Note: Descriptions are shown in the official language in which they were submitted.
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BENZIMIDAZOLE COMPOUNDS AND USES IN TREATING PROLIFERATIVE DISORDERS
FIELD OF THE INVENTION
[0001] The present invention relates to hydroxamate compounds that are
inhibitors
of histone deacetylase (HDAC). More particularly, the present invention
relates to
benzimidazole containing compounds and methods for their preparation. These
compounds may be useful as medicaments for the treatment of proliferative
disorders
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 cells,
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, 51 65-51 70 (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,
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due to the in vivo instability of these compounds they are less desirable as
anti-cancer
drugs. Recently, other small molecule HDAC inhibitors have become available
for
clinical evaluation [US6,552,065]. Additional HDAC inhibiting compounds have
been
reported in the literature [Bouchain 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): 10230-10237; Science, 1998; 281:
1001-
1005; Dinarello C.A. and Moldawer L.L. Proinflammatory and anti-inflammatory
cytokines in rheumatoid arthritis, A primer for clinicians, 2rid Edition,
Amergen Inc.,
2000].
[0004] Nevertheless, there is still a need to provide further HDAC inhibitors
that
would be expected to have useful, improved pharmaceutical properties in the
treatment
of diseases such as cancer, neurodegenerative diseases, disorders involving
angiogenesis and inflammatory and/or immune system disorders. With a view to
meeting this need a number of small organic moiety scaffolds have been
investigated
including a number of heterocyclic systems, especially bicyclic heterocyclic
ring
systems. One heterocyclic system that has been investigated has been the
benzimidazole ring system. We have now found that judicious selection of the
substituents on the 5 membered ring of the benzimidazole ring system leads to
the
production of a family of compounds with improved pharmacokinetic properties
when
compared with the compounds of the prior art. The compounds within the family
exhibit microsomal stability and thereby demonstrate improved half lives in
the plasma
when compared to the compounds of the prior art. The compounds within the
family
typically provide a longer duration of action due to the increased in vivo
exposure (i.e.,
area under the curve, AUCo_last) 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):
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X R3
N N/
R2 1 -Z -- 3
R1
Formula (I)
wherein
[0006] R1 is an optionally substituted heteroaryl group, an optionally
substituted
heterocycloalkyl group or a group of formula:
-(CR20R21)m_(c R22 R23)._( c R24 R25)._ N R26 R27;
[0007] 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;
[0008] R3 is selected from the group consisting of H, C1 -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, -NO2, -CF3, -0CF3, 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, -
C001-1 -C(0)0R5, -COR5, -SH, -SR6, -OW acyl and -NR7R5, each of which may be
optionally substituted;
[0010] each 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: alkyl,
alkenyl,
alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl,
each of which
may be optionally substituted;
[0012] each R6 is independently selected from the group consisting of: alkyl,
alkenyl,
alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
each of which
may be optionally substituted;
[0013] each R7 and R5 is independently selected from the group consisting of:
H,
alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,
aryl,
heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl
and acyl,
each of which may be optionally substituted;
[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, -NO2, -CF3, -0CF3, alkyl, alkenyl, alkynyl,
haloalkyl,
haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl,
heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl,
arylalkyl,
heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl,
heterocycloalkylheteroalkyl,
heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,
alkoxyalkyl,
alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy,
cycloalkylkoxy,
heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy heteroaryloxy,
amino,
alkylamino, acylamino, aminoalkyl, arylamino, alkoxycarbonyl,
alkylaminocarbonyl,
sulfonyl, alkylsulfonyl, aminosulfonyl, arylsulfonyl, arylsulfinyl -COON, -
C(0)0R5, -
COR5, -SH, -SR6, -OW and acyl, each of which may be optionally substituted; or
R2 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
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,
5 heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,
cycloalkylheteroalkyl,
heterocycloalkylheteroalkyl, heteroarylheteroalkyl,
aryl heteroalkyl, 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 a bond or 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 o are integers independently selected from the group
consisting of 0,
1, 2, 3 and 4;
[0020] or a pharmaceutically acceptable salt or prodrug thereof.
[0021] In one embodiment of the invention R4 is H and the compounds are those
of
formula (la):
X 0
OH
R3
R1
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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X 0
R2-- 3 I 4 5 ¨Z OH
., 61
R1
Formula (lb)
[0025] or a pharmaceutically acceptable salt or prodrug thereof
[0026] wherein Ize, R2, R3, 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..(c R24R25)04NR26R27;
[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 (lc):
X 0 ,R3
R2-- 31 I 4 5j-Z 0-R4
NN
R1
Formula (lc)
wherein R1 is a group of formula
_(cRR),,r(cR22R23),r(
2021 cR24R25)0_NR26R27
[0031] and R2, R3, R4, X, Y, Z, R20, R21, R22, R23, R24, R25, R26,
K m,
n and o are as
defined for compounds of formula (I).
CA 02540459 2006-03-21
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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 that the sum of m+n+o is an integer selected from the group
consisting of
2 and 3.
[0033] In one specific embodiment the sum of m+n+o is 2. When this occurs R1
is
selected from the group consisting of:
c R20 R21 )2_N R26R27;
c R22 R23 )2_ NR26R27;
R24R25)2_NR26R27;
.(cR20R21 )-(cR22R23)_NR26R27;
_(cR20R21)-(cR24R25)_NR26R27;
R22R23xc R24R25)-NR26R27;
[0034] In one form of this embodiment R1 is the group:
_(cR20R21 )-(cR22R23)_NR26R27;
[0035] This provides compounds of the formula (II):
X 0 R3
N'
R2-- 3 I 4 5 2-Z 0-R4
1 7 9
R2o
R22
R21 <
N R23
26
R27
Formula (II)
[0036] wherein X, Y, Z, R2, R3, R4, R20, R21, R22, R23, R26 and K.-.27
are as defined in
=
formula (I).
[0037] In a specific form of this embodiment R4 is H which provides compounds
of
formula (11a):
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R3
X
NI/
R24 3Z O¨H
7<><R22
R21
R26-"N\ R23
R27
.Formula (11a)
[0038] wherein X, Y, Z, R2, R3, R20, R21, R22, R23, R26 and 11.-.27
are as defined in
formula (I).
[0039] In another specific form R3 is H leading to compounds of formula (11b):
X
N
R2-- 31 I 4 56-hZ 0¨H
y
1R2o7
R22
R2
oR N R23
R27
Formula (11b)
[0040] wherein X, Y, Z, R2, R20, R21, R22, R23, R26 and
11 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 (11c):
X 0\\
4 5
31 7 -1--Z O¨H
pj
R26,-N\
R27
Formula (11c)
[0042] wherein X, Y, Z, R2, R26 and R27 are as defined in formula (I).
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[0043] In another embodiment the sum of m+n+o is 3. When this occurs R1 is
selected from the group consisting of:
..(cR2oR21)3_NR26R27;
_(cR22R23)3_NR26R27;
_(cR2.4R25)3_NR26R27;
-(CR2 R21)2-(CR22R23)-NR26R27
-(CR2 R21)2_(cR24R25).NR26R27
4cR'20R21xcR22R23)2_NR26R27
-(C R22R23)2-(CR24R25)-NR26 R27
_(cR20R21 )-(cR24R25)2-N R261:127
4cR22R23)..(c R24R25)2_NR26R27
-(CR20R21 )-(cR22R23)_(c R24R25)_NR2eR27;
[0044] In one form of this embodiment R1 is a group of the formula:
-(CR20R21)_(c R22R23)-(c R24R25yNR26R27.
[0045] This provides compounds of the formula (III):
X 0
11/R3
R2 I 4 6T-Z NN
0-R4
R20
R22
R21
R24 R23
R25 N
R27
Formula (III)
[0046] wherein X,Y, Z, R2, R3, R4, R20, R21, R22, R231R24, R25, -26
K and R27 are as
defined in formula (I).
[0047] In a specific form of this embodiment R4 is H which provides compounds
of
formula (111a).
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X 0 R3
N/
31 I 4 5 I
AT-Z O¨H
7 ,`:,1
N'
R2o
R22
R21
R24 R23
R25 R26
R27
Formula (111a)
[0048] wherein X,Y, Z, R2, R3, Ra, R20, R21, R22, R231R24, R25, R26 and K.-.27
are as
5 defined in formula (1).
[0049] In another specific form R3 is H leading to compounds of formula
(111b):
X 0
3 I 4 5 I
-Z O¨H
1 7
R22
R21
R24 R23
R25 /N
R27
Formula (111b)
10 [0050] wherein X,Y, Z, R2, R3, Fe, R20, R21, R22, R23,R24, R25, K.-.26
and R27 are as
defined in formula (I).
[0051] In an even more specific form of this embodiment R20, R21, R24, R25 are
H, and
R22 and R23 are methyl providing compounds of formula (111c).
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11
X 0 /1-1
N
R2-- 3Dt1 I 4 5 -2> NO¨H
7 ,9
N
R26
R27
Formula (111c)
[0052] wherein X,Y, Z, R2, R3, R4, R20, R21, R22, R23, R24, R25, R26 and
11 are as
defined in formula (I).
[0053] In each of the above embodiments of the invention R2 and R21 may
represent
a number of different variables. In one embodiment R2 and R21 are
independently
selected from the group consisting of H, alkyl, alkenyl and alkynyl. In
another
embodiment R2 and R21 are independently selected from the group consisting of
H and
alkyl. In a specific embodiment R2 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 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 R24 and R25 are independently selected from the group
consisting
of H and alkyl. 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.
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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-dimethyl-butyl, 2-ethyl-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:
N/
R28 "R28
R28
[0059] wherein R28 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, arylacyl,
sulfonyl,
alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, 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-triflouro-propyl; butyl;
isobutyl; 3,3-
, dimethyl-butyl; pentyl; 2,4,4-trimethyl-pentyl; penten-4-yl, hexyl;
heptyl, octyl, nonyl, 2-
methoxy nonyl, benzyl, 2-phenyl-ethyl, 2-phenyl-acetyl, 3-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. It is
particularly
CA 02540459 2006-03-21
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preferred that R1 is selected from the group consisting of piperidine-3-yl,
piperidine-4-y1
and pyrollidin-3-y.
[0062] In another embodiment R1 is a heteroaryl group.
[0063] In another embodiment R1 is a group selected from the group consisting
of:
(32.4.N
N
(32.2 N N
N La?7- N N
NH
,CNH
N
NH
0
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14
N
N
N N N
CA 02540459 2006-03-21
NH
N
5
N
[0064] In one specific embodiment R1 is a group of formula:
'Z'etNH2
[0065] In another specific embodiment R1 is a group of formula:
CA 02540459 2006-03-21
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[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:
N/
[0069] In another specific embodiment R1 is a group of formula:
N/
[0070] In another specific embodiment R1 is a group of formula:
[0071] In another specific embodiment R1 is a group of
formula:
CA 02540459 2006-03-21
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[0072] In another specific embodiment R1 is a group of formula:
Lh2,N
[0073] In one embodiment R2 is selected from the group consisting of H, alkyl,
cycloalkyl, heteroalkyl, alkenyl, alkynyl, alkoxyalkyl and cycloalkylalkyl.
[0074] In one form of this embodiment R2 is alkyl. In one embodiment the alkyl
is a
C1-C10 alkyl. In anotherform of this embodiment the alkyl is a C,-C6 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 y a Ci-Cio alkeny. In another form of this embodiment the
alkenyl is a C1-
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-l-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-, R11S(0)2R13-, R11c(o)N(R12)R13-, R11S02N(R12)R13-,
R11N(R12)C(0)R13-,
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R11N(R12)S02R13-, and RN(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 Cr
06 alkyl. In a specific form of this embodiment R13 is methyl or ethyl. In one
form of thsi
embodiment R12 is H or C1-C6alkyl. A specific value for R12 is H. In one form
of thsi
embodiment R11 is 01-06 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 CH3(CH2)2CONH(CH2)-=
[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-
methansulfanyl-
ethyl; 2,2,2-triflouro-ethyl; propyl; 2-2-dimethyl-propyl; isopropyl; 3,3,3-
trifiouro-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-2y1; 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-; (CF13)3CCONH(CH2)- and CH3(0H2)2CONH(CH2)-=
[0078] In one embodiment X and Y may be the same or different and are selected
from the group consisting of H, halogen, 01-04 alkyl, -CF3, -NO2, -C(0)R5, -
SR6, -
ON 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, C1-C6 alkyl, or acyl. In another embodiment
R3 is
H or C1-C4 alkyl. A specific value for R3 is H;
[0083] In one embodiment R4 is H or C1-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 R5 is C1-C4 alkyl, heteroalkyl or acyl. A specific
value for
R5 is 01-04 alkyl;
CA 02540459 2006-03-21
19
10086] In one embodinnentR7 and R5 are selected from the group consisting of
H, C1-
C6 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, -NO2, -CF3, -
0CF3,
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)0R5, -SH, -SR5, -0R6and acyl;
[0088] In a further embodiment the optional substituents are selected from the
group
consisting of: halogen, =0, =S, -CN, -NO2, alkyl, alkenyl, heteroalkyl,
haloalkyl, alkynyl,
aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy,
alkylamino,
aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl,
arylsulfonyl,
aminosulfonyl, -C(0)0R5, 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.
CA 02540459 2006-03-21
[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
5 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 -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 (1) 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.
CA 02540459 2006-03-21
21
[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 including Type 2 diabetes; Degenerative Diseases
of
the Eye including Glaucoma, Age-related macular degeneration, macular myopic
degeneration, Rubeotic glaucoma, Interstitial keratitis, Diabetic retinopathy,
Peters
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
CA 02540459 2006-03-21
22
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
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
(1). 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
CA 02540459 2012-12-19
23
system disorder is rheumatoid arthritis. In another embodiment the
inflammatory
disease and/or immune system disorder is Systemic Lupus Erythematosus.
[0109] The invention also provides agents for the treatment of
inflammatory
disease 5 and/or immune system disorder including a compound of formula (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 10 embodiment, the eye disease is macular degeneration. In
another
embodiment, the eye disease is glaucoma. In another embodiment, the eye
disease
is retinal degeneration.
[0111] The invention also relates to the use of compounds of formula (I)
in
the 15 preparation of a medicament for the treatment of inflammatory disease
and/or
immunesystem 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.
[0111a] In accordance with an aspect of the present invention there is
provided
a compound of the formula (I):
X
N /R3
R2 ___________________ < 0-R4
N
R1
Formula I
wherein
R1 is a group of formula:
_( CR20-R 21
)õ,-( cR22R2),-(CR24R25 )0_NR26R27;
R2 is selected from the group consisting of: alkyl and heteroalkyl, each of
which may be optionally substituted with one or more optional substituents
wherein
CA 02540459 2012-12-19
23a
each optional substituent is selected from the group consisting of halogen,
=0, -CN,
alkenyl, alkynyl and alkoxy;
R3 is H;
X and Y are H;
R4 is H;
each R5 is independently selected from the group consisting of: H, alkyl,
alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl,
each of which
may be optionally substituted;
each R6 is independently selected from the group consisting of: H, alkyl,
alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
each of which
may be optionally substituted;
each R20, R21, R22, R23, R24 and R25 is independently selected from the group
consisting of: H, halogen, -ON, -NO2, -CF3, -0CF3, alkyl, alkenyl, alkynyl,
haloalkyl,
haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl,
heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl,
arylalkyl,
heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl,
heterocycloalkylheteroalkyl,
heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,
alkoxyalkyl,
alkoxyaryl, alkoxyheteroaryl, alkenyloxy,
alkynyloxy, cycloalkylkoxy,
heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy heteroaryloxy,
amino,
alkylamino, acylamino, aminoalkyl, arylamino, alkoxycarbonyl,
alkylaminocarbonyl,
sulfonyl, alkylsulfonyl, aminosulfonyl, arylsulfonyl, arylsulfinyl -COOH, -
C(0)0R5, -
COR5, -SH, -SR6, -0R6 and acyl, each of which may be optionally substituted;
or
R2 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
R24 and R25 when taken together may form a group of formula =0 or =S;
CA 02540459 2012-12-19
23b
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;
m, n and o are integers independently selected from the group consisting of 0,
1, 2, 3 and 4;
Z is ¨CH=CH- and is attached at ring position 5;
or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0112] In this specification a number of terms are used which are well
known
to a skilled addressee. Nevertheless for the purposes of clarity a number of
terms will
be defined.
[0113] As used herein, the term unsubstituted means that there is no
substituent or that the only substituents are hydrogen.
[0114] The term "optionally substituted" as used throughout the
specification
denotes that the group may or may not be further substituted or fused (so as
to form a
condensed polycyclic system), with one or more substituent groups. Preferably
the
substituent groups are one or more groups independently selected from the
group
consisting of halogen, =0, =S, -CN, -NO2, -CF3, -0CF3, alkyl, alkenyl,
alkynyl,
haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalylalkyl,
heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl,
heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl,
cycloalkylheteroalkyl,
heterocycloalkyiheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy,
CA 02540459 2011-10-04
23c
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;
m, n and o are integers independently selected from the group consisting of
0, 1, 2, 3 and 4;
or a pharmaceutically acceptable salt or prod rug thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0112] In this specification a number of terms are used which are well
known to
a skilled addressee. Nevertheless for the purposes of clarity a number of
terms will be
defined.
[0113] As used herein, the term unsubstituted means that there is no
substituent or that the only substituents are hydrogen.
[0114] The term "optionally substituted" as used throughout the
specification
denotes that the group may or may not be further substituted or fused (so as
to form a
condensed polycyclic system), with one or more substituent groups. Preferably
the
substituent groups are one or more groups independently selected from the
group
consisting of halogen, =0, =S, -CN, -NO2, -CF3, -0CF3, alkyl, alkenyl,
alkynyl,
haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalylalkyl,
heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl,
heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl,
cycloalkylheteroalkyl,
heterocycloalkyiheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy,
CA 02540459 2006-03-21
24
hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl,
alkoxyaryl,
alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy,
cycloalkyloxy, 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)0R5, CONHR5, NHCOR5, NHCOOR5, NHCONHR5, C(=NOH)R5, -SH, -
SR5, -0R5 and acyl.
[0115] "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 C1-C6 unless otherwise noted. Examples of suitable straight and
branched
C1-C6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl,
sec-butyl, t-
butyl, hexyl, and the like.
[0116] "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 C1-
C6 alkyl group.
[0117] "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
C6 alkyl group.
[0118] "Arylamino" includes both mono-arylamino and di-arylamino unless
specified.
Mono-arylamino means a group of formula aryl NH-, in which aryl is as defined
herein.
di-arylamino means a group of formula (ary12) N- where each aryl may be the
same or
different and are each as defined herein for aryl.
[0119] "Acyl" means an alkyl-CO- group in which the alkyl group is as
described
herein. Examples of acyl include acetyl and benzoyl. The alkyl group is
preferably a Cr
C6 alkyl group.
CA 02540459 2006-03-21
[0120] "Alkenyl" as a group or part of a group denotes an aliphatic
hydrocarbon
group containing at least one carbon-carbon double bond and which may be
straight or
branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon
atoms,
most preferably 2-6 carbon atoms, in the normal chain. The group may contain a
5 plurality of double bonds in the normal chain and the orientation about
each is
independently E or Z. Exemplary alkenyl groups include, but are not limited
to, ethenyl,
propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
[0121] "Alkoxy" refers to an ¨0-alkyl group in which alkyl is defined herein.
10 Preferably the alkoxy is a C1-C6alkoxy. Examples include, but are not
limited to,
nnethoxy and ethoxy.
[0122] "Alkenyloxy" refers to an -0- alkenyl group in which alkenyl is as
defined
herein. Preferred alkenyloxy groups are C1-C6alkenyloxy groups.
[0123] "Alkynyloxy" refers to an ¨0-alkynyl group in which alkynyl is as
defined
herein. Preferred alkynyloxy groups are C1-C6alkynyloxy groups.
[0124] "Alkoxycarbonyl" refers to an ¨C(0)-0-alkyl group in which alkyl is as
defined
herein. The alkyl group is preferably a C1-C6 alkyl group. Examples include,
but not
limited to, methoxycarbonyl and ethoxycarbonyl.
[0125] "Akylsulfinyl" means a ¨S(0)-alkyl group in which alkyl is as defined
above.
The alkyl group is preferably a C1-C6 alkyl group. Exemplary alkylsulfinyl
groups
include, but not limited to, methylsulfinyl and ethylsulfinyl.
[0126] "Alkylsulfonyl" refers to a ¨S(0)2-alkyl group in which alkyl is as
defined
above. The alkyl group is preferably a C1-C6 alkyl group. Examples include,
but not
limited to methylsulfonyl and ethylsulfonyl.
[0127] "Alkynyl as a group or part of a group means an aliphatic hydrocarbon
group
containing a carbon-carbon triple bond and which may be straight or branched
preferably having from 2-14 carbon atoms, more preferably 2-12 carbon atoms,
more
preferably 2-6 carbon atoms in the normal chain. Exemplary structures include,
but are
not limited to, ethynyl and propynyl.
CA 02540459 2006-03-21
26
[0128] "Alkylaminocarbonyl" refers to an alkylamino-carbonyl group in which
alkylamino is as defined above.
[0129] "Cycloalkyl" refers to a saturated or partially saturated, monocyclic
or fused or
spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per
ring, such as
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.
[0130] "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.
[0131] The above discussion of alkyl and cycloalkyl substituents also applies
to the
alkyl portions of other substituents, such as without limitation, alkoxy,
alkyl amines,
alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester
substituents and
the like.
[0132] "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the
cycloalkyl and
alkyl moieties are as previously described. Exemplary monocycloalkylalkyl
groups
include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and
cycloheptylmethyl.
[0133] "Halogen" represents chlorine, fluorine, bromine or iodine.
[0134] "Heterocycloalkyl" refers to a saturated or partially saturated
monocycli,
bicyclic, or polycyclic ring containing at least one heteroatom selected from
nitrogen,
sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each
ring is
preferably from 3 to 10 membered, more preferably 4 to 7 membered. Examples of
suitable heterocycloalkyl substituents include
pyrrolidyl, tetrahydrofuryl,
tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino,
1,3-diazapane,
1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane.
[0135] "Heterocycloalkenyl" refers to a heterocycloalkyl as described above
but
containing at least one double bond.
CA 02540459 2006-03-21
27
[0136] "Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl group in
which the
heterocycloalkyl and alkyl moieties are as previously described. Exemplary
heterocycloalkylalkyl groups include (2-
tetrahydrofuryl)methyl,
(2-tetra hydrothiofura nyl)methyl.
[0137] "Heteroalkyl" refers to a straight- or branched-chain alkyl group
preferably
having from 2 to 14 atoms, more preferably 2 to 10 atoms in the chain, one or
more of
which is a heteroatom selected from S, 0, and N. Exemplary heteroalkyls
include alkyl
ethers, secondary and tertiary alkyl ainines, alkyl sulfides, and the like.
[0138] "Aryl" as a group or part of a group denotes (i) an optionally
substituted
monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having
ring atoms
that are all carbon) preferably having from 5 to 12 atoms per ring. Examples
of aryl
groups include phenyl, naphthyl, and the like; (ii) an optionally substituted
partially
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.
[0139] "Arylalkenyl" means an aryl-alkenyl- group in which the aryl and
alkenyl are
as previously described. Exemplary arylalkenyl groups include phenylallyl.
[0140] "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl
moieties are
as previously described. Preferred arylalkyl groups contain a C1.-5 alkyl
moiety.
Exemplary arylalkyl groups include benzyl, phenethyl and naphthelenemethyl.
[0141] "Arylacyl" means an aryl-acyl- group in which the aryl and acyl
moieties are as
previously described. In general the aryl moiety is attached to the alkyl
portion of the
acyl moiety, typically to the terminal carbon of the alkyl portion of the acyl
moiety.
Preferred arylacyl groups contain a C1..5 alkyl moiety in the acyl moiety.
Exemplary
arylacyl groups include 2-phenyl-acetyl.
[0142] "Heteroaryl" either alone or part of a group refers to groups
containing an
aomatic ring (preferably a 5 or 6 membererd aromatic ring) having one or more
heteroatoms as ring atoms in the aromatic ring with the remainder of the ring
atoms
being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.
Examples of hetreoaryl include thiophene, benzothiophene, benzofuran,
benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-
b]thiophene,
CA 02540459 2006-03-21
28
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- isoquinoliny11-, 2-, or 3- indolyl, and 2-, or 3-thienyl.
[0143] "Heteroarylalkyl" means a heteroaryl-alkyl group in which the
heteroaryl and
alkyl moieties are as previously described. Preferred heteroarylalkyl groups
contain a
lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
[0144] "Lower alkyl" as a group means unless otherwise specified, an aliphatic
hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms
in
the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-
propyl or
isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
[0145] 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 hydrolyzed would provide the acidic moiety. In some embodiments the
acidic
moiety may be attached to the ring position through an alkylene group such as
¨CH2-
or ¨CH2CH2-, or an alkenylene group such as -CH=CH-. Preferred positions for
attachment of the acidic moiety are the 5¨ and 6¨ring positions.
[0146] It is understood that included in the family of compounds of
Formula (I) are
isomeric forms including diastereoisomers, enantiomers, tautomers, and
geometrical
isomers in "E" or "Z" configurational 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.
[0147] Some of the compounds of the disclosed embodiments may exist as single
stereoisomers, racemates, and/or mixtures of enantiomers and /or
diastereomers. All
CA 02540459 2006-03-21
29
such single stereoisomers, racemates and mixtures thereof are intended to be
within
the scope of the subject matter described and claimed.
[0148] Additionally, Formula (1) is intended to cover, where applicable,
solvated as
well as unsolvated forms of the compounds. Thus, each formula includes
compounds
having the indicated structure, including the hydrated as well as the non-
hydrated
forms.
[0149] In addition to compounds of the Formula (I), the HDAC inhibiting agents
of the
various embodiments include pharmaceutically acceptable salts, prodrugs, and
active
metabolites of such compounds, and pharmaceutically acceptable salts of such
metabolites.
[0150] The term "Pharmaceutically acceptable salts" refers to salts that
retain the
desired biological activity of the above-identified compounds, and include
pharmaceutically acceptable acid addition salts and base addition salts.
Suitable
pharmaceutically acceptable acid addition salts of compounds of Formula (1)
may be
prepared from an inorganic acid or from an organic acid. Examples of such
inorganic
acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic
acids may be
selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and
sulfonic
classes of organic acids, examples of which are formic, acetic, propionic,
succinic,
glycolic, gluconic, lactic, mak, tartaric, citric, fumaric, maleic, alkyl
sulfonic,
arylsulfonic. Suitable pharmaceutically acceptable base addition salts of
compounds of
Formula (1) include metallic salts made from lithium, sodium, potassium,
magnesium,
calcium, aluminium, and zinc, and organic salts made from organic bases such
as
choline, diethanolamine, morpholine. Other examples of organic salts are:
ammonium
salts, quatemary salts such as tetramethylammonium salt; amino acid addition
salts
such as salts with glycine and arginine. Additional information on
pharmaceutically
acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th
Edition,
Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids,
it is
understood by those skilled in the art that the inventive compounds, agents
and salts
may exist in different crystalline or polymorphic forms, all of which are
intended to be
within the scope of the present invention and specified formulae.
[0151] "Prodrug" means a compound which is convertible in vivo by metabolic
means (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
CA 02540459 2006-03-21
. 30
may be convertible by hydrolysis in vivo to the parent molecule. Suitable
esters of
compounds of formula (I) containing a hydroxyl group, are for example
acetates,
citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates,
succinates,
fumarates, maleates, methylene-bis-f3-hydroxynaphthoates, gestisates,
isethionates,
di-p-toluoyltartrates, methanesulphonates, ethanesulphonates,
benzenesulphonates, p-
toluenesulphonates, cyclohexylsulphamates and quinates. As another example an
ester prodrug of a compound of formula (1) 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).
[0152] Preferred HDAC inhibiting agents include those having an IC50 value of
10 0.4
or less.
[0153] Specific compounds of the invention include the following:
341-(3-Dimethylamino-2,2-dimethyl-propy1)-2-
(
(2,2-dimethyl-propy1)-1H-benzoimidazol-5-y1]-N-
N
hydroxy-acrylamide
0
<
341-(3-Dimethylamino-2,2-dimethyl-propy1)-2-
isopropy1-1H-benzoimidazol-5-y1]-N-hydroxy-
-/ acrylamide
312-Buty1-1-(3-dimethylamino-2,2-dimethyl-
propy1)-1H-benzoimidazol-5-y1]-N-hydroxy-
acrylamide
0
3-[1-(3-Dimethylamino-2,2-dimethyl-propyI)-2-(2-
io11 nnethylsulfanyl-ethyl)-1H-benzoimidazol-5-
A-N-
- ________________________________ hydroxy-acrylamide
CA 02540459 2006-03-21
31
OH
3-[1-(3-Dimethylamino-2,2-dimethyl-propy1)-2-
ethoxyrnethy1-1H-benzoimidazol-5-y1]-N-
N hydroxy-acrylamide
/N
0
3-[1-(3-Dimethylamino-2,2-dimethyl-propy1)-2-
( N.
isobuty1-1H-benzoimidazol-5-y1]-N-hydroxy-
N
a cryla m ide
0
3-[1-(2-Diethylamino-ethyl)-2-isobuty1-1H-
( __ c" 40 benzoimidazol-5-y1]-N-hydroxy-acrylamide
r-N)
0
342-Buty1-1-(2-diethylamino-ethyl)-1H-
\ 10
N
benzoimidazol-5-y1FN-hydroxy-acrylamide
r-N)
312-But-3-yny1-1-(3-dimethylamino-2,2-dimethyl-
\ 40 propy1)-1H-benzoimidazol-5-y1]-N-hydroxy-
N
acrylamide
H OH 342-But-3-eny1-1-(3-dimethylamino-2,2-
dimethyl-propy1)-1H-benzoimidazol-5-y1]-N-
.
hydroxy-acrylamide
N OH 3-[2-But-3-eny1-1-(2-diethylamino-ethyl)-1H-
iobenzoimidazol-5-y1]-N-hydroxy-acrylamide
r-N)
CA 02540459 2006-03-21
32
342-But-3-yny1-1-(2-diethylamino-ethyl)-1H-
- ______ 10 0E1
benzoimidazol-5-y11-N-hydroxy-acrylamide
r-N)
HNcm 341-(3-Dimethylamino-2,2-d imethyl-propy1)-2-
\ (3,3,3-trifluoro-propy1)-1H-benzoirnidazol-5-y1]-N-
hydroxy-acrylamide
HN
F 3-[1-(2-Diethylaminc-ethyl)-2-(3,3,3-trifluoro-
F F o propyl)-1 H-benzoimidazol-5-y1]-N-hydroxy-
N acrylamide
õN H 341-(2-Diethylamino-ethyl)-2-ethoxymethy1-1 H-
\ _____ o<
N
40 benzoimidazol-5-y1FN-hydroxy-acrylamide
HN/ H 3-[1-(3-Dimethylamino-2,2-dimethyl-propyI)-2-
0 methyl-1 H-benzoimidazol-5-y1]-N-hydroxy-
acrylamide
(6,
341-(2-Diethylamino-ethyl)-2-(2,2-dimethyl-
NH
,CH propyI)-1 H-benzoimidazol-5-y1]-N-hydroxy-
N
acrylamide
r)
0 OH
N! N-Hydroxy-311-(3-isopropylamino-propy1)-2-
(3,3, 3-trifluoro-propy1)-1 H-benzoimidazo1-5-y1]-
N acrylamide
CA 02540459 2006-03-21
33
o 3-[2-(2,2-Dimethyl-propyI)-1-(2-isopropylamino-
ethyl)-1H-benzoimidazol-5-y1]-N-hydroxy-
N
acrylamide
/ NH
0
341-(2-Diisopropylamino-ethyl)-2-(2,2-dimethyl-
propy1)-1H-benzoimidazol-5-A-N-hydroxy-
N
acrylamide
0
341-(2-Diisopropylamino-ethyl)-2-isobuty1-1 H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide
0
311-(3-Dimethylamino-2,2-dimethyl-propy1)-2-
/ <
hex-3-eny1-1H-benzoimidazol-5-A-N-hydroxy-
acrylamide
3-[1-(3-Dimethylamino-2,2-dimethyl-propyI)-2-
io(2,4,4-trimethyl-penty1)-1H-benzoimidazol-5-y11-
7& ( N-hydroxy-acrylamide
/N
o
312-Cyclohexy1-1-(3-dimethylamino-2,2-
(JRNN = dimethyl-propy1)-1H-benzoimidazol-5-y1]-N-
\N-- hydroxy-acrylamide
342-Bicyclo[2.2.1]hept-5-en-2-y1-1-(3-
; dimethylamino-2,2-dimethyl-propyI)-1H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide
341-(2-Diethylamino-ethyl)-2-hex-3-eny1-1 H-
/ 40 benzoimidazol-5-y9-N-hydroxy-acrylamide
rN)
CA 02540459 2006-03-21
34
341-(2-Diisopropylamino-ethyl)-2-hex-3-eny1-1
/ ___ NN IP IHN benzoimidazol-5-y1FN-hydroxy-acrylamide
N)"
342-Hex-3-eny1-1-(2-isopropylamino-ethyl)-1
N
= benzoimidazol-5-y1FN-hydroxy-acrylamide
0
342-Hex-3-eny1-1-(3-isopropylamino-propy1)-1
/ 10
benzoimidazol-5-y1]-N-hydroxy-acrylamide
0
3-[1-(2-Ethylamino-ethyl)-2-hex-3-eny1-1H-
/ NN benzoimidazol-5-y1]-N-hydroxy-acrylamide
3-[1-(2-Diethylamino-ethyl)-2-hexyl-1 H-
benzoimidazol-5-yll-N-hydroxy-acrylamide
N-Hydroxy-3-[1-(3-isopropylamino-propyI)-2-
(2,4,4-trimethyl-penty1)-1H-benzoimidazol-5-y1]-
N acrylamide
0
3-[2-(2,2-Dimethyl-propyI)-1-(3-isopropylamino-
propyI)-1 H-benzoimidazol-5-y1FN-hydroxy-
N
acrylamide
,11
1" 341-(2-Diisopropylamino-ethyl)-2-(3,3,3-trifluoro-
propyI)-1 H-benzoimidazol-5-y1]-N-hydroxy-
F 111 acrylamide
F
CA 02540459 2006-03-21
N-Hydroxy-3[2-isobuty1-1 -(2-isopropylamino-
K a r ethyl)-1 H-benzoimidazol-5-y1]-acrylamide
N ''Illre-
3
/ NH
0
342-(2,2-Dimethyl-propy1)-1 -(2-ethylamino-
)( 0 ethyl)-1H-benzoimidazol-5-y11-N-hydroxy-
. 'P
\-- , acrylamide
0
341 -(2-Ethylami no-ethyl)-2-isobuty1-1 H-
K a TH benzoimidazol-5-y1]-N-hydroxy-acrylamide
HN
)
0
341 -(2-Diisopropylamino-ethyl)-2-(2,4,4-
( <
r
HO trimethyl-pentyI)-1 H-benzoi midazol-5-yll-
N-
hydroxy-acrylamide
)N)--
.
N-Hydroxy-341-(2-isopropylamino-ethyl)-2-
( < 10 : (2,4,4-trimethyl-pentyI)-1 H-benzoimidazol-
5-y1J-
N
)---- acrylamide
N
3-[1-(2-Ethylamino-ethyl)-2-(2,4,4-trimethyl-
. (I\ pentyI)-1 H-benzoimidazol-5-y1]-N-hydroxy-
NH--- .1" acrylamide
341 -(2-Diethylamino-ethyl)-2-(2,4,4-trimethyl-
(N 41 \ pentyI)-1 H-benzoimidazo1-5-y1]-N-hydroxy-
/) H''' acrylamide
341 -(2-Diethylamino-ethyl)-2-propy1-1 H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide
,
1"7,y" 40 \ -,,,,,
/'---
L---- 0
CA 02540459 2006-03-21
36
312-Buty1-1-(2-diisopropylamino-ethyl)-1H-
[.
= benzoimidazol-5-y1J-N-hydroxy-acrylamide
HO
gp-(2-ethylamino-ethyl)-1
benzoimidazol-5-A-N-hydroxy-acrylamide
H
f, 311 -(2-Diethylam ino-ethyl)-2-(2-methylsulfanyl-
ethyl)-1H-benzoimidazol-5-y1FN-hydroxy-
/ acrylamide
o 3[2-Buty1-1-(2-isopropylamino-ethyl)-1
benzoimidazol-5-y1FN-hydroxy-acrylamide
/ NH
0
OF1 342-Buty1-1-(3-isopropylamino-propy1)-1H-
\
benzoimidazol-5-y1]-N-hydroxy-acrylamide
0
341-(1-Benzyl-piperidin-4-y1)-2-buty1-1 H-
\ 40 benzoimidazol-5-A-N-hydroxy-acrylamide
44,
0
342-But-3-eny1-1-(2-ethylamino-ethyl)-1
/ 40 benzoimidazol-5-y1]-N-hydroxy-acrylamide
rNH
CA 02540459 2006-03-21
37
3[2-Hexy1-1-(2-isopropylamino-ethyl)-1 H-
\
benzoimidazol-5-A-N-hydroxy-acrylamide
/ NH
)(' 0 341-(2-Dimethylamino-ethyl)-2-(2,4,4-trimethyl-
(pentyI)-1 H-benzoimidazol-5-y1]-N-hydroxy-
rj acrylamide
341-(2-Ethylamino-ethyl)-2-hexyl-1 H-
40 NIH benzoimidazol-5-y11-N-hydroxy-acrylamide
0
N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-
' I \
(3,3,3-trifluoro-propyI)-1 H-benzoimidazol-5-y1]-
N
acrylamide
HN\
3-[1-(2-Dimethylamino-ethyl)-2-hex-3-eny1-1 H-
/ __ <
ip benzoinnidazol-5-yll-N-hydroxy-acrylamide
0
3-[1-(2-Amino-ethy1)-2-(2,4,4-trimethyl-penty1)-
< 40 OH 1 H-benzoimidazol-5-y1J-N-hydroxy-acrylamide
(-7(
112,4
0
3-[1-(2-Amino-ethyl)-2-(2-methoxy-nony1)-1H-
OH /
benzoimidazol-5-y1]-N-hydroxy-acrylamide
/ 11
Hp
õAN 342-Buty1-1-(2-dimethylamino-ethyl)-1H-
\ vi
benzoimidazol-5-y1]-N-hydroxy-acrylamide
CA 02540459 2006-03-21
38
o 311-(2-Dimethylamino-ethyl)-2-hexy1-1 H-
401
benzoimidazol-5-y1]-N-hydroxy-acrylamide
0
N-{2-[1-(2-Diethylamino-ethyl)-5-(2-
"" OH
hydroxycarbamoyl-vinyI)-1 H-benzoimidazol-2-
ylj-ethyl)-3,3-dimethyl-butyramide
o 3-{1-(2-Diethylamino-ethyl)-242-(2,2-dimethyl-
HN¨\ propionylamino)-ethy1]-1 H-benzoimidazol-5-y1}-
N
N-hydroxy-acrylamide
\
3-{1 -(2-Diethylam ino-ethyl)-2-[(2, 2-dimethyl-
r propionylamino)-methy1]-1 H-benzoimidazol-5-
y1}-N-hydroxy-acrylamide
rN)
N-E1-(2-Diethylamino-ethyl)-5-(2-
hydroxycarbamoyl-viny1)-1 H-benzoimidazol-2-
N
ylmethyli-butyramide
3-[1-(2-ethylamino-ethyl) -2-(3,3-dimethyl-butyI)-
____ (N
1 H-benzoimidazol-5-yli-N-hydroxy-acrylamide
OH
NH
0
3-[2-(3,3-Dimethyl-butyI)-1-(2-Dimethylamino-
)\ __
ethyl)-1 H-benzoimidazol-5-y1]-N-hydroxy-
N
acrylamide
¨4\
CA 02540459 2006-03-21
39
341-(2-Dimethylamino-ethyl)-2-penty1-1 H-
. 411 \ 0
benzoimidazol-5-y1]-N-hydroxy-acrylamide
F ___________ F
3-[1-(2-Dimethylamino-ethyl)-2-(2,2,2-trifluoro-
ethyl)-1H-benzoimidazol-5-yli-N-hydroxy-
N
4100 \0 acrylamide
HN-OH
=
0
N-Hydroxy-341-(5-methy1-1H-pyrazol-3-y1)-2-
õ
( 10 : (2,4,4-trimethyl-penty1)-1H-benzoimidazol-5-y9-
acrylamide
A /60/
341-(2-Ethylamino-ethyl)-2-penty1-I H-
2 isbenzoimidazol-5-y9-N-hydroxy-acrylamide
HN\
342-Butyl-I -pyrrolidin-3-y1-1 H-benzoimidazol-5-
ioyI)-N-hydroxy-acrylamide
NH
0
3-(2-Buty1-1-piperidin-4-y1-1H-benzoimidazol-5-
yI)-N-hydroxy-acrylamide
N
0
N-Hydroxy-311-(2-isopropylamino-ethyl)-2-
,
/ OH penty1-1H-benzoimidazol-5-y1Facrylamide
HN
0 N-Hydroxy-341-(2-methylamino-ethyl)-2-non-
3-
,
eny1-1H-benzoimidazol-5-y1]-acrylamide
__________________ 401
_---NH
CA 02540459 2006-03-21
N-Hydroxy-341-(2-methylamino-ethyl)-2-non-6-
10 eny1-1H-benzoinnidazol-5-y1]-acrylamide
io[r H 342-Hexy1-1-(2-methylannino-ethyl)-1H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide
0
N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-pentyl-
/ __ <
ioOH
1H-benzoimidazol-5-A-acrylamide
"N\
N-Hydroxy-3-[1-(2-methylamino-ethy1)-2-octyl-
11101 1H-benzoimidazol-5-y1Facrylamide
FIN \
0
341-(2-Amino-ethyl)-2-octy1-1H-benzoimidazol-
TH 5-y11-N-hydroxy-acrylannide
N2N
0
3-{2-Buty1-142-(isopropyl-methyl-amino)-ethy1]-
OH / <
1H-benzoimidazol-5-y1}-N-hydroxy-acrylamide
3-{112-(Ethyl-methyl-amino)-ethy1]-2-penty1-1
r(H-
ON
benzoimidazol-5-y1}-N-hydroxy-acrylamide
r-N\
CA 02540459 2006-03-21
41
0
0,4 3-(2-Hexy1-1-pyrrolidin-3-y1-1H-benzoimidazol-5-
2
yI)-N-hydroxy-acrylamide
OH 3[2-Buty1-1-(1-methyl-pyrrolidin-3-y1)-1 H-
a
N '"W"'
benzoimidazol-5-yli-N-hydroxy-acrylamide
N\
OH
3-(2-Butyl-1 -piperidin-3-y1-1 H-benzoimidazol-5-
a
N
yI)-N-hydroxy-acrylamide
0.4 3-(2-Hexy1-1-piperidin-3-y1-1H-benzoimidazol-5-
)
yI)-N-hydroxy-acrylamide
0 3-(1-{2-[Ethyl-(2-methoxy-ethyl)-amino]-ethyl}-2-
N
11101 N-0H penty1-1H-benzoimidazol-5-y1)-N-hydroxy-
H
acrylamide
0
0 3-{2-Butyl-1 42-(ethyl-methyl-amino)-ethy1]-1H-
N
H benzoimidazol-5-y1}-N-hydroxy-acrylamide
r
0 N-Hydroxy-341-(1-methyl-piperidin-3-y1)-2-
OH
r/1 401 penty1-1H-benzoimidazol-5-y1]-acrylamide
CA 02540459 2006-03-21
42
0 3-{142-(Ethyl-hexyl-amino)-ethy11-1
401 NOH
benzoimidazol-5-y1}-N-hydroxy-acrylamide
0 3-{142-(Ethyl-pentyl-amino)-ethy1]-1H-
401 N OH
benzoimidazol-5-y1}-N-hydroxy-acrylamide
o 3-{142-(Ethyl-heptyl-amino)-ethy1]-1H-
"N N,OH
benzoimidazol-5-y1}-N-hydroxy-acrylamide
jj-j-
0
(E)-3-(2-hexy1-1-(1-(2-hydroxyethyl)piperidin-3-
NH
\oH yl )- 1 H-benzo[d]imidazol-5-y1)-N-
hydroxyacrylamide
0
3-(2-Buty1-1-{24ethyl-(3-hydroxy-propyl)-amino]-
\NOH ethy11-1H-benzoimidazol-5-y1)-N-hydroxy-
. acrylamide
3-(1-{2-[Ethyl-(3-hydroxy-propy1)-amino]-ethyll-
/
/ ____ < S 2-penty1-1H-benzoimidazol-5-y1)-N-hydroxy-
acrylamide
CA 02540459 2006-03-21
43
o (E)-N-hydroxy-3-(1 -(1 -phenethylpyrrolidin-3-y1)-
1 H-benzo[d]imidazol-5-yl)acrylamide
o =(E)-N-hydroxy-3-(1 -(1 -pentylpiperidin-3-y1)-1
N--
\N benzo[d]imidazol-5-yl)acrylamide
3-{1-[2-(Butyl-ethyl-amino)-ethy1]-1H-
benzoimidazol-5-yll-N-hydroxy-acrylarnide
rrN)
0
(E)-N-hydroxy-3-(1-(1-phenethylpiperidin-3-y1)-
c,,
1 H-benzo[d]imidazol-5-ypacrylamide
o = (E)-N-hydroxy-3-(1-(1-(3-phenylpropyppiperidin-
Nc'H
H 3-y1)-1 H-benzo[d]imidazol-5-yl)acrylamide
41,
(E)-N-hydroxy-3-(1-(1-(3-phenylpropyl)pyrrolidin-
3-y1)-1 H-benzo[d]imidazol-5-yl)acrylamide
CA 02540459 2006-03-21
44
o 3-{141-(3,3-Dimethyl-buty1)-pyrrolidin-3-y1]-1 H-
N = voH
benzoimidazol-5-y1)-N-hydroxy-acrylamide
=
0 (E)-3-(1-(2-(diethylamino)ethyl)-1H-
N
1101
benzo[djimidazol-5-y1)-N-hydroxyacrylamide
rN)
0
- ___________________ õõ 3-[2-(4-Cyano-butyl)-1-(2-diethylamino-ethyl)-
\
C'El 1 H-benzoimidazol-5-y1FN-hydroxy-acrylamide
o (E)-3-(1-(1-butylpiperidin-3-y1)-1 H-
N
benzo[d]imidazol-5-y1)-N-hydroxyacrylamide
NH
OH
0 (E)-N-hydroxy-3-(1-(1-(pent-4-enyl)piperidin-3-
OH y1)-1 H-benzo[d]imidazol-5-yl)acrylamide
CA 02540459 2006-03-21
(E)-3-(1-(1-(3,3-dimethylbutyl)piperidin-4-y1)-1H-
benzo[d]imidazol-5-y1)-N-hydroxyacrylamide
tr,ori 3-[1-(2-Diethylamino-ethy1)-2-propylamino-1H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide
O (E)-N-hydroxy-3-(1 -(2-
N 4101 OH
(isopropyl(propyl)amino)ethyl)-1 H-
N benzo[d]imidazol-5-ypacrylamide
Ny
o 3-{142-(Butyl-isopropyl-amino)-ethy1]-1
benzoimidazol-5-y11-N-hydroxy-acrylamide
0 N-Hyd roxy-3-{1 -[2-(isopropyl-pentyl-amino)-
OH
ethyI]-1 H-benzoimidazol-5-y1}-acrylamide
\\r-N
3-[2-(5-Cyano-penty1)-1-(2-diethylamino-ethyl)-
\ 1 H-benzoimidazol-5-y11-N-hydroxy-acrylamide
1:
CA 02540459 2006-03-21
46
0 3-(1-{2-[(3,3-Dimethyl-buty1)-ethyl-aminoFethyl}-
401 ( H1 H-benzoimidazol-5-y1)-N-hydroxy-acrylamide
0 3-{1-[2-(Ethyl-propyl-am ino)-ethy1]-1
OH
110 benzoimidazol-5-y1}-N-hydroxy-acrylamide
0 N-Hyd roxy-3-(1 -{24isopropyl-(2-methyl-penty1)-
OH
amino]-ethyl}-1 H-benzoimidazol-5-y1)-acrylamide
140
o
"\r¨N
(E)-N-hydroxy-3-(1-(2-(isopropy1(4,4,4-
40, V trifluorobutypamino)ethyl)-1 H-benzo[d]imidazol-
N 5-yl)acrylamide
F F
0
3-[1-(3-Dimethylamino-2,2-dimethyl-propyI)-2-
OH
1101 propylamino-1 H-benzoinnidazol-5-y1]-N-hydroxy-
N acrylamide
CA 02540459 2006-03-21
47
o 3-{142-(Ethyl-hexyl-amino)-ethy11-2-methyl-1H-
i)
OH benzoimidazol-5-y1}-N-hydroxy-acrylamide
rN
o
3-{142-(Butyl-ethyl-amino)-ethy1]-2-
F __
N trifluoromethy1-1H-benzoimidazol-5-y1}-N-
NH
hydroxy-acrylamide
FrJ
0
3-{142-(Ethyl-hexyl-amino)-ethy1]-2-
F N OH
F __
trifluoromethy1-1H-benzoimidazol-5-y1}-N-
FriN hydroxy-acrylamide
rN
o
(E)-3-(1-(2-(dibutylamino)ethyl)-2-propy1-1H-
/,,
benzo[d]imidazol-5-y1)-N-hydroxyacrylamide
0 341-(2-Dipropylamino-ethyl)-1H-benzoimidazol-
OH
N
5-y1]-N-hydroxy-acrylamide
CA 02540459 2006-03-21
48
o N-Hydroxy-3-(1-{2-psopropyl-(3-methyl-butyl)-
amino]-ethyl}-1 H-benzoimidazol-5-y1)-acrylamide
O 3-(1-{2-[(3,3-Dimethyl-buty1)-methyl-amino]-
(OH
ethyl}-1 H-benzoimidazol-5-y1)-N-hydroxy-
7
acrylamide
N
O 3-(1-{2-[(2-Ethyl-butyl)-methyl-amino]-ethyl}-1
40/ ( H
\N benzoimidazo1-5-y1)-N-hydroxy-acrylamide
0
(E)-3-(1-(2-(bis(3,3-dimethylbutyl)amino)ethyly
N,,OH
1 H-benzo[d]imidazol-5-y1)-N-hydroxyacrylamide
0 (E)-3-(1-(2-(diisobutylamino)ethyl)-1H-
NVOH benzo[d]imidazol-5-y1)-N-hydroxyacrylamide
0 3-{14243,3-Dimethyl-butylamino)-ethy1]-1 H-
N
N/OH
benzoimidazol-5-y1}-N-hydroxy-acrylamide
HN
CA 02540459 2006-03-21
49
0 N-Hydroxy-3-{1-[2-(methyl-pent-4-enyl-amino)-
N SI N/OH
ethyl]-1H-benzoimidazol-5-y1}-acrylamide
N
N
,
0 3-(1-{2-[(3,3-Dimethyl-buty1)-propyl-amino]-
/) 40 õ, Nõ..õ...OH
N
ethyl}-1 H-benzoimidazol-5-y1)-N-hydroxy-
acrylamide
0 3-[1-(3-Dimethylamino-2,2-dimethyl-propyI)-2-
OH
\ 110 rr methylsulfanyl-1 H-benzoimidazol-5-y1]-N-
N hydroxy-acrylamide
N"----
/ o
3-{142-(3,3-Dimethyl-butylamino)-ethy1]-2-
õ.
propyl-1 H-benzoimidazo1-5-y1}-N-hydroxy-
acrylamide
\---- 0
34142-(3,3-Dimethyl-butylamino)-ethyl]-2-(2,2-
dimethyl-propy1)-1 H-benzoimidazo1-5-y1]-N-
7(
hydroxy-acrylamide
HN
k
CA 02540459 2006-03-21
0 3-
[1-{2-[Bis-(3,3-dimethyl-butyl)-amino]-ethyl)-2-
7(
< =
(2,2-dimethyl-propy1)-1H-benzoimidazol-5-A-N-
. hydroxy-acrylamide
0 3-{1-[2-(2,2-Dimethyl-propylam ino)-
ethyl]-1H-
OH
benzoimidazol-511}-N-hydroxy-acrylamide
3-(1-{2-[(2,2-Dimethyl-propyI)-propyl-amino]-
ethyll-1H-benzoimidazol-5-y1)-N-hydroxy-
acrylamide
0
3-{1 42-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl-
N OH
1H-benzoimidazol-5-y1)-N-hydroxy-acrylamide
NH
[0154] The compounds disclosed are hydroxamate compounds containing a
hydroxamic acid type moiety in one of the substituents that may be inhibitors
of
deacetylases, including but not limited to inhibitors of histone deacetylases.
The
5 hydroxamate compounds may be suitable for prevention or treatment of
a disorder
caused by, associated with or accompanied by disruptions of cell proliferation
and/or
angiogenesis when used either alone or together with a pharmaceutically
acceptable
carrier, diluent or excipient. An example of such a disorder is cancer. .
10
[0155] Administration of compounds within Formula (I) to humans can be by any
of
the accepted modes for enteral administration such as oral or rectal, or by
parenteral
administration such as subcutaneous, intramuscular, intravenous and
intradermal
routes. Injection can be bolus or via constant or intermittent infusion. The
active
CA 02540459 2006-03-21
51
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.
[0156] As used herein the term 'cancer' is a general term intended to
encompass the
vast number of conditions that are characterised by uncontrolled abnormal
growth of
cells.
[0157] It is anticipated that the compounds of the invention will be useful in
treating
various cancers including but not limited to bone cancers including Ewing's
sarcoma,
osteosarcoma, chondrosarcoma and the like, brain and CNS tumours including
acoustic neuronia, neuroblastomas, glioma and other brain tumours, spinal cord
tumours, breast cancers, colorectal cancers, advanced colorectal
adenocarcinomas,
colon cancers, endocrine cancers including adenocortical carcinoma, pancreatic
cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer,
multiple
endocrine neoplasma, gastrointestinal cancers including stomach cancer,
esophageal
cancer, small intestine cancer, Liver cancer, extra hepatic bile duct cancer,
gastrointestinal carcinoid tumour, gall bladder cancer, genitourinary cancers
including
testicular cancer, penile cancer, prostate cancer, gynaecological cancers
including
cervical cancer, ovarian cancer, vaginal cancer, uterus/endometrium cancer,
vulva
cancer, gestational trophoblastic cancer, fallopian tube cancer, uterine
sarcoma, head
and neck cancers including oral cavity cancer, lip cancer, salivary gland
cancer, larynx
cancer, hypopharynx cancer, orthopharynx cancer, nasal cancer, paranasal
cancer,
nasopharynx cancer, leukemias including childhood leukemia, acute lymphocytic
leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic
myeloid
leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell
leukemia,
myelomas, haematological disorders including myelodysplastic syndromes,
myeloproliferative disorders, aplastic anemia, Fanconi anemia, Waldenstroms
Macroglobulinemia, lung cancers including small cell lung cancer, non-small
cell lung
cancer, lymphomas including Hodgkin's disease, non-Hodgkin's lymphoma,
cutaneous
T-cell lymphoma, peripheral T-cell lymphoma, AIDS related Lymphoma, B-cell
lymphoma, Burkitt's lymphomaõ eye cancers including retinoblastoma,
intraocular
melanoma, skin cancers including melanoma, non-melanoma skin cancer, merkel
cell
cancer, soft tissue sarcomas such as childhood soft tissue sarcoma, adult soft
tissue
sarcoma, Kaposi's sarcoma, urinary system cancers including kidney cancer,
Wilms
tumour, bladder cancer, urethral cancer, and transitional cell cancer.
CA 02540459 2006-03-21
52
[0158] Exemplary cancers that may be treated by the compounds of the present
invention are breast cancer, lung cancer, ovarian cancer, prostate cancer,
head and
neck cancer, renal cancer (e.g. renal cell carcinoma), gastric cancer, colon
cancer,
colon cancer, colorectal cancer and brain cancer.
[0159] Exemplary cancers that may be treated by compounds of the present
inventions include but are not limited to B-cell lymphoma (e.g. Burkitt's
lymphoma),
leukemias (e.g. acute promyeiocytiC leukemia), cutaneous T-cell lymphoma
(CTCL)
and peripheral T-cell lymphoma.
[0160] Exemplary cancers that may be treated by compounds of the present
invention include solid tumors and hematologic malignancies. In another
embodiment,
preferred cancers that may be treated the compounds of the present invention
are
colon cancer, prostate cancer, hepatoma and ovarian cancer.
[0161] The compounds may also be used in the treatment of a disorder
involving,
relating to or, associated with dysregulation of histone deacetylase (HDAC).
[0162] There are a number of disorders that have been implicated by or known
to be
mediated at least in part by HDAC activity, where HDAC activity is known to
play a role
in triggering disease onset, or whose symptoms are known or have been shown to
be
alleviated by HDAC inhibitors. Disorders of this type that would be expected
to be
amenable to treatment with the compounds of the invention include the
following but
not limited to: Proliferative disorders (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;
CA 02540459 2006-03-21
53
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.
[0163] In using the compounds of the invention they can be administered in any
form
or mode which makes the compound bioavailable. One skilled in the art of
preparing
formulations can readily select the proper form and mode of administration
depending
upon the particular characteristics of the compound selected, the condition to
be
treated, the stage of the condition to be treated and other relevant
circumstances. We
refer the reader to Remingtons Pharmaceutical Sciences, 19th edition, Mack
Publishing
Co. (1995) for further information.
[0164] The compounds of the present invention can be administered alone or in
the
form of a pharmaceutical composition in combination with a pharmaceutically
acceptable carrier, diluent or excipient. The compounds of the invention,
while
effective themselves, are typically formulated and administered in the form of
their
pharmaceutically acceptable salts as these forms are typically more stable,
more easily
crystallised and have increased solubility.
[0165]The compounds are, however, typically used in the form of pharmaceutical
compositions which are formulated depending on the desired mode of
administration.
As such in a further embodiment the present invention provides a
pharmaceutical
composition including a compound of Formula (I) and a pharmaceutically
acceptable
CA 02540459 2006-03-21
54
carrier, diluent or excipient. The compositions are prepared in manners well
known in
the art.
[0166] 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 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.
[0167] 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).
[0168] In addition to being able to be administered in combination with one or
more
additional drugs that include chemotherapeutic drugs or HDAC inhibitor drugs
the
compounds of the invention may be used in a combination therapy. When this is
done
the compounds are typically administered in combination with each other. Thus
one or
more of the compounds of the invention may be administered either
simultaneously (as
' a combined preparation) or sequentially in order to achieve a desired
effect. This is
especially desirable where the therapeutic profile of each compound is
different such
that the combined effect of the two drugs provides an improved therapeutic
result
[0169] Pharmaceutical compositions of this invention for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions,
CA 02540459 2006-03-21
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),
5 and
suitable mixtures thereof, vegetable oils (such as olive oil), and injectable
organic
esters such as ethyl oleate. Proper fluidity can be maintained, for example,
by the use
of coating materials such as lecithin, by the maintenance of the required
particle size in
the case of dispersions, and by the use of surfactants.
10
[0170] These compositions may also contain adjuvants such as preservative,
wetting
agents, emulsifying agents, and dispersing agents. Prevention of the action of
microorganisms may be ensured by the inclusion of various antibacterial and
antifungal
agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
It may
also be desirable to include isotonic agents such as sugars, sodium chloride,
and the
15 like.
Prolonged absorption of the injectable pharmaceutical form may be brought
about
by the inclusion of agents that delay absorption such as aluminium
monostearate and
gelatin.
[0171] If desired, and for more effective distribution, the compounds can be
20
incorporated into slow release or targeted delivery systems such as polymer
matrices,
liposomes, and microspheres.
[0172] The injectable formulations can be sterilized, for example, by
filtration through
a bacterial-retaining filter, or by incorporating sterilizing agents in the
form of sterile
25 solid
compositions that can be dissolved or dispersed in sterile water or other
sterile
injectable medium just prior to use.
[0173] Solid dosage forms for oral administration include capsules, tablets,
pills,
powders, and granules. In such solid dosage forms, the active compound is
mixed with
30 at least one inert, pharmaceutically acceptable excipient or carrier
such as sodium
citrate or 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
35 carbonate, potato or tapioca starch, alginic acid, certain silicates,
and sodium
carbonate, e) solution retarding agents such as paraffin, f) absorption
accelerators
such as quaternary ammonium compounds, g) wetting agents such as, for example,
CA 02540459 2006-03-21
56
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.
[0174] Solid compositions of a similar type may also be employed as fillers in
soft
and hard-filled gelatin capsules using such excipients as lactose or milk
sugar as well
as high molecular weight polyethylene glycols and the like.
[0175] The solid dosage forms of tablets, dragees, capsules, pills, and
granules can
be prepared with coatings and shells such as enteric coatings and other
coatings well
known in the pharmaceutical formulating art. They may optionally contain
opacifying
agents and can also be of a composition that they release the active
ingredient(s) only,
or preferentially, in a certain part of the intestinal tract, optionally, in a
delayed manner.
Examples of embedding compositions which can be used include polymeric
substances and waxes.
[0176] If desired, and for more effective distribution, the compounds can be
incorporated into slow release or targeted delivery systems such as polymer
matrices,
liposomes, and microspheres.
[0177] The active compounds can also be in microencapsulated form, if
appropriate,
with one or more of the above-mentioned excipients.
[0178] Liquid dosage forms for oral administration include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition
to the
active compounds, the liquid dosage forms may contain inert diluents commonly
used
in the art such as, for example, water or other solvents, solubilizing agents
and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
acetate,
benzyl 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.
[0179] Besides inert diluents, the oral compositions can also include
adjuvants such
as wetting agents, emulsifying and suspending agents, sweetening, flavoring,
and
perfuming agents.
CA 02540459 2006-03-21
57
[0180] Suspensions, in addition to the active compounds, may contain
suspending
agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene
sorbitol and
sorbitan esters, microcrystalline cellulose, aluminium metahydroxide,
bentonite, agar-
s agar, and tragacanth, and mixtures thereof.
[0181] Compositions for rectal or vaginal administration are preferably
suppositories
which can be prepared by mixing the compounds of this invention with suitable
non-
irritating excipients or carriers such as cocoa butter, polyethylene glycol or
a
suppository wax which are solid at room temperature but liquid at body
temperature
and therefore melt in the rectum or vaginal cavity and release the active
compound.
[0182] Dosage forms for topical administration of a compound of this invention
include powders, patches, sprays, ointments and inhalants. The active compound
is
mixed under sterile conditions with a pharmaceutically acceptable carrier and
any
needed preservatives, buffers, or propellants which may be required.
[0183] The term "therapeutically effective amount" or "effective amount" is an
amount
sufficient to effect beneficial or desired results. An effective amount can be
administered in one or more administrations. An effective amount is typically
sufficient
to palliate, ameliorate, stabilize, reverse, slow or delay the progression of
the disease
state. A therapeutically effective amount can be readily determined by an
attending
diagnostician by the use of conventional techniques and by observing results
obtained
under analogous circumstances. In determining the therapeutically effective
amount a
number of factors are to be considered including but not limited to, the
species of
animal, its size, age and general health, the specific condition involved, the
severity of
the condition, the response of the patient to treatment, the particular
compound
administered, the mode of administration, the bioavailability of the
preparation
administered, the dose regime selected, the use of other medications and other
relevant circumstances.
[0184] A preferred dosage will be a range from about 0.01 to 300 mg per
kilogram of
body weight per day. A more preferred dosage will be in the range from 0.1 to
100 mg
per kilogram of body weight per day, more preferably from 0.2 to 80 mg per
kilogram of
body weight per day, even more preferably 0.2 to 50 mg per kilogram of body
weight
per day. A suitable dose can be administered in multiple sub-doses per day.
CA 02540459 2006-03-21
58
[0185] 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 preferred histone deacetylase
inhibitors
are those that interact with, and/or reduce the activity of a histone
deacetylase which is
involved in tumorigenesis, and these compounds may be useful for treating
proliferative
diseases. Examples of such cell proliferative diseases or conditions include
cancer
(include any metastases), psoriasis, and smooth muscle cell proliferative
disorders
such as restenosis. The inventive compounds may be particularly useful for
treating
tumors such as breast cancer, colon cancer, lung cancer, ovarian cancer,
prostate
cancer, head and/or neck cancer, or renal, gastric, pancreatic cancer and
brain cancer
as well as hematologic malignancies such as lymphomas and leukemias. In
addition,
the inventive compounds may be useful for treating a proliferative disease
that is
refractory to the treatment with other chemotherapeutics; and for treating
hyperproliferative condition such as leukemias, psoriasis and restenosis. In
other
embodiments, compounds of this invention can be used to treat 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.
[0186] Additionally compounds of the various embodiments disclosed herein may
be
useful for treating neurodegenerative diseases, and inflammatory diseases
and/or
immune system disorders.
[0187] In one embodiment the disorder is selected from the group consisting of
cancer, inflammatory diseases and/or immune system disorders (e.g. rheumatoid
CA 02540459 2006-03-21
59
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.
[0188] The histone deacetylase inhibitors of the invention have significant
antiproliferative effects and promote differentiation, cell cycle arrest in
the G1 or G2
phase, and induce apoptosis.
SYNTHESIS OF DEACETYLASE INHIBITORS
[0189] The agents of the various embodiments may be prepared using the
reaction
routes and synthesis schemes as described below, employing the techniques
available
in the art using starting materials that are readily available. The
preparation of
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, Td Edition, John Wiley & Sons, 1999. Alternatively, other reactions
disclosed herein or known in the art will be recognized as having
applicability for
preparing other compounds of the various embodiments.
[0190] Reagents useful for synthesizing compounds may be obtained or prepared
according to techniques known in the art.
[0191] In the examples described below, unless otherwise indicated, all
temperatures in the following description are in degrees Celsius and all parts
and
percentages are by weight, unless indicated otherwise.
[0192] Various starting materials and other reagents were purchased from
commercial suppliers, such as Aldrich Chemical Company or Lancaster Synthesis
Ltd.,
and used without further purification, unless otherwise indicated.
Tetrahydrofuran
(THE) and N,N-dimethylformamide (DMF) were purchased from Aldrich in SureSeal
CA 02540459 2006-03-21
bottles and used as received. All solvents were purified by using standard
methods in
the art, unless otherwise indicated.
[0193] The reactions set forth below were performed under a positive pressure
of
5 nitrogen, argon or with a drying tube, at ambient temperature (unless
otherwise stated),
in anhydrous solvents, and the reaction flasks are fitted with rubber septa
for the
introduction of substrates and reagents via syringe. Glassware was oven-dried
and/or
heat-dried. Analytical thin-layer chromatography was performed on glass-backed
silica
gel 60 F 254 plates (E Merck (0.25 mm)) and eluted with the appropriate
solvent ratios
10 (v/v). The reactions were assayed by TLC and terminated as judged by the
consumption of starting material.
[0194] The TLC plates were visualized by UV absorption or with a p-
anisaldehyde
spray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20wt% in
ethanol)
15 which was activated with heat, or by staining in iodine chamber. Work-
ups were
typically done by doubling the reaction volume with the reaction solvent or
extraction
solvent and then washing with the indicated aqueous solutions using 25% by
volume of
the extraction volume (unless otherwise indicated). Product solutions were
dried over
anhydrous sodium sulfate prior to filtration, and evaporation of the solvents
was under
20 reduced pressure on a rotary evaporator and noted as solvents removed in
vacuo.
Flash column chromatography [Still et al, J. Org. Chem., 43, 2923 (1978)] was
conducted using Silica gel 60 (Merck KGaA, 0.040-0.063 mm, 230-400 mesh ASTM)
and a silica gel:crude material ratio of about 20:1 to 50:1, unless otherwise
stated.
Hydrogenolysis was done at the pressure indicated or at ambient pressure.
[0195] NMR spectra were recorded on a Bruker AVANCE 400 spectrometer
operating at 400 MHz for 11-I 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-d6
(2.50
and 39.5 ppm) or an internal tetramethylsilane standard (0.00 ppm) when
appropriate.
Other NMR solvents were used as needed. When peak multiplicities are reported,
the
following abbreviations are used: s = singlet, d = doublet, t = triplet, q =
quartet, m =
multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplets.
Coupling
constants, when given, are reported in Hertz.
[0196] Mass spectra were obtained using LC/MS either in ESI or APCI. All
melting
points are uncorrected.
CA 02540459 2006-03-21
61
[0197] All final products had greater than 90% purity (by HPLC at wavelengths
of
254 nm and/or 220 nm). Analytical HPLC conditions for purity check: Xterra
RP18 3.5
gm 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%6 for additional 0.1 min; Solvent A: H20 with 0.1% TFA;
Solvent B:
acetonitrile with 0.1% TFA.
[0198] The following examples are intended to illustrate the embodiments
disclosed
and are not to be construed as being limitations thereto. Additional
compounds, other
than those described below, may be prepared using the following described
reaction
scheme or appropriate variations or modifications thereof.
SYNTHESIS
[0199] Scheme I and ll illustrates the procedure 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 ll starting with a substituted cinnamic acid (e.g. trans-3-nitro-
4-chloro-
cinnamic acid), appropriate amine component (R1NF12), carboxylic acid
component
(R2CO2H, Scheme I) or aldehyde (R2CHO, Scheme II), and appropriate
hydroxylamine
or N-alkyl hydroxylamine (NHR3OH where R3 is defined as above in Formula la).
[0200] Specifically, the hydroxamate compounds Formula lb can be synthesized
by
the synthetic route shown in Scheme I. The reaction of trans-4-chloro-3-
nitrocinnamic
acid (I) with an amine R1NH2 in the present 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, the
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 R2CO2H 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).
CA 02540459 2006-03-21
62
Scheme I
0 WNH0 0
02N la 02N
OH Base la OH Me0H 02N lb 0v
pp.
CI IW dioxane WN H2SO4
H ii H iii
0
Me0H o, RiNH2,/
02N
H+ Base
CI IW dioxane
la
0
SnCl2 H2N R2CO2H
AcOH/MedHN coupling reagent
IV
0 NH2 0
n
0 NH
RV and/orO' .,R2
NH 0 N
R' W
V
0 0
ItpLILs.... R44 40 , NH2OH.H.C1 R2 -\N pl N.OH
NaOCH3
R' VI vii
[0201] 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
R2CH0 0
SnCl2 or Zn N
0
02N AcOH/Me0H N
4
R'
WN Ilirvi
H Ill HCO2H, SnCl2
__________________________________________ )1,- VI (R2 = H)
Me0H
[0202] in both Schemes I & II, the benzimidazole ring may be constructed by a
cyclization step involving either an aldehyde or a carboxylic acid. The
following
reaction steps 1-4 refer to the use of carboxylic acid for the cyclization of
(IV) via (V) to
form benzimidazole derivatives (VI), followed by the conversion of ester (VI)
to the
CA 02540459 2006-03-21
63
hydroxamate (VII). For one-pot cycylization of (III) to (VI), see the
procedures under
Example 1.
Step 1: Reduction of nitro group
[0203] 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 Na2SO4 for 1 hour. It was filtered and
concentrated; the diamino product (IV) was purified by flash chromatography.
Step 2: Amide formation
[0204] To a pre-stirred solution of carboxylic acid (1.1 mmol), diamino
product (IV,
1.0 mmol) and PyBOP (1.1 mmol) in 10 mL of dried dichloromethane, was added
DIEA
(3.0 mmol) via a syringe. The resulting mixture was stirred at room
temperature for 4
hours. The amide product (V) was purified by silica gel column chromatography.
Step 3: Cyclization
[0205] The amide product (V), obtained in Step 2, was treated with 5 mL of
glacial
acetic acid, the resulting solution was heated to 75 C for 24 hours. After
cooling down
to it, the solvent was removed under vacuum to give product (VI) near
quantitatively.
Step 4: Hydroxamic acid formation
[0206] To a stirred solution of ester (VI) and NH2OH=FICI (10 equiv.) in Me0H
(0.5
M) was added Na0Me 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. IN 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 TEA salt (isolated yield varies
between
40 - 70%).
[0207] 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(Ri2)so2R13_, R11N(R12)C(0)N(R12)R13- and heteroalkyl.
For
example, in the case of Z is -CH=CH- and attached to C5-position in Formula
lb, such
compound(s) (XIII) can be synthesized by analogous method illustrated in
Schemes I &
CA 02540459 2006-03-21
64
starting with appropriate (III), appropriate Fmoc protected amino acids,
appropriate acid
chlorides or aldehydes, and hydroxylamine.
Scheme III
o o
OMe
02N
SnC12/H+ H2N lei
0
OMe I.
R1-N Me0H HN
i
H III R1 IV ,
- -
H 0 A Fmoc-HN-0-14 i 0
Fmoc-N n
n OH 0 H2N 0
and/or 0 OMe
__________________ N. 40 ',
I
- HN Fmoc-HN n R1
1 -
R1 VIII IX
Me0H/H+
0 0
N 0
OMe 20% Piperidine N
nN 4g _________ if/ _____ 1 40 OMe
n
H2N 1 Fmoc-HN rj
Ri XI R1 x
R12-CHO
NaBH(OAc)3 R12-COCI [or R12-S02C1]
0
CH3COOH 0 Triethyl amine
1 N
0
z 1 Iµl 0
OMe 0 z __ i 40 m
-N1--i n FJ e
i-NH 1 n r1 R12 R1 XII
R"12 Ri XiV [R12-S02] NH2OH.HCI
NH2OH.HCI
N
N Na0Me 0
a0Me 0
0
n 11101
NH 0 NH
1 )1\ii i <N OH
.
OH R12 H
rN1-1 n ri RI 1
n=1, 2
n=1, 2
[0208] 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-
, R"C(0)N(R12)R13-, Fe1s02N(R12)R13_, R11N(R12)C(0)R13-, R11N(R12)S02R13-,
R11N(R12)C(0)N(R12)R13- and heteroalkyl; and Z is attached to C5-position, can
be
synthesized by the synthetic route shown in Scheme Ill. Appropriate
intermediate (Ill)
was reduced with tin chloride to the corresponding diamines (IV). The coupling
reaction
with appropriate Fmoc protected amino acids in the presence of PyBOP gave
coupling
product(s) (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)
CA 02540459 2006-03-21
with an appropriate acid chloride or an appropriate sulfonyl chloride gave
(XII) and the
target compounds (XIII) were obtained by using similar method described in
Scheme I.
[0209] When (XI) was reacted with an appropriate aldehyde under reduction
5 conditions (NaBH(OAc)3 /CH3CO2H), (XIV) was obtained and can be transformed
to
corresponding hydroxamate derivatives (XV) by the same methods described
above.
[0210] Scheme IV illustrates some reactions to further modify R1 side chain.
If the R1
side chain contained a protecting group such as Boc in compound (Vial), it
could be
10 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 (VIlb, Vlic, Viid and Vile) through new intermediates (Vib, Vic,
Vid and
Vie). The above described methods were also applied to R1 = heterocycles,
e.g., R1 =
N-Boc-piperidin-3-yl, N-Boc-piperidin-4-y1 and N-Boc-pyrrolidin-3-yl.
CA 02540459 2006-03-21
66
Scheme IV
o o 0
R2-N SI OMe H4*
--).- R2-<'
N fa `- OMe NH OKHCI N 0 NH
2 ,... R2_</
N N W-P N OH
1
Vial H
NaOCH3 -.. Vla L.i Vila
BOCN .Ri 1 HN..R11 H14..
R11
0
N
OMe
NH2OH.HCI R2_.N fa 0
R12CO2H or R2-<' 0
N NOH.
(Rump ______,...
N iqP H
v. L----. Vlb NaOCH3
H VIlb
. ' Y. Ri 1 12
R N. u
0 it R
o
o
o
OMe 0
N 12
R CHO R2--N liffl N id N,OH
R2- 1101 OMe NH2OH.HCI R2_.
ip. .
N
N 14-F H
Reductive H Vic NaOCH3 H
L-1 via VlIc
amination Ri2 NRi 1,
---....õ--
HN,Ri 1 0.12 m
rl 1'1' R11
0
N0
N N-OH
R12X N NH2OH.HCI R2_<, 0
H
N
H Vld NaOCH3
(X = halide) R12____N, H I/11d
R11
R1 2._ pd,
R11
0 ''
\ 0
OMe N-
OH
R2-INI 1111 N
H
N
R12S0201 Vie NaOCH3
1:3 IfIle
R124-N,Ril
8 R12_g-N-Ril
II
0
[0211] Scheme V illustrates some alternative method to prepared (Via) and
(Vic).
The primary amine (II1a2) was prepared either from (la) or via (Mai). The
derivertization of the amino group (e.g., reductive amination) could be
performed either
from (111a2) or (VIa2). The products, i.e., (111a2-1) and (VIa2-1), could be
further
derivertized (e.g., reductive amination of the secondary amine).
CA 02540459 2006-03-21
67
Scheme V
0
H2N''-'NHBoc 02N
02N io o, ________ HN H+ 02N
CI H 111a1 HN
la
NHBoc HNH2 111
a2
H2N,
¨ NH2
0
0 0
02N n R2CHO or HCO2H R24 al 1
R12CH0 __ R241
SCI2 or Zn N 11W
HN
11182 V1a2 reductive amination
Vla2-1
NH2 H2N
R12CHO HN
reductive amination
R2CHO or HCO2H R12
SnCl2 or Zn N
(y"
02N = 0.- 0 fa 2N
0
N
HN HN IWP
Vla2-2
111a2-1
R12
\¨N
R1`2,..¨ NH
[0212] The following preparations and examples are given to enable those
skilled in the
art to more clearly understand and to practice the subject matter hereof. They
should
not be considered as limiting the scope of the disclosure, but merely as being
illustrative and representative thereof.
Preparation of intermediates III
[0213] Compound (III) was prepared either from (I) via (II) or from (I) via
(la)
(Scheme I and V). The following are examples of (III).
Intermediate 1
3-[4-(2-Dimethylamino-ethylamino)-3-nitro-phenyn-acrylic acid methyl ester
[0214] A mixture of 3-(4-chloro-3-nitro-phenyl)acrylic acid methyl ester (la,
0.658 g,
2.72 mmol), N,N-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 Na2CO3. The DCM (x3)
, extracts were concentrated and the residue was added Et0Ac-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 Fi]). 1H NMR (CDCI3 CD30D)
8 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
CA 02540459 2006-03-21
68 =
(2H, t, J = 6.4 Hz), 2.23 (6H, s); 13C NMR (CDCI3 + CD30D) 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
344-(2-Diethylamino-ethylamino)-3-nitro-phenylFacrylic acid methyl ester.
[0215] Yellow solid. LCMS (ESI) m/z: 322 ([M + HIP). 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
344-(2-Ethylamino-ethylamino)-3-nitro-phenylFacrylic acid methyl ester
[0216] Red solid. LCMS (ESI) m/z: 294 ([kl H]). 1H NMR (DMSO-d6) 58.49 (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
344-(2-lsopropylamino-ethylamino)-3-nitro-phenylFacrylic acid methyl ester
[0217] Red solid. LCMS (ESI) m/z: 308 ([M H]+). 1H NMR (DMSO-d6) 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 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
344-(3-Dimethylamino-2,2-dimethyl-propylamino)-3-nitro-phenylFacrylic
acid
methyl ester.
[0218] Red solid. LCMS (ESI) m/z: 336 ([M + Hr.). 1H NMR (CDCI3) 8 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 = 16.1 Hz),
6.88 (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
CA 02540459 2006-03-21
69
[0219] Yellow solid. LCMS (ESI) m/z: 350 UM + Hr). 1H NMR (CDCI3) 8 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
[0220] Red solid. LCMS (ESI) m/z: 280 ([M + H]4). 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, d, J = 15.9 Hz), 3.80 (3H, s),
3.45 (2H, td,
J = 5.8, 5.6 Hz), 2.96 (2H, t, J = 6.2 Hz), 2.50 (3H, s).
Intermediate 8
314-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-pheny1]-acrylic acid
methyl
ester (111a1)
Step 1:
[0221] A suspension of trans-4-chloro-3-nitrocinnamic acid (1, 5.057 g, 22.22
mmol)
in Me0H (40 mL) and DCM (20 mL) was stirred and cooled in a dry-ice/acetone
bath.
SOCl2 (1.0 mL, 13.8 mmol) was added to the above mixture. Dry-ice bath was
removed, then the mixture was warmed to room temperature and stirred at 40 C
till the
reaction completed. The solution was evaporated to dryness to a pale yellow
solid
(5.364 g, 99.9%). HPLC purity at 254 nm: 99.5%; tR = 2.96 min. LCMS (ESI) m/z:
210
and 212 (very weak signal, [M+H-Me0H]+).
Step 2:
[0222] A mixture of 3-(4-chloro-3-nitro-phenyl)acrylic acid methyl ester (la,
0.243 g,
1.00 mmol), N-Boc-ethylenediamine (0.316 mL, 2.0 mmol) and triethylamine (0.50
mL,
3.59 mmoL) in dioxane (7 mL) was heated at 80 C for about 80 h. The solution
was
evaporated and the residue was added Me0H. The resulting solid was filtered
and
washed with Me0H. 344-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-pheny1]-
, acrylic acid methyl ester (111a1) was obtained as bright yellow solid
(9.193 g, 52.6%).
HPLC purity at 254 nm: 96.0-98.1%; tR = 3.27 min. LCMS (ESI) m/z: 366 (DM +
HIE),
310 (M+H-56), 266 (M+H-Boc). 1H NMR (CDCI3) 68.41 (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,
CA 02540459 2006-03-21
s); 13C NMR (CDCI3) 8 166.9, 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
5 3-(4-(2-Amino-ethylamino)4-nitro-phenylFacrylic acid methyl ester (111a2)
[0223] Method 1:
Remove Boc protecting group from (111a1) under acidic condition: 1) HCl/Me0H;
2)
TFA/DCM.
[0224] Method 2:
10 To the ester (la, 2.47 g, 10.2 mmol) in dioxane (102 mL, 0.1 M) was
added
ethylenediamine (Merck. Product no. 8.00947, 2.04 mL, 30.6 mmol) followed by
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 111a2 tR = 1.6 min, starting material la tR = 3.1 min). Upon
completion,
15 solvent was removed and the crude was dissolved in DCM. The solution was
washed
with water, brine, dried over Na2SO4 and filtered. The filtrate after removal
of the
solvent gave the titled compound 111a2. Yield =98 %, LCMS m/z: 266 ([M+H]).
Example 1
20 Preparation of
311 -(3-Dimethylamino-2,2-dimethyl-propy1)-2-(2,2-dimethyl-
propy1)-1H-benzoimidazol-5-A-N-hydroxy-acrylamide (1)
[0225] The titled compound (1) was prepared according to Scheme 1 and 11, by
using appropriate starting materials.
Step 1:
25 [0226]
To a pre-stirred solution of trans-4-chloro-3-nitrocinnamic acid (1, 11g,
48 '
mmol) in dioxane (200 mL) was added triethylamine (20 mL, 126 mmol), followed
by 3-
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
30 dissolve the residue. Conc. HCI was added till pH 1 with orange
precipitation. The
suspension was filtered and residue was washed with H20 several times to
obtain (11)
as orange solid (13 g, 84%). LCMS (ESI) m/z: 322 ([M+H]).
Step 2:
[0227] Compound (11,13 g, 40.5 mmol) was dissolved in Me0H (250 mL) followed
by
35
the addition of conc. 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. Na2CO3 was added till pH 8-9, subsequently, Me0H was added and
CA 02540459 2006-03-21
71
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:
[0228] To a stirred solution of ester (III, 1 equiv) and SnC12=2H20 (5 equiv)
in AcOH
and Me0H (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 conc. 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:
[0229] To a stirred solution of ester (VI) and NH2OH.HCI (10 equiv.) in Me0H
(0.5M)
was added Na0Me (20 equiv.) at ¨ 78 C. The reaction mixture was then allowed
to
warm up slowly to room temperature. The reaction was monitored by LC/MS and
was
completed in around 15 min. 1N HCI was then added slowly into the reaction
mixture at
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 di-TFA
salt
(isolated yield varies between 40 ¨ 70%). HPLC purity at 254 nm: 100%, tR =
0.78 min.
LCMS (ESI) m/z: 387 ([M+H]). 1H NMR (DMSO-d6) 8 0.99 (15H, s), 2.91 (6H, s),
2.92
(2H, s), 3.32 (2H, bs), 4.30 (2H, s), 6.49 (1H, d, J = 15.8 Hz), 7.56 (1H, d,
J = 9.0 Hz),
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-d6) 8 162.6, 154.2, 138.0, 135.3 (br), 134.7, 131.5,
122.8,
119.2, 115.2, 114.0,66.5, 51.1, 46.7, 38.4, 38.3, 33.6, 29.1, 22.8.
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Example 2
Preparation of 3-[1-(3-Dimethylamino-2,2-dimethyl-propy1)-2-isopropyl-1H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide (2)
[0230] 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 (ES!) miz: 359 ([M+H]+). 1H NMR (DMSO-d6) 6 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-propy1)-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (3)
[0231] 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%, tR = 0.89 min. LCMS (ES!) m/z: 373 ([M + 1H
NMR
(CD30D) 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 (CD30D) 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 341-(3-D imethylamino-2,2-di methyl-propyI)-2-(2-methylsu
Ifanyl-
ethyl)-1H-benzoimidazol-5-y1FN-hydroxy-acrylamide (4)
[0232] The titled compound (4) was prepared according to the procedures
described
in Example 1, by using appropriate starting materials. Yield: 17 mg as TFA
salt. HPLC
purity at 254 nm: 96.2%, tR = 0.75 min. LCMS (ES!) miz: 391 UM + 1H
NMR
(CD30D) 8 8.02 (1H, d, J = 8.3 Hz), 7.92 (1H, s), 7.80 (1H, d, J = 8.7 Hz),
7.69 (1H, d, J
= 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 (21-I, s),
3.03 (2H, t, J = 7.2 Hz), 2.95 (6H, s), 2.18 (3H, s), 1.25 (6H, s); 13C NMR
(CD30D) 8
163.7, 154.6, 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.
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73
Example 5
Preparation of 3-
[1-(3-Dimethylamino-2,2-dimethyl-propy1)-2-isobutyl-1H-
benzoimidazol-5-yl]-N-hydroxy-acrylamide (6)
[0233] 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-d6): 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 341-(2-Diethylamino-ethyl)-2-isobuty1-1H-benzoimidazol-5-yli-N-
hydroxy-acrylamide (7)
[0234] 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-d6): 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
342-Buty1-1-(2-diethylamino-ethyl)-1 H-benzoimidazol-5-y1]-N-
hydroxy-acrylamide (8)
[0235] 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
(EM +
Hr). 1H NMR (CD30D) 67.89 (1H, d, J = 8.6 Hz), 7.80 (1H, s), 7.71 (1H, d, J =
8.5 Hz),
7.45 (1H, d, J = 15.7 Hz), 6.44 (1H, d, J = 15.7 Hz), 4.90 (2H, overlapped
with DHO,
identified by COSY), 3.64 (2H, t-like, J = 7.6 Hz), 3.39 (4H, q, J = 7.6 Hz),
3.21 (2H, t, J
= 7.9 Hz), 1.89 (2H, pentet, J = 7.5 Hz), 1.52 (2H, m), 1.35 (6H, t, J. = 7.2
Hz), 1.00
(3H, t, J = 7.3 Hz); 13C NMR (CD30D) 8 163.6, 155.7, 138.1, 132.8, 132.1,
131.9,
124.6, 118.0, 113.2, 111.7, 48.3, 46.8 (2C), 38.6, 27.5, 24.7, 21.4, 12.0, 7.0
(2C)
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74
Example 8
Preparation of 342-But-3-yny1-1-(3-dimethylamino-2,2-dimethyl-propy1)-1H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide (9)
[0236] 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) rn/z: 369 ([K4 +Fi]). 1H NMR (DMSO-d6) 8 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) 5 162.8, 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 342-But-3-eny1-1-(3-dimethylamino-2,2-dimethyl-propy1)-1H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide (10)
[0237] The titled compound (10) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 99 %; tR = 0.80 min; LCMS (ESI) rn/z: 371 ([M + H].). 1H NMR (CD30D) 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 (CD30D) 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.
Example 10
Preparation of 342-But-3-eny1-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-y1]-
N-
hydroxy-acrylamide (11)
[0238] The titled compound (11) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC: 99.4
CYO tR =
0.52 min; LCMS (ESI) m/z: 357 ([M+H]+1). 1H NMR (CD30D) 5 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,
1= 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 (CD30D) 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.
CA 02540459 2006-03-21
Example 11
Preparation of 3-[2-But-3-yny1-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-y1]-
N-
' hydroxy-acrylamide (12)
[0239] The titled compound (12) was prepared according to the procedures
5 described in Example 1, by using appropriate starting materials. HPLC:
99.6 %; tiR =
0.37 min; LCMS (ESI) m/z: 355 ([M+H]). 1H NMR (CD300) 8 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, 6.0 Hz, 2H), 2.30 (t, J = 2.5 Hz, 1H),
1.21 (t, J = 7.2
10 Hz, 6H); 13C NMR (CD30D) 8 165.9, 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 341-(3-Dimethylamino-2,2-dimethyl-propy1)-2-(3,3,3-trifluoro-
15 propy1)-1H-benzoimidazol-5-y1]-N-hydroxy-acrylamide (13)
[0240] The titled compound (13) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 96.5 %; tR = 0.80 min; LCMS (ESI) m/z: 413 ([M+H]).
20 Example 13
Preparation of
341-(2-Diethylamino-ethyl)-2-(3,3,3-trifluoro-propy1)-1H-
benzoimidazol-5-y11-N-hydroxy-acrylamide (14)
[0241] The titled compound (14) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity:
96.4%; tR
25 = 1.37 min; LCMS (ESI) m/z: 399 ([M+H]). 1H NMR (DMSO-d6) 8 1.25 (6H,
t), 2.96
(2H, m), 3.31 (6H, 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
30 Preparation of 341-(2-Diethylamino-ethyl)-2-ethoxymethy1-1H-benzoimidazol-5-
y1]-N-hydroxy-acrylamide (15)
, [0242] The titled compound (15) was prepared according to the
procedures
described in Example 1, by using appropriate starting materials. HPLC purity:
98.1%; tR
= 0.48 min; LCMS (ESI) m/z: 361([M+H]).
CA 02540459 2006-03-21
76
Example 15
Preparation of
341-(3-Dimethylamino-2,2-dimethyl-propy1)-2-methy1-1H-
benzoimidazol-5-yli-N-hydroxy-acrylamide (16)
[0243] 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) 8 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-propy1)-1H-
benzoimidazol-5-y1FN-hydroxy-acrylamide (17)
[0244] The titled compound (17) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 99.9%, tR = 0.95 min. LCMS (ESI) m/z: 373 ([M+Hr). 1H NMR (CD30D) 8 7.85
(2H, t, J = 8.3 Hz), 7.75 (1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 15.8 Hz), 6.51
(1H, d, J =
15.8 Hz), 4.93 (2H, t, J = 6.1 Hz), 3.54 (2H, t, J = 8.1 Hz), 3.31 (4H, qt, J
= 7.3 Hz),
3.10 (2H, s), 1.27 (6H, t, J = 7.3 Hz), 1.06 (9H, s); 13C NMR (CD30D) 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-propy1)-2-(3,3,3-trifluoro-
propy1)-1H-benzoimidazol-5-y11-acrylamide (18)
[0245] The titled compound (18) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity:
96.8%; tR
= 0.72 min. LCMS (ESI) m/z: 399 ([M+H]). 1H NMR (DMSO-d6) 8 1.18 (6H, d), 2.07
(2H, m), 2.95 (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
342-(2,2-Dimethyl-propy1)-1-(2-isopropylamino-ethyl)-1H-
benzoimidazol-5-y1FN-hydroxy-acrylamide (19)
[0246] The titled compound (19) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 98.1%, tR = 0.86 min. LCMS (ESI) m/z: 359 ([M+H]+). 1H NMR (CD30D) 8 7.86
(1H, d, 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,
CA 02540459 2006-03-21
77 =
qt, J = 6.5 Hz), 3.13 (2H, s), 1.26 (6H, d, J = 6.2 Hz), 1.04 (9H, s); 13C NMR
(CD30D)
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 341-(2-Diisopropylamino-ethyl)-2-(2,2-dimethyl-propyl)-1H-
benzoimidazol-5-y1FN-hydroxy-acrylamide (20)
[0247] The titled compound (20) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 96.8%, tR = 0.94 min. LCMS (ESI) rn/z: 400 ([M+1-11+). 1H NMR (CD30D) 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 (CD30D) 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-Dilsopropylamino-ethyl)-2-isobuty1-1H-benzoimidazol-5-
y1]-
N-hydroxy-acrylamide (21)
[0248] The titled compound (21) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 95.3%, tR = 0.76 min. LCMS (ESI) m/z: 387 aM+Hr). 1H NMR (CD30D) 8 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).
Example 21
Preparation of 3-[1-(3-Dimethylami no-2,2-d i methyl-propy1)-2-hex-3-
eny1-1H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide (22)
[0249] The titled compound (22) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 99.9%; tR = 1.24 min; LCMS (ESI) m/z: 399 ([M+Hr). 1H NMR (CD30D) 8 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 (CD30D) 8 165.7, 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.
CA 02540459 2006-03-21
78
Example 22
Preparation of 3-0-(3-Dimethylamino-2,2-dimethyl-propy1)-2-(2,4,4-trimethyl-
pentyl)-1H-benzoimidazol-5-y11-N-hydroxy-acrylamide (23)
[0250] 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]). 1H NMR (CD30D) 8 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 (CD300) 8 165.6, 157.4, 139.9, 135.2, 135.1, 132.9, 126.4,
120.6,
115.7, 114.6, 68.6, 53.3, 51.4, 47.9, 39.7, 36.3, 31.9, 31.3, 30.2, 23.8,
22.3.
Example 23
Preparation of 342-Cyclohexy1-1-(3-dimethylamino-2,2-dimethyl-propy1)-1H-
benzoimidazol-5-y11-N-hydroxy-acrylamide (24)
[0251] The titled compound (24) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 99.9%; tR = 0.96 min; LCMS (ESI) m/z: 399([M+Hr). 1F1 NMR (CD300): 8 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 (CD30D) 8 165.7, 161.3, 140.1, 135.4, 134.8, 134.0, 126.1, 120.3,
119.6, 116.7, 115.5, 114.9, 68.7, 53.1, 47.9, 39.2, 37.0, 32.4, 26.5, 26.3,
23.6.
Example 24
Preparation of 342-Bicyclo[2.2.1]hept-5-en-2-y1-1-(3-dimethylamino-2,2-
dimethyl-
propy1)-1H-benzoimidazol-5-ylj-N-hydroxy-acrylamide (25)
[0252] The titled compound (25) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 99.9%; tR = 0.91 min; LCMS (ESI) m/z: 409 ([M+H]+).
Example 25
Preparation of 3-[1-(2-Diethylamino-ethyl)-2-hex-3-eny1-1H-benzoimidazol-5-y1]-
N-
hydroxy-acrylamide (26)
[0253] The titled compound (26) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC: 99.9%;
tR
1.14 min; LCMS (ESI) m/z: 385 ([M+H]). 1H NMR (CD30D) 87.95 (d, J = 8.6 Hz,
1H),
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79
7.87 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 15.8 Hz, 1H), 6.50 (d, J
= 15.8 Hz,
1H), 5.57 - 5.44 (m, 2H), 3.72 - 3.68 (m, 2H), 3.44 (q, J = 7.2 Hz, 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 (CD30D) 6 165.6, 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 341 -(2-Diisopropylamino-ethyl)-2-hex-3-eny1-1 H-benzoimidazol-
5-
yli-N-hydroxy-acrylamide (27)
[0254] The titled compound (27) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC: 99.9%;
tR =
1.22 min; LCMS (ESI) m/z: 413 ([M+H]). 1H NMR (CD30D) 8 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 (q, J = 7.2 Hz, 2H), 2.08 - 2.01 (m, 2H), 1.50 (d, J = 6.5 Hz, 12H), 0.89
(t, J = 7.5
Hz, 3H); 13C NMR (CD30D) 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 342-Hex-3-eny1-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-
y1FN-hydroxy-acrylamide (28)
[0255] 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%; = 1.12 min; LCMS (ESI) m/z: 371 (EM+Hl+). 1H NMR (CD30D) 68.00 (d,
J = 9.1 Hz, 1H), 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 341-(2-Ethylamino-ethyl)-2-hex-3-eny1-1H-benzoimidazol-5-y1FN-
, hydroxy-acrylamide (29)
[0256] 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%; tR = 1.23 min; LCMS (ESI) m/z: 385 ([M+H]+). 1H NMR (CD300) 6 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),
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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
(CD30D) 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.
5
Example 29
Preparation of 342-Hex-3-eny1-1-(3-isopropylamino-propy1)-1H-benzoimidazol-5-
y1]-N-hydroxy-acrylamide (30)
[0257] The titled compound (30) was prepared according to the procedures
10 described in Example 1, by using appropriate starting materials. HPLC
purity at 254
nm: 99.9%; tR = 1.04 min; LCMS (ESI) m/z: 357([M+H]+). 1H NMR (CD30D) 8 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
15 Hz, 3H); 13C NMR (CD30D) 5 165.6, 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-Diethylam i no-ethyl)-2-hexy1-1H-benzoimidazol-5-
y1]-N-
20 hydroxy-acrylamide (31)
[0258] The titled compound (31) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 100%, tR = 1.31 min. LC-MS m/z: 387 ([M+H]+). 1H NMR (DMSO-d6) 8 0.88 (3H,
t,
J = 7.0 Hz), 1.26 (6H, t, J = 7.2 Hz), 1.34 (4H, m), 1.44 (2H, m), 1.85 (2H,
m), 3.12
25 (2H, t, J = 7.7 Hz), 3.31 (4H, m), 3.52 (2H, t, J = 7.7 Hz), 4.81 (2H,
t, J = 7.7 Hz), 6.59
(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
30 Preparation of 3-[1-(3-isopropylamino-propy1)-2-(2,4,4-trimethyl-penty1)-1H-
benzoimidazol-5-y1FN-hydroxy-acrylamide (32)
[0259] The titled compound (32) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: HPLC: 97.5%, tR = 1.68 min. LC-MS m/z: 415 ([M+H]+). 1H NMR (DMSO-d6) 5
0.89
35 (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),
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81
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 342-(2,2-Dimethyl-propy1)-1-(3-isopropylamino-propy1)-1H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide (33)
[0260] The titled compound (33) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 99%, tR = 1.01 min. LC-MS m/z: 375 ([M+Hr). 1H NMR (DMSO-d6) 80.98 (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-ethyl)-2-(3,3,3-trifluoro-propy1)-1H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide (34)
[0261] The titled compound (34) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC: 97.5%;
tR =
0.93 min. LCMS (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 (211, 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-342-isobuty1-1-(2-isopropylamino-ethyl)-1H-
benzoimidazol-5-y1]-acrylamide (35)
[0262] The titled compound (35) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 98.3%, tR = 0.51 min. LCMS (ESI) m/z: 345 ([M-I-H]). 1H NMR (CD30D) 8 7.78
(1H, d, J = 8.7 Hz), 7.76 (1H, s), 7.68 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J =
15.8 Hz),
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 (CD30D) 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.
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82
Example 35
Preparation of 342-(2,2-Dimethyl-propy1)-1-(2-ethylamino-ethyl)-
1H-
benzoimidazol-5-*N-hydroxy-acrylamide (36)
[0263] 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%, tR = 0.71 min. LCMS (ESI) m/z: 345 ([M+H]+). 1H NMR
(CD30D) 5 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
(CD30D) 5 161.0, 153.3, 138.5, 132.7, 132.2, 124.2, 117.5, 113.9, 111.9, 44.2,
43.0,
41.0, 37.4, 33.0, 27.9, 9.5.
Example 36
Preparation of 3-[1-(2-Ethylami no-ethyl)-2-isobuty1-1H-benzoimidazol-5-yl]-N-
hydroxy-acrylamide (37)
[0264] The titled compound (37) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 99.9%, tR = 0.40 min. LCMS (ESI) m/z: 331 ([M+1-1]+). 1H NMR (CD30D) 6
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), 4.74 (2H, t, J= 6.7 Hz), 3.54 (2H, t, J= 6.5 Hz),
3.10 (211, 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 (CD30D) 8 163.7, 161.1, 154.8, 138.6, 133.2, 132.6,
132.4,
124.2, 117.2, 113.9, 111.6, 44.4, 43.0, 40.5, 33.4, 27.3, 20.6, 9.5.
Example 37
Preparation of 341-(2-Diisopropylamino-ethyl)-2-(2,4,4-trimethyl-penty1)-1H-
benzoimidazol-5-yli-N-hydroxy-acrylamide (38)
[0265] The titled compound (38) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC: 99.0 %;
tR
1.62 min; LCMS (ESI) m/z: 443 ([M4-Hr). 1H NMR (CD30D) 6 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, 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 (CD30D) 8 165.5,
156.5,
140.1, 134.8, 134.7, 134.0, 126.5, 120.0, 114.6, 113.6, 56.9, 51.7, 45.2,
42.0, 35.9,
31.9, 30.6, 30.2, 22.6, 18.3.
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83
Example 38
Preparation of N-Hydroxy-311-(2-isopropylamino-ethyl)-2-(2,4,4-trimethyl-
pentyl)-
1H-benzoimidazol-5-yl]-acrylamide (39)
[0266] 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 (CD30D) 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 (CD30D) 8 165.5, 156.9, 140.5, 134.7,
134.4,
126.3, 118.9, 115.9, 113.8, 53.2, 51..5, 44.2, 42.8, 35.7, 31.9, 30.9, 30.2,
29.6, 19.1,
18.8.
Example 39
Preparation of 341-(2-Ethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-
benzoimidazol-5111-N-hydroxy-acrylamide (40)
[0267] The titled compound (40) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 100.0%; tR = 1.57 min; LCMS (ESI) miz: 387 ([M+H]+). 1H NMR (CD30D) 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 (CD30D) 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-E1 -(2-D iethylam ino-ethyl)-2-(2,4,4-trimethyl-
penty1)-1 H-
benzoim idazol-5-yll-N-hydroxy-acrylam i de (41)
[0268] The titled compound (41) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 85.6%, tR = 1.55 min. LC-MS m/z: 415 ([M+H]). 1H NMR (CD30D) a 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, s, 10H); 13C NMR (CD30D) 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,
9Ø
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84
Example 41
Preparation of 341-(2-Diethylamino-ethyl)-2-propy1-1H-benzoimidazol-5-yll-N-
hydroxy-acrylamide (42)
[0269] The titled compound (42) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254nm:
99.0%, tR = 0.68 min. LC-MS (ESI) miz: 345 ([M+H]). 1H NMR (CD30D) 8 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 (CD30D) 8 165.5,157.4, 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-y1]-N-hydroxy-acrylamide (45)
[0270] The titled compound (45) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. Yield:17 mg
(in two
steps) as TFA salt. HPLC purity at 254 nm: 80%, tR = 0.50 min. LCMS (ESI) miz:
377
+ Hr). 1H NMR (CD300) 8 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 342-Buty1-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yli-N-
hydroxy-acrylamide (46)
[0271] The titled compound (46) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 98.4%; tR = 1.56 min. LCMS m/z: 345 ([M+Hr). 1H NMR (DMSO-d6) 60.95 (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:
[0272] 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 by adding sodium methoxide solution (20 eq.). HPLC showed the
reaction completed after 20 min, less than 1% of the acid was observed.
CA 02540459 2006-03-21
[0273] 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 NaHCO3, the precipitate which was formed was collected by filtration.
The
solid was washed with water once. The above solid was suspended in methanol
and
5 water again and was treated with 6N HCI until all dissolved, the pH value
was carefully
adjusted to around 7-8 using NaOH and NaHCO3. The precipitate, which was
formed,
was again collected by filtration; the freebase compound was obtained by
drying in
vacuo, the yield was around 80%-85%.
10 Preapration of the hydrochloric acid salt of the titled compound:
[0274] The above freebase compound was suspended in methanol and water and
was treated with 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 342-Butyl-1-(3-isopropylamino-propy1)-1H-benzoimidazol-5-y11-N-
hydroxy-acrylamide (47)
[0275] The titled compound (47) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 98.2%; tR = 1.72 min. LCMS (ESI) m/z: 359 ([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 341-(1-Benzyl-piperidin-4-y1)-2-butyl-1H-benzoimidazol-5-y1]-N-
hydroxy-acrylamide (48)
[0276] The titled compound (48) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 96.7%, tR = 1.35 min. LC-MS m/z: 433 ([M+H]). 1H NMR (DMSO-d6) 6 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).
CA 02540459 2006-03-21
86
Example 46
Preparation of 342-B utyl-1-(2-ethylam no-ethyl)-1H-benzoimidazol-5-
yll-N-
hydroxy-acrylamide (44)
[0277] The titled compound (44) was prepared according to the procedures
described
in Example 1, by using appropriate starting materials. HPLC purity at 254 nm:
98%;
LC-MS m/z: 331 ([M+H]). 1H NMR (DMSO-d6) 6 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); 130 NMR (DMSO-d6) 5 162.6, 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 342-But-3-eny1-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yli-N-
hydroxy-acrylamide (49)
[0278] The titled compound (49) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC: 99.0 %;
tR =-
1.61 min; LCMS m/z: 329 ([M+H]). 1H NMR (CD30D) 8 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); 130 NMR (CD30D) 8 178.3, 157.1, 140.7,
136.5,
133.9, 125.9, 118.8, 117.6, 116.2, 113.2, 101.5, 67.6, 46.4, 44.9, 42.4, 31.6,
26.7, 20.7,
11.4.
Example 48
Preparation of 342-Hexy1-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-y1]-N-
hydroxy-acrylamide (50)
[0279] The titled compound (50) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 94.4%, tR = 1.32 min. LCMS (ESI) m/z: 373 ([M+H]). 1H NMR (CD30D) 5 7.80
(1H, d, J = 8.5 Hz), 7.74 (1H, s), 7.64 (1H, d, J = 9.0 Hz), 7.50 (1H, d, J =
13. 6 Hz),
6.42 (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).
CA 02540459 2006-03-21
87
Example 49
Preparation of 3-[1-(2-Dimethylamino-ethyl)-2-(2,4,4-trimethyl-
penty1)--1H-
benzoimidazol-5-yli-N-hydroxy-acrylamide (51)
[0280] 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) 60.85 (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 = 8.4 Hz).
Example 50
Preparation of 341-(2-Ethylamino-ethyl)-2-hexy1-1H-benzoimidazol-5-y13-N-
hydroxy-acrylamide (52)
[0281] The titled compound (52) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. The modified
or
detailed procedures were described as below.
Step 3:
[0282] To a stirred solution of 344-(2-ethylamino-ethylamino)-3-nitro-
phenylFacrylic
acid methyl ester (8.174 g, 27.87 mmol) and heptaldehyde (4.85 g, 42.47 mmol,
1.52
eq) in AcOH and Me0H (1:9 v/v, 300mL) was added SnC122H20 (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
Et0Ac (50 mL) then basified (pH >10) with saturated aqueous Na2CO3 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 (Na2SO4), filtered, and evaporated to dryness.
The
resulting oily residue was purified by flash column chromatography (silica,
4)67 x 65
mm, solvent Me0H/DCM gradient from 0 to 10%). 341-(2-ethylamino-ethyl)-2-hexyl-
1H-benzoimidazol-5-y11-acrylic acid methyl ester was obtained as yellow solid
(4.445 g,
44.6%). HPLC purity at 254 nm: 98.8%, tR = 1.71 min. LCMS (ESI) m/z: 358 (RA +
Hr).
1H NMR (CDCI3) 8 7.88 (1H, d, J = 1.2 Hz), 7.83 (1H, d, J = 16.0 Hz), 7.43
(1H, dd, J =
8.4, 1.4 Hz), 7.33 (1H, d, J = 8.4 Hz), 6.43 (1H, d, J = 15.9 Hz), 4.22 (1H,
t, J = 6.6 Hz),
3.80 (3H, s), 3.01 (2H, t, J = 6.6 Hz), 2.89 (2H, t, J = 7.9 Hz), 2.65 (2H, q,
J = 7.1 Hz),
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%.
CA 02540459 2006-03-21
88
[0283] In another experiment starting with 2.725 g of 3-[4-(2-ethylamino-
ethylamino)-
3-nitro-pheny1]-acrylic acid methyl ester, the titled compound was obtained in
52.8%
yield (1.753 g).
Step 4:
[0284] To a solution of 341-(2-ethylamino-ethyl)-2-hexy1-1H-benzoimidazol-5-
y1]-
acrylic acid methyl ester (4.428 g, 12.39 mmol) and NH201-11-1C1 (8.66 g,
124.7 mmol)
in dry Me0H (50 mL) which was stirred and cooled in a dry-ice acetone bath,
added
Na0Me solution in Me0H (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 Me0H-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 Me0H-Ethyl acetate to give a
white
or pale yellow solid.
Step 5: hydrochloric acid salt formation.
[0285] The above freebase was dissolved in Me0H and excess 6N HCI (final pH
<2)
and the clear solution was evaporated to dryness and then diluted with Me0H,
co-
evaporated with PhMe (x1) and Et0Ac (x2). The solid was recrystallized from
Me0H-
Et0Ac 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 (CD30D) 5
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 (CD300) 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.
CA 02540459 2006-03-21
89
Example 51
Preparation of N-Hydroxy-341-(2-isopropylamino-ethyl)-2-(3,3,3-trifluoro-
propy1)-
1H-benzoimidazol-5-y1Facrylamide (53)
[0286] 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 ([1v1+H]+).
Example 52
Preparation of 341-(2-Dimethyla mino-ethyl)-2- hex-3-eny1-1 H-benzoimidazol-5-
y1]-
N-hydroxy-acrylamide (54)
[0287] The titled compound (54) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 99.9%, tR = 0.96 min. LCMS (ESI) m/z: 357 ([M+H]1). 1H NMR (CD30D) 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 (CD30D) 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 341-(2-Amino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-
5-
y1]-N-hydroxy-acrylamide (55)
0
02N OCH3
SnC12.2H20 N e
ga
_v __ (
HN 41F
HOAc-Me0H (1:9) \
HN,
HN,Boc Illal
Boc
0 0
INJe N
HCl/Me0H ( NH2OH/Na0Me (
NHOH
N
H2N
Via-1 H2N Vila-1
Step 1:
[0288] To a stirred solution of 344-(2-tert-Butoxycarbonylamino-ethylamino)-3-
nitro-
phenylFacrylic acid methyl ester (111a1, 65.2 mg, 0.178 mmol) and 3,5,5-
trimetylhexanal
CA 02540459 2006-03-21
(45 AL, 0.26 mmol) in a mixed solvent of Ac0H-Me0H (1:9 v/v, 2 mL) and DCM (1
mL)
was added SnC12-2H20 (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
resultant residue was added saturated aqueous Na2CO3 and extracted with Et0Ac
5 (x3). The extracts gave the crude (Vial-1, 91 mg) with HPLC purity at 254
nm: 49.3%,
tR = 3.02 min and 7.9%, tR = 1.97 min (de-Boc product). LCMS (ESI) m/z: 458
(IM
Hr) and 358 ([M + de-Boc product).
Step 2:
10 [0289] The above crude (Vial-1) was dissolved in Me0H (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 Me0H (x1). The residue (crude Vla-1, 81.9 mg) was
spilt to two parts (43.4 mg, equal to 0.0945 mmol of Mat and 38.5 mg equal to
0.0839
mmol of !Hai).
Step 3:
[0290] The titled compound (55) was prepared according to the Step 4 described
in
Example 1, by using crude (Via-I, 38.5 mg). VIla-1 was obtained as TFA salt
(2.3 mg,
4.7% from 111a1). HPLC purity at 254 nm: 92.7%, tR = 1.46 min. LCMS (ESI) m/z:
359
([M + H]+). 1H NMR (CD30D) 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, br d, 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, br s 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 341-(2-Amino-ethyl)-2-(2-methoxy-nony1)-1H-benzoimidazol-5-y11-
N-hydroxy-acrylamide (56)
[0291] 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 (ESI) m/z: 403 UM + Fin. 1H NMR (CD30D) 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).
CA 02540459 2006-03-21
91
Example 55
Preparation of 342-Butyl-1-(2-dimethylamino-ethyl)-1H-benzoimidazol-5-y1]-N-
hydroxy-acrylamide (57)
[0292] 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 (WI H]+). 1H NMR (DMSO-d6) 5 0.97 (3H,
t,
J = 7.3 Hz), 1.49 (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 342-Hexy1-1-(2-dimethylamino-ethyl)-1H-benzoimidazol-5-y1141-
hydroxy-acrylamide (58)
[0293] The titled compound (58) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 100%, tR = 0.42 min. LC-MS m/z: 359 (EM + Hr). 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-ethyl)-242-(2,2-dimethyl-propionylamino)-
ethyl]-1H-benzoimidazol-5-y1)-N-hydroxy-acrylamide (61)
[0294] The titled compound (61) was prepared according to the procedures
=
described below, Steps 1 & 2 were performed as in Scheme I:
Step 3:
02 N v,,, H2N io
HN
HN
AcOH, Me0H,
45 C
r.N
I 61-1
rr 61-2
[0295] To a pre-stirred solution of 344-(2-diethylamino-ethylamino)-3-nitro-
pheny1]-
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
CA 02540459 2006-03-21
92
stirred for 30 minutes. The organic layer was dried (MgSO4), filtered and
concentrated
to an oily residue. 100 mL diethyl ether was added and stirred for 4 hours.
The product
3-[3-amino-4-(2-diethylamino-ethylamino)-phenyl]-acrylic acid methyl ester was
obtained in 54.9% yield (207.6 mg). LCMS m/z: 292 ([M+H]).
Step 4
H2N Fmoc. N
HN 1W-P 0"
EDC, HOBt.H20, H HN CO2Me
0
z_Th.e0F1 DrolEAon temp. ; DCMp. HN 111V
W
r 0 H 0
61-2 614 r N OA
[0296] To a pre-stirred solution of 343-amino-4-(2-diethylamino-ethylamino)-
phenyl]-
acrylic acid methyl ester (61-2, 1.93 g, 6.65 mmol) and dichloromethane (13.3
mL) was
added a cocktail solution of N-(3-dimethylaminopropy1)-N1-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+H]).
Step 5
Fmoc,NO
HN CO2Me
AcOH, 70 C Fmoc¨NH N 40 CO2Me
HN
r1-4 I I 61-5
[0297] Glacial acetic acid (8.9 mL) was added into 313-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
CA 02540459 2006-03-21
93
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-y1}-acrylic acid methyl
ester (61-
5) was obtained in 66.1 % (1.62 g). LCMS m/z: 553 ([M+H]).
Step 6
Fmoc¨NH N CO2Me H2N N io .02.
piperidine,
DCM, rm temp
1N h
61-5 61-6
[0298] To a pre-stirred solution of 3-{1-(2-dethylamino-ethyl)-2-[(9H-fluoren-
9-
ylmethoxycarbonylamino)-methy1]-1H-benzoimidazol-5-y1}-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 iin
vacuo. The desired product was separated by reverse phase preparative HPLC.
After
lyopholyzation, 0.52 g (53.6 %) of 342-aminomethy1-1-(2-diethylamino-ethyl)-1H-
benzoimidazo1-5-y1]-acrylic acid methyl ester was obtained as powder. LCMS
rn/z: 331
([M+H]+).
Step 7
H2N N CO2Me
2¨NH N .02.
I>,
DIEA, DCM
r r61-6 61-7
[0299] To a pre-stirred solution of 3-[2-aminomethy1-1-(2-diethylamino-ethyl)-
1H-
benzoimidazol-5-y1]-acrylic acid methyl ester (61-6, 0.10 g, 0.23 mmol), N,N-
diisopropylethylamine (97 pL, 0.58 mmol) and dichloromethane (1.17 mL) was
added
2,2-dimethyl-propionyl chloride (34.6 pL, 0.28 mmol) and the resulting
reaction mixture
was stirred at room temperature for 1 h. 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 Na2SO4. The mixture was filtered and concentrated in vacuo. The
product 3-
{1-(2-diethylami no-ethyl)-2-[(2,2-di methyl-propionylamino)-methy1]-1H-
benzoim idazol-
CA 02540459 2006-03-21
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5-yI}-acrylic acid methyl ester (61-7) was obtained in 76.6 % (74.1 mg). LCMS
m/z: 415
([M+H]).
Step 8
0
N
CO2Me H N
NH
NH2OH.HCI, /Z¨N\ _______________________________ </N 010 OH
Na0Me, Me0Hir
r - 78 C
I I 61-7 r 61
[0300] To a stirred solution of 3-{1-(2-diethylamino-ethyl)-24(2,2-dimethyl-
propionylamino)-methyl]-1H-benzoimidazol-5-y1}-acrylic acid methyl ester (61-
7, 73.8
mg, 0.18 mmol) and hydroxylamine hydrochloride (124 mg, 1.78 mmol) in Me0H
(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. IN 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-y11-
N-hydroxy-acrylamide was obtained as powder. HPLC purity: 99.5%, tR = 0.94min.
LCMS m/z: 416 ([M+Hr). 1H NMR (CD30D) 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 (CD30D) 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-viny1)-1H-
benzoimidazol-2-y11-ethyl}-3,3-dimethyl-butyramide (59)
[0301] The titled compound (59) was prepared according to the procedures
described in Example 57, by using appropriate starting materials. HPLC purity
at 254
nm: 94.0%; tR = 0.99 min. LC-MS m/z: 444 DA +
CA 02540459 2006-03-21
Example 59
Preparation of N-[1-(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoyl-viny1)-1H-
benzoimidazol-2-ylmethyli-butyramide (62)
[0302] The titled compound (62) was prepared according to the procedures
5 described in Example 57, by using appropriate starting materials. HPLC
purity at 254
nm: 85.1 %; tR = 0.58 min; LCMS m/z: 402 ([M + H]4). 1H NMR (CD30D) 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), 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
(CD300) 8
10 117.1, 165.9, 154.6, 140.9, 129.6, 128.4, 127.3, 125.9, 118.6, 112.8,
111.5, 50.7, 40.4,
38.4, 36.4, 19.9, 14.0, 9Ø
Example 60
Preparation of 342-(3,3-Dimethyl-buty1)-1-(2-ethylamino-ethyl)-1H-
benzoimidazol-
15 5-y1J-N-hydroxy-acrylamide (63)
[0303] The titled compound (63) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC: 99.0 %;
tFt =
0.93 min; LCMS m/z: 359 ([M + Hr). 1H NMR (CD30D) 8 7.5 (d, J = 8.4 Hz, 1H),
7.75
¨7.74 (m, 2H), 7.16 (d, J = 15.7 Hz, 1H), 6.31 (d, J = 15.7 Hz, 1H), 4.89
(brs, 2H), 3.72
20 (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 (CD30D) 5 165.7, 158.4, 140.4, 134.9, 134.5, 134.2, 126.2, 122.5,
119.2, 115.6, 113.4, 55.3, 44.0, 40.8, 40.7, 31.3, 29.3, 22.9.
Example 61
25 Preparation of 341-(2-Dimethylamino-ethyl)-2-(3,3-dimethyl-buty1)-1H-
benzoimidazol-5-y1]-N-hydroxy-acrylamide (64)
[0304] The titled compound (64) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC: 99.0 %;
tR =
0.83 min; LCMS m/z: 359 ([M + 1H NMR (CD30D) 5 7.94 (d, J = 7.8 Hz, 1H),
7.81
30 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 15.7 Hz, 1H), 6.64 (d, J
= 15.7 Hz, 1H),
4.93 (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 (CD30D) 8 165.4, 158.4, 140.2, 134.5, 134.2, 133.2,
126.5,
118.8, 115.3, 113.9, 46.4, 45.1, 42.9, 40.6, 31.3, 29.2, 22.9, 11.4.
35 Example 62
Preparation of 341-(2-Dimethylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-y11-N-
hydroxy-acrylamide (65)
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[0305] 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), 10.42 (1H, bs).
Example 63
Preparation of
341-(2-Dimethylamino-ethyl)-2-(2,2,2-trifluoro-ethyl)-1H-
benzoimidazol-5-yli-N-hydroxy-acrylamide (64)
[0306] The titled compound (64) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 91.1%; tR = 0.68 min. LCMS m/z: 357 ([M+Fi]+).
Example 64
Preparation of 341-(2-Ethylamino-ethyl)-2-penty1-1H-benzoimidazol-5-y1]-N-
hydroxy-acrylamide (68)
[0307] The titled compound (68) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 98.4%; tR = 0.87 min. LCMS m/z: 345([M+H])-
Example 65
Preparation of N-
Hydroxy-341-(2-isopropylamino-ethyl)-2-penty1-1H-
benzoimidazol-5-y1]-acrylamide (71)
[0308] The titled compound (71) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 97.4%; tR = 0.95 min. LCMS m/z: 359 (DM + Hr). 1H NMR (DMSO-d6) 8 0.89
(3H,
m), 1.22 (6H, d), 1.38 (4H, m), 1.82 (2H, m), 2.99 (3H, m), 4.56 (2H, m), 6.51
(1H, d),
7.59 (2H, d), 7.64 (1H, m), 7.88 (1H, m), 8.74 (2H, bs).
Example 66
Preparation of 342-Hexy1-1-(2-methylamino-ethyl)-1H-benzoimidazol-5-yli-N-
hydroxy-acrylamide (74)
[0309] The titled compound (74) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 96.0%, tR = 1.12 min. LCMS m/z: 345 ([M+H]+). 1H NMR (CD30D) 8 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 =
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5.1 Hz), 1.46 (2H, m), 1.33 (4H, m), 0.85 (3H, t, J = 7.1 Hz); 13C NMR (CD300)
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-341-(2-methylamino-ethyl)-2-penty1-1H-benzoimidazol-
5-y1]-acrylamide (75)
[0310] The titled compound (75) was prepared according to the procedures
described in Example 1, by using appropriate starting materials. HPLC purity
at 254
nm: 97.8%; tR = 0.80 min. LCMS m/z: 331 (EM + H]+). 1H NMR (DMSO-d6) 8 0.89
(3H,
m), 1.38 (4H, m), 1.84 (2H, m), 2.51 (3H, s), 3.14 (2H, m), 3.38 (2H, t), 4.70
(2H, m),
6.57 (1H, d), 7.62 (1H, d), 7.73 (1H, m), 7.96 (2H, m), 9.13 (2H, s).
Example 68
Preparation of 3-(2-Buty1-1-pyrrolidin-3-y1-1H-benzoimidazol-5-y1)-N-hydroxy-
acrylamide (69)
NH2
02N io 0
OMe 0
OMe
02N is
OMe Boc
HN
CI Et3N SnC12, Me0H/ AcOH
la Heat
IEloc I3oc
69-2 69-3
0 0
HCl/Me0H OMe /
NH2OH NHOH,
69-4 69
Step1
[0311] To a solution of methyl trans-4-Chloro-3-nitrocinnamate (la, 4.8 g, 20
mmol) in
triethyl amine (5.5 mL, 40 mmol) was added 3-Amino-pyrrolidine-1-carboxylic
acid 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
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98
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
[0312] To a solution of compound 69-2 (7.84 g, 20.0 mmol) in 100 mL of Me0H
and
AcOH mixture (1:9) was added corresponding aldehyde (3.0 mL, 30.0 mmol) and
tin
chloride (22.6 g, 100 mmol), the resulting mixture was stirred at 42 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:Et0Ac = 1:2) to give a pale-yellow solid
69-3 (3.8
g, 44%). LC-MS m/z: 456 (EM + H]+).
Step 3
[0313] To a flask charged with compound 69-3 (456 mg, 1 mmol) was added 1.25 M
HCI in Me0H (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 +
Fi]).
Step 4
[0314] To a solution of above crude 69-4 (around 0.16 mmol) product in Me0H
(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-Buty1-
1-pyrrolidin-3-y1-1H-benzoimidazol-5-y1)-N-hydroxy-acrylamide. HPLC purity:
98%; LC-
MS m/z: 329 ([M + H]+). 1H NMR (CD30D) 8 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).
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Example 69
Preparation of 3-(2-Buty1-1-piperldin-4-y1-1H-benzoimidazol-5-y1)-N-hydroxy-
acrylamide (70)
[0315] The titled compound (70) was prepared according to the procedures
described in Example 78, by using appropriate starting materials. HPLC purity:
98%;
LCMS m/z: 343 ([M + Hr). 1H NMR (CD30D) 6 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).
Example 70
Preparation of 3-(2-Hexy1-1-pyrrolidin-3-y1-1H-benzoimidazol-5-y1)-N-hydroxy-
acrylamide (80)
[0316] The titled compound (80) was prepared according to the procedures
described
in Example 68, by using appropriate starting materials. HPLC purity: 98%; LCMS
m/z:
357 ([M + H]+). 1H NMR (CD30D) 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 342-Buty1-1-(1-methyl-pyrrolidin-3-y1)-1H-benzoimidazol-5-y1]-N-
hydroxy-acrylamide (81)
[0317] The titled compound (81) was prepared according to the procedures
described
in Example 68, by using 69-4 via reductive amination to introduce a methyl
group.
HPLC purity: 98%; LCMS m/z: 343 ([M + H]). 1H NMR (CD300) 6 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-Hexy1-1-piperidin-3-y1-1H-benzoimidazol-5-y1)-N-hydroxy-
acrylamide (82)
[0318] The titled compound (82) was prepared according to the procedures
described
in Example 68, by using appropriate starting materials. HPLC purity: 97%; LCMS
m/z:
343 ([M + Hr). 1H NMR (CD30D) 6 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,
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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-y1-1H-benzoimidazol-5-0)-N-hydroxy-
acrylamide (83)
[0319] The titled compound (83) was prepared according to the procedures
described
in Example 68, by using appropriate starting materials. HPLC purity: 97%; LCMS
m/z:
371 ([M + H]). 1H NMR (CD30D) 8 0.88 (3H, t, J = 7.2 Hz), 1.22-1.42 (4H, m),
1.47
(2H, m), 1.84 (211, m), 2.04 (1H, m), 2.20 (2H, m), 2.62 (1H, m), 3.12-3.22
(2H, m),
3.48(111, m), 3.68 (1H, m), 3.78 (1H, t, J = 12.0 Hz), 5.01 (1H, m), 6.53 (1H,
d, J= 15.8
Hz), 7.62 (1H, d, J = 15.8 Hz), 7.70 (1H, d, J = 9.2 Hz), 7.86 (111, s), 8.06
(1H, d, J =
8.8 Hz).
Example 74
Preparation of
(E)-N-hydroxy-3-(1-(1-methylpiperidin-3-y1)-2-penty1-1H-
benzo[d]imidazol-5-yOacrylamide (86)
[0320] The titled compound (86) was prepared according to the procedures
described
in Example 71, by using appropriate starting materials.HPLC purity: 99.3 %, tR
=1.06
min; LCMS m/z: 371 ([M + H]). 1H NMR (CD30D) 8 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 (CD30D) 8165.6, 157.6, 139.9, 134.6, 134.1,
132.5, 126.3,
120.4, 115.5, 115.2, 54.9, 54.4, 53.3, 44.1, 32.4, 27.5, 27.3, 26.8, 23.2,
23.1, 14.2.
Example 75
Preparation of
(E)-3-(2-hexy1-1-(1-(2-hydroxyethyl)piperidin-3-y1)-1H-
benzo[d]imidazol-5-y1)-N-hydroxyacrylamide (90)
[0321] The titled compound (90) was prepared according to the procedures
described
in Example 68, by using appropriate starting materials and alkylation of the
piperidine
with 2-bromoethanol. LCMS m/z: 415 ([M +H]).
CA 02540459 2006-03-21
101
Example 76
Preparation of N-Hydroxy-3-[1-(1-pentyl-piperidin-3-y1)-1H-benzoimidazol-5-y1]-
acrylamide (94)
[0322] 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 rn/z: 357 ([M+H]). 1H NMR (CD30D) 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 ¨10 1.80 (m, 2H), 1.39 ¨ 1.29 (m, 4H), 0.94 (t, 3H, J= 6.8 Hz).
Example 77
Preparation of N-Hydroxy-3-[1-(1-phenethyl-piperidin-3-y1)-1H-benzoimidazol-5-
y1]-acrylamide (96)
[0323] The titled compound (96) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 98.6%; LC-
MS
rn/z: 391([M+H]). 1H NMR (CD30D) 6 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-{141-(3-phenyl-propyl)-piperidin-3-y1]-
1H-
benzoimidazol-5-y1}-acrylamide (97)
[0324] The titled compound (97) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 94.5%; LC-
MS:
405 ([M+Hr) 1H NMR (CD30D) 8 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-(141-(3,3-Dimethyl-butyl)-pyrrolidin-3-y1]-1H-benzoimidazol-5-
y1}-N-hydroxy-acrylamide (99)
[0325] The titled compound (99) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 91.9%; tR
= 1.10
min. LC-MS rn/z: 357 ([MH]+). 1H NMR (DMSO-d6) 6 0.91 (9H, s), 1.52 (4H, m),
3.09
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(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-{142-(Ethyl-methyl-amino)-ethy1]-2-penty1-1H-benzoimidazol-5-
y1)-N-hydroxy-acrylamide (79)
[0326] The titled compound (79) was prepared according to the procedures
described
in Example 1, by using appropriate starting materials. HPLC purity: 99%; tR =
0.68 min.
LC-MS m/z: 359 ([M+H]). 1H NMR (DMSO-d6) 60.89 (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).
Example 81
Preparation of 3-{2-Buty1-142-(ethyl-methyl-amino)-ethy1]-1H-benzoimidazol-5-
y1}-
N-hydroxy-acrylamide (85)
[0327] The titled compound (85) was prepared according to the procedures
described
in Example 1, by using appropriate starting materials. HPLC purity: 95.8%; tR
=1.04
min. LC-MS m/z: 345 ([M+H]). 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-Buty1-1-{2-[ethyl-(3-hydroxy-propy1)-amino]-
ethyl}-1H-
benzoimidazol-5-y1)-N-hydroxy-acrylamide (91)
[0328] The titled compound (91) was prepared according to the procedures
described =
in Example 1, by using appropriate starting materials. HPLC purity: 93.5%; tR=
0.50
min. LC-MS (m/z): 389 ([MH]-). 1F1 NMR (DMSO-d6) 8 0.94 (3H, m), 1.25 (311,
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-propy1)-amino]-ethyl}-2-pentyl-1H-
benzoimidazol-5-y1)-N-hydroxy-acrylamide (92)
[0329] The titled compound (92) was prepared according to the procedures
described
in Example 1, by using appropriate starting materials. HPLC purity: 93.5%; tR
= 0.50
min. LC-MS (m/z): 389 ([M+H]4) 1H NMR (DMSO-d6) 60.94 (3H, m), 1.25 (3H, m),
1.46
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(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-{142-(Butyl-ethyl-amino)-ethy1]-1H-benzoimidazol-5-y1}-N-
hydroxy-acrylamide (95)
[0330] The titled compound (95) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 99.9%; LC-
MS
miz: 331([M+H]). 1H NMR (CD30D) 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).
Example 85
Preparation of 3-[2-(4-Cyano-butyl)-1-(2-diethylamino-ethyl)-1H-benzoimidazol-
5-
yli-N-hydroxy-acrylamide (101)
[0331] The titled compound (101) was prepared according to the procedures
described
in Example 57, by using appropriate starting materials. HPLC purity at 254 nm:
99.9%.
LC-MS (ESI) m/z: 384 ([M+H]). 1H NMR (CD300) 6 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-{142-(Butyl-isopropyl-amino)-ethyl]-1H-benzoimidazol-5-y1}-19-
hydroxy-acrylamide (108)
[0332] The titled compound (108) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 98.8%; tR
= 1.33
min. LC-MS mk: 345 ([M+Hr). 1H NMR (DMSO-d6) 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).
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Example 87
Preparation of N-Hydroxy-3-{142-(isopropyl-pentyl-amino)-ethyl]-
1H-
benzoimidazol-5-y1}-acrylamide (109)
[0333] The titled compound (109) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. LC-MS m/z: 359
([M+H]). 1H
NMR (DMSO-d6) 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 342-(5-Cyano-penty1)-1-(2-diethylamino-ethyl)-1H-benzoimidazol-
5-y11-N-hydroxy-acrylamide (110)
[0334] The titled compound (110) was prepared according to the procedures
described
in Example 57, by using appropriate starting materials. HPLC purity at 254 nm:
95.4%.
LC-MS (ESI) m/z: 347 ([M+H]). 1H NMR (CD30D) 8 7.96 (1H, d, J = 8.5 Hz),
7.90(1H,
s) 7.81 (1H, d, J = 8.5 Hz), 7.59 (1H, d. J = 15.6 Hz), 6.55 (1H, d, J = 15.5
Hz), 4.96
(2H, t, J = 7.3 Hz), 3.69 (2H, t, J = 7.1 Hz), 3.44 (4H, qt, J = 7.2 Hz), 3.31
(2H,
embedded in Me0D peak), 2.51 (2H, t, J = 6.9Hz), 2.05-1.98 (2H, m), 1.78 (2H,
m, J =
7.4 Hz), 1.70 (2H, m, J = 6.4 Hz), 1.41(3H, t, J = 7.2 Hz);
Example 89
Preparation of 3-(1-{2-[(3,3-Dimethyl-butyl)-ethyl-amino]-ethyl}-1H-
benzoimidazol-
5-y1)-N-hydroxy-acrylamide (111)
[0335] The titled compound (111) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. TFA salt. HPLC purity:
97.7%;
LC-MS m/z: 359 ([M+H]). 1H NMR (CD30D) 8 9.10 (s, 1H), 7.89 (d, 1H, J = 8.9
Hz),
7.88 (s, 1H), 7.74 (d, 1H, J = 8.6 Hz), 7.51 (d, 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);
[0336] HCI salt. 1H NMR (DMSO-d6) 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).
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Example 90
Preparation of 3-{1-12-(Ethyl-propyl-amino)-ethyl]-1H-benzoimidazo1-5-y1)-N-
hydroxy-acrylamide (112)
[0337] The titled compound (112) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 98.1%; LC-
MS
m/z: 315 ([M+H]). 1H NMR (CD30D) 8 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-penty1)-amino]-ethyl}-1H-
benzoimidazol-5-y1)-acrylamide (113)
[0338] The titled compound (113) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. LC-MS m/z: 373RM+H)1].
1H
NMR (DMSO-d6) 8 0.86 ¨ 0.97 (7H, m), 1.14 ¨1.28 (12H, m), 4.70 (2H, b), 6.49
(1H, d),
7.58 ¨7.62 (2H, m), 7.73 (1H, d), 7.91 (1H, s), 8.48 (1H, s)
Example 92
Preparation of 3-{142-(Ethyl-hexyl-amino)-ethyl]-2-methyl-1H-benzoimidazol-5-
y1}-N-hydroxy-acrylamide (116)
[0339] The titled compound (116) was prepared according to the procedures
described
in Example 57, by using appropriate starting materials. HPLC purity at 254 nm:
98.2%,
tR = 1.27 min. LC-MS (ESI) m/z: 373 ([M+Hr). 1H NMR (CD30D) 8 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-am i no)-ethyl]-2-trifluoromethy1-1H-
benzoi midazol-5-y1)-N-hydroxy-acrylamide (117)
[0340] The titled compound (117) was prepared according to the procedures
described
in Example 57, by using appropriate starting materials. HPLC purity at 254 nm:
97.3%,
tR = 1.50 min. LC-MS (ESI) m/z: 399 (1M+Hr). 1H NMR (CD30D) 8 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).
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Example 94
Preparation of 3-
{142-(Ethyl-hexyl-amino)-ethyl]-2-trifluoromethy1-1H-
benzoimidazol-5-y1)-N-hydroxy-acrylamide (118)
[0341] The titled compound (118) was prepared according to the procedures
described
in Example 57, by using appropriate starting materials. HPLC purity at 254 nm:
94.6%,
tR = 2.07 min. LC-MS (ESI) m/z: 427 ([M+111+). 1H NMR (CD30D) 8 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 341-(2-Dipropylamino-ethyl)-1H-benzoimidazol-5-y11-N-hydroxy-
acrylamide (120)
[0342] The titled compound (120) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 100%. LC-
MS
m/z: 331 ([M+H]). 1H NMR (DMSO-d6) 8 0.86 (6H, d), 1.64 (4H, m), 3.09 (4H, m),
3.60
(2H, m), 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-{24isopropyl-(3-methyl-butyl)-aminoFethyl}-1H-
benzoimidazol-5-y1)-acrylamide (121)
[0343] The titled compound (121) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 98.7%; tR
= 1.02
min. LC-MS (m/z): 358 ([M+H]). 1H NMR (DMSO-d6) 8 0.88 (6H, d), 1.28 (6H, m),
1.59
(3H, m), 3.10 (3H, m), 3.68 (2H, m), 4.71 (2H, m), 6.50 (1H, d), 7.50 (2H, m),
7.59 (1H,
m), 7.63 (1H, m), 8.52 (1H, m), 9.50 (1H, bs), 10.70 (11-1, bs).
Example 97
Preparation of 3-
(1-{2-[(3,3-Dimethyl-butyl)-methyl-aminoFethyl}-1H-
benzoimidazol-5-y1)-N-hydroxy-acrylamide (122)
[0344] The titled compound (122) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity at 254 nm:
97.8%;
tR = 0.93 min. LC-MS m/z: 345 ([M+H]). 1H NMR (DMSO-d6) 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).
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Example 98
Preparation of 3-(1-{2-[(2-Ethyl-buty1)-methyl-amino]-ethy1}-1H-benzoimidazol-
5-
y1)-N-hydroxy-acrylamide (123)
[0345] 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-d6) 5 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;rn), 8.80 (1H, m), 9.54 (1H, bs).
Example 99
Preparation of 3-{142-(3,3-Dimethyl-butylamino)-ethy1]-1H-benzoimidazol-5-y1}-
N-
hydroxy-acrylamide (126)
[0346] The titled compound (126) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 100%; tR
= 1.01
min. LC-MS m/z: 331 ([M-I+11+). 1H NMR (DMSO-d6) 8 0.88 (9H, s), 1.44 (2H, m),
2.92
(2H, m), 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-{1-12-(methyl-pent-4-enyl-amino)-ethy1]-1H-
benzoimidazol-5-y1}-acrylamide (127)
[0347] The titled compound (127) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 100%; tR
= 0.92
min. LC-MS m/z: 329 ([M+H]+). 1H NMR (DMSO-d6) 8 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 (11-1,
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-buty1)-propyl-aminoFethyl}-1H-
benzoimidazol-5-y1)-N-hydroxy-acrylamide (128)
[0348] The titled compound (128) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 99.0%;
tR=1.18
min. LC-MS m/z: 373 ([M-I-Hr). 1H NMR (DMSO-d6) 60.88 (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).
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Example 102
Preparation of 3-{142-(3,3-Dimethyl-butylamino)-ethy1]-2-propy1-
1H-
benzoimidazol-5-y1)-N-hydroxy-acrylamide (130)
[0349] Step 1: Cyclization
0 0
0
02N 40 401
OMe OMe
______________________________________ - ______ N
HN
Zn, Me0H/AcOH
50 C
NH2 H2N
[0350] To the starting material (111a2, 3.34 g, 12.6 mmol) in 20% AcOH in Me0H
(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 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% Me0H in DCM) to
give 3-
[1-(2-Amino-ethyl)-2-propyl-1H-benzoimidazol-5-A-acrylic acid methyl ester.
Yield = 25
c/o, LC-MS m/z: 288 ([M+H]).
[0351] Step 2: Reductive-amination
0
0
0 </N so ___________________________________________________ OMe
;4 OMe
/ (14
NaCNBH3,
AcOH/ Me0H ,y¨NH
H2N
[0352] To 341-(2-Amino-ethyl)-2-propy1-1H-benzoimidazol-5-y1]-acrylic acid
methyl
ester (1.2 g, 4.2 mmol) in Me0H (40 mL) was added 3,3-Dimethyl-butyraldehyde
(0.524 mL, 4.2 mmol). The resulting mixture was stirred at it 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 it for another 30 minutes. Solvent was removed and
the
residual was dissolved in DCM upon which was washed with aqueous sodium
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bicarbonate, water and brine. The combined organic layer, after workup, was
purfied by
flash chromatography (silica, 4% Me0H in DCM). LC-MS m/z: 372 ([M+H]).
[0353] Step 3: hydroxannic 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 (CD30D) 8
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).
HCI salt of 130: HPLC purity: 98.1 %; LC-MS m/z: 373 ([M+H]). 1H NMR (CD30D)
8.06 (d, 1H, J = 8.3 Hz), 7.90 (s, 1H), 7.88 (d, 1H, J = 8.4 Hz), 7.59 (d, 1H,
J = 15.8
Hz), 6.56 (d, 1H, J= 15.8 Hz), 4.91 ¨ 4.81 (m, 2Hz), 3.60 ¨ 3.66 (m, 2H), 3.31
¨ 3.35
(m, 2H), 3.17 ¨ 3.13 (m, 2H), 2.05¨ 1.97 (m, 2H), 1.70¨ 1.66 (m, 2H), 1.20 (t,
3H, J=
7.3 Hz), 0.98 (s, 9 H).
Example 103
Preparation of 34142-(3,3-Dimethyl-butylamino)-ethyl]-2-(2,2-dimethyl-propy1)-
1H-benzoimidazol-5-y1FN-hydroxy-acrylamide (131)
[0354] The titled compound (131) was prepared according to the procedures
described
in Example 102, by using appropriate starting materials. HPLC purity: 92%; LC-
MS
m/z: 401([M+H]4). 1H NMR (CD30D) 8 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 341-{2-[Bis-(3,3-dimethyl-butyl)-amino]-ethyl}-2-(2,2-dimethyl-
propy1)-1H-benzoimidazol-5-y1FN-hydroxy-acrylamide (132)
[0355] The titled compound (132) was prepared according to the procedures
described
in Example 102, by using appropriate starting materials. HPLC purity: 96%; LC-
MS
nn/z: 485([M+H]). 1H NMR (CD30D) 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).
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Example 105
Preparation of 3-{142-(2,2-Dimethyl-propylamino)-ethy1]-1H-benzoimidazol-5-y1}-
N-hydroxy-acrylamide (133)
[0356] The titled compound (133) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 99.9%; LC-
MS
m/z: 317([M+H]). 1H NMR (CD30D) 8 8.82 (s, 1H), 7.94 (s, 1H), 7.83 (d, 1H, J =
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-D imethyl-propy1)-propyl-amino]-
ethy1}-1H-
benzoimidazol-5-y1)-N-hydroxy-acrylamide (134)
[0357] The titled compound (134) was prepared according to the procedures
described
in Example 76, by using appropriate starting materials. HPLC purity: 99.9%;
LCMS
m/z: 359 ([M+H]). 1H NMR (CD30D) 8 9.07 (s, 1H), 7.95 (s, 1H), 7.92 (d, 1H, J
= 8.7
Hz), 7.78 (d, 1H, J= 8.4 Hz), 7.66 (d, 1H, J= 15.8 Hz), 6.56 (d, 1H, J= 15.8
Hz), 4.99
¨ 4.97 (m, 2H), 3.74 (t, 2H = 7.0 Hz), 3.32 ¨ 3.20 (m, 4H), 1.85¨ 1.82 (m,
2H), 1.03 (s,
9H), 0.92 (t, 3H, J = 7.1 Hz).
Example 107
Preparation of 3-{142-(3,3-Dimethyl-butylamino)-ethy1]-2-ethyl-1H-
benzoimidazol-
5-y1}-N-hydroxy-acrylamide (135)
[0358] The titled compound (135) was prepared according to the procedures
described
in Example 102, by using appropriate starting materials. HPLC purity: 94.3%;
LCMS
m/z: 359 ([M+H]). 1H NMR (CD30D) 6 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 341-(2-Diethylamino-ethyl)-2-propylamino-1H-benzoimidazol-5-y1)-
, N-hydroxy-acrylamide (105)
[0359] The titled compound (105) was made according to the following synthetic
scheme.
CA 02540459 2006-03-21
111
0
0
H2N 110
0 S H 0
F \rN
rjiN NE 1'W \ __ \ H2N
rHy
= and h)r
1-
0
0
DCC \ N NH2OH N RN¨<'\ 14-OH
w HN-14
(00
riN
r'5 r"?
[0360] HPLC purity: 100%. 11-1-NMR (DMSO-d6) 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)
5
Example 109
Preparation of 341-(3-Dimethylamino-2,2-dimethyl-propy1)-2-propylamino-1H-
benzoimidazol-5-yli-N-hydroxy-acrylamide (115)
[0361] The titled compound (115) was made by using method analogous to
compound
(105).HPLC purity: 97%.111-NMR (DMSO-d6) 8 0.97 (3H, t, J = 7.28), 1.15 (6H,
s), 1.69
(2H, m, J = 7.28 Hz), 2.89 (6H, s), 3.28 (2H, s), 3.42 (2H, m), 4.15 (2H, s),
6.47 (2H, d,
J = 15.80), 7.49-7.75 (4H, m), 8.94 (1H, bs), 9.42 (1H, bs), 10.81 (1H, bs),
13.44 (1H,
bs).
[0362] The following compounds are representative examples prepared by methods
disclosed or analogous to those disclosed in above Examples 1-109:
Cmpd rniz
Structure NAME
No [M+H]
341-(3-Dimethylamino-
( 2,2-dimethyl-propyI)-2-
387
(2,2-dimethyl-propyI)-
1
1H-benzoimidazol-5-
/ yfl-N-hydroxy-
=
acrylamide
CA 02540459 2006-03-21
112
Cmpd m/z
Structure NAME
No [M+H]
. 3-[1-(3-Dimethylamino-
.4
'' 2,2-dimethyl-propy1)-2-
N
359 isopropyl-1H-
2
benzoimidazol-5-y1]-N-
/ hydroxy-acrylamide
,
_
. 342-Buty1-1-(3-
\_
r'. H dimethylamino-2,2-
3 i 373 dimethyl-propy1)-1H-
benzoimidazol-5-A-N-
hydroxy-acrylamide
_
3-[1-(3-Dimethylamino-
.
\ 2,2-dimethyl-propy1)-2-
,,,OH
H
(2-methylsulfanyl-
4 /N 391
c ¨ ethyl)-1H-
benzoimidazol-5-yli-N-
I
hydroxy-acrylamide
OH
3-[1-(3-Dimethylamino-
40 ' . 2,2-dimethyl-propy1)-2-
375 ethoxymethy1-1H-
benzoimidazol-5-yl]-N-
- hydroxy-acrylamide
%
O 3-[1-(3-Dimethylamino-
( =Ntc.....
2,2-dimethyl-propy1)-2-
N
6
373 isobuty1-1H-
benzoimidazol-5-y1]-N-
%-- hydroxy-acrylamide
,
. .
3-[1 -(2-Diethylamino-
( ethyl)-2-isobuty1-1H-
7
359 benzoimidazol-5-A-N-
rN) hydroxy-acrylamide
CA 02540459 2006-03-21
113
Cmpd m/z
Structure NAME
No [M+H]
-
' 342-Buty1-1-(2-
\ .`"
\ .
diethylamino-ethy1)-1H-
8
N
359 benzoimidazol-5-y1]-N-
ri
r-N) hydroxy-acrylamide
.
342-But-3-yny1-1-(3- -
.õ dimethylamino-2,2-
¨ \ 0 ' vi'
9 .
,..,\-----\\N ----
/ 369 dimethyl-propy1)-1H-
benzoimidazol-5-y1]-N-
hydroxy-acrylamide
. 342-But-3-eny1-1-(3-
\ 10 ' g' dimethylamino-2,2-
10 .
\----\,_.¨ 371 dimethyl-propy1)-1H-
benzoimidazol-5-y11-N-
/ hydroxy-acrylamide
_
a
µ
3-[2-But-3-eny1-1-(2-
.- ,AH
\ 0 ri diethylamino-ethyl)-1H-
.
11
357 benzoimidazol-5-yI]-N-
hydroxy-acrylamide
r-)
_
342-But-3-yny1-1-(2-
¨ \ 0 ' n' diethylamino-ethyl)-1H-
N
12
hydroxy-acrylamide
355 benzoimidazol-5-y1FN-
r)
OH 3-[1-(3-Dimethylamino-
.
F I \ io . 2,2-dimethyl-propy1)-2-
(3,3,3-trifluoro-propy1)-
N
C6--
1H-benzoimidazol-5-
13 413
y1]-N-hydroxy-
/ acrylamide
CA 02540459 2006-03-21
114
Cmpd m/z
Structure NAME
No [WM+
/ H
HN 3-[1-(2-Diethylamino-
' I \ 0 ethyl)-2-(3,3,3-trifluoro-
14 N 399 propyI)-1H-
benzoimidazol-5-A-N-
hydroxy-acrylamide
_
_
,," 3-[1-(2-Diethylamino-
.
\___._ io ethyl)-2-ethoxymethyl-
.
15 N 361 1H-benzoimidazol-5-
\--. yI]-N-hydroxy-
acrylamide
õõ"i 3-0 -(3-Dimethylamino-
0 . 2,2-dimethyl-propyI)-2-
331 methyl-1H-
benzoimidazol-5-yli-N-
16
hydroxy-acrylamide
3-[1-(2-Diethylamino-
. )c < 0
NH
,c,õ ethyl)-2-(2,2-dimethyl-
17
373 propy1)-1H-
benzoimidazol-5-y1]-N-
r) hydroxy-acrylamide
. .
. (.,.
/ N-Hydroxy-3-[1-(3-
isopropylamino-propyl)-
NI 11 2-(3,3,3-trifluoro-
F 399
F)cr'N\ propy1)-1H-
18
benzoimidazol-5-y11-
):-- acrylamide
_
- 342-(2,2-Dimethyl-
)( 0 Li propyI)-1-(2-
isopropylannino-ethyl)
19
N
359
,
3 1H-benzoirnidazol-5-
/ NH y1]-11-hydroxy-
acrylamide
I
CA 02540459 2006-03-21
115
Cmpd . miz
Structure NAME
No [M+H]
_
3-[1-(2-
.
40 r Diisopropylamino-
ethyl)-2-(2,2-dimethyl-
N
propyI)-1H-
401
)n' benzoimidazol-5-y1]-N-
,
hydroxy-acrylamide
. _
3-[1-(2-
( io
1: Diisopropylamino-
N
21
387 ethyl)-2-isobuty1-1H-
)
benzoimidazol-5-y1]-N-
n" hydroxy-acrylamide
-
_
O
3-[1-(3-Dimethylamino-
2,2-dimethyl-propyI)-2-
z NN io
OH
399 hex-3-eny1-1H-
22
.--- benzoimidazol-5-y1]-N-
/ hydroxy-acrylamide
3-[1-(3-Dimethylamino-
0
2,2-dimethyl-propy1)-2-
429 (2,4,4-trimethyl-penty1)-
i -- \----\_- 1H-benzoimidazol-5-
23
/ yll-N-hydroxy-
acrylamide
O
_
342-Cyclohexy1-1-(3-
_
399 dimethylamino-2,2-
dimethyl-propyI)-1H-
V-\-- benzoimidazol-5-yli-N-
hydroxy-acrylamide
342-Bicyclo[2.2.1]hept-
0
5-en-2-y1-1-(3-
4, /N
"
. 0
1".
409 dimethylamino-2,2-
\---\_.- dimethyl-propyI)-1H-
/ benzoimidazol-5-y1]-N-
hydroxy-acrylamide
CA 02540459 2006-03-21
116
Cmpd m/z
Structure NAME
No [WM+
3-[1-(2-Diethylamino-
/ ''. 10 NE, ethyl)-2-hex-3-eny1-1H-
26 ( 385 benzoimidazol-5-y1FN-
hydroxy-acrylamide
r.)
_ .
. 341-(2-
,,N, =' Ni:
<
/ Diisopropylamino-
27 413 ethyl)-2-hex-3-eny1-1H-
benzoimidazol-5-ylj-N-
N)-- hydroxy-acrylamide
. 342-Hex-3-eny1-1-(2-
isopropylamino-ethyl)-
/ <N S NH
1.
28
CH
N 371 1H-benzoimidazol-5-
yli-N-hydroxy-
acrylamide
342-Hex-3-eny1-1-(3-
0
isopropylam ino-propy1)-
29 / : SI .
1. 385 1H-benzoimidazol-5-
( y1FN-hydroxy-
H
acrylamide
. . 3-[1-(2-Ethylamino-
N
/ 110 ' NH
I
. 357 ethyl)-2-hex-3-eny1-1H-
( Cvi benzoimidazol-5-y1FN-
\,...- hydroxy-acrylamide
_
.
7---- . 341-(2-Diethylamino-
_
\ .
ti' ethyl)-2-hexy1-1H-
.
31
387 benzoimidazol-5-y11-N-
hydroxy-acrylamide
)
. .
CA 02540459 2006-03-21
117
N-Hydroxy-341-(3-
.
isopropylamino-propyI)-
< 16"2-(2,4,4-trimethyl-
32 415
pentyI)-1H-
benzoimidazol-5-y1]-
acrylamide
34242,2-Dimethyl-
propyI)-143-
40
isopropylamino-propy1)-
33 373
1H-benzoimidazol-5-
yI]-N-hydroxy-
N
acrylamide
34142-
_
Diisopropylamino-
ethyl)-243,3,3-tritluoro-
34
F F)4. 427 propy1)-1H-
benzoimidazol-5-y1]-N-
hydroxy-acrylamide
o N-Hydroxy-342-
( r
35 isobutyl-142-
345 isopropylamino-ethyl)-
1H-benzoimidazol-5-
yll-acrylamide
o 3-[2-(2,2-Dimethyl-
NH propyI)-1-(2-
36 345 ethylamino-ethyl)-1H-
benzoimidazol-5-y11-N-
hydroxy-acrylamide
34142-Ethylamino-
ethyl)-2-isobuty1-1H-
37 331 benzoimidazol-5-y1J-N-
.
hydroxy-acrylamide
CA 02540459 2006-03-21
118
3-[1-(2-
0
. , Diisopropylamino-
H
/ NN * IN ethyl)-2-(2,4,4-
38 \ 443
trimethyl-penty1)-1H-
N benzoimidazol-5-y1]-N-
hydroxy-acrylamide
N-Hydroxy-3-[1 -(2-
0
isopropylamino-ethyl)
\ 01
NH
/ N N
401 2-(2,4,4-trimethyl-
39
C¨H
N \ _
r penty1)-1H-
benzoimidazol-5-A-
acrylamide
3-[1-(2-Ethylamino-
N
ethyl)-2-(2,4,4-
387 trimethyl-pentyI)-1H-
CNH--, HNH/ benzoimidazol-5-y1]-N-
hydroxy-acrylamide
3-[1-(2-Diethylamino-
N
/
ethyl)-2-(2,4,4-
41 .
415 trimethyl-penty1)-1 H-
HN.õ
91 benzoimidazol-5-A-N-
hydroxy-acrylamide
,
42
3-[1-(2-Diethylamino-
r'l ethyl)-2-propy1-1H-
H 345
/-,¨/N 11 \ Nõõ benzoimidazol-5-y1]-N-
7---N\
hydroxy-acrylamide
¨)N>¨ 3-12-Buty1-1-(2-
43 \ 387 diisopropylamino-
ethyl)-1H-
/ \ < 0 0 benzoimidazol-5-A-N-
NEI hydroxy-acrylamide
,,,,
.-.-.-.
7----NI 342-Buty1-1-(2-
ethylamino-ethyl)-1 H-
44 / \ < 40 331
benzoimidazol-5-A-N-
"" 0
hydroxy-acrylamide
..
_
CA 02540459 2006-03-21
,
119
3-[1-(2-Diethylamino-
0
\ethyl)-2-(2-
. B¨\ .1 0
./ 11
H
N
methylsulfanyl-ethyl)-
ri 377
1H-benzoimidazol-5-
r) yll-N-hydroxy-
acrylamide
_
= 342-Buty1-1-(2-
\ ,..
\ N 10 n isopropylamino-ethyl)-
46
345 1H-benzoimidazol-5-
3 yI]-N-hydroxy-
/ NH acrylamide
...
3-[2-Buty1-1-(3-
\ , ..., ..,,Ø
\ 0 H isopropylamino-propyI)-
47
_.-- 359 1H-benzoimidazol-5-
y1]-N-hydroxy-
.
----c acrylamide
. .
\ r 3-[1-(1-Benzyl-
\ 10 '
N piperidin-4-y1)-2-
butyl-
6 433 1H-benzoimidazo1-5-
48
y1]-N-hydroxy-
Oacrylamide
.
342-But-3-eny1-1-(2-
/ <NN 0 C'" ethylamino-ethyl)-1H-
49 // 329 benzoimidazol-5-yli-N-
hydroxy-acrylamide
i----
_
\ . 342-Hexy1-1-(2-
\
NH
111 isopropylamino-ethyl)-
N
\_.,.. 373 1H-benzoimidazol-5-
y1]-N-hydroxy-
/ NH acrylamide
. 3-[1-(2-Dimethylamino-
0
ethyl)-2-(2,4,4-
51 )(¨( la
NH
b. 387
N
trimethyl-penty1)-1H-
rj benzoimidazo1-5-y1]-11-
---"\ hydroxy-acrylamide
CA 02540459 2006-03-21
120
\ 0 341-(2-Ethylamino-
\¨\ 0I. 359 ethyl)-2-hexy1-1H-
52 N benzoimidazol-5-yli-N-
\ hydroxy-acrylamide
N.,....-NH
N-Hydroxy-3-[1-(2-
0
I- I 40 ,...
H isopropylamino-ethyl)
\ 2-(3,3,3-trifluoro-
53
. 385
propyI)-1H-
H N\ _
r benzoimidazol-5-y1]-
acrylamide
3-[1-(2-Dimethylamino-
54
1õ
Iti fa ...., OH
/
1r
357 ethyl)-2-hex-3-eny1-1H-
benzoimidazol-5-y1]-N-
)
hydroxy-acrylamide
_--\
.
3-[1-(2-Amino-ethyl)-2-
"40 ' 'OH (2,4,4-trimethyl-penty1)-
55 c< __ < 359 1H-benzoimidazol-5-
y1]-11-hydroxy-
acrylamide
3-[1-(2-Amino-ethyl)-2-
<,"ti...,,OH
/
(2-methoxy-nonyI)-1H-
56 / N Willi
403 benzoimidazol-5-yli-N-
, /
/ ,ip hydroxy-acrylamide
___________________________________________________________________ _
. 342-Buty1-1-(2-
\
dimethylamino-ethyl)-
57 N
331 1H-benzoimidazol-5-
y1FN-hydroxy-
acrylamide
___________________________________________________________________ _
\ a 311-(2-Dimethylamino-
\ .
N /
, ethyl)-2-hexy1-1H-
58
359 benzoimidazol-5-A-N-
hydroxy-acrylamide
_ __________________________________________________________________
CA 02540459 2006-03-21
121
N-{241 -(2-
,
( . Diethylamino-
ethyl)-5-
HN \ ,0H
a (2-
hydroxycarbamoyl-
N
59 444 viny1)-1H-
benzoimidazol-2-A-
/ ethy1}-3,3-
dimethyl-
butyramide
,
_
3-{1-(2-Diethylamino-
Y. ethyl)-242-(2,2-
\IT(OH
dimethyl-
N
430 propionylamino)-
ethyly
\ 1H-
benzoimidazol-5-
õN\
/ yI}-N-hydroxy-
acrylamide
3-{1-(2-Diethylamino-
07,,_, s
ethyl)-2-[(2,2-dimethyl-
/ 0 ' L
H
N propionylamino)-
61
416
methyl)-1H-
r-N) benzoimidazol-5-
y1}-N-
hydroxy-acrylamide
_
N-0-(2-Diethylamino-
0
Ml N
i ethyl)-5-(2-
OH hyd
roxycarbamoyl-
62
402
viny1)-1H-
r) benzoimidazol-2-
ylmethy1}-butyramide
_
. 341-(2-
ethylamino-
___\\ \ _<7 0
NH
i" 359 ethyl) -2-(3,3-
dimethyl-
63 N buty1)-1H-
\ benzoimidazol-5-y11-N-
H hydroxy-
acrylamide
3-[2-(3,3-Dimethyl-
0
butyl)-1-(2-
)F\ 40 10:1 Dimethylamino-ethyl)
64 N
359
1H-benzoimidazol-5-
y1FN-hydroxy-
,\
acrylamide
CA 02540459 2006-03-21
122
2
3-[1-(2-Dimethylamino-
0
65 345 ethyl)-2-penty1-1H-
.
..-0. benzoimidazol-5-y1FN-
--õ,
\ hydroxy-acrylamide
_
' 3-[1-(2-Dimethylamino-
F F
ethyl)-2-(2,212-trifluoro-
66
ethyl)-1H-
benzoimidazol-5-y1W-
, ..
----N
\ hydroxy-acrylamide
_
N-Hydroxy-3-[1-(5-
0
methy1-1H-pyrazol-3-
67 <N. SLi 396 yI)-2-(2,4,4-trimethyl-
/c( penty1)-1H-
7,11/ benzoimidazol-5-y11-
acrylamide
,
341 -(2-Ethylamino-
,A.
F7 < 10 ti ethyl)-2-penty1-1H-
68
345 benzoimidazol-5-y1]-N-
hydroxy-acrylamide
.)
. 0 3-(2-Butyl-1 -pyrrolidin-
0 \ (-ad
69 __---.<,
329 3-y1-1H-benzoimidazol-
6
NH 5-yI)-N-hydroxy-
acrylamide
0 3-(2-Butyl-1 -piperidin-
70 __,,
N 'S\ '-rcµH 343 4-y1-1H-benzoimidazol-
5-yI)-N-hydroxy-
IIN acrylamide
. _
N-Hydroxy-3-[1-(2-
O 14-OH
71 N
/¨ 'Ic isopropylamino-ethyl)
359
/ 2-penty1-1H-
benzoimidazol-5-y1]-
,
r acrylamide
CA 02540459 2006-03-21
123
\ N-Hydroxy-3-[1-(2-
\
= methylamino-ethyl)-2-
.
72 . 385 non-3-eny1-1H-
I.
N benzoimidazol-5-yli-
rj acrylamide
NH
/ N-Hydroxy-3-[1-(2-
: 385 methylamino-ethyl)-2-
non-6-eny1-1H-
73
benzoimidazol-5-yll-
acrylamide
ri
\ . 342-Hexy1-1-(2-
N /CM
1
345 methylamino-ethyI)-1H-
benzoimidazol-5-y1]-N-
hydroxy-acrylamide
--4,-,
. N-Hydroxy-341 -(2-
7 40 ' ' methylamino-ethyl)-2-
75 / 331 penty1-1H-
benzoimidazol-5-y1]-
'IN\ acrylamide
N-Hydroxy-3-[1-(2-
0 Nr. methylamino-ethyl)-2-
76 N 373
octy1-1H-
benzoimidazol-5-y1]-
\ HN \
acrylamide
3-[1-(2-Amino-ethy1)-2-
_________________________ 40 r
. octyl-1H-
77 N
359 benzoimidazol-5-yli-N-
H2N hydroxy-acrylamide
\
3-12-Butyl-I-[2-
N
40 ' '
, /--/ <c (isopropyl-methyl-
78
/ 359 amino)-ethy1]-1H-
-N\ benzoimidazol-5-y1}-N-
hydroxy-acrylamide
CA 02540459 2006-03-21
124
341424Ethyl-methyl-
-
/ <
;,, 0 N- aminoyethy1]-2-pentyl-
79 _/
359 1 H-benzoimidazol-5-
y1}-N-hydroxy-
r-N\ acry1amide
.
.
342-(2-1-pyrrolidin-
_
O.
; 6 357 . 3-y1-1 H-benzoimidazol-
80 0, 5-yI)-N-hydroxy-
acrylamide '
H
0
3-[2-Butyl-1-(1-methyl-
-
tr
, 40 O" pyrrolidin-3-yI)-1H-
81 343 benzoimidazol-5-y1FN-
:I> hydroxy-acrylamide
N\ , .
.
342-Hexy1-1-piperidin-
_
,.,--'3"
a
N 'IIIIV- H
371 3-y1-1 H-benzoimidazol-
82
5-yI)-N-hydroxy-
a
acrylamide
_ .
0 342-Butyl-I -piperidin-
_
_,.0H
.....õ,õ...............õ......,.,<N -...... 0, 3-y1-1 H-benzoimidazol-
83 N 343 5-yI)-N-hydroxy-
acrylamide
dil
- _
_ 0 3-(1-{2-[Ethyl-(2-
N
/ <
/ le '- NOH
H
/ N methoxy-ethyl)-amino]-
ethy1}-2-penty1-1H-
/
84 403 benzoimidazol-5-y1)-N-
N hydroxy-acrylamide
r co
1
H
0 3-{2-Butyl-1I 424ethyl-
N si ,,, N,OH
methyl-aminoyethyli-
/ N I H-benzoimidazol-5-
85 /
345
yI}-N-hydroxy-
N
r \ acrylamide
_________________________________________________________________ _
CA 02540459 2006-03-21
125
0 N-Hydroxy-3-[1-(1-
NõOH
methyl-piperidin-3-y1)-
H
' N 2-penty1-1H-
86371
benzoimidazol-5-y11-
a acrylamide
. 0 - 3-{142-(Ethy)-hexyl-
N
N -., N,OH
, H amino)-ethy1]-1H-
benzoimidazol-5-A-N-
87 359 hydroxy-acrylamide
N
[if
,
_
0 3-{142-(Ethyl-
pentyl-
N
N N_OH
H aminoyethy1]-1H-
benzoimidazol-5-y1}-N-
88
345 hydroxy-acrylamide
N
j---1¨
-
_
0 3-{142-(Ethyl-
heptyl-
N
0
H arnino)-ethy1]-1 H-
N
benzoimidazol-5-y1}-N-
89 373 hydroxy-acrylamide
N
7
\ 0 3-{2-Hexy1-141 -(2-
1
\=hydroxy-ethyl)-
N
\ =1 0 -,,, 1=61HH
piperidin-3-y1]-1H-
90 415 benzoimidazol-5-yll-N-
al
. .
hydroxy-acrylamide
ZOH
CA 02540459 2006-03-21
.126
0 3-(2-Butyl-1 42-[ethyl-
1 NH
(3-hydroxy-propy1)-
N 40
OH amino]-ethyl}-1H-
91 r----1 389 benzoimidazol-5-y1)-N-
N \ hydroxy-acrylamide
rff /
HO
_ -
_
. 3-(142-[Ethyl-(3-
- hydroxy-propy1)-
/
/ 0
403 amino]-ethyI}-2-pentyl-
92
1H-benzoimidazol-5-
yI)-N-hydroxy-
acrylamide
_
0 1(0.
(E)-N-hydroxy-3-(1-(1-
-
-- c
--,, phenethylpyrrolidin-3-
93 377
yI)-1H-
benzo[d]imidazol-5-
ypacrylamide
ill
_
_ 0
(E)-N-hydroxy-3-(1-(1-
_
N pentylpiperidin-3-yI)-
94 357
1H-benzo[dlimidazol-5-
N ypacrylamide
-
0
iii 0
34142-(Butyl-ethyl-
N
amino)-ethyl]-1H-
331
benzoimidazol-5-y1}-N-
N hydroxy-acrylamide
,
-
CA 02540459 2006-03-21
127
U
N opN,...AH
(E)-N-hydroxy-3-(1-(1-
phenethylpiperidin-3-
N
96 391 y1)-1 H-
benzo[d]imidazol-5-
N
ypacrylamide
=0 .
(E)-N-hydroxy-3-(1-(1 -
N 110
OH
(3-
N phenylpropyl)piperidin-
97 405 3-y1)-1 H-
benzo[d]imidazol-5-
N
41, yl)acrylamide
0
---õ, õAi,
lei
N (E)-N-hydroxy-3-(1-(1-
(3-
98 -------
--N 391 phenylpropyl)pyrrolidin-
3-y1)-1 H-
benzo[d]imidazol-5-
ypacrylamide
II _
N 0 N /OH
3-{141-(3,3-Dimethyl-
N buty1)-pyrrolidin-3-y1F
99
3 357 1 H-benzoimidazol-5-
N y1}-N-hydroxy-
acrylamide
0
OH (E)-3-(1-(2-
(diethylamino)ethyl)-
N
100
303 1 H-benzo[d]imidazol-5-
y1)-N-
N hydroxyacrylamide
r)
CA 02540459 2006-03-21
128
3-[2-(4-Cyano-butyI)-1
N- \
(2-diethylamino-ethyl)-
101
384 1H-benzoimidazol-5-
y11-N-hydroxy-
N
r acrylamide
u
la
NH
111 (E)-3-(1-(1-
N
butylpiperidin-3-yI)-1H-
,
102 343
benzo[d]imidazol-5-y1)-
N-hydroxyacrylamide
N
- 0
N
11H
401
OH (E)-N-hydroxy-3-(1-(1-
(pent-4-enyl)piperidin-
N
103
di 355 3-yI)-1H-
benzo[d]imidazol-5-
\---\-- yl)acrylamide
0
=-õ ,....,
0 ri OH (E)-3-(1-(1-(3,3-
o 371 dimethylbutyl)piperidin-
104
4-y1)-1H-
N
benzo[d]imidazol-5-y1)-
-----\ N-hydroxyacrylamide
.
\
0 '4c" 3-[1-(2-Diethylamino-
ethyl)-2-propylamino-
N
105
360 1H-benzoimidazol-5-
yll-N-hydroxy-
r) acrylamide
u
,l OH (E)-N-hydroxy-3-(1-(2-
ei
(isopropyl(propyl)amino
N
107
331 )ethyl)-1H-
benzo[d]imidazol-5-
yl)acrylamide
CA 02540459 2006-03-21
129
_ 0
N....AH
3-{142-(Butyl-
-..,
'
N H isopropyl-amino)-ethyl]-
108 345 1H-benzoimidazol-5-
\-----N___ yI)-N-hydroxy-
ff acrylamide
'
0
OH N-Hydroxy-3-{1-(2-
' 0 r,
(isopropyl-pentyl-
N ,
109
359 amino)-ethy1]-1H-
benzoimidazol-5-y1)-
\ acrylamide
_
\ 342-(5-Cyano-penty1)-
.
\ 1-(2-diethylamino-
110 \K 0 r
398 ethyl)-1H-
ri benzoimidazol-5-yli-N-
r) hydroxy-acrylamide
_ 0
......õ.0H 40 3- 1- 2- 3 3-Dimeth
( { R 1-
, Y '
N butyl)-ethyl-amino]-
111
359 ethyl)-1H-
benzoimidazol-5-y1)-N-
N\
--------r / hydroxy-acrylamide
_ 0
N 110 3-{142-(Ethyl-propyl-
N amino)-ethyl]-1H-
112
317
benzoimidazo1-5-y1)-N-
hydroxy-acrylamide
N
-1--- )
0
OH
i 0 N
\ N-Hydroxy-3-(1-{2-
N
,
373 [isopropyl-(2-methyl-
113pentyl)-amino]-ethyl}-
r-N 1H-benzoimidazol-5-
y1)-acrylamide
CA 02540459 2006-03-21
130
. (E)-N-hydroxy-3-(1-(2-
i 40 Nc'H
\N (isopropy1(4,4,4-
trifluorobutyl)amino)eth
114 ><1 \ \ (iN 399
y1)-1H-
benzo[d]imidazol-5-
)-- yl)acrylamide
.
\3-[1-(3-Dimethylamino- ,
<i) 40 ...,, N,,, OH
2,2-dimethyl-propyI)-2-
N
115
((_____. 374 propylamino-1H-
benzoimidazol-5-y1]-N-
hydroxy-acrylamide
N-
/ -
U
2; -,...... NH.OH
N 3-{142-(Ethyl-hexyl-
rj aminoyethy1]-2-methyl-
116
1H-benzoimidazol-5-
r 373
y1}-N-hydroxy-
acrylamide
U
F F le NH
1,H 3-{142-(Butyl-ethyl-
FriN amino)-ethyl]-2-
117399 trifluoromethy1-1H-
r,N
/ benzoimidazol-5-y1}-N-
hydroxy-acrylamide
.
F 24 0 ,...., ,OH
F
Frici 3-{142-(Ethyl-hexyl-
amino)-ethy1]-2-
118
rN 427 trifluoromethy1-1H-
benzoimidazol-5-y1}-N-
hydroxy-acrylamide
CA 02540459 2006-03-21
131
U
/ io -..., N...,,,ON
(E)-3-(1-(2-
(dibutylamino)ethyl)-2-
119 401 propy1-1H-
) benzo[d]innidazol-5-y1)-
_ N-hydroxyacrylamide
- U r
OH
N 0 N,/'
3-[1-(2-Dipropylamino-
7
ethyl)-1H-
120
331 benzoimidazol-5-A-N-
-----\_¨N hydroxy-acrylamide
. 0
N-Hydroxy-3-(1-{2-
/ 40, rii....
[isopropyl-(3-methyl-
121
359 butylyaminoj-ethyl)-
1H-benzoimidazol-5-
yl)-acrylamide
_ 0 3-(1-{2-[(3,3-Dimethyl-
<iN 401 rrAH buty1)-methyl-aminol-
122
345 ethy11-1H-
benzoimidazol-5-y1)-N-
hydroxy-acrylamide
_
0 3-(1-{2-[(2-Ethyl-butyl)-
methyl-amino]-ethyl}-
123N 345 1H-benzoimidazol-5-
yI)-N-hydroxy-
acrylamide
(E)-3-(1-(2-(bis(3,3-
<,
" 40 'c'l dimethylbutyl)amino)et
124
415 hyl)-1H-
\/---\____. benzo[d]innidazol-5-y1)-
VN-hydroxyacrylamide
CA 02540459 2006-03-21
132
o
(E)-3-(1-(2-
40 Nc'H
(diisobutylamino)ethyl)-
N
125
359 1H-benzo[d]imidazol-5-
y1)-N-
hydroxyacrylamide
U
N N 40 Nõ,,,,
3-{1-[2-(3,3-Dimethyl-
331 butylaminoyethy1]-1H-
126
benzoimidazol-5-y1}-N-
HN
hydroxy-acrylamide
.
' Ni' N-Hydroxy-3-{142-
N (methyl-pent-4-enyl-
127 329 amino)-ethyI]-1H-
,N
benzoimidazol-5-y1}-
acrylamide
3-(1-{2-[(3,3-Dimethyl-
ti
butyI)-propyl-aminol-
128
373 ethy1}-1H-
benzoimidazol-5-y1)-N-
hydroxy-acrylamide
0
3-0-(3-Dimethylamino-
,, .."..,OH
\ lel Vi
N 2,2-dimethyl-propyI)-2-
129 363 methylsulfany1-1H-
benzoimidazol-5-y1FN-
N------- hydroxy-acrylamide
1 _
.
/ 7;\ lei N OH 3-{1-[2-(3,3-Dimethyl-
N butylamino)-ethylj-2-
130
373 propyl-1H-
FIN benzoimidazol-5-y1}-N-
hydroxy-acrylamide
CA 02540459 2006-03-21
133
. 3-[1-[2-(3,3-Dimethyl-
NriAilko, ....', ....AH
7( * butylaminoyethy1]-2-
/ 401 (2,2-dimethyl-propyI)-
131
1H-benzoimidazol-5-
\---- yI]-N-hydroxy-
acrylamide
. 311-{2-[Bis-(3,3-
N NAgib...
< * dimethyl-butyI)-amino]-
/
132
Ni 485 ethy11-242,2-dimethyl-
propy1)-1H-
- benzoimidazol-5-y1FN-
hydroxy-acrylamide
u
2, 014
le ....., r
3-0 -[2(2,2-Dimethyl-
N
133
317 propylamino)-ethy1]-1H-
benzoimidazol-5-y1}-N-
HN hydroxy-acrylamide
4 .
2, =,..., 14 ......õOH 341424(2,2-Dimethyl-
N propyI)-propyl-amino]-
134
359 ethy11-1H-
benzoimidazol-5-y1)-N-
4----N hydroxy-acrylamide
. .F4
3-{14243,3-Dimethyl-
/ -1 0 butylaminoyethy1]-2-
N
135
359 ethy1-1H-
benzoimidazol-5-y1}-N-
ifNH
hydroxy-acrylamide
_
BIOLOGICAL TESTING AND ENZYME ASSAYS
Recombinant GST-HDAC1 Protein expression and purification
[0363] 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 pDEST20 vector (GATEWAY Cloning Technology, Invitrogen
CA 02540459 2006-03-21
134
Pte Ltd). The pDEST20-HDAC1 construct was confirmed by DNA sequencing.
Recombinant baculovirus was prepared using the Bac-To-Bac method following the
manufacturer's instruction (lnvitrogen Pte Ltd). Baculovirus titer was
determined by
plaque assay to be about 108 PFU/ml.
[0364] Expression of GST-HDAC1 was done by infecting SF9 cells (Invitrogen Pte
Ltd) with pDEST20-HDAC1 baculovirus at M01=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 NaC1 and
3mM MgC12. 20% Glycerol was added to purified GST-HDAC1 protein before storage
at -80 C.
In vitro HDAC assay for determination of IC50 values
[0365] 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 NaCl, 2.7 mM KCI, 1 mM
MgCl2, 1
mg/ml BSA, tested compounds, an appropriate concentration of HDAC1 enzyme, 500
uM Flur de lys generic substrate for HDAC1 enzyme and subsequently was
incubated
at room temperature for 2 h. Flur de lys Developer was added and the reaction
was
incubated for 10 min. Briefly, deacetylation of the substrate sensitizes it to
the
developer, which then generates a fluorophore. The fluorophore is excited with
360 nm
light and the emitted light (460 nm) is detected on a fluorometric plate
reader (Tecan
Ultra Microplate detection system, Tecan Group Ltd.).
[0366] The analytical software, Prism 3.0 (GraphPad Software Inc) has been
used to
generate IC50 from a series of data.
[0367] The HDAC enzyme inhibition results of representative compounds are
shown
in Table 1 (unit is micromolar).
CA 02540459 2006-03-21
135
[0368] Table 1. HDAC1 enzyme activity IC 50 (unit is micromolar).
Compound..,, No No Compound Compound
No
IC50 (invi) IC50 (uM) IC50 (PM)
1 0.042 46 0.049 - 91 ' 0.060
2 0.38 47 0.21 92 0.050
_
3 0.15 48 0.43 93 - 0.23
4 0.12 49 0.11 94 0.064
0.17 50 0.036 95 0.052 _.
6 0.18 51 0.066 96 0.080
_
7 0.091 52 0.025 97 0.10
8 0.052 53 0.10 98 0.32
_
9 0.21 54 0.048 99 0.12
0.14 55 0.037 100 . 0.19
11 0.070 56 0.029 101 ' 0.08
12 0.064 57 0.090 102 0.54
13 0.42 58 0.030 103 0.10
.._
14 '0.077 59 0.077 104 0.41
0.085 60 0.10 105 - 0.13
_
17 0.13 61 0.070 107 0.074
19 0.064 62 - 0.054 108 - 0= .043
0.26 63 0.051 109 . 0.048
21 0.38 64 0.10 110 - 0= .044
22 0.064 65 0.078 111 0.029 _
_
23 0.045 66 0.34 112 0.12
24 0.51 68 0.034 113 0.016
0.23 70 0.068 . 114 ' 0= .063
26 0.040 71 0.040 116 0.10
27 0.23 72 0.017 117 0.19
28 0.021 73 0.026 118 0.48
29 0.13 74 0.028 119 0.18
0.021 75 0.050 120 0.11 _
31 0.045 76 0.018 121 0.079
32 - 0.060 77 0.026 122 0.037
33 0.23 78 0.044 123 0.027
34 0.88 79 0.040 124 0.085 _
0.082 . 80 0.040 125 - 0.16 _
_
CA 02540459 2006-03-21
136
36 0.096 81 0.12 126 0.042
37 0.091 82 = 0.10 127 0.078
= 38 0.56 83 0.19 128 0.031
39 0.024 84 0.063 129 0.77
40 0.027 85 0.11 130 = 0= .036
41 0.062 86 0.16 131 = 0= .066
42 0.15 - 8= 7 0.10 133 0.072
= 43 = 0.33 - 8= 8 0.047 134 0.22
¨4-4 0.054 89 0.080 135 0.074
45 0.053 90 0.51
Cell-based proliferation assay for determination of G150 values
[0369] Human colon cancer cell lines (Co10205, HCT116), Ovarian cancer cell
line
[0370] The cell activity results of representative compounds are shown in
Table 2
and 3. The data indicated that the compounds of this invention are active in
the
CA 02540459 2006-03-21
137
[0371] Table 2. Cellular or Growth Inhibition Activity in Co1o205 cells (unit
is
micromolar)
Compound Compound Compound
G150 (I1M) GIN (IA) GI50 (0)
No No No
_
1 0.50 46 0.48 - 91 2.40
_ .
2 2.12 47 3.6 92 1.82
_ .
3 2.22 48 0.78 93 2.14
_ . .
4 2.62 - 49 . 1.75 - 94 0.60
_ .
2.58 50 0.17 - 95 0.57
. .
6 , 2.69 51 0.26 '96 0.70
7 0.81 52 0.21 97 0.67
. .
8 0.56 53 1.05 - 99 1.89
9 - 1.87 - 54 0.46 '100 2.25
_.
1.77 55 0.91 '101 2.44
11 '0.48 56 0.90 102 ' 2.08 .
12 0.51 57 0.65 103 0.48 '
13 - 5.5 58 0.38 ' 104 1.99
14 - 0.63 59 2.28 105 1.77 .
- 1.50 60 2.48 107 0.63 _
17 - 1.19 ' 61 1.32 ' 108 0.44 _
19 '0.53 62 2.60 109 0.49
'2.66 63 0.54 ' 110 1.74 _
21 '2.51 64 0.73 111 0.21 _
22 ' 0.75 65 0.56 112 0.88 _
23 '0.19 66 8.8 113 0.61 _
24 2.99 68 0.52 114 0.72 _
2.38 70 7.0 116 0.70
26 '0.37 71 0.24 117 1.80 _
27 '1.42 72 0.16 118 1.88 _
28 0.18 73 0.23 119 0.77 _
29 ' 1.92 74 0.55 120 0.49
_
0.31 75 1.20 - 121 0.49 _
31 0.42 76 0.29 122 0.15 _
32 0.74 77 0.67 123 0.15 _
33 2.11 78 0.54 - 124 0.54 _
_
CA 02540459 2006-03-21
138
34 4.4 79 0.45 125 0.68
_
35 0.66 80 1.37 126 0.42
_
36 0.86 81 1.00 127 0.34
_
37 1.09 82 1.23 128 0.14
_
38 1.94 83 4.9 129 3.9
_ .
39 0.23 84 1.03 130 0.15
_
40 0.16 85 1.52 -131 0.33 .
41 0.92 86 2.08 133 . 0.56
42 0.98 ' 87 ' 1.07 134 2.30
43 1.86 88 0.55 -135 0.26
_
44 0.87 89 0.87
_
45 0.54 90 8.1
[0372] Table 3. Cellular or Growth Inhibition Activity in Various Cancer Cell
Lines
Cell lines
Compound' HCT116 A2780 PC3 HEP3B
1 ' ++ +++ +++ ++
7 + + ++ Not tested
8 ++ ++ +++ +
22 + +++ +++ Not tested
23 ++ +++ +++ Not tested
30 - ++ +++ +++ Not tested
40 +++ +44 +++ Not tested
44 + ++ +++ Not tested
46 +++ +++ +++ ++
50 +++ . +++ +++ Not tested
52 +++ +++ +++ Not tested
58 +++ +++ +++ +++
71 +++ +++ +++ Not tested
- 111 Not tested Not testediNot tested +++
_
130 +++ +++ +++ Not tested
("+++" for G150 < 0.5 M, "++" for G150 between 0.5 and 1.0 M," +" for GI50
between 1.0 JIM to 5.0 NI)
CA 02540459 2006-03-21
139
Histone H3 acetylation assay
[0373] A hallmark of histone deacetylase (HDAC) inhibition is the increase in
the
acetylation level of histones. Histone acetylation, including H3, H4 and H2A
can be
detected by immuno-blotting (western-blot). Co10205 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 10 I.JM final
concentration.
After 24 h, cells were harvested and lysed according to the instruction from
Sigma
Mammalian Cell Lysis Kit. The protein concentration was quantified using BCA
method
(Sigma Pte Ltd). The protein lysate was separated using 4-12% bis-tris SDS-
PAGE gel
membrane was probed using primary antibody specific for acetylated histone H3
(Upstate Pte Ltd). The detection antibody, goat anti rabbit antibody
conjugated with
HRP was used according to the manufacturing instruction (Pierce Pte Ltd).
After
removing the detection antibody from the membrane, an enhanced
chemiluminescent
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
protein.
[0374] The results of immuno-blotting assay using acetylated histone H3
antibody are
shown in Table 4 for representative compounds of this invention.
CA 02540459 2006-03-21
140
[0375] Table 4
Histone Histone Histone
Acetylation Acetylation
Acetylation
activities activities activities
Compound (Histone-3) Compound (Histone-3) Compound (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 - 40 Active 65 Active
14 Active - 41 Active 68 Active
17 Active 42 Active 71 Active
19 Active 44 Active 74 Active
22 Active 45 Active 130 Active
26 Active 46 Active
28 Active 48 Active
[0376] These data demonstrate that compounds of this invention inhibit histone
deacetylases, thereby resulting in the accumulation of acetylated histones
such as H3.
Measurement of Microsomal stability
[0377] Metabolic stability measurements in the in vitro using liver microsomes
aids in
the prediction of the in vivo hepatic clearance and the compound stability
towards
phase I biotransformation reactions mediated by P450 isozymes.
[0378] Pooled human liver microsome (HLM was purchased from BD Gentest (BD
BioSciences). The incubations consisted of test compound (5 pM) or control
compound
(Verapamil), NADPH-generating system solution A (25 mM NADP+, 66 mM glucose-6-
phosphate, 66 mM MgC12 in H20), NADPH-generating system solution B (40 Wm(
,15 glucose-6-phosphate dehydrogenase in 5 mM sodium citrate) and 1.0 mg/ml
microsomal protein, respectively, in 100 mM potassium phosphate buffer (pH
7.4).
Samples are incubated for 0, 5, 15, 30, 45, 60min. Reaction is terminated with
ice-cold
80% acetonitrile and 20% DMSO. Samples are subsequently centrifuged at 4 C for
15
min at 2,000 rpm. 100 pL of the supernatant is transferred to the LC-MS Plate
for
analysis. Before quantitative analysis, the compound is tuned in LC/MS machine
to get
CA 02540459 2006-03-21
141
the optimized MS condition. Liquid chromatography is performed on a Luna C18
column (Phenomenex U.S.A, Torrance, CA) (2x5Omm, 5 pM). % remaining of
compound (by area) of each time point is calculated with respect to time 0.
Plot
%remaining against time (min) to obtain the curve and use the Prism software
to obtain
the t112. These are demonstrated in table 5.
[0379] Table 5.
Compound No T1/2 (min) Compound No T1/2 (min)
1 >30 52 >30
2 >30 58 >30
8 >30 63 >30
11 >30 68 >30
12 >30 71 >30
14 >30 74 >30
19 >30 78 >30
35 >30 80 >30
40 >30 88 >30
44 >30 108 >30
46 >30 130 >30
[0380] The measured in vitro 11/2 >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.
[0381] The above results demonstrated the compounds of formula (I) were
metabolically stable in human liver microsme 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
[0382] Compound is dissolved in appropriate solution (saline or DMA and
Cremaphor
in saline) at 1 mg/ml for intravenous (IV) administration, or in 0.5% methyl
cellulose,
0.1% Tween 80 in water at 5 mg/ml for oral administration. Mice are randomized
according to body weight, grouped three per time point. Mice are administered
single
IV dose (10 mg/kg) via tail vein, or single oral dose (50 mg/kg) via gavage.
At pre-
defined time points (predose, 5 or 10, 30min, 1, 2, 4, 8, and 24h), one group
of mice is
sacrificed by overdose CO2 and blood samples are collected by cardiac
puncture. The
blood samples are centrifuged immediately for 10 min at 3000 rpm to separate
plasma,
and plasma is kept frozen at ¨80 C until analysis by LC/MS/MS. Before sample
CA 02540459 2006-03-21
142
analysis, the method is developed for LC/MS/MS assay. The method is validated
for
signal-response of the calibration standards, auto-sampler stability for ¨15
hours intra-
day and inter-day calibration curve using eight calibration standards
excluding the
blank plasma. QC samples at three different concentrations in triplicates were
prepared
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 are analysed using the validated method.
Data are
analyzed by the non-compartmental model using WinNolin 4.0 software
(Pharsight,
Mountain View, CA, USA). The mean values for the plasma compound concentration-
time profiles are used in mouse PK study.
[0383] The PK parameter AUG 0-last providing the information on the overall
exposure
of the drug in vivo is one of the key PK/PD parameters that helps in
predicting the
efficacy of a anticancer compound. The higher the AUC value, the better will
be the
efficacy of the compound. Pharmacokinetic data of selected compounds in Table
5
were shown in Table 6 below.
[0384] Table 6. Representative pharmacokinetic data [compounds were in
hydrochloric acid salt form (2HCI), dosed at 50 mg/kg, p.o.]
Compound AUCo-last (ng.h/m1)
1 1868
8 1836
130 1050
[0385] The data in Table 6 further demonstrated that compounds with high
metabolic
stability as shown by representative compounds in Table 5 together with the
appropriate physicochemical properties, e.g., molecular weight, logP, and high
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:
[0386] The efficacy of the compounds of the invention can then be determined
using
in vivo animal xenograft studies. The animal xenograft model is one of the
most
commonly used in vivo cancer models.
CA 02540459 2006-03-21
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[0387] 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 or orally daily for 21 days. The
dosing volume
will be 0.01m1/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) = (w2 x 1)/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
disease such as
cancer.
[0388] The details of specific embodiments described in this invention are not
to be
construed as limitations. Various equivalents and modifications may be made
without
departing from the essence and scope of this invention, and it is understood
that such
equivalent embodiments are part of this invention.
