08 (q, 2H, J = 7.7 Hz, Pr-CH2), 3.05 (br s,
2H), 1.81 (m, 2H), 1.45 (m, 2H), 1.18 (t, 3H, J = 7.1 Hz), 0.95 (t, 3H, J = 7.0 Hz); 13C NMR
(DMSO-d6) 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-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (49)
[0372] 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
m/z: 329 ([M+H]+). 1H NMR (CD3OD) 5 7.85 (d, J = 8.5 Hz, 1H), 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), 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); 13C
NMR (CD3OD) 5 178.3, 157.1, 140.7, 136.5, 133.9, 125.9, 118.8, 117.6, 116.2, 113.2,
101.5, 67.6, 46.4, 44.9, 42.4, 31.6, 26.7, 20.7, 11.4.
Example 48
Preparation of 3-[2-Hexyl-1-(2-isopropylamino-ethyl)-1H-benzoirnidazol-5-yl]-N-
hydroxy-acrylamide (50)
[0373] The titled compound (50) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 94.4%, tR =
1.32 min. LCMS (ESI) m/z: 373 ([M+H]+). 1H NMR (CD3OD) S 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 (1H, d, J = 15.8 Hz),
4.65 (2H, d, J = 6.6 Hz), 3.48 (2H, d, J = 6.6 Hz), 3.38 (1H, qt, J = 6.5 Hz), 3.13 (2H, t, J =
5.9 Hz) 1.82 (2H, t, J = 6.7 Hz), 1.44 (2H, t, J = 7.0 Hz) 1.29 (7H, m) 0.84 (6H, d, J = 7.0
Hz).

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Example 49
Preparation of 3-[1-(2-Dimethylamino-ethy!)-2-(2,4,4-trimethyl-perityl)--1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (51)
[0374] The titled compound (51) was prepared according to the procedures 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+H]+). 1H NMR (DMSO-d6) 6 0.85 (9H, s), 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=8.4Hz).
Example 50
Preparation of 3-[1-(2-Ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide (52)
[0375] The titled compound (52) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. The modified or detailed procedures
were described as below.
Step 3:
[0376] To a stirred solution of 3-[4-(2-ethylamino-ethylamino)-3-nitro-phenyl]-acrylic acid
methyl ester (8.174 g, 27.87 mmol) and heptaldehyde (4.85 g, 42.47 mmol, 1.52 eq) in
AcOH and MeOH (1:9 v/v, 300mL) was added SnCI22H20 (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 Na2C03 and extracted 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 (Na2SC>4), filtered, and evaporated to dryness. The resulting oily
residue was purified by flash column chromatography (silica, 67 x 65 mm, solvent
MeOH/DCM gradient from 0 to 10%). 3-[1-(2-ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-
5-yl]-acrylic acid methyl ester was obtained as yellow solid (4.445 g, 44.6%). HPLC purity
at 254 nm: 98.8%, fe = 1.71 min. LCMS (ESI) m/z: 358 ([M + H]+). 1H NMR (CDCI3) 5 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 (2H, 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), 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%.

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[0377] 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).
Step 4:
[0378] To a solution of 3-[1-(2-ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-acrylic
acid methyl ester (4.428 g, 12.39 mmol) and NH2OHHCI (8.66 g, 124.7 mmol) in dry
MeOH (50 mL) which was stirred and cooled in a dry-ice acetone bath, added 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 Milli-Q water, adjusted pH ~8 by 1N NaOH
and evaporated to remove the organic solvent. The resultant 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 254 nm = 98%). The free base could be recrystallized from
MeOH-Ethyl acetate to give a white or pale yellow solid.
Step 5: hydrochloric acid salt formation.
[0379] The above freebase was dissolved in MeOH and excess 6N HCI (final pH and the clear solution was evaporated to dryness and then diluted with MeOH, co-
evaporated with PhMe (x1) 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 + H]+). 1H NMR (CD3OD) 8 9.33
(residual NH), 8.03 (1H, d, J = 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
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 (2H, 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); 13C NMR (CD3OD) 5 163.4, 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.
Anal. (C2oH3oN402»2HCI) CI: calcd, 16.44; found, 16.00.
Example 51
Preparation of N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1 H-
benzoimidazol-5-yl]-acrylamide(53)

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[0380] The titled compound (53) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC: 98.1%; tR = 0.63 min. LC-MS
m/z: 385 ([M+H]+).
Example 52
Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (54)
[0381] 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%, tR =
0.96 min. LCMS (ESI) m/z: 357 ([M+H]+). 1H NMR (CD3OD) 8 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 = 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); 13C NMR (CD3OD) 8 163.6, 160.0, 155.1, 138.1, 134.1, 133.1,
131.9, 131.6, 124.7, 123.9, 118.2, 117.2, 114.3, 113.1, 111.8, 53.2, 42.1, 38.8, 24.8, 23.3,
19.4, 12.4.
Example 53
Preparation of 3-[1-(2-Amino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1 H-benzoimidazol-5-
yrj-N-hydroxy-acrylamide (55)

Step 1:
[0382] 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
(45 \xl, 0.26 mmol) in a mixed solvent of AcOH-MeOH (1:9 v/v, 2 ml_) and DCM (1 mL)
was added SnCI2"2H20 (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

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resultant residue was added saturated aqueous Na2C03 and extracted with EtOAc (x3).
The extracts gave the crude (Vla1-1, 91 mg) with HPLC purity at 254 nm: 49.3%, tp = 3.02
min and 7.9%, tR = 1.97 min (de-Boc product). LCMS (ESI) m/z: 458 ([M + H]+) and 358
([M + H]+, de-Boc product).
Step 2: '
[0383] The above crude (Vla1-1) was dissolved in MeOH (4 mL) and 6N HCI (1 mL) and
heated at 70°C for 30 min. The solution was evaporated to dryness and co-evaprote dwith
PhMe (x2) and MeOH (x1). The residue (crude Vla-1, 81.9 mg) was spilt to two parts
(43.4 mg, equal to 0.0945 mmol of lllal, and 38.5 mg equal to 0.0839 mmol of lllal).
Step 3:
[0384] The titled compound (55) was prepared according to the Step 4 described in
Example 1, by using crude (Vla-1, 38.5 mg). Vlla-1 was obtained as TFA salt (2.3 mg,
4.7% from lllal). HPLC purity at 254 nm: 92.7%, tR = 1.46 min. LCMS (ESI) m/z: 359 ([M
+ H]+). 1H NMR (CD3OD) 8 7.81 (1H, s), 7.70 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 8.4 Hz),
7.59 (1H, d, J = 15.8 Hz), 6.47 (1H, brd, J = 14.6 Hz), 4.63 (2H,t, J = 5.4 Hz), 3.38 (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), 2.20 (1H, brs
or m), 1.33 (1H, dd, J = 14.1, 3.4 Hz), 1.25 (1H, dd, J = 14.0, 6.6 Hz), 0.98 (3H, d, J = 6.2
Hz), 0.83 (9H, s).
Example 54
Preparation of 3-[1-(2-Amino-ethyl)-2-(2-methoxy-nonyl)-1 H-benzoimidazoi-5-yl]-N-
hydroxy-acrylamide (56)
[0385] The titled compound (56) was prepared according to the procedures described in
Example 53, by using appropriate starting materials. HPLC purity at 254 nm: 91.8%, tR =
1.93 min. LCMS (ES!) m/z: 403 ([M + H]+). 1H NMR (CD3OD) 8 some identified peaks:
7.81 (1H, s), 7.70 ~ 7.58 (3H, m), 6.46 (1H, br d, J = 14.4 Hz), 4.62 (2H, m), 3.69 (1H, br s
or m), 3.38 (2H, t, J = 7.3 Hz), 1.67 (1H, m), 1.56 (1H, m), 1.50-1.20 (10H, m), 0.82 (3H, t,
J = 6.2 Hz).
Example 55
Preparation of 3-[2-Butyl-1-(2-dimethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (57)
[0386] The titled compound (57) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100%, tR =
0.42 min. LC-MS m/z: 331 ([M + H]+). 1H NMR (DMSO-d6) 8 0.97 (3H, t, J = 7.3 Hz), 1.49

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(3H, 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).
Example 56
Preparation of 3-[2-Hexyl-1-(2-dimethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (58)
[0387] The titled compound (58) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 100%, k =
0.42 min. LC-MS m/z: 359 ([M + H]+). 1H NMR (DMSO-d6) 8 0.89 (3H, t, J = 6.9 Hz), 1.28-
1.54 (6H, m), 1.85 (2H, m), 2.92 (6H, 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).
Example 57
Preparation of 3-{1-(2-Diethylamino-ethyI)-2-[2-(2,2-dimethyl-propionylamino)-ethyl]-
1 H-benzoimidazol-5-yl}-N-hydroxy-acrylamide (61)
[0388] The titled compound (61) was prepared according to the procedures described
below, Steps 1 & 2 were performed as in Scheme I:
Step 3:

[0389] To a pre-stirred solution of 3~[4-(2-diethylamino-ethylamino)-3-nitro-phenyl]-
acrylic acid methyl ester (61-1, 280 mg, 1.0 mmol) in glacial acetic acid (5 ml_), tin chloride
was added (1.18 g, 10.0 mmol). The resulting solution was heated to 45°C for 17 hours
and then cooled to room temperature. The solvent was removed under vacuum. Water
(20 mL) and dichloromethane (20 mL) was added to the residue and stirred for 30
minutes. The organic layer was dried (MgS04), filtered and concentrated to an oily
residue. 100 mL diethyl ether was added and stirred for 4 hours. The product 3-[3-amino-
4-(2-diethylamino-ethylamino)-phenyl]-acrylic acid methyl ester was obtained in 54.9%
yield (207.6 mg). LCMS m/z: 292 ([M+H]+).

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Step 4



[0390] To a pre-stirred solution of 3-[3-amino-4-(2-diethylamino-ethylamino)-phenyl]-
acrylic acid methyl ester (61-2, 1.93 g, 6.65 mmol) and dichloromethane (13.3 mL) was
added a cocktail solution of W-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride
(2.55 g, 13.31 mmol), 1-hydroxybenzotriazole hydrate (2.04 g, 13.31 mmol), N,N-
diisopropylethylamine (2.20 mL, 13.31 mmol) and dichloromethane (26.6 mL). After
stirring for 0.5h, Fmoc-Gly-OH (61-3, 2.97 g, 9.98 mmol) was added. When the starting
material has fully reacted, ethyl acetate (100 mL) was added to dilute the mixture. The
organic contents were washed with saturated sodium hydrogencarbonate (2 x 25 mL) and
brine (2 x 25 mL), before drying in sodium sulphate. The mixture was then filtered and
concentrated in vacuo. The product 3-[3-amino-4-(2-diethylamino-ethylamino)-phenyl]-
acrylic acid methyl ester was obtained in 67.3% yield (2.54 g). LCMS m/z: 571 ([M+Hf).
Step 5

[0391] Glacial acetic acid (8.9 mL) was added into 3-[3-amino-4-(2-diethylamino-
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 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]-1H-benzoimidazol-5-yl}-acrylic acid methyl ester (61-5) was obtained in 66.1 .%
(1.62 g). LCMS m/z: 553 ([M+Hf).


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Step 6
[0392] To a pre-stirred solution of 3-{1-(2-dethylamino-ethyl)-2-[(9H-fluoren-9-
ylmethoxycarbonylamino)-methyl]-1H-benzoimidazol-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 \in 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-ethyi)-1H-benzoimidazol-5-yl]-
acrylic acid methyl ester was obtained as powder. LCMS m/z: 331 ([M+H]+).
Step 7

[0393] To a pre-stirred solution of 3-[2-aminomethyl-1-(2-diethylamino-ethyl)-1H-
benzoimidazol-5-yl]-acrylic acid methyl ester (61-6, 0.10 g, 0.23 mmol), N,N-
diisopropylethylamine (97 uL, 0.58 mmol) and dichloromethane (1.17 mL) was added 2,2-
dimethyl-propionyl chloride (34.6 uL, 0.28 mmol) and the resulting reaction mixture was
stirred at room temperature for 1h. When the reaction has completed, ethyl acetate (20
mL) was added to dilute the mixture. The organic contents were washed with saturated
sodium hydrogencarbonate (2 x 20 mL) and brine (2 x 20 mL), before drying in Na2S04-
The mixture was filtered and concentrated in vacuo. The product 3-{1-(2-diethylamino-
ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1 H-benzoimidazol-5-yl}-acrylic acid methyl
ester (61-7) was obtained in 76.6 % (74.1 mg). LCMS m/z: 415 ([M+H]+).

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Step 8
[0394] To a stirred solution of 3-{1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl-
propionylamino)-methyl]-1H-benzoimidazol-5-yl}-acrylic acid methyl ester (61-7, 73.8 mg,
0.18 mmol) and hydroxylamine hydrochloride (124 mg, 1.78 mmol) in MeOH (0.3 mL) was
added sodium methoxide (30% in methanol) (0.8 mL, 3.6 mmol) at - 78 °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 0 °C. The desired product was separated by reverse phase
preparative HPLC. After lyopholyzation, 22.2 mg (24.3 %) of 3-{1-(2-diethylamino-ethyl)-2-
[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide was
obtained as powder. HPLC purity: 99.5%, tp = 0.94min. LCMS m/z: 416 ([M+Hf). 1H
NMR (CD3OD) 5 7.89 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.73 (d, J= 8.4 Hz, 1H), 7.55 (d, J
= 15.8 Hz, 1H), 6.53 (d, J = 15.8 Hz, 1H), 4.98 (t, J = 7.3 Hz, 2H), 4.73 (s, 2H), 3.75 (t, J =
7.5 Hz, 2H), 3.42 (q, J = 7.2 Hz, 4H), 1.37 (t, J = 7.3 Hz, 6H), 1.22 (s, 9H); 13C NMR
(CD3OD) 8 182.5, 168.9, 162.2, 161.9, 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-hydroxycarbamoyl-vinyl)-1 H-
benzoimidazol-2-yl]-ethyl}-3,3-dimethyl-butyramide(59)
[0395] 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%; tR =
0.99 min. LC-MS m/z: 444 ([M + H]+).
Example 59
Preparation of N-[1-(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoyl-vinyl)-1 H-
benzoimidazol-2-ylmethyl]-butyramide (62)
[0396] The titled compound (62) was prepared according to the procedures described in
Example 57, by using appropriate starting materials. HPLC purity at 254 nm: 85.1 %; tR =
0.58 min; LCMS m/z: 402 ([M + H]+). 1H NMR (CD3OD) 8 7.88 - 7.56 (m, 2H), 7.73 (s,
1H), 7.60 (d, J = 15.8 Hz, 1H), 6.51 (d, J = 15.8 Hz, 1H), 4.99 - 4.79 (m, masked peaks),

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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); 13C NMR (CD3OD) 5 117.1, 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-benzoimidazoI-5-
yl]-N-hydroxy-acrylamide (63)
[0397] The titled compound (63) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC: 99.0 %; tR = 0.93 min; LCMS
m/z: 359 ([M + H]+). 1H NMR (CD3OD) 5 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 (brs, 2H), 3.29 - 3.18
(m, 4H), 1.90 - 1.86 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.09 (s, 9H); 13C NMR (CD3OD) 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
Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-(3,3-dimethy!-butyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (64)
[0398] The titled compound (64) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC: 99.0 %; tR = 0.83 min; LCMS
m/z: 359 ([M + H]+). 1H NMR (CD3OD) 8 7.94 (d, J = 7.8 Hz, 1H), 7.81 (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 (brs, 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, 9H); 13C NMR
(CD3OD) 8 165.4, 158.4, 140.2, 134.5, 134.2, 133.2, 126.5, 118.8, 115.3, 113.9, 46.4,
45.1, 42.9, 40.6, 31.3, 29.2, 22.9, 11.4.
Example 62
Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-pentyl-1 H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (65)
[0399] 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]+). 1H NMR(DMSO-d6) 8 0.89 (3H, m), 1.38 (4H, m),
1.83 (2H, m), 2.93 (6H, s), 3.04 (2H, m), 3.50 (2H, t), 4.70 (2H, m), 6.55 (1H, d), 7.57 (1H,
d), 7.61 (1H, m), 7.81 (2H, m), io.42 (1H, bs).

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Example 63
Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-(2,2,2-trifluoro-ethyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (64)
[0400] 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. LCMS m/z: 357 ([M+H]+).
Example 64
Preparation of 3-[1-(2-Ethylamino-ethyl)-2-pentyl-1 H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide (68)
[0401] The titled compound (68) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 98.4%; tR =
0.87 min. LCMS m/z: 345([M+H]+).
Example 65
Preparation of N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-pentyl-1H-benzoimidazol-
5-yrj-acrylamide (71)
[0402] The titled compound (71) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 97.4%; tR =
0.95 min. LCMS m/z: 359 ([M + Hf). 1H NMR(DMSO-d6) 5 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 (1H, d), 7.59 (2H, d), 7.64
(1H, m), 7.88 (1H, m), 8.74 (2H, bs).
Example 66
Preparation of 3-[2-Hexyl-1-(2-methylamino-ethyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (74)
[0403] The titled compound (74) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 96.0%, tR =
1.12 min. LCMS m/z: 345 ([M+H]+). 1H NMR (CD3OD) 5 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 (2H, d, J = 5.7 Hz), 3.49
(2H, bs), 3.15 (2H, dt, J = 4.8 Hz), 2.71 (3H, s), 1.85 (2H, qn, J = 5.1 Hz), 1.46 (2H, m),
1.33 (4H, m), 0.85 (3H, t, J = 7.1 Hz); 13C NMR (CD3OD) 5 163.7, 157.8, 138.5, 132.7,
124.2, 117.6, 113.7, 111.2, 40.2, 32.2, 30.5, 28.0, 25.6, 25.1, 21.6, 12.3.
Example 67
Preparation of N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-pentyl-1 H-benzoimidazol-5-
yl]-acrylamide (75)

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[0404] The titled compound (75) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity at 254 nm: 97.8%; fe =
0.80 min. LCMS m/z: 331 ([M + H]+). 1H NMR(DMSO-d6) 5 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, s).

Example 68
Preparation of
acrylamide (69)

3-(2-Butyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-


Stepl.
[0405] To a solution of methyl trans-4-Chloro-3-nitrocinnamate (la, 4.8 g, 20 mmol) in
triethyl amine (5.5 mL, 40 mmol) was added 3-Amino-pyrrolidine-1-carboxylic acid 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-Chloro-3-nitrocinnamate (4.8 g, 20 mmol) and
triethyl amine (5.5 mL, 40 mmol) was added, the resulting mixture was allowed to stir
overnight at 100 °C, then reaction was quenched by adding 200 mL of DCM and 80 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 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]+).
Step 2.
[0406] 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

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chloride (22.6 g, 100 mmol), the resulting mixture was stirred at 42 °C for 24 hrs. Then the
mixture was diluted using ethyl acetate (300 ml_) at room temperature, and was 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 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]+).
Step 3.
[0407] To a flask charged with compound 69-3 (456 mg, 1mmol) 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 + H]+).
Step 4.
[0408] To a solution of above crude 69-4 (around 0.16 mmol) product in MeOH (0.5 mL)
was added a pre-prepared NH2OH stock solution (2.0 M, 2 mL). The resulting mixture was
stirred at room temperature for 2 hrs. After quenching with TFA (0.4 mL), the resulting
mixture was subjected to HPLC purification to afford 25 mg of 3-(2-Butyl-1-pyrrolidin-3-yl-
1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide. HPLC purity: 98%; LC-MS m/z: 329 ([M +
H]+). 'H NMR (CD3OD) 5 0.95 (3H, t, J = 7.2 Hz), 1.46 (2H, m), 1.77 (2H, m), 2.52-2.82
(2H, m), 3.10-3.17 (2H, m), 3.48 (1H, m), 3.80 (2H, m), 5.55 (1H, 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).
Example 69
Preparation of 3-(2-Butyl-1-piperidin-4-yl-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide (70)
[0409] The titled compound (70) was prepared according to the procedures described in
Example 78, by using appropriate starting materials. HPLC purity: 98%; LCMS rh/z: 343
([M + H]+). 1H NMR (CD3OD) 8 0.96 (3H, t, J = 7.2 Hz), 1.46 (2H, m), 1.79 (2H, m), 2.21
(2H, m), 2.82 (2H, m), 3.10-3.17 (2H, m), 3.26 (1H, m), 3.60 (2H, m), 4.96 (1H, m), 6.49
(1H, d, J= 15.8 Hz), 7.60 (1H, d, J= 15.8 Hz), 7.66 (1H, d, J = 8.0 Hz), 7.82 (1H, s) (1H,
d, J = 8.0 Hz).

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Example 70
Preparation of 3-(2-Hexyl-1-pyrrolidin-3-yl-1 H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide (80)
[0410] The titled compound (80) was prepared according to the procedures described in
Example 68, by using appropriate starting materials. HPLC purity: 98%; LCMS m/z: 35.7
([M + H]+). 1H NMR (CD3OD) 8 0.84 (3H, t, J = 7.2 Hz), 1.22-1.38 (4H, m), 1.44 (2H, m),
1.81 (2H, m), 2.52-2.82 (2H, m), 3.10-3.17 (2H, m), 3.48 (1H, m), 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 (1H,
s), 7.90 (1H,d, J = 9.2 Hz).
Example 71
Preparation of 3-[2-Butyl-1-(1-methyl-pyrrolidin-3-yl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (81)
[0411] The titled compound (81) was prepared according to the procedures described in
Example 68, by using 69-4 via reductive amination to introduce a methyl group. HPLC
purity: 98%; LCMS m/z: 343 ([M + H]+). 1H NMR (CD3OD) 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, m), 6.51 (1H, d, J = 16.0 Hz), 7.58 (1H, d, J = 16.0 Hz), 7.69 (1H,
d, J = 8.0 Hz), 7.88 (1H, s), 8.00 (1H, d, J = 9.2 Hz).
Example 72
Preparation of 3-(2-Hexyl-1-piperidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide (82)
[0412] The titled compound (82) was prepared according to the procedures described in
Example 68, by using appropriate starting materials. HPLC purity: 97%; LCMS m/z: 343
([M + H]+). 1H NMR (CD3OD) 5 0.99 (3H, t, J = 7.2 Hz), 1.52 (2H, m), 1.84 (2H, m), 2.04
(1H, m), 2.20 (2H, m), 2.61 (1H, m), 3.12-3.22 (2H, m), 3.49 (1H, m), 3.67 (1H, m), 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
Preparation of 3-(2-Butyl-1-piperidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide (83)
[0413] 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]+). 1H NMR (CD3OD) 8 0.88 (3H, t, J = 7.2 Hz), 1.22-1.42 (4H, m), 1.47 (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),

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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).
Example 74
Preparation of (E)-N-hydroxy-3-(1-(1-methylpiperidin-3-yl)-2-pentyl-1H-
benzo[d]imidazol-5-yI)acrylamide (86)
[0414] The titled compound (86) was prepared according to the procedures described in
Example 71, by using appropriate starting materials.HPLC purity: 99.3 %, ta =1.06 min;
LCMS m/z: 371 ([M + H]+). 1H NMR (CD3OD) 5 8.18 (d, J = 7.9 Hz, 1H), 7.92 (s, 1H), 7.77
(d, J = 8.1 Hz, 1H), 7.61 (d, J = 15.7 Hz, 1H), 6.58 (d, J = 15.7 Hz, 1H), 5.21 (brs, 1H),
3.69 (brs, 2H), 3.69 - 3.66 (m, 1H), 3.37 - 3.27 (masked peaks), 3.03 (s, 3H), 2.66 (brs,
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,
3H); 13C NMR (CD3OD) 5165.6, 157.6, 139.9, 134.6, 134.1, 132.5, 126.3, 120.4, 115.5,
115.2, 54.9, 54.4, 53.3, 44.1, 32.4, 27.5, 27.3, 26.8, 23.2, 23.1, 14.2.
Example 75
Preparation of (E)-3-(2-hexyl-1-(1-(2-hydroxyethyl)piperidin-3-yl)-1H-
benzo[d]imidazol-5-yl)-N-hydroxyacrylamide (90)
[0415] 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]+).
Example 76
Preparation of N-Hydroxy-3-[1-(1-pentyl-piperidin-3-yl)-1H-benzoimidazol-5-yl]-
acrylamide (94)
[0416] The titled compound (94) was prepared according to the procedures described in
Example 68, by using appropriate starting materials (formic acid for benzimdiazoel ring
formation and reductive amination of the piperidine with pentanal). HPLC purity: 95%; LC-
MS m/z: 357 ([M+H]+). 1H NMR (CD3OD) 8 9.04 (s, 1H), 7.94 (brs, 2H), 7.78 (d, 1H, J =
8.2 Hz), 7.70 (d, 1H, J= 15.7 Hz), 6.57 (d, 1H, J= 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 - 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-yl)-1 H-benzoimidazol-5-yl]-
acrylamide (96)

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[0417] 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 (CD3OD) 5 8.93 (s, 1H), 7.95 (s, 1H), 7.91 (d, 1H, J = 8.5 Hz), 7.76
(d, 1H, 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 - 3.45 (m, 2H), 3.15 - 3.11 (m, 2H),
2.46-2.13 (m,6H).
Example 78
Preparation of N-Hydroxy-3-{1 -[1 -(3-phenyl-propyl)-piperidin-3-yl]-1 H-
benzoimidazol-5-yl}-acrylamide (97)
[0418] 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+H]*) 1H NMR (CD3OD) 5 8.68 (s, 1H), 7.94 (s, 1H), 7.80 (d, 1H, J = 8.4 Hz), 7.71 (d,
1H, J= 15.7 Hz), 7.69 (d, 1H, J= 8.2 Hz), 7.31 -7.17 (m, 6H), 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), 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)-pyrrolidin-3-yl]-1H-benzoimidazol-5-yl}-N-
hydroxy-acrylamide (99)
[0419] 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 ([MHf). 1H NMR (DMSO-d6) 5 0.91 (9H, s), 1.52 (4H, m), 3.09 (1H, m),
3.29 (6H, m), 6.52 (1H, d), 7.43 (2H, m), 7.62 (1H, m), 7.80 (1H, m), 8.82 (1H, s), 10.25
(1H, bs).
Example 80
Preparation of 3-{1-[2-(Ethyl-methyl-amino)-ethyl]-2-pentyl-1 H-benzoimidazol-5-yl}-
N-hydroxy-acrylamide (79)
[0420] The titled compound (79) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity: 99%; tR = 0.68 min. LC-
MS m/z: 359 ([M+H]+). 1H NMR (DMSO-d6) 8 0.89 (3H, m), 1.23 (3H, m), 1.38 (4H, m),
1.84 (2H, m), 2.92 (3H, s), 3.10 (2H, m), 3.28 (2H, m), 3.52 (2H, m), 4.77 (2H, m), 6.58
(1H, d), 7.61 (1H, d), 7.71 (1H, m), 7.92 (2H, m), 10.48 (1H, bs).

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Example 81
Preparation of 3-{2-Butyl-1-[2-(ethyl-methyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-
hydroxy-acrylamide (85)
[0421] The titled compound (85) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity: 95.8%; fe =1.04 min. LC-
MS m/z: 345 ([M+Hf). 1H NMR (DMSO-d6) 8 0.95 (3H, m), 1.25 (3H, m), 1.46 (2H, m),
1.81 (2H, m), 2.92 (3H, s), 3.13 (2H, m), 3.27 (2H, m), 3.54 (2H, m), 4.80 (2H, m), 6.60
(1H, d), 7.62 (1H, d), 7.75 (1H, 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-
benzoimidazol-5-yl)-N-hydroxy-acrylamide (91)
[0422] 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]+). 1H NMR(DMSO-d6) 8 0.94 (3H, m), 1.25 (3H, m), 1.46 (2H, m),
1.83 (4H, m), 3.04 (2H, m), 3.31 (4H, m), 3.50 (4H, m), 4.72 (2H, m), 6.54 (1H, d), 7.61
(1H, m), 7.69 (1H, m), 7.80 (1H, m), 7.90 (1H, m), 10.20 (1H, bs).
Example 83
Preparation of 3-(1-{2-[Ethyl-{3-hydroxy-propyl)-amino]-ethyl}-2-pentyl-1 H-
benzoimidazol-5-yl)-N-hydroxy-acrylamide(92)
[0423] The titled compound (92) was prepared according to the procedures described in
Example 1, by using appropriate starting materials. HPLC purity: 93.5%; tR = 0.50 min.
LC-MS (m/z): 389 ([M+Hf) 1H NMR (DMSO-d6) 8 0.94 (3H, m), 1.25 (3H, m), 1.46 (2H,
m), 1.83 (4H, m), 3.04 (2H, m), 3.31 (4H, m), 3.50 (4H, m), 4.72 (2H, m), 6.54 (1H, d),
7.61 (1H, m), 7.69 (1H, m), 7.80 (1H, m), 7.90 (1H, m), 10.20 (1H, bs).
Example 84
Preparation of 3-{1-[2-(Butyl-ethyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-
acrylamide (95)
[424] 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]+). 1H NMR (CD3OD) 8 9.29 (s, 1H), 7.99 - 7.95 (m, 2H), 7.82 (d, 1H, J = 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 = 13.3, 7.1 Hz), 3.28-3.26 (m, 2H), 1.74-1.71 (m, 2H), 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).

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Example 85
Preparation of 3-[2-(4-Cyano-butyl)-1-(2-diethylamino-ethyl)-1 H-benzoimidazol-5-yl]-
N-hydroxy-acrylamide (101)
[0425] 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]+). 1H NMR (CD3OD) 8 7.78 (1H, s) 7.76 (1H, d, J = 8.5 Hz),
7.63 (1H, d, J= 16.9 Hz), 7.58 (1H, d. J= 5.1 Hz), 6.44 (1H, d, J= 15.3 Hz), 4.70 (2H, in
water peak), 3.50 (2H, t, J = 7.6 Hz), 3.32 (4H, qt, J = 7.3 Hz), 3.07 (2H, t, J = 8.0 Hz),
2.50 (2H, t, J = 7.0 Hz), 1.99 (2H, q, J = 7.5 Hz), 1.78 (2H, q, J = 7.3 Hz), 1.29 (6H, t, J =
7.3 Hz).
Example 86
Preparation of 3-{1-[2-(Butyl-isopropyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-
hydroxy-acrylamide (108)
[0426] The titled compound (108) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. HPLC purity: 98.8%; fo = 1.33 min.
LC-MS m/z: 345 ([M+H]+). 1H NMR (DMSO-cfe) 8 0.90 (3H, m), 1.25 (6H, d), 1.35 (2H, m),
1.64 (2H, m), 3.09 (2H, m), 3.51 (1H, m), 3.73 (2H, m), 4.74 (2H, m), 6.52 (1H, d), 7.53
(2H, m), 7.64 (1H, m), 7.80 (1H, m), 8.62 (1H, m), 9.40 (1H, bs), 10.72 (1H, bs).
Example 87
Preparation of N-Hydroxy-3-{1-[2-(isopropyl-pentyl-amino)-ethyl]-1 H-benzoimidazol-
5-yl}-acrylamide (109)
[0427] The titled compound (109) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. LC-MS m/z: 359 ([M+H]+). 1H NMR
(DMSO-cfe) 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, s), 8.65 (1H, s), 9.46 (1H, b).
Example 88
Preparation of 3-[2-(5-Cyano-pentyl)-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-
yl]-N-hydroxy-acrylamide (110)
[0428] The titled compound (110) was prepared according to the procedures described in
Example 57, by using appropriate starting materials. HPLC purity at 254 nm: 95.4%. LC-
MS (ESI) m/z: 347 ([M+H]+). (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 (2H, t, J = 7.1 Hz), 3.44 (4H, qt, J = 7.2 Hz), 3.31 (2H, embedded in MeOD

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peak), 2.51 (2H, t, J = 6.9Hz), 2.05-1.98 (2H, m)r 1.78 (2H, m, J = 7.4 Hz), 1.70 (2H, m, J
= 6.4 Hz), 1.41(3H, t, J= 7.2 Hz).
Example 89
Preparation of 3-(1-{2-[(3,3-Dimethy1-butyl)-ethyl-amino]-ethyl}-1 H-benzoimidazol-5-
yl)-N-hydroxy-acry!amide (111)
[0429] The titled compound (111) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. TFA salt. HPLC purity: 97.7%; LC-
MS m/z: 359 ([M+H]+). 1H NMR (CD3OD) 5 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, 1H, 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, J = 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 (s, 9H).
[0430] HCI salt. 1H NMR (DMSO-cfe) 8 9.90 (bs, 1H), 8.65 (s, 1H), 7.93 (s, 1H), 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, 1H, 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).
Example 90
Preparation of 3-{1-[2-(Ethyl-propyl-amino)-ethyl]-1 H-benzoimidazol-5-yl}-N-
hydroxy-acrylamide (112)
[0431] The titled compound (112) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. HPLC purity: 98.1%; LC-MS m/z: 315
([M+H]+). 1H NMR (CD3OD) 5 9.43 (s, 1H), 7.99 (d, 1H, J = 8.5 Hz), 7.93 (s, 1H), 7.82 (d,
1H, 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).
Example 91
Preparation of N-Hydroxy-3-(1-{2-[isopropyl-(2-methyl-pentyl)-amino]-ethyl}-1 H-
benzoimidazol-5-yl)-acry!amide (113)
[0432] The titled compound (113) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. LC-MS m/z: 373[(M+H)+]]. 1H NMR
(DMSO-d6) 5 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).

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Example 92
Preparation of 3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-methyl-1 H-benzoimidazol-5-yl}-N-
hydroxy-acrylamide (116)
[0433] The titled compound (116) was prepared according to the procedures described in
Example 57, by using appropriate starting materials. HPLC purity at 254 nm: 98.2%, tR =
1.27 min. LC-MS (ESI) m/z: 373 ([M+H]+). 1H NMR (CD3OD) 5 7.85 (1H, s), 7.78 (1H, d, J
= 8.4 Hz), 7.70 (1H, d, J= 8.7 Hz), 7.15 (1H, d. J= 15.9 Hz), 6.53 (1H, d, J= 15.9 Hz),
4.81 (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 (11H, m), 0.93 (3H, t, J = 6.9 Hz).
Example 93
Preparation of 3-{1-[2-(Butyl-ethyl-amino)-ethyl]-2-trifluoromethyl-1H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide (117)
[0434] 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]+). 1H NMR (CD3OD) 5 7.95 (1H, s), 7.70 (2H, s),
7.62 (1H, d, J = 15.9 Hz), 6.46 (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).
Example 94
Preparation of 3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-trifluoromethyl-1H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide (118)
[0435] 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]+). 1H NMR (CD3OD) 5 8.04 (1H, s), 7.80 (2H, s),
7.72 (1H, d, J - 15.8 Hz), 6.56 (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, m), 1.39 (9H, m, J = 7.5 Hz), 0.93 (3H, t, J =
7.0 Hz).
Example 95
Preparation of 3-[1-(2-Dipropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide (120)
[0436] 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]+). 1H NMR(DMSO-d6) 5 0.86 (6H, d), 1.64 (4H, m), 3.09 (4H, m), 3.60 (2H, m),

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4.76 (2H, m), 6.53 (1H, d), 7.55 (2H, m), 7.65 (1H, m), 7.88 (1H, m), 8.75 (1H, m), 9.93
(1H, bs).
Example 96
Preparation of N-Hydroxy-3-(1-{2-[isopropyl-(3-methyl-butyi)-amino]-ethyl}-1 H-
benzoimidazol-5-yl)-acrylamide (121)
[0437] The titled compound (121) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. HPLC purity: 98.7%; tR = 1.02 min.
LC-MS (m/z): 358 ([M+H]+). 1H NMR (DMSO-cf6) 6 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 (1H, bs), 10.70 (1H, bs).
Example 97
Preparation of 3-(1-{2-[(3,3-Dimethyl-butyl)-methyl-amino]-ethyl}-1H-benzoimidazol-
5-yl)-N-hydroxy-acrylamide (122)
[0438] The titled compound (122) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. HPLC purity at 254 nm: 97.8%; tR =
0.93 min. LC-MS m/z: 345 ([M+H]+). 1H NMR (DMSO-cfe) 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).
Example 98
Preparation of 3-(1-{2-[(2-Ethyl-butyl)-methyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-
N-hydroxy-acrylamide (123)
[0439] The titled compound (123) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. HPLC purity at 254 nm: 97.7%; tR=
0.87 min. LC-MS m/z: 345 ([M+H]+). 1H NMR (DMSO-o*6) 8 0.81 (6H, m), 1.29 (4H, m),
1.69 (1H, m), 2.89 (3H, s), 3.08 (2H, m), 3.59 (2H, m), 4.77 (2H, m), 6.53 (1H, d), 7.52
(2H, m), 7.86 (1H, m), 7.94 (1H, m), 8.80 (1H, m), 9.54 (1H, bs).
Example 99
Preparation of 3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-1H-benzoimidazol-5-yl}-N-
hydroxy-acrylamide (126)
[0440] The titled compound (126) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. HPLC purity: 100%; \R = 1.01 min.
LC-MS m/z: 331 ([M+H]+). 1H NMR (DMSO-cf6) 8 0.88 (9H, s), 1.44 (2H, m), 2.92 (2H, m),

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3.50 (2H, m), 4.66 (2H, m), 6.54 (1H, d), 7.58 (2H, m), 7.82 (1H, m), 7.90 (1H, m), 8.74
(1H, m).
Example 100
Preparation of N-Hydroxy-3-{1-[2-(methyl-pent-4-enyl-amino)-ethyl]-1H-
benzoimidazol-5-yl}-acrylamide(127)
[0441] The titled compound (127) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. HPLC purity: 100%; fo = 0.92 min.
LC-MS m/z: 329 ([M+H]+). 1H NMR (DMSO-cfe) 6 1.17 (2H, 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), 6.57 (1H, d), 7.60
(1H, d), 7.69 (1H, m), 7.90 (1H, m), 7.97 (1H, m), 8.92 (1H, m), 10.29 (1H, bs).
Example 101
Preparation of 3-(1-{2-[(3,3-Dimethyl-butyl)-propyl-amino]-ethyl}-1 H-benzoimidazoi-
5-yl)-N-hydroxy-acrylamide (128)
[0442] The titled compound (128) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. HPLC purity: 99.0%; tR=1.18 min.
LC-MS m/z: 373 ([M+H]+). 1H NMR (DMSC-ofe) 8 0.88 (12H, m), 1.51 (2H, m), 1.64 (2H,
m), 3.10 (4H, m), 3.63 (2H, m), 4.76 (2H, m), 6.54 (1H, d), 7.65 (2H, m), 7.80 (1H, m),
7.94 (1H, m), 8.83 (1H, m), 9.93 (1H, bs).
Example 102
Preparation of 3-{1-[2-(3,3-Dimethy!-butylamino)-ethyl]-2-propyl-1 H-benzoimidazol-
5-yl}-N-hydroxy-acrylamide (130)
[0443] Step 1: Cyclization

[0444] To the starting material (Illa2, 3.34 g, 12.6 mmol) in 20% AcOH in MeOH (33 mL,
0.2 M) was added butyraldehyde (1.7 mL, 18.9 mmol) followed by zinc powder (4.12 g, 63
mmol). The resulting mixture was heat up to 50 °C and stirred at this temperature for 30
minutes. The completion of reaction was monitored by HPLC and LCMS. The solvent was
then evaporated to dryness and the crude was dissolved with ethyl acetate, subsequently
saturated aqueous sodium carbonate was added till pH = 9 and the mixture was

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centrifuged spin at 9000 rpm for 10 min. The liquid was decanted and solid was rinsed
with ethyl acetate (sonicated). The liquid was extracted with ethyl acetate and then purifed
by flash chromatography (silica, 3% MeOH in DCM) to give 3-[1-(2-Amino-ethyl)-2-propyl-
1H-benzoimidazol-5-yl]-acrylic acid methyl ester. Yield = 25 %, LC-MS m/z: 288 ([M+H]+).
[0445] Step 2: Reductive-amination

[0446] To 3-[1-(2-Amino-ethyl)-2-propyl-1H-benzoimidazol-5-yl]-acrylic acid methyl ester
(1.2 g, 4.2 mmol) in MeOH (40 mL) was added 3,3-Dimethyl-butyraldehyde (0.524 ml_, 4.2
mmol). The resulting mixture was stirred at rt for 2 hours prior to the addition of acetic acid
(2 mL) and sodium cyanoborohydride (0.395 g, 6.3 mmol) and the reaction was stirred at
rt for another 30 minutes. Solvent was removed and the residual was dissolved in DCM
upon which was washed with aqueous sodium bicarbonate, water and brine. The
combined organic layer, after workup, was purified by flash chromatography (silica, 4%
MeOH in DCM). LC-MS m/z: 372 ([M+H]+).
[0447] Step 3: hydroxamic acid formation.
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 m/z: 373 ([M+H]+). 1H NMR (CD3OD) 5 7.89
(d, 1H, J = 8.6 Hz), 7.81 (s, 1H), 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 - 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). Dihydrochloride salt of 130 was prepared according to the procedures described in
Example 50, Step 4 and 5, by using appropriate starting materials. HPLC purity: 98.1 %;
LC-MS m/z: 373 ([M+H]+). 1H NMR (DMSO-d6) 8 10.89 (1H, br s), 9.77 (2H, b, -NH2+-),
8.12 (1H, d, J = 8.6 Hz), 7.97 (1H, s), 7.78 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 15.8 Hz),
6.64 (1H, d, J = 15.8 Hz), 4.88 (2H, t, J = 5.8 Hz), 3.41 (2H, m), 3.26 (2H, t J = 76 Hz),
2.91 (2H, m), 1.90 (2H, sextet, J = 7.6 Hz), 1.56 (2H, m), 1.05 (3H, t, J = 7.3 Hz), 0.88
(9H, s); 13C NMR (DMSO-cfe) 5 162.4, 155.9, 137.4 (CH), 132.8, 132.4, 131.8 (br), 124.6

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(CH), 120.2 (CH), 113.2 (CH), 113.0 (CH), 44.9, 44.0, 41.1, 38.6, 29.4 (Cq), 28.9, 27.1,
19.9, 13.5.
Example 103
Preparation of 3-[1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-(2,2-dimethyl-propyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide(131)
[0447] 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]+). 1H NMR (CD3OD) 5 7.89 (s, 1H), 7.85 (d, 1H, J = 8.5 Hz), 7.77 (d, 1H, J =
8.7 Hz), 7.63 (d, 1H, J = 15.8 Hz), 6.55 (d, 1H, J = 15.7 Hz), 4.91-4.81 (m, 2H), 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)-amino]-ethyl}-2-(2,2-dimethyl-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide (132)
[0448] 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+Hf). 1H NMR (CD3OD) 8 7.93 (s, 1H), 7.88 (d, 1H, J = 8.5 Hz), 7.80 (d, 1H, J =
8.7 Hz), 7.72 (d, 1H, J= 15.8 Hz), 6.59 (d, 1H, J= 15.8 Hz), 5.00 (t, 2H, J = 6.5 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).
Example 105
Preparation of 3-{1-[2-(2,2-Dimethyi-propyIamino)-ethyl]-1 H-benzoimidazol-5-yl}-N-
hydroxy-acrylamide (133)
[0449] The titled compound (133) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. HPLC purity: 99.9%; LC-MS m/z:
317([M+H]+). 1H NMR (CD3OD) 8 8.82 (s, 1H), 7,94 (s, 1H), 7,83 (d, 1H, •/= 8.5 Hz), 7.75
(d, 1H, 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).
Example 106
Preparation of 3-(1-{2-[(2,2-Dimethyl-propyl)-propyl-amino]-ethyl}-1 H-
benzoimidazol-5-yl)-N-hydroxy-acrylamide(134)
[0450] The titled compound (134) was prepared according to the procedures described in
Example 76, by using appropriate starting materials. HPLC purity: 99.9%; LCMS m/z: 359
([M+H]+). 1H NMR (CD3OD) 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),

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3.74 (t, 2H = 7.0 Hz), 3.32 - 3.20 (m, 4H), 1.85 - 1.82 (m, 2H), 1.03 (s, 9H), 0.92 (t, 3H, J
= 7.1 Hz).
Example 107
Preparation of 3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethy!-1H-benzoimidazoJ-5-
yl}-N-hydroxy-acrylamide (135)
[0451] The titled compound (135) was prepared according to the procedures described in
Example 102, by using appropriate starting materials. HPLC purity: 94.3%; LCMS m/z:
359 ([M+H]+). 1H NMR (CD3OD) S 7.69 (d, 1H, J= 8.0 Hz), 7.54 (s, 1H), 7.53 (d, 1H, J =
9.8 Hz), 6.89 (d, 1H, 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).
Example 108
Preparation of 3-[1-(2-Diethylamino-ethyl)-2-propylamino-1 H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (105)
[0452] The titled compound (105) was made according to the following synthetic scheme.

[0453] HPLC purity: 100%. 1H-NMR (DMSO-cfe) 8 0.97 (3H, t, J = 7.32 Hz), 1.22 (6H, m),
1.68 (2H, m), 3.09-3.60 (10H, m), 6.47 (1H, d, J = 15.80 Hz), 7.52-7.64 (4H, m), 9.03 (2H,
bs), 10.10 (1H,s), 10.81 (1H,s).
Example 109
Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-propylamino-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (115)
[0454] The titled compound (115) was made by using method analogous to compound
(105).HPLC purity: 97%. 1H-NMR (DMSO-cfe) S 0.97 (3H, t, J = 7.28), 1.15 (6H, s), 1.69

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(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).
Example 110
Preparation of 3-(1 -{2-[(3,3-Dimethyl-butyl)-methyl-amino]-ethyl}-2-propyl-1 H-
benzoimidazol-5-yl)-N-hydroxy-acrylamide(136)
[0455] The titled compound (136) was prepared by reacting of 3-{1-[2-(3,3-dimethyl-
butylamino)-ethyl]-2-propyl-1 H-benzoimidazol-5-yl}-N-hydroxy-acrylamide (130) with
formaldehyde (10 eq.) and NaBH3CN (3 eq.) in MeOH. TFA salt of 136: HPLC purity at
254 nm, 99.8%; LCMS (ESI) m/z: 387 ([M + H]+). 1H NMR (CD3OD) 5 7.85 (1H, d, J = 8.5
Hz), 7.84 (1H, s), 7.74 (1H,d, J = 8.3 Hz), 7.63 (1H, d, J = 15.8 Hz), 6.52 (1H, d, J = 15.5
Hz), 4.81 (2H, m), 3.62 (2H, br t -like), 3.20 (2H, m), 3.13 (2H, t, J = 7.3 Hz), 3.01 (3H, s),
1.93 (2H, m), 1.63 (2H, m), 1.10 (3H, t, J = 7.2 Hz), 0.93 (9H, s).
Example 111
Preparation of 3-(1-{2-[(3,3-Dimethyl-butyl)-(2,2f2-trifluoro-ethyl)-amino]-ethyl}-1H-
benzoimidazol-5-yl)-N-hydroxy-acrylamide (137)
[0456] The titled compound (137) was prepared as TFA salt according to the
procedures described as below.

Stepl
[0457] To a solution of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (la, 3 g, 12
mmol) in dioxane (100 mL) was added 2-aminoethanol (2.2 mL, 37 mmol) and
triethylamine (3.4 mL, 25 mmol). The reaction mixture was heated at 90 °C for 48 hours
where all the starting material has been converted to the product. Solvent was evaporated

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resulting in compound 137-1. The solid was washed with water (x 3) and dried over
Na2S04. Yield: 88%. Purity at 254 nm: 98 %, tR = 2.4 min. LCMS m/z: 267 ([M+H]+).
Step 2
[0458] To a solution of 3-[4-(2-hydroxy-ethylamino)-3-nitro-phenyl]-acrylic acid methyl
ester (137-1, 0.200 g, 0.75 mmol) in MeOH (3.7 mL) was added HC02H (0.226 mL, 6
mmol) and SnCl2.2H20 (0.982 g, 3.7 mmol). The reaction mixture was allowed to stir at 50
°C for 16 hours. Solvent was removed and the residue was basified and then extracted
with ethyl acetate. The unpurified crude was used for the next step. LCMS m/z: 247
([M+HD.
Step3
[0459] To a solution of crude 3-[1-(2-hydroxy-ethyl)-1H-benzoimidazol-5-yl]-acrylic acid
methyl ester (137-2, 0.120 g, 0.49 mmol) in CH2CI2 (3.5 mL) was added PPh3 (0.383 g,
1.46 mmol) and CBr4 (0.485 g, 1.46 mmol). The reaction mixture was stjrred at room
temperature for 30 minutes and then washed with water (x2) and brine (x1), dried over
Na2S04 and concentrated. Compound 137-3 was purified by reverse phase preparative
HPLC. Yield: 80%. Purity at 254 nm: 99.9 %, t„ = 1.2 min. LCMS m/z: 309/311 ([M+H]+).
Step 4
[0460] To a solution of 3-[1-(2-bromo-ethyl)-1H-benzoimidazol-5-yl]-acrylic acid methyl
ester (137-3, 72 mg, 0.23 mmol) in anhydrous N, N -dimethylformamide (2.5 mL) in a 4
mL vial was added 2,2,2-trifluoroethylamine (185 \x), 2.32 mmol) and triethylamine (321 \x\,
2.32 mmol). The reaction mixture was stirred at 80 °C for 16 hours. Ethyl acetate and
water was added to the reaction mixture. The aqueous layer was extracted with ethyl
acetate (x2). Then, the combined organic layer was washed with water (x1) and brine
(x1). The unpurified crude was used for the next step of reaction. LCMS m/z: 328
([M+H]+).
Step 5
[0461] The above crude 3-{1-[2-(2,2,2-trifluoroethylamino)ethyl]-1H-benzoimldazol-5-yl}-
acrylic acid methyl ester (137-4) was dissolved in MeOH (2 mL) and AcOH (0.5 mL).
Then, 3,3-dimethylbutyraldehyde (42 u,l, 0.336 mmol) was added and the resulting mixture
was stirred for 2 hours prior to the addition of NaCNBH3 (21 mg, 0.336 mmol). The
reaction mixture was stirred for 30 minutes. Solvent was removed and the residue was re-
dissolved in CH2CI2 and washed w'rth sat. NaHC03 (x2), water (x2) and brine (x1). The
crude 137-5: LCMS m/z: 412 ([M+H]+).

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Step 6
[0462] The crude 137-5 was then converted to the tilted compound (137) as TFA salt
according to the procedures described in Example 1. HPLC purity at 254 nm: 99.9 %, k =
2.4 min. LCMS m/z: 413 ([M+Hf). 1H NMR (CD3OD) 5 0.79 (9H, s), 1.04 - 1.08 (2H, m),
2.60 - 2.64 (2H, m), 3.11 (2H, t, J = 5.4 Hz), 3.20 (2H, q, J = 9.7 Hz), 4.54 (2H, t, J = 5.3
Hz), 6.61 (1H, d, J = 15.7 Hz), 7.74 (1H, d, J = 15.7 Hz), 7.85 - 7.96 (2H, m), 7.99 (1H, s),
9.11 (1H,s).
Example 112
Preparation of 3-(1-{2-[Butyl-(2,2,2-trifluoro-ethyl)-amino]-ethyl}-1H-benzoimidazol-
5-yl)-N-hydroxy-acrylamide (138)
[0463] The titled compound (138) was prepared according to the procedures described
in Example 111, by using appropriate starting materials.

[0464] HPLC purity at 254 nm: 99.9 %, fo = 2.8 min. LCMS m/z: 385 ([M+H]+). 1H NMR
(CD3OD) 8 0.79 (3H, t, J =7.2 Hz), 1.15 - 1.24 (4H, m), 2.64 (2H, t, J = 6.9 Hz), 3.12 (2H,
t, J = 5.5 Hz), 3.20 (2H, q, J = 9.7 Hz), 4.55 (2H, t, J = 5.4 Hz), 6.60 (1H, d, J = 15.7 Hz),
7.74 (1H, d, J = 15.8 Hz), 7.83 - 7.92 (2H, m), 7.98 (1H, s), 9.07 (1H, s).
[0465] The following compounds are representative examples prepared by methods
disclosed or analogous to those disclosed in above Examples 1-112:


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BIOLOGICAL TESTING AND ENZYME ASSAYS
Recombinant GST-HDAC1 Protein expression and purification
[0466] Human cDNA library was prepared using cultured SW620 cells. Amplification of
human HDAC1 coding region from this cDNA library was cloned separately into the
baculovirus expression pQEST20 vector (GATEWAY Cloning Technology, Invitrogen Re
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 108 PFU/ml.
[0467] 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 was eluted by
elution buffer containing 50 mM Tris, pH8.0, 150mM NaCI, 1% Triton X-100 and 10mM or
20mM reduced Glutathione. The purified GST-HDAC1 protein was dialyzed with HDAC
storage buffer containing 10mM Tris, pH7.5,100mM NaCI and 3mM MgCI2. 20% Glycerol
was added to purified GST-HDAC1 protein before storage at -80°C.
In vitro HDAC assay for determination of iC50 values
[0468] The assay has been carried out in 96 well format and the BIOMOL fluorescent-
based HDAC activity assay has been applied. The reaction composed of assay buffer,
containing 25 mM Tris pH 7.5, 137 mM NaCI, 2.7 mM KCI, 1 mM MgCl2, 1 mg/ml BSA,

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tested compounds, an appropriate concentration of HDAC1 enzyme, 500 uM Flur de lys
generic substrate for HDAC1 enzyme and subsequently was incubated at room
temperature for 2 h. Flur de lys Developer was added and the reaction was incubated for
10 min. Briefly, deacetylation of the substrate sensitizes it to the developer, which then
generates a fluorophore. The fluorophore is excited with 360 nm light and the emitted
light (460 nm) is detected on a fluorometric plate reader (Tecan Ultra Microplate detection
system, Tecan Group Ltd.).
[0469] The analytical software, Prism 4.0 (GraphPad Software Inc) has been used to
generate IC50 from a series of data. ICso is defined as the concentration of compound
required for 50% inhibition of HDAC enzyme activity.
[0470] The HDAC enzyme inhibition results of representative compounds are shown in
Table 1 (unit is micromolar).

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[0471] Table 1. HDAC1 enzyme activity IC50 (unit is nrticromolar).

Compound IC50 (MM) Compound IC5o (MM) Compound IC50(HM)
1 0.042 47 0.21 93 0.23
2 0.38 48 0.43 94 0.064
3 0.15 49 0.11 95 0.052
4 0.12 50 0.036 96 0.080
5 0.17 51 0.066 97 0.10
6 0.18 52 0.025 98 0.32
7 0.091 53 0.10 99 0.12
8 0.052 54 0.048 100 0.19
9 0.21 55 0.037 101 0.08
10 0.14 56 0.029 102 0.54
11 0.070 57 0.090 103 0.10
12 0.064 58 0.030 104 0.41
13 0.42 59 0.077 105 0.13
14 0.077 60 0.10 107 0.074
15 0.085 61 0.070 108 0.043
17 0.13 62 0.054 109 0.048
19 0.064 63 0.051 110 0.044
20 0.26 64 0.10 111 0.029
21 0.38 65 0.078 112 0.12
22 0.064 66 0.34 113 0.016
23 0.045 68 0.034 114 0.063
24 0.51 70 0.068 116 0.10
25 0.23 71 0.040 117 0.19
26 0.040 72 0.017 118 0.48
27 0.23 73 0.026 119 0.18
28 0.021 74 0.028 120 0.11
29 0.13 75 0.050 121 0.079
30 0.021 76 0.018 122 0.037
31 0.045 77 0.026 123 0.027
32 0.060 78 0.044 124 0.085
33 0.23 79 0.040 125 0.16
34 0.88 80 0.040 126 0.042
35 0.082 81 0.12 127 0.078
36 0.096 82 0.10 128 0.031

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Compound IC50 (uM) Compound IC50 (uM) Compound IC50 (uM)
37 0.091 83 0.19 129 0.77
38 0.56 84 0.063 130 0.036
39 0.024 85 0.11 131 0.066
40 0.027 86 0.16 133 0.072
41 0.062 87 0.10 134 0.22
42 0.15 88 0.047 135 0.074
43 0.33 89 0.080 136 0.053
44 0.054 90 0.51 137 0.093
45 0.053 91 0.060 138 0.10
46 0.049 92 0.050
Cell-based proliferation assay for determination of G!sn values
[0472] Human colon cancer cell lines (Colo205, HCT116), Ovarian cancer cell line
(A2780), Hepatoma cell line (HEP3B), Prostate cancer cell line (PC3) were obtained from
ATCC or ECACC. Colo205 cells were cultivated in RPMI 1640 containing 2 mM L-
Glutamine, 5%FBS, 1.0 mM Na Pyruvate, 1 U/ml of penicillin and 1 \ig 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 \ig of streptomycin. A2780 cells were
cultivated in RPMI 1640 containing 2 mM L-Glutamine, 5% FBS, 1 U/ml of penicillin and 1
|4.g of streptomycin. HEP3B cells were cultivated in EMEM containing 2 mM L-giutamine,
5%FBS, 1% non essential amino acid, 1mM Na Pyruvate, 1 U/ml of penicillin and 1 \ig of
streptomycin. PC3 cells were cultivated in F12K, 2 mM L-glutamine, 5%FBS, 1 U/ml of
penicillin and 1 ng of streptomycin. PC3, Colo205, and HCT116 cells were seeded in 96-
wells plate at 1000, 5000 and 6000 cells per well respectively. A2780 and HEP3B cells
were seeded in 96-wells plate at 4000 cells per well respectively. The plates were
incubated at 37°C, 5% C02, for 24 h. Cells were treated with compounds at various
concentrations for 96 h. Cell growth was then monitored using CyQUANTocell proliferation
assay (Invitrogen Re Ltd). Dose response curves were plotted to determine Gl50 values
for the compounds using XL-fit (ID Business Solution, Emeryville, CA). Gl50 is defined as
the concentration of compound required for 50% inhibition of cell growth.
[0473] The cellular or growth inhibition activity results of representative compounds are
shown in Table 2 and 3. The data indicated that the compounds of this invention are
active in the inhibition of tumour cell growth.

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[0474] Table 2. Cellular or Growth inhibition Activity in Colo205 cells (unit is
micromolar)

Compound GUo (nM) Compound Glso (n-IWI) Compound Gl50 (VM)
1 0.50 47 3.6 93 2.14
2 2.12 48 0.78 94 0.60
3 2.22 49 1.75 95 0.57
4 2.62 50 0.17 96 0.70
5 2.58 51 0.26 97 0.67
6 2.69 52 0.21 99 1.89
7 0.81 53 1.05 100 2.25
8 0.56 54 0.46 101 2.44
9 1.87 55 0.91 102 2.08
10 1.77 56 0.90 103 0.48
11 0.48 57 0.65 104 1.99
12 0.51 58 0.38 105 1.77
13 5.5 59 2.28 107 0.63
14 0.63 60 2.48 108 0.44
15 1.50 61 1.32 109 0.49
17 1.19 62 2.60 110 1.74
19 0.53 63 0.54 111 0.21
20 2.66 64 0.73 112 0.88
21 2.51 65 0.56 113 0.61
22 0.75 66 8.8 114 0.72
23 0.19 68 0.52 116 0.70
24 2.99 70 7.0 117 1.80
25 2.38 71 0.24 118 1.88
26 0.37 72 0.16 119 0.77
27 1.42 73 0.23 120 0.49
28 0.18 74 0.55 121 0.49
29 1.92 75 1.20 122 0.15
30 0.31 76 0.29 123 0.15
31 0.42 77 0.67 124 0.54
32 0.74 78 0.54 125 0.68
33 2.11 79 0.45 126 0.42
34 4.4 80 1.37 127 0.34

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Compound Glso (nM) Compound Gi50 (m Compound Glso (nM)
35 0.66 81 1.00 128 0.14
36 0.86 82 1.23 129 3.9
37 1.09 83 4.9 130 0.15
38 1.94 84 1.03 131 0.33
39 0.23 85 1.52 133 0.56
40 0.16 86 2.08 134 2.30
41 0.92 87 1.07 135 0.26
42 0.98 88 0.55 136 0.39
43 1.86 89 0.87 137 1.97
44 0.87 90 8.1 138 1.96
45 0.54 91 2.40
46 0.48 92 1.82
[0475] Table 3. Cellular or Growth Inhibition Activity in Various Cancer Cell Lines

Cell lines
Compound HCT116 A2780 PC3 HEP3B
1 ++ +++ +++ ++
7 + + ++
8 ++ ++ +++ +
22 + +++ +++
23 ++ +++ +++
30 ++ +++ +++
40 +++ +++ +++
44 + ++ +++
46 +++ +++ +++ ++
50 +++ +++ +++
52 +++ +++ +++
58 +++ +++ +++ +++
71 +++ +++ +++
111 +++
130 +++ +++ +++
("+++" for Gl50 5 1.0 nM to 5.0 }M)

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Histone H3 acetylation assay
[0476] 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 x105 cells,
were seeded in the previously described medium, cultivated for 24 h and subsequently
treated with HDAC inhibitory agents and a positive control at a final concentration of 10
uM. After 24 h, cells were harvested and lysed according to the instruction from Sigma
Mammalian Cell Lysis Kit. The protein concentration was quantified using BCA method
(Sigma Pte Ltd). The protein lysate was separated using 4-12% bis-tris SDS-PAGE gel
(Invitrogen Re Ltd) and was transferred onto PVDF membrane (BioRad Re 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 waaused
according to the manufacturing instruction (Pierce Pte Ltd). After removing the detection
antibody from the membrane, an enhanced chemiluminescent substrate for detection of
HRP (Pierce Pte Ltd) was added onto the membrane. After removing the substrate, the
membrane was exposed to an X-ray film (Kodak) for 1 sec - 20 mins. 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 Bioimaging software (UVP, Inc,
Upland, CA). The values were then normalized against the density of actin in the
corresponding samples to obtain the expression of the protein.
[0477] The results of immuno-blotting assay using acetylated histone H3 antibody are
shown in Table 4 for representative compounds of this invention.

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[0478] Table 4

Compound Histone
Acetyl ation
activities
(Histone-3) Compound Histone
Acetylation
activities
(Histone-3) Compound Histone
Acetylation
activities
(Histone-3)
1 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 4fr 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
[0479] 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
[0480] 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.
[0481] Pooled human liver microsome (HLM was purchased from BD Gentest (BD
BioSciences). The incubations consisted of test compound (5 uM) or control compound
(Verapamil), NADPH-generating system solution A (25 mM NADP+, 66 mM glucose-6-
phosphate, 66 mM MgCI2 in H20), NADPH-generating system solution B (40 U/ml
glucose-6-phosphate dehydrogenase in 5 mM sodium citrate) and 1.0 mg/ml microsomal
protein, respectively, in 100 mM potassium phosphate buffer (pH 7.4). Samples were
incubated for 0, 5, 15, 30, 45, 60min. Reaction was terminated with ice-cold 80%
acetonitrile and 20% DMSO. Samples were subsequently centrifuged at 4°C for 15 min at
2,000 rpm. 100 uL of the supernatant was transferred to the LC-MS Plate for analysis.
Before quantitative analysis, the compound was tuned in LC/MS machine to get the

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optimized MS condition. Liquid chromatography was performed on a Luna C18 column
(Phenomenex U.S.A, Torrance, CA) (2x50mm, 5 uM). % of the compound remaining (by
area) at each time point is calculated with respect to time 0 min. Plot %remaining against
time (min) to obtain the curve and use the Prism software to obtain the t1/2. These are
5 demonstrated in table 5.
[0482] Table 5.

Compound ti/2 (min) Compound tn/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
[0483] The measured in vitro t1/2>30 mins for the above compounds signifies that the
contribution towards the clearance of the compound due to metabolism is expected to be
low in the in vivo situation and thus help in yielding longer half-life and increased exposure
of the compounds.
[0484] The above results demonstrated the compounds of formula (I) were metabolically
stable in human liver microsome assay. Together with the appropriate physicochemical
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.
In vivo Pharmacokinetic (PK) studies
[0485] Compound was dissolved in appropriate solution (saline or DMA and Cremaphor
in saline) at 1 mg/ml for intravenous (IV) administration, or in 0.5% methyl cellulose, 0.1%
Tween 80 in water at 5 mg/ml for oral administration. Mice were randomized according to
body weight, grouped three per time point. Mice were administered single IV dose (10
mg/kg) 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 was sacrificed by
overdose COz and blood samples were collected by cardiac puncture. The blood samples
were centrifuged immediately for 10 min at 3000 rpm to separate plasma, and plasma was
kept frozen at -80 °C until analysis by LC/MS/MS. Before sample analysis, the method

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was developed for LC/MS/MS assay. The method was 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 to determine the
accuracy and precision. The extracted QC samples were compared to unextracted
samples to determine the extraction efficiency of the analyte. LLOQ was determined by
using triplicate samples of 1ng/mL and 2ng/mL to obtain accuracy and precision at the low
end. Samples were analysed using the validated method. Data was analyzed by the non-
compartmental model using WinNolin 4.0 software (Pharsight, Mountain View, CA, USA).
The mean values for the plasma compound concentration-time profiles were used in
mouse PK study.
[0486] The PK parameter AUC 0-iast providing the information on the overall exposure of
the drug in vivo is one of the key PK/PD parameters that helps in predicting the efficacy of
an anti-cancer compound. The higher the AUC value, the better will be the in vivo efficacy
of the compound at similar in vitro potency. Pharmacokinetic data of selected compounds
in Table 5 were shown in Table 6 below.
[0487] Table 6. Representative pharmacokinetic data [compounds were in
hydrochloric acid salt form (2HCI), dosed at 50 mg/kg, p.o.]

Compound AUCo-iast (ng.h/ml)
1 1868
8 1836
130 1050
[0488] 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 solubility, were able to
yield adequate pharmacological exposure and effect in the animal when administrated
orally.
In vivo antineoplastic (or anti-tumor) effect of HDAC inhibiting agents:
[0489] The efficacy of the compounds of the invention can then be determined using in
vivo animal xenograft studies. The animal xenograft model is one of the most commonly
used in vivo cancer models.

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[0490] In these studies Female athymic nude mice (Harlan), 12-14 weeks of age would
be implanted subcutaneously in the flank with 5 x 106 cells of HCT116 human colon tumor
cells, or with 5 x 106 cells of A2780 human ovarian tumor cells, or with 5 x 106 cells of PC3
prostate cancer cells. When the tumor reaches the size 100 mm3, the 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, intravenously or orally daily for 14-21 days. The dosing volume will be
0.01 ml/g body weight. Paclitaxol, used as positive control, will be prepared for intravenous
administration in an appropriate vehicle. The dosing volume for Paclitaxol will be 0.01
ml/g body weight. Tumor volume will be calculated every second day or twice-a-week of
post injection using the formula: Volume (mm3) = (w2x l)/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 group when measured
shall be accumulated. The result will therefore indicate that compounds of this invention
are efficacious in treating a proliferative disorder/disease such as cancer.
[0491] The details of specific embodiments described in this invention are not to be
construed as limitations. Various equivalents and modifications may be made without
departing from the essence and scope of this invention, and it is understood that such
equivalent embodiments are part of this invention.

162
What is claimed is:
A compound of the formula (I):

wherein
R1 is an optionally substituted heteroaryl group, an optionally substituted
heterocycloalkyl group or a group of formula:
-(CR20R21)m-(CR22R23)n-(CR24R25)o-NR26R27;
R2 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl,
cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkoxyalkyl, R11S(0)R13-, R11S(0)2R13-,
R11C(0)N(R12)R13-, R11S02N(R12)R13-, R11N(R12)C(0)R13-, R11N(R12)S02R13-,
R11N(R12)C(0)N(R12)R13- and acyl, each of which may be optionally substituted;
R3 is selected from the group consisting of H, CT -C6 alkyl, and acyl, each of
which may be optionally substituted;
X and Y are the same or different and are independently selected from the group
consisting of: H, halogen, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl,
alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy,
heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl,
heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino,
sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, -COOH
-C(0)OR5, -COR5, -SH, -SR6, -OR6 acyl and -NR7R8, each of which may be optionally
substituted;
each R4 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl,
haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,

163
heterocycloalkyialkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally
substituted;
each R5 is independently selected from the group consisting of: H, alkyl, alkenyl,
alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkyialkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally
substituted;
each R6 is independently selected from the group consisting of: H, alkyl, alkenyl,
alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkyialkyl, arylalkyl, heteroarylalkyl and acyl; each of which may be optionally
substituted;
each R7 and R8 is independently selected from the group consisting of: H, alkyl,
alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkyialkyl, arylalkyl, heteroarylalkyl and acyl, each of which
may be optionally substituted;
each R11 and R12 is independently selected from the group consisting of H, alkyl,
alkenyl, and alkynyl, each of which may be optionally substituted;
each R13 is a bond or is independently selected from the group consisting of:
alkyl, alkenyl, and alkynyl, each of which may be optionally substituted;
each R20, R21, R22, R23, R24 and R25 is independently selected from the group
consisting of: H, halogen, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyialkyl, arylalkyl,
heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,
heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,
alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy,
aryloxy, arylalkyloxy, phenoxy, benzyloxy heteroaryloxy, amino, alkylamino, acylamino,
aminoalkyl, arylamino, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl,
aminosulfonyl, arylsulfonyl, arylsulfinyl -COOH, -C(0)OR5, -COR5, -SH, -SR6, -OR6 and
acyl, each of which may be optionally substituted; or
R20 and R21 when taken together may form a group of formula =0 or =S, and/or
R22 and R23 when taken together may form a group of formula =0 or =S, and/or

164
Rz and R25 when taken together may form a group of formula =0 or =S;
each R26 and R27 is independently selected from the group consisting of is
selected 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, heterocycloalkyloxy, aryloxy, arylalkyloxy, heteroaryloxy, amino,
alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH,
alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl,
arylsulfinyl, aminosulfonyl, SR5, and acyl, each of which may be optionally substituted,
or R26 and R27 when taken together with the nitrogen atom to which they are attached form
an optionally substituted heterocycloalkyl group;
Z is selected from the group consisting of -CH2-, -CH2CH2-, -CH=CH-, C3-C6
alkylene, C3-C6 alkenylene, C3-C6 alkynylene, C3-C6 cycloalkyl, unsubstituted or
substituted with one or more substituents independently selected from the group
consisting of CVC4 alkyl;
m, n and o are integers independently selected from the group consisting of 0, 1,
2, 3 and 4;
or a pharmaceutical^ acceptable salt or prodrug thereof.
2. A compound according to claim 1 wherein Z is -CH=CH-, and is attached at ring
position 5.
3. A compound according to claim 1 or 2 wherein R3 = H, R4 = H, X = H and Y = H.
4. A compound according to any one of claims 1 to 3 wherein the sum of m+n+o is
2 or 3.
5. A compound according to any one of claims 1 to 4 wherein R1 is selected from
the group consisting of:
-£CR20R21)2-NR26R27;
-(CR22R23)2-NR26R27;

165
-(CR24R25)2-NR26R27;
-(CR20R21)-(CR22R23)-NR26R27;
-(CR20R21)(CR24R25)-NR26R27;
-(CR22R23)-(CR24R25)-NR26R27;
-(CR20R21)3-NR26R27;
-(CR22R23)3-NR26R27;
-(CR24R25)3-NR26R27;
-(CR20R21)2-(CR22R23)-NR26R27;
-(CR20R21)2-(CR24R25)-NR26R27;
-(CR20R21)-(CR22R23)2-NR26R27;
-(CR22R23)2-(CR24R25)-NR26R27;
-(CR20R21)-(CR24R25)2-NR26R27;
-(CR22R23)-(CR24R25)2-NR26R27;and
-(CR20R21)-(CR22R23)-(CR24R25)-NR26R27.
6. A compound according to any one of claims 1 to 5 wherein the compound is
selected from the group consisting of:

and


166
7. A compound according to any one of claims 1 to 6 wherein R20, R21, R22, R23, R24
and R25 are independently selected from the group consisting of H, alkyl, alkenyl and
alkynyl.
8. A compound according to any one of claims 1 to 7 wherein R20, R21 R22, R23, R24
and R25 are independently selected from the group consisting of H and alkyl.
9. A compound according to any one of claims 1 to 8 wherein R20 and R21 are H.
10. A compound according to any one of claims 1 to 9 wherein R22 and R23 are
methyl.
11. A compound according to any one of claims 1 to 10 wherein R24 and R25 are H.
12. A compound according to any one of claims 1 to 11 wherein R26 and R27 are
independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, alkoxyalkyl,
and acyl.
13. A compound according to any one of claims 1 to 12 wherein R26 and R27 are
independently selected from the group consisting of H, methyl, ethyl, isopropyl, propyl,
butyl, isobutyl, pentyl, hexyl, heptyl, acetyl and 2-methoxy-ethyl.
14. A compound according to any one of claims 1 to 6 wherein R1 is a group of
formula:


167


168

15. A compound according to any one of claims 1 to 14 wherein R2 is selected from
the group consisting of H, alkyl, cycloalkyl, heteroalkyl, alkenyl, alkynyl, alkoxyalkyl and
cycloalkylalkyl each of which may be unsubstituted or substituted.

169
16. A compound according to any one of claims 1 to 15 wherein R2 is selected from
the group consisting of: H; methyl; ethoxymethyl; [Bicylco[2.2.1]2-ylmethyl; Adamantan-2-
ylmethyl; 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; Bicyclo[2.2.1]hept-5-en-2yl; hexyl; hex-3-enyl; octyl; non-3-
enyl; non-6-enyl; 2-methoxy-nonyl, 2-phenyl-cyclopropyl; cyclohexyl;
(CH3)3CCH2CONH(CH2)2-; (CH3)3CCONH(CH2)2-; (CH3)3CCONH(CH2)- and
CH3(CH2)2CONH(CH2)-.
17. A compound according to any one of claims 1 to 16 wherein the optional
substituent is selected from the group consisting of: halogen, =0, =S, -CN, -N02, -CF3, -
OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl,
cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl,
alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy,
cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy,
arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl,
arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky,
-COOH, -COR5, -C(0)OR5, -SH, -SR5, -OR6and acyl.
18. 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-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
isopropyl-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[2-Butyl-1-(3-dimethylamino-2,2-dimethyl-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide

170








3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2-
methylsulfanyl-ethyl)-1 H-benzoim idazol-5-yl]-N-
hyd roxy-acryla m ide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
ethoxymethyl-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1 -(2-Diethylamino-ethyl)-2-isobutyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-Butyl-1-(2-diethylamino-ethyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-But-3-ynyl-1-(3-dimethylamino-2,2-dimethyl-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[2-But-3-enyl-1-(3-dimethylamino-2,2-
dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide

171



3-[2-But-3-eny!-1 -(2-diethylamino-ethyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-But-3-ynyl-1-(2-diethylamino-ethyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide






3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide
3-[1-(2-Diethylamino-ethyl)-2-(3,3,3-trifluoro-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Diethylamino-ethyl)-2-ethoxymethyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
methyl-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Diethylamino-ethyl)-2-(2,2-dimethyl-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide

172








N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-
(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-
acrylamide
3-[2-(2,2-Dimethyl-propyl)-1-(2-isopropylamino-
ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Diisopropylamino-ethyl)-2-(2,2-dimethyl-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1 -(2-Diisopropylamino-ethyl)-2-isobutyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-
N-hydroxy-acrylamide
3-[2-Cyclohexyl-1-(3-dimethylamino-2,2-
dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide

173









3-[2-Bicyclo[2.2.1]hept-5-en-2-yl-1-(3-
dimethylamino-2,2-dimethyl-propyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1 -(2-Diethylamino-ethyl)-2-hex-3-enyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1 -(2-Diisopropylamino-ethyl)-2-hex-3-enyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-Hex-3-enyl-1-(2-isopropylamino-ethyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-Hex-3-enyl-1 -(3-isopropylamino-propyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1 -(2-Ethylamino-ethyl)-2-hex-3-enyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1 -(2-Diethylamino-ethyl)-2-hexyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-
(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-
acrylamide

174









3-[2-(2,2-Dimethyl-propyl)-1-(3-isopropylamino-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Diisopropylamino-ethyl)-2-(3,3,3-trifluoro-
propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
N-Hydroxy-3-[2-isobutyl-1-(2-isopropylamino-
ethyl)-1H-benzoimidazol-5-yl]-acrylamide
3-[2-(2,2-Dimethyl-propyl)-1-(2-ethylamino-
ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1 -(2-Ethylamino-ethyl)-2-isobutyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1-(2-Diisopropylamino-ethyl)-2-(2,4,4-
trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-
hyd roxy-acry la m ide
N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-
(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-
acrylamide
3-[1-(2-Ethylamino-ethyl)-2-(2,4,4-trimethyl-
pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide

175



3-[1-(2-Diethylamino-ethyl)-2-(2,4,4-trimethyl-
pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Diethylamino-ethyl)-2-propyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide






3-[2-Butyl-1 -(2-diisopropylamino-ethyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-Butyl-1 -(2-ethylam ino-ethyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1-(2-Diethylamino-ethyl)-2-(2-methylsulfanyl-
ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[2-Butyl-1 -(2-isopropylamino-ethyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-Butyl-1 -(3-isopropylamino-propyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide

176









3-[1 -(1 -Benzyl-piperidin-4-yl)-2-butyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-But-3-enyl-1 -(2-ethylamino-ethyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[2-Hexyl-1 -(2-isopropylamino-ethyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1-(2-Dimethylamino-ethyl)-2-(2,4,4-trimethyl-
pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Ethylamino-ethyl)-2-hexyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-
(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-
acrylamide
3-[1 -(2-Dimethylamino-ethyl)-2-hex-3-enyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1-(2-Amino-ethyl)-2-(2,4,4-trimethyl-pentyl)-
1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

177


3-[1 -(2-Amino-ethyl)-2-(2-methoxy-nonyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide







3-[2-Butyl-1 -(2-dimethylamino-ethyl)-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-[1-(2-Dimethylamino-ethyl)-2-hexyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
N-{2-[1-(2-Diethylamino-ethyl)-5-(2-
hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2-
yl]-ethyl}-3,3-dimethyl-butyramide
3-{1-(2-Diethylamino-ethyl)-2-[2-(2,2-dimethyl-
propionylamino)-ethyl]-1H-benzoimidazol-5-yl}-
N-hydroxy-acrylamide
3-{1-(2-Diethylamino-ethyl)-2-[(2,2-dimethyl-
propionylamino)-methyl]-1H-benzoimidazol-5-
yl}-N-hydroxy-acrylamide
N-[1-(2-Diethylamino-ethyl)-5-(2-
hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2-
ylmethyl]-butyramide

178




3-[1-(2-ethylamino-ethyl) -2-(3,3-dimethyl-butyl)-
1 H-benzoim idazol-5-y l]-N-hydroxy-acrylam ide
3-[2-(3,3-Dimethyl-butyl)-1-(2-Dimethylamino-
ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
3-[1-(2-Dimethylamino-ethyl)-2-pentyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide






3-[1-(2-Dimethylamino-ethyl)-2-(2,2,2-trifluoro-
ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide
N-Hydroxy-3-[1 -(5-methyl-1 H-pyrazol-3-yl)-2-
(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-
acrylamide
3-[1 -(2-Ethylamino-ethyl)-2-pentyl-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-(2-Butyl-1 -pyrrolidin-3-yl-1 H-benzoimidazol-5-
yl)-N-hydroxy-acrylam ide
3-(2-Butyl-1 -piperidin-4-yl-1 H-benzoimidazol-5-
yl)-N-hydroxy-acrylamide

179



N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-
pentyl-1H-benzoimidazol-5-yl]-acrylamide
N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-non-3-
enyl-1H-benzoimidazol-5-yl]-acrylamide





N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-non-6-
enyl-1H-benzoimidazol-5-yl]-acrylamide
3-[2-Hexyl-1-(2-methylamino-ethyl)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-pentyl-
1H-benzoimidazol-5-yl]-acrylamide
N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-octyl-
1H-benzoimidazol-5-yl]-acrylamide


3-[1-(2-Amino-ethyl)-2-octyl-1H-benzoimidazol-
5-yl]-N-hydroxy-acrylam ide

180









3-{2-Butyl-1-[2-(isopropyl-methyl-amino)-ethyl]-
1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-{1 -[2-(Ethyl-methyl-amino)-ethyl]-2-pentyl-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-(2-Hexyl-1 -pyrrolidin-3-yl-1 H-benzoimidazol-5-
yl)-N-hydroxy-acrylamide
3-[2-Butyl-1-(1-methyl-pyrrolidin-3-yl)-1H-
benzoimidazol-5-yl]-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-
yl)-N-hydroxy-acrylamide
3-(1-{2-[Ethyl-(2-methoxy-ethyl)-amino]-ethyl}-2-
pentyl-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide
3-{2-Butyl-1-[2-(ethyl-methyl-amino)-ethyl]-1H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide

181








N-Hydroxy-3-[1-(1-methyl-piperidin-3-yl)-2-
pentyl-1H-benzoimidazol-5-yl]-acrylamide
3-{1 -[2-(Ethyl-hexyl-amino)-ethyl]-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-{1 -[2-(Ethyl-pentyl-amino)-ethyl]-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-{1 -[2-(Ethyl-heptyl-amino)-ethyl]-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-{2-Hexyl-1-[1-(2-hydroxy-ethyl)-piperidin-3-yl]-
1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-(2-Butyl-1-{2-[ethyl-(3-hydroxy-propyl)-amino]-
ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide
3-(1-{2-[Ethyl-(3-hydroxy-propyl)-amino]-ethyl}-
2-pentyl-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide

182






(E)-N-hydroxy-3-(1 -(1 -phenethylpyrrolidin-3-yl)-
1H-benzo[d]imidazol-5-yl)acrylamide
(E)-N-hydroxy-3-(1 -(1 -pentylpiperidin-3-yl)-1 H-
benzo[d]imidazol-5-yl)acrylamide
3-{1-[2-(Butyl-ethyl-amino)-ethyl]-1H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
(E)-N-hydroxy-3-(1 -(1 -phenethylpiperidin-3-yl)-
1H-benzo[d]imidazol-5-yl)acrylamide
(E)-N-hydroxy-3-(1 -(1 -(3-phenylpropyl)piperidin-
3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide

183






(E)-N-hydroxy-3-(1 -(1 -(3-phenylpropyl)pyrrolidin-
3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide
3-{1-[1-(3,3-Dimethyi-butyl)-pyrrolidin-3-yl]-1H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
(E)-3-(1-(2-(diethylamino)ethyl)-1H-
benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
3-[2-(4-Cyano-butyl)-1-(2-diethylamino-ethyl)-
1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide
(E)-3-(1-(1-butylpiperidin-3-yl)-1H-
benzo[d]imidazol-5-yl)-N-hydroxyacrylamide

184







(E)-N-hydroxy-3-(1 -(1 -(pent-4-enyl)piperidin-3-
yl)-1H-benzo[d]imidazol-5-yl)acrylamide
(E)-3-(1-(1-(3,3-dimethylbutyl)piperidin-4-yl)-1H-
benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
3-[1 -(2-Diethylamino-ethyl)-2-propylamino-1 H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide
(E)-N-hydroxy-3-(1-(2-
(isopropyl(propyl)amino)ethyl)-1H-
benzo[d]imidazol-5-yl)acrylamide
3-{1 -[2-(Butyl-isopropyl-amino)-ethyl]-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
N-Hydroxy-3-{1-[2-(isopropyl-pentyl-amino)-
ethyl]-1H-benzoimidazol-5-yl}-acryiamide

185







3-[2-(5-Cyano-pentyl)-1-(2-diethylamino-ethyl)-
1H -benzoimidazol-5-yl]-N-hydroxy-acrylamide
3-(1-{2-[(3,3-Dimethyl-butyl)-ethyl-amino]-ethyl}-
1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide
3-{1 -[2-(Ethyl-propyl-amino)-ethyl]-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
N-Hydroxy-3-(1-{2-[isopropyl-(2-methyl-pentyl)-
amino]-ethyl}-1H-benzoimidazol-5-yl)-acrylamide
(E)-N-hydroxy-3-(1-(2-(isopropyl(4,4,4-
trifluorobutyl)amino)ethyl)-1H-benzo[d]imidazol-
5-yl)acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
propylamino-1H-benzoimidazol-5-yl]-N-hydroxy-
acrylamide

186






3-{1 -[2-(Ethyl-hexyl-amino)-ethyl]-2-methyl-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-{1-[2-(Butyl-ethyl-amino)-ethyl]-2-
trifluoromethyl-1H-benzoimidazol-5-yl}-N-
hydroxy-acrylamide
3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-
trifluoromethyl-1H-benzoimidazol-5-yl}-N-
hydroxy-acrylamide
(E)-3-(1 -(2-(dibutylamino)ethyl)-2-propyl-1 H-
benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
3-[1 -(2-Dipropylamino-ethyl)-1 H-benzoimidazol-
5-yl]-N-hydroxy-acrylamide

187







N-Hydroxy-3-(1-{2-[isopropyl-(3-methyl-butyl)-
amino]-ethyl}-1H-benzoimidazol-5-yl)-acrylamide
3-(H2-[(3,3-Dimethyl-butyl)-methyl-amino]-
ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide
3-(1 -{2-[(2-Ethyl-butyl)-methyl-amino]-ethyl}-1 H-
benzoimidazol-5-yl)-N-hydroxy-acrylamide
(E)-3-(1-(2-(bis(3,3-dimethylbutyl)amino)ethyl)-
1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
(E)-3-(1-(2-(diisobutylamino)ethyl)-1H-
benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
3-{1 -[2-(3,3-Dimethyl-butylamino)-ethyl]-1 H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide

188






N-Hydroxy-3-{1-[2-(methyl-pent-4-enyl-amino)-
ethyl]-1H-benzoimidazol-5-yl}-acrylamide
3-(1-{2-[(3,3-Dimethyl-butyl)-propyl-amino]-
ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-
methylsulfanyl-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide
3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-
propyl-1H-benzoimidazol-5-yl}-N-hydroxy-
acrylamide
3-[1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-(2,2-
dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide

189





3-[1-{2-[Bis-(3,3-dimethyl-butyl)-amino]-ethyl}-2-
(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide
3-{1-[2-(2,2-Dimethyl-propylamino)-ethyl]-1H-
benzoimidazol-5-yl}-N-hydroxy-acrylamide
3-(1-{2-[(2,2-Dimethyl-propyl)-propyl-amino]-
ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide
3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl-
1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide



3-(1-{2-[(3,3-Dimethyl-butyl)-methyl-amino]-
ethyl}-2-propyl-1H-benzoimidazol-5-yl)-N-
hydroxy-acrylamide
3-(1-{2-[(3,3-Dimethyl-butyl)-(2,2,2-trifluoro-
ethyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-
hydroxy-acrylamide

190


3-(1-{2-[Butyl-(2,2,2-trifluoro-ethyl)-amino]-
ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-
acrylamide

19. A pharmaceutical composition including a compound according to any one of
claims 1 to 18 and a pharmaceutical^ acceptable diluent, excipient or carrier.
20. Use of a compound according to any one of claims 1 to 18 in the preparation of a
medicament for the treatment of a disorder caused by, associated with or accompanied by
disruptions of cell proliferation and/or angiogenesis.
21. A use according to claim 20 wherein the disorder is a proliferative disorder.
22. A use according to claim 21 wherein the proliferative disorder is cancer.
23. A use according to claim 22 wherein the cancer is colon cancer, prostate cancer,
hepatoma and ovarian cancer.
24. Use of a compound according to any one of claims 1 to 18 in the preparation of a
medicament for the treatment of a disorder that can be treated by inhibition of histone
deacetylase.
25. A use according to claim 24 wherein the disorder is selected from the group
consisting of 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 haemorrhage Primary
lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic
interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary
spastic paraplegia, Progressive ataxia and Shy-Drager syndrome; Metabolic diseases
including Type 2 diabetes; Degenerative Diseases of the Eye including Glaucoma, Age-
related macular degeneration, macular myopic degeneration, Rubeotic glaucoma,

191
Interstitial keratitis, Diabetic retinopathy, Peter's anomaly, retinal degeneration,
Cellophane Retinopathy; Cogan's Dystrophy; Corneal Dystrophy; Iris Neovascularization
(Rubeosis); Neovascularization of the Cornea; Retinopathy of Prematurity; Macular
Edema; Macular Hole; Macular Pucker; Marginal Blepharitis, Myopia, nonmalignant
growth of the conjunctiva; Inflammatory diseases and/or Immune system disorders
including Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus
Host disease, Psoriasis, Asthma, .Spondyloarthropathy, Crohn's Disease, inflammatory
bowel disease, Colitis Ulcerosa, Alcoholic hepatitis, Diabetes, Sjoegrens's syndrome,
Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain,
Systemic Lupus Erythematosus, allergic contact dermatitis; Disease involving
angiogenesis including cancer, psoriasis, rheumatoid arthritis; Psychological disorders
including bipolar disease, schizophrenia, depression and dementia; Cardiovascular
Diseases including Heart failure, restenosis, cardiac hypertrophy and arteriosclerosis;
Fibrotic diseases including liver fibrosis, lung fibrosis, cystic fibrosis and angiofibroma;
Infectious diseases including Fungal infections, such as Candida Albicans, Bacterial
infections, Viral infections, such as Herpes Simplex, Protozoal infections, such as Malaria,
Leishmania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidiosis and
Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.
26. The use of a compound according to any one of claims 1 to 18 in the manufacture
of a medicament for the treatment of cancer.
27. A use according to claim 26 wherein the cancer is a hematologic malignancy or a
solid tumor.
28. A use according to claim 27 wherein the hematologic malignancies are selected
from a group consisting of B-cell lymphoma, T-cell lymphoma and leukemia.
29. A use according to claim 27 wherein the solid tumor is selected from the group
consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck
cancer, renal cancer, gastric cancer, colon cancer, pancreatic cancer and brain cancer.
30. A use according to claim 26 wherein the cancer is selected from the group
consisting of coion cancer, prostate cancer, hepatoma and ovarian cancer.
31. A method of synthesis of compounds of formula I as defined in claim 1

192

wherein R1, R2, R3, R4, X, Y and Z are as defined in claim 1, the method including
(a) providing a compound of the formula (A1):

wherein X, Y and Z are as defined in claim 1 and L is a leaving group,
(b) protecting the carboxyl group to produce a compound of the formula (A2):

wherein X, Y and Z are as defined in claim 1, L is a leaving group and Pc is a carboxyl
protecting group,
(c) displacing the leaving group with an amine of formula R1NH2 to produce a compound
of the formula:


193
wherein X, Y, Z are as defined in claim 1, R1 is as defined in claim 1 or a protected form
thereof, and Pc is a carboxyl protecting group
(d) optionally reacting the compound to further functionalise R1
(e) reducing the nitro group;
(f) reacting the reduced product with a compound of formula R2C02H or a compound of
formula R2CHO and cyclising the product thus produced to produce a compound of the
formula (A4):

wherein X, Y, Z are as defined in claim 1, R1 and R2 are as defined in claim 1 or protected
forms thereof, and Pc is a carboxyl protecting group
(g) converting the compound to a compound of formula I;
wherein (d) can be carried out after any one of (c) (e) or (f) and further wherein (e) and (f)
can be carried out sequentially or simultaneously.

25
wherein R1, R2, R3, R4, X, Y and Z are as defined in claim 1, the method including:
(a) providing an aldehyde of the formula (B1)
32. A method of synthesis of compounds of formula I as defined in claim 1

194

wherein R1, R2, X, and Y are as defined in claim 1,
5 (b) subjecting the aldehyde to reaction with an appropriately substituted olefination agent
to produce a compound of formula (B2)

wherein R1, R2, X, and Y, Z are as defined in claim 1, and Pc is H or a carboxyl protecting
group
(c) converting the compound to a compound of formula I.
33. A method according to claim 32 wherein (a) includes:
(a1) providing a compound of the formula (B3):

wherein X and Y are as defined in claim 1, L is a leaving group and Pc is a carboxyl
protecting group,
(a2) displacing the leaving group with an amine of formula R1NH2 to produce a compound
of the formula (B4):

195

wherein X and Y are as defined in claim 1, R1 is as defined in claim 1 or a protected form
thereof, and Pc is a carboxyl protecting group
(a3) optionally reacting the compound to further functionalise R1
(a4) reducing the nitro group;
(a5) reacting the reduced product with a compound of formula R2C02H or a compound of
formula R2CHO and cyclising the product thus produced to produce a compound of the
formula (B5):

wherein X and Y are as defined in claim 1, R1 and R2 are as defined in claim 1 or
protected forms thereof, and Pc is a carboxyl protecting group
(a6) converting the protected carboxyl group to the corresponding aldehyde;
wherein (a3) can be carried out after any one of (a2), (a4), (a5) or (a6) and further wherein
(a4) and (a5) may be carried out sequentially or simultaneously.
34. A method of synthesis of compounds of formula I as defined in claim 1



196
wherein R\ R% R3, R4, X, Y and Z are as defined in claim 1, the method including:
(a) providing a compound of the formula (C1)

wherein X and Y are as defined in claim 1, R1 and R2 are as defined in claim 1 or
protected forms thereof, and L1 is a leaving group
(b) converting the compound in (a) to a compound of formula (C2);

wherein X, Y and Z are as defined in claim 1, R1 and R2 are as defined in claim 1 or
protected forms thereof, and Pc is H or a carboxyl protecting group
(c) converting the compound to a compound of formula I;
35. A method according to claim 34 wherein (a) includes:
(a1) providing a compound of the formula (C3):

wherein X and Y are as defined in claim 1 and L and L1 are leaving groups,

197
(a2) displacing the leaving group (L) with an amine of formula R1NH2 to produce a
compound of the formula (C4):

wherein X, and Y, are as defined in claim 1, R1 is as defined in claim 1 or a protected form
thereof, and L1 is a leaving group;
(a3) optionally reacting the compound to further functionalise R1
(a4) reducing the nitro group;
(a5) reacting the reduced product with a compound of formula R2C02H or a compound of
formula R2CHO and cyclising the product thus produced to produce a compound of the
formula (C1):

wherein (a3) can be carried out after any one of (a2), (a4) or (a5) and further wherein (a4)
and (a5) may be carried out sequentially or simultaneously.
36. A method according to any one of claims 31 to 35 wherein the compound
produced has the formula:

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 for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with enzymes having
histone deacetylase (HDAC) activities.

Documents:

00997-kolnp-2008-abstract.pdf

00997-kolnp-2008-claims 1.0.pdf

00997-kolnp-2008-claims 1.1.pdf

00997-kolnp-2008-correspondence others.pdf

00997-kolnp-2008-description complete.pdf

00997-kolnp-2008-form 1.pdf

00997-kolnp-2008-form 3.pdf

00997-kolnp-2008-form 5.pdf

00997-kolnp-2008-gpa.pdf

00997-kolnp-2008-international publication.pdf

00997-kolnp-2008-international search report.pdf

00997-kolnp-2008-translated copy of priority document.pdf

997-KOLNP-2008-(03-07-2013)-CLAIMS.pdf

997-KOLNP-2008-(03-07-2013)-CORRESPONDENCE.pdf

997-KOLNP-2008-(03-07-2013)-FORM-13.pdf

997-KOLNP-2008-(03-07-2013)-FORM-2.pdf

997-KOLNP-2008-(03-07-2013)-FORM-3.pdf

997-KOLNP-2008-(03-07-2013)-OTHERS.pdf

997-KOLNP-2008-(03-07-2013)-PETITION UNDER RULE 137.pdf

997-KOLNP-2008-(04-02-2013)-ANNEXURE TO FORM 3.pdf

997-KOLNP-2008-(04-02-2013)-CORRESPONDENCE.pdf

997-KOLNP-2008-(04-02-2013)-OTHERS-1.pdf

997-KOLNP-2008-(04-02-2013)-OTHERS-2.pdf

997-KOLNP-2008-(04-02-2013)-OTHERS.pdf

997-KOLNP-2008-ASSIGNMENT-1.1.pdf

997-KOLNP-2008-ASSIGNMENT.pdf

997-KOLNP-2008-CORRESPONDENCE 1.1.pdf

997-KOLNP-2008-CORRESPONDENCE 1.2.pdf

997-KOLNP-2008-CORRESPONDENCE 1.3.pdf

997-KOLNP-2008-CORRESPONDENCE.pdf

997-KOLNP-2008-EXAMINATION REPORT.pdf

997-KOLNP-2008-FORM 1 1.1.pdf

997-KOLNP-2008-FORM 13-1.1.pdf

997-KOLNP-2008-FORM 13.pdf

997-KOLNP-2008-FORM 18-1.1.pdf

997-kolnp-2008-form 18.pdf

997-KOLNP-2008-FORM 3.1.pdf

997-KOLNP-2008-FORM 5 1.1.pdf

997-KOLNP-2008-GPA.pdf

997-KOLNP-2008-GRANTED-ABSTRACT.pdf

997-KOLNP-2008-GRANTED-CLAIMS.pdf

997-KOLNP-2008-GRANTED-DESCRIPTION (COMPLETE).pdf

997-KOLNP-2008-GRANTED-FORM 1.pdf

997-KOLNP-2008-GRANTED-FORM 2.pdf

997-KOLNP-2008-GRANTED-FORM 3.pdf

997-KOLNP-2008-GRANTED-FORM 5.pdf

997-KOLNP-2008-GRANTED-SPECIFICATION-COMPLETE.pdf

997-KOLNP-2008-INTERNATIONAL PUBLICATION.pdf

997-KOLNP-2008-OTHERS-1.1.pdf

997-KOLNP-2008-OTHERS.pdf

997-KOLNP-2008-PCT PRIORITY DOCUMENT NOTIFICATION.pdf

997-KOLNP-2008-PETITION UNDER RULE 137.pdf

997-KOLNP-2008-REPLY TO EXAMINATION REPORT.pdf

997-KOLNP-2008-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf


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Patent Number 259541
Indian Patent Application Number 997/KOLNP/2008
PG Journal Number 12/2014
Publication Date 21-Mar-2014
Grant Date 17-Mar-2014
Date of Filing 06-Mar-2008
Name of Patentee S*BIO PTE LTD
Applicant Address 1 SCIENCE PARK ROAD, #05-09 THE CAPRICORN SINGAPORE SCIENCE PARK II, SINGAPORE
Inventors:
# Inventor's Name Inventor's Address
1 CHEN DIZHONG BLOCK 212, #11-126 CHUA CHU KANG CENTRAL, SINGAPORE 680212
2 LEE KEN CHI LIK BLOCK 627 #24-186, SENJA ROAD, SINGAPORE 670627
3 LYE PEK LING BLOCK 290D BUKIT BATOK EAST AVENUE 3, #02-370 SINGAPORE 651290
4 WANG HAISHAN 54 WEST COAST ROAD #02-62, SINGAPORE 126837 REPUBLIC OF SINGAPORE
5 YU NIEFANG APARTMENT 802, BLOCK 8 TIANFENG MINGYUAN (TIANFENG GARDEN) 198 TONGZIPO ROAD, CHANGSHA 410006
6 SUN ERIC T 52 CORONATION ROAD WEST #01-03 ASTRID MEADOWS, SINGAPORE 269265
7 DENG WEIPING APT #75, RM 34, DONGAN ERCHUN, ZHONGSHAN ROAD NO 2 (SOUTH), SHANGHAI 200032
PCT International Classification Number C07D 235/04
PCT International Application Number PCT/SG2006/000217
PCT International Filing date 2006-08-01
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/714827 2005-09-08 U.S.A.
2 60/783819 2006-03-21 U.S.A.