ES2367811T3 - HETEROCYCLIC COMPOUNDS. - Google Patents

Abstract

A compound of formula (I): Formula 1 in which R1 is a group of formula: 10 - (CR20R21) m- (CR22R23) n- (CR24R25) or-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, each optional substituent being selected from the group consisting of halogen, = O, -CN, alkenyl, alkynyl and alkoxy; each R20, R21, R22, R23, R24 and R25 is independently selected from the group consisting of: H, halogen, -CN, NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocicloalquiloxilo, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, aminosulfonyl, arylsulfonyl, arylsulfinyl -COOH, -C-S-C-O-C, O3, C-R-C, O3, C-R-C, O3, C-R-6, O-3 , -OR6 and acyl, each of which may be optionally substituted they; or R20 and R21 when taken together can form a group of formula = O o = S, and / or R22 and R23 when taken together can form a group of formula = O o = S, and / or R24 and R25 when taken together they can form a group of formula = O or = S; each R5 is independently selected from the group consisting of H and alkyl; each R6 is independently selected from the group consisting of H and an alkyl; each R28 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, aryl, heteroarylalkyl, aryl , cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocicloalquiloxilo, 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 they form an optionally substituted heterocycloalkyl group; m, n and o are whole numbers independently selected from the group consisting of 0, 1, 2, 3 and 4; or a pharmaceutically acceptable salt thereof.

Description

Field of the Invention

The present invention relates to hydroxamate compounds that are histone deacetylase (HDAC) inhibitors. More particularly, the present invention relates to heterocyclic compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases that involve, related to or associated with enzymes that have histone deacetylase (HDAC) activities.

Background of the invention

The architecture of the local chromatin 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 histones that are the protein components. Reversible histone acetylation is a key component in the regulation of gene expression by altering the accessibility of DNA transcription factors. In general, increased levels of histone acetylation are associated with increased transcription activity, while 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 (HDAC) and histone acetyltransferase together control the level of acetylation of histones to maintain a balance. Inhibition of HDAC results in the accumulation of acetylated histones, which results in a variety of cell-dependent cell responses, such as apoptosis, necrosis, differentiation, cell survival, proliferation inhibition and cytostasis.

HDAC inhibitors have been studied to determine their therapeutic effects on cancer cells. For example, suberylanilide-hydroxamic acid (SAHA) is a potent inducer of differentiation and / or apoptosis in myeloma, bladder and murine erythroleukemia cell lines [Richon V.M. et al., Proc. Natl Acad. Sci. USA, 93: 57055708 (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, 51655170 (2000)]. Other HDAC inhibitors that have been extensively studied to determine their anticancer 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)]. Tricostatin A is a reversible inhibitor of mammalian HDAC. Trapoxin B is a cyclic tetrapeptide, which is an irreversible inhibitor of mammalian HDAC. However, due to the in vivo instability of these compounds they are less desirable as anticancer drugs. Recently, other small molecule HDAC inhibitors have become available for clinical evaluation [US 6,552,065]. Additional HDAC inhibition 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 example, HDAC inhibitors stop polyglutamine-dependent neurodegeneration [Nature, 413 (6857): 739-43, October 18, 2001]. In addition, it has also been known that HDAC inhibitors inhibit the production of cytokines such as TNF, IFN, IL-1 that are known to be involved in inflammatory diseases and / or immune system disorders. [J. Biol. Chem. 1990; 265 (18): 10232-10237; Science, 1998; 281: 1001-1005; Dinarello C.A. and Moldawer L.L. Proinflammatory and anti-inflammatory cytokines in rheumatoid arthritis, A first for clinicians, 3rd edition, Amgen Inc., 2002].

However, there is still a need to provide additional HDAC inhibitors that would be expected to have improved, useful pharmaceutical properties in the treatment of diseases such as cancer, neurodegenerative diseases, disorders involving angiogenesis and inflammatory and / or immune system disorders. In order to meet this need, several major structures of small organic residues including several heterocyclic systems, especially bicyclic heterocyclic ring systems, have been investigated. A heterocyclic system that has been investigated has been the benzimidazole ring system. It has now been found that the successful 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 compared to the prior art compounds. Compounds within the family exhibit microsomic stability and thereby demonstrate improved half-lives in plasma compared to prior art compounds. Compounds within the family normally provide a longer duration of action due to increased in vivo exposure (i.e., area under the curve, AUC0-last) thereby producing improved tumor growth profiles in xenograft models.

Summary of the invention

The present invention relates only to compounds of formula (1) and specific examples that are encompassed by the current set of claims. All other structures are reference embodiments.

In one aspect a compound of formula (I) is described:

image 1

Formula (I)

in which

R1 is an optionally substituted heteroaryl group, an optionally substituted heterocycloalkyl group or a group of the formula:

- (CR20R21) m- (CR22R23) n- (CR24R25) or-NR26R27;

R2 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkoxyalkyl, R11S (O) R13-, R11S (O) 2R13-, R11C (O) N (R12) R13-, R11SO2N (R12) R13-, R11N (R12) C (O) R13-, R11N (R12) SO2R13-, R11N (R12) C (O) N (R12) R13- and acyl, each option being optionally substituted one of them;

R3 is selected from the group consisting of H, C1-C6 alkyl and acyl, each of which may be optionally substituted;

X and Y are the same or different and are independently selected from the group consisting of: H, halogen, -CN, NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl,

25 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocicloalquiloxilo, heterocicloalqueniloxilo, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino , aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -C (O) OR5, -COR5, -SH, -SR6, -OR6 acyl and -NR7R8, optionally

30 replaced each of them;

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;

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 optionally be 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 them may be optionally substituted;

each R7 and R8 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each optionally substituted from them;

each R11 and R12 is independently selected from the group consisting of H, alkyl, alkenyl and alkynyl, each of which may be optionally substituted;

Each R13 is a bond or is independently selected from the group consisting of: alkyl, alkenyl and alkynyl, each of which may be optionally substituted; each R20, R21, R22, R23, R24 and R25 is independently selected from the group consisting of: H, halogen, -CN, NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkyl, cycloalkyl heteroalkyl, heterocycloalkyl heteroalkyl,

Heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, arylalkyl, alkyloxylamino, amino, alkyloxylamino, alkyloxylamino, amino, alkyloxylamino, alkyloxylamino, amino, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino alkylsulfonyl, aminosulfonyl, arylsulfonyl, arylsulfinyl-COOH, -C (O) OR5, -COR5, -SH, -SR6, -OR6 and acyl, each of which may be optionally substituted; or

10 R20 and R21 when taken together can form a group of formula = O o = S, and / or

R22 and R23 when taken together can form a group of formula = O o = S, and / or

R24 and R25 when taken together can form a group of formula = O or = S;

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, aryl, heteroaryl alkyl, hetero ,

20 cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocicloalquiloxilo, aryloxy, arylalkyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl , alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR5 and acyl, each of which may be optionally substituted, or

R26 and R27 when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group;

Z is selected from the group consisting of -CH2-, -CH2CH2-, -CH = CH-, C3-C8 alkylene, C3-C8 alkenylene,

C3-C8 alkynylene, C3-C8 cycloalkyl, substituted or unsubstituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl;

m, n and o are whole numbers independently selected from the group consisting of 0, 1, 2, 3 and 4;

35 or a prodrug or a pharmaceutically acceptable salt thereof.

In one embodiment R4 is H and the compounds are those of formula (Ia):

image 1

Formula (Ia) 40 or a prodrug or an acceptable pharmaceutical salt thereof; wherein R1, R2, R3, X, and Y Z are as defined for the compounds of formula (I). In another embodiment R3 and R4 are H and the compounds are of formula (Ib):

Four. Five

image 1

Formula (Ib)

or a prodrug or a pharmaceutically acceptable salt thereof;

wherein R1, R2, X, and Y Z are as defined for the compounds of formula (I).

5

As with any group of structurally related compounds that have a particular utility, it

they prefer certain groups for the compounds of formula (I), (Ia) and (Ib) in their end use application.

In one embodiment the group R1 is a group of formula 10

- (CR20R21) m- (CR22R23) n (CR24R25) or-NR26R27;

in which m, n and o are whole numbers independently selected from the group consisting of 0, 1, 2, 3 and 4.

Accordingly, in one embodiment they are compounds of formula (Ic):

image 1

Formula (Ic)

in which R1 is a group of formula:

20 - (CR20R21) m- (CR22R23) n- (CR24R25) or-NR26R27

and R2, R3, R4, X, Y, Z, R20, R21, R22, R23, R24, R25, R28, R27, m, n and o are as defined for the compounds of formula (I).

25 Since the values of m, n and n are integers ranging from 0 to 4, the sum of m + n + or is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12. In one embodiment the sum of m + n + o is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8 In another embodiment the sum of m + n + o is an integer selected from the group consisting of 0, 1, 2, 3 and 4. In another embodiment the sum of m + n + o is an integer selected from the group which consists of 2 and 3.

30 In a specific embodiment the sum of m + n + or is 2: when this occurs R1 is selected from the group consisting of:

- (CR20R21) 2-NR26R27; 35 - (CR22R23) 2-NR26R27;

- (CR24R25) 2-NR26R27;

40 - (CR20R21) - (CR22R23) -NR26R27;

- (CR20R21) - (CR24R25) -NR26R27;

- (CR22R23) - (CR24R25) -NR26R27; In one form of this embodiment R1 is the group: - (CR20R21) - (CR22R23) -NR26R27; This provides compounds of formula (II):

image 1

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

image 1

Formula (IIa) in which X, Y, Z, R2, R3, R20, R21, R22, R23, R26 and R27 are as defined in formula (I). In another specific form R3 is H leading to compounds of formula (IIb):

image 1

Formula (IIb) 20 wherein X, Y, Z, R2, R20, R21, R22, R23, R26 and R27 are as defined in formula (I).

In an even more specific form of this embodiment R20, R21, R22 and R23 are H providing compounds of formula (IIc):

image 1

Formula (IIc)

5

Wherein X, Y, Z, R2, R26 and R27 are as defined in formula (I). In another embodiment the sum of m + n + or is 3. When this occurs R1 is selected from the group consisting of:

10 -CR20R21) 3-NR26R27; - (CR22R23) -NR26R27; - (CR24R25) 3-NR26R27;

fifteen

- (CR20R21) 2- (CR22R23) -NR26R27; - (CR20R21) 2- (CR24R25) -NR26R27; 20 - (CR20R21) - (CR22R23) 2-NR26R27; - (CR22R23) 2- (CR24R25) -NR26R27; - (CR20R21) - (CR24R25) 2-NR26R27;

25

- (CR22R23) - (CR24R25) 2-NR26R27; - (CR20R21) - (CR22R23) - (CR24R25) -NR26R27;

In one form of this embodiment R1 is a group of the formula: - (CR20R21) - (CR22R23) - (CR24R25) -NR26R27. This provides compounds of formula (III):

35

image 1

Formula (III) wherein X, Y, Z, R2, R3, R4, R20, R21, R22, R23, R24, R25, R26 and R27 are as defined in formula (I). In a specific form of this embodiment R4 is H which provides compounds of formula (IIIa):

image 1

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

image 1

Formula (IIIb) in which X, Y, Z, R2, R20, R21, R22, R23, R24, R25, R26 and R27 are as defined in formula (I). In an even more specific form of this embodiment R20, R21, R24 and R25 are H, and R22 and R23 are methyl providing compounds of formula (IIIc):

image 1

Formula (IIIc)

wherein X, Y, Z, R2, R26 and R27 are as defined in formula (I).

In each of the previous embodiments of the invention R20 and R21 can represent various different variables. In one embodiment R20 and R21 are independently selected from the group consisting of H, alkyl, alkenyl and alkynyl. In another embodiment R20 and R21 are independently selected from the group consisting of H and alkyl. In yet another embodiment R20 and R21 are independently selected from the group consisting of H, methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl , 2-ethyl-butyl, pentyl, 2-methyl, pentyl, pent-4-enyl, hexyl, heptyl and octyl. In a specific embodiment R20 and R21 are both H.

In each of the previous embodiments of the invention R22 and R23 can represent various different variables. In one embodiment R22 and R23 are independently selected from the group consisting of H, alkyl, alkenyl and alkynyl. In another embodiment R22 and R23 are independently selected from the group consisting of H and alkyl. In yet another embodiment R22 and R23 are independently selected from the group consisting of H, methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl , 2-ethyl-butyl, pentyl, 2-methyl, pentyl, pent-4-enyl, hexyl, heptyl and octyl. In a further embodiment R22 and R23 are independently selected from the group consisting of alkyl. In a more specific embodiment R22 and R23 are both methyl.

In each of the previous embodiments of the invention R24 and R25 can represent various 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 yet another embodiment R24 and R25 are independently selected from the group consisting of H, methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl , 2-ethyl-butyl, pentyl, 2-methyl, pentyl, pent-4-enyl, hexyl, heptyl and octyl. In a specific embodiment R24 and R25 are both H.

In each of the previous embodiments there are various values for R26 and R27. In one embodiment R26 and R27 are independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, alkoxyalkyl and acyl. In another embodiment R26 and R27 are independently selected from the group consisting of: H, alkyl and acyl. In a further embodiment R28 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.

In another embodiment R1 is a heterocycloalkyl group that may optionally be substituted.

In one form of this embodiment, the heterocycloalkyl group is selected from the group consisting of: in which 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, arylalkyl, cycloalkylheteroalkyl, heterocycloalkyl heteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxyl, alkoxyalkyl, hydroxy alkyl

image 1

5 alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocicloalquiloxilo, 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.

In one embodiment R28 is selected from the group consisting of H, alkyl, alkenyl, arylalkyl and arylacil. Specific values of R28 are H, methyl; ethyl; propyl; 2-methyl-propyl, 2-2-dimethyl-propyl; isopropyl; 3,3,3-trifluoro-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,

In another embodiment, the heterocycloalkyl group is pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane and 1,4-oxathiapane. In a specific embodiment R1 is selected from the group consisting of piperidin-3-yl, piperidin-4-yl and pyrolidin-3-yl.

In another embodiment R1 is a heteroaryl group.

In another embodiment R1 is a group selected from the group consisting of:

image2

image3

image 1

In a specific embodiment R1 is a group of formula:

image 1

In another specific embodiment R1 is a group of formula:

image 1

In another specific embodiment R1 is a group of formula:

image4

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

image 1

In another specific embodiment R1 is a group of formula:

image 1

In another specific embodiment R1 is a group of formula:

image3

In another specific embodiment R1 is a group of formula:

image 1

In another specific embodiment R1 is a group of formula:

image 1

In another specific embodiment R1 is a group of formula:

image 1

In one embodiment R2 is selected from the group consisting of H, alkyl, cycloalkyl, heteroalkyl, alkenyl, alkynyl, alkoxyalkyl and cycloalkylalkyl, each of which may be optionally substituted.

In one form of this embodiment R2 is alkyl. In one embodiment the alkyl is a C1-C10 alkyl. In another form of this embodiment the alkyl is a C1-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-trifluoro-propyl; butyl;

Isobutyl; 3,3-dimethyl-butyl; pentyl; 2,4,4-trimethyl-pentyl; hexyl; heptyl, octyl, nonyl and 2-methoxylnonyl.

In one form of this embodiment R2 is alkenyl. In one form of this embodiment the alkenyl is a C1C10 alkenyl. 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-1-enyl, but-2-enyl but-3-enyl, pent

1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-5 -enilo.

In another embodiment R2 is selected from the group consisting of R11S (O) R13-, R11S (O) 2R13-, R11C (O) N (R12) R13-, R11SO2N (R12) R13-, R11N (R12) C (O ) R13-, R11N (R12) SO2R13-, and R11N (R12) C (O) N (R12) R13-. In one form of this embodiment R2 is a group of formula R11C (O) N (R12) R13-. In one form of this embodiment R13 is a C1-C6 alkyl. In a specific form of this embodiment R13 is methyl or ethyl. In one form of this embodiment R12 is H or C1-C6 alkyl. A specific value for R12 is H. In one form of this embodiment R11 is a C1-C6 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) -.

The specific values of R2 are selected from the group consisting of: H; methyl; ethoxymethyl; [bicyclo [2.2.1] 2-methyl]; adamantan-2-ylmethyl; 2-methanesulfanyl ethyl; 2,2,2-trifluoroethyl; propyl; 2-2-dimethylpropyl; isopropyl; 3,3,3trifluoro-propyl; butyl; isobutyl; 3,3-dimethyl-butyl; but-3-enyl; but-3-inyl; pentyl; 2,4,4-trimethyl-pentyl; bicyclo [2.2.1] hept-5-en-2-yl; hexyl; hex-3-enyl; octyl; non-3-enyl; non-6-enyl; 2-methoxy-nonyl, 2-phenyl-cyclopropyl; cyclohexyl; (CH3) 3CCH2CONH (CH2) 2-; (CH3) 3CCONH (CH2) 2-; (CH3) 3CCONH (CH2) - and CH3 (CH2) 2CONH (CH2) -.

In one embodiment X and Y may be the same or different and are selected from the group consisting of H, halogen, C1-C4 alkyl, -CF3, -NO2, -C (O) R5, -OR6, -SR6, -CN and NR7R8.

In one embodiment X is H;

In one embodiment Y is H;

In an embodiment X and Y (if present) they are in positions 4 and 7 of the aromatic ring.

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;

In one embodiment R4 is H or C1-C4 alkyl. A specific value for R4 is H;

In one embodiment R5 is C1-C4 alkyl, heteroalkyl or acyl. A specific value for R5 is methyl;

In one embodiment R6 is C1-C4 alkyl, heteroalkyl or acyl. A specific value for R6 is C1-C4 alkyl;

In one embodiment R7 and R8 are selected from the group consisting of H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl.

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, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl , haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocicloalquiloxilo, heterocicloalqueniloxilo, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy , -amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR5, -C (O) OR5, -SH, -SR5, -OR6 and acyl.

In a further embodiment the optional substituents are selected from the group consisting of: halogen, = O, = S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxyl, hydroxyalkyl , alkoxy, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C (O) OR5, COOH, SH and acyl.

In one embodiment, the Z moiety is in the 5 or 6 position. In a specific embodiment the Z moiety is in the 5 position. In one embodiment the Z moiety is a group of the formula -CH = CH-. If the remainder Z is such a group it is preferably in the "E" configuration.

In addition to the compounds of formula (I), the disclosed embodiments also refer 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 sometimes collectively referred to herein as "HDAC inhibitors" or "HDAC inhibitors."

The invention also relates to pharmaceutical compositions that include a compound of the invention with a pharmaceutically acceptable carrier, diluent or carrier.

Even in a further aspect the present invention provides a compound of formula (I), especially in a therapeutically effective amount, for use in a method of treating a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis. The disclosed embodiments also relate to pharmaceutical compositions each comprising a therapeutically effective amount of an HDAC inhibitor of the described embodiments with a pharmaceutically acceptable diluent or carrier for treating cell proliferative ailments, for example, inhibition of the proliferation of malignant cancer cells, benign tumor cells or other proliferative cells.

In one embodiment the method includes the administration of a compound of formula (Ia) or (Ib) as described herein.

In one embodiment the disorder is selected from the group consisting of but not limited to cancer (for example, breast cancer, colon cancer, prostate cancer, pancreatic cancer, leukemia, 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, acute and chronic neurodegenative disease such as nervous tissue disorders, Huntington's disease and infectious diseases such as fungal, bacterial and viral infections In another embodiment the disorder is a proliferative disorder In one embodiment the proliferative disorder is cancer The cancer may include solid tumors or hematological malignancies.

The invention also provides agents for the treatment of a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis including a compound of formula (I) as disclosed herein. In one embodiment the agent is an anticancer agent. In another embodiment the agent is an antiangiogenesis agent.

In one embodiment the agent contains a compound of formula (Ia) or (Ib).

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 alterations of cell proliferation and / or angiogenesis. In one embodiment the disorder is a proliferative disorder. In a specific embodiment the disorder is a cancer.

The compounds of the present invention show surprisingly low toxicity, together with a potent antiproliferative activity.

Even in a further embodiment the invention provides a compound of formula (I), especially in a therapeutically effective amount, for use in a method of treating a disorder, disease or condition that can be treated by inhibition of histone deacetylase.

In one embodiment the method includes the administration of a compound of formula (Ia) or (Ib) as described herein.

In one embodiment the disorder is selected from the group consisting of but not limited to proliferative disorders (eg cancer); neurodegenerative diseases including Huntington's disease, polyglutamine diseases, Parkinson's disease, Alzheimer's disease, seizures, nigrostriatal degeneration, progressive supranuclear paralysis, torsion dystonia, spasmodic torticollis and dyskinesia, family tremor, Gilles de la Tourette syndrome, body disease Diffuse Lewy, Pick's disease, intracerebral hemorrhage, primary lateral sclerosis, spinal muscular atrophy, amyotrophic lateral sclerosis, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, progressive ataxia and Shy-Drager syndrome; metabolic diseases including type 2 diabetes; degenerative diseases of the eye including glaucoma, age-related macular degeneration, macular myopic degeneration, rubeotic glaucoma, interstitial keratitits, diabetic retinopathy, Peter's anomaly, retinal degeneration, cellophane retinopathy; Cogan's dystrophy; corneal dystrophy; neovascularization of the iris (rubeosis); neovascularization of the cornea; retinopathy of prematurity; macular edema; macular hole; Macular pucker, marginal blepharitis, myopia, benign conjunctiva growth; inflammatory diseases and / or diseases of the immune system including rheumatoid arthritis (RA), osteoarthritis, juvenile chronic arthritis, graft versus host disease, psoriasis, asthma, spondyloarthropathy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, alcoholic hepatitis, diabetes , Sjoegrens syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, discogenic pain, systemic lupus erythematosus, allergic contact dermatitis; disease that involves 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, pulmonary 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 hematopoietic disorders including thalassemia, anemia and sickle cell anemia.

The invention also provides agents for the treatment of a disorder, disease or condition that can be treated by inhibition of histone deacetylase including a compound of formula (I) as disclosed herein. In one embodiment the agent is an anticancer agent.

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 inhibition of histone deacetylase.

The invention also provides a compound of formula (I), especially in an effective amount, a method of inhibiting cell proliferation.

Even in an even further aspect the invention provides a method of treating a disorder.

Neurodegenerative in a patient that includes the administration of a therapeutically effective amount of a compound of formula (I). In one embodiment the method includes the administration of a compound of formula (Ia) or (Ib) as described herein. In one embodiment the neurodegenerative disorder is Huntington's disease.

The invention also provides agents for the treatment of a neurodegenerative disorder including a compound of formula (I) as disclosed herein. In one embodiment the agent is preferably a Huntington's disease agent.

The invention also relates to the use of compounds of formula (I) in the preparation of a medicament for

20 treatment of a neurodegenerative disorder. In one embodiment the neurodegenerative disorder is Huntington's disease.

Even in a still further aspect the invention provides a compound of formula (I), especially in a therapeutically effective amount, for use in a method of treating an inflammatory disease and / or a

25 immune system disorder in a patient. In one embodiment the method includes the administration of a compound of formula (Ia) or (Ib) as described herein. In one embodiment the inflammatory disease and / or immune system disorder is rheumatoid arthritis. In another embodiment the inflammatory disease and / or immune system disorder is systemic lupus erythematosus.

The invention also provides agents for the treatment of an inflammatory disease and / or an immune system disorder including a compound of formula (I) as disclosed herein.

The invention also provides agents for the treatment of an eye disease mediated by HDAC inhibition including a compound of formula (I) as disclosed herein. In one embodiment, the eye disease is macular degeneration. In another embodiment, the eye disease is glaucoma. In another embodiment, the eye disease is retinal degeneration.

The invention also relates to the use of compounds of formula (I) in the preparation of a medicament for the treatment of an inflammatory disease and / or an immune system disorder. In one embodiment, the inflammatory disease and / or the immune system disorder is rheumatoid arthritis, in another embodiment the inflammatory disease and / or the immune system disorder is systemic lupus erythematosus.

The invention also provides methods of preparing the compounds of the invention. In one embodiment the invention provides a method of synthesis of compounds of formula I as defined above including the method:

(a) provide a compound of formula (A1):

image 1

wherein X, and Y Z are as defined above and L is a leaving group;

(b)

 protect the carboxyl group to produce a compound of formula (A2):

wherein X, and Y Z are as defined above L is a leaving group and PC is a carboxyl protecting group;

(C)

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

image 1

image 1

10 wherein X, Y, Z are as defined above, R1 is as defined above or a protected form thereof, and PC is a carboxyl protecting group;

(d) optionally reacting the compound to further functionalize R1; 15 (e) reduce the nitro group;

(f) reacting the reduced product with a compound of formula R2CO2H or a compound of formula R2CHO and cycling the product thus produced to produce a compound of formula (A4):

image5

wherein X, Y, Z are as defined above, R1 and R2 are as defined above or protected forms thereof, and PC is a carboxyl protecting group;

(G) converting the compound into a compound of formula I;

in which (d) can be carried out after any one of (c) (e) or (f) and also in which (e) and (f) can be carried out sequentially or simultaneously.

Even in a still further aspect the invention provides a method of synthesis of compounds of formula I as defined above:

image 1

Formula I in which R1, R2, R3, R4, X, and Y Z are as defined above, including the method:

(a) provide an aldehyde of formula (B1):

image 1

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

10 (b) subjecting the aldehyde to reaction with an appropriately substituted olefining agent to produce a compound of formula (B2):

image 1

Wherein R1, R2, X, Y, and Z are as defined above, and PC is H or a carboxyl protecting group;

(c) convert the compound into a compound of formula I. In an embodiment of this method (a) it includes:

twenty

(a1) provide a compound of formula (B3):

image 1

Wherein X and Y are as defined above, L is a leaving group and PC is a carboxyl protecting group;

(a2) displacing the leaving group with an amine of formula R1NH2 to produce a compound of formula (B4):

image 1

5 in which X, and Y are as defined above, R1 is as defined above or a protected form thereof, and PC is a carboxyl protecting group;

(a3) optionally reacting the compound to further functionalize R1; 10 (a4) reduce the nitro group;

(a5) react the reduced product with a compound of formula R2CO2H or a compound of formula R2CHO and cycle the product thus produced to produce a compound of formula (B5):

image 1

wherein X, and Y are as defined above, R1 and R2 are as defined above or protected forms thereof, and PC is a carboxyl protecting group; 20 (a6) converting the compound of formula (B5) into the corresponding aldehyde;

in which (a3) can be carried out after any one of (a2), (a4), (a5) or (a6) and also in which (a4) and (a5) can be carried out sequentially or simultaneously.

Even in a still further aspect, the invention provides a method of synthesizing compounds of formula I as defined above:

image 1

Formula I in which R1, R2, R3, R4, X, and Y Z are as defined above, including the method:

(to)

 provide a compound of formula (C1):

wherein X and Y are as defined above, R1 and R2 are as defined above or protected forms thereof, and L1 is a leaving group;

(b)

 converting compound (C1) into a compound of formula (C2):

image 1

image 1

Wherein X, and Y Z are as defined above, R1 and R2 are as defined above or protected forms thereof, and PC is H or a carboxyl protecting group;

(c) convert the compound into a compound of formula I.

In one form of this embodiment (a) it includes: (a1) providing a compound of formula (C3):

image 1

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

image2

wherein X and Y are as defined above, R1 is as defined above or a protected form thereof, and L1 is a leaving group; 30 (a3) optionally reacting the compound to further functionalize R1; (a4) reduce the nitro group;

(a5) react the reduced product with a compound of formula R2CO2H or a compound of formula R2CHO and cycle the product thus produced to produce a compound of formula (C1):

image3

in which (a3) can be carried out after any one of (a2), (a4) or (a5) and also in which (a4) and (a5) can be carried out sequentially or simultaneously.

10 Detailed description of the invention

In this specification a certain number of terms that are well known to an expert recipient are used. However, for the sake of clarity several terms will be defined.

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

The term "optionally substituted" as used throughout the specification indicates that the group may or may not be additionally substituted or condensed (so that it forms a condensed polycyclic system), with one

20 or more substituent groups. Preferably the substituent groups are one or more groups independently selected from the group consisting of halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkenyl, heteroarylalkyl, cycloalkyl, cycloalkyl

25 heterocicloalquilheteroalquilo, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alcoxiheterocicloalquilo, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocicloalquiloxilo, heterocicloalqueniloxilo, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, arylalkyl , heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkylloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino,

30 sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -COOH, -COR5, -C (O) OR5, CONHR5, NHCOR5, NHCOOR5, NHCONHR5, C (= NO, -5) R (C = NO SR5, -OR5 and acyl.

"Alkyl", as a group or part of a group refers to a linear or branched aliphatic hydrocarbon group,

Preferably a C1-C14 alkyl, more preferably C1-C10 alkyl, most preferably C1-C6 unless otherwise indicated. Examples of suitable linear and branched C1-C6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl and the like. The group can be a terminal group or a bridge group.

"Alkylamino" includes both monoalkylamino and dialkylamino, unless specified. "Monoalkylamino" means an -NH-alkyl group, in which the alkyl is as defined above. "Dialkylamino" means a group -N (alkyl) 2, in which each alkyl may be the same or different and each is as defined herein for alkyl. The alkyl group is preferably a C1-C6 alkyl group. The group can be a terminal group or a bridge group.

"Arylamino" includes both mono-arylamino and di-arylamino unless specified. Mono-arylamino means a group of formula aryl-NH-, in which the aryl is as defined herein. Di-arylamino means a group of formula (aryl2) N- in which each aryl may be the same or different and each is as defined herein for aryl. The group can be a terminal group or a bridge group.

"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 C1-C6 alkyl group. The group can be a terminal group or a bridge group.

"Alkenyl" as a group or part of a group indicates an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be linear or branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain. The group may contain a plurality of double bonds in the normal chain and the orientation with respect to each is E or Z independently. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. The group can be a terminal group or a bridge group.

"Alkoxy" refers to an -O-alkyl group in which alkyl is as defined herein. Preferably the alkoxy is a C1-C6 alkoxy. Examples include, but are not limited to, methoxy and ethoxy. The group can be a terminal group or a bridge group.

"Alkenyloxy" refers to a group -O-alkenyl in which alkenyl is as defined herein. Preferred alkenyloxy groups are C1-C6 alkenyloxy groups. The group can be a terminal group or a bridge group.

"Alkynyloxy" refers to a group -O-alkynyl in which the alkynyl is as defined herein. Preferred alkynyloxy groups are C1-C6 alkynyloxy groups. The group can be a terminal group or a bridge group.

"Alkoxycarbonyl" refers to a group -C (O) -O-alkyl in which the alkyl is as defined herein. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group can be a terminal group or a bridge group.

"Alkylsulfinyl" means a group -S (O) -alkyl in which the alkyl is as defined above. The alkyl group is preferably a C1-C6 alkyl group. Exemplary alkylsulfinyl groups include, but are not limited to, methylsulfinyl and ethylsulfinyl. The group can be a terminal group or a bridge group.

"Alkylsulfonyl" refers to a group -S (O) 2-alkyl in which the alkyl is as defined above. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to methylsulfonyl and ethylsulfonyl. The group can be a terminal group or a bridge group.

"Alkynyl as a group or part of a group means an aliphatic hydrocarbon group that contains a carbon-carbon triple bond and which may be linear or branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms. , more preferably 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group can be a terminal group or a bridge group.

"Alkylaminocarbonyl" refers to an alkylaminocarbonyl group in which alkylamino is as defined above. The group can be a terminal group or a bridge group.

"Cycloalkyl" refers to a saturated or partially saturated carbocycle, monocyclic or condensed or polycyclic spiro, preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified . It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems, such as decalin, and polycyclic systems such as adamantane. The group can be a terminal group or a bridge group.

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

The above discussion of alkyl and cycloalkyl substituents also applies to the alkyl parts of other substituents, such as without limitation, alkoxy substituents, alkylamines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl esters and the like.

"Cycloalkylalkyl" means a cycloalkyl-alkyl group in which the cycloalkyl and alkyl moieties are as described above. By way of example, the monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The group can be a terminal group or a bridge group.

"Halogen" represents chlorine, fluorine, bromine or iodine.

"Heterocycloalkyl" refers to a saturated or partially saturated monocyclic, bicyclic or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring preferably has from 3 to 10 members, more preferably from 4 to 7 members. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane and 1,4-oxathiapane. The group can be a terminal group or a bridge group.

"Heterocycloalkenyl" refers to a heterocycloalkyl as described above but containing at least one double bond. The group can be a terminal group or a bridge group.

"Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl group in which the heterocycloalkyl and alkyl moieties are as described above. By way of example, heterocycloalkylalkyl groups include (2-tetrahydrofuryl) methyl, (2-tetrahydrothiofuranyl) methyl. The group can be a terminal group or a bridge group.

"Heteroalkyl" refers to a straight or branched chain alkyl group preferably having from 2 to 14 atoms, more preferably from 2 to 10 atoms in the chain, one or more of these is a heteroatom selected from S, O, and N Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkylamines, alkyl sulfides and the like. The group can be a terminal group or a bridge group.

"Aryl" as a group or part of a group indicates (i) an optionally substituted aromatic, polycyclic or condensed or monocyclic carbocycle (ring structure having ring atoms that are all carbons) 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 condense together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group can be a terminal group or a bridge group.

"Arylalkenyl" means an aryl-alkenyl group in which the aryl and alkenyl are as described above. Exemplary arylalkenyl groups include phenylalkyl. The group can be a terminal group or a bridge group.

"Arylalkyl" means an aryl-alkyl group in which the aryl and alkyl moieties are as described above. Preferred arylalkyl groups contain a C1-5 alkyl moiety. By way of example, arylalkyl groups include benzyl, phenethyl and naphthelemethyl. The group can be a terminal group or a bridge group.

"Arylacil" means an aryl-acyl group in which the aryl and acyl moieties are as described above. In general, the aryl moiety is attached to the alkyl part of the acyl moiety, usually in the terminal carbon of the alkyl part of the acyl moiety. Preferred arylacil groups contain a C1-5 alkyl moiety in the acyl moiety. By way of example, arylacyl groups include 2-phenyl-acetyl. The group can be a terminal group or a bridge group.

"Heteroaryl" either alone or part of a group refers to groups containing an aromatic ring (preferably an aromatic ring of 5 or 6 members) having one or more heteroatoms as ring atoms in the aromatic ring being the rest of ring atoms carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulfur. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazol, benzothiazole, bencisothiazole, naphtho [2,3-b] thiophene, furan, isoindolizine, xantholene, phenoxyatin, pyrrole, imidazole, pyrazole, pyridine, pyrazimine, pyrazimine , indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazan, 3-, phenoxaz or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5isoquinolinyl, 1-, 2- or 3-indolyl and 2- or 3-thienyl. The group can be a terminal group or a bridge group.

"Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as described above. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group can be a terminal group or a bridge group.

"Lower alkyl" as a group means unless otherwise specified, a group of aliphatic hydrocarbon which can be linear 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 tert-butyl). The group can be a terminal group or a bridge group.

In the formula (I), as well as in the formulas (Ia) - (Ib) defining subsets of compounds within the formula (I), a benzimidazole ring system is shown. Within this ring system, there are substitutable positions in ring positions 4, 5, 6 and 7. In each of the formulas (I), (Ia) and (Ib), there is a requirement for the union of a residue acid in one of the ring positions. This acidic moiety can be provided by, but is not limited to the groups containing, a hydroxamic acid or salt derivatives of such acid that when hydrolyzed it would provide the acidic moiety. In some embodiments, the acid 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 joining the acid moiety are ring positions 5 and 6.

It is understood that in the family of the compounds of formula (I) areomeric forms including diastereoisomers, enantiomers, tautomers and geometric isomers are included in the "E" or "Z" configurational isomer or a mixture of the E and Z isomers. It is understood that some isomeric forms such as diastereomers, enantiomers and geometric isomers can be separated by physical and / or chemical methods and by those skilled in the art.

Some of the compounds of the disclosed embodiments may exist as individual racemate stereoisomers, and / or mixtures of enantiomers and / or diastereomers. All individual stereoisomers, racemates, and mixtures of this type thereof are intended to be within the scope of the content described and claimed.

Additionally, formula (I) is intended to cover, when applicable, solvated as well as non-solvated forms of the compounds. Therefore, each formula includes compounds that have the indicated structure, including hydrated and non-hydrated forms.

In addition to the compounds of formula (I), the HDAC inhibiting agents of the various embodiments include prodrugs, pharmaceutically acceptable salts and active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of

The compounds identified above, and include base addition salts and pharmaceutically acceptable acid addition salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula (I) can be prepared from an inorganic acid or an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric and phosphoric acid. Appropriate organic acids may be selected from classes of aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and organic acids.

20 sulfonic, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkylsulfonic, arylsulfonic. Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include metal salts prepared from lithium, sodium, potassium, magnesium, calcium, aluminum and zinc, and organic salts prepared from organic bases such as choline , diethanolamine, morpholine. Other examples of organic salts are: ammonium salts, quaternary salts such

25 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 solid, it is understood by those skilled in the art that salts, agents and inventive compounds may exist in different crystalline or polymorphic forms, of which all are intended to be within the scope of the present invention and

30 specified formulas.

"Prodrug" means a compound that can be converted in vivo by metabolic means (for example by hydrolysis, reduction or oxidation) into a compound of formula (I). For example, an ester prodrug of a compound of formula (I) containing a hydroxyl group can be converted by in vivo hydrolysis into an original molecule. Suitable esters of the compounds of formula (I) containing a hydroxyl group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, smokers, maleates, methylene-bis-�-hydroxynaphtates, gestisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates. As another example an ester prodrug of a compound of formula (I) containing a carboxyl group can be converted by

In vivo hydrolysis in the original molecule. (Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 18: 379, 1987).

Preferred HDAC inhibitors include those with an IC50 value of 10 µM or less.

The specific compounds of the invention include the following:

image 1

3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2- (2,2-dimethylpropyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-isopropyl-1H-benzoimidazol5-yl] -N-hydroxy-acrylamide

image 1

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

3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2- (2-methylsulfanylethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

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

3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-isobutyl-1H-benzoimidazol5-yl] -N-hydroxy-acrylamide

3- [1- (2-Diethylamino-ethyl) -2-isobutyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

3- [2-Butyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

image 1

3- [2-but-3-inyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

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

3- [2-But-3-enyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

3- [2-but-3-inyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2- (3,3,3-trifluoropropyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

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

image 1

3- [1- (2-Diethylamino-ethyl) -2-ethoxymethyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

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

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

N-hydroxy-3- [1- (3-isopropylamino-propyl) -2- (3,3,3-trifluoropropyl) -1Hbenzoimidazol-5-yl] -acrylamide

3- [2- (2,2-Dimethyl-propyl) -1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5yl] -N-hydroxy-acrylamide

image 1

3- [1- (2-diisopropylamino-ethyl) -2- (2,2-dimethyl-propyl) -1H-benzoimidazol5-yl] -N-hydroxy-acrylamide

3- [1- (2-Diisopropylamino-ethyl) -2-isobutyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-hex-3-enyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2- (2,4,4-trimethylpentyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

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

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

3- [2-hex-3-enyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

image 1

3- [2-hex-3-enyl-1- (3-isopropylamino-propyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

3- [1- (2-ethylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

3- [1- (2-Diethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

N-hydroxy-3- [1- (3-isopropylamino-propyl) -2- (2,4,4-trimethylpentyl) -1Hbenzoimidazol-5-yl] -acrylamide

3- [2- (2,2-Dimethyl-propyl) -1- (3-isopropylamino-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

3- [1- (2-Diisopropylamino-ethyl) -2- (3,3,3-trifluoro-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

image 1

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

3- [2- (2,2-Dimethyl-propyl) -1- (2-ethylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

3- [1- (2-ethylamino-ethyl) -2-isobutyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

3- [1- (2-Diisopropylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

N-hydroxy-3- [1- (2-isopropylamino-ethyl) -2- (2,4,4-trimethylpentyl) -1Hbenzoimidazol-5-yl] -acrylamide

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

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

image 1

3- [1- (2-Diethylamino-ethyl) -2-propyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

3- [2-Butyl-1- (2-diisopropylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

3- [2-Butyl-1- (2-ethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

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

3- [2-Butyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

3- [2-Butyl-1- (3-isopropylamino-propyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

3- [2-But-3-enyl-1- (2-ethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

image 1

3- [2-Hexyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

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

3- [1- (2-ethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

N-hydroxy-3- [1- (2-isopropylamino-ethyl) -2- (3,3,3-trifluoropropyl) -1Hbenzoimidazol-5-yl] -acrylamide

3- [1- (2-Dimethylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

3- [1- (2-Amino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

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

image 1

3- [2-Butyl-1- (2-dimethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

3- [1- (2-Dimethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

N- {2- [1- (2-Diethylamino-ethyl) -5- (2-hydroxycarbamoyl-vinyl) -1Hbenzoimidazol-2-yl] -ethyl} -3,3-dimethyl-butylamide

3- {1- (2-diethylamino-ethyl) -2- [2- (2,2-dimethylpropionylamino) -ethyl] -1Hbenzoimidazol-5-yl} -N-hydroxyacrylamide

3- {1- (2-Diethylamino-ethyl) -2 - [(2,2-dimethyl) -propionylamino) -methyl] -1Hbenzoimidazol-5-yl} -N-hydroxy-acrylamide

N- [1- (2-Diethylamino-ethyl) -5- (2-hydroxycarbamoyl-vinyl) -1Hbenzoimidazol-2-ylmethyl] -butylamide

image 1

3- [1- (2-ethylamino-ethyl) -2- (3,3-dimethyl-butyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

3- [2- (3,3-dimethyl-butyl) -1- (2-dimethylamino-ethyl) -1H-benzoimidazol-5-yl] N-hydroxy-acrylamide

3- [1- (2-Dimethylamino-ethyl) -2-pentyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

3- [1- (2-Dimethylamino-ethyl) -2- (2,2,2-trifluoro-ethyl) -1H-benzoimidazol-5yl] -N-hydroxy-acrylamide

3- [1- (2-ethylamino-ethyl) -2-pentyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

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

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

image 1

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

3- [2-Hexyl-1- (2-methylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

N-hydroxy-3- [1- (2-methylamino-ethyl) -2-pentyl-1H-benzoimidazol-5-yl] acrylamide

N-hydroxy-3- [1- (2-methylamino-ethyl) -2-octyl-1H-benzoimidazol-5-yl] acrylamide

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

3- {2-Butyl-1- [2- (isopropyl-methyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide

image 1

3- {1- [2- (ethyl-methyl-amino) -ethyl] -2-pentyl-1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide

3- (1- {2- [ethyl- (2-methoxy-ethyl) -amino] -ethyl} -2-pentyl-1 H -benzoimidazol-5-yl) -N-hydroxy-acrylamide

3- {2-Butyl-1- [2- (ethyl-methyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide

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

3- (1- {2- [ethyl- (3-hydroxy-propyl) -amino] -ethyl} -2-pentyl-1H-benzoimidazol5-yl) -N-hydroxy-acrylamide

3- [2- (4-Cyano-butyl) -1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

3- [1- (2-Diethylamino-ethyl) -2-propylamino-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

image 1

3- [2- (5-Cyano-pentyl) -1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-propylamino-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

3- {1- [2- (ethyl-hexyl-amino) -ethyl] -2-methyl-1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide

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

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

image 1

(E) -3- (1- (2- (dibutylamino) ethyl) -2-propyl-1H-benzo [d] imidazol-5-yl) -Nhydroxyacrylamide

3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-methylsulfanyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

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

3- [1- [2- (3,3-Dimethyl-butylamino) -ethyl] -2 (2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

3- [1- {2- [bis- (3,3-dimethyl-butyl) -amino] -ethyl} -2- (2,2-dimethylpropyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

image 1

3- {1- [2- (3,3-Dimethyl-butylamino) -ethyl] -2-ethyl-1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide

3- (1- {2 - [(3,3-dimethyl-butyl) -methyl-amino] -ethyl} -2-propyl-1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide

The compounds disclosed are hydroxamate compounds that contain a hydroxamic acid type moiety in one of the substituents that may be deacetylase inhibitors, including but not limited to histone deacetylase inhibitors. Hydroxamate compounds may be suitable for prevention or

5 treatment of a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis when used either alone or together with a pharmaceutically acceptable carrier, diluent or carrier. An example of such a disorder is cancer.

The administration of compounds within the formula (I) to humans can be any of the modes

10 accepted for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. The injection can be bolus or through constant or intermittent infusion. The active compound is normally included in a pharmaceutically acceptable diluent or carrier and in an amount sufficient to administer to the patient a therapeutically effective dose. In various embodiments, the inhibitor compound may be selectively toxic or more toxic to proliferating cells.

15 quickly, for example cancerous tumors, than for normal cells.

As used herein, the term "cancer" is a general term that is intended to encompass the enormous number of states that are characterized by abnormal uncontrolled cell growth.

It is anticipated that the compounds of the invention will be useful in the treatment of various cancers including but not limited to bone cancers including Ewing sarcoma, osteosarcoma, chondrosarcoma and the like, brain and CNS tumors including acoustic neuroma, neuroblastomas, glioma and others. brain tumors, spinal cord tumors, breast cancers including ductal adenocarcinoma, ductal metastatic breast carcinoma, colorectal cancers, advanced colorectal adenocarcinomas, colon cancers, endocrine cancers

25 including adenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, multiple endocrine neoplasia, gastrointestinal cancers including stomach cancer, esophageal cancer, small bowel cancer, liver cancer, duct cancer Extra hepatic biliary, gastrointestinal carcinoid tumor, gallbladder cancer, genitourinary cancers including testicular cancer, penile cancer, prostate cancer, gynecological cancers including cervical cancer, cancer

30 ovarian, vaginal cancer, uterine / endometrial cancer, vulvar cancer, gestational trophoblastic cancer, fallopian tube cancer, uterine sarcoma, head and neck cancers including oral cavity cancer, lip cancer, cancer of the salivary gland, larynx cancer, hypopharyngeal cancer, orthopharyngeal cancer, nasal cancer, paranasal cancer, nasopharyngeal cancer, leukemia including childhood leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, leukemia cells

35 hairy, acute promyelocytic leukemia, plasma cell leukemia, erythroleukemia, myelomas, hematologic disorders including myelodysplastic syndromes, myeloproliferative disorders, aplastic anemia, Fanconi anemia, Waldenstrom macroglobulinemia, lung cancers including small cell lung cancer, lung cancer non-small cell, mesothelioma, lymphomas including Hodgkin's disease, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, lymphoma related to

40 AIDS, B-cell lymphoma, Burkitt lymphoma, eye cancers including retinoblastoma, intraocular melanoma, skin cancers including melanoma skin cancer, non-melanoma, squamous cell carcinoma, Merkel cell cancer, soft tissue sarcomas such as Soft tissue sarcoma in children, soft tissue sarcoma in adults, Kaposi's sarcoma, urinary system cancers including kidney cancer, Wilms tumor, bladder cancer, urethra cancer and transitional cell cancer.

By way of example, cancers that can be treated by the compounds of the present invention are breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, renal cancer (for example renal cell carcinoma), gastric cancer, colon cancer, colorectal cancer and brain cancer.

Exemplary cancers that can be treated by the compounds of the present invention include but are not limited to leukemias such as erythroleukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, acute T-cell leukemia and lymphoma such as lymphoma. B cells (for example Burkitt lymphoma), cutaneous T-cell lymphoma (LCCT) and peripheral T-cell lymphoma.

Exemplary cancers that can be treated by the compounds of the present invention include solid tumors and hematological malignancies. In another embodiment, the preferred cancers that can be treated with the compounds of the present invention are colon cancer, prostate cancer, hepatoma and ovarian cancer.

In another embodiment, the cancers that can be treated with the compounds of the present invention by way of example are non-small cell lung cancer, small cell lung cancer and mesothelioma.

In another embodiment, the cancers that can be treated with the compounds of the present invention by way of example are clear cell carcinoma / mesonephroma, intestinal cancer and pancreatic cancer.

The compounds may also be used in the treatment of a disorder that involves, which is related to or associated with the deregulation of histone deacetylase (HDAC).

There are several disorders that have been implicated by or known to be mediated at least in part by HDAC activity, knowing that HDAC activity plays a role in triggering the onset of the disease, or whose symptoms are known to be or have been shown to be relieved by HDAC inhibitors. Disorders of this type that would be expected to be susceptible to treatment with the compounds of the invention include the following but are not limited to: proliferative disorders (eg cancer); neurodegenerative diseases including Huntington's disease, polyglutamine diseases, Parkinson's disease, Alzheimer's disease, seizures, nigrostriatal degeneration, progressive supranuclear paralysis, torsion dystonia, spasmodic torticollis and dyskinesia, family tremor, Gilles de la Tourette syndrome, body disease Diffuse Lewy, Pick's disease, intracerebral hemorrhage, primary lateral sclerosis, spinal muscular atrophy, amyotrophic lateral sclerosis, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, progressive ataxia and Shy-Drager syndrome; metabolic diseases including type 2 diabetes; degenerative diseases of the eye including glaucoma, age-related macular degeneration, macular myopic degeneration, rubeotic glaucoma, interstitial keratitits, diabetic retinopathy, Peter's anomaly, retinal degeneration, cellophane retinopathy; Cogan's dystrophy; corneal dystrophy; neovascularization of the iris (rubeosis); neovascularization of the cornea; retinopathy of prematurity; macular edema; macular hole; Macular pucker; marginal blepharitis, myopia, benign growth of the conjunctiva; inflammatory diseases and / or diseases of the immune system including rheumatoid arthritis (RA), osteoarthritis, juvenile chronic arthritis, graft versus host disease, psoriasis, asthma, spondyloarthropathy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, alcoholic hepatitis, diabetes , Sjoegrens syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, discogenic pain, systemic lupus erythematosus, allergic contact dermatitis; disease that involves 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, pulmonary fibrosis, cystic fibrosis and angiofibroma; infectious diseases including fungal infections, such as Candida Albicans, bacterial infections, viral infections, such as herpes simplex, protozoan infections, such as malaria, Leishmania infection, Trypanosoma brucei infection, toxoplasmosis and coccidiosis, and hematopoietic disorders including thalassemia, anemia and sickle cell anemia.

In the use of the compounds of the invention they can be administered in any form or manner that makes the compound bioavailable. One skilled in the art of preparing formulations can quickly select the appropriate form and mode of administration depending on the particular characteristics of the selected compounds, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. The reader is referred to Remingtons Pharmaceutical Sciences, 19th edition, Mack Publishing Co. (1995) for additional information.

The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable excipient, diluent or carrier. The compounds of the invention, although effective in themselves, are normally formulated and administered in the form of their pharmaceutically acceptable salts since these forms are normally more stable, crystallize more easily and have increased solubility.

The compounds are used, however, in the form of pharmaceutical compositions that are formulated depending on the desired mode of administration. As such in a further embodiment the present invention provides a pharmaceutical composition that includes a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or carrier. The compositions are prepared in ways well known in the art.

The invention in other embodiments provides a pharmaceutical kit or package comprising one or more containers loaded with one or more of the components of the pharmaceutical compositions of the invention. In a kit or container of this type a content can be found that has a unit dosage of the agent (s). The kits may include a composition comprising an effective agent or as concentrates (including lyophilized compositions), which may be further diluted before use or may be provided in the use concentration, in which the vials may include one or more dosages . Conveniently, in the kits, single dosages can be provided in sterile vials so that the doctor can directly use the vials, in which the vials will have the desired amount and concentration of agent (s). Associated with such container (s) can be found several written materials such as instructions for use, or a notification in the manner prescribed by a government agency that regulates the manufacture, use or sale of pharmaceutical or biological products, notification which reflects the approval by the manufacturing, use or sale agency for administration in humans.

The compounds of the invention can be used or administered in combination with one or more additional drugs that are chemotherapeutic drugs or HDAC inhibitor drugs and / or methods (eg 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 can be administered sequentially or simultaneously with the other drug (s).

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 can be used in a combination therapy. When this is done the compounds are usually administered in combination with each other. Thus one or more of the compounds of the invention can be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable when the therapeutic profile of each compound is different so that the combined effect of the two drugs provides an improved therapeutic result.

The pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous emulsions, suspensions, dispersions or solutions, as well as sterile powders for the reconstitution of sterile injectable dispersions or solutions just prior to use. Examples of suitable vehicles, solvents, diluents, aqueous and non-aqueous carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. The 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.

These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be guaranteed by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be caused by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

If desired, and for the most efficient distribution, the compounds can be incorporated into directed delivery or slow release systems such as polymer matrices, liposomes and microspheres.

Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just before use.

Solid pharmaceutical forms for oral administration include capsules, tablets, pills, powders and granules. In such solid pharmaceutical forms, the active compound is mixed with at least one inert pharmaceutically acceptable carrier or excipient such as sodium citrate or dicalcium phosphate and / or) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol and acid. silicic acid, b) binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato starch or tapioca , 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, ethyl alcohol and monostearate of glycerol, h) absorbents such as kaolin and bentonite clay, ei) lubricants such as talc, calcium stearate, magnesium stearate, p solid olyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the pharmaceutical form may also comprise buffering agents.

Solid compositions of a similar type can also be used as fillers in soft and hard loaded gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Solid pharmaceutical forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and crusts such as enteric coatings and other well known coatings, in the pharmaceutical formulation technique. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient (s) only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

If desired, and for the most efficient distribution, the compounds can be incorporated into directed delivery or slow release systems such as polymer matrices, liposomes and microspheres.

The active compounds may also be in microencapsulated form, if appropriate, with one or more of the excipients mentioned above.

Liquid pharmaceutical forms for oral administration include pharmaceutically acceptable elixirs, syrups, suspensions, solutions and emulsions. In addition to the active compounds, liquid pharmaceutical 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, dimethylformamide, oils (in particular, cottonseed oils, peanut, corn, germ, olive, castor and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids and mixtures thereof.

In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, suspending and emulsifying agents, sweetening, flavoring and perfume agents.

The suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and gum tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this invention with suitable excipients or non-irritating vehicles such as cocoa butter, polyethylene glycol or a suppository wax that is solid at room temperature but liquid at temperature. body and therefore fuse in the rectum or vaginal cavity and release the active compound.

Pharmaceutical 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 necessary preservative, buffer, or propellant that may be required.

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 usually sufficient to alleviate, improve, stabilize, reverse, slow or slow the evolution of the pathological state. A therapeutically effective amount can be easily determined by a diagnostic doctor in charge through the use of conventional techniques and by the observed results obtained under analogous circumstances. In determining the therapeutically effective amount, several factors are considered, including but not limited to, the species of the animal, its size, age and general health, the specific status involved, the severity of the condition, the patient's response to the treatment, the compound Particularly administered, the mode of administration, the bioavailability of the administered preparation, the selected dose regimen, the use of other medications and other relevant circumstances.

A preferred dosage will be in 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 of 0.1 to 100 mg per kilogram of body weight per day, more preferably 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. An appropriate dose can be administered in multiple sub-doses per day.

As discussed above, the compounds of the disclosed embodiments 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 may be either from the same histone deacetylase class or from a different histone deacetylase class. In some different embodiments, the histone deacetylase 5 inhibitor interacts and reduces the activity of primarily a histone deacetylase, for example HDAC-1, HDAC-2, HDAC-3 or HDAC-8 belonging to class I HDAC enzymes [De Ruijter AJM et al., Biochem. J., 370, 737-749 (2003)]. HDACs can also target substrates other than histone to regulate a variety of biological functions involved in the pathogenesis of the disease. These substrates other than histone include Hsp90, 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 that is involved in tumorigenesis, and these compounds may be useful for the treatment of proliferative diseases. Examples of such states or cell proliferative diseases include cancer (includes any metastases), psoriasis, and proliferative disorders of smooth muscle cells 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 or pancreatic cancer and brain cancer. as well as hematological malignancies such as lymphomas and leukemia. In addition, the inventive compounds may be useful for treating a proliferative disease that is resistant to treatment with other chemotherapeutic agents; and to treat a hyperproliferative state such as leukemia, psoriasis and restenosis. In other embodiments, the compounds of this invention can be used to treat conditions before cancer or hyperplasia including familial adenomatous polyposis, colonic adenomatous polyps, myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia with atypia, cervical dysplasia, intraepithelial vaginal neoplasia, benign prostatic hyperplasia , larynx papillomas, actinic and solar kerastosis, seborrheic kerastosis and keratoacanthoma. In an exemplary preferred embodiment hyperplasia or conditions prior to cancer that can be treated by the compounds of this invention are familial adenomatous polyposis, polyps

25 colonic adenomatous and myeloid dysplasia.

Additionally, the compounds of the various embodiments disclosed herein may be useful for treating neurodegenerative diseases, and inflammatory diseases and / or immune system disorders.

In one embodiment the disorder is selected from the group consisting of cancer, inflammatory diseases and / or immune system disorders (eg rheumatoid arthritis, systemic lupus erythematosus), angiofibroma, cardiovascular diseases, fibrotic diseases, diabetes, autoimmune diseases, neurodegenative disease acute and chronic such as Huntington's disease, Parkinson's disease, tissue alterations

35 nervous and infectious diseases such as fungal, bacterial and viral infections. In another embodiment the disorder is a proliferative disorder. In yet another embodiment, the proliferative disorder is cancer.

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. 40 SYNTHESIS OF DEACETILASE INHIBITORS

The present invention also provides various synthetic routes to synthesize the compounds of the invention.

In one embodiment the method of synthesis of compounds of formula I as defined above:

image 1

Formula I includes: 50 (a) providing a compound of formula (A1):

image 1

(b) protect the carboxyl group to produce a compound of formula (A2):

image3

(C)

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

(d)

 optionally reacting the compound to further functionalize R1;

(and)

 reduce the nitro group;

image 1

10

(F) reacting the reduced product with a compound of formula R2CO2H or a compound of formula R2CHO and cycling the product thus produced to produce a compound of formula (A4):

image 1

20 (g) converting the compound into a compound of formula 1;

in which (d) can be carried out after any one of (c) (e) or (f) and also in which (e) and (f) can be carried out sequentially or simultaneously.

The reaction sequence used above normally uses a carboxyl protecting group. The term "protecting group" refers to a chemical group that has the following characteristics: 1) reacts selectively with the desired functionality in good performance to give a protected substrate that is stable against the projected reactions for which protection is desired; 2) can be selectively removed from the protected substrate to produce the desired functionality; and 3) can be removed in good performance by

30 reagents compatible with the other functional group (s) present (s) or generated (s) in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1991) Protective Groups In Organic Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York). Various well-known carboxyl protecting groups can be used and the methodology chosen to join the protecting group will depend on the choice of the protecting group to be used as would be understood by a recipient skilled in the art. In one embodiment the protective group is an alkyl protecting group to form the ether. These can be produced in various ways, however it is normally found that they can be easily accessed through the reaction of the free acid with an alcohol under acidic conditions. An example of a suitable alcohol for this purpose is methanol however other alcohols such as ethanol, propanol, butanol and the like can also be used.

The reaction sequence detailed above also takes advantage of a leaving group suitably located in the starting material to facilitate the reaction with the amine in (b). A leaving group is a chemical group that moves easily through the desired chemical residue. Therefore in any situation the choice of the outgoing group will depend on the ability of the particular group to move through the chemical residue that enters. Suitable leaving groups are well known in the art, see for example "Advanced Organic Chemistry" Jerry March 4th Ed. 351-357, Oak Wick and Sons NY (1997). Examples of suitable leaving groups include, but are not limited to, halogen, alkoxy (such as ethoxy, methoxy), sulfonyloxy, optionally substituted arylsulfonyl, and the like. Specific examples include chlorine, iodine, bromine, fluoro, ethoxy, methoxy, methylsulfonyl, triflate and the like. It is preferred that the leaving group be either chlorine or bromine. Displacement of the leaving group is usually carried out by reacting the compound containing the leaving group with a nucleophile such as an amine undergoing nucleophilic aromatic substitution to displace the leaving group. This normally involves reaction of the compound containing the leaving group in a solvent that does not interfere with an excess of amine. The amine may vary and is normally chosen to provide the appropriate substitution pattern after displacement of the leaving group. The substitution reaction can also be catalyzed by any of several catalysts well known in the art such as palladium, copper and the like.

In some embodiments, it may be desired to further functionalize the group R1 introduced in the displacement either in this phase or in a final phase in the synthesis. This can be achieved in various ways depending on the exact functionality of the R1 group introduced. For example, if group R1 contains an NH group then it can be further reacted with other agents to add additional functionality. For example, it can be reacted with an acid, an acid chloride or an acid anhydride under conventional conditions to introduce an amide bond. Alternatively, it can be reacted with an aldehyde under reducing conditions (reductive amination) to form an alkylamine (through the imine). Alternatively, it can be reacted with an alkylating agent such as an alkyl halide to produce the corresponding alkylated amine. The amine can also be reacted with an aryl or alkylsulfonyl chloride to introduce an aryl or alkylsulfonyl group into the amine. It may also be that the introduced amine is in a protected form in which case it may be necessary to remove the amine protecting group under conventional conditions before carrying out the modifications discussed above. If this is done, the protective group is normally removed under conventional conditions (depending on the exact nature of the protective group) and then reacted as discussed above.

The reaction sequence also implies a reduction of the nitro group. The reduction of the nitro group can be carried out using any technique well known in the art. For example it can be reduced using strong reducing agents such as LiAlH4 or NaBH4 (usually in an alcoholic solvent). It can also be achieved by reaction with triphenylphosphine in water or by reaction with SnCl2 or Zn (usually in an alcoholic solvent or acetic acid or a combination thereof). The reduction can be carried out in any suitable solvent although it is usually carried out in a hydroxylic solvent such as methanol or ethanol in the presence of acetic acid.

The process normally then involves the reaction of the reduced nitro moiety with a carboxyl group or an aldehyde to produce a product that is then cycled to produce the cyclized product. This normally involves the addition of a stoichiometric amount of the carboxyl group or the aldehyde to a solution of the diamine under suitable reaction conditions. These conditions normally induce dehydration of the reaction product such as the Dean Stark apparatus or the presence of a coupling agent such as DCC.

The reduction of the nitro moiety to produce a reduced product and the reaction of the reduced product with a carbonyl moiety (acid or aldehyde) followed by intramolecular cyclization can be carried out in a sequential manner or can be carried out simultaneously in an operation in a single vessel. :

The synthesis involves the conversion of the compounds thus formed into the compounds of the invention. This can be accomplished in various ways but is most conveniently achieved by reaction with hydroxylamine hydrochloride to produce the free hydroxamic acid. The entry into other species of hydroxamic acid within the scope of the invention can be easily achieved through the use of different hydroxylamine derivatives.

In another embodiment the method of synthesis of the compounds of formula I as defined above:

image 1

Formula I includes:

(a) provide an aldehyde of formula (B1):

image 1

10 (b) subjecting the aldehyde to reaction with an appropriately substituted olefining agent to produce a compound of formula (B2):

image 1

(C) convert the compound into a compound of formula 1.

This sequence uses an olefination to introduce the desired functionality into the six-member ring. The olefining agent used can be any olefining agent well known in the art. In one embodiment, the olefining agent is a Wittig reagent (a phosphorus or phosphorous ilide). Can be accessed

20 easily to reagents of this type by reacting a phosphonium salt with a base. In another embodiment, the olefining agent is a Horner Emmons or Wadsworth Emmons reagent which is a phosphonate (RO) 2P (O) -CH2R ilium which can be easily accessed through the Arbuzov reaction. In each of these examples, the reaction is carried out under conventional conditions. Successful reagent selection allows access to a wide variety of products.

As with the above sequence, the product is then converted to the compounds of the invention using the techniques described above.

The aldehyde used as a starting material in the sequence described above can be provided using any methodology well known in the art. In one embodiment the aldehyde is produced:

(one)

 providing a compound of formula (B3) as described above:

(2)

 turning the compound into the aldehyde.

image 1

The compound (B5) can be converted to the aldehyde through a variety of techniques well known in the art. In one embodiment, the conversion first includes the reduction of the carboxyl group protected to alcohol followed by oxidation of the alcohol. The reduction of the carboxyl group can be carried out using any technique well known in the art. For example, it may include the treatment of the carboxyl group protected with a strong reducing agent such as DIBAL, LiAlH4, LiBH4, lithium trimethylborohydride, BH3-SMe2 (in THF at reflux) and

Triethoxysilane in a solvent that does not interfere. Alternatively, instead of reducing the carboxyl group protected entirely to alcohol, it can be selectively reduced directly to aldehyde using conventional conditions.

Once the alcohol has been obtained, it can be oxidized to the aldehyde using several techniques well known in the

15 technique. This may involve the reaction of alcohol with oxidants such as acid dichromate, KMnO4, BR2, MNO2, ruthenium tetroxide and the like. The reaction can also be carried out by using Jones reagent. The conversion can also be carried out by catalytic dehydrogenation or by reaction with agents such as N-bromosuccinimide or related compounds. These oxidation conditions are usually carried out under conventional conditions.

The compound of formula (B5) can be provided in any manner well known in the art. In one embodiment, providing the compound of formula (B5) includes:

(1) provide a compound of formula (B4):

image 1

(2) reduce the nitro group;

30 (3) react the reduced product with a compound of formula R2CO2H or a compound of formula R2CHO and cycle the product thus produced to produce (B5).

The reduction of the nitro compound and the reaction of the reduced product thus produced followed by cyclization are normally carried out using the methodologies as discussed above. 35 Providing a compound of formula (B4) generally includes:

(one)

 provide a compound of formula (B3):

(2)

 displacing the leaving group with an amine of formula R1NH2 to produce a compound of formula (B4): The reaction of the amine to displace the leaving group normally occurs in the presence of a base. May

image 1

Any suitable base including examples of suitable hindered tertiary amines, alkaline earth metal carbonates and any inorganic base, which is compatible with the exemplary protected carboxylic group may be used. Specific bases include sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.

In another embodiment a method of synthesis of compounds of formula I is provided as defined above:

image 1

Formula I

(a) provide a compound of formula (C1):

fifteen

image 1

(b)

 convert the compound of formula (C1) into a compound of formula (C2):

(C)

 converting the compound into a compound of formula 1.

image5

The conversion of the compound of formula (C1) into a compound of formula (C2) can be carried out using

Any of a wide range of conditions well known in the art. In general, any electrophilic aromatic substitution reaction can be used to introduce the desired functionality. An example of a suitable reaction is a Heck reaction.

The compound of formula (C1) can be provided (1) by providing a compound of formula (C4) and converting a compound of formula (C4) into a compound of formula (C1). This normally involves (a4) reducing the nitro group to produce a reduced product and reacting the reduced product with a compound of formula R2CO2H or a compound of formula R2CHO followed by intramolecular cyclization of the product thus produced to produce a compound of formula (C1) . These procedures are normally carried out using the methodology as discussed above.

The compound of formula (C4) is normally provided by providing a compound of formula (C3):

image6

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

image 1

The displacement reaction is normally carried out using the methodology as discussed above.

The agents of the various embodiments can be prepared using reaction paths and synthesis schemes as described below, using techniques available in the art using starting materials.

20 that are readily available. The preparation of particular compounds of the embodiments is described in detail in the following examples, but the expert will recognize that the chemical reactions described can be easily adapted to prepare several other agents of the various embodiments. For example, the synthesis of compounds not shown by way of example can be carried out satisfactorily by obvious modifications to those skilled in the art, for example by appropriately protecting the interfering groups,

By switching to other suitable reagents known in the art, or by making routine modifications of reaction conditions. A list of suitable protecting groups in organic synthesis can be found in T.W. Greene’s Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, 1991. Alternatively, it will be recognized that other reactions disclosed herein or known in the art have applicability to prepare other compounds of the various embodiments.

Useful reagents to synthesize the compounds according to techniques known in the art can be obtained or prepared.

In the examples described below, unless otherwise indicated, all temperatures in the following

The description is in degrees Celsius and all parts and percentages are by weight, unless otherwise indicated.

Various starting materials and other reagents were purchased from commercial suppliers, such as Aldrich Chemical Company or Lancaster Synthesis Ltd., and were used without further purification, unless indicated.

40 opposite. Tetrahydrofuran (THF) and N, N-dimethylformamide (DMF) were purchased from Aldrich in bottles with a guarantee seal and used as received. All solvents were purified using conventional methods in the art, unless otherwise indicated.

The reactions exposed below were carried out at a nitrogen pressure, positive argon or with a drying tube, at room temperature (unless otherwise indicated), in anhydrous solvents, and the reaction flasks are equipped with rubber partitions. for the introduction of substrates and reagents by syringe. The oven dried and / or the glassware was heated in the oven. Analytical thin layer chromatography was performed on 60 F 254 plates of silica gel with glass support (E Merck (0.25 mm)) and eluted with the appropriate solvent ratios (v / v). The reactions were tested by TLC and terminated as assessed by the consumption of starting material.

The CCF plates were visualized by UV absorption or with a p-anisaldehyde spray reagent or a phosphomolibic acid reagent (Aldrich Chemical, 20% by weight in ethanol) which was activated with heat, or stained in iodine chamber. Final treatments were usually performed 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). The product solutions were dried over anhydrous sodium sulfate before filtration, and evaporation of the solvents was under reduced pressure on a rotary evaporator and it was observed how the solvents were removed in vacuo. Flash column chromatography was performed [Still et al., J. Org. Chem., 43, 2923 (1978)] using silica gel 60 (Merck KGaA, 0.040-0.063 mm, ASTM 230-400 mesh) and a silica gel ratio: rough material of approximately

20: 1 to 50: 1, unless otherwise indicated. Hydrogenolysis was performed at the indicated pressure or at ambient pressure.

NMR spectra were recorded on a Bruker AVANCE 400 spectrometer that operated at 400 MHz for 1HRMN and 100 MHz for 13C-NMR. NMR spectra are obtained as solutions in CDCl3 (notified in ppm), using chloroform as a 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 necessary. When multiplicities of peaks are notified, the following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, a = widened, dd = doublet doublet, dt = doublet doublet. Coupling constants, when provided, are reported in Hertz.

Mass spectra were obtained using LC / MS either in ESI or APCI. No melting point is corrected.

All final products had a purity greater than 90% (by HPLC at wavelengths of 254 nm and / or 220 nm). Analytical HPLC conditions to check purity: IS Xterra® RP18 column 3.5 m 4.6 x 20 mm; 2.0 ml / min., Gradient of 5-65% B over 4 min., Then 65-95% b over 1 min. and 95% B over 0.1 min. additional; solvent A: H2O with 0.1% trifluoroacetic acid (TFA); solvent B: acetonitrile with 0.1% TFA.

The following examples are intended to illustrate the embodiments disclosed and should not be construed as limiting them. Additional compounds, other than those described below, can be prepared using the following described reaction scheme or appropriate variations or modifications thereof.

SYNTHESIS

Schemes I and II illustrate the procedures used to prepare compounds of formula Ib, in which X and Y are hydrogens, compounds (VII) of formula Ia can be prepared by an analogous procedure, for example, by choosing the starting material appropriate. For example, in the case where Z is -CH = CH- and is attached at position C5 in formula Ib, such compound (s) can be synthesized by the analogous method illustrated in scheme I and II starting from a substituted cinnamic acid (for example trans-3-nitro-4-chlorocinnamic acid), appropriate amine component (R1NH2), carboxylic acid component (R2CO2H, scheme I) or aldehyde (R2CHO, scheme II), and appropriate hydroxylamine or N-alkylhydroxylamine (NHR3OH in which R3 is as defined above in formula la).

Specifically, the hydroxamate compounds of formula Ib can be synthesized by the synthetic route shown in Scheme I. The reaction of trans-4-chloro-3-nitrocinamic acid (I) with an R1NH2 amine in the presence of a base (for example triethylamine ) in an appropriate solvent (for example dioxane) gave (II). Treatment of (II) in methanol under acid catalysis (for example sulfuric acid) resulted in esterification providing (III). Alternatively, the carboxylic acid (I) can be esterified to the methyl ester (Ia) 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 (for example tin (II) chloride) and the resulting phenylenediamine (IV) was coupled with an acidic R2CO2H giving amide (V) which was subsequently cycled in an appropriate solvent ( for example acetic acid) giving benzimidazole (VI) (J. Med. Chem. 2001, 44, 1516-1529). Hydroxamate compounds (VI) were obtained from methyl ester (VI) by a known synthesis method (J. Med. Chem., 2002, 45, 753-757).

image 1

Alternatively, as depicted in Scheme II, the compound (VI) was prepared by reaction with an appropriate aldehyde component R2CHO in the presence of a nitro group reducing agent (for example tin (II) chloride, or zinc powder ) in a single container (Tetrahedron Letters, 2000, 41, 9871-9874). Formic acid was used to prepare compound (VI) when R2 = H.

image 1

In both schemes I and II, the benzimidazole ring can be constructed by a cyclization step that involves

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) through (V) to form benzimidazole (VI) derivatives, followed by the conversion of the ester (VI) to hydroxamate (VII) ). For cyclization in a single vessel from (III) to (VI), see the procedures in example 1.

Stage 1: Reduction of the nitro group

To a previously stirred solution of starting material (III, 1.0 mmol) in 50 ml of co-solvent (glacial acetic acid: methanol = 2: 8), tin chloride (5.0 mmol) was added. The resulting solution was heated to 55 overnight and then cooled to room temperature. The solvent was removed and the mixture was neutralized with sodium bicarbonate at pH 8. The crude product was extracted with dichloromethane (20 ml) three times. The organic extracts were combined and washed with water (15 ml) twice and brine (15 ml) once and dried further over Na2SO4 for 1 hour. It was filtered and concentrated; The diamino (IV) product was purified by flash chromatography.

Stage 2: Amide Formation

To a previously stirred solution of carboxylic acid (1.1 mmol), diamino product (IV, 1.0 mmol) and PyBOP (1.1 mmol) in 10 ml of dry dichloromethane, DIEA (3.0 mmol) was added ) through a syringe. The resulting mixture was stirred at room temperature for 4 hours. The amide product (V) was purified by silica gel column chromatography.

Stage 3: Cycling

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 to rt, the solvent was removed in vacuo to give the product (VI) almost quantitatively.

Stage 4: Hydroxamic acid formation

To a stirred solution of ester (VI) and NH 2 OH · HCl (10 equiv.) In MeOH (0.5 M) was added NaOMe solution (20 equiv.) At -78 ° C. The reaction mixture was then allowed to warm slowly to room temperature. The reaction was monitored by LC / MS and completed in approximately 15-60 min. Then 1N HCl was slowly added in the reaction mixture at 0 ° C. The desired product was separated by preparative reverse phase HPLC and the fractions containing the desired product were lyophilized. The hydroxamate (VI) product was obtained as TFA salt (the isolated yield varies between 40-70%).

Scheme III illustrates another alternative process used to prepare compounds of formula Ib, wherein X and Y are hydrogens and R2 is selected from the group R11S (O) R13-, R11S (O) 2R13-, R11C (O) N (R12 ) R13-, R11SO2N (R12) R13-, R11N (R12) C (O) R13-, R11N (R12) SO2R13-, R11N (R12) C (O) N (R12) R13- and heteroalkyl. For example, in the case where Z is -CH = CH- and joins position C5 in formula Ib, such compound (s) (XIII) can be synthesized by the analogous method illustrated in the Scheme I and starting from appropriate (III), appropriate Fmoc protected amino acids, aldehydes or chlorides of appropriate acids and hydroxylamine.

image 1

More specifically, for example, the hydroxamate compounds of formula Ib, wherein X and Y are hydrogens, R2 is selected from the group R11S (O) R13-, R11S (O) 2R13-, R11C (O) n (R12) R13-, R11SO2N (R12) R13-, R11N (R12) C (O) R13-, 5 R11N (R12) SO2R13-, R11N (R12) C (O) n (R12) R13- and heteroalkyl; and Z is attached to position C5, they can be synthesized by the synthetic route shown in scheme III. The appropriate intermediate (III) is reduced with tin chloride to give 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, they were subjected (VIII) and / or (IX) to cyclization under acidic conditions and benzimidazole (X) was produced. The product

The key intermediate (XI) can be obtained by treating (X) with 20% piperidine. Treatment of (XI) with an appropriate acid chloride or an appropriate sulfonyl chloride gave (XII) and the objective compounds (XIII) were obtained using a similar method described in Scheme I.

When (XI) was reacted with an appropriate aldehyde under reducing conditions (NaBH (OAc) 3 / CH3COpH),

15 was obtained (XIV) and can be transformed into corresponding hydroxamate derivatives (XV) by the same methods described above.

Scheme IV illustrates some reactions to further modify the side chain of R1. If the side chain of R1 contained a protective group such as Boc in the compound (VIa1), it could be removed before conversion into

20 the final hydroxamic acid (VIIa). The intermediate product (VIa) could be modified by acylation, reductive alkylation, alkylation or sulfonylation to form new analogs (VIIb, VIIc, VIId and VIIe) through new intermediate products (VIb, VIc, VId and VIe). The methods described above in R1 = heterocycles were also applied, for example, R1 = N-Boc-piperidin-3-yl, N-Boc-piperidin-4-yl and N-Boc-pyrrolidin-3-yl.

image 1

Scheme V illustrates some alternative method of preparing (VIa) and (VIc). The primary amine (IIIa2) was prepared either from (Ia) or through (IIIa1). The derivatization of the amino group (for example, reductive amination) could be carried out either from (IIIa2) or from (VIa2). The products, that is, (IIIa2-1) and (VIa2-1), could be further derivatized (eg, reductive amination of the secondary amine).

image 1

Schemes VI and VII illustrate some alternative methods for preparing (VI) by first forming the benzimidazole ring and then introducing the double bond.

In scheme VI, the compound (XVI) was reacted with an R1NH2 amine in the presence of a base (for example triethylamine) in an appropriate solvent (for example dioxane) giving (XVII). The benzimidazole ring (XVIII) was formed by reacting the compound (XVII) with R2CHO aldehyde in the presence of a nitro group reducing agent (for example tin (II) chloride, zinc powder or other appropriate reducing agent) in a single

10 bowl The ester (XVIII) was converted into the aldehyde (XX) through a reduction and oxidation process. Finally, (VI) was obtained by reacting the aldehyde (XX) with a Wittig or Wittig-Homer reagent.

image 1

In scheme VII, the compound (XXI) was reacted with an R1NH2 amine in the presence of a base (for example triethylamine) in an appropriate solvent (for example dioxane) giving (XXII). The benzimidazole ring (XXIII) was formed by reacting the compound (XXII) with R2CHO aldehyde in the presence of a nitro group reducing agent (for example tin chloride (II), zinc powder or other appropriate reducing agent) in a single container. Finally, bromide (XXIII) was converted to (VI) in Heck's reaction condition.

image3

The following preparations and examples are provided to allow those skilled in the art to understand more clearly and practice the content thereof. They should not be considered as limiting the scope of the description, but merely that they are illustrative and representative thereof.

10 Preparation of intermediate products III

Compound (III) was prepared either from (I) through (II) or from (I) through (Ia) (scheme I and V). The following are examples of (III). 15 Intermediate product 1

3- [4- (2-Dimethylamino-ethylamino) -3-nitro-phenyl] -acrylic acid methyl ester

A mixture of 3- (4-chloro-3-nitro-phenyl) -acrylic acid (Ia, 0.688 g, 2.72 mmol), N, N-dimethylethylenediamine (0.90 ml, 8.20 mmol) was heated ) and triethylamine (1.2 ml, 8.6 mmol) in dioxane (20 ml) at 80 ° C for 5

h. The solution was evaporated and DCM and aqueous Na2CO3 were added to the residue. DCM extracts (x3) were concentrated and EtOAc-hexane was added to the residue. The resulting red solid was filtered to give the title compound (0.672 g, 84.2%). HPLC purity at 254 nm: 99.2%, t R = 1.59 min. LC-MS (ESI) m / z: 294 ([M + H] +). 1H-NMR (CDCl3

25 + CD3OD)  8.21 (1H, d, J = 2.1 Hz), 7.56 (1H, dd, J = 9.0, 2.1 Hz), 7.48 (1H, d, J = 16.0 Hz), 6.81 (1H, d, J = 9.0 Hz), 6.20 (1H, d, J = 15.9 Hz), 3.70 (3H, s), 3, 34 (2H, t, J = 6.5 Hz), 2.56 (2H, t, J = 6.4 Hz), 2.23 (6H, s); 13C-NMR (CDCl3 + CD3OD) 

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, one.

Intermediate 2 30 3- [4- (2-Diethylamine-ethylamino) -3-nitro-phenyl] -acrylic acid methyl ester.

Solid yellow. LC-MS (ESI) m / z: 322 ([M + H] +). 1H-NMR (CDCl3) ,7 8.73 (1H, similar at, 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 Product 3

3- [4- (2-Ethylamino-ethylamino) -3-nitro-phenyl] -acrylic acid methyl ester

40 Red solid. LC-MS (ESI) m / z: 294 ([M + H] +). 1H-NMR (DMSO-d6) 9 8.49 (1H, t, J = 6.1 Hz), 8.35 (1H, d, J = 2.0 Hz), 7.96 (1H, dd, J = 9.1, 1.9 Hz), 7.62 (1H, d, J = 16.0 Hz), 7.20 (1H, d, J = 9.1 Hz), 6.52 (1H, d , J = 16.0 Hz), 3.75 (2H, td, J = 6.5, 6.2 Hz), 3.70 (3H, s), 3.08 (2H, t, J = 6, 5 Hz), 2.93 (4H, q, J = 7.2 Hz), 1.17 (6H, t, J = 7.2 Hz).

45 Intermediate product 4

3- [4- (2-Isopropylamino-ethylamino) -3-nitro-phenyl] -acrylic acid methyl ester Red solid. LC-MS (ESI) m / z: 308 ([M + H] +). 1H-NMR (DMSO-d6)  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 the water peak, identified by COZY), 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 Product 5

3- [4- (3-Dimethylamino-2,2-dimethyl-propylamino) -3-nitro-phenyl] -acrylic acid methyl ester.

Solid red. LC-MS (ESI) m / z: 336 ([M + H] +). 1H-NMR (CDCl3)  9.73 (1H, saot), 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 Product 6

3- [4- (2-Diisopropylamino-ethylamino) -3-nitro-phenyl] -acrylic acid methyl ester

Solid yellow. LC-MS (ESI) m / z: 350 ([M + H] +). 1H-NMR (CDCl3) ,7 8.76 (1H, similar at, 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 product 7

3- [4- (2-Methylamino-ethylamino) -3-nitro-phenyl] -acrylic acid methyl ester

Solid red. LC-MS (ESI) m / z: 280 ([M + H] +). 1H-NMR (CDCl3) ,5 8.54 (1H, similar at, 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

3- [4- (2-tert-Butoxycarbonylamino-ethylamino) -3-nitro-phenyl] -acrylic acid methyl ester (IIIa1)

Stage 1:

A suspension of trans-4-chloro-3-naphtrocinamic acid (I, 5,057 g, 22.22 mmol) in MeOH (40 ml) and DCM (20 ml) was stirred and cooled in a bath with carbon snow / acetone. SOCl2 (1.0 ml, 13.8 mmol) was added to the previous mixture. The bath was removed with carbonic snow, then the mixture was heated to room temperature and stirred at 40 ° C until the reaction was complete. The solution was evaporated to dryness to give a pale yellow solid (5.364 g, 99.9%). HPLC purity at 254 nm: 99.5%; tR = 2.96 min. LC-MS (ESI) m / z: 210 and 212 (very weak signal, [M + H-MeOH] +).

Stage 2:

A mixture of 3- (4-chloro-3-nitro-phenyl) -acrylic acid (Ia, 0.243 g, 1.00 mmol), N-Bocetylenediamine (0.316 ml, 2.0 mmol) and triethylamine was heated (0.50 ml, 3.59 mmol) in dioxane (7 ml) at 80 ° C for approximately 80 h. The solution was evaporated and MeOH was added to the residue. The resulting solid was filtered and washed with MeOH. 3- [4- (2-tert-Butoxycarbonylamino-ethylamino) -3-nitro-phenyl] -acrylic acid (IIIa1) methyl ester was obtained as a bright yellow solid (0.193 g, 52.6%). HPLC purity at 254 nm: 96.0-98.1%; tR = 3.27 min. LC-MS (ESI) m / z: 366 ([M + H] +), 310 (M + H-56), 266 (M + H-Boc). 1H-NMR (CDCl3) ,4 8.41 (1H, similar ata, NHAr), 8.31 (1H, d, J = 1.8 Hz), 7.63 (1H, dd, J = 9.0, 1 , 7 Hz), 7.57 (1H, d, J = 16.0 Hz), 6.98 (1H, d, J = 8.9 Hz), 6.30 (1H, d, J = 15.9 Hz), 3.80 (3H, s), 3.52 (2H, m), 3.45 (2H, m), 1.45 (9H, s); 13C-NMR (CDCl3)  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 Product 9

3- [4- (2-Amino-ethylamino) -3-nitro-phenyl] -acrylic acid methyl ester (IIIa2)

Method 1:

Remove the Boc protecting group from (IIIa1) in acidic condition: 1) HCl / MeOH; 2) TFA / DCM.

Method 2:

To the ester (la, 2.47 g, 10.2 mmol) in dioxane (102 ml, 0.1 M) was added ethylenediamine (Merck product No. 8.00947, 2.04 ml, 30.6 mmol) followed by triethylamine (2.8 ml, 20.47 mmol). The resulting mixture was heated to 90 ° C and stirred for 20 hours. It was confirmed that the reaction was completed using HPLC (in which the product IIIa2 tR = 1.6 min., Starting material Ia tR = 3.1 min.). After completion, the solvent was removed and the crude product 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 title compound IIIa2. Yield = 98%, LC-MS m / z: 266 ([M + H] +).

Example 1

Preparation of 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2- (2,2-dimethyl-propyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide (1)

The title compound (1) was prepared according to scheme 1 and II, using appropriate starting materials.

Stage 1:

To a previously stirred solution of trans-4-chloro-3-nitrocinamic acid (I, 11 g, 48 mmol) in dioxane (200 ml) was added triethylamine (20 ml, 126 mmol), followed by 3-dimethylamino-2 , 2-dimethylpropylamine (20 ml, 143 mmol). The reaction mixture was allowed to stir at 100 ° C for 1-2 days until all the starting material had been completely converted. Then, the solvent was removed in vacuo followed by the addition of H2O (250 ml) to dissolve the residue. HCl conc. up to pH ≈ 1 with orange precipitation. The suspension was filtered and the residue was washed with H2O several times to obtain (II) as an orange solid (13 g, 84%). LC-MS (ESI) m / z: 322 ([M + H] +).

Stage 2:

The compound (II, 13 g, 40.5 mmol) was dissolved in MeOH (250 ml) followed by the addition of conc. H2SO4. (5 ml). The reaction mixture was allowed to stir at 80 ° C for 18 h. The solvent was removed in vacuo and H2O (250 ml) was added to dissolve the residue. Na2CO3 was added until pH ≈ 8-9, subsequently, MeOH was added and stirred for 1 hour. Then, the suspension was filtered under vacuum and the residue was washed with H2O several times to obtain the ester (III) as an orange solid (10 g, 74%). LC-MS (ESI) m / z: 336 ([M + H] +).

Stage 3:

To a stirred solution of ester (III, 1 equiv.) And SnCl2 · 2H2O (5 equiv.) In AcOH and MeOH (0.2 M, mixture 1: 9) 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 monitored by LC / MS. When the reaction was completed, the solvent was removed under reduced pressure at 30-35 ° C. To the resulting solid, 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 the addition of conc. NH3 · H2O. The mixture was stirred for half an hour, followed by centrifugation if necessary to separate the organic phase. The organic phase was collected. The aqueous phase and the residue (oily solid precipitate) were extracted another 3 times with ethyl acetate as described above. The combined organic contents were dried over sodium sulfate, filtered and evaporated to dryness. The resulting oily residue was purified by flash column chromatography (the isolated yield of the cycled product (VI) varies between 50-90%). LCMS (ESI) m / z: 386 ([M + H] +).

Stage 4:

To a stirred solution of ester (VI) and NH2OH.HCl (10 equiv.) In MeOH (0.5 M) was added NaOMe (20 equiv.) At -78 ° C. The reaction mixture was then allowed to warm slowly to room temperature. The reaction was monitored by LC / MS and completed in approximately 15 min. Then 1N HCl was slowly added in the reaction mixture at 0 ° C. The desired product was separated by prep HPLC. and the fractions containing the desired product were lyophilized. The product (VII) was obtained as TFA salt (the isolated yield varies between 40

- 70%). HPLC purity at 254 nm: 100%, t R = 0.78 min. LC-MS (ESI) m / z: 387 ([M + H] +). 1 H-NMR (DMSO-d6)  1.05 (15H, s), 2.91 (6H, s), 2.92 (2H, s), 3.32 (2H, sa), 4.35 (2H , s), 6.49 (1H, d, J = 15.8 Hz), 7.56 (1H, d, J = 9.0 Hz), 7.61 (1H, d, J = 15.76 Hz ), 7.83 (1H, d, J = 9.0 Hz), 7.85 (1H, s), 9.22 (1H, sa), 10.72 (1H, sa); 13C-NMR (DMSOd6)  162.6, 154.2, 138.0, 135.3 (a), 134.7, 131.5, 122.8, 119.2, 115.2, 114.0, 66.5, 51.1, 46.7, 38.4, 38.3, 33.6, 29.1, 22.8.

Example 2

Preparation of 3- [1- (3-dimethyl) amino-2,2-dimethyl-propyl) -2-isopropyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide (2)

The title compound (2) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 100%, t R = 0.54 min. LC-MS (ESI) m / z: 359 ([M + H] +). 1 H-NMR (DMSO-d6)  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, sa), 10.80 (1H, sa).

Example 3

Preparation of 3- [2-Butyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (3)

The title compound (3) was prepared according to the procedures described in example 1, using appropriate starting materials. Yield: 74 mg as TFA salt. HPLC purity at 254 nm: 99.0%, t R = 0.89 min. LC-MS (ESI) m / z: 373 ([M + H] +). 1H-NMR (CD3OD)  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, whit, J = 7.2 Hz), 1.49 (2H, m), 1.21 (6H, s ), 0.98 (3H, t, J = 7.3 Hz); 13C-NMR (CD3OD)  165.5 (a), 158.2, 139.8, 135.3, 135.1, 132.4, 126.4, 120.6 (a), 115.6, 114 , 3, 68.7, 53.5, 47.8 (Mex2), 39.5, 29.9, 27.2, 23.6 (Mex2), 23.3, 13.9.

Example 4

Preparation of 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2- (2-methylsulfanylethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide (4)

The title compound (4) was prepared according to the procedures described in example 1, using appropriate starting materials. Yield: 17 mg as TFA salt. HPLC purity at 254 nm: 96.2%, t R = 0.75 min. LC-MS (ESI) m / z: 391 ([M + H] +). 1H-NMR (CD3OD)  8.02 (1H, d, J = 8.3 Hz), 7.92 (1H, s), 7.80 (1H, d, J = 8.7 Hz), 7, 69 (1H, d, J = 15.8 Hz), 6.60 (1H, d, J = 15.8 Hz), 4.49 (2H, s), 3.50 (2H, t, J = 7 , 2 Hz), 3.37 (2H, s), 3.03 (2H, t, J = 7.2 Hz), 2.95 (6H, s), 2.18 (3H, s), 1, 25 (6H, s); 13C-NMR (CD3OD)  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.

Example 5

Preparation of 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2-isobutyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (6)

The title compound (6) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 96.2%, t R = 0.82 min. LC-MS (ESI) m / z: 373 ([M + H] +). 1HRMN (DMSO-d6):  10.80 (1H, s), 9.47 (1H, s), 7.93 (1H, s), 7.90 (1H, d, J = 6.6 Hz) , 7.64 (1H, d, J = 7.4 Hz), 7.62 (1H, d, J = 15.5 Hz), 6.54 (1H, d, J = 15.8 Hz), 4 , 39 (2H, s), 3.33 (2H, s), 2.97 (2H, d, J = 7.26 Hz), 2.92 (6H, s), 2.35 (1H, qn) , 1.09 (6H, s), 0.97 (6H, d, J = 6.6 Hz).

Example 6

Preparation of 3- [1- (2-diethylamino-ethyl) -2-isobutyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (7)

The title compound (7) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99.0%, t R = 0.56 min. LC-MS (ESI) m / z: 359 ([M + H] +). 1HRMN (DMSO-d6):  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)  162.7, 158.5, 158.2 , 155.2, 138.4, 133.9, 131.0, 123.0, 118.6, 116.0, 111.6, 48.8, 46.8, 34.1, 27.1, 22 , 2, 8.5.

Example 7

Preparation of 3- [2-Butyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (8)

The title compound (8) was prepared according to the procedures described in example 1, using appropriate starting materials. Yield: 61 mg (20% in two stages) as TFA salt. HPLC purity at 254 nm: 98.1%, t R = 0.59 min. LC-MS (ESI) m / z: 359 ([M + H] +). 1H-NMR (CD3OD)  7.94 (1H, d, J = 8.6 Hz), 7.85 (1H, s), 7.76 (1H, d, J = 8.5 Hz), 7, 50 (1H, d, J = 15.7 Hz), 6.49 (1H, d, J = 15.7 Hz), 4.96 (2H, overlapped with DHO, identified by COZY), 3.69 (2H , similar at, J = 7.6 Hz), 3.44 (4H, q, J = 7.6 Hz), 3.26 (2H, t, J = 7.9 Hz), 1.94 (2H, Pentete, J = 7.5 Hz), 1.57 (2H, m), 1.40 (6H, t, J = 7.2 Hz), 1.05 (3H, t, J = 7.3 Hz) ; 13C-NMR (CD3OD)  165.5, 157.7, 140.0, 134.8, 134.0, 133.8, 126.5, 119.9, 115.1, 113.6, 50.2 , 48.7 (2C), 40.5, 29.4, 26.6, 23.3, 13.9, 8.9 (2C). (TFA peak 163.4, 163.0, 162.7, 162.3; 122.3, 119.5, 116.6). The dihydrochloride salt of 8 was prepared according to the procedures described in example 50, steps 4 and 5, using appropriate starting materials. 1H-NMR (DMSOd6)  11.79 (sa, 1H), 10.92 (very wide s, 1H), 8.18 (1H, d, J = 8.6 Hz), 7.97 (1H, s ), 7.79 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J = 15.8 Hz), 6.65 (1H, d, J = 15.8 Hz), 5.01 (2H, similar at, J = 7.7 Hz), 3.48 (2H, m), 3.30-3.19 (6H, m), 1.87 (2H, whit, J = 7 , 8 Hz), 1.47 (2H, sextet, J = 7.5 Hz), 1.29 (6H, t, J = 7.2 Hz), 0.97 (3H, t, J = 7.3 Hz); 13C-NMR (DMSO-d6)  162.3, 156.0, 137.3 (CH), 132.8, 132.3, 132.0 (a, identified by HMBC), 124.7 (CH), 120.2 (CH), 113.1 (2xCH), 48.2, 46.3, 39.0, 28.1, 25.0, 21.7, 13.6, 8.3.

Example 8

Preparation of 3- [2-but-3-inyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1 H -benzoimidazol-5-yl] -N-hydroxyacrylamide (9)

The title compound (9) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 98.3%; tR = 0.52 min .; LC-MS (ESI) m / z: 369 ([M + H] +). 1HRMN (DMSO-d6)  9.49 (sa, 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 (DMSOd6)  162.8, 155.3, 138.4, 138.0, 135.9, 130.5, 122.3, 118.4, 117.8, 116.4, 114.9 , 112.9, 111.9, 82.8, 72.3, 66.9, 50.9, 46.7. 25.8, 22.8, 16.2.

Example 9

Preparation of 3- [2-but-3-enyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide (10)

The title compound (10) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99%; tR = 0.80 min .; LC-MS (ESI) m / z: 371 ([M + H] +). 1HRMN (CD3OD)  7.95 (d, J = 8.8 Hz, 1H), 7.85 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.63 ( d, J = 15.8 Hz, 1H), 6.54 (d, J = 15.8 Hz, 1H), 5.94 - 5.84 (m, 1H), 5.10 (dd, J = 1 , 4, 17.1 Hz, 1H), 5.03 (dd, J = 1.1, 10.2 Hz, 1H), 4.51 (s, 2H), 3.40 (s, 2H), 3 , 32 (t, J = 7.6 Hz, 2H), 2.99 (s, 6H), 2.66 (q, J = 7.5 Hz, 2H), 1.19 (s, 6H); 13C-NMR (CD3OD)  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 3- [2-but-3-enyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (11)

The title compound (11) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC: 99.4%; tR = 0.52 min .; LC-MS (ESI) m / z: 357 ([M + H] +1). 1H-NMR (CD3OD)  7.94 (d, J = 8.7 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7, 50 (d, J = 15.87 Hz, 1H), 6.46 (d, J = 15.8 Hz, 1H), 5.96-5.86 (m, 1H), 5.13 (dd, J = 1.4, 17.1 Hz, 1H), 5.05 (dd, J = 1.1, 10.2 Hz, 1H), 4.93 (t, J = 7.9 Hz, 2H), 3 , 62 - 3.58 (m, 2H), 3.38 - 3.31 (m, 6H), 2.65 (q, J = 7.6 Hz, 2H), 1.35 - 1.32 (m , 6H); 13C-NMR (CD3OD)  165.8, 157.0, 140.5, 136.6, 135.9, 134.6, 134.2, 126.1, 119.5, 117.7, 116.0 , 113.3, 50.4, 40.4, 31.7, 26.7, 9.1.

Example 11

Preparation of 3- [2-but-3-inyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (12)

The title compound (12) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC: 99.6%; tR = 0.37 min .; LC-MS (ESI) m / z: 355 ([M + H] +). 1H-NMR (CD3OD)  7.82 (d, J = 8.7 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7, 31 (d, J = 15.8 Hz, 1H), 6.31 (d, J = 15.8 Hz, 1H), 4.87-4.79 (masked peaks), 3.54-3.50 ( m, 2H), 3.37 (t, J = 7.1 Hz, 2H), 3.24 (q, J = 7.2 Hz, 4H), 2.73 (dt, J = 2.4, 6 , 9 Hz, 2H), 2.30 (t, J = 2.5 Hz, 1H), 1.21 (t, J = 7.2 Hz, 6H); 13C-NMR (CD3OD)  165.9, 156.1, 140.9, 138.1, 135.2, 133.4, 125.6, 118.8, 117.0, 112.8, 82.4 , 72.1, 50.6, 40.2, 26.7, 26.4, 17.3, 9.1.

Example 12

Preparation of 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2- (3,3,3-trifluoro-propyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide (13)

The title compound (13) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 96.5%; tR = 0.80 min .; LC-MS (ESI) m / z: 413 ([M + H] +).

Example 13

Preparation of 3- [1- (2-diethylamino-ethyl) -2- (3,3,3-trifluoro-propyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (14) The compound was prepared of title (14) according to the procedures described in example 1, using appropriate starting materials. HPLC purity: 96.4%; tR = 1.37 min .; LC-MS (ESI) m / z: 399 ([M + H] +). 1H-NMR (DMSOd6)  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, sa).

Example 14

Preparation of 3- [1- (2-diethylamino-ethyl) -2-ethoxymethyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (15)

The title compound (15) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity: 98.1%; tR = 0.48 min .; LC-MS (ESI) m / z: 361 ([M + H] +).

Example 15

Preparation of 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2-methyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (16)

The title compound (16) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity: 99.5%; tR = 0.30 min .; LC-MS (ESI) m / z: 331 ([M + H] +). 1H-NMR (DMSOd6)  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, sa), 10.81 (1H, sa) .

Example 16

Preparation of 3- [1- (2-diethylamino-ethyl) -2- (2,2-dimethyl-propyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (17)

The title compound (17) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99.9%, t R = 0.95 min. LC-MS (ESI) m / z: 373 ([M + H] +). 1HRMN (CD3OD) 5 7.85 (2H, t, J = 8.3 Hz), 7.75 (1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 15.8 Hz), 6.51 (1H, d, J = 15.8 Hz), 4.93 (2H, t, J = 6.1 Hz), 3.54 (2H, t, J = 8.1 Hz) , 3.31 (4H, qt, J = 7.3 Hz), 3.10 (2H, s), 1.27 (6H, t, J = 7.3 Hz), 1.06 (9H, s) ; 13C-NMR (CD3OD)  163.7, 153.3, 138.3, 133.1, 131.9, 124.5, 118.3, 117.1, 113.5, 111.8, 48.1 , 39.1, 37.5, 32.9, 27.8, 7.1.

Example 17

Preparation of N-hydroxy-3- [1- (3-isopropylamino-propyl) -2- (3,3,3-trifluoro-propyl) -1H-benzoimidazol-5-yl] -acrylamide

(18)

The title compound (18) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity: 96.8%; tR = 0.72 min. LC-MS (ESI) m / z: 399 ([M + H] +). 1H-NMR (DMSOd6)  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, sa).

Example 18

Preparation of 3- [2- (2,2-dimethyl-propyl) -1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (19)

The title compound (19) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 98.1%, t R = 0.86 min. LC-MS (ESI) m / z: 359 ([M + H] +). 1HRMN (CD3OD) 6 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, qt, J = 6.5 Hz), 3.13 (2H, s), 1.26 (6H, d, J = 6.2 Hz) , 1.04 (9H, s); 13C-NMR (CD3OD)  161.2, 153.4, 138.3, 133.0, 124.4, 113.6, 112.0, 51.1, 41.8, 41.1, 37.3 , 33.1, 27.8, 17.2.

Example 19

Preparation of 3- [1- (2-diisopropylamino-ethyl) -2- (2,2-dimethyl-propyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (20)

The title compound (20) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 96.8%, t R = 0.94 min. LC-MS (ESI) m / z: 400 ([M + H] +). 1HRMN (CD3OD) 6 7.86 (1H, s), 7.80 (1H, d, J = 8.7 Hz), 7.76 (1H, d, J = 8.6 Hz), 7.62 ( 1H, d, J = 15.8 Hz), 6.52 (1H, d, J = 16.0 Hz), 4.96 (2H, t, J = 5.2 Hz), 3.84 (2H, m), 3.53 (2H, t, J = 8.3 Hz), 3.06 (2H, s), 1.38 (12H, d, J = 6.5 Hz), 1.05 (9H, s); 13C-NMR (CD3OD)  160.2, 153.1, 138.2, 133.2, 131.9, 124.6, 113.5, 111.8, 54.9, 423.0, 40.5 , 37.7, 33.0, 27.8, 16.3.

Example 20

Preparation of 3- [1- (2-diisopropylamino-ethyl) -2-isobutyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (21)

The title compound (21) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 95.3%, t R = 0.76 min. LC-MS (ESI) m / z: 387 ([M + H] +). 1HRMN (CD3OD) 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-dimethylamino-2,2-dimethyl-propyl) -2-hex-3-enyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide (22)

The title compound (22) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99.9%; tR = 1.24 min .; LC-MS (ESI) m / z: 399 ([M + H] +), 1HRMN (CD3OD)  8.22 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 15.8 Hz, 1H). 6.68 (d, J = 15.8 Hz, 1H), 5.69-5.59 (m, 2H), 4.79 (s, 2H), 3.66 (s, 2H), 3.55 (t, J = 7.3 Hz, 2H), 3.24 (s, 6H), 2.91 (q, J = 6.8 Hz, 2H), 2.21 - 2.11 (m, 2H) , 1.44 (s, 6H), 1.02 (t, J = 7.5 Hz, 3H); 13C-NMR (CD3OD)  165.7, 157.9, 140.2, 135.8, 134.6, 134.5, 126.1, 125.9, 120.1, 115.2, 114.6 , 68.7, 533, 47.9, 39.6, 27.6, 25.9, 23.7, 21.4, 14.4.

Example 22

Preparation of 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2- (2,4,4-trimethyl-pentyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide (23)

The title compound (23) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 98.6%; tR = 1.61 min .; LC-MS (ESI) m / z: 429 ([M + H] +). 1HRMN (CD3OD)  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 (sa, 2H), 1.50-1.45 (m, 2H), 1.36 (d, J = 3.8 Hz, 6H), 1.12 (d, J = 5.5 Hz, 3H), 1.02 (s, 6H); 13C-NMR (CD3OD)  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 (Reference Example)

Preparation of 3- [2-cyclohexyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide (24)

The title compound (24) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99.9%; tR = 0.96 min .; LC-MS (ESI) m / z: 399 ([M + H] +). 1HRMN (CD3OD):  8.21 (d, J = 8.8 Hz, 1H). 8.06 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 15.8 Hz, 1H), 6.76 (d, J = 15 , 8 Hz, 1H), 4.79 (s, 2H), 3.65 (s, 2H), 3.60 - 3.51 (m, 1H), 3.22 (s, 6H), 3.29 - 3.26 (m, 2H), 2.12 - 2.09 (m, 2H), 2.03 -1.92 (m, 3H), 1.78 -1.59 (m, 3H), 1 , 41 (s, 6H); 13C-NMR (CD3OD)  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, 26.6, 26.3, 23.6.

Example 24 (Reference example)

Preparation of 3- [2-bicyclo [2.2.1] hept-5-en-2-yl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1H-benzoimidazol-5-yl] -N- hydroxyacrylamide (25)

The title compound (25) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99.9%; tR = 0.91 min .; LC-MS (ESI) m / z: 409 ([M + H] +).

Example 25

Preparation of 3- [1- (2-diethylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (26)

The title compound (26) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC: 99.9%; tR = 1.14 min .; LC-MS (ESI) m / z: 385 ([M + H] +). 1H-NMR (CD3OD)  7.95 (d, J = 8.6 Hz, 1H), 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 (CD3OD)  165.6, 157.2, 140.2, 135.9, 134.8, 134.6, 134.2, 126.4, 126.1, 119.8, 115.6 , 113.5, 50.4, 40.5, 26.9, 25.4, 21.4, 14.4, 8.9.

Example 26

Preparation of 3- [1- (2-diisopropylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (27)

The title compound (27) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC: 99.9%; tR = 1.22 min .; LC-MS (ESI) m / z: 413 ([M + H] +). 1H-NMR (CD3OD)  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), 3.36-2.26 (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 (CD3OD)  165.6, 157.0, 140.2, 135.9, 135.4, 134.5, 134.3, 126.6, 126.3, 126.2, 119.8 , 115.8, 113.3, 56.9, 45.3, 41.9, 27.2, 25.5, 21.4, 18.2, 14.4.

Example 27

Preparation of 3- [2-hex-3-enyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (28)

The title compound (28) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99.9%; tR = 1.12 min .; LC-MS (ESI) m / z: 371 ([M + H] +). 1HRMN (CD3OD)  8.00 (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 3- [1- (2-ethylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (29)

The title compound (29) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99.9%; tR = 1.23 min .; LC-MS (ESI) m / z: 385 ([M + H] +). 1HRMN (CD3OD)  7.94 (d, J = 8.6 Hz, 1H), 7.89 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.56 ( d, J = 15.8 Hz, 1H), 6.55 (d, J = 15.7 Hz, 1H), 5.57-5.42 (m, 2H), 4.62 (t, J = 7 , 5 Hz, 2H), 3.42 - 3.33 (m, 1H), 3.32 - 3.30 (masked peaks), 3.28 - 3.24 (m, 2H), 2.71 (q , J = 7.2 Hz, 2H), 2.33 (sa, 2H), 2.03 - 1.94 (m, 2H), 1.36 (d, J = 6.5 Hz, 6H), 0 , 84 (t, J = 7.5 Hz, 3H); 13C-NMR (CD3OD)  165.6, 156.3, 139.9, 136.8, 136.2, 135.2, 133.8, 132.8, 126.7, 125.8, 120.4 , 114.6, 114.1, 52.2, 43.5, 42.9, 27.2, 26.5, 25.5, 21.4, 19.2, 14.4.

Example 29

Preparation of 3- [2-hex-3-enyl-1- (3-isopropylamino-propyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (30)

The title compound (30) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99.9%; tR = 1.04 min .; LC-MS (ESI) m / z: 357 ([M + H] +). 1HRMN (CD3O)  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 (sa, 2H), 3.35 - 3.30 (masked peaks), 3.22 - 3.17 (m, 2H ), 2.72 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H); 13C-NMR (CD3OD)  165.6, 157.3, 140.5, 135.8, 134.9, 134.6, 134.2, 126.2, 126.1, 118.7, 115.9 , 113.7, 113.6, 46.5, 45.0, 42.7, 26.4, 25.4, 21.4, 14.4, 11.4.

Example 30

Preparation of 3- [1- (2-diethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (31)

The title compound (31) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 100%, t R = 1.31 min. LC-MS m / z: 387 ([M + H] +). 1 H-NMR (DMSO-d6)  0.88 (3H, t, J = 7.0 Hz), 1.26 (6H, t, J = 7.2 Hz), 1.34 (4H, m), 1.44 (2H, m), 1.85 (2H, m), 3.12 (2H, t, J = 7.7 Hz), 3.31 (4H, m), 3.52 (2H, t , J = 7.7 Hz), 4.81 (2H, t, J = 7.7 Hz), 6.59 (1H, d, J = 15.8 Hz), 7.63 (1H, d, J = 15.8 Hz), 7.73 (1H, d, J = 8.8 Hz), 7.93 (1H, d, J = 8.8 Hz), 7.94 (1H, s).

Example 31

Preparation of 3- [1- (3-Isopropylamino-propyl) -2- (2,4,4-trimethyl-pentyl) -1 H -benzoimidazol-5-yl] -N-hydroxyacrylamide (32)

The title compound (32) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: HPLC: 97.5%, t R = 1.68 min. LC-MS m / z: 415 ([M + H] +). 1HRMN (DMSO-d6)  0.89 (9H, s), 0.98 (3H, d, J = 6.6 Hz), 1.23 (6H, d, J = 6.5 Hz), 2, 08-2.29 (4H, m), 2.27 (1H, m), 2.98-3.12 (4H, m), 3.29 (1H, m), 4.53 (2H, t, J = 7.4 Hz), 6.60 (1H, d, J = 15.8 Hz), 7.65 (1H, d, J = 15.8 Hz), 7.75 (1H, d, J = 9.0 Hz), 7.96 (1H, d, J = 9.0 Hz), 7.98 (1H, s), 8.75 (2H, sa).

Example 32

Preparation of 3- [2- (2,2-dimethyl-propyl) -1- (3-isopropylamino-propyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (33)

The title compound (33) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99%, t R = 1.01 min. LC-MS m / z: 375 ([M + H] +). 1 H-NMR (DMSO-d6) ,9 0.98 (9H, s), 1.24 (6H, sa), 2.17 (2H, sa), 3.14 (4H, m), 3.28 (1H , sa), 4.53 (2H, sa), 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, sa).

Example 33

Preparation of 3- [1- (2-diisopropylamino-ethyl) -2- (3,3,3-trifluoro-propyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide (34)

The title compound (34) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC: 97.5%; tR = 0.93 min. LC-MS (ESI) m / z: 427 ([M + H]). 1H-NMR (DMSO-d6)  1.35 (12H, m), 2.94 (2H, m), 3.24 (2H, m), 3.45 (2H, t), 3.80 (2H , m), 4.68 (2H, t), 6.48 (1H, m), 7.55 (3H, m), 7.85 (1H, m), 9.48 (1H, sa).

Example 34

Preparation of N-hydroxy-3- [2-isobutyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] -acrylamide (35)

The title compound (35) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 98.3%, t R = 0.51 min. LC-MS (ESI) m / z: 345 ([M + H] +). 1HRMN (CD3OD) ,7 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 (CD3OD)  160.3, 155.3, 138.5, 134.1, 131.5, 124.2, 113.9, 111.4, 51.1, 42.0, 40.3 , 33.4, 27.3, 20.6, 17.2.

Example 35

Preparation of 3- [2- (2,2-dimethyl-propyl) -1- (2-ethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (36)

The title compound (36) was prepared according to the procedures described in example 1, using appropriate starting materials. Yield: 74%. HPLC purity at 254 nm: 99.9%, t R = 0.71 min. LC-MS (ESI) m / z: 345 ([M + H] +). 1H-NMR (CD3O)  7.81 (1H, d, J = 8.6 Hz), 7.75 (1H, s), 7.69 (1H, d, J = 8.5 Hz), 7, 36 (1H, d, J = 15.7 Hz), 6.40 (1H, d, J = 15.3 Hz), 4.81 (2H, t, J = 6.4 Hz), 3.51 ( 2H, t, J = 6.3 Hz), 3.10 (2H, s), 3.06 (2H, qt, J = 7.3 Hz), 1.23 (3H, t, J = 7.2 Hz), 1.04 (9H, s); 13C-NMR (CD3OD)  161.0, 153.3, 138.5, 132.7, 132.2, 124.2, 117.5, 113.9, 111.9, 44.2, 43.0 , 41.0, 37.4, 33.0, 27.9, 9.5.

Example 36

Preparation of 3- [1- (2-ethylamino-ethyl) -2-isobutyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (37)

The title compound (37) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99.9%, t R = 0.40 min. LC-MS (ESI) m / z: 331 ([M + H] +). 1HRMN (CD3OD) 1 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 (2H, d, J = 7.4 Hz), 3.06 (2H, d, J = 9.5 Hz), 2.21 (1H, m) , 1.23 (3H, t, J = 7.3 Hz), 1.04 (6H, d, J = 6.6 Hz); 13C-NMR (CD3OD)  163.7, 161.1, 154.8, 138.6, 133.2, 132.6, 132.4, 124.2, 117.2, 113.9, 111.6 , 44.4, 43.0, 40.5, 33.4, 27.3, 20.6, 9.5.

Example 37

Preparation of 3- [1- (2-diisopropylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide (38)

The title compound (38) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC: 99.0%; tR = 1.62 min .: LC-MS (ESI) m / z: 443 ([M + H] +). 1H-NMR (CD3OD)  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 (CD3O)  165.5, 156.5, 140.1, 134.8, 134.7, 134.0, 126.5, 120.0, 114.6, 113.6, 56.9 , 51.7, 45.2, 42.0, 35.9, 31.9, 30.6, 30.2, 22.6, 18.3.

Example 38

Preparation of N-hydroxy-3- [1- (2-isopropylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1H-benzoimidazol-5-yl] -acrylamide (39)

The title compound (39) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 97.9%; tR = 1.49 min .; LC-MS (ESI) m / z: 401 ([M + H] +). 1HRMN (CD3OD)  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), 3.34-2.28 (masked peaks), 3.22 3.15 (m, 1H), 2.31-2.29 (m, 1H), 1.39-1.38 (m , 9H), 1.07 (d, J = 6.6 Hz, 3H), 0.9 (s, 9H); 13C-NMR (CD3OD)  165.5, 156.9, 140.5, 134.7, 134.4, 126.3, 118.9, 115.9, 113.8. 53.2, 51.5, 44.2, 42.8, 35.7, 31.9, 30.9, 30.2, 29.6, 19.1, 18.8.

Example 39

Preparation of 3- [1- (2-ethylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (40)

The title compound (40) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 100.0%; tR = 1.57 min .; LC-MS (ESI) m / z: 387 ([M + H] +). 1HRMN (CD3OD)  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), 3.36-2.28 (masked peaks), 3.26-3.14 (m, 3H), 2.31-2.30 (m, 1H), 1.40-1 , 32 (m, 5H), 1.07 (d, J = 6.6 Hz, 3H), 0.92 (s, 9H); 13C-NMR (CD3OD)  165.6, 156.9, 140.6, 134.9, 134.5, 134.2, 126.2, 118.7, 116.0, 113.7, 51.6 , 46.5, 45.0, 42.7, 35.8, 31.9, 30.8, 30.2, 22.6, 11.4.

Example 40

Preparation of 3- [1- (2-diethylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (41)

The title compound (41) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 85.6%, t R = 1.55 min. LC-MS m / z: 415 ([M + H] +). 1H-NMR (CD3OD)  7.91 (d, 2H, J = 6.0 Hz), 7.80 (a, d, 1H, J = 8.9 Hz), 7.68 (d, 2H, J = 15.8 Hz), 6.58 (d, 1H, J = 15.8 Hz), 4.96 (a, q, 2H), 3.64 (a, q, 2H), 3.43 (q , 4H, J = 7.3 Hz), 1.40 (t, 8H), 1.09 (a, d, 4H, J = 6.6 Hz), 0.94 (a, s, 10H); 13CRMN (CD3OD)  156.8, 140.4, 135.8, 134.4, 134.3, 126.1, 115.8, 113.2, 119.7, 119.2, 61.6, 50 , 3, 40.3, 35.8, 31.9, 22.6, 9.0.

Example 41

Preparation of 3- [1- (2-diethylamino-ethyl) -2-propyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (42)

The title compound (42) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 99.0%, t R = 0.68 min. LC-MS (ESI) m / z: 345 ([M + H] +). 1HRMN (CD3OD) ,1 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 (a, t, 2H), 3.70 (a, t, 2H), 3.44 (a, m, 4H), 3.35 (t, 2H), 2.03 (a , m, 2H), 1.44 (t, 6H, J = 7.2 Hz), 1.20 (t, 3H); 13C-NMR (CD3OD)  165.5, 157.4, 139.8, 135.5, 133.5, 132.3, 120.7, 120.7, 114.5, 114.3, 40.8 , 28.5, 21.0, 13.9, 9.1.

Example 42

Preparation of 3- [1- (2-diethylamino-ethyl) -2- (2-methylsulfanyl-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (45)

The title compound (45) was prepared according to the procedures described in example 1, using appropriate starting materials. Yield: 17 mg (in two stages) as TFA salt. HPLC purity at 254 nm: 80%, t R = 0.50 min. LC-MS (ESI) m / z: 377 ([M + H] +). 1H-NMR (CD3OD) 9 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 COZY), 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, overlapping t).

Example 43

Preparation of 3- [2-butyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (46)

The title compound (46) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 98.4%; tR = 1.56 min. LC-MS m / z: 345 ([M + H] +). 1HRMN (DMSO-d6) ,95 0.95 (3H, t), 1.22 (6H, m), 1.42 (2H, m), 1.80 (2H, m), 3.13 (2H, m ), 3.41 (3H, t), 4.69 (2H, t), 6.58 (1H, m), 7.56 (1H, m), 7.73 (1H, m), 7.90 (2H, m), 9.14 (2H, sa).

Preparation of the free base of the title compound:

To a previously stirred solution of the methyl ester (1 eq.) In dry methanol, NH2OH.HCl (12 eq.) Was added. The mixture was stirred in an ice water bath for approximately 10 min., Followed by the addition of sodium methoxide solution (20 eq.). HPLC showed the reaction completed after 20 min., Less than 1% of the acid was observed.

The above crude product was treated with 1 M HCl until all the precipitate dissolved (pH of about 1-2). The pH value was carefully adjusted to approximately 7-8 using NaOH or NaHCO3, the precipitate that formed was collected by filtration. The solid was washed with water once. The above solid was suspended in methanol and water again and treated with 6 N HCl until everything dissolved, the pH value was carefully adjusted to approximately 7-8 using NaOH and NaHCO3. The precipitate that formed was collected again by filtration; The free base compound was obtained by drying under vacuum, the yield was approximately 80% 85%.

Preparation of the hydrochloric acid salt of the title compound:

The above free base compound was suspended in methanol and water and treated with 6 N HCl (2.8 eq.). The solution became transparent. After removing the methanol in a rotary evaporator, the hydrochloric acid salt was obtained by lyophilization. It was further recrystallized from methanol (HPLC purity at 254 nm:> 99%).

Example 44

Preparation of 3- [2-butyl-1- (3-isopropylamino-propyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (47)

The title compound (47) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 98.2%; tR = 1.72 min. LC-MS (ESI) m / z: 359 ([MH] +). 1H-NMR (DMSOd6) ,95 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, sa).

Example 45 (Reference Example)

Preparation of 3- [1- (1-Benzyl-piperidin-4-yl) -2-butyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (48)

The title compound (48) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 96.7%, t R = 1.35 min. LC-MS m / z: 433 (lM + H] +). 1 H-NMR (DMSO-d6) ,9 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).

Example 46

Preparation of 3- [2-Butyl-1- (2-ethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (44)

The title compound (44) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 98%; LC-MS m / z: 331 ([M + H] +). 1H-NMR (DMSO-d6)  10.88 (sa, 1H), 9.12 (sa, 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 (similar at, 2H), 3.42 (sa, 2H), 3.08 (q, 2H, J = 7.7 Hz, Pr-CH2), 3.05 (sa, 2H), 1, 81 (m, 2H), 1.45 (m, 2H), 1.18 (t, 3H, J = 7.1 Hz), 0.95 (t, 3H, J = 7.0 Hz); 13C-NMR (DMSO-d6)  162.6, 156.2, 138.0, 135.0, 133.5, 131.6, 123.5, 119.2, 114.8, 112.1, 44 , 5, 42.4, 40.6, 28.2, 25.2, 21.7.13.5, 10.8.

Example 47

Preparation of 3- [2-but-3-enyl-1- (2-ethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (49)

The title compound (49) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC: 99.0%; tR = 1.61 min .; LC-MS m / z: 329 ([M + H] +). 1H-NMR (CD3OD)  7.85 (d, J = 8.5 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7, 38 (d, J = 15.7 Hz, 1H), 6.40 (d, J = 15.5 Hz, 1H), 6.02-5.92 (m, 1H), 5.19 (dd, J = 17.1, 1.3 Hz, 1H), 5.12 (dd, J = 10.2, 0.9 Hz, 1H), 4.80 (t, J = 6.4 Hz, 2H), 3 , 62 (t, J = 6.2 Hz, 2H), 3.22 3.16 (m, 2H), 2.71 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H); 13C-NMR (CD3OD)  178.3, 157.1, 140.7, 136.5, 133.9, 125.9, 118.8, 117.6, 116.2, 113.2, 101.5 , 67.6, 46.4, 44.9, 42.4, 31.6, 26.7, 20.7.11.4.

Example 48

Preparation of 3- [2-hexyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (50)

The title compound (50) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 94.4%, t R = 1.32 min. LC-MS (ESI) m / z: 373 ([M + H] +). 1HRMN (CD3OD)  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).

Example 49

Preparation of 3- [1- (2-dimethylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (51)

The title compound (51) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 100%, t R = 1.49 min. LC-MS m / z: 331 ([M + H] +). 1 H-NMR (DMSO-d6)  0.85 (9H, s), 1.03 (2H, d, J = 6.4 Hz), 1.34 (2H, m), 2.27 (1H, m ), 3.00 (6H, s), 3.24-3.27 (4H, m), 4.79 (3H, m), 6.53 (1H, d, J = 15.72 Hz), 7 , 62 (1H, d, J = 15.7 Hz), 7.75 (1H, d, J = 8.4 Hz), 7.86 (1H, s), 7.87 (1H, d, J = 8.4 Hz).

Example 50

Preparation of 3- [1- (2-ethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (52)

The title compound (52) was prepared according to the procedures described in example 1, using appropriate starting materials. Modified or detailed procedures were described as follows.

Stage 3:

To a stirred solution of 3- [4- (2-ethylamino-ethylamino) -3-nitro-phenyl] -acrylic acid methyl ester (8.174 g, 27.87 mmol) and heptaldehyde (4.85 g, 42.47) mmol, 1.52 eq.) in AcOH and MeOH (1: 9 v / v, 300 ml) SnCl2 · 2H2O (31.45 g, 139.4 mmol, 5 eq.) was added in portions. The resulting mixture was heated to 40 ° C with stirring. The progress of the reaction was monitored by LC / MS. When the reaction was completed, the solvent was removed under reduced pressure below 40 ° C. The resulting residue was diluted with EtOAc (50 ml) then basified (pH> 10) with saturated aqueous Na2CO3 and extracted with dichloromethane (x3). Filtration may be necessary to remove white precipitates or tin-derived suspension in order to obtain clearly separated phases. The organic extracts were combined, dried (Na2SO4), filtered and evaporated to dryness. The resulting oily residue was purified by flash column chromatography (silica, Ø67 x 65 mm, MeOH / DCM gradient of solvent from 0 to 10%). The 3- [1- (2-ethylamino-ethyl) -2-hexylH-benzoimidazol-5-yl] -acrylic acid methyl ester was obtained as a yellow solid (4,445 g, 44.6%). HPLC purity at 254 nm: 98.8%, t R = 1.71 min. LC-MS (ESI) m / z: 358 ([M + H] +). 1H-NMR (CDCl3) 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 (2H, t, J = 6.6 Hz), 3.80 (3H, s), 3.01 (2H, t, J = 6.6 Hz), 2.89 (2H, t, J = 7.9 Hz), 2, 65 (2H, q, J = 7.1 Hz), 1.91 (2H, whit, 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 can be recrystallized from hexanes-ether to give a pale yellow or white solid with purity by HPLC at 254 nm: 99.2%.

In another experiment starting with 2,725 g of 3- [4- (2-ethylamino-ethylamino) -3-nitro-phenyl] acrylic acid methyl ester, the title compound was obtained in 52.8% yield (1,753 g) .

Stage 4:

To a solution of 3- [1- (2-ethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] -acrylic acid methyl ester (4,428 g, 12.39 mmol) and NH2OH · HCl (8 , 66 g, 124.7 mmol) in dry MeOH (50 ml) which was stirred and cooled in a bath with carbonic snow-acetone, a solution of NaOMe in MeOH (25%, 4.37 M) was added. 55 ml, 240 mmol). The reaction mixture was then stirred at room temperature. The progress of the reaction was monitored by LC / MS (usually the reaction is completed within 30-90 min.) And quenched by the addition of 6 N HCl (40 ml). The mixture (HPLC purity at 254 nm = 94.6%) was added to Milli-Q water, the pH was adjusted to -8 by 1 N NaOH and evaporated to remove the organic solvent. The resulting residue was washed with Milli-Q water (x3) and redissolved in MeOH-DCM, the solution was filtered and diluted with Milli-Q water. The suspension was evaporated to remove the organic solvent and the resulting residue was washed with Milli-Q water (x2). The free base of the title compound was obtained (HPLC purity at 254 nm = 98%). The free base could be recrystallized from MeOH-ethyl acetate to give a pale yellow or white solid.

Stage 5: Hydrochloric acid salt formation.

The above free base was dissolved in MeOH and excess 6 N HCl (final pH <2) and the clear solution was evaporated to dryness and then diluted with MeOH, evaporated together with PhMe (x1) and EtOAc (x2). The solid was recrystallized from MeOH-EtOAc to give a pale yellow or white solid (3,298 g, 61.7%) Purity by PLC at 254 nm: 98.4-99.6%, t R = 1.23 min. LC-MS (ESI) m / z: 359 ([M + H] +). 1H-NMR (CD3OD)  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 COZY), 3.63 (2H, similar ata), 3.32 (2H, d, J = 7.9 Hz), 3.15 (2H, q, J = 7.1), 1.94 (2H, Pentete, J = 7.1), 1.53 (2H, Pentete, 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);

10 13C-NMR (CD3OD)  163.4, 155.8, 138.1, 133.0, 132.0, 130.3, 125.1, 117.4, 112.8, 112.5, 44, 5, 43.2, 41.1, 30.5, 28.0, 25.3, 25.2, 21.6, 12.4, 9.6, Anal. (C20H30N4O2 • 2HCl) Cl: calculated, 16.44; found, 16.00.

Example 51

Preparation of N-hydroxy-3- [1- (2-isopropylamino-ethyl) -2- (3,3,3-trifluoro-propyl) -1H-benzoimidazol-5-yl] -acrylamide (53)

The title compound (53) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC: 98.1%; tR = 0.63 min. LC-MS m / z: 385 ([M + H] +).

20 Example 52

Preparation of 3- [1- (2-dimethylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (54)

The title compound (54) was prepared according to the procedures described in example 1, using materials of

25 appropriate heading. HPLC purity at 254 nm: 99.9%, t R = 0.96 min. LC-MS (ESI) m / z 357 ([M + H] +). 1H-NMR (CD3OD)  7.87 (1H, d, J = 8.6 Hz), 7.80 (1H, d. J = 8.8 Hz), 7.72 (1H, d, J = 8 , 3 Hz), 7.49 (1H, d, J = 15.8 Hz), 6.44 (1H, d, J = 15.8 Hz), 5.44 (1H, m), 5.38 ( 1H, m), 4.84 (2H, t, J = 6.1 Hz), 3.61 (2H, t, J = 7.7 Hz), 3.20 (2H, t, J = 4.2 Hz) 2.97 (6H, s), 2.61 (4H, qt, J = 7.1 Hz), 1.93 (2H, qn, J = 7.7 Hz), 0.78 (3H, t , J = 7.5 Hz); 13C-NMR (CD3OD)  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,

30 38.8, 24.8, 23.3, 19.4, 12.4.

Example 53

Preparation of 3- [1- (2-amino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (55) 35

image 1

Stage 1:

To a stirred solution of 3- [4- (2-tert-butoxycarbanylamino-ethylamino) -3-nitrophenyl] -acrylic acid (IIIa1, 65.2 mg, 0.178 mmol) and 3,5,5-trimethylhexanal acid methyl ester (45 µL, 0.26 mmol) in a mixed solvent of AcOH-MeOH (1: 9 v / v, 2 ml) and DCM (1 ml) SnCl2 2H2O (184 mg, 0.815 mmol) was added. The resulting mixture was heated to 40 ° C with stirring overnight. The solvent was removed under reduced pressure and the resulting residue was added to saturated aqueous Na2CO3 and extracted with EtOAc (x3). The extracts gave the gross product

45 (VIa1-1, 91 mg) with HPLC purity at 254 nm: 49.3%, t R = 3.02 min. and 7.9%, t R = 1.97 min. (product des-Boc). LC-MS (ESI) m / z: 458 ([M + H] +) and 358 ([M + H] +, product des-Boc).

Stage 2:

The above crude product (VIa1-1) was dissolved in MeOH (4 ml) and 6 N HCl (1 ml) and heated at 70 ° C for 30 min. The solution was evaporated to dryness and evaporated together with PhMe (x2) and MeOH (x1). The residue (crude product VIa-1, 81.9 mg) was divided into two parts (43.4 mg, equal to 0.0945 mmol of IIIa1, and 38.5 mg equal to 0.0839 mmol of IIIa1).

Stage 3:

The title compound (55) was prepared according to step 4 described in example 1, using crude product (VIa-1, 38.5 mg). VIIa-1 was obtained as TFA salt (2.3 mg, 4.7% of IIIa1). HPLC purity at 254 nm: 92.7%, t R = 1.46 min. LC-MS (ESI) m / z: 359 ([M + H] +). 1H-NMR (CD3OD)  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, ad, 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, sa om), 1.33 (1H, dd, J = 14.1, 3.4 Hz), 1.25 (1H, dd, J = 14.0, 6.6 Hz ), 0.98 (3H, d, J = 6.2 Hz), 0.83 (9H, s).

Example 54

Preparation of 3- [1- (2-amino-ethyl) -2- (2-methoxy-nonyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (56)

The title compound (56) was prepared according to the procedures described in example 53, using appropriate starting materials. HPLC purity at 254 nm: 91.8%, t R = 1.93 min. LC-MS (ESI) m / z: 403 ([M + H] +). 1HRMN (CD3OD)  some peaks identified: 7.81 (1H, s), 7.70 ~ 7.58 (3H, m), 6.46 (1H, ad, J = 14.4 Hz), 4.62 (2H, m), 3.69 (1H, saom), 3.38 (2H, t, J = 7.3 Hz), 1.67 (1H, m), 1.58 (1H, m), 1 , 50-1.20 (10H, m), 0.82 (3H, t, J = 6.2 Hz).

Example 55

Preparation of 3- [2-Butyl-1- (2-dimethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (57)

The title compound (57) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 100%, t R = 0.42 min. LC-MS m / z: 331 ([M + H] +). 1 H-NMR (DMSO-d6) ,9 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, sa).

Example 56

Preparation of 3- [2-hexyl-1- (2-dimethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (58)

The title compound (58) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 100%, t R = 0.42 min. LC-MS m / z: 359 ([M + H] +). 1 H-NMR (DMSO-d6)  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, sa).

Example 57

Preparation of 3- {1- (2-diethylamino-ethyl) -2- [2- (2,2-dimethyl-propionylamino) -ethyl] -1H-benzoimidazol-5-yl} -N-hydroxyacrylamide (61)

The title compound (61) was prepared according to the procedures described below, steps 1 and 2 were performed as in Scheme I:

Stage 3:

image 1

5 To a previously stirred solution of 3- [4- (2-diethylamino-ethylamino) -3-nitro-phenyl] -acrylic acid methyl ester (61-1, 280 mg, 1.0 mmol) in glacial acetic acid ( 5 ml), tin chloride (1.18 g, 10.0 mmol) was added. The resulting solution was heated to 45 ° C for 17 hours and then cooled to room temperature. The solvent was removed in vacuo. Water (20 ml) and dichloromethane (20 ml) were added to the residue and stirred for 30 minutes. The organic phase was dried (MgSO4), filtered and concentrated to give an oily residue. 100 were added

10 ml of diethyl ether and stirred for 4 hours. The 3- [3-amino-4- (2-diethylamino-ethylamino) -phenyl] -acrylic acid methyl ester product was obtained in a yield of 54.9% (207.6 mg). LC-MS m / z: 292 ([M + H] +).

Stage 4

image4

To a previously stirred solution of 3- [3-amino-4- (2-diethylamino-ethylamino) -phenyl] -acrylic acid methyl ester (61-2, 1.93 g, 6.65 mmol) and dichloromethane (13 , 3 ml) was added a cocktail solution of N- (3dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (2.55 g, 13.31 mmol), 1-hydroxybenzotriazole hydrate (2.04 g, 13.31 20 mmol), N, N-diisopropylethylamine (2.20 ml, 13.31 mmol) and dichloromethane (26.6 ml). After stirring for 0.5 h, Fmoc-Gly-OH (61-3, 2.97 g, 9.98 mmol) was added. When the starting material has reacted completely, ethyl acetate (100 ml) was added to dilute the mixture. The organic contents were washed with saturated sodium hydrogen carbonate (2 x 25 ml) and brine (2 x 25 ml), before drying in sodium sulfate. The mixture was then filtered and concentrated in vacuo. The product 3- [3-amino-4- (2-diethylamino-ethylamino) -phenyl] methyl ester product was obtained

25 acrylic with a yield of 67.3% (2.54 g). LC-MS m / z: 571 ([M + H] +).

Stage 5

image 1

Glacial acetic acid (8.9 ml) was added to 3- [3-amino-4- (2-diethylamino-ethylamino) -phenyl] -acrylic acid methyl ester (61-4, 2.54 g, 4.46 mmol) and the reaction mixture was stirred at 70 ° C for 14 h. When the reaction is complete, the mixture was concentrated in vacuo. Saturated sodium hydrogen carbonate (20 ml) was added and dichloromethane (3 x 20 ml) was used to extract the aqueous phase. The combined organic contents were dried over sodium sulfate before filtering and concentrated in vacuo. The product 3- {1- (2-dethylaminoethyl) -2 - [(9H-fluoren-9-ylmethoxycarbonylamino) -methyl] -1H-benzoimidazol-5-yl} -acrylic acid (61-5) was obtained with 66.1% (1.62 g). LCMS m / z: 553 ([M + H] +).

Stage 6

image 1

10 To a previously stirred solution of 3- {1- (2-dethylamino-ethyl) -2 - [(9-fluoren-9ylmethoxycarbonylamino) -methyl] -1H-benzoimidazol-5-yl} -acrylic acid methyl ester (61 -5, 1.62 g, 2.94 mmol) and dichloromethane (8.90 ml), piperidine (1.45 ml, 14.69 mmol) was added. When the reaction is complete, the mixture was concentrated in vacuo. The desired product was separated by preparative reverse phase HPLC. After lyophilization, 0.52 g was obtained.

15 (53.6%) of 3- [2-aminomethyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -acrylic acid methyl ester as powder. LC-MS m / z: 331 ([M + H] +).

Stage 7

image5

To a previously stirred solution of 3- [2-aminomethyl-1- (2-diethylamino-ethyl) -1Hbenzoimidazol-5-yl] -acrylic acid methyl ester (61-6, 0.10 g, 0.23 mmol) , N, N-diisopropylethylamine (97 µL, 0.58 mmol) and dichloromethane (1.17 mL), 2,2-dimethyl-propionyl chloride (34.6 µL, 0.28 mmol) was added and stirred the mixture of

25 resulting reaction at room temperature for 1 h. When the reaction is complete, ethyl acetate (20 ml) was added to dilute the mixture. The organic contents were washed with saturated sodium hydrogen carbonate (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-diethylaminoethyl) -2 - [(2,2-dimethylpropionylamino) -methyl] -1 H -benzoimidazol-5-yl} acrylic acid (61-7) in 76, was obtained 6% (74.1 mg). LC-MS m / z: 415 ([M + H] +).

Stage 8

image 1

To a stirred solution of 3- {1- (2-diethylamino-ethyl) -2 - [(2,2-dimethyl-propionylamino) -methyl] -1Hbenzoimidazol-5-yl} -acrylic acid methyl ester (61-7 , 73.8 mg, 0.18 mmol) and hydroxylamine hydrochloride (124 mg, 1.78 mmol) in MeOH (0.3 ml) sodium methoxide (30% in methanol) was added (0.8 ml , 3.6 mmol) at -78 ° C. The reaction mixture was then allowed to warm slowly to room temperature. The reaction was monitored by LC / MS and completed in approximately 15 min. Then 1N HCl was added slowly to the reaction mixture at 0 ° C. The desired product was separated by preparative reverse phase HPLC. After lyophilization, 22.2 mg (24.3%) of 3- {1- (2-diethylamino-ethyl) -2 - [(2,2-dimethyl-propionylamino) -methyl] -1H-benzoimidazole- 5-yl} -N-hydroxyacrylamide as a powder. HPLC purity: 99.5%, t R = 0.94 min. LC-MS m / z: 416 ([M + H] +). 1H-NMR (CD3OD) 9 7.89 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7, 55 (d, J = 15.8 Hz, 1H), 6.53 (d, J = 15.8 Hz, 1H), 4.98 (t, J = 7.3 Hz, 2H), 4.73 ( s, 2H), 3.75 (t, J = 7.5 Hz, 2H), 3.42 (q, J = 7.2 Hz, 4H), 1.37 (t, J = 7.3 Hz, 6H), 1.22 (s, 9H); 13C-NMR (CD3OD)  182.5, 168.9, 162.2, 161.9, 154.8, 140.8, 137.9, 135.0, 133.9, 126.0, 119.3 , 117.1, 112.9, 50.9, 40.5, 39.7, 36.7, 27.6, 9.1.

Example 58

Preparation of N- {2- [1- (2-diethylamino-ethyl) -5- (2-hydroxycarbamoyl-vinyl) -1H-benzoimidazol-2-yl] -ethyl} -3,3-dimethylbutylamide (59)

The title compound (59) was prepared according to the procedures described in example 57, using appropriate starting materials. HPLC purity at 254 nm: 94.0%; tR = 0.99 min. LC-MS m / z: 444 ([M + H] +).

Example 59

Preparation of N- [1- (2-diethylamino-ethyl) -5- (2-hydroxycarbamoyl-vinyl) -1H-benzoimidazol-2-ylmethyl] -butylamide (62)

The title compound (62) was prepared according to the procedures described in example 57, using appropriate starting materials. HPLC purity at 254 nm: 85.1%; tR = 0.58 min .; LC-MS m / z: 402 ([M + H] +). 1H-NMR (CD3OD)  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 (CD3OD)  117.1, 165.9, 154.6, 140.9, 129.6, 128.4, 127.3, 125.9, 118.6, 112.8, 111.5 , 50.7, 40.4, 38.4, 36.4, 19.9, 14.0, 9.0.

Example 60

Preparation of 3- [2- (3,3-dimethyl-butyl) -1- (2-ethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (63)

The title compound (63) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC: 99.0%; tR = 0.93 min .; LC-MS m / z: 359 ([M + H] +). 1H-NMR (CD3OD)  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 (sa, 2H), 3.72 (sa, 2H), 3.29-3.18 (m, 4H), 1 , 90-1.86 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.09 (s, 9H); 13C-NMR (CD3OD)  165.7, 158.4, 140.4, 134.9, 134.5, 134.2, 126.2, 122.5, 119.2, 115.6, 113.4 , 55.3, 44.0, 40.8, 40.7, 31.3, 29.3, 22.9.

Example 61

Preparation of 3- [1- (2-dimethylamino-ethyl) -2- (3,3-dimethyl-butyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (64)

The title compound (64) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC: 99.0%; tR = 0.83 min .; LC-MS m / z: 359 ([M + H] +). 1H-NMR (CD3OD)  7.94 (d, J = 7.8 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7, 42 (d, J = 15.7 Hz, 1H), 6.64 (d, J = 15.7 Hz, 1H), 4.93 (sa, 2H), 3.76 (sa, 2H), 3, 22 (t, J = 7.7 Hz, 2H), 3.09 (s, 6H), 1.91-1.87 (m, 2H), 1.08 (s, 9H); 13C-NMR (CD3OD)  165.4, 158.4, 140.2, 134.5, 134.2, 133.2, 126.5, 118.8, 115.3, 113.9, 46.4 , 45.1, 42.9, 40.6, 31.3, 29.2, 22.9, 11.4.

Example 62

Preparation of 3- [1- (2-dimethylamino-ethyl) -2-pentyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (65)

The title compound (65) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 98.5%; tR = 0.78 min. LC-MS m / z: 345 ([M + H] +). 1H-NMR (DMSO-d6)  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, sa).

Example 63

Preparation of 3- [1- (2-dimethylamino-ethyl) -2- (2,2,2-trifluoro-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (64)

The title compound (64) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 91.1%; tR = 0.68 min. LC-MS m / z: 357 ([M + H] +).

Example 64

Preparation of 3- [1- (2-ethylamino-ethyl) -2-pentyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (68)

The title compound (68) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 98.4%; tR = 0.87 min. LC-MS m / z: 345 ([M + H] +).

Example 65

Preparation of N-hydroxy-3- [1- (2-isopropylamino-ethyl) -2-pentyl-1H-benzoimidazol-5-yl] -acrylamide (71)

The title compound (71) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 97.4%; tR = 0.95 min. LC-MS m / z: 359 ([M + H] +). 1H-NMR (DMSO-d6)  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, sa).

Example 66

Preparation of 3- [2-hexyl-1- (2-methylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (74)

The title compound (74) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 96.0%, t R = 1.12 min. LC-MS m / z: 345 ([M + H] +). 1H-NMR (CD3OD) ,7 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, sa), 3.15 (2H, dt, J = 4.8 Hz), 2.71 (3H, s), 1.85 (2H, qn, J = 5.1 Hz), 1, 46 (2H, m), 1.33 (4H, m), 0.85 (3H, t, J = 7.1 Hz); 13C-NMR (CD3OD)  163.7, 157.8, 138.5, 132.7, 124.2, 117.6, 113.7, 111.2, 40.2, 32.2, 30.5 , 28.0, 25.6, 25.1, 21.6, 12.3.

Example 67

Preparation of N-hydroxy-3- [1- (2-methylamino-ethyl) -2-pentyl-1H-benzoimidazol-5-yl] -acrylamide (75)

The title compound (75) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity at 254 nm: 97.8%; tR = 0.80 min. LC-MS m / z: 331 ([M + H] +). 1HRMN (DMSO-d6)  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).

Preparation of 3- (2-Butyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl) -N-hydroxy-acrylamide (69)

image7

Stage 1

To a solution of methyl trans-4-chloro-3-nitrocinamate (Ia, 4.8 g, 20 mmol) in triethylamine (5.5 ml, 40 mmol)

10 3-amino-pyrrolidin-1-carboxylic acid tert-butyl ester (11.2 g, 60 mmol) was added, then the resulting mixture was heated to 100 ° C for 8 hours, then another portion of trans-4 was added -methylchloro-3-nitrocinamate (4.8 g, 20 mmol) and triethylamine (5.5 ml, 40 mmol), the resulting mixture was allowed to stir overnight at 100 ° C, then the reaction was quenched by the addition of 200 ml of DCM and 80 ml of a solution of HCl 1

M. After separation of the DCM phase, the aqueous solution was extracted with DCM once more, and combined with

The previous DCM solution, which was then washed with brine, dried over sodium sulfate, then filtered through a short silica gel column, and rinsed with a mixture of ethyl acetate and hexanes (2: 1) until the orange band had cleared completely. After removal of the solvent under reduced pressure, residue 69-2 (approximately 80% yield in most cases) was obtained as an orange solid, which is pure enough (95% purity by HPLC) for the following stage. LC-MS m / z: 292 ([M-Boc + H] +).

20 Stage 2

To a solution of compound 69-2 (7.84 g, 20.0 mmol) in 100 ml of a mixture of MeOH and AcOH (1: 9) was added the corresponding aldehyde (3.0 ml, 30.0 mmol) and tin chloride (22.6 g, 100 mmol), the

25 resulting mixture at 42 ° C for 24 h. The mixture was then diluted using ethyl acetate (300 ml) at room temperature, and then quenched with sat. Sodium carbonate. (30 ml). The resulting mixture was stirred for an additional 1 hour, then the organic phase was decanted into another conical flask. The remaining solid in the reaction flask was suspended with another portion of ethyl acetate (300 ml), which was then decanted and combined with an earlier portion of ethyl acetate and then filtered through a short gel column. silica and cleared with

Ethyl acetate, after removal of the filtrate under reduced pressure, the residue was pure enough for the next step and can also be purified on a column (hexanes: EtOAc = 1: 2) to give a pale yellow solid 693 (3.8 g, 44%). LC-MS m / z: 456 ([M + H] +).

Stage 3

To a flask charged with compound 69-3 (456 mg, 1 mmol), 1.25 M HCl in MeOH (4 mL) was added, then the resulting mixture was heated at reflux for 2 hours, which was then evaporated to dryness under reduced pressure giving compound 4 as HCl salt, which is quite pure for the next step without any purification. LCMS m / z: 356 ([M + H] +).

40 Stage 4

To a solution of the above crude product 69-4 (approximately 0.16 mmol) in MeOH (0.5 ml) was added a stock solution of previously prepared NH2OH (2.0 M, 2 ml). The resulting mixture was stirred at temperature

45 room for 2 h. After extinction with TFA (0.4 ml), the resulting mixture was subjected to purification by HPLC yielding 25 mg of 3- (2-butyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl) -N -hydroxy-acrylamide. HPLC purity: 98%; LC-MS m / z: 329 ([M + H] +). 1H-NMR (CD3OD) ,95 0.95 (3H, t, J = 7.2 Hz), 1.46 (2H, m), 1.77 (2H, m), 2.52-2.82 (2H , m), 3.10-3.17 (2H, m), 3.48 (1H, m), 3.80 (2H, m), 5.55 (1H, m), 6.48 (1H, d, J = 16.0 Hz), 7.58 (1H, d, J = 16.0 Hz), 7.67 (1H, d, J = 8.0 Hz), 7.78-7.92 ( 2H, m).

Example 69 (Reference example)

Preparation of 3- (2-Butyl-1-piperidin-4-yl-1H-benzoimidazol-5-yl) -N-hydroxy-acrylamide (70)

The title compound (70) was prepared according to the procedures described in example 78, using appropriate starting materials. HPLC purity: 98%; LC-MS m / z: 343 ([M + H] +). 1H-NMR (CD3OD) ,9 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), 4.98 (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 = 8.0Hz).

Example 70 (Reference example)

Preparation of 3- (2-hexyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl) -N-hydroxy-acrylamide (80)

The title compound (80) was prepared according to the procedures described in example 68, using appropriate starting materials. HPLC purity: 98%; LC-MS m / z: 357 ([M + H] +). 1H-NMR (CD3OD) 8 0.84 (3H, t, J = 7.2 Hz), 1.22-1.38 (4H, m), 1.44 (2H, m), 1.81 (2H , m), 2.52-2.82 (2H, m), 3.10-3.17 (2H, m), 3.48 (1H, m), 3.80 (2H, m), 5, 56 (1H, m), 6.48 (1H, d, J = 15.8 Hz), 7.56 (1H, d, J = 15.8 Hz), 7.65 (1H, d, J = 9 , 2 Hz), 7.84 (1H, s), 7.90 (1H, d, J = 9.2 Hz).

Example 71 (Reference example)

Preparation of 3- [2-Butyl-1- (1-methyl-pyrrolidin-3-yl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (81)

The title compound (81) was prepared according to the procedures described in example 68, using 69-4 through reductive amination to introduce a methyl group. HPLC purity: 98%; LC-MS m / z: 343 ([M + H] +) 1 H-NMR (CD3OD)  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, a .), 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 (Reference Example)

Preparation of 3- (2-hexyl-1-piperidin-3-yl-1H-benzoimidazol-5-yl) -N-hydroxy-acrylamide (82)

The title compound (82) was prepared according to the procedures described in example 68, using appropriate starting materials. HPLC purity: 97%; LC-MS m / z: 343 ([M + H] +). 1H-NMR (CD3OD) ,99 0.99 (3H, t, J = 7.2 Hz), 1.52 (2H, m), 1.84 (2H, m), 2.04 (1H, m), 2.20 (2H, m), 2.61 (1H, m), 3.12-3.22 (2H, m), 3.49 (1H, m), 3.67 (1H, m), 3 , 78 (1H, t, J = 12.0 Hz), 4.98 (1H, m), 6.53 (1H, d, J = 15.8 Hz), 7.63 (1H, d, J = 15.8 Hz), 7.70 (1H, d, J = 9.2 Hz), 7.86 (1H, s), 8.06 (1H, d, J = 8.8 Hz).

Example 73 (Reference Example)

Preparation of 3- (2-Butyl-1-piperidin-3-yl-1H-benzoimidazol-5-yl) -N-hydroxy-acrylamide (83)

The title compound (83) was prepared according to the procedures described in example 68, using appropriate starting materials. HPLC purity: 97%; LC-MS m / z: 371 ([M + H] +). 1H-NMR (CD3OD)  0.88 (3H, t, J = 7.2 Hz), 1.22-1.42 (4H, m), 1.47 (2H, m), 1.84 (2H , m), 2.04 (1H, m), 2.20 (2H, m), 2.62 (1H, m), 3.12-3.22 (2H, m), 3.48 (1H, m), 3.68 (1H, m), 3.78 (1H, t, J = 12.0 Hz), 5.01 (1H, m), 6.53 (1H, d, J = 15.8 Hz), 7.62 (1H, d, J = 15.8 Hz), 7.70 (1H, d, J = 9.2 Hz), 7.86 (1H, s), 8.06 (1H, d, J = 8.8 Hz).

Example 74 (Reference example)

Preparation of (E) -N-hydroxy-3- (1- (1-methylpiperidin-3-yl) -2-pentyl-1 H -benzo [d] imidazol-5-yl) acrylamide (86)

The title compound (86) was prepared according to the procedures described in example 71, using appropriate starting materials. HPLC purity: 99.3%, t R = 1.06 min .; LC-MS m / z: 371 ([M + H] +). 1H-NMR (CD3OD) ,1 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 (sa, 1H), 3.69 (sa, 2H), 3, 69-3.66 (m, 1H), 3.37-2.27 (masked peaks), 3.03 (s, 3H), 2.66 (sa, 1H), 2.29 2.22 (m, 3H), 1.94-1.90 (m, 2H), 1.54-0.94 (m, 4H), 0.96 (t, J = 7.1 Hz, 3H); 13C-NMR (CD3OD)  165.6, 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 (Reference Example)

Preparation of (E) -3- (2-hexyl-1- (1- (2-hydroxyethyl) piperidin-3-yl) -1 H -benzo [d] imidazol-5-yl) -N-hydroxyacrylamide (90)

The title compound (90) was prepared according to the procedures described in example 68, using appropriate starting materials and alkylation of piperidine with 2-bromoethanol. LC-MS m / z: 415 ([M + H] +).

Example 76 (Reference example)

Preparation of N-hydroxy-3- [1- (1-pentyl-piperidin-3-yl) -1H-benzoimidazol-5-yl] -acrylamide (94)

The title compound (94) was prepared according to the procedures described in Example 68, using appropriate starting materials (formic acid for the formation of the benzimidazole ring and reductive amination of piperidine with pentanal). HPLC purity: 95%; LC-MS m / z: 357 ([M + H] +). 1H-NMR (CD3OD) ,0 9.04 (s, 1H), 7.94 (sa, 2H), 7.78 (d, 1H, J = 8.2 Hz), 7.70 (d, 1H, J = 15.7 Hz), 6.57 (d, 1H, J = 15.9 Hz), 5.14-5.10 (m, 1H), 3.85 (dd, 2H, J = 88.0, 9.0 Hz), 3.48 - 3.13 (m, 4H), 2.43 - 2.12 (m, 4H), 1.94 -1.80 (m, 2H), 1.39 -1 , 29 (m, 4H), 0.94 (t, 3H, J = 6.8 Hz).

Example 77 (Reference example)

Preparation of N-hydroxy-3- [1- (1-phenethyl-piperidin-3-yl) -1H-benzoimidazol-5-yl] -acrylamide (96)

The title compound (96) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 98.6%; LC-MS m / z: 391 ([M + H] +). 1H-NMR (CD3OD)  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 (Reference example)

Preparation of N-hydroxy-3- {1- [1- (3-phenyl-propyl) -piperidin-3-yl] -1 H -benzoimidazol-5-yl} -acrylamide (97)

The title compound (97) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 94.5%; LC-MS: 405 ([M + H] +) 1H-NMR (CD3OD) 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 (Reference Example)

Preparation of 3- {1- [1- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (99)

The title compound (99) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 91.9%; tR = 1.10 min. LC-MS m / z: 357 ([MH] +). 1H-NMR (DMSO-d6) ,9 0.91 (9H, s), 1.52 (4H, m), 3.09 (1H, m), 3.29 (6H, m), 6.52 (1H , d), 7.43 (2H, m), 7.62 (1H, m), 7.80 (1H, m), 8.82 (1H, s), 10.25 (1H, sa).

Example 80 (Reference example)

Preparation of 3- {1- [2- (ethyl-methyl-amino) -ethyl] -2-pentyl-1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (79)

The title compound (79) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity: 99%; tR = 0.68 min. LC-MS m / z: 359 ([M + H] +). 1H-NMR (DMSO-d6)  0.89 (3H, m), 1.23 (3H, m), 1.38 (4H, m), 1.84 (2H, m), 2.92 (3H , s), 3.10 (2H, m), 3.28 (2H, m), 3.52 (2H, m), 4.77 (2H, m), 6.58 (1H, d), 7 , 61 (1H, d), 7.71 (1H, m), 7.92 (2H, m), 10.48 (1H, sa).

Example 81

Preparation of 3- {2-butyl-1- [2- (ethyl-methyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (85)

The title compound (85) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity: 95.8%; tR = 1.04 min. LC-MS m / z: 345 ([M + H] +). 1 H-NMR (DMSO-d6) ,95 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, sa).

Example 82

Preparation of 3- (2-Butyl-1- {2- [ethyl- (3-hydroxy-propyl) -amino] -ethyl} -1H-benzoimidazol-5-yl) N-hydroxy-acrylamide (91)

The title compound (91) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity: 93.5%; tR = 0.50 min. LC-MS (m / z): 389 ([MH] +). 1 H-NMR (DMSO-d6) ,9 0.94 (3H, m), 1.25 (3H, m), 1.46 (2H, m), 1.83 (4H, m), 3.04 (2H , m), 3.31 (4H, m), 3.50 (4H, m), 4.72 (2H, m), 6.54 (1H, d), 7.61 (1H, m), 7 , 69 (1H, m), 7.80 (1H, m), 7.90 (1H, m), 10.20 (1H, sa).

Example 83

Preparation of 3- (1- {2- [ethyl- (3-hydroxy-propyl) -amino] -ethyl} -2-pentyl-1 H -benzoimidazol-5-yl) -N-hydroxyacrylamide (92)

The title compound (92) was prepared according to the procedures described in example 1, using appropriate starting materials. HPLC purity: 93.5%; tR = 0.50 min. LC-MS (m / z): 389 ([M + H] +) 1 H-NMR (DMSO-d6) ,9 0.94 (3H, m), 1.25 (3H, m), 1.46 (2H , m), 1.83 (4H, m), 3.04 (2H, m), 3.31 (4H, m), 3.50 (4H, m), 4.72 (2H, m), 6 , 54 (1H, d), 7.61 (1H, m), 7.69 (1H, m), 7.80 (1H, m), 7.90 (1H, m), 10.20 (1H, sa).

Example 84 (Reference example)

Preparation of 3- {1- [2- (butyl-ethyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (95)

The title compound (95) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 99.9%; LC-MS m / z: 331 ([M + H] +). 1H-NMR (CD3OD)  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), 3.28-2.26 (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-yl] -N-hydroxy-acrylamide (101)

The title compound (101) was prepared according to the procedures described in example 57, using appropriate starting materials. HPLC purity at 254 nm: 99.9%. LC-MS (ESI) m / z: 384 ([M + H] +). 1H-NMR (CD3OD) ,7 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, at 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 (Reference Example)

Preparation of 3- {1- [2- (butyl-isopropyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (108)

The title compound (108) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 98.8%; tR = 1.33 min. LC-MS m / z: 345 ([M + H] +). 1H-NMR (DMSO-d6) ,90 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, sa), 10.72 (1H, sa).

Example 87 (Reference Example)

Preparation of N-hydroxy-3- {1- [2- (isopropyl-pentyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -acrylamide (109)

The title compound (109) was prepared according to the procedures described in example 76, using appropriate starting materials. LC-MS m / z: 359 ([M + H] +). 1H-NMR (DMSO-d6)  0.88 (3H, t), 1.25 (10H, m), 1.64 (2H, m), 3.12 (2H, m), 3.51 (1H , a), 3.60 (1H, a), 3.73 (1H, a), 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, a).

Example 88

Preparation of 3- [2- (5-cyano-pentyl) -1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (110)

The title compound (110) was prepared according to the procedures described in example 57, using appropriate starting materials. HPLC purity at 254 nm: 95.4%. LC-MS (ESI) m / z: 347 ([M + H] +). 1H-NMR (CD3OD)  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, included in the MeOD peak), 2.51 (2H, t, J = 6.9Hz), 2.05-1.98 (2H, m), 1.78 (2H, m, J = 7.4 Hz), 1.70 (2H, m, J = 6.4 Hz), 1.41 (3H, t, J = 7, 2 Hz)

Example 89 (Reference example)

Preparation of 3- (1- {2 - [(3,3-dimethyl-butyl) -ethyl-amino] -ethyl} -1H-benzoimidazol-5-yl) -N-hydroxy-acrylamide (111)

The title compound (111) was prepared according to the procedures described in example 76, using appropriate starting materials. Get out of TFA. HPLC purity: 97.7%; LC-MS m / z: 359 ([M + H] +). 1H-NMR (CD3OD)  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).

HCl salt 1H-NMR (DMSO-d6) ,90 9.90 (sa, 1H), 8.65 (s, 1H), 7.93 (s, 1H), 7.82 (d, 1H, J = 8.5 Hz ), 7.64 (d, 1H, J = 8.1 Hz), 7.61 (d, 1H, J = 15.6 Hz), 7.52 (d, 1H, J = 15.8 Hz), 4.76-4.72 (t, 2H, J = 7.0), 3.65-3.60 (m, 2H), 3.32 3.24 (m, 2H), 3.17-3, 08 (m, 2H), 1.52 -1.47 (m, 2H), 1.22 (t, 3H, J = 7.2 Hz), 0.87 (s, 9Hz).

Example 90 (Reference Example)

Preparation of 3- {1- [2- (ethyl-propyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (112)

The title compound (112) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 98.1%; LC-MS m / z: 315 ([M + H] +). 1H-NMR (CD3OD)  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 (Reference Example)

Preparation of N-hydroxy-3- (1- {2- [isopropyl- (2-methyl-pentyl) -amino] -ethyl} -1H-benzoimidazol-5-yl) -acrylamide (113)

The title compound (113) was prepared according to the procedures described in example 76, using appropriate starting materials. LC-MS m / z: 373 [(M + H) +]]. 1H-NMR (DMSO-d6)  0.86-0.97 (7H, m), 1.14-1.28 (12H, m), 4.70 (2H, a), 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- {1- [2- (ethyl-hexyl-amino) -ethyl] -2-methyl-1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (116)

The title compound (116) was prepared according to the procedures described in example 57, using appropriate starting materials. HPLC purity at 254 nm: 98.2%, t R = 1.27 min. LC-MS (ESI) m / z: 373 ([M + H] +). 1HRMN (CD3OD) 5 7.85 (1H, s), 7.78 (1H, d, J = 8.4 Hz), 7.70 (1H, d, J = 8.7 Hz), 7.15 ( 1H, d. J = 15.9 Hz), 6.53 (1H, d, J = 15.9 Hz), 4.81 (2H), 3.63 (2H, t, J = 7.7 Hz) , 3.41 (2H, qt, J = 7.2 Hz), 3.29 (2H), 2.82 (3H, s), 1.74 (2H, m), 1.37 (11H, m) , 0.93 (3H, t, J = 6.9 Hz).

Example 93

Preparation of 3- {1- [2- (butyl-ethyl-amino) -ethyl] -2-trifluoromethyl-1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (117)

The title compound (117) was prepared according to the procedures described in example 57, using appropriate starting materials. HPLC purity at 254 nm: 97.3%, t R = 1.50 min. LC-MS (ESI) m / z: 399 ([M + H] +). 1HRMN (CD3OD)  7.95 (1H, s), 7.70 (2H, s), 7.62 (1H, d, J = 15.9 Hz), 6.46 (1H, d, J = 15 , 8 Hz), 5.24 (2H), 3.50 (2H, t, J = 8.8 Hz), 3.31 (2H, qt, J = 7.2 Hz), 3.17 (2H) , 1.63 (2H, m), 1.35 (2H, qt, J = 7.5 Hz), 1.29 (3H, t, J = 7.2 Hz), 0.92 (3H, t, J = 7.4 Hz).

Example 94

Preparation of 3- {1- [2- (ethyl-hexyl-amino) -ethyl] -2-trifluoromethyl-1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (118)

The title compound (118) was prepared according to the procedures described in example 57, using appropriate starting materials. HPLC purity at 254 nm: 94.6%. tR = 2.07 min. LC-MS (ESI) m / z: 427 ([M + H] +). 1HRMN (CD3OD) ,0 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 (Reference Example)

Preparation of 3- [1- (2-dipropylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (120)

The title compound (120) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 100%. LC-MS m / z: 331 ([M + H) +]. 1H-NMR (DMSO-d6)  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, sa).

Example 96 (Reference Example)

Preparation of N-hydroxy-3- (1- {2- [isopropyl- (3-methyl-butyl) -amino] -ethyl} -1H-benzoimidazol-5-yl) -acrylamide (121)

The title compound (121) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 98.7%; tR = 1.02 min. LC-MS (m / z): 358 ([M + H] +). 1H-NMR (DMSO-d6)  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, sa), 10.70 (1H, sa).

Example 97 (Reference Example)

Preparation of 3- (1- {2 - [(3,3-dimethyl-butyl) -methyl-amino] -ethyl} -1H-benzoimidazol-5-yl) -N-hydroxy-acrylamide (122)

The title compound (122) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity at 254 nm: 97.8%; tR = 0.93 min. LC-MS m / z: 345 ([M + H] +). 1H-NMR (DMSOd6)  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, sa).

Example 98 (Reference Example)

Preparation of 3- (1- {2 - [(2-ethyl-butyl) -methyl-amino] -ethyl} -1H-benzoimidazol-5-yl) -N-hydroxy-acrylamide (123)

The title compound (123) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity at 254 nm: 97.7%; tR = 0.87 min. LC-MS m / z: 345 ([M + H] +). 1H-NMR (DMSOd6)  0.81 (6H, m), 1.29 (4H, m), 1.69 (1H, m), 2.89 (3H, s), 3.08 (2H, m ), 3.59 (2H, m), 4.77 (2H, m), 6.53 (1H, d), 7.52 (2H, m), 7.86 (1H, m), 7.94 (1H, m), 8.80 (1H, m), 9.54 (1H, sa).

Example 99 (Reference Example)

Preparation of 3- {1- [2- (3,3-Dimethyl-butylamino) -ethyl] -1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (126)

The title compound (126) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 100%; tR = 1.01 min. LC-MS m / z: 331 ([M + H] +). 1 H-NMR (DMSO-d6)  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 (Reference Example)

Preparation of N-hydroxy-3- {1- [2- (methyl-pent-4-enyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -acrylamide (127)

The title compound (127) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 100%; tR = 0.92 min. LC-MS m / z: 329 ([M + H] +). 1 H-NMR (DMSO-d6)  1.17 (2H, m), 2.06 (2H, m), 2.90 (3H, s), 3.10 (2H, m), 3.65 (2H , m), 4.80 (2H, m), 5.03 (2H, m), 5.75 (1H, m), 6.57 (1H, d), 7.60 (1H, d), 7 , 69 (1H, m), 7.90 (1H, m), 7.97 (1H, m), 8.92 (1H, m), 10.29 (1H, sa).

Example 101 (Reference Example)

Preparation of 3- (1- {2 - [(3,3-dimethyl-butyl) -propyl-amino] -ethyl} -1H-benzoimidazol-5-yl) -N-hydroxy-acrylamide (128)

The title compound (128) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 99.0%; tR = 1.18 min. LC-MS m / z: 373 ([M + H] +). 1 H-NMR (DMSO-d6)  0.88 (12H, m), 1.51 (2H, m), 1.64 (2H, m), 3.10 (4H, m), 3.63 (2H , m), 4.76 (2H, m), 6.54 (1H, d), 7.65 (2H, m), 7.80 (1H, m), 7.94 (1H, m), 8 , 83 (1H, m), 9.93 (1H, sa).

Example 102

Preparation of 3- {1- [2- (3,3-dimethyl-butylamino) -ethyl] -2-propyl-1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (130) Step 1: Cycling

image 1

To the starting material (IIIa2, 3.34 g, 12.6 mmol) in 20% AcOH in MeOH (33 ml, 0.2 M) was added

10 butyraldehyde (1.7 ml, 18.9 mmol) followed by zinc powder (4.12 g, 63 mmol). The resulting mixture was heated to 50 ° C and stirred at this temperature for 30 minutes. After completing the reaction, it was monitored by HPLC and LC-MS. The solvent was then evaporated to dryness and the crude product was dissolved with ethyl acetate, then saturated aqueous sodium carbonate was added until pH = 9 and the mixture was centrifuged at 9000 rpm for 10 min. The liquid was decanted and the solid was rinsed with ethyl acetate (sonicated). The liquid was extracted

15 with ethyl acetate and then purified by flash chromatography (silica, 3% MeOH in DCM) to give 3- [1- (2-amino-ethyl) -2-propyl-1H-benzoimidazol-5- acid methyl ester il] -acrylic. Yield = 25%, LC-MS m / z: 288 ([M + H] +).

Stage 2: Reductive Amination 20

image 1

To the 3- [1- (2-amino-ethyl) -2-propyl-1H-benzoimidazol-5-yl] -acrylic acid methyl ester (1.2 g, 4.2 mmol) in MeOH (40 ml) is 3,3-dimethyl-butyraldehyde (0.524 ml, 4.2 mmol) was added. The resulting mixture was stirred at rt for 2

25 hours before the addition of acetic acid (2 ml) and sodium cyanoborohydride (0.395 g, 6.3 mmol) and the reaction was stirred at rt for an additional 30 minutes. The solvent was removed and the residue was dissolved in DCM, after which it was washed with aqueous sodium bicarbonate, water and brine. The combined organic phase was purified, after the final treatment, by flash chromatography (silica, 4% MeOH in DCM). LC-MS m / z: 372 ([M + H] +).

30 Stage 3: Formation of hydroxamic acid.

The title compound (130) was prepared according to the procedures described in example 1 (step 4), using appropriate starting materials. TFA salt of 130: HPLC purity: 99.9%; LC-MS m / z: 373 ([M + H] +). 1HRMN (CD3OD) 9 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, 35 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). The dihydrochloride salt of 130 was prepared according to the procedures described in example 50, steps 4 and 5, using appropriate starting materials. HPLC purity: 98.1%; LC-MS m / z: 373 ([M + H] +). 1H-NMR (DMSO-d6)  10.89 (1H, sa), 9.77 (2H, a, -NH2 + -), 8.12 (1H, d, J = 8.6 Hz), 7.97 (1H, s), 7.78 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 15.8 Hz), 6.64 (1H, d, J = 15, 8 Hz), 4.88 (2H, t, J = 5.8

40 Hz), 3.41 (2H, m), 3.26 (2H, t, J = 7.6 Hz), 2.91 (2H, m), 1.90 (2H, sextet, J = 7, 6 Hz), 1.56 (2H, m), 1.05 (3H, t, J = 7.3 Hz), 0.88 (9H, s); 13C-NMR (DMSO-d6)  162.4, 155.9, 137.4 (CH), 132.8, 132.4, 131.8 (a), 124.6 (CH), 120.2 ( CH), 113.2 (CH), 113.0 (CH), 44.9, 44.0, 41.1, 38.6, 29.4 (Cq), 28.9, 27.1, 19, 9, 13.5.

Example 103

Preparation of 3- [1- [2- (3,3-dimethyl-butylamino) -ethyl] -2- (2,2-dimethyl-propyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide

(131)

The title compound (131) was prepared according to the procedures described in example 102, using appropriate starting materials. HPLC purity: 92%; LC-MS m / z: 401 ([M + H] +). 1H-NMR (CD3OD) 9 7.89 (s, 1H), 7.85 (d, 1H, J = 8.5 Hz), 7.77 (d, 1H, J = 8.7 Hz), 7, 63 (d, 1H, J = 15.8 Hz), 6.55 (d, 1H, J = 15.7 Hz), 4.91-4.81 (m, 2H), 3.58 (t, 2H , J = 6.5 Hz), 3.13-3.08 (m, 4H), 1.63-1.58 (m, 2H), 1.13 (s, 9H), 0.96 (s, 9H).

Example 104

Preparation of 3- [1- {2- [bis- (3,3-dimethyl-butyl) -amino] -ethyl} -2- (2,2-dimethyl-propyl) -1H-benzoimidazol-5-yl] - N-hydroxyacrylamide (132)

The title compound (132) was prepared according to the procedures described in example 102, using appropriate starting materials. HPLC purity: 96%; LC-MS m / z: 485 ([M + H] +). 1H-NMR (CD3OD)  7.93 (s, 1H), 7.88 (d, 1H, J = 8.5 Hz), 7.80 (d, 1H, J = 8.7 Hz), 7, 72 (d, 1H, J = 15.8 Hz), 6.59 (d, 1H, J = 15.8 Hz), 5.00 (t, 2H, J = 6.5 Hz), 3.67 ( t, 2H, J = 7.5 Hz), 3.13-3.08 (m, 2H), 1.68-1.64 (m, 4H), 1.14 (s, 9H), 0.96 (s, 18H).

Example 105 (Reference Example)

Preparation of 3- {1- [2- (2,2-dimethyl-propylaminoethyl] -1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (133)

The title compound (133) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 99.9%; LC-MS m / z: 317 ([M + H] +). 1H-NMR (CD3OD)  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 (Reference Example)

Preparation of 3- (1- {2 - [(2,2-dimethyl-propyl) -propyl-amino] -ethyl} -1H-benzoimidazol-5-yl) -N-hydroxy-acrylamide (134)

The title compound (134) was prepared according to the procedures described in example 76, using appropriate starting materials. HPLC purity: 99.9%; LC-MS m / z: 359 ([M + H] +). 1H-NMR (CD3OD)  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- {1- [2- (3,3-dimethyl-butylamino) -ethyl] -2-ethyl-1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide (135)

The title compound (135) was prepared according to the procedures described in example 102, using appropriate starting materials. HPLC purity: 94.3%; LC-MS m / z: 359 ([M + H] +). 1H-NMR (CD3OD)  7.69 (d, 1H, J = 8.0 Hz), 7.54 (s, 1H), 7.53 (d, 1H, J = 9.8 Hz), 6, 89 (d, 1H, J = 16.1 Hz), 6.08 (d, 1H, J = 15.7 Hz), 4.80 - 4.70 (m, 2H), 3.55 - 3.45 (m, 2H), 3.20-3.19 (m, 2H), 2.95-2.90 (m, 2H), 1.56-1.52 (m, 2H), 1.42 (t , 3H, 7.4 Hz), 0.81 (s, 9H).

Example 108

Preparation of 3- [1- (2-diethylamino-ethyl) -2-propylamino-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide (105) The title compound (105) was prepared according to the following synthetic scheme .

image 1

HPLC purity: 100%. 1 H-NMR (DMSO-d6) ,9 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, sa), 10.10 (1H, s), 10.81 (1H, s).

Example 109

Preparation of 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2-propylamino-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

(115)

The title compound (115) was prepared using the method analogous to compound (105). HPLC purity: 97%. 1 H-NMR (DMSO-d6) ,9 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, sa), 9.42 (1H, sa), 10.81 (1H, sa), 13.44 (1H, sa).

Example 110

Preparation of 3- (1- {2 - [(3,3-dimethyl-butyl) -methyl-amino] -ethyl} -2-propyl-1H-benzoimidazol-5-yl) -N-hydroxyacrylamide (136)

The title compound (136) was prepared by reacting 3- {1- [2- (3,3-dimethyl-butylamino) -ethyl] -2-propyl-1Hbenzoimidazol-5-yl} -N-hydroxy-acrylamide (130 ) with formaldehyde (10 eq.) and NaBH3CN (3 eq.) in MeOH. TFA salt of 136: HPLC purity at 254 nm, 99.8%; LC-MS (ESI) m / z: 387 ([M + H] +). 1H-NMR (CD3OD)  7.85 (1H, d, J = 8.5 Hz), 7.84 (1H, s), 7.74 (1H, d, J = 8.3 Hz), 7, 63 (1H, d, J = 15.8 Hz), 6.52 (1H, d, J = 15.5 Hz), 4.81 (2H, m), 3.62 (2H, similar ata), 3 , 20 (2H, m), 3.13 (2H, t, J = 7.3 Hz), 3.01 (3H, s), 1.93 (2H, m), 1.63 (2H, m) , 1.10 (3H, t, J = 7.2 Hz), 0.93 (9H, s).

Example 111 (Reference Example)

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

(137) The title compound (137) was prepared as TFA salt according to the procedures described as follows.

image 1

Stage 1

To a solution of 3- (4-chloro-3-nitro-phenyl) -acrylic acid (Ia, 3 g, 12 mmol) in dioxane (100 ml) was added 2-aminoethanol (2.2 ml, 37 mmol) and triethylamine (3.4 ml, 25 mmol). The reaction mixture was heated at 90 ° C for 48 hours when all the starting material has become the product. The resulting solvent was evaporated in compound 137-1. The solid was washed with water (x 3) and dried over Na2SO4. Yield: 88%. Purity at 254 nm: 98%, t R = 2.4 min. LC-MS m / z: 267 ([M + H] +).

Stage 2

To a solution of 3- [4- (2-hydroxy-ethylamino) -3-nitro-phenyl] -acrylic acid methyl ester (137-1, 0.200 g, 0.75 mmol) in MeOH (3.7 ml) HCO2H (0.226 ml, 6 mmol) and SnCl2, 2H2O (0.982 g, 3.7 mmol) were added. The reaction mixture was allowed to stir at 50 ° C for 16 hours. The solvent was removed and the residue was basified and then extracted with ethyl acetate. Unprocessed crude product was used for the next step. LC-MS m / z: 247 ([M + H] +).

Stage 3

To a solution of crude 3- [1- (2-hydroxy-ethyl) -1 H -benzoimidazol-5-yl] -acrylic acid methyl ester (137-2, 0.115 g, 0.49 mmol) in CH 2 Cl 2 (3, 5 ml) PPh3 (0.383 g, 1.46 mmol) and CBR4 (0.485 g, 1.46 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes and then washed with water (x2) and brine (x1), dried over Na2SO4 and concentrated. Compound 137-3 was purified by preparative reverse phase HPLC. Yield: 80%. Purity at 254 nm: 99.9%, t R = 1.2 min. LC-MS m / z: 309/311 ([M + H] +).

Stage 4

To a solution of 3- [1- (2-bromo-ethyl) -1H-benzoimidazol-5-yl] -acrylic acid methyl ester (137-3, 72 mg, 0.23 mmol) in N, N-dimethylformamide Anhydrous (2.5 ml) in a 4 ml vial were added 2,2,2-trifluoroethylamine (185 ml, 2.32 mmol) and triethylamine (321 ml, 2.32 mmol). The reaction mixture was stirred at 80 ° C for 16 hours. Ethyl acetate and water were added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (x2). Then, the combined organic phase was washed with water (x1) and brine (x1). Unprocessed crude product was used for the next reaction step. LC-MS m / z: 328 ([M + H] +).

Stage 5

The crude crude 3- {1- [2- (2,2,2-trifluoroethylamino) ethyl] -1 H -benzoimidazol-5-yl} -acrylic acid methyl ester (137-4) was dissolved in MeOH (2 ml) and AcOH (0.5 ml). Then, 3,3-dimethylbutyraldehyde (42 ml, 0.336 mmol) was added and the resulting mixture was stirred for 2 hours before the addition of NaCNBH3 (21 mg, 0.336 mmol). The reaction mixture was stirred for 30 minutes. The solvent was removed and the residue was redissolved in CH2Cl2 and

washed with sat. NaHCO3. (x2), water (x2) and brine (x1). Gross 137-5: LC-MS m / z 412 ([M + H] +). Step 6 5 Then the crude 137-5 was converted into the title compound (137) as TFA salt according to the procedures described in Example 1. HPLC purity at 254 nm: 99.9%, t R = 2.4 min . LC-MS m / z: 413 ([M + H] +). 1H-NMR (CD3OD)  0.79 (9H, s), 1.04 -1.08 (2H, m), 2.60 - 2.64 (2H, m), 3.11 (2H, t, J = 5.4 Hz), 3.20 (2H, q, J = 9.7 Hz), 4.54 (2H, t, J = 5.3 Hz), 6.61 (1H, d, J = 15.7 Hz), 7.74 (1H, d, J = 15.7 Hz), 7.85 - 7.96 (2H, m), 7.99 (1H, s), 9.11 (1H, s).

Example 112 (Reference example) Preparation of 3- (1- {2- [butyl- (2,2,2-trifluoro-ethyl) -amino] -ethyl} -1H-benzoimidazol-5-yl) -N- hydroxy-acrylamide (138) The title compound (138) was prepared according to the procedures described in example 111, using materials

15 appropriate starting.

image 1

HPLC purity at 254 nm: 99.9%, t R = 2.8 min. LC-MS m / z: 385 ([M + H] +). 1H-NMR (CD3OD)  0.79 (3H, t, J

20 = 7.2 Hz), 1.15 - 1.24 (4H, m), 2.64 (2H, t, J = 6.9 Hz), 3.12 (2H, t, J = 5.5 Hz), 3.20 (2H, q, J = 9.7 Hz), 4.55 (2H, t, J = 5.4 Hz), 6.60 (1H, d, J = 15.7 Hz) , 7.74 (1H, d, J = 15.8 Hz), 7.83-7.92 (2H, m), 7.98 (1H, s), 9.07 (1H, s).

The following compounds are representative examples prepared by the methods disclosed or analogous to those disclosed in Examples 1-112 above:

25

Compound

Structure m / z [M + H] +  NAME

one

image 1 387 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2- (2,2-dimethylpropyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide

2

image 1 359 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2-isopropyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

3

image 1 373 3- [2-Butyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

4

image 1 391 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2- (2-methylsulfanylethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

Compound

Structure m / z [M + H] +  NAME

5

image 1 375 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2-ethoxymethyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

6

image 1 373 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2-isobutyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

7

image 1 359 3- [1- (2-diethylamino-ethyl) -2-isobutyl-1H-benzoimidazol-5-yl] N-hydroxy-acrylamide

8

image 1 359 3- [2-Butyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

9

image 1 369 3- [2-but-3-inyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

10

image 1 371 3- [2-but-3-enyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

eleven

image 1 357 3- [2-but-3-enyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5yl] -N-hydroxy-acrylamide

12

image 1 355 3- [2-but-3-inyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5yl] -N-hydroxy-acrylamide

13

image 1 413 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2- (3,3,3trifluoropropyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

Compound

Structure m / z [M + H] +  NAME

14

image 1 399 3- [1- (2-diethylamino-ethyl) -2- (3,3,3-trifluoro-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

fifteen

image 1 361 3- [1- (2-diethylamino-ethyl) -2-ethoxymethyl-1 H -benzoimidazol-5-yl] -N-hydroxy-acrylamide

16

image 1 331 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-methyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

17

image 1 373 3- [1- (2-diethylamino-ethyl) -2- (2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

18

image 1 399 N-hydroxy-3- [1- (3-isopropylamino-propyl) -2- (3,3,3trifluoropropyl) -1H-benzoimidazol-5-yl] -acrylamide

19

image 1 359 3- [2- (2,2-dimethyl-propyl) -1- (2-isopropylamino-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

twenty

image 1 401 3- [1- (2-diisopropylamino-ethyl) -2- (2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

twenty-one

image 1 387 3- [1- (2-diisopropylamino-ethyl) -2-isobutyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

Compound

Structure m / z [M + H] +  NAME

22

image 1 399 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2-hex-3-enyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

2. 3

image 1 429 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2- (2,4,4-trimethylpentyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide

24

image 1 399 3- [2-Cyclohexyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

25

image 1 409 3- [2-bicyclo [2.2.1] hept-5-en-2-yl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide

26

image 1 385 3- [1- (2-diethylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5yl] -N-hydroxy-acrylamide

27

image 1 413 3- [1- (2-diisopropylamino-ethyl) -2-hex-3-enyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

28

image 1 371 3- [2-hex-3-enyl-1- (2-isopropylamino-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

29

image 1 385 3- [2-hex-3-enyl-1- (3-isopropylamino-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

30

image 1 357 3- [1- (2-ethylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5yl] -N-hydroxy-acrylamide

Compound

Structure m / z [M + H] +  NAME

31

image 1 387 3- [1- (2-diethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

32

image 1 415 N-hydroxy-3- [1- (3-isopropylamino-propyl) -2- (2,4,4-trimethylpentyl) -1H-benzoimidazol-5-yl] -acrylamide

33

image 1 373 3- [2- (2,2-dimethyl-propyl) -1- (3-isopropylamino-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

3. 4

image 1 427 3- [1- (2-diisopropylamino-ethyl) -2- (3,3,3-trifluoro-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

35

image 1 345 N-hydroxy-3- [2-isobutyl-1- (2-isopropylamino-ethyl) -1Hbenzoimidazol-5-yl] -acrylamide

36

image 1 345 3- [2- (2,2-dimethyl-propyl) -1- (2-ethylamino-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

37

image 1 331 3- [1- (2-ethylamino-ethyl) -2-isobutyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

38

image 1 443 3- [1- (2-diisopropylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

39

image 1 401 N-hydroxy-3- [1- (2-isopropylamino-ethyl) -2- (2,4,4-trimethylpentyl) -1H-benzoimidazol-5-yl] -acrylamide

Compound

Structure m / z [M + H] +  NAME

40

image 1 387 3- [1- (2-ethylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

41

image 1 415 3- [1- (2-diethylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

42

image 1 345 3- [1- (2-diethylamino-ethyl) -2-propyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

43

image 1 387 3- [2-Butyl-1- (2-diisopropylamino-ethyl) -1H-benzoimidazol-5yl] -N-hydroxy-acrylamide

44

image 1 331 3- [2-Butyl-1- (2-ethylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

Four. Five

image 1 377 3- [1- (2-diethylamino-ethyl) -2- (2-methylsulfanyl-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

46

image 1 345 3- [2-Butyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] N-hydroxy-acrylamide

47

image 1 359 3- [2-Butyl-1- (3-isopropylamino-propyl) -1H-benzoimidazol5-yl] -N-hydroxy-acrylamide

48

image 1 433 3- [1- (1-Benzyl-piperidin-4-yl) -2-butyl-1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide

49

image 1 329 3- [2-But-3-enyl-1- (2-ethylamino-ethyl) -1H-benzoimidazol-5-yl] N-hydroxy-acrylamide

Compound

Structure m / z [M + H] +  NAME

fifty

image 1 373 3- [2-Hexyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5yl] -N-hydroxy-acrylamide

51

image 1 387 3- [1- (2-Dimethylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

52

image 1 359 3- [1- (2-ethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

53

image 1 385 N-hydroxy-3- [1- (2-isopropylamino-ethyl) -2- (3,3,3trifluoropropyl) -1H-benzoimidazol-5-yl] -acrylamide

54

image 1 357 3- [1- (2-Dimethylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol5-yl] -N-hydroxy-acrylamide

55

image 1 359 3- [1- (2-amino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

56

image 1 403 3- [1- (2-amino-ethyl) -2- (2-methoxy-nonyl) -1H-benzoimidazol5-yl] -N-hydroxy-acrylamide

57

image 1 331 3- [2-Butyl-1- (2-dimethylamino-ethyl) -1H-benzoimidazol-5-yl] N-hydroxy-acrylamide

58

image 1 359 3- [1- (2-dimethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] N-hydroxy-acrylamide

Compound

Structure m / z [M + H] +  NAME

59

image 1 444 N- {2- [1- (2-diethylamino-ethyl) -5- (2-hydroxycarbamoyl-vinyl) 1H-benzoimidazol-2-yl] -ethyl} -3,3-dimethyl-butylamide

60

image 1 430 3- {1- (2-diethylamino-ethyl) -2- [2- (2,2-dimethylpropionylamino) ethyl] -1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide

61

image 1 416 3- {1- (2-diethylamino-ethyl) -2 - [(2,2-dimethyl) -propionylamino) methyl] -1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide

62

image 1 402 N- [1- (2-diethylamino-ethyl) -5- (2-hydroxycarbamoyl-vinyl) -1Hbenzoimidazol-2-ylmethyl] -butylamide

63

image 1 359 3- [1- (2-ethylamino-ethyl) -2- (3,3-dimethyl-butyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

64

image 1 359 3- [2- (3,3-dimethyl-butyl) -1- (2-dimethylamino-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

65

image 1 345 3- [1- (2-Dimethylamino-ethyl) -2-pentyl-1H-benzoimidazol-5-yl] N-hydroxy-acrylamide

66

image 1 357 3- [1- (2-dimethylamino-ethyl) -2- (2,2,2-trifluoro-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

67

image 1 396 N-hydroxy-3- [1- (5-methyl-1H-pyrazol-3-yl) -2- (2,4,4-trimethylpentyl) -1H-benzoimidazol-5-yl] -acrylamide

Compound

Structure m / z [M + H] +  NAME

68

image 1 345 3- [1- (2-ethylamino-ethyl) -2-pentyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

69

image 1 329 3- (2-Butyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl) -Nhydroxy-acrylamide

70

image 1 343 3- (2-Butyl-1-piperidin-4-yl-1H-benzoimidazol-5-yl) -Nhydroxy-acrylamide

71

image 1 359 N-hydroxy-3- [1- (2-isopropylamino-ethyl) -2-pentyl-1Hbenzoimidazol-5-yl] -acrylamide

72

image 1 385 N-hydroxy-3- [1- (2-methylamino-ethyl) -2-non-3-enyl-1Hbenzoimidazol-5-yl] -acrylamide

73

image 1 385 N-hydroxy-3- [1- (2-methylamino-ethyl) -2-non-6-enyl-1Hbenzoimidazol-5-yl] -acrylamide

74

image 1 345 3- [2-Hexyl-1- (2-methylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

75

image 1 331 N-hydroxy-3- [1- (2-methylamino-ethyl) -2-pentyl-1Hbenzoimidazol-5-yl] -acrylamide

76

image 1 373 N-hydroxy-3- [1- (2-methylamino-ethyl) -2-octyl-1Hbenzoimidazol-5-yl] -acrylamide

Compound

Structure m / z [M + H] +  NAME

77

image 1 359 3- [1- (2-amino-ethyl) -2-octyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

78

image 1 359 3- {2-butyl-1- [2- (isopropyl-methyl-amino) -ethyl] -1Hbenzoimidazol-5-yl} -N-hydroxy-acrylamide

79

image 1 359 3- {1- [2- (ethyl-methyl-amino) -ethyl] -2-pentyl-1H-benzoimidazol5-yl} -N-hydroxy-acrylamide

80

image 1 357 3- (2-hexyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl) -Nhydroxy-acrylamide

81

image 1 343 3- [2-Butyl-1- (1-methyl-pyrrolidin-3-yl) -1H-benzoimidazol-5-yl] N-hydroxy-acrylamide

82

image 1 371 3- (2-hexyl-1-piperidin-3-yl-1H-benzoimidazol-5-yl) -Nhydroxy-acrylamide

83

image 1 343 3- (2-Butyl-1-piperidin-3-yl-1H-benzoimidazol-5-yl) -Nhydroxy-acrylamide

84

image 1 403 3- (1- {2- [ethyl- (2-methoxy-ethyl) -amino] -ethyl} -2-pentyl-1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide

85

image 1 345 3- {2-Butyl-1- [2- (ethyl-methyl-amino) -ethyl] -1H-benzoimidazol-5yl} -N-hydroxy-acrylamide

86

image 1 371 N-hydroxy-3- [1- (1-methyl-piperidin-3-yl) -2-pentyl-1Hbenzoimidazol-5-yl] -acrylamide

Compound

Structure m / z [M + H] +  NAME

87

image 1 359 3- {1- [2- (ethyl-hexyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide

88

image 1 345 3- {1- [2- (ethyl-pentyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide

89

image 1 373 3- {1- [2- (ethyl-heptyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide

90

image 1 415 3- {2-hexyl-1- [1- (2-hydroxyethyl) -piperidin-3-yl] -1Hbenzoimidazol-5-yl} -N-hydroxy-acrylamide

91

image 1 389 3- (2-Butyl-1- {2- [ethyl- (3-hydroxy-propyl) -amino} -ethyl} -1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide

92

image 1 403 3- (1- {2- [ethyl- (3-hydroxy-propyl) -amino] -ethyl} -2-pentyl-1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide

93

image 1 377 (E) -N-hydroxy-3- (1- (1-phenethylpyrrolidin-3-yl) -1Hbenzo [d] imidazol-5-yl) acrylamide

Compound

Structure m / z [M + H] +  NAME

94

image 1 357 (E) -N-hydroxy-3- (1- (1-pentylpiperidin-3-yl) -1Hbenzo [d] imidazol-5-yl) acrylamide

95

image 1 331 3- {1- [2- (butyl-ethyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide

96

image 1 391 (E) -N-hydroxy-3- (1- (1-phenethylpiperidin-3-yl) -1Hbenzo [d] imidazol-5-yl) acrylamide

97

image 1 405 (E) -N-hydroxy-3- (1- (1- (3-phenylpropyl) -piperidin-3-yl) -1Hbenzo [d] imidazol-5-yl) acrylamide

98

image 1 391 (E) -N-hydroxy-3- (1- (1- (3-phenylpropyl) -pyrrolidin-3-yl) -1Hbenzo [d] imidazol-5-yl) acrylamide

99

image 1 357 3- {1- [1- (3,3-dimethyl-butyl) -pyrrolidin-3-yl] -1Hbenzoimidazol-5-yl} -N-hydroxy-acrylamide

100

image 1 303 (E) -3- (1- (2- (diethylamino) ethyl) -1H-benzo [d] imidazol-5-yl) -Nhydroxy-acrylamide

Compound

Structure m / z [M + H] +  NAME

101

image 1 384 3- [2- (4-cyano-butyl) -1- (2-diethylamino-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

102

image 1 343 (E) -3- (1- (1-Butylpiperidin-3-yl) -1H-benzo [d] imidazol-5-yl) N-hydroxy-acrylamide

103

image 1 355 (E) -N-hydroxy-3- (1- (1- (pent-4-enyl) piperidin-3-yl) -1Hbenzo [d] imidazol-5-yl) acrylamide

104

image 1 371 (E) -3- (1- (1- (3,3-dimethylbutyl) -piperidin-4-yl) -1Hbenzo [d] imidazol-5-yl) -N-hydroxy-acrylamide

105

image 1 360 3- [1- (2-diethylamino-ethyl) -2-propylamino-1H-benzoimidazol5-yl] -N-hydroxy-acrylamide

107

image 1 331 (E) -N-hydroxy-3- (1- (2- (isopropyl- (propyl) amino) ethyl) -1Hbenzo [d] imidazol-5-yl) acrylamide

108

image 1 345 3- {1- [2- (butyl-isopropyl-amino) -ethyl] -1H-benzoimidazol-5-yl-N-hydroxy-acrylamide

109

image 1 359 N-hydroxy-3- {1- [2- (isopropyl-pentylamino) -ethyl] -1Hbenzoimidazol-5-yl} -acrylamide

Compound

Structure m / z [M + H] +  NAME

110

image 1 398 3- [2- (5-cyano-pentyl) -1- (2-diethylamino-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

111

image 1 359 3- (1- {2 - [(3,3-dimethyl-butyl) -ethylamino] -ethyl} -1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide

112

image 1 317 3- {1- [2- (ethyl-propyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide

113

image 1 373 N-hydroxy-3- (1- {2- [isopropyl- (2-methyl-pentyl) -amino] -ethyl} 1 H -benzoimidazol-5-yl) -acrylamide

114

image 1 399 (E) -N-hydroxy-3- (1- (2- (isopropyl (4,4,4-trifluorobutyl) amino) ethyl) -1H-benzo [d] imidazol-5-yl) acrylamide

115

image 1 374 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-propylamino-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

116

image 1 373 3- {1- [2- (ethyl-hexyl-amino) -ethyl] -2-methyl-1H-benzoimidazol5-yl} -N-hydroxy-acrylamide

Compound

Structure m / z [M + H] +  NAME

117

image 1 399 3- {1- [2- (butyl-ethyl-amino) -ethyl] -2-trifluoromethyl-1Hbenzoimidazol-5-yl} -N-hydroxy-acrylamide

118

image 1 427 3- {1- [2- (ethyl-hexyl-amino) -ethyl] -2-trifluoromethyl-1Hbenzoimidazol-5-yl} -N-hydroxy-acrylamide

119

image 1 401 (E) -3- (1- (2- (dibutylamino) ethyl) -2-propyl-1Hbenzo [d] imidazol-5-yl) -N-hydroxy-acrylamide

120

image 1 331 3- [1- (2-Dipropylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide

121

image 1 359 N-hydroxy-3- (1- {2- [isopropyl- (3-methyl-butyl) -amino] -ethyl} -1Hbenzoimidazol-5-yl) -acrylamide

122

image 1 345 3- (1- {2 - [(3,3-dimethyl-butyl) -methylamino] -ethyl} -1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide

123

image 1 345 3- (1- {2 - [(2-ethyl-butyl) -methylamino] -ethyl} -1H-benzoimidazol5-yl) -N-hydroxy-acrylamide

Compound

Structure m / z [M + H] +  NAME

124

image 1 415 (E) -3- (1- (2- (bis (3,3-dimethyl-butyl) amino) ethyl) -1Hbenzo [d] imidazol-5-yl) -N-hydroxy-acrylamide

125

image 1 359 (E) -3- (1- (2- (diisobutylamino) -ethyl) -1H-benzo [d] imidazol-5yl) -N-hydroxy-acrylamide

126

image 1 331 3- {1- [2- (3,3-dimethylbutylamino) -ethyl] -1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide

127

image 1 329 N-hydroxy-3- {1- [2- (methyl-pent-4-enyl-amino) -ethyl] -1Hbenzoimidazol-5-yl} -acrylamide

128

image 1 373 3- (1- {2 - [(3,3-dimethyl-butyl) -propylamino] -ethyl} -1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide

129

image 1 363 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2-methylsulfanyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide

130

image 1 373 3- {1- [2- (3,3-dimethyl-butylamino) -ethyl] -2-propyl-1Hbenzoimidazol-5-yl} -N-hydroxy-acrylamide

Compound

Structure m / z [M + H] +  NAME

131

image 1 401 3- [1- [2- (3,3-dimethyl-butylamino) -ethyl] -2 (2,2-dimethyl-propyl) 1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide

132

image 1 485 3- [1- {2- [bis- (3,3-dimethyl-butyl) -amino] -ethyl} -2- (2,2-dimethylpropyl) -1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide

133

image 1 317 3- {1- [2- (2,2-dimethylpropylamino) -ethyl] -1H-benzoimidazol-5yl} -N-hydroxy-acrylamide

134

image 1 359 3- (1- {2 - [(2,2-dimethyl-propyl) -propylamino] -ethyl} -1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide

135

image 1 359 3- {1- [2- (3,3-dimethyl-butylamino) -ethyl] -2-ethyl-1Hbenzoimidazol-5-yl} -N-hydroxy-acrylamide

136

image 1 387 3- (1- {2 - [(3,3-dimethyl-butyl) -methyl-amino] -ethyl} -2-propyl-1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide

137

image 1 413 3- (1- {2 - [(3,3-dimethyl-butyl) - (2,2,2-trifluoro-ethyl) -amino] -ethyl} 1 H -benzoimidazol-5-yl) -N-hydroxy- acrylamide

Compound

Structure m / z [M + H] +  NAME

138

image 1 385 3- (1- {2- [butyl- (2,2,2-trifluoroethyl) -amino] -ethyl} -1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide

BIOLOGICAL TESTS AND ENZYMATIC TESTS

Purification and expression of recombinant GST-HDAC1 protein

5 A human cDNA library was prepared using cultured SW620 cells. The amplification of the human HDAC1 coding region of this cDNA library was cloned separately in the baculovirus expression pDEST20 vector (GATEWAY Cloning Technology, Invitrogen Pte Ltd). The pDEST20HDAC1 builder was confirmed by DNA sequencing. Recombinant baculovirus was prepared using the Bac-To-Bac method

10 following the manufacturer's instructions (Invitrogen Pte Ltd). The baculovirus titer was determined by plaque assay to be approximately 108 PFU / ml.

GST-HDAC1 expression was performed by infecting SF9 cells (Invitrogen Pte Ltd) with baculovirus pDEST20HDAC1 at MOI = 1 for 48 h. The soluble cell lysate was incubated with balanced glutathione-Sepharose 4B beads

15 previously (Amersham) at 4 ° C for 2 h. The peels were washed with PBS buffer 3 times. The GST-HDAC1 protein was eluted by elution buffer containing 50 mM Tris, pH 8.0, 150 mM NaCl, 1% Triton X-100 and 10 mM or 20 mM reduced glutathione. The purified GST-HDAC1 protein was dialyzed with HDAC storage buffer containing 10 mM Tris, pH 7.5, 100 mM NaCl and 3 mM MgCl2. 20% glycerol was added to the purified GSTHDAC1 protein before storage at -80 ° C.

20 In vitro HDAC assay for the determination of IC5O values

The assay was carried out in a 96-well format and the BIOMOL fluorescence based HDAC activity assay was applied. The reaction was composed of assay buffer, containing 25 mM Tris, 25 pH 7.5, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2, 1 mg / ml BSA, compounds tested, an appropriate concentration of Enzyme HDAC1, generic substrate Flur of lys 500 uM for enzyme HDAC1 and subsequently incubated at room temperature for 2 h. The Flur de lys developer was added and the reaction was incubated for 10 min. In summary, deacetylation of the substrate sensitizes the developer, which then generates a fluorophore. The fluorophore is excited with light at 360 nm and the emitted light (460 nm) is detected in a fluorometric plate reader (system of

30 Tecan Ultra Microplate detection, Tecan Group Ltd.).

The analytical software, Prism 4.0 (GraphPad Software Inc) has been used to generate the IC50 of a series of data. IC50 is defined as the concentration of compound required for 50% inhibition of HDAC enzyme activity.

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

Table 1. IC50 of the activity of the HDAC1 enzyme (the unit is micromolar)

Compound

IC50 (M)  Compound IC50 (M)  Compound IC50 (M)

one

0.042 47  0.21  93  0.23

2

0.38 48  0.43  94 0.064

3

0.15 49  0.11  95 0.052

4

0.12 fifty  0.036 96  0.080

5

0.17 51 0.066 97 0.10

6

0.18 52 0.025 98 0.32

7

0.091 53  0.10  99  0.12

Compound

IC50 (M)  Compound IC50 (M)  Compound IC50 (M)

8

0.052 54  0.048 100  0.19

9

0.21 55  0.037 101  0.08

10

0.14 56  0.029 102  0.54

eleven

 0.070 57  0.090 103  0.10

12

 0.064 58  0.030 104  0.41

13

0.42 59  0.077 105  0.13

14

 0.077 60 0.10 107 0.074

fifteen

 0.085 61  0.070 108 0.043

17

 0.13 62 0.054 109 0.048

19

 0.064 63  0.051 110 0.044

twenty

 0.26 64 0.10 111 0.029

twenty-one

0.38 65  0.078 112  0.12

22

 0.064 66 0.34 113 0.016

2. 3

 0.045 68  0.034 114 0.063

24

0.51 70  0.068 116  0.10

25

0.23 71  0.040 117  0.19

26

 0.040 72  0.017 118  0.48

27

0.23 73  0.026 119  0.18

28

 0.021 74  0.028 120  0.11

29

 0.13 75 0.050 121 0.079

30

 0.021 76  0.018 122 0.037

31

 0.045 77  0.026 123 0.027

32

 0.060 78  0.044 124 0.085

33

0.23 79  0.040 125  0.16

3. 4

 0.88 80 0.040 126 0.042

35

 0.082 81 0.12 127 0.078

36

 0.096 82 0.10 128 0.031

37

 0.091 83 0.19 129  0.77

38

 0.56 84 0.063 130 0.036

39

 0.024 85 0.11 131 0.066

40

 0.027 86 0.16 133 0.072

41

 0.062 87 0.10 134  0.22

Compound

IC50 (M)  Compound IC50 (M)  Compound IC50 (M)

42

 0.15 88 0.047 135 0.074

43

 0.33 89 0.080 136 0.053

44

 0.054 90 0.51 137 0.093

Four. Five

 0.053 91  0.060 138  0.10

46

 0.049 92  0.050

Cell-based proliferation assay to determine GI50 values

Human colon cancer cell lines (Colo205, HCT116), ovarian cancer cell line were obtained

5 (A2780), hepatoma cell line (HEP3B), prostate cancer cell line (PC3) from ATCC or ECACC. Colo205 cells were cultured in RPMI 1640 containing 2 mM L-glutamine, 5% FBS, 1.0 mM Na pyruvate, 1 U / ml penicillin and 1 µg streptomycin. HCT116 cells were cultured in McCoy’s containing RPMI 1640 containing 2 mM L-glutamine, 5% FBS, 1 U / ml penicillin and 1 µg streptomycin. A2780 cells were grown in RPMI 1640 containing 2 mM L-glutamine, 5% FBS, 1 U / ml penicillin and 1 µg streptomycin. Be

10 cultured HEP3B cells in EMEM containing 2 mM L-glutamine, 5% FBS, 1% non-essential amino acid, 1 mM Na pyruvate, 1 U / ml penicillin and 1 µg streptomycin. PC3 cells were grown in F12K, 2 mM L-glutamine, 5% FBS, 1 U / ml penicillin and 1 µg streptomycin. PC3, Colo205 and HCT116 cells were seeded in 96-well plate at 1000, 5000 and 6000 cells per well respectively. A2780 and HEP3B cells were seeded in 96-well plate at 4000 cells per well respectively. Plates were incubated at 37 ° C, CO2 at

15 5%, for 24 h. Cells were treated with compounds at various concentrations for 96 h. Cell growth was then monitored using CyQUANT® cell proliferation assay (Invitrogen Pte Ltd). Dose response curves were plotted to determine IC50 values for compounds using XL-fit (ID Business Solution, Emeryville, CA). IC50 is defined as the concentration of compound required for 50% inhibition of cell growth.

20 The results of the growth inhibitory or cellular activity of representative compounds are shown in Tables 2 and 3. The data indicated that the compounds of this invention are active in inhibiting the growth of tumor cells.

Table 2. Growth inhibition or cellular activity in Colo205 cells (the unit is micromolar)

Compound

IC50 (M)  Compound IC50 (M)  Compound IC50 (M)

one

0.50 47 3.6 93 2.14

2

2.12  48 0.78  94 0.60

3

2.22  49 1.75  95 0.57

4

2.62  fifty 0.17  96 0.70

5

2.58  51 0.26  97 0.67

6

2.69  52 0.21  99 1.89

7

0.81 53 1.05 100 2.25

8

0.56 54 0.46 101 2.44

9

1.87 55 0.91 102 2.08

10

 1.77 56 0.90 103 0.48

eleven

 0.48 57 0.65 104 1.99

12

 0.51 58 0.38 105 1.77

13

 5.5 59 2.28 107 0.63

14

 0.63 60 2.48 108 0.44

fifteen

 1.50 61 1.32 109 0.49

17

 1.19 62 2.60 110 1.74

19

 0.53 63 0.54 111 0.21

Compound

IC50 (M)  Compound IC50 (M)  Compound IC50 (M)

twenty

 2.66 64 0.73 112 0.88

twenty-one

 2.51 65 0.56 113 0.61

22

0.75  66 8.8  114 0.72

2. 3

 0.19 68 0.52 116 0.70

24

2.99  70 7.0  117 1.80

25

 2.38 71 0.24 118 1.88

26

 0.37 72 0.16 119 0.77

27

 1.42 73 0.23 120 0.49

28

 0.18 74 0.55 121 0.49

29

 1.92 75 1.20 122 0.15

30

 0.31 76 0.29 123 0.15

31

 0.42 77 0.67 124 0.54

32

 0.74 78 0.54 125 0.68

33

 2.11 79 0.45 126 0.42

3. 4

 4.4 80 1.37 127 0.34

35

 0.66 81 1.00 128 0.14

36

 0.86 82 1.23 129  3.9

37

1.09  83 4.9  130 0.15

38

 1.94 84 1.03 131 0.33

39

 0.23 85 1.52 133 0.56

40

 0.16 86 2.08 134 2.30

41

 0.92 87 1.07 135 0.26

42

 0.98 88 0.55 136 0.39

43

 1.86 89 0.87 137 1.97

44

0.87  90 8.1  138 1.96

Four. Five

 0.54 91 2.40

46

 0.48 92 1.82

Table 3. Growth or cell inhibition activity in several cancer cell lines

 Cell lines

Compound

 HCT116 A2780 PC3 HEP3B

one

 ++ +++ +++ ++

7

 + + ++

8

 ++ ++ +++ +

22

 + +++ +++

2. 3

 ++ +++ +++

30

 ++ +++ +++

40

 +++ +++ +++

44

 + ++ +++

46

 +++ +++ +++ ++

fifty

 +++ +++ +++

 Cell lines

Compound

 HCT116 A2780 PC3 HEP3B

52

 +++ +++ +++

58

 +++ +++ +++ +++

71

 +++ +++ +++

111

+++

130

 +++ +++ +++

(“+++” for IC50 <0.5 M, “++” for IC50 between 0.5 and 1.0 M, ”+” for IC50 between 1.0 M to 5.0 M )

Histone H3 Acetylation Assay

5 A hallmark of histone deacetylase (HDAC) inhibition is the increase in the level of histone acetylation. The acetylation of histones, including H3, H4 and H2A can be detected by immunoblot (Western type). Colo205 cells, approximately 5 x 105 cells, were seeded in the medium described above, cultured for 24 h and subsequently treated with HDAC inhibitors and a positive control at a final concentration of 10 µM. After 24 h, the cells were collected and lysed according to the lysis kit instructions

10 Sigma mammal cell. Protein concentration was quantified using the BCA method (Sigma Pte Ltd). The protein lysate was separated using 4-12% SDS-PAGE bis-tris gel (Invitrogen Pte Ltd) and transferred onto a PVDF membrane (BioRad Pte Ltd). The membrane was screened using acetylated histone H3 specific primary antibody (Upstate Pte Ltd). The detection antibody, goat anti-rabbit antibody conjugated with HRP was used according to the manufacturing instructions (Pierce Pte Ltd). After removing the antibody from

After membrane detection, an enhanced chemiluminescent substrate was added for the detection of HRP (Pierce Pte Ltd) on the membrane. After removal of the substrate, the membrane was exposed to an X-ray film (Kodak) for 1 s-20 min. The X-ray film was developed using the X-ray film processor. The density of each band observed on the revealed film could be analyzed qualitatively using UVP Bioimaging software (UVP, Inc, Upland, CA). The values were then normalized against the density of actin in the

20 corresponding samples to obtain protein expression.

The results of the immunoblot assay using acetylated anti-histone H3 antibody are shown in Table 4 for representative compounds of this invention.

25 Table 4

Compound

Histone acetylation activities (Histone 3)  Compound Histone acetylation activities (Histone 3)  Compound Histone acetylation activities (Histone 3)

one

Active 30 Active 49 Active

2

Active 32 Active fifty Active

3

Active 35 Active 52 Active

7

Active 36 Active 55 Active

8

Active 37 Active 58 Active

eleven

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 Four. Five  Active 130 Active

26

Active 46 Active

28

Active 48 Active

These data demonstrate that the compounds of this invention inhibit histone deacetylases, thereby resulting in the accumulation of acetylated histones such as H3.

Measurement of microsomic stability

Measurements of metabolic stability in the in vitro assay using liver microsomes help in predicting liver clearance in vivo and the stability of the compound towards the reactions of phase I biotransformation mediated by P450 isozymes.

The combined human liver microsome (HLM) was acquired from BD Gentest (BD BioSciences). The incubations consisted of the test compound (5 M) or control compound (verapamil), solution A of the NADPH generating system (NADP + 25 mM, glucose-6-phosphate 66 mM, MgCl2 66 mM in H2O), solution B of the 10 NADPH generator system (glucose-6-phosphate dehydrogenase 40 U / ml in 5 mM sodium citrate) and 1.0 mg / ml microsomal protein, respectively, in 100 mM potassium phosphate buffer (pH 7.4). Samples were incubated for 0.5, 15, 30, 45, 60 min. The reaction was terminated with 80% acetonitrile cooled with ice and 20% DMSO. Samples were subsequently centrifuged at 4 ° C for 15 min. at 2,000 rpm. 100 µl of the supernatant was transferred to the LC-MS plate for analysis. Prior to the quantitative analysis, the CL / EM machine compound was adjusted to obtain the

15 optimized MS condition. Liquid chromatography was performed on a Luna C18 column (Phenomenex U.S.A., Torrance, CA) (2 x 50 mm, 5 mM). The% of the compound that remains (by area) is calculated at each time point with respect to time 0 min. The remaining% is plotted against time (min.) To obtain the curve and use the Prism software to obtain the t1 / 2. These are shown in table 5.

20 Table 5

Compound

 t1 / 2 (min.) Compound t1 / 2 (min.)

one

> 30 52 > 30

2

> 30 58 > 30

8

> 30 63 > 30

eleven

 > 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

It is expected that t1 / 2> 30 min. In vitro measured for the above compounds means that the contribution to the clearance of the compound due to the metabolism is expected to be low in the in vivo situation and thus help in the production of a longer half-life and an increase in the exposure of the compounds.

The previous results demonstrated that the compounds of formula (I) were metabolically stable in the human liver microsome assay. Together with the appropriate physicochemical properties, for example, molecular weight, logP and high solubility, the above compounds could have a suitable pharmacological exposure and effect in the organism when administered intravenously or especially orally.

30 Pharmacokinetic (PK) studies in vivo

The compound was dissolved in an appropriate solution (saline solution or DMA and Cremaphor in saline solution) at 1 mg / ml for intravenous (iv) administration, or in 0.5% methylcellulose, 0.1% Tween 80 in water at 5 mg / ml 35 for oral administration. Mice were randomized according to body weight, grouped into three per time point. Doses IV were administered to the mice. single (10 mg / kg) through the tail vein, or single oral doses (50 mg / kg) through the nasogastric tube. At the predefined time points (before the dose, 5 or 10, 30 min., 1, 2, 4, 8 and 24 h), a group of mice was sacrificed by CO2 overdose and blood samples were taken by puncture cardiac Blood samples were immediately centrifuged for 10 min. at 40 3000 rpm to separate the plasma, and the frozen plasma was kept at -80 until analysis by LC / MS / MS. Prior to sample analysis, the method for the LC / MS / MS assay was developed. The method for the signal response of the calibration standards was validated, the automatic injector stability for the intraday and interday calibration curve of -15 hours using eight calibration standards excluding the plasma blank. The QC samples were prepared at three different concentrations in triplicate to determine the accuracy and precision. The extracted QC samples were compared with non-extracted samples to determine the extraction efficiency of the

analyte The LLOQ was determined using triplicate samples of 1 ng / ml and 2 ng / ml to obtain accuracy and precision at the lower end. Samples were analyzed using the validated method. Data were analyzed using the non-compartmental model using WinNolin 4.0 software (Pharsight, Mountain View, CA, USA). The average values were used for the concentration-time profiles of the plasma compound in the PK study in

5 mice

The PK AUC 0-last parameter that provides information on the global exposure of the drug in vivo is one of the key PK / PD parameters that helps in predicting the efficacy of an anticancer compound. The higher the AUC value, the better the in vivo efficacy of the compound at a similar in vitro potency. They were shown

10 the pharmacokinetic data of compounds selected in table 5 and table 6 below.

Table 6. Representative pharmacokinetic data [the compounds were in the form of a hydrochloric acid salt (2HCl), dosed at 50 mg / kg, v.o.]

Compound

 AUC0-last (ng.h / ml)

one

1868

8

1836

130

 1050

The data in Table 6 further demonstrated that compounds with high metabolic stability as shown by the representative compounds in Table 5 together with the appropriate physicochemical properties, for example, molecular weight, logP and high solubility, allowed to produce an exposure. Appropriate pharmacological and effect on the animal when administered orally.

20 Antineoplastic (or antitumor) effect in vivo of HDAC inhibitor agents:

The efficacy of the compounds of the invention can then be determined using xenograft studies in animals in vivo. The xenograft model in animals is one of the most commonly used in cancer models in vivo.

25 In these studies, female nude mice (Harlan), 12-14 weeks old, would be implanted subcutaneously at the side, 5x106 human colon tumor cell cells HCT116, or 5x106 tumor cell cells of human ovary A2780, or 5x106 PC3 prostate cancer cell cells. When the tumor reaches the size of 100 mm3, nude mice with xenograft would be combined in pairs in various

30 treatment groups Selected HDAC inhibitors can be dissolved in appropriate vehicles and administered to nude mice with xenograft intraperitoneally, intravenously or orally daily for 14-21 days. The dosage volume will be 0.01 ml / g body weight. Paclitaxol, used as a positive control, will be prepared for intravenous administration in an appropriate vehicle. The dosage volume for paclitaxol will be 0.01 ml / g body weight. Tumor volume will be calculated every two days or two

35 times a week after injection using the formula: Volume (mm3) = (w2x l) / 2, in which w = width and l = length in mm of an HCT116 or A2780 or PC3 tumor. The compounds of this invention that are tested would show a significant reduction in tumor volume with respect to vehicle-only controls. The acetylated histone in relation to the vehicle treated control group when measured will accumulate. Therefore, the result will indicate that the compounds of this invention are effective in the treatment of a disease / disorder.

40 proliferative such as cancer.

The details of the specific embodiments described in this invention are not to be construed as limitations.

Claims (26)

1. A compound of formula (I): image 1 Formula 1 5 in which R1 is a group of formula: 10 - (CR20R21) m- (CR22R23) n- (CR24R25) or-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, each optional substituent being selected from the group consisting of halogen, = O, -CN, alkenyl, alkynyl and alkoxy; Each R20, R21, R22, R23, R24 and R25 is independently selected from the group consisting of: H, halogen, -CN, NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl , cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkyl, cycloalkylheteroalkyl, heterocycloalkyl heteroalkyl, Heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, arylalkyl, alkyloxylamino, amino, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkyloxylamino, amino, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkoxy, alkyloxylamino, amino, alkoxy, alkylamino, amino alkylsulfonyl, aminosulfonyl, arylsulfonyl, arylsulfinyl -COOH, -C (O) OR3, -COR5, -SH, -SR6, -OR6 and acyl, each of which may be optionally substituted; or R20 and R21 when taken together can form a group of formula = O o = S, and / or R22 and R23 when taken together can form a group of formula = O o = S, and / or R24 and R25 when taken together can form a group of formula = O or = S; each R5 is independently selected from the group consisting of H and alkyl; each R6 is independently selected from the group consisting of H and an alkyl; Each R28 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, heteroylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, alkyl , alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, arylalkyl, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, arylamino, alkylsulfonyl, alkyls , aminosulfonyl, SR5, and acyl, each of which may be optionally substituted, or R26 and R27 45 when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group; m, n and o are whole numbers independently selected from the group consisting of 0, 1, 2, 3 and 4; 50 or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein the sum of m + n + or is 2 or 3. 3. A compound according to any one of claims 1 to 2, wherein R1 is selected from the group consisting of: - (CR20R21) 2-NR28R27; 5 - (CR22R23) 2-NR28R27; - (CR24R25) 2-NR26R27; 10 - (CR20R21) - (CR22R23) -NR28R27; - (CR20R21) (CR24R25) -NR26R27; - (CR22R23) - (CR24R25) -NR26R27; 15 - (CR20R21) 3-NR26R27; - (CR22R23) 3-NR26R27; 20 - (CR24R23) 3-NR26R27; - (CR20R21) 2- (CR22R23) -NR28R27; - (CR20R21) 2- (CR24R25) -NR26R27; 25 - (CR20R21) - (CR22R23) 2-NR26R27; - (CR22R23) 2- (CR24R25) -NR28R27; 30 - (CR20R21) - (CR324R25) 2-NR26R27; - (CR22R23) - (CR24R25) 2-NR26R27; Y - (CR20R21) - (CR22R23) - (CR24R25) -NR26R27. 35 4. A compound according to any one of claims 1 to 3, the compound being selected from the group consisting of: image 1 Y image 1 5. A compound according to any one of claims 1 to 4, wherein R20, R21, R22, R23, R24 and R25 are independently selected from the group consisting of H, alkyl, alkenyl and alkynyl.

6.

 A compound according to any one of claims 1 to 5, wherein R20, R21 R22, R23, R24 and R25 5 are independently selected from the group consisting of H and alkyl.

7. A compound according to any one of claims 1 to 6, wherein R20 and R21 are H.

8.

 A compound according to any one of claims 1 to 7, wherein R22 and R23 are methyl. 10

9.

 A compound according to any one of claims 1 to 8, wherein R24 and R25 are H.

10.

 A compound according to any one of claims 1 to 9, wherein R26 and R27 are selected

regardless of the group consisting of: H, alkyl, alkenyl, alkynyl, alkoxyalkyl and acyl. fifteen 11. A compound according to any one of claims 1 to 10, wherein R26 and R27 are independently selected from the group consisting of H, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, acetyl and 2-methoxy ethyl. A compound according to any one of claims 1 to 4, wherein R1 is a group of the formula: image2 image3 image4 14. A compound according to any one of claims 1 to 12, wherein R2 is selected from the group consisting of: methyl; ethoxymethyl; 2-methanesulfanyl ethyl; 2,2,2-trifluoroethyl; propyl; 2-2-dimethylpropyl; isopropyl; 3,3,3-trifluoropropyl; butyl; isobutyl; 3,3-dimethyl-butyl; but-3-enyl; but-3-inyl; pentyl; 2,4,4-trimethyl 10 pentyl; hexyl; hex-3-enyl; octyl; non-3-enyl; non-6-enyl; 2-methoxy-nonyl, (CH3) 3CCH2CONH (CH2) 2-; (CH3) 3CCONH (CH2) 2-; (CH3) 3CCONH (CH2) - and CH3 (CH2) 2CONH (dH2) -. 15. A compound according to any one of claims 1 to 14, wherein the optional substituent is selected from the group consisting of: halogen, = O = S, -CN, -NO2, -CF3, -OCF3, alkyl , alkenyl, alkynyl, 15 haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocicloalquiloxilo, heterocicloalqueniloxilo, aryloxy, heteroaryloxy, arylalkyl , heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -SH and acyl. twenty 16. The compound of claim 1, wherein the compound is selected from compounds, and their pharmaceutically acceptable salts, selected from the group consisting of: image 1 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2- (2,2-dimethylpropyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide image 1 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-isopropyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [2-Butyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2- (2-methylsulfanylethyl) 1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-ethoxymethyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-isobutyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (2-Diethylamino-ethyl) -2-isobutyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide image 1 3- [2-Butyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide 3- [2-but-3-inyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [2-But-3-enyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [2-But-3-enyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [2-but-3-inyl-1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2- (3,3,3-trifluoropropyl) 1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide image 1 3- [1- (2-Diethylamino-ethyl) -2- (3,3,3-trifluoro-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (2-Diethylamino-ethyl) -2-ethoxymethyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-methyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (2-Diethylamino-ethyl) -2- (2,2-dimethyl-propyl) -1H-benzoimidazol5-yl] -N-hydroxy-acrylamide N-hydroxy-3- [1- (3-isopropylamino-propyl) -2- (3,3,3-trifluoropropyl) 1H-benzoimidazol-5-yl] -acrylamide 3- [2- (2,2-Dimethyl-propyl) -1- (2-isopropylamino-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide image 1 3- [1- (2-diisopropylamino-ethyl) -2- (2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (2-Diisopropylamino-ethyl) -2-isobutyl-1H-benzoimidazol-5-yl] N-hydroxy-acrylamide 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-hex-3-enyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2- (2,4,4-trimethylpentyl) 1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (2-Diethylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [1- (2-Diisopropylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5yl] -N-hydroxy-acrylamide image 1 3- [2-hex-3-enyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] N-hydroxy-acrylamide 3- [2-hex-3-enyl-1- (3-isopropylamino-propyl) -1H-benzoimidazol-5yl] -N-hydroxy-acrylamide 3- [1- (2-ethylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [1- (2-Diethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide N-hydroxy-3- [1- (3-isopropylamino-propyl) -2- (2,4,4-trimethylpentyl) 1H-benzoimidazol-5-yl] -acrylamide 3- [2- (2,2-Dimethyl-propyl) -1- (3-isopropylamino-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide image 1 3- [1- (2-Diisopropylamino-ethyl) -2- (3,3,3-trifluoro-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide N-hydroxy-3- [2-isobutyl-1- (2-isopropylamino-ethyl) -1Hbenzoimidazol-5-yl] -acrylamide 3- [2- (2,2-Dimethyl-propyl) -1- (2-ethylamino-ethyl) -1H-benzoimidazol-5yl] -N-hydroxy-acrylamide 3- [1- (2-ethylamino-ethyl) -2-isobutyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [1- (2-Diisopropylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide N-hydroxy-3- [1- (2-isopropylamino-ethyl) -2- (2,4,4-trimethylpentyl) -1Hbenzoimidazol-5-yl] -acrylamide image 1 3- [1- (2-ethylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1H-benzoimidazol5-yl] -N-hydroxy-acrylamide 3- [1- (2-Diethylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (2-Diethylamino-ethyl) -2-propyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [2-Butyl-1- (2-diisopropylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [2-Butyl-1- (2-ethylamino-ethyl) -1H-benzoimidazol-5-yl] -N-hydroxyacrylamide 3- [1- (2-Diethylamino-ethyl) -2- (2-methylsulfanyl-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [2-Butyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide image 1 3- [2-Butyl-1- (3-isopropylamino-propyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [2-But-3-enyl-1- (2-ethylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [2-Hexyl-1- (2-isopropylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [1- (2-Dimethylamino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (2-ethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide N-hydroxy-3- [1- (2-isopropylamino-ethyl) -2- (3,3,3-trifluoropropyl) 1H-benzoimidazol-5-yl] -acrylamide image 1 3- [1- (2-Dimethylamino-ethyl) -2-hex-3-enyl-1H-benzoimidazol-5-yl] N-hydroxy-acrylamide 3- [1- (2-Amino-ethyl) -2- (2,4,4-trimethyl-pentyl) -1H-benzoimidazol-5yl] -N-hydroxy-acrylamide 3- [1- (2-Amino-ethyl) -2- (2-methoxy-nonyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [2-Butyl-1- (2-dimethylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [1- (2-Dimethylamino-ethyl) -2-hexyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide N- {2- [1- (2-Diethylamino-ethyl) -5- (2-hydroxycarbamoyl-vinyl) -1Hbenzoimidazol-2-yl] -ethyl} -3,3-dimethyl-butylamide image 1 3- {1- (2-diethylamino-ethyl) -2- [2- (2,2-dimethylpropionylamino) -ethyl] -1Hbenzoimidazol-5-yl} -N-hydroxy-acrylamide 3- {1- (2-Diethylamino-ethyl) -2 - [(2,2-dimethyl) -propionylamino) -methyl] 1H-benzoimidazol-5-yl} -N-hydroxy-acrylamide N- [1- (2-Diethylamino-ethyl) -5- (2-hydroxycarbamoyl-vinyl) -1Hbenzoimidazol-2-ylmethyl] -butyramide 3- [1- (2-ethylamino-ethyl) -2- (3,3-dimethyl-butyl) -1H-benzoimidazol-5yl] -N-hydroxy-acrylamide 3- [2- (3,3-Dimethyl-butyl) -1- (2-dimethylamino-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (2-Dimethylamino-ethyl) -2-pentyl-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide image 1 3- [1- (2-Dimethylamino-ethyl) -2- (2,2,2-trifluoro-ethyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- [1- (2-ethylamino-ethyl) -2-pentyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide N-hydroxy-3- [1- (2-isopropylamino-ethyl) -2-pentyl-1Hbenzoimidazol-5-yl] -acrylamide N-hydroxy-3- [1- (2-methylamino-ethyl) -2-non-3-enyl-1Hbenzoimidazol-5-yl] -acrylamide N-hydroxy-3- [1- (2-methylamino-ethyl) -2-non-6-enyl-1Hbenzoimidazol-5-yl] -acrylamide 3- [2-Hexyl-1- (2-methylamino-ethyl) -1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide image 1 N-hydroxy-3- [1- (2-methylamino-ethyl) -2-pentyl-1 H -benzoimidazol-5-yl] -acrylamide N-hydroxy-3- [1- (2-methylamino-ethyl) -2-octyl-1H-benzoimidazol-5-yl] acrylamide 3- [1- (2-Amino-ethyl) -2-octyl-1H-benzoimidazol-5-yl] -N-hydroxyacrylamide 3- {2-Butyl-1- [2- (isopropyl-methyl-amino) -ethyl] -1H-benzoimidazol-5yl} -N-hydroxy-acrylamide 3- {1- [2- (ethyl-methyl-amino) -ethyl] -2-pentyl-1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide 3- (1- {2- [ethyl- (2-methoxy-ethyl) -amino] -ethyl} -2-pentyl-1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide image 1 3- {2-Butyl-1- [2- (ethyl-methyl-amino) -ethyl] -1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide 3- (2-Butyl-1- {2- [ethyl- (3-hydroxy-propyl) -amino} -ethyl} -1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide 3- (1- {2- [ethyl- (3-hydroxy-propyl) -amino] -ethyl} -2-pentyl-1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide 3- [2- (4-Cyano-butyl) -1- (2-diethylamino-ethyl) -1H-benzoimidazol-5-yl] N-hydroxy-acrylamide 3- [1- (2-Diethylamino-ethyl) -2-propylamino-1H-benzoimidazol-5-yl] -Nhydroxy-acrylamide 3- [2- (5-Cyano-pentyl) -1- (2-diethylamino-ethyl) -1H-benzoimidazol-5il] -N-hydroxy-acrylamide image 1 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-propylamino-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- {1- [2- (ethyl-hexyl-amino) -ethyl] -2-methyl-1H-benzoimidazol-5-yl} -Nhydroxy-acrylamide 3- {1- [2- (Butyl-ethyl-amino) -ethyl] -2-trifluoromethyl-1H-benzoimidazol5-yl} -N-hydroxy-acrylamide 3- {1- [2- (ethyl-hexyl-amino) -ethyl] -2-trifluoromethyl-1H-benzoimidazol5-yl} -N-hydroxy-acrylamide image 1 (E) -3- (1- (2- (dibutylamino) ethyl) -2-propyl-1H-benzo [d] imidazol-5-yl) N-hydroxyacrylamide 3- [1- (3-Dimethylamino-2,2-dimethyl-propyl) -2-methylsulfanyl-1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide 3- {1- [2- (3,3-Dimethyl-butylamino) -ethyl] -2-propyl-1H-benzoimidazol5-yl} -N-hydroxy-acrylamide 3- [1- [2- (3,3-Dimethyl-butylamino) -ethyl] -2 (2,2-dimethyl-propyl) -1Hbenzoimidazol-5-yl] -N-hydroxy-acrylamide image5 3- [1- {2- [bis- (3,3-dimethyl-butyl) -amino] -ethyl} -2- (2,2-dimethylpropyl) 1H-benzoimidazol-5-yl] -N-hydroxy-acrylamide 3- {1- [2- (3,3-Dimethyl-butylamino) -ethyl] -2-ethyl-1H-benzoimidazol5-yl} -N-hydroxy-acrylamide 3- (1- {2 - [(3,3-dimethyl-butyl) -methyl-amino] -ethyl} -2-propyl-1Hbenzoimidazol-5-yl) -N-hydroxy-acrylamide. 17. A pharmaceutical composition that includes a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier, excipient or diluent. 19. A compound according to claim 18, wherein the disorder is a proliferative disorder. A compound according to claim 19, wherein the proliferative disorder is cancer. 21. A compound according to claim 20, wherein the cancer is colon cancer, prostate cancer, hepatoma and ovarian cancer. 22. A compound according to any one of claims 1 to 16 for the treatment of a disorder that can be treated by inhibition of histone deacetylase. 23. A compound according to claim 22, wherein the disorder is selected from the group consisting of proliferative disorders (eg cancer); neurodegenerative diseases including Huntington's disease, polyglutamine diseases, Parkinson's disease, Alzheimer's disease, seizures, nigrostriatal degeneration, progressive supranuclear paralysis, torsion dystonia, spasmodic torticollis and dyskinesia, family tremor, Gilles de la Tourette syndrome, disease with Diffuse Lewy bodies, Pick's disease, intracerebral hemorrhage, primary lateral sclerosis, spinal muscular atrophy, amyotrophic lateral sclerosis, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, spastic paraplegia Hereditary, 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 keratitits, diabetic retinopathy, Peter's anomaly, retinal degeneration, cellophane retinopathy; Cogan's dystrophy; corneal dystrophy; neovascularization of the iris (rubeosis); neovascularization of the cornea; retinopathy of prematurity; macular edema; macular hole; Macular pucker; marginal blepharitis, myopia, benign growth of the conjunctiva; inflammatory diseases and / or diseases of the immune system including rheumatoid arthritis (RA), osteoarthritis, juvenile chronic arthritis, 5 graft versus host disease, psoriasis, asthma, spondyloarthropathy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, alcoholic hepatitis, diabetes, Sjoegrens syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, discogenic pain, systemic lupus erythematosus, allergic contact dermatitis; disease that involves 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, pulmonary 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 hematopoietic disorders including thalassemia, anemia and 15 sickle cell anemia. 24. A compound according to any one of claims 1 to 16, in the manufacture of a medicament for the treatment of cancer. A compound according to claim 24, wherein the cancer is a hematological malignancy or a solid tumor. 26. A compound according to claim 25, wherein the hematological malignancies are selected from a group consisting of B-cell lymphoma, leukemia and T-cell lymphoma. 25 27. A compound according to claim 25, wherein the solid tumor is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, kidney cancer, cancer gastric, colon cancer, pancreatic cancer and brain cancer. A compound according to claim 24, wherein the cancer is selected from the group consisting of colon cancer, prostate cancer, hepatoma and ovarian cancer. 29. A method of synthesizing compounds of formula I as defined in claim 1: image6 wherein R1 and R2 are as defined in claim 1, including the method: (a) provide a compound of formula (A1): image 1 in which L is a leaving group, (B) protect the carboxyl group to produce a compound of formula (A2): image 1 in which L is a leaving group and PC is a carboxyl protecting group, (c) displacing the leaving group with an amine of formula R1NH2 to produce a compound of formula: image 1 wherein R1 is as defined in claim 1 or a protected form thereof, and PC is a carboxyl protecting group 10 (d) optionally reacting the compound to further functionalize R1 (e) reduce the nitro group; fifteen (f) reacting the reduced product with a compound of formula R2CO2H or a compound of formula R2CHO and cycling the product thus produced to produce a compound of formula (A4): image 1 Wherein R1 and R2 are as defined in claim 1 or protected forms thereof, and PC is a carboxyl protecting group. (g) converting the compound into a compound of formula I; 25 in which (d) can be carried out after any one of (c) (e) or (f) and also in which (e) and (f) can be carried out sequentially or simultaneously. 30. A method of synthesizing compounds of formula I as defined in claim 1: 30 image 1 wherein R1 and R2 are as defined in claim 1, including the method: (a) provide an aldehyde of formula (B1): image3 wherein R1 and R2 are as defined in claim 1, (b) subjecting the aldehyde to reaction with an appropriately substituted olefining agent to produce a compound of formula (B2): image 1 wherein R1 and R2 are as defined in claim 1, and PC is H or a carboxyl protecting group, fifteen (c) convert the compound into a compound of formula I. 31. A method according to claim 30, wherein (a) includes: (a1) providing a compound of formula (B3): image 1 in which L is a leaving group and PC is a carboxyl protecting group, (a2) displacing the leaving group with an amine of formula R1NH2 to produce a compound of formula (B4): image 1 wherein R1 is as defined in claim 1 or a protected form thereof, and PC is a carboxyl protecting group, (3) optionally reacting the compound to further functionalize R1, (a4) reduce the nitro group, 10 (a5) react the reduced product with a compound of formula R2CO2H or a compound of formula R2CHO and cycle the product thus produced to produce a compound of formula (B5): image 1 Wherein R1 and R2 are as defined in claim 1 or protected forms thereof, and PC is a carboxyl protecting group, (a6) convert the protected carboxyl group into the corresponding aldehyde, 20 in which (a3) can be carried out after any one of (a2), (a4), (a5) or (a6) and also in which (a4) and (a5) can be carried out sequentially or simultaneously. 32. A method of synthesizing compounds of formula I as defined in claim 1: image2 wherein R1 and R2 are as defined in claim 1, including the method:

(to)

 provide a compound of formula (C1):

wherein R1 and R2 are as defined in claim 1 or protected forms thereof, and L1 is a leaving group,

(b)

 convert the compound into (a) a compound of formula (C2):

image 1 image 1 Wherein R1 and R2 are as defined in claim 1 or protected forms thereof, and PC is H or a carboxyl protecting group, (c) convert the compound into a compound of formula I. A method according to claim 32, wherein (a) includes: (a1) providing a compound of formula (C3): image 1 in which L and L1 are outgoing groups, (a2) displacing the leaving group (L) with an amine of formula: R1NH2 to produce a compound of formula (C4): image2 wherein R1 is as defined in claim 1 or a protected form thereof, and L1 is a leaving group, (a3) optionally reacting the compound to further functionalize R1, 30 (a4) reduce the nitro group, (a5) react the reduced product with a compound of formula R2CO2H or a compound of formula R2CHO and cycle the product thus produced to produce a compound of formula (C1): image 1 in which (a3) can be carried out after any one of (a2), (a4) or (a5) and also in which (a4) and (a5) can be carried out sequentially or simultaneously. 34. A method according to any one of claims 29 to 33, wherein the compound produced has the formula: