MXPA06004735A

MXPA06004735A - Acylurea connected and sulfonylurea connected hydroxamates.

Info

Publication number: MXPA06004735A
Application number: MXPA06004735A
Authority: MX
Inventors: Ze-Yi Lim; Haishan Wang; Yan Zhou
Original assignee: S Bio Pte Ltd
Priority date: 2003-10-27
Filing date: 2004-10-26
Publication date: 2006-12-14
Also published as: TW200530166A; WO2005040101A1; EP1685094A4; JP2007509930A; AR046920A1; CA2543570A1; EP1685094A1; AU2004284030A1

Abstract

The present invention relates to hydroxamate compounds which are inhibitors of histone deacetylase. More particularly, the present invention relates to acylurea/sulfonylurea containing compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with enzymes having histone deacetylase activities.

Description

A greater transcription activity, while reduced levels of acetylation are associated with the repression of gene expression [Wade P. A. Hum. Mol. Genet 10, 693-698 (2001), De Ruijter A.J.M. et al., Biochem. J., 370, 737-749 (2003)]. In normal cells, histone deacetylases (HDACs) and histone acetyltransferase together control the level of acetylation of histones to maintain a balance. The inhibition of HDACs results in the accumulation of acetylated histones, which results in a variety of cellular responses dependent on the cell type, such as apoptosis, necrosis, differentiation, cell survival, inhibition of proliferation and cytostasis. HDAC inhibitors were studied in regard to their therapeutic effects on cancer cells. For example, suberoylanilide hydroxamic acid (SAHA) is a potent inducer of differentiation and / or apoptosis in murine erythroleukemia, bladder and myeloma cell lines [Richon V. M. et al, Proc. Nati Acad. Sci. USA, 93: 5705-5708 (1996), Richon V. M. et al, Proc. Nati Acad. Sci. USA, 95: 3003-3007 (1998)]. It was shown that SAHA suppresses the growth of prostate cancer cells in vitro and in vivo [Butler L. M. et al, Cancer Res. 60, 5165-5170 (2000)]. Other inhibitors of HDAC that were studied intensively in terms of their anticancer activities are trichostatin A (TSA) and trapoxin B [Yoshida M. et al, J. Biol. Chem., 265, 17174 (1990), Kijima. et al, J. Biol. Chem., 268, 22429 (1993)]. Trichostatin A is a reversible inhibitor of mammalian HDAC. Trapoxin B is a cyclic tetrapeptide that is an irreversible mammalian HDAC inhibitor. However, due to the in vivo instability of these compounds, they are less desirable as anticancer drugs. Recently, other small molecule HDAC inhibitors were made available for clinical evaluation [US 6,552,065]. Additional HDAC inhibitor compounds were reported in the literature [Bouchain G. et al, J. Med. Chem., 46, 820-830 (2003)] and in patents [WO 03 / 066579A2, WO 01/38322 Al] . The in vivo activity of inhibitors of this type can be directly controlled by their ability to increase the amount of acetylated histones in the biological sample. It was reported that HDAC inhibitors interfere with neurodegenerative processes, for example, HDAC inhibitors arrest polyglutamine-dependent neurodegeneration [Nature, 413 (6857): 739-43, October 18, 2001]. In addition, HDAC inhibitors are also known to inhibit the production of cytokines such as TNF, IFN, IL-1, which are known to be involved in inflammatory diseases and / or disorders of the immune system. [J. Biol. Chem. 1990; 265 (18): 10230-10237; Science, 1998; 281: 1001-1005; Dinarello C.A. and Moldawer L. L. Proinflammatory and anti-inflammatory cytokines in rheumatoid arthritis. A first for clinicians. 2 * edition, Amergen Inc., 2000]. However, there is still a need to provide other HDAC inhibitors, which would be expected to have improved pharmaceutical properties and useful in the treatment of diseases such as cancer, neurodegenerative diseases and inflammatory and / or immune system disorders.

SUMMARY OF THE INVENTION In one aspect, the present invention provides compounds of the formula (I) Formula (I) wherein R is a linking moiety; R1 is selected from the group consisting of H, alkyl Ci-C6 and acyl; it is selected from the group consisting of O, S, NH, NR4, OH and ÑOR4; R 2 is selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, phenoxy, benzyloxy, COOR4, CONHR4 , NHCOR4, NHCOOR4, NHCONHR4, C (= NOH) R4, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted; or R2 together with the nitrogen to which it is attached and a portion of R form an optionally substituted heterocycloalkyl group; R3 is selected from the group consisting of H, halogen, alkyl, alkenyl, alkenyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl , arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, phenoxy, benzyloxy, GOOR4, CO HR4, HCOR4, NHCOOR4, HCO HR4, C (= N0H) R4, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted; Q is selected from the group consisting of -S (0) 2-, - C (= 0) - and -C (= S) -; G is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; each R4 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, ethercycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each of which may be optionally substituted; or one of its pharmaceutically acceptable salts or prodrugs. In a preferred embodiment, the present invention provides compounds having the formula (2) Formula (2) wherein R1 is selected from the group consisting of H, C6-alkyl and acyl; L is a single bond or is a C1-C5 hydrocarbon chain which may contain 0 to 2 multiple bonds independently selected from double bonds and triple bonds and wherein the chain may be optionally interrupted by at least one of - O-, -S-, -S (0) - and -S (0) 2- and the chain may be optionally substituted with one or more substituents selected, independently, from the group consisting of Ci-C4 alkyl; Z is selected from the group consisting of a single bond, NCR1), O, S, S (0) and S (0) 2; A is selected from the group consisting of a single bond, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene and optionally substituted heterocycloalkylene; B is selected from the group consisting of a single bond, optionally substituted aminoacyl, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted arylalkylene, optionally substituted heteroarylalkylene, optionally substituted alkylarylene, optionally substituted alkylheteroarylene, optionally substituted C 1 -C 3 alkylene, optionally substituted heteroalkylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene and - (CH2) mC (O) -N (R4) (C¾) n- optionally substituted, wherein n is an integer from 0 to 6, m is an integer from 0 to 6; M is selected from the group consisting of 0, S, NH, NR4, NOH and ÑOR4; R 2 is selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl , arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, phenoxy, benzyloxy, COOR4, CONHR4, NHCOR4 , NHCOOR4, HCONHR4, C (= NOH) R4, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted; or R2 together with the nitrogen to which it is attached and a portion of B form an optionally substituted heterocycloalkyl group; R3 is independently selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, ethercycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, ethercycloalkylheteroalkyl, heteroaryl heteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, phenoxy, benzyloxy , C00R4, CONHR4, NHCOR4, NHCOOR4, NHCONHR4, C (= NOH) R4, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted; Or it is selected from the group consisting of -S (0) 2-, C (= 0) - and -C (= S) -; G is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; each R4 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each of which may be optionally substituted; or one of its pharmaceutically acceptable salts or prodrugs. In a particularly preferred embodiment of the compounds of the formula (2) are compounds of the formula Formula (2a) wherein R1 is selected from the group consisting of H, Ci-C6 alkyl and acyl; L is a single bond or is a Ci-C5 hydrocarbon chain which may contain 0 to 2 multiple bonds independently selected from double bonds and triple bonds, and wherein the chain may be optionally interrupted by at least one of - 0-, -S-, -S (O) - and -S (O) 2- and the chain may be optionally substituted with one or more substituents selected, independently, from the group consisting of Ci-C4 alkyl; Z is selected from the group consisting of a single bond, NCR1), O, S, S (O) and S (0) 2; A is selected from the group consisting of a single bond, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene and optionally substituted heterocycloalkylene; B is selected from the group consisting of a single bond, optionally substituted aminoacyl, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted arylalkylene, optionally substituted heteroarylalkylene, optionally substituted alkylarylene, optionally substituted alkylheteroarylene, optionally substituted C ± -C3 alkylene, optionally substituted heteroalkylene , optionally substituted cycloalkylene, optionally substituted and optionally substituted heterocycloalkylene - (CH2) mC (O) -N (R4) (CH2) n-, where n is an integer from 0 to 6, m is an integer from 0 to 6; M is selected from the group consisting of O, S, NH, NR4, NOH and OR4; R2 is selected from the group consisting of H, Ci-Cio alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl (for example, cyclopropylmethyl), arylalkyl (for example benzyl), heteroarylalkyl (for example pyridylmethyl), hydroxyl, hydroxyalkyl, alkoxy, amino, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C (0) OR 4, -CONHR 4, -NHCONHR 4, C (= NOH) ) R4 and acyl; R3 is selected from the group consisting of H, C1-C10 alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl (for example, cyclopropylmethyl), arylalkyl (for example benzyl), heteroarylalkyl (eg pyridylmethyl), hydroxyl, hydroxyalkyl, alkoxy, amino, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C (0) 0R4, - CONHR4, -NHCONHR4, C (= NOH) ) R4 and acyl; Or it is selected from the group consisting of -S (0) 2-, -C0- and -C (= S) -; G is selected from optionally substituted aryl, optionally substituted heteroaryl, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl, wherein substituents are independently selected from the group consisting of X, Y, R4 , hydroxyl, hydroxyalkyl, alkoxy, amino, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C (0) OR 4, -C (0) OH, -SH, -CONHR 4, -NHCONHR 4 and C (= NOH) R4; R 4 is selected from the group consisting of C 1 -d alkyl, heteroalkyl, aryl, heteroaryl and acyl; X and Y are the same or different and are independently selected from the group consisting of H, halo, CX-C4 alkyl, N02, OR4, SR4, C (0) R5 and NR6R7; R5 is Ci-C4 alkyl; R6 and R7 are the same or different and are independently selected from the group consisting of H, CX-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, tetracarbaryl, arylalkyl and heteroarylalkyl or one of its salts or prodrugs pharmaceutically acceptable The compounds of the formula (2) of particular preference are those of the formula (2b) and (2c) Formula (2b) or one of its pharmaceutically acceptable salts or prodrugs.

Formula (2c) or one of its pharmaceutically acceptable salts or prodrugs. Another subgroup of preferred compounds are those of the formula (2d), wherein R1 = R3 = H; R2, X, Y, Z, A, B, R3 and R4 are the same as those of formula (2).

Formula (2d) or one of its pharmaceutically acceptable salts or prodrugs. In other embodiments, a compound of the formula (2e) is described, wherein R1 = R3 = H; R2, X, Y, Z, A, B, R3 and R4 are the same as those of formula (2).

Formula (2e) or one of its pharmaceutically acceptable salts or prodrugs. In other embodiments, a compound of the formula (2f) is described, wherein R2, X, Y, L, A, B, G, R3 and R4 are the same as those of the formula (2).

Formula (2f) or one of its pharmaceutically acceptable salts or prodrugs. In other embodiments, a compound of the formula (2g) is described, wherein R2, X, Y, L, B, G and R4 are the same as those of the formula (2).

Formula (2g) or one of its pharmaceutically acceptable salts or prodrugs. In another embodiment, a compound of the formula (2h) is described Formula (2h) wherein n = integer from 1 to 8, Q = -C (0) - or -S02-, G and 2 are as in formula (I), or one of its pharmaceutically acceptable salts or prodrugs. In another embodiment, a compound of the formula (2i) is provided Formula (2i) wherein Q = -C (0) - or -S02-7 and G and R2 are as in formula (I), or one of its pharmaceutically acceptable salts or prodrugs.

In another embodiment, a compound is provided with the formula (2j) Formula (2j) wherein Q = -C (0) - or -SO2-, and G and R2 are as in formula (I), or one of its pharmaceutically acceptable salts or prodrugs. A compound of the formula (2k) is also provided Formula (2k) wherein Q = -C (0) - or -SO2-, and G and R2 are as in formula (I), or one of its pharmaceutically acceptable salts or prodrugs. Also provided are compounds of the formula (21) Formula (21) wherein Q = -C (O) - or -S02-, and G and R2 are as in formula (I), or one of its pharmaceutically acceptable salts or prodrugs. In another embodiment, compounds of the formula (2m) are provided Formula (2m) wherein Q = -C (0) - or -S02-, and G and R2 are as in formula (I), or one of its pharmaceutically acceptable salts or prodrugs. In other embodiments, a compound of the formula (2n) is described, wherein B is a single bond or CH2, L is a single bond or is selected from CH2, CH2CH2 / -CH = CH-, -C-triple bond -C-. B is attached at the meta or para position of phenylene to L and G is selected from aryl, heteroaryl, alkyl and alkoxyalkyl Formula (2n) or one of its pharmaceutically acceptable salts or prodrugs. In other embodiments, a compound of the formula (2p) is described, wherein n is an integer from 1 to 8; G is selected from aryl, heteroaryl, alkyl and heteroalkyl. R2 is selected from H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, arylheteroalkyl, heteroarylalkyl and heteroarylheteroalkyl Formula (2p) or one of its pharmaceutically acceptable salts or prodrugs.

In other embodiments, a compound of the formula (2q) is described, wherein B is a single bond or CH2, L is a single bond or is selected from CH2, CH2CH2, -CH = CH-, -C-triple bond -C-, R2 is selected from H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, heteroalkyl, heteroarylalkyl, heteroarylheteroalkyl. X is selected from H, halo, CX-C4 alkyl, alkoxy, alkylamino; B is joined in the meta or para position of phenylene with respect to L.

Formula 2 (g) or one of its pharmaceutically acceptable salts or prodrugs. In other embodiments, a compound of the formula (2r) is described, wherein n is an integer from 1 to 8, X is selected from H, halo, alkyl ± -Ci, alkoxy, alkylamino Formula (2r) or one of its pharmaceutically acceptable salts or prodrugs. As with any group of structurally related compounds possessing a particular utility, certain groups are preferred for the compounds of the formula (I), (2), (2a), (2b), (2c), (2d), (2e) ), (2f), (2g), (2h), (2i), (2j), (2k), (21), (2m), (2n), (2p), (2q) and (2r) in regarding its final application. In those embodiments in which it is present, R1 is preferably H or C -C ^ alkyl, more preferably H or methyl, most preferably H. M is preferably O or S, most preferably O. Q is preferably S (0) 2 or CO, most preferably CO. G is preferably optionally substituted aryl, more preferably optionally substituted phenyl, most preferably 4-methylphenyl or phenyl. R2 is preferably selected from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylheteroalkyl, optionally substituted heteroarylalkyl, heteroarylheteroalkyl optionally substituted, optionally substituted cycloalkylalkyl and optionally substituted heterocycloalkylalkyl. In a particularly preferred embodiment, R2 is selected from the group consisting of H, 2- (lH-indol-3-yl) -ethyl, 2- (2-methyl-lH-indol-3-yl) -ethyl, pyridine 3-ylmethyl, 3-hydroxy-propyl, 2-pyridin-2-yl-ethyl, 2-pyridin-3-yl-ethyl, pyridin-3-ylmethyl, 2-pyridin-4-yl-ethyl, benzyl, phenyl-propyl, 2-phenoxy-ethyl, morpholin-4-yl, pyridin-2-yl, phenethyl, 2- (4-bromo-phenyl) -ethyl, 2- (4-fluoro-phenyl) -ethyl, -imidazol-l-yl-propyl, 2- (lH-imidazol-4-yl) -ethyl, lH-benzoimidazol-2-ylmethyl, 2-piperidin-l-yl-ethyl, 2-pyrrolidin-l-yl-ethyl , 2-cyclohex-1-enyl-ethyl, 2-ethyl-hexyl, 2-thiophen-2-yl-ethyl, 3,3-diphenyl-propyl, 2-biphenyl-4-yl-ethyl, 4-phenoxy-phenyl , 2- (3-phenoxy-phenyl) -ethyl, 2- (2,3-dimethoxy-phenyl, 2- (2,4-dichloro-phenyl) -ethyl, cyclohexylmethyl, hexyl, isobutyl, 3-isopropoxy-propyl, 2-phenoxy-ethyl, 2-isopropoxy-ethyl, 3-methoxy-benzyl, 4- [1, 2, 3] thiadiazol-4-yl-benzyl, 2,4-dichloro-benzyl, 2- (2-methoxy) phenyl) -ethyl, 2- (3-fluoro-phenyl) -ethyl, 2- (2-fluoro-phenyl) -ethyl, 2,2-diphenyl-ethyl, 2- (4-methoxy-phenyl) -ethyl, 2- (3-chloro-phenyl) -ethyl, 4-phenyl-butyl, 3-phenyl-propyl, 3,3-diphenyl-propyl, 3- (4-methyl) - piperazin-1-yl, 3-morpholin-4-yl-propyl, 3- (2-oxo-pyrrolidin-1-yl) -propyl, 3-pyrrolidin-1-yl-propyl-tetrahydrofuran-2-ylmethyl, 1, 5-dimethyl-hexyl, 2-diethylamino-ethyl and 2-dimethylamino-ethyl It is further preferred that R2 be selected from the group consisting of H, 2- (lH-indol-3-yl) -ethyl, 2- (2 -methyl-lH-indol-3-yl) -ethyl, pyridin-3-ylmethyl, 3-idroxy-propyl, 2-pyridin-2-yl-ethyl, 2-pyridin-3-yl-ethyl, pyridin-2- ilmethyl, pyridin-3-ylmethyl, 2-pyridin-4-yl-ethyl, benzyl, 3-phenyl-propyl, 2-phenoxy-ethyl, 2-morpholino-ethyl, 2-phenyl-ethyl, 2- (4-bromo) phenyl) -ethyl, 2- (4-fluoro-phenyl) -ethyl, 3-imidazol-1-yl-propyl, 2- (1H-imidazol-4-yl) -ethyl, lH-benzoimidazol-2-ylmethyl, 2-piperidin-l-yl-ethyl and 2-pyrrolidin-1-yl-ethyl In a most preferred embodiment, R 2 is selected from the group consisting of H, 2- (lH-indol-3-yl) - ethyl, 2- (2-methyl) l-lH-indol-3-yl) -ethyl, 2-phenyl-ethyl, 2-piperidin-1-yl-ethyl and 2-pyrrolidin-1-yl-ethyl. It is preferred that R3 is H. It is preferred that L is selected from the group consisting of a single bond, -CH2-, ~ (CH2) 2- and -CH = CH-. Accordingly, in a preferred embodiment, L is a link. In another preferred embodiment, L is a group of the formula -CH2-. In another preferred embodiment, L is a group of the formula -CH = CH-. The group of the formula -CH = CH- is preferably in the configuration "WE".

Z is preferably a single bond. A is preferably an optionally substituted arylene. In a preferred embodiment, A is selected from the group consisting of 1,4-phenylene and 1,3-phenylene. It is particularly preferred that A is 1,4-phenylene.

It is preferred that B be selected from the group consisting of a single bond, methylene, ethylene, propylene, alkylarylene and heteroalkylene. In a preferred embodiment, B is methylene. In another preferred embodiment, B is a link. In another preferred embodiment, B is ethylene. In another preferred embodiment, B is propylene. In a preferred embodiment, the identities of B, A, Z and L are such that the BAZL group is a group of the formula - (CH2) n-, where n is an integer from 1 to 7. In another Preferred embodiment, the identities of B, A, Z are such that the BAZ group is a group of the formula - (CH2) -phenyl-. In a particularly preferred embodiment the identities of B, A, Z and L are such that the BAZL group is selected from the group consisting of it's a simple link In many of the formulas given herein, it is stated that the substituents are optionally substituted. When substituents are present, it is preferred that the optional substituents are selected from the group consisting of halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl , cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cicloalilalquilo, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocicloalquilalquenilo, arylalkenyl, heteroarylalkenyl, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, arylheteroalkyl, eteroarilheteroalquilo, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alcoxiheterocicloalquilo, alkoxyaryl , alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocic loalquilalquilo, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinilaminoalquilo, -COOH, -COR 5, - C (0) OR5, CO HR5, NHCOR 5, NHCOOR5, NHCONHR5, C (= NOH) R 5, -SH, - SR5, -0R5 and acyl, or wherein each R5 is selected independently, the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted. In addition to the compounds of the invention as described above, the described embodiments are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs and pharmaceutically active metabolites of said compounds, and to pharmaceutically acceptable salts of said metabolites. On occasion, said compounds, salts, prodrugs and metabolites are collectively referred to herein as "HDAC inhibiting agents" or "HDAC inhibitors". In certain embodiments, the described compounds are used to modify the activity of deacetylase, in some cases, the activity of histone deacetylase, and in some cases, HDAC 8 or HDAC 1 activity. The embodiments described are also refer to pharmaceutical compositions, wherein each comprises a therapeutically effective amount of an HDAC inhibitor agent of the described embodiments with a pharmaceutically acceptable carrier or diluent for the treatment of cellular proliferative diseases. The term "effective amount", as used herein, indicates an amount necessary to administer to a host to obtain a therapeutic result, e.g., inhibition of proliferation of malignant cancer cells, tumor cells benign or other proliferative cells .

The invention also relates to pharmaceutical compositions that include a compound of the invention with a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, the present invention provides a method for the treatment of a disorder caused by, associated with or accompanied by interruptions of cell proliferation and / or angiogenesis that includes administration of a therapeutically effective amount of a compound of the formula I). Preferably, the method includes the administration of a compound of the formula (2), more preferably a compound of the formula (2a) or (2b) or (2c), still more preferably a compound of (2e) a ( 2r). Preferably, the disorder is selected from the group consisting of, without limitation, cancer (eg, breast cancer, colon cancer, prostate cancer, pancreatic cancer, leukemia, lymphoid), inflammatory diseases / immune system disorders, angiofibroma, cardiovascular diseases (eg restenosis, arteriosclerosis), fibrotic diseases (eg liver fibrosis), diabetes, autoimmune diseases, acute and chronic neurodegenerative diseases such as nervous tissue disruptions, Huntington's disease and infectious diseases such as fungal, bacterial and viral infections . In another embodiment, the disorder is a proliferative disorder. Preferably, the proliferative disorder is cancer. Cancer may include solid tumors or hematologic malignancies. The invention also provides agents for the treatment of a disorder caused by, associated with or accompanied by interruptions of cell proliferation and / or angiogenesis including a compound of the formula (I), as described herein. Preferably, the agent is an anticancer agent. Preferably, the agent contains a compound of the formula (2), more preferably a compound of the formula (2a) or (2b) or (2c), still more preferably a compound of the formula (2e) a (2r) ). The invention also relates to the use of compounds of the formula (I) in the preparation of a medicament for the treatment of a disorder caused by, associated with or accompanied by interruptions of cell proliferation and / or angiogenesis. Preferably, the disorder is a proliferative disorder, most preferably cancer. Surprisingly, the compounds of the present invention show low toxicity, together with a powerful antiproliferative activity.

In yet another embodiment, the invention provides a method of treating a disorder, disease or pathological condition that can be treated by the inhibition of histone deacetylase, which includes the administration of a therapeutically effective amount of a compound of the formula ( I). In yet another embodiment, the invention provides a method of treating a disorder, disease or pathological condition mediated by deacetylase activity, for example of histone deacetylase, which includes the administration of a therapeutically effective amount of a compound of the formula ( I). Preferably, the method includes the administration of a compound of the formula (2), more preferably a compound of the formula (2a) or (2b) or (2c), more preferably a compound of the formula (2e) a ( 2r), as described herein. Preferably, the disorder is selected from the integrated group, without limitations, by proliferative disorders (e.g. cancer); neurodegenerative diseases such as Huntington's disease, polyglutamine diseases, Parkinson's disease, Alzheimer's disease, seizures, degeneration of the black and striated nuclei, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis and dyskinesia, familial tremor, Gilles syndrome Tourette, diffuse Lewy body disease, progressive supranuclear palsy, 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 such as type 2 diabetes; degenerative diseases of the eye, including glaucoma, macular degeneration associated with age, rubeotic glaucoma, interstitial keratitis, diabetic retinopathy; inflammatory diseases and / or disorders of the immune system, for example 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; diseases related to angiogenesis, such as cancer, psoriasis, rheumatoid arthritis; psychological disorders such as bipolar illness, schizophrenia, depression and dementia; cardiovascular diseases such as heart failure, restenosis and arteriosclerosis; fibrotic diseases such as hepatic fibrosis, cystic fibrosis and angiofibroma; infectious diseases such as fungal infections, for example 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 such as thalassemia, anemia and sickle cell anemia. The invention also provides agents for the treatment of a disorder, disease or pathological condition that can be treated by the inhibition of histone deacetylase which includes a compound of the formula (I), as described herein. Preferably, the agent is an anticancer agent. The invention also relates to the use of compounds of the Formula (I) in the preparation of a medicament for the treatment of a disorder, disease or pathological condition that can be treated by the inhibition of histone deacetylase. In another embodiment, the invention provides a method for modifying deacetylase activity that includes contacting deacetylase with a compound of formula (I). Preferably, the deacetylase activity is deacetylase history activity, even more preferably the histone deacetylase activity of class I. Preferably, the histone deacetylase is HDAC1 or HDAC8. The invention also provides a method for inhibiting cell proliferation, including administering an effective amount of a compound according to the formula (1) . In still another aspect, the invention provides a method for the treatment of a neurodegenerative disorder in a patient that includes the administration of a therapeutically effective amount of a compound of the formula (I). Preferably, the method includes the administration of a compound of the formula (2), more preferably a compound of the formula (2a) or (2b) or (2c), even more preferably a compound of (2e) to (2r), as described herein. Preferably, the neurodegenerative disorder is Huntington's disease. The invention also provides agents for the treatment of neurodegenerative disorders that include a compound of Formula (I), as described herein. Preferably, the agent is anti Huntington agent.

The invention also relates to the use of the compounds of the Formula (I) in the preparation of a medicament for the treatment of a neurodegenerative disorder. Preferably, the neurodegenerative disorder is Huntington's disease. In still another aspect, the invention provides a method of treating an inflammatory disease and / or an immune system disorder in a patient, which includes administering a therapeutically effective amount of a compound of the formula (I). Preferably, the method includes the administration of a compound of the formula (2), more preferably a compound of the formula (2a) or (2b) or (2c), even more preferably a compound of the formula (2e) a (2r), as described herein. In one embodiment, the inflammatory disease and / or disorder of the immune system 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 inflammatory diseases and / or disorders of the immune system that include a compound of Formula (I), as described herein. The invention also relates to the use of compounds of the Formula (I) in the preparation of a medicament for the treatment of inflammatory diseases and / or disorders of the immune system. In one embodiment, the inflammatory disease and / or disorder of the immune system is rheumatoid arthritis. In another embodiment, the inflammatory disease and / or immune system disorder is systemic lupus erythematosus. In another embodiment, the present invention provides the use of a compound of Formula (I) to modify the activity of deacetylase, preferably the activity of histone deacetylase, with even greater preference HDAC1 or HDAC8. The invention also provides the use of a compound of Formula (I) to treat cancer. In another embodiment, the cancer is selected from a group that includes, without limitation, breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, kidney cancer, gastric cancer, colon cancer , pancreatic cancer and brain cancer. The present invention also provides the use of a compound of the Formula (I) in the preparation of a medicament for the treatment of hematological malignancies. Preferably, the hematological malignancy is selected from the group consisting of B-cell lymphoma, T-cell lymphoma and leukemia.

The invention also provides a method for the treatment of a hematological malignancy that includes the administration of an effective amount of a compound of the Formula (I). The invention also provides an agent for the treatment of a hematological malignancy that includes a compound of Formula (I). The invention also provides the use of a compound of Formula (I) in the preparation of a medicament for the treatment of solid tumors. The solid tumor is preferably selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, kidney cancer, gastric cancer, colon cancer, pancreatic cancer and brain cancer. The invention also provides a method for the treatment of a solid tumor that includes the administration of an effective amount of a compound of Formula (I). The solid tumor is preferably selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, ovarian cancer, prostate cancer, head and neck cancer, kidney cancer, gastric cancer, colon cancer and brain cancer. .

The invention also provides agents for the treatment of solid tumors that include a compound of the formula (I). In still another aspect, the invention provides the use of a compound of the formula (I) in the preparation of a medicament for the induction of cell death, such as apoptosis of tumor cells. The invention also provides a method for inhibiting the proliferation of tumor cells, for example by the administration of a compound according to formula (I). The invention also provides a method for inhibiting histone deacetylase activity which includes contacting the histone deacetylase with an effective amount of a compound according to formula (I). The invention also provides the use of a compound of the formula (I) in the preparation of medicaments for the induction of apoptosis of tumor cells. In another embodiment, the invention provides a method for inducing apoptosis in tumor cells that includes the administration of an effective amount of a compound of the formula (I).

DETAILED DESCRIPTION OF THE INVENTION Hydroxamate compounds are described, for example acylurea / sulfonylurea containing hydroxamic acid in one of the substituents, which may be inhibitors of deacetylases, for example, without limitations, histone deacetylase inhibitors. The hydroxamate compounds may be suitable for the prevention or treatment of a disorder caused by, associated with or accompanied by interruptions of cell proliferation and / or angiogenesis when used alone or together with a pharmaceutically acceptable carrier, diluent or excipient. An example of such a disorder is cancer. As used herein, the term "cancer" is a general term intended to encompass the vast number of pathological conditions that are characterized by the uncontrolled abnormal growth of cells. It is anticipated that the compounds of the invention will be useful for the binding of various cancers, for example, without limitation, bone cancers such as Ewing's sarcoma, osteosa coma, chondrous coma and the like, brain tumors and CNS tumors such as acoustic neuroma, neuroblastomas, gliomas and other brain tumors, spinal cord tumors, breast cancer, colorectal cancers, colon cancer, advanced colorectal adenocarcinomas, endocrine cancers such as adenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, cancer parathyroid, thymic cancer, multiple endocrine neoplasm, gastrointestinal cancers such as gastric cancer, esophageal cancer, small bowel cancer, liver cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumor, gallbladder cancer, genitourinary cancers such as cancer of testicle, cancer of the penis, cancer of pros tata, gynecological cancers such as cervical cancer, ovarian cancer, vaginal cancer, uterine / endometrial cancer, vulvar cancer, trophoblastic gestational cancer, fallopian tube cancer, uterine sarcoma, head and ncancer, for example, oral cavity cancer , lip cancer, salivary gland cancer, laryngeal cancer, hypopharyngeal cancer, orthopharyngeal cancer, nasal cancer, paranasal cancer, nasopharyngeal cancer, leukemias such as childhood leukemia, acute lymphocytic leukemia, acute myeloid leukemia, lymphocytic leukemia chronic, chronic myeloid leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia, myelomas, hematological disorders such as myelodysplastic syndromes, myeloproliferative disorders, aplastic anemia, Fanconi anemia, Waldenstrom's macroglobulinemia, lung cancers, for example cancer of small cell lung, lung cancer of non-small cells, lympholas such as Hodgkin's disease, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, AIDS-related lymphoma, B-cell lymphoma, Burkitt's lymphoma, eye cancers such as retinoblastoma, intraocular melanoma, skin cancers such as melanoma, non-melanoma skin cancer, Merkel cell cancer, soft tissue sarcomas such as soft tissue sarcoma of childhood, adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancers such as kidney cancer, Wilms tumor, bladder cancer, urethral cancer, and transitional cell cancer. Preferably, cancers that can be treated with the compounds of the present invention include, without limitation, breast cancer, colon cancer, pancreatic cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer , kidney cancer, gastric cancer and brain cancer. Preferably, cancers that can be treated with the compounds of the present invention include, without limitation, B-cell lymphoma (e.g., Burkitt's lymphoma), leukemias (e.g., acute promyelocytic leukemia), cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma. Preferably, cancers that can be treated with compounds of the present invention include without limitation solid tumors and hematologic malignancies. The compounds can also be used for the treatment of a disorder related to, related to or associated with the dysregulation of histone deacetylase (HDAC). Numerous disorders have been linked to or are known to be mediated at least in part by HDAC activity, where HDAC activity is known to play an important role in triggering the onset of a disease, or whose symptoms are known, or demonstrated that they are relieved with HDAC inhibitors. Among disorders of this type, which are expected to be susceptible to treatment with the compounds of the invention, include, without limitation, the following: proliferative disorders (e.g., cancer); neurodegenerative diseases such as Huntington's disease, polyglutamine diseases, Parkinson's disease, Alzheimer's disease, seizures, degeneration of the black and striated nuclei, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis and dyskinesia, familial tremor, Gilles syndrome Tourette, diffuse disease of Lewy bodies, progressive supranuclear palsy, 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, ataxia Progressive and Shy-Drager syndrome; metabolic diseases such as type 2 diabetes; degenerative diseases of the eye such as glaucoma, macular degeneration associated with age, rubeotic glaucoma, interstitial keratitis, diabetic retinopathy; inflammatory diseases and / or disorders of the immune system such as 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; diseases including angiogenesis such as cancer, psoriasis, rheumatoid arthritis; psychological disorders such as bipolar illness, schizophrenia, mania, depression and dementia; cardiovascular diseases such as heart failure, restenosis and arteriosclerosis; fibrotic diseases such as hepatic fibrosis, guia fibrosis and angiofibroma; infectious diseases such as fungal infections, for example 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 such as thalassemia, anemia and sickle cell anemia. The hxdroxamate compounds of the present invention have the following structure (I): Formula (I) wherein R is a linking moiety; R1 is selected from the group consisting of H, Ci-C6 alkyl and acyl; M is selected from the group consisting of O, S, H, NR4, NOH and OR4; R 2 is selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalguenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl , arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, phenoxy, benzyloxy, COOR4, CO HR4, NHCOR4, NHCOOR4, NHCONHR4, C (= NOH) R4, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted; or R2 together with the nitrogen to which it is attached and a portion of R form an optionally substituted heterocycloalkyl group; R3 is selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkyl, heteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulphonylamino, phenoxy, benzyloxy, C00R4, CONHR4, HCOR4, HCOOR4 NHCONHR4, C (= N0H) R4, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted; Q is selected from the group consisting of -S (0) 2-, - C (= 0) - and -C (= S) -; G is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; each R4 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; or one of its pharmaceutically acceptable salts or prodrugs. In a preferred embodiment, the compounds having the formula (2) Formula (2) wherein R1 is selected from the group consisting of H, Ci-C6 alkyl and acyl; L is a single bond or is a Cx-C5 hydrocarbon chain which may contain 0 to 2 multiple bonds independently selected from double bonds and triple bonds and wherein the chain may optionally be interrupted by at least one of -O -, -S-, - S (O) - and -S (0) 2- and the chain may be optionally substituted with one or more substituents selected, independently, from the group consisting of Ci-C alkyl; Z is selected from the group consisting of a single bond, (R1), 0, S, S (0) and S (0) 2; A is selected from the group consisting of a single bond, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene and optionally substituted heterocycloalkylene; B is selected from the group consisting of a simple linkoptionally substituted acylamino, optionally substituted aminoacyl, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted arylalkylene, optionally substituted heteroarylalkylene, optionally substituted alkylarylene, optionally substituted alkylheteroarylene, optionally substituted Cx-C3 alkylene, optionally substituted heteroalkylene, optionally substituted cycloalkylene, optionally heterocycloalkylene substituted and - (CH2) mC (O) -N (R4) - (CH2) n- optionally substituted, wherein n is an integer from 0 to 6, m is an integer from 0 to 6; M is selected from the group consisting of O, S, NH, NR4, NOH and ÑOR4; R 2 is selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkyl, heteroalkyl , heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalipyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, phenoxy, benzyloxy, COOR4, CONHR4 , NHCOR4, NHC00R4, NHCONHR4, C (= NOH) R4, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulphonyl, alkylsulfinyl, aryl-l-phonyl, aryl-l-linoyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted; or R2 together with the nitrogen to which it is attached and a portion of B form an optionally substituted heterocycloalkyl group; R3 is independently selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, phenoxy, benzyloxy, COOH, COOR4, SH, CONHR4, HCOR4, NHCOOR4, NHCONHR4, C (= N0H) R4, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted; Q is selected from the group consisting of -S (0) 2-, - C (= 0) - and -C (= S) -; G is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; each R4 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; or one of its pharmaceutically acceptable salts or prodrugs. In another preferred embodiment of the compounds of the formula (2) are compounds of the formula (2a) Formula (2a) wherein R1 is selected from the group consisting of H, Ci-C6 alkyl and acyl; L is a single bond or is a Ci-C3 hydrocarbon chain which may contain 0 to 2 multiple bonds independently selected from double bonds and triple bonds and wherein the chain may be optionally interrupted by at least one of -O -, -S-, - S (O) - and -S (O) 2- and the chain can be optionally substituted with one or more substituents selected, independently, from the group consisting of Ci-C4 alkyl; Z is selected from the group consisting of a single bond, (R1), O, S, s (0) and S (0) 2; A is selected from the group consisting of a single bond, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene and optionally substituted heterocycloalkylene; B is selected from the group consisting of a single bond, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted arylalkylene, optionally substituted heteroarylalkylene, optionally substituted alkylarylene, optionally substituted alkylheteroarylene, optionally substituted Ci-C3 alkylene, optionally substituted heteroalkylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, and - (CH 2) m -C (O) -N (4) - (CH 2) n- optionally substituted, wherein n is an integer from 0 to 6, m is an integer from 0 to 6; M is selected from the group consisting of O, S, NH, NR4, NOH and OR4; R 2 is selected from the group consisting of H, C 1 -C 10 alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C 4 -C 9 heterocycloalkylalkyl, cycloalkylalkyl (for example, cyclopropylmethyl), arylalkyl (for example benzyl), heteroarylalkyl (for example pyridylmethyl), hydroxyl, hydroxyalkyl, alkoxy, amino, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C (0) 0R4, -CONHR4, -NHCONHR4, C (= NOH) R4 and acyl R3 is selected from the group consisting of H, C1-C10 alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, ethercycloalkyl, heteroaryl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl (eg, cyclopropylmethyl), arylalkyl (eg benzyl example), heteroarylalkyl (for example pyridylmethyl), hydroxyl, hydroxyalkyl, alkoxy, amino, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsu lfonil, arylsulfonyl, aminosulfonyl, -C (0) OR4, - CONHR4, -NHCONHR4, C (= NOH) R4 and acyl, · Q is selected from the group consisting of -S (0) 2- / -C0- and -C (= S) -; G is selected from optionally substituted aryl, optionally substituted heteroaryl, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl, wherein substituents are independently selected from the group consisting of X, Y, R4 , hydroxyl, hydroxyalkyl, alkoxy, amino, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C (0) OR 4, -C (0) OH, -SH, - CONHR 4, -NHCONHR 4 and C (= NOH) R4; R 4 is selected from the group consisting of C 1 -C 4 alkyl, heteroalkyl, aryl, heteroaryl and acyl; X and Y are the same or different and are independently selected from the group consisting of H, halo, alkyl Ca-C4, N02, OR4, SR4, C (0) R5 and NR6R7; R5 is Ci-C alkyl; R6 and R7 are the same or different and are independently selected from the group consisting of H, Ci-C6 alkyl, C-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl or one of its salts or prodrugs pharmaceutically acceptable Particularly preferred embodiments within the scope of these formulas are as previously described. In particular embodiments, the compound is selected from the group consisting of the following compounds listed in the following table 8- [3- (4-methyl-benzenesulfonyl) -ureido]) -octanoic acid hydroxyamide, 7- [3- (4- (4-methyl-benzenesulfonyl) -ureido] hydroxyamide - heptanoic acid hydroxyamide 6- [3- (4- methylbenzenesulfonyl) -ureido]) - hexanoic, 6- [3- (benzenesulfonyl) -ureido]) -hexanoic acid hydroxyamide N-hydroxy-4- [3- (4-methylbenzenesulfonyl) ureido] methylbenzamide, N-hydroxy- 2-. { 4- [3- ilbenzenesulfonyl] eido] -phenyl} - etamida, N-hydroxy-2-. { 3- [3- lbencensulfoni1 ido] -phenyl} - acetamide, N-idroxy-3-. { 4- [3- ilbenzenesulfoni-1-eido] -phenyl} - acrylamide, N-hydroxy-3-. { 3- [3- ureido) -hexaenoic acid 7- (3-benzoylureido) -heptanoic acid hydroxyamide, 8- (3-benzoylureido) -octanoic acid hydroxyamide, 6- [3-benzoyl-1- (3-phenyl) hydroxyamide -propyl) -ureido] -hexanoic acid 4- (3-benzoyl-ureidomethyl) -N-hydroxy-benzamide, 2- [4- (3-benzoyl-ureido) -phenyl] -N-hydroxy-acetamide, 2- [3 - (3-benzoyl-ureido) -phenyl] -N-hydroxy-acetamide, 3- [4- (3-benzoyl-ureido) -phenyl] -N-hydroxy-acrylamide, 3- (4. {3-benzoyl-l- [2- (lH-indol-3-yl) -ethyl} ] -ureidomethyl.}. - phenyl) -N-hydroxy-acrylamide, 3- [4- (3-benzoyl-l-pyridin-3-ylmethyl-ureidomethyl) -phenyl] -N-hydroxy-acrylamide, 3-. { 4- [3-benzoyl-1- (3-hydroxy-propyl) -ureidomethyl] -phenyl} -N-hydroxy acrylamide, 4-. { 3-benzoyl-l- [2- (lH-indol-3-yl) -ethyl] -ureidomethyl} - N-hydroxybenzamide, 4- (3-benzoyl-ureido) -N-hydroxy-N-butyramide, 4- (3-benzoyl-l-benzyl-reidomethyl) -N-hydroxy-benzamide, 4- [3- benzoyl-1- (2-pyridin-2-yl-ethyl) -ureidomethyl] -N-hydroxy-benzamide, 4- [3-benzoyl-1- (3-hydroxy-propyl) -ureidomethyl] -N-idroxy-benzamide , 3- [4- (3-benzoyl-l-benzyl-ureidomethyl) -phenyl] -N-hydroxy-acrylamide, 3-. { 4- [3-benzoyl-1- (3-phenyl-propyl) -uretimethyl] -phenyl} -N-hydroxy acrylamide, 3-. { 4- [3-benzoyl-1- (2-phenoxy-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide, 4- [3-benzoyl-l- (3-phenyl-propyl) -ureidomethyl] -N-hydroxy-benzamide, 4- (3-benzoyl-l-pyridin-3-ylmethyl-ureidomethyl) -N-hydroxy-benzamide, (S) -6- [2- (3-benzoyl-reido) -3- (lH-indol-3-yl) -propionylamino] -hexanoic acid idroxyamide, 4- (4-) benzoylaminocarboni 1-piperazin-1-ylmethyl) -N-hydroxy-benzamide, 7- (3-benzoyl-l-pyridin-2-ylmethyl-ureido) -heptanoic acid hydroxyamide, 6- (3-benzoyl) hydroxyamide -pyridin-2-ylmethyl-ureido) -hexanoic, 3-. { 4- [3-benzoyl-l- (2-morpholin-4-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide, 7- (3-benzoyl-1-benzyl-ureido) -heptanoic acid hydroxyamide, 6- (3-Benzoyl-1-benzyl-ureido) -hexanoic acid hydroxyamide, 3-. { 4- [3-benzoyl-1- (2-pyridin-2-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide, 3- [4- (3-benzoyl-l-phenethyl-ureidomethyl) -phenyl] -N-hydroxy-acrylamide, 3- (4-. {3-benzoyl-1- [2- (4-bromo-phenyl) ethyl] -ureidomethyl} phenyl) -N-hydroxy-acrylamide, 3- (4. {3-benzoyl-l- [2- (4-fluoro-phenyl) -ethyl} - ureidomethyl.}. - phenyl) -N-hydroxy acrylamide, hydroxycarbamoyl-vinyl) -benzyl] -piperazine-1-carbonyl} - benzamide,, 3-. { 4- [3-benzoyl-1- (3-imidazol-1-yl-propyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide, 3- (4-. {3-benzoyl-l- - 15 acrylamide, 6- (3-benzoyl-thioureido) -hexanoic acid hydroxyamide, 20 il- - acrylamide, 3-. { 4- [3-benzoyl-l- (2-pyridin-3-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy acrylamide, 3-. { 4- [3-benzoyl-l- (2-pyridin-4-yl-ethyl) -ureidomethyl] · 10 phenyl} -N-hydroxy acrylamide, 3-. { 4- [3-benzoyl-l- (2-piperidin-l-yl-ethyl) -ureidomethyl] 15 phenyl } -N-hydroxy acrylamide, 3- . { 4- [3-benzoyl-1- (2-pyrrolidin-1-yl ethyl) -ureidomethyl] phenyl} -N-hydroxy acrylamide 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 denotes that the group may or may not be substituted or condensed (so as to form a condensed polycyclic system), with one or several groups of substituents. Preferably, the groups of substituents are one or more groups independently selected from the group consisting of halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cicloalilalquilo, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocicloalquilalquenilo, arylalkenyl, heteroarylalkenyl, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, arylalkyl, heteroarylalkyl, cycloalkylalkyl , heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -COOH, -COR5, -C (0) OR5, CO HR5 , NHCOR5, NHCOOR5, HCO HR5, C (= NOH) R5, -SH, -SR5, -0R5 and acyl. "Halogen" represents chlorine, fluorine, bromine or iodine. "Alkyl" as a group or part of a group refers to a linear or branched aliphatic hydrocarbon group, preferably a Ci-Ci4 alkyl, more preferably Ci-Cao alkyl, most preferably Ci-C6, unless otherwise indicated . Examples of linear and branched C x C 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like. "Alkylamino" includes both monoalkylamino and dialkylamino, unless specified. "Monoalkylamino" means a group -NH-alkyl, "dialkylamino" means a group - (alkyl) 2 / wherein the alkyl is as defined above. The alkyl group is preferably a Ci-C6 alkyl group. "Arylamino" includes both mono-arylamino and di-arylamino, unless specified. "Monoarylamino" means a group of the formula "aryl-NH-, di-arylamino" means a group of the formula (aryl2) -N-, where the aryl is as defined herein. "Acyl" means a group R-C (= 0) - or G-C (= S) -, wherein R is selected from aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, arylalkyl and heteroarylalkyl, as described herein. G could also be substituted. Examples of acyl include acetyl, benzoyl, phenylacetyl. "Alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be linear or branched, preferably with 2-14 carbon atoms, more preferably 2-12 carbon atoms. carbon, most preferably 2-6 carbon atoms, in the chain. The group may contain a plurality of double bonds in the normal chain and the orientation of each is, independently, E or Z. The example alkenyl group includes, but is not limited to, ethenyl and propenyl. "Alkoxy" refers to an -O-alkyl group, wherein alkyl is defined herein. Preferably, the alkoxy is a Ci-C6 alkoxy. Examples include, but are not limited to, methoxy and ethoxy.

"Alkenyloxy" refers to an -O-alkenyl group wherein the alkenyl is as defined herein. Preferred alkenyloxy groups are Ci-C5 alkenyloxy groups.

"Alkynyloxy" refers to an -O-alkynyl group, wherein the alkynyl is as defined herein. Preferred alkynyloxy groups are C ± C6 alkynyloxy groups.

"Alkoxycarbonyl" refers to a group -C (O) -0-alkyl, wherein the alkyl is as defined herein. The alkyl group is preferably a Cx-C6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. "Alkylsulfinyl" means a group -S (O) -alkyl, wherein the alkyl is as defined above. The alkyl group is preferably a Ci-C6 alkyl group. Exemplary alkylsulfinyl groups include, but are not limited to, methylsulfinyl and ethylsulfinyl. "Alkylsulfonyl" refers to a -S (0) 2-alkyl group, wherein the alkyl is as defined above. The alkyl group is preferably a Ci-C6 alkyl group. Examples include, but are not limited to, methylsulfonyl and ethylsulfonyl. "Alkynyl" as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be linear or branched, preferably with 2-14 carbon atoms, more preferably 2-12 carbon atoms in the chain, preferably 2-6 carbon atoms in the chain.

Exemplary structures include, but are not limited to, ethinyl and propinyl. "Alkylaminocarbonyl" refers to an alkylaminocarbonyl group, wherein alkylamino is as defined above. "Aminoacyl" refers to the formula -C (O) - (CH2) m- (CH) (NR6R7) - (CH2) n -R6, wherein R6 and R7 are as defined above, m and n are selected integers from 0 to 6. "Aryl" as a group or part of a group denotes (i) an aromatic, monocyclic or fused polycyclic, optionally substituted carbocycle (cyclic structure having ring atoms that are carbon in its entirety), preferably with 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) a partially saturated, optionally substituted bicyclic aromatic carbocyclic moiety, wherein a phenyl and a C5-7 cycloalkyl or C5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetra idronaphthyl, indenyl or indanyl. The aryl group may be substituted by one or more substituent groups. When the aryl ring is divalent, it refers to "arylene" in this application.

"Arylalkenyl" means an aryl-alkenyl group, wherein the aryl and the alkenyl are as previously described. Exemplary arylalkenyl groups include phenylallyl. "Arylalkyl" means an aryl-alkyl group, wherein the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Ca-5 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthelenylmethyl. "Cycloalkyl" refers to a saturated or partially saturated, monocyclic or condensed or polycyclic spiro carbocycle, preferably with 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. The foregoing for the alkyl and cycloalkyl substituents, also applies to the alkyl portions of other substituents, such as, without limitation, alkoxy substituents, alkylamines, alkylketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester, and the like. "Cycloalkylalkyl" means a cycloalkylalkyl- group, wherein the cycloalkyl and alkyl moieties are as previously described. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. "Heterocycloalkyl" refers to a ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms. Each ring preferably has 3 to 4 members, more preferably 4 to 7 members. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydroranyl, morphino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane and 1,4-oxatiapane. "Heterocycloalkenyl" refers to a heterocycloalkyl as described above, but with at least one double bond. "Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl group, wherein the heterocycloalkyl and alkyl moieties are as previously described Example heterocycloalkylalkyl groups include (2-tetrahydrofuryl) methyl, (2-tetrahydrothiofranyl) methyl "Heteroalkyl" refers to a straight or branched chain alkyl group preferably having from 2 to 14 carbon atoms, more preferably 2 to 10 carbon atoms in the chain, wherein one or more of the carbon atoms were replaced by a heteroatom selected from S, 0, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkylamines, alkyl sulfides and the like. "Cycloalkenyl" means a system of an optionally substituted non-aromatic monocyclic or multicyclic ring containing at least one carbon double bond -carbon and preferably having from 5 to 10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloperdenyl. The cycloalkenyl group may be substituted by one or more substituent groups. "Heteroaryl" refers to a monocyclic or condensed polycyclic aromatic heterocycle (ring structure preferably having a 5- to 10-membered aromatic ring containing one or more heteroatoms selected from N, O and S). Typical heteroaryl substituents include furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine, indole, benzimidazole and the like. When the heteroaryl ring is divalent, it refers to "heteroarylene" in this application.

"Heteroarylalkyl" means a heteroarylalkyl group, wherein the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.

"Lower alkyl" as a group means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched with 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary butyl. "Sulfonyl" means a group R-S02-, wherein R is selected from aryl, heteroaryl, alkyl, cycloalkyl, ethercycloalkyl, arylalkyl and heteroarylalkyl , as described herein, G could also be substituted, Examples of sulfonyl include methanesulfonyl, benzenesulfonyl, 4-methylbenzenesulfonyl, naphthalene-2-sulfonyl, and the like, which are understood to be included in the family of compounds of formula I , as well as in formulas 2 to 2k, the isomeric forms including diastereoisomers, enantiomers, tautomers and geometric isomers in the "E" or "Z" configuration isomer or a mixture of the E and Z isomers. Tam 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 invention may exist as stereoisomers, racemates and / or mixtures of enantiomers and / or diastereomers. All of these stereoisomers, racemates and mixtures thereof are within the scope of the present invention. In addition, formula I is intended to cover, when appropriate, solvated and non-soldered forms of the compounds. Accordingly, each formula includes compounds with the indicated structure, for example the hydrated and non-hydrated forms. In addition to the compounds of the formula I, the HDAC inhibiting agents of the various embodiments include salts, pharmaceutically acceptable prodrugs and active metabolites of said compounds, and pharmaceutically acceptable salts of said metabolites. The term "pharmaceutically acceptable salts" refers to salts that maintain the biological activity of interest of the compounds identified above, and include acid addition salts and pharmaceutically acceptable base addition salts. Salts by the addition of pharmaceutically acceptable acids of the compounds of the formula I can be prepared from an inorganic acid or from an organic acid. Examples of said inorganic acids are hydrochloric, sulfuric and phosphoric acid. Suitable organic acids can be selected from classes of organic acids aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric acids , 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 as tetramethylammonium salt; salts by addition of amino acids 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 that for those skilled in the art the compounds, agents and Salts of the present invention may exist in different crystalline or polymorphic forms, all this with the intention of staying within the scope of the present invention and the specific formulas. "Prodrug" means a compound that is convertible in vivo by metabolic means (for example by hydrolysis, reduction or oxidation) to a compound of the formula I. For example, a prodrug ester of a compound of the formula I containing a hydroxyl group can be converted by hydrolysis in vivo into the original molecule. Suitable esters of the compounds of formula (I) which contain a hydroxyl group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-S-hydroxynaphthalates , gestises, isethionates, di-p-toluoyl tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and kinatos. As another example, a prodrug ester of a compound of the formula I containing a carboxy group can be converted by hydrolysis in vivo into the original molecule. (Examples of prodrug esters are those described by F. J. Leinweber, Drug Metab. Res., 18: 379, 1987). Among the possible HDAC inhibitors are those that have an IC50 value of 5 μ? or less. The administration of compounds of formula I to humans can be by any of the accepted modes of enteral administration, such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. The injection can be by bolus or by constant or intermittent infusion. In general, the active compound is included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver a therapeutically effective dose to the patient. In various embodiments, the inhibitor compound may be selectively toxic or more toxic to rapidly proliferating cells, eg, cancerous tumors, than to normal cells. The term "therapeutically effective amount" or "effective amount" is an amount sufficient to obtain beneficial or desirable clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to alleviate, alleviate, stabilize, reverse, slow or delay the progression of the disease state. The therapeutically effective amount can be determined easily by an expert by using conventional techniques or observing the results obtained in analogous circumstances. To determine the effective amount several factors are considered, for example the species of patients, their size, age, general health, the specific disease treated, the degree or severity of the disease, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability of the compound, the selected dosage regimen, the use of other medications and other relevant circumstances.

In order to use 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 easily select the appropriate form and administration mode, according to the particular characteristics of the selected compound, the pathological condition being treated, the stage of the pathological condition being treated and other circumstances Relevant We refer the reader to Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing Co. (1995) for more 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 carrier, diluent or excipient. The compounds of the invention, while effective themselves, are generally formulated and administered in the form of pharmaceutically acceptable salts, since in general these forms are more stable, crystallize more easily and have greater solubility. However, in general the compounds are used in the form of pharmaceutical compositions that are formulated according to the mode of administration sought. As such, another embodiment of the present invention provides a pharmaceutical composition that includes a compound of the formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. The compositions are prepared by methods well known in the art. In other embodiments, the invention provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. In such a case, the package or kit can be a container with a unit dose of the agent (s). The kits may include a composition comprising an effective agent as a concentrate (e.g., lyophilized compositions), which may be further diluted before use or may be provided at the use concentration, where the vials may include one or more dosages. For convenience, unique dosages in sterile vials can be provided in the kits so that the physician can use the vials directly, where the vials have the quantity and the sought concentration of the agent (s). With said container (s) various written materials such as instructions for use or a notification may be associated in the form prescribed by a governmental agency that regulates the manufacture, use or sale of pharmaceutical or biological products, where said Notification reflects the approval by that agency of the manufacture, use or sale for human administration.

The compounds of the invention may be used or administered in combination with one or more additional drugs including chemotherapeutic drugs or HDAC inhibitor drugs and / or methods (eg, surgery, radiotherapy) for the treatment of the above-mentioned disorders / diseases. The components can be administered in the same formulation or in different formulations. If administered in different formulations, the compounds of the invention can be administered sequentially or simultaneously with the other drug (s). In addition to being administered in combination with one or more additional drugs including chemotherapeutic drugs or HDAC inhibitor drugs, the compounds of the invention can be used in a combination therapy. In this case, the compounds are generally administered in combination with each other. Accordingly, one or more of the compounds of the invention can be administered simultaneously (as a combined preparation) or sequentially, in order to achieve a desired effect. This is of special interest when the therapeutic profile of each compound is different, so that the effect of the two drugs provides a better therapeutic result. The pharmaceutical compositions of the present invention for parenteral injection comprise pharmaceutically acceptable forms of solutions, sterile aqueous or non-aqueous aqueous dispersions, suspensions or emulsions, as well as sterile powders for reconstitution in sterile injectable solutions or dispersions just before use. Examples of suitable carriers, diluents, solvents or aqueous and non-aqueous vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and the corresponding suitable mixtures, vegetable oils (such as olive oil). ), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of cover materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers and dispersants. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid, and the like. It may also be convenient to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable dosage forms can be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin. If desired, and for a more effective distribution, the compounds can be incorporated into slow-release or targeted delivery systems, such as polymer matrices, liposomes and microspheres. Injectable formulations can be sterilized, for example, by filtration through a bacteria retention filter, or by the incorporation of 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 so. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In said solid dosage forms the active compound is mixed with at least one excipient or an inert pharmaceutically acceptable carrier, such as sodium citrate or disodium phosphate and / or a) fillers or expanders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia, 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) humectants such as, for example, cetyl alcohol and glycerol monostearate , h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycols solids, sodium lauryl sulphate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form can also comprise buffering agents. Solid compositions of a similar type can also be used as fillings of soft and hard gelatin capsules, with excipients such as lactose or lactulose, as well as high molecular weight polyethylene glycols and the like.

The solid substance dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with covers and leaflets, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. Optionally they may contain opacifying agents and may also consist of a composition for releasing the active ingredient (s) alone, or preferably in a certain part of the intestinal tract, optionally in a delayed manner.

Examples of included compositions that may be used include polymeric substances and waxes. If desired, and for a more effective distribution, the compounds can be incorporated into slow-release or targeted systems, such as polymer matrices, liposomes and microspheres. The active compounds may also have microencapsulated form, if appropriate, with one or more of the aforementioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable forms of emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as for example water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate. , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids and mixtures thereof.

In addition to the inert diluents, the oral compositions may also include adjuvants such as humectants, emulsifiers and suspending, sweetening, flavoring and perfuming agents. In addition to the active compounds, the suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan ethers, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature but liquid at body temperature, so it melts in the rectum or vaginal cavity and releases the active compound. Dosage forms for topical administration of a compound of the present invention include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any suitable preservative, buffer or propellant that may be required.

A preferred dosage will be in the range of 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, still more preferably 0.2 to 50 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day. As discussed above, the compounds of the described embodiments inhibit histone deacetylases. The enzymatic activity of a histone deacetylase can be measured by 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 histone deacetylase in the cell, which may be of the same histone deacetylase class or different histone deacetylase class. In some other embodiments, the histone deacetylase inhibitor interacts and / or predominantly reduces the activity of a histone deacetylase, for example HDAC-1, HDAC-3 or HDAC-8 belonging to HDAC class I enzymes [De Ruijter AJM et al, Biochem . J., 370, 737-749 (2003)]. Certain inhibitors of histone deacetylase preference 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 diseases or cell proliferative pathological conditions include cancer (including any metastases), psoriasis, smooth muscle cell proliferative disorders such as restenosis. The compounds of the invention may have particular utility for the treatment of tumors such as breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, head and / or neck cancer, or renal, gastric cancer, of pancreas and brain cancer, as well as hematological malignancies such as lymphoid and leukemias. In addition, the compounds of the invention may be useful for the treatment of a proliferative disease that is refractory to treatment with other chemotherapeutic agents.; and for the treatment of hyperproliferative pathological conditions such as leukemia, psoriasis and restenosis. In other embodiments, the compounds in this invention can be used to treat precancerous pathological conditions such as myeloid dysplasia, endometrial dysplasia and cervical dysplasia.

In addition, the compounds of the various embodiments described herein may be useful for the treatment of neurodegenerative diseases, and inflammatory diseases and / or disorders of the immune system. Preferably, the disorder of the group composed of cancer, inflammatory diseases and / or disorders of the immune system (for example, rheumatoid arthritis, systemic lupus erythematosus), angiofibroma, cardiovascular diseases, fibrotic diseases, diabetes, autoimmune diseases, acute neurodegenerative diseases and diseases is selected. Chronic diseases such as Huntington's disease, Parkinson's disease, interruptions of nervous tissue and infectious diseases such as fungal, bacterial and viral infections. In another embodiment, the disorder is a proliferative disorder. The histone deacetylase inhibitors of the invention have significant antiproliferative effects and favor differentiation, for example, cell cycle arrest in the Gl or G2 phases, and induce apoptosis.

Synthesis of deacetylase inhibitors The compounds of this invention can be prepared using the reaction pathways and synthesis schemes described below, employing techniques available in the art and starting materials that are readily available. The preparation of the particular embodiments is described in detail in the following examples, but the skilled person will recognize that the described chemical reactions can easily be adapted to prepare other agents different from the different embodiments. For example, the synthesis of non-exemplified compounds can be successfully carried out by means of modifications obvious to those skilled in the art, for example, by appropriately protecting the interfering groups, switching to other appropriate reagents known in the art or making modifications. from routine to reaction conditions. A list of suitable protecting groups can be found in organic synthesis in Protective Groups in Organic Synthesis by TW Greene and PGM Wut, 3rd edition, Wiley-InterScience, 1999. Alternatively, it will be recognized that other reactions disclosed herein or known in the art has applicability for the preparation of other compounds of the different embodiments. Reagents useful for synthesizing compounds can be obtained or prepared according to techniques known in the art. In the examples described below, unless otherwise indicated, all temperatures in the following description are in degrees Celsius and all parts and percentages are by weight, unless otherwise indicated. Various starting materials and other reagents were purchased from commercial suppliers, such as Aldric Chemical Company or Lancaster Synthesis Ltd., and were used without further purification, unless otherwise indicated. Tetrahydrofuran (THF) and?,? - dimethylformamide (DMF) were purchased from Aldrich in SureSeal flasks and used as received. All solvents were purified using standard methods in the art, unless otherwise indicated. The reactions shown below were performed under positive pressure of nitrogen, argon or with a drying tube, at room temperature (unless otherwise stated), in anhydrous solvents, and the reaction bottles are equipped with rubber septa to introduce substrates and reagents by means of a syringe. The glassware was dried in an oven and / or dried with heat. Thin-layer analytical chromatography was carried out on plates with silica gel 60 of F 254 bake glass (E Merck (0.25 mm)) and eluted with the appropriate solvent ratios (v / v). The reactions were tested by CCD and terminated when the starting material had been consumed.

The CCD plates were visualized by means of UV absorption or with a p-anisaldehyde spray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20% in ethanol) that was activated by heat, or by staining in an iodine chamber. The elaborations were typically carried out by doubling the reaction volume with the reaction solvent or the extraction solvent and then washing with the indicated aqueous solutions with 25% by volume of the extraction volume (unless otherwise indicated). The product solutions were dried over anhydrous sodium sulfate before filtering, and the evaporation of the solvents was carried out under reduced pressure in a rotary evaporator and scored as solvents removed in vacuo. Flash column chromatography [Still et al, J. Org. Chem., 43, 2923 (1978)] was performed using Merck grade E flash silica gel (47-61 mm) and a ratio of silica gel: crude material from about 20: 1 to 50: 1, unless otherwise indicated another thing. Hydrogenolysis was carried out at the indicated pressure or at ambient pressure. Reverse phase preparative HPLC (RPHPLC) was performed using a C18 column (5 um, 21.2 x 150 mm) at a flow rate of 20 ml / min and a linear gradient of 5 to 95% CH3CN + 0, 1% TFA (trifluoroacetic acid) for 18 min. The high-performance mass-dependent purification system (reverse phase HPLC) (HTP) was carried out using a Cie column (5 μm, 19 x 50 mm) at a flow rate of 30 ml / min and a linear gradient from 5 to 95% CH3CN + 0.05% TFA for 9 min. The fractions containing the desired product were lyophilized or evaporated to dryness in vacuo to provide the dry compound, or evaporated to remove the volatile organic solvent, then extracted with organic solvents (if necessary, ethyl acetate or dichloromethane, the pH of the aqueous solution could also be adjusted in order to obtain a free base, an acidic compound or the neutral compound). ¾ NMR spectra were recorded on a Bruker AV 00 instrument operating at 400 MHz, and the 13 C-NMR spectra were recorded operating at 100 MHz. The NMR spectra are obtained as CDC13 solutions (reported in ppm), using chloroform as reference standard (7.26 ppm and 77.00 ppm), CD30D (3.3 and 49.3 ppm), DMSO-d6 (2.50 and 39.5 ppm), or an internal standard of tetramethylsilane ( 0.00 ppm) when appropriate. Other NMR solvents were used when necessary. When reporting multiplicities of peaks, the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, bo br = width, dd = doublet of doublets, dt = doublet of triplets, tt = triple triplet. Coupling constants, when given, are reported in Hertz. The mass spectra were obtained using LC-MS in either ESI or APCL. No melting point was corrected.

All final products had a purity greater than 90% (by HPLC at wavelengths of 220 nm and 254 nm). The following examples are intended to illustrate the embodiments described and are not constructed to constitute limitations. Additional compounds, other than those described below, may be prepared using the reaction scheme described below or appropriate variations or modifications thereof.

Synthesis Scheme 1 illustrates the process used to prepare compounds of the formula (I), wherein 1 = R 3 = H, M = S (O) 2 or C = 0.

Formula (I) In scheme 1, R is a linking moiety or is equal to -BAZL- as defined for formula (2), R "is R minus one CH2, R11 is a Ci-C6 alkyl or benzyl , R21 is R2 minus one CH2 and R2 is as defined for formula (I).

The intermediate (2) in Scheme 1 could be prepared by (i) alkylation of amine (2a) with R2X (3af X is halo, eg, Br ", Cl ~ or a good leaving group), or (ii) reductive amination of amine (2a) with aldehyde (3b), or (iii) reductive amination of aldehyde (2b) with amine R2NH2 (3c).

Synthesis of sulfonylurea bound to hydroxamic acid (8) Scheme 1. The amine (2) or amine (2a, for 2 = H) is reacted with sulfonyl isocyanate (4) to give sulfonylurea (6) which is subsequently converted to hydroxamic acid (8) by amination of the ester with hydroxylamine. The hydroxamic acid (8) bound to sulfonylurea could also be synthesized by a synthetic route as described in Scheme 2. R12 is a protecting group; examples are benzyl, 2,4-dimethoxybenzyl, tetrahydro-pyran-2-yl and tert-butyl-dimethyl-silyl.

Scheme 2 The ester (6) is hydrolysed in the acid (6a). The acid is then converted to the hydroxamic acid (8) either by method A or method B.

Method A. (i) The acid is converted to acid chloride by treatment with C1C0C0C1 or S0C12, or other reagents under conditions of neutrality (such as Ph3P with CBr4, or 2, 4, 6-trichloro- [1, 3, 5 ] triazine); or (ii) the acid is converted to an active ester by reacting it with isobutyl chloroformate; (iii) the acid chloride or the active ester is reacted with hydroxylamine or the O-protected hydroxylamine [e.g., 0-benzylhydroxylamine, O- (2, -dimethoxybenzyl) -hydroxylamine,?,? -bis- (2, -dimethoxy-benzyl) -hydroxylamine, O- (tetrahydro-pyran-2-yl) -hydroxylamine, O- (tert-butyl-dimethyl-silyl) -hydroxylamine] to give the hydroxamic acid or the hydroxamic acid protected with O, in where the protecting group is subsequently removed by means of methods known in the literature such as hydrogenolysis to remove the benzyl group or acid cleavage to separate acid labile protecting groups.

Method B. Coupling of the acid with hydroxylamine or hydroxylamine protected with O (R12ONH2) with a coupling reagent, followed by removal of the protection group by means of methods known in the literature.

Synthesis of hydroxamic acid bound to acylurea (9) The hydroxamic acid (9) bound to acylurea could be synthesized by means of analogous methods to those used for the synthesis of hydroxamic acid (8) bound to sulfonylurea. Scheme 1. The amine (2) or the amine (2a, for R2 = H) is reacted with acylisocyanate (5) to give acylurea (7) which is subsequently converted to hydroxamic acid (9) by amination of the ester with hydroxylamine. The hydroxamic acid (9) bound to acylurea could also be synthesized by the method described in Scheme 3.

Scheme 3 On the other hand, the hydroxamic acid (8) bound to sulfonylurea and the hydroxamic acid (9) attached to acylurea could also be synthesized by a synthesis route described in the Scheme. Hydroxamate starting material protected with O amine (2c) or aldehyde (2d) is used to prepare the hydroxamate intermediate protected with O (2P) which is subsequently converted into the corresponding sulfonylurea (8a) and acylurea (9a). After removing the protection group, the sulfonylurea (8) and the acylurea (9) are obtained.

Scheme 4 Scheme 5 illustrates the process used to prepare compounds of the formula (I), wherein R1 = H, M = S (0) 2- R13 is selected from R11 or R12. Due to the acidity of the sulfonylurea (6), the R3 group could be introduced by alkylation of 6 with R3X (X = 1 ~, Br ~ or C1-) or by reaction with R3OH under a Mitsunobu reaction condition. The product (6b) could be converted to the hydroxamic acid (8b) using a condition similar to that described for (8) in Scheme 1, 2 or 4.

Scheme 5 (8b) The following preparation and the following examples are provided to enable those skilled in the art to understand more clearly and to implement the object of the present. They should not consider the scope of the invention as limiting, but merely illustrative and representative.

Intermediary 1 Preparation of 6- [3- (benzenesulfonyl) ureido] -hexanoic acid methyl ester To a mixture of 6-amino-hexanoic acid methyl ester (0.10 g, 0.5 mmol), triethylamine (0.12 g, 1.2 mmol, 0.17 mL) and DMAP (0.06 g, 0.05 mmol) in the presence of CH2C12 (5 mL) was added phenylsulfonyl isocyanate (0.12 g, 0.6 mmol). The reaction mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with water (10 mL) and extracted with CH2C12 (3 x 10 mL). The combined organic extracts were dried over gSO4, filtered and the solvent removed in vacuo. The crude residue was chromatographed (silica) with 1-10% MeOH in CH20 to give 6- [3- (benzenesulfonyl) ureido] -hexanoic acid methyl ester (0.1 g, 0.3 mmol, 58%) in the form of a colorless oil that solidified at rest. ¾ MN (CDC13) d 7.95-7.89 (2H, m), 7.66-7.53 (3H, m), 3.67 (3H, s), 3.22 (2H, q, J = 6.9 Hz), 2.29 (2H, t, J = 7.4 Hz), 1.62 (2 H, m, J = 7.4 Hz), 1.50 (2 H, m, J = 7.4 Hz) and 1.31-1.27 (2H, m).

Intermediary 2 Preparation of 4- [3- (toluene-4-sulfonyl) ureidomethyl-benzoic acid methyl ester Procedure as described in broker 1 above, but using the appropriate starting materials. Performance: 67%. Light yellow solid; LC-MS (ESI, positive mode) m / z 363 ([M + H] +). ¾ RM (DMSO-d6) d 10.78 (bs, 1 H), 7.85 (d, 2H, J = 8.2 Hz), 7.78 (d, 2H, J = 8.2 Hz), 7.40 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.1 Hz), 4.22 (d, 2H, J = 5.9 Hz), 3, 84 (s, 3H), 2.40 (s, 3H).

Intermediary 3 Preparation of 6- (3-benzoylureido) -hexanoic acid methyl ester To a mixture of 6-amino-hexanoic acid methyl ester hydrochloride (0.05 g, 0.27 mmol), triethylamine (0.069 g, 0.6 mmol, 0.096 ml) and DMAP (0.03 g, 0, 027 mmol) in the presence of CH2C12 (2 mL) was added benzoyl isocyanate (0.048 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with water (10 mL) and extracted with CH2C12 (3 x 10 mL). The combined organic extracts were dried over MgSO4, filtered and the solvent removed in vacuo. The crude residue was chromatographed with 1-10% MeOH in CH2C12 to give 6- (3-benzoylureido) -hexanoic acid methyl ester (0.087 g, 0.2 mmol, quantitative yield) as a colorless oil which solidified Resting. XH RM (CDC13) d 8.66 (br s, 2H), 7.89-7.87 (m, 2H), 7.62-7.48 (m, 3H), 3.67 (s, 3H) , 3.39 (q, 2H, J = 7.0 Hz), 2.33 (t, 2H, J = 7.4 Hz), 1.70-1.60 (m, 4H) and 1.45- 1.40 (m, 2 H).

Large scale To a mixture of 6-amino-hexanoic acid methyl ester hydrochloride (0.363 g, 2.00 mmol), triethylamine (0.588 mL, 4.00 mmol) and DMAP (0.024 g, 0.20 mmol) in the presence of CH2C12 (10 mL) was added benzoyl isocyanate (0.276 mL, 2.20 mmol). The reaction mixture was stirred at room temperature for 6 h. To the reaction mixture was added brine and extracted with 10% methanol in dichloromethane. The extract was dried and concentrated and purified by reverse phase preparative HPLC to give 6- (3-benzoyl-ureido) -hexanoic acid methyl ester (0.459 g, 79%).

Intermediary 4 Preparation of 6- (3-benzoyl-ureido) -hexanoic acid To a solution of 6- (3-benzoyl-ureido) -hexanoic acid methyl ester (0.043 g, 0.14 mmol) in dry MeOH (2 mL) was added NH2OH-HCl (0.015 g, 0.2 mmol) followed NaOMe (0.08 ml, 5.38 M, 0.4 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 hours, and then diluted with acetonitrile and the solvent removed in vacuo. The crude residue was purified by http induced by mass. No hydroxamic acid was obtained, but the corresponding 6- (3-benzoyl-ureido) -hexanoic acid was obtained in the form of white fluffy solid. ¾ NMR (DMSO-d6) d 10.6 (1 H, s), 8.60 (1H, bs), 7.92-7.90 (2H, m), 7.58-7.55 (1H, m), 7.47-7.43 (2H, m), 3.20- 3.15 (2 H, m), 2.16 (2 H, t, J = 7.3 Hz), 1.52 -1.42 (4 H, m) and 1.30-1.24 (2H, m).

Intermediary 5 Preparation of 4- (3-benzoyl-ureidomethyl) -benzoic acid methyl ester To a solution of 4-aminomethyl-benzoic acid methyl ester hydrochloride (0.425 g, 2.11 mol), triethylamine (0.60 ml, 0.4.31 mmol) and DMAP (0.020 g, 0.16 mmol) in CH2C12 (10 mL) was added benzoyl isocyanate (Sigma-Aldrich, 90% pure, 0.413 g, 0.2.53 mmol). The reaction mixture was stirred at room temperature for 2.5 h and evaporated to dryness. To the white residue was added water, filtered and the solid substance was washed with water (x 4) and dried. 4- (3-Benzoyl-ureidomethyl) -benzoic acid methyl ester was obtained as a white solid substance (0.586 g, 89%). Purity by HPLC at 254 nm: 99.7%; LC-MS (ESI, positive mode) m / z 313 ([+ H] +); ¾ NMR (DMSO-dg) d 9.12 (1 H, t, J = 5.4 Hz), 8.68 (1 H, S), 8.04 (2H, dt, J = 8.4, 1 , 8 Hz), 7.89 (2H, dt, J = 8.2, 1.6 Hz), 7.62 (1 H, tt, J = 7.4, 1.8 Hz), 7.50 ( 2H, t, J = 8.0 Hz), 7.44 (2H, d, J = 8.4 Hz), 4.64 (2H, d, J = 6.0 Hz), 3.93 (3H, s).

Intermediary 6 Preparation of 3- (4- (3-benzoyl-l- [2- (lH-indol-3-yl) -ethyl] -ureidomethyl} -phenyl) -acrylic acid methyl ester To a solution of 3- (4- ([2- (1H-indol-3-yl) -ethylamino] -methyl] -phenyl) -acrylic acid methyl ester (0.100 g, 0.300 mmol), triethylamine (0.063) mi, 0.45 mmol) and D AP (0.004 g, 0.03 mmol) in CH2C12 (3 mL) was added benzoyl isocyanate (90% pure, 0.045 mL, 0.36 5 mmol). The mixture was stirred at room temperature for 22 h and extracted with ethyl acetate.The extract was dried (MgSO.sub.4) and concentrated, The residue was purified by HTP, and 3- (4- (3-benzoyl-1-methyl) methyl ester was obtained. [2- (1H-indol-3-yl) -ethyl] -ureidomethyl] -phenyl) -acrylic acid in the form of a pale yellow solid (0.072 g, 50%).

(ESI, positive mode) m / z 482 ([+ H] +); XH NMR (SO-d6 D) 5 10.82 (1H, s), 10.25 (1H, bs), 7.83 (2H, d, J = 8.1 Hz, PhH), 7.74 (1 H, d, J = 16.0 Hz), 7.61 (1 H, t, J = 7.3 Hz), 7 , 50 (2H, t, J = 7.5 Hz), 7.45 (2H, br type d), 7.38-7.35 (1 H, br m), 7.31 (1 H, d, J = 8.1 Hz), 7.10 (1 H, type bs), 7.02 (1 H, t, J = 7.2 Hz), 6.90-6.70 (1 H, s very wide) ), 6.66 (1 H, d, J = 16.0 Hz), 4.69 (2H, s), 3.73 (3H, s), 3.52 (2H, t, J = 7.7 Hz), 2.97 (2H, t, J = 7.5 Hz); 13C NMR (DMSO-d6) d 166.7, 166.4, 154.1 (br), 144.2, 140.3, 136.1, 133.2, 133.0, 132.2, 128.5 , 128.4, 127.9, 127.8, 126.9, 122.9, 120.9, 118.2, 118.0, 117.6, 111.4, 110.7, 51.4, 49 , 5 *, 49.3 *, 24.4 * (*: very wide and weak peaks, identified by ^ - "c HSQC).

Intermediary 7 Preparation of 8-amino-octanoic acid methyl ester hydrochloride To a 100 ml round-bottom container was added 8-amino-octanoic acid (2.116 g, 13.29 mmol) and methanol (50 ml). The mixture was stirred and cooled in a dry ice / acetone bath under nitrogen. SOCl 2 (1.5 ml, 20.7 mmol) was added via syringe, then the dry ice bath was removed and the mixture was stirred at room temperature for 2.5 h. The solution was evaporated and diethyl ether was added to the residue. The solid substance was filtered and dried in vacuo. 8-Amino-octanoic acid methyl ester hydrochloride was obtained as a white solid substance (2.772 g, 99.8%). LC-MS (ESI, positive mode) m / z 376 ([M-C1] +). E NMR (DMSO-d6) d 8.24 (3H, s, NH3 +), 3.67 (3H, s, 0CH3), 3.00 (2H, m), 2.30 (2H, t, J = 7 , 5 Hz), 1.78 (2H, penta, J = 7.3 Hz), 1.61 (2H, penta, J = 7.2 Hz), 1.41 (2H, m), 1.39- 1.32 (4H, m); 13 C NMR (DMS0-d 6) 6 174.1, 51.4, 39.9, 33.9, 28.6, 27.5, 26.3, 24.7.

Intermediary 8 Preparation of methyl ester 8- [3- (4-methylbenzenesulfonyl) ureido] octanoic acid To a mixture of 8-amino-octanoic acid methyl ester hydrochloride (0.601 g, 2.865 mmol), triethylamine (1.0 mL, 7.18 mmol) and DMAP (0.0313 g, 0.256 mmol) in CH2C12 (20 mL). mi) was added p-toluenesulfonyl isocyanate (0.63 ml, 4.12 mmol). The reaction mixture was stirred at room temperature for 19.5 h. The reaction mixture was diluted with 1 N HC1 and extracted with CH2C12 (100 ml x 1.50 ml x 2). The combined organic extracts were dried over MgSO4, filtered and the solvent removed in vacuo. The crude residue was chromatographed (silica) with 2-10% MeOH in CH2C12 to give 8- [3- (4-methylbenzenesulfonyl) ureido] octanoic acid methyl ester (0.730 g, 69%) as a solid substance White color. LC-MS (ESI, positive mode) m / z 371 ([M + H] +). XH NMR (CDC13) d 8.80 (1 H, bs), 7.78 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.1 Hz), 6, 52 (1 H, t, J = 5.2 Hz), 3.67 (3H, s, OCH3). 3.19 (2H, q, J = 6.6 Hz), 2.44 (3H, s, Ar-CH3), 2.30 (2H, t, J = 7.5 Hz), 1.63-, 1.58 (2H, m), 1.48-1.42 (2H, m), 1.31-1.22 (6H, m) 13C NMR (DMSO-d6) d 174.3, 151.9, 144.6, 136.8, 129.6, 127.0, 51.5, 40.2, 34.0, 29.4, 28.9, 28.8, 26.6, 24.8, 21, 6 Intermediary 9 Preparation of 8- [3-methyl-3- (4-methyl-benzenesulfonyl) ureido] octanoic acid methyl ester To a mixture of 8- [3- (4-methylbenzenesulfonyl) ureido] octanoic acid methyl ester (0.161 g, 0.435 mmol), 2CO3 (0.572 g, 4.14 mmol) and acetonitrile (4 mL) was added Mel (0.270 g). mi, 4.35 mmol). The reaction mixture was stirred at room temperature under nitrogen for 17 h. The reaction mixture was diluted with 1N HCl and extracted with ethyl acetate (Na2S203 was added to the aqueous layer to reduce I2). The combined organic extracts were dried over MgSO 4, filtered and the solvent removed in vacuo. XH NMR of the crude residue (0.166 g) showed that the molar ratio of 8- [3- (4-methylbenzenesulfonyl) ureido] octanoic acid methyl ester to 4, N, N-trimethyl-benzenesulfonamide degraded product was 3: 1 . LC-MS (ESI, positive mode) m / z 385 ([M + H] +). ¾ NMR (CDC13) d 7.70 (2H, d, J = 8.3 Hz), 7.34 (2H, d, J = 8.5 Hz), 3.66 (3H, s, OCH3), 3 , 24 (2H, g, J = 5.7 Hz), 3.12 (3H, S, NCH3), 2.43 (3H, s, Ar-CH3), 2.31 (2H, t, J = 7 , 5 Hz), 1.65-1.60 (2H, m), 1.55-1.51 (2H, m), 1.33-1.26 (6H, m).

Intermediary 10 Preparation of 8- (3-benzoylureido) -octanoic acid methyl ester To a solution of 8-amino-octanoic acid methyl ester hydrochloride (0.423 g, 2.02 mmol), triethylamine (0.56 mL, 4.02 mmol) and DMAP (0.022 g, 0.18 mmol) in CH2C12. (10 mL) was added benzoyl isocyanate (90% pure, 0.370 g, 2.26 mmol). The reaction mixture was stirred at room temperature for 2 h and silica gel was added and filtered through silica and washed with ethyl acetate. The filtrate was evaporated to dryness to give a colorless oil (0.691 g, 106%), which was solidified at room temperature under vacuum. LC-MS (ESI, positive mode) m / z 321 ([M + H] +). X H NMR (CDC13) d 10.52 (1 H, s), 8.92 (1 H, t, J = 5.6 Hz), 8.09 (2 H, d, J = 7.2 Hz), 7 , 56 (1H, type t), 7.45 (2H, t, J = 7.7 Hz), 3.64 (3H, s, OCH3), 3.35 (2H, q, J = 6.0 Hz) ), 2.29 (2H, t, J = 7.5 Hz), 1.63-1.56 (4H, m), 1.39-1.32 (6H, m); 13 C NMR (CDC13) d 173.6, 168.1, 154.6, 132.3, 132.0, 128.0, 127.7, 50.9, 39.3, 33.5, 29.0, 28.5, 28.4, 26.3, 24.3.

Intermediary 11 Preparation of 7-amino-heptanoic acid methyl ester hydrochloride Procedure as described in intermediate 7 above, but using the appropriate starting materials (7-amino-heptanoic acid), the compound in the title was prepared as a white solid substance (0.490 g, 100% ).

Intermediary 12 Preparation of 7- (3-benzoyl-ureido) -heptanoic acid methyl ester Procedure as described in the previous broker 10, but using the appropriate starting materials (7-amino-heptanoic acid methyl ester hydrochloride), the crude compound in the title was obtained as an oil which was solidified in vacuo and could be used in the next step of reaction without further purification. LC-MS (ESI, positive mode) m / z 307 ([+ H] +). XH NMR (CDC13) d 10.30 (1 H, s), 8.90 (1 H, t, J = 5.4 Hz), 8.05 (2H, d, J = 7.5 Hz), 7 , 57 (1 H, t, J = 7.4 Hz), 7.47 (2H, d, J = 7.6 Hz), 3.65 (3H, s, OCH3), 3.35 (2H, q , J = 6.6 Hz), 2.30 (2H, t, J = 7.5 Hz), 1.68-1.56 (4H, m), 1.45-1.35 (4H, m); 13C RN (CDC13) d 173.6, 168.1, 154.5, 132.4, 132.0, 128.1, 127.6, 51.0, 39.3, 33.5, 28.9, 28.3, 26.1, 24.3.

Intermediary 13 Preparation of a 6- (3-phenyl-propylamino) -hexanoic acid methyl ester salt To a 100 ml vessel were added 6-amino-hexanoic acid methyl ester hydrochloride (0.555 g, 3.06 mmol), NaBH (0Ac) 3 (0.782 g, 3.69 mmol), 3-phenyl-propionaldehyde ( 0.47 mL, 3.21 mmol), dichloromethane (10 mL) and triethylamine (0.43 mL, 3.09 mmol). The above mixture was sonicated for 1 min, then stirred at room temperature overnight. Aqueous Na 2 CO 3 was added to the reaction mixture and extracted with dichloromethane (x 2). The extract was dried and purified by reverse phase preparative HPLC to give the title compound in the form of an oil (0.202 g, 30% calculated as TFA salt). LC-MS (ESI, positive mode) m / z 264 ([M + H] +). ¾ NMR (CDC13) 8 11.82 (1 H, s), 8.62 (2H, s, -NH2 + -), 7.26 (2H, t, J = 7.3 Hz), 7.18 (1 H, t, J = 7.3 Hz), 7.11 (2H, d, J = 7.0 Hz), 3.64 (3H, s, 0CH3), 2.94 and 2.92 (each of 2H, superimposed, identified by COZY), 2.63 (2H, t, J = 7.5 Hz), 2.26 (2H, t, J = 7.3 Hz), 2.00 (2H, perita, J = 7.6 Hz), 1.65 (2H, penta, J = 7.5 Hz), 1.55 (2H, penta, J = 7.7 Hz), 1.33 (2H, m); 13C RN (CDC13) d 173.6, 139.2, 128.2, 127.7, 126.0, 51.1, 47.3, 47.1, 32.9, 32.0, 26.9, 25.2, 25.0, 23.4.

Intermediary 14 Preparation of 6- [3-benzoyl-l- (3-phenyl-propyl) -ureido] -hexanoic acid methyl ester Process as described in the above intermediate 10, but using the appropriate starting materials (a 6- (3-phenyl-propylamino) -hexanoic acid methyl ester salt with 2 TFA), the crude compound contained in titer was purified by reverse phase preparative HPLC and flash chromatography (silica, 5% methanol in dichloromethane) to give the pure compound as a gum (0.063 g, 43%). LC-MS (ESI, positive mode) m / z 411 ([M + H] +).

X H NMR (CDCl 3) d 8.20 (1 H, bs), 7.78 (2 H, bs), 7.54 (1 H, t, J = 7.4 Hz), 7.43 (2 H, t, J = 7.6 Hz), 7.24 (2H, d, J = 7.2 Hz), 7.18-7.13 (3H, m), 3.65 (3H, s), 3.36 [ 4H, mo 3.38 (2H, m) and 3.36 (2H, m)], 2.64 (2H, t, J = 7.4 Hz), 2.30 (2H, t, J = 7, 4 Hz), 1.96 (2H, penta, J = 7.4 Hz), 1.66-1.56 (4H, m), 1.31 (2H, m); 13 C RM (CDCl 3) d 173.5, 165.8 (br), 153.4 (br), 140.7 (br), 132.7, 132.1, 128.1, 128.0, 127.9 , 127.3, 125.6, 51.0, 46.9 (br, 2 x CH2N), 33.4, 32.4, 28.9, 27.1 (br), 25.8, 24.1 .

Intermediary 15 Preparation of methyl ester of 4- acid. { [2- (lH-indol-3-yl) -ethylamino] -methyl) -benzoic acid To a 250 ml vessel were added tryptamine hydrochloride (0.582 g, 2.96 mmol), 4-formyl-benzoic acid methyl ester (0.488 g, 2.97 mmol), dichloromethane (25 mL), methanol (10 mL). ) and triethylamine (0.50 ml, 3.59 mmol) and the mixture was stirred at room temperature for 4 h, then evaporated to dryness. The residue was dissolved in dichloromethane (25 ml), NaBH (OAc) 3 (0.805 g, 3.80 mmol) was added and the mixture was stirred at room temperature overnight. To the mixture was added aqueous NaHCO3, extracted with dichloromethane (x3) and dried (MgSO4). The residue was purified by reverse phase preparative HPLC and the desired fractions were combined and evaporated to remove the organic solvent. The resulting solution was neutralized with aqueous NaHCO3 and extracted with dichloromethane (x3), dried (MgSO4) to give the title compound in the form of gum (0.437 g, 48%). LC-MS (ESI, positive mode) m / z 309 ([M + H] +). ¾ NMR (CDC13) d 8.24 (1H, s), 7.95 (2H, d, J = 8.3 Hz), 7.59 (1H, d, J = 7.9 Hz), 7.32 (3H, superimposed by CH x 2 and CH, d, J = 8.2 Hz), 7.18 (1 H, td, J = 7.5, 1.1 Hz), 7.10 (1 H, td , J = 7.5, 1.0 Hz), 6.98 (1 H, d, J = 2.3 Hz), 3.89 (3 H, S), 3.84 (2 H, s), 2, 99-2.95 (4H, m); 13 C NMR (CDCl 3) d 166.7, 145.4, 136.0, 129.2, 128.3, 127.5, 127.0, 121.6 (two superimposed CH), 118.8, 118.4 , 113.3, 110.8, 53.0 (CH2N), 51.6 (OCH3), 48.9, 25.3.

Intermediary 16 Preparation of methyl ester of 4- acid. { [(pyridin-ylmethyl) -amino] -methyl) -benzoic acid Process as described in Intermediary 15 above, but using the appropriate starting materials 3- (aminomethyl) pyridine and 1 equivalent of acetic acid (no triethylamine or methanol was added). After working up, the crude extract was used for the next reaction step without further purification. LC-MS (ESI, positive mode) m / z 257 ([M + H] +).

Intermediary 17 Preparation of 4- (benzylamino-methyl) -benzoic acid methyl ester Process as described in Intermediary 16 above, but using the appropriate benzylamine starting material. After working up, the crude extract was used for the next reaction step without further purification. LC-MS (ESI, positive mode) m / z 256 ([M + H] +).

Intermediary 18 Preparation of 4- [(3-hydroxy-propylamino) -methyl] -benzoic acid methyl ester Process as described in Intermediary 16 above, but using the appropriate starting material 3-amino-propan-1-ol. After working up, the crude extract was used for the next reaction step without further purification. LC-MS (ESI, positive mode) m / z 224 ([M + H] +).

Intermediary 19 Preparation of 4- [(2-pyridin-2-yl-ethylamino) -methyl] -benzoic acid methyl ester Process as described in Intermediary 16 above, but using the appropriate starting material 2-pyridin-2-yl-ethylamine. After working up, the crude extract was used for the next reaction step without further purification. LC-MS (ESI, positive mode) m / z 271 ([M + H] +).

Intermediary 20 Preparation of 4- (phenethylamino-methyl) -benzoic acid methyl ester Process as described in Intermediary 16 above, but using the appropriate phenethylamine starting material. After working up, the crude extract was used for the next reaction step without further purification. LC-MS (ESI, positive mode) m / z 270 ([M + H] +).

Intermediary 21 Preparation of 3- (4- ([(pyridin-3-ylmethyl) -amino] -methyl] -phenyl) -acrylic acid methyl ester Process as described in Intermediary 16 above, but using the appropriate starting materials 3- (4-formylphenyl) -acrylic acid methyl ester, 3- (aminomethyl) pyridine. After working up, the crude extract was used for the next reaction step without further purification. LC-MS (ESI, positive mode) m / z 283 ([M + H] +).

Intermediary 22 Preparation of methyl ester of 3- acid. { 4- [(2-pyridin-2-yl-ethylamino) -methyl] -phenyl} -acrylic Process as described in Intermediary 16 above, but using the appropriate starting materials 3- (4-formyl-phenyl) -acrylic acid methyl ester and 2-pyridin-2-yl-ethylamine. After working up, the crude extract was used for the next reaction step without further purification. LC-MS (ESI, positive mode) m / z 297 ([M + H] +).

Intermediary 23 Preparation of 3- (4- [(3-idroxy-propylamino) -methyl] -phenyl] methyl ester} -acrylic Process as described in Intermediary 16 above, but using the appropriate starting materials 3- (4-formyl-phenyl) -acrylic acid methyl ester and 3-amino-propan-1-ol. After working up, the crude extract was used for the next reaction step without further purification. LC-MS (ESI, positive mode) m / z 250 ([M + H] +).

Intermediary 24 Preparation of methyl ester of 3- acid. { 4- [3-benzoyl-1- (3-hydroxy-propyl) -ureidomethyl] -phenyl} -acrylic Procedure as described in Intermediary 6 above, but using the appropriate starting materials. LC-MS (ESI, positive mode) m / z 397 ([M + H] +).

Intermediary 25 Preparation of 3-methyl ester. { 4- [3-benzoyl-l- (2-pyridin-2-yl-ethyl) -ureidomethyl] -phenyl) -acrylic Procedure as described in Intermediary 6 above, but using the appropriate starting materials. LC- S (ESI, positive mode) m / z 444 ([M + H] +).

Intermediary 26 Preparation of 3- [4- (3-benzoyl-l-pyridin-3-ylmethyl-ureidomethyl) -phenyl] -acrylic acid methyl ester Procedure as described in Intermediary 6 above, but using the appropriate starting materials. Performance: 67%. LC-MS (ESI, positive mode) m / z 430 ([M + H] +). ½ NMR (CDC13) d 9.68 (1 H, bs), 8.49 (1 H, d, J = 3.3 Hz), 8.44 (1 H, s), 7.86 (2H, d) , J = 7.5 Hz), 7.69 (1 H, m), 7.66 (1 H, d, J = 16.0 Hz), 7.50 (1 H, J = 7.3 Hz) , 7.47 (2H, d, J = 8.2 5 Hz), 7.38 (2H, t, J = 7.7 Hz), 7.27-7.23 (3H, m), 6.42 (1 H, d, J = 16.0 Hz), 4.57 (2H, s), 4.56 (2H, S), 3.79 (3H, s); 13C R (CDC13) d 166.8, 166.6, 155.3, 148.7, 148.5, 143.6, 137.8, 133.5, 132.3, 132.2, 123.3, 117.6, 51.2, 50.5, 47.6.

Intermediary 27 Preparation of 4-methyl ester. { 3-benzoyl-l- [2- (lH-indol-3-yl) -ethyl] -ureidomethyl} -benzoic Procedure as described in Intermediary 6 above, but using the appropriate starting materials. Performance 65%. LC- S (ESI, positive mode) m / z 456 ([M + H] +). NMR (CDC13) d 9.08 (1H, bs), 7.96 (2H, d, J = 8.2 Hz), 7.45-7.05 [10H, including 7.43 (2H, d, J = 7.6 Hz), 7.17 (2H, bs), 7.11 (1 H, t, J = 7.6 Hz), 6.98 (1 H, t, J = 7.4 Hz) ), 6.91 (1 H, bs), 4.65 (2H, s), 3.87 (3H, s), 3.57 (2H, br type t, J = 5.8 Hz), 2, 98 (2H, br t, J = 5.4 Hz); 13 C NMR (CDCl 3) d 169.3, 166.0, 153.9, 141.7, 136.1, 132.3, 131.9, 129.6, 129.0, 128.0, 127.3, 127.0, 126.2, 123.0, 121.7, 1191.1, 117.6, 111.4, 110.7, 51.7, 49.3 (identified by HSQC), 48.2, 23 ,2.

Intermediary 28 Preparation of 4- [3-benzoyl-l- (3-hydroxy-propyl) -ureidomethyl] -benzoic acid methyl ester Procedure as described in Intermediary 6 above, but using the appropriate starting materials. LC-MS (ESI, positive mode) m / z 371 ([M + H] +).

Intermediary 29 Preparation of 4- [3-benzoyl-l- (2-pyridin-2-yl-ethyl) -ureidomethyl] -benzoic acid methyl ester Procedure as described in Intermediary 6 above, but using the appropriate starting materials. LC-MS (ESI, positive mode) m / z 418 ([M + H] +).

Intermediary 30 Preparation of 4- (3-benzoyl-l-pyridin-3-ylmethyl-ureidomethyl) -benzoic acid methyl ester Procedure as described in Intermediary 6 above, but using the appropriate starting materials. LC-MS (ESI, positive mode) m / z 404 ([M + H] +).

Intermediary 31 Preparation of 4- (3-benzoylureido) -butyric acid methyl ester Procedure as described in Intermediary 6 above, but using the appropriate starting materials. LC-MS (ESI, positive mode) m / z 279 ([M + H] +). H NMR (CDC13) d 10.38 (1H, s), 8.96 (1H, t, J = 5.6 Hz, 8.06 (2H, t, J = 7.5 Hz), 7.58 ( 1 H, t, J = 7.4 Hz), 7.48 (2H, t, J = 7.6 Hz), 4.12 (2H, q, J = 7.1 Hz), 3.42 (2H , td, J = 6.7 and 6.3 Hz), 2.40 (2H, t, J = 7.4 Hz), 1.95 (2H, penta, J = 7.2 Hz); 13C NMR ( CDCI3) d 172.5, 168.1, 154.7, 132.5, 131.9, 128.1, 127.6, 59.9, 38.7, 31.1, 24.5, 13.7 .

Intermediary 32 Preparation of 4-piperazin-1-ylmethyl-benzoic acid methyl ester (2 * TFA salt) To a solution of 4-formylbenzoic acid methyl ester (0.167 g, 1.02 mmol) and piperazine (0.557 g, 6.47 mmol) in a mixed solvent of MeOH (5 mL) and DCM (5 mL), NaBH 3 CN (0.111 g, 1.76 mmol) was added and followed by acetic acid (0.75 ml, 13.1 mmol). After stirring at room temperature for 1 h, the reaction mixture was basified with aqueous Na 2 CO 3 and extracted with DCM (x 2). After working-up, the residue was purified by reverse phase preparative HPLC and the compound in the title was obtained as a 2 * TFA salt (0.195 g, 42%). Purity by HPLC (254 nm) = 98%; LC- S (ESI, positive mode) m / z 235 ([M + H] +). aH NMR (CD3OD) d 8.01 (d, 2H, J = 8.3 Hz), 7.58 (d, 2H, J = 8.3 Hz), 4.39 (s, 2H), 3.84 (s, 3H, OCH3), 3.52-3.47 (m, 8H); 13C NMR (CD3OD) d 167.7, 135.3, 132.4, 131.2, 61.1, 52.9, 49.5, 42.2.

Intermediary 33 Preparation of 3- (4-piperazin-1-ylmethyl-phenyl) acrylic acid methyl ester Process as described in Intermediary 32 above, but using the appropriate starting material (3- (4-formylphenyl) -acrylic acid methyl ester). LC-MS (ESI, positive mode) m / z 261 ([M + H] +).

Intermediary 34 Preparation of O- (2, -dimethoxy-benzyl) -hydroxylamine This compound was prepared according to the procedure described in the publication (Barlaam B., et al, Tetrahedron Lett, 39: 7865-7868 (1998)).

Intermediate 35 Preparation of 6- amino-hexanoic acid (2, -dimethoxy-benzyloxy) -amide Scheme 6 6-Amino-hexanoic acid (13.1 g, 100 mmol) was dissolved in 10% aqueous Na2CO3 solution (300 mL), then dioxane (200 mL) was added to the above solution. Fmoc-Cl (26 g, 1 mmol) was added to the above mixture in portions, and the resulting reaction mixture was stirred for 12 h. The mixture was extracted with ether (150 ml X 2), and the aqueous part was acidified with 6 N HCl. The mixture was filtered, and the solid substance was washed with water and dried to give 6- (9H-fluoren- 9-ylmethoxycarbonylamino) -hexanoic in the form of a white solid substance (31 g, 81%). 6- (9H-Fluoren-9-ylmethoxycarbonylamino) -hexanoic acid (9.17 g, 25 mmol) and 0- (2, -dimethoxy-benzyl) -hydroxylamine (36 g, 26 mmol) were dissolved in DC (250 ml). ), then DCC (6.18 g, 30 mmol) was added in portions. The resulting mixture was stirred for 3 h at room temperature, then cooled to 0 ° C, filtered and washed with DCM. The organic solution was evaporated to dryness to give the crude [9- (2, 4-dimethoxybenzyloxycarbamoyl) -pentyl] -carbamic acid 9H-fluoren-9-ylmethyl ester. The crude ester was reacted with piperidine (5 mL) in MeOH (150 mL) at room temperature for 12 h. The solution was evaporated and the residue was purified by flash chromatography (silica, EtOAc: MeOH = 5: 1). 6-Amino-hexanoic acid (2,4-dimethoxybenzyloxy) amide was obtained as a white solid substance (4.15 g, 56%).

Intermediate 36 Preparation of 7-amino-heptanoic acid (2, -dimethoxy-benzyloxy) -amide. Process as described in Intermediary 35 above, but using the appropriate starting materials. Intermediary 37 Preparation of 8-amino-octanoic acid (2, -dimethoxy-benzyloxy) -amide Process as described in Intermediary 35 above, but using the appropriate starting materials.

Example 1 Preparation of 6- [3- (toluene-4-sulfonyl) ureido] -hexanoic acid hydroxyamide To a solution of 6- [3- (toluene-4-sulfonyl) ureido] -hexanoic acid methyl ester (0.035 g, 0.1 mmol) in dry MeOH (2 mL) was added NH20H-HC1 (0.021 g, , 3 mmol) followed by NaOMe (0.11 mL, 5.38 M, 0.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. The formation of hydroxamic acid followed LCMS. Once the starting material was consumed, the reaction mixture was diluted with acetonitrile and the solvent was removed in vacuo. The crude residue was purified by a mass-induced HPLC purification system to give 6- [3- (toluene-4-sulfonyl) ureido] -hexanoic acid hydroxyamide as a pale yellow / off-white solid substance. XH EMN (DMSO-ds) d 10.37 (1H, bs), 10.13 (1H, s), 8.46 (1 H, s), 7.60 (2H, d, J = 8.3 Hz, aromatic CH), 7.23 (2H, d, J = 8.0 Hz, CH), 6.27 (1 H , t, J = 5.2 Hz), 2.92 (2H, q, J = 6.1 Hz), 2.39 (3H, s), 1.89 (2H, t, J = 7.5 Hz 1.43 (2H, penta, J = 7.5 Hz), 1.31 (2H, penta, J = 7.4 Hz), 1, 17-1, 09 (2H, m).

Example 2 Preparation of N-hydroxy-. { 3- [4- [3- (toluene-4-sulfonyl) ureido] -phenyl) -acrylamide Process as described in Example 1 above, but using the appropriate starting materials. Yield: 5% of the corresponding methyl ester. White solid substance. Purity by HPLC at 254 nm: 93%; LC-MS (ESI, positive mode) m / z 376 ([M + H] +).

Example 3 Preparation of N-hydroxy-3-. { 3- [3- (4-Methylbenzenesulfonyl) ureido] -phenyl) -acrylamide Process as described in Example 1 above, but using the appropriate starting materials. Performance: 64%. White solid substance. Purity by HPLC at 254 nm: 95%. LC-MS (ESI, positive mode) m / z 376 ([M + H] +). ¾ RM (DMSO-d6) d 7.70 (d, 2H, J = 6.0 Hz), 7.36 (d, 2H, J = 8.1 Hz), 7.30 (d, 1 H, J = 15.8 Hz), 7.25 (s, 1 H), 7.11 (t, 1 H, J = 7.7 Hz), 6.80 (d, 1 H, J = 8.2 Hz) , 6.68 (d, 1H, J = 7.6 Hz), 6.33 (d, 1H, J = 15.8 Hz), 2.37 (s, 3H, -CH3).

Example 4 Preparation of 4- [3- (toluene-4-sulfonyl) ureidomethyl-N-hydroxy-benzamide. Process as described in Example 1 above, but using the appropriate starting materials. Yield: 58%. White solid substance. Purity by HPLC at 254 nm: 100%. LC-MS (ESI, positive mode) m / z 364 ([+ H] +); 4? NMR (DMSO-d6) d 11.14 (s, 1H), 10.74 (s, 1H), 8.98 (d, 1H, J = 1.7 Hz), 7.79 (d, 2H, J = 8.3), 7.65 (d, 2H, J = 8.3) Hz), 7.41 (d, 2H, J = 8.0 Hz), 7.18 (d, 2H, J = 8.2 Hz), 7.05 (t, 1 H, J = 5.8 Hz), 4.19 (d, 2H, J = 5.9), 2.47 (s) , 3H).

Example 5 Preparation of N-hydroxy-2- (4- [3- (toluene-4-sulfonyl) ureido] -phenyl) -acetamide Process as described in Example 1 above, but using the appropriate starting materials. Performance: 99%. White solid substance. Purity by HPLC at 254 nm: 99%. LC-MS (ESI, positive mode) m / z 364 ([M + H] +); XH NMR (DMS0-d6) d 10.47 (s, 1H), 8.64 (s, H), 7.73 (d, 2H, J = 8.2 Hz), 7.32 (d, 2H, J = 8.1 Hz),, 13 (d, 2H, J = 8.5 Hz), 7.02 (d, 2H, J = 8.3 Hz), 3.08 (S, 2H), 2.29 (S, 2H); 13 C R N (DMSO-d6) d 167.0, 149.2, 141.9, 137.1, 130.8, 129.4, 129.2, 127.4, 125.6, 118.8, 38.6, 21.0.

Example 6 Preparation of 4- (3-benzoyl-ureidomethyl) -N-hydroxy-benzamide To a solution of 4- (3-benzoyl-ureidomethyl) -benzoic acid methyl ester (0.030 g, 0.096 mmol) in dry MeOH (0.5 mL) was added NH2OH-HCl (0.020 g, 0.288 mmol) followed by solution 30% NaOMe (5.38, 0.106 mL, 0.576 mmol). The reaction mixture was stirred at room temperature under nitrogen for 22 hours, then neutralized with the addition of concentrated hydrochloric acid. The mixture was subjected to RPHPLC for purification. 4- (3-Benzoyl-ureidomethyl) -N-hydroxy-benzamide was obtained as a white solid substance (yield 47%). Purity by HPLC at 254 nm: 99.7%, tR = 4.55 min. LC- S (ESI, positive mode) m / z 314 ([M + H] +); ¾ NMR (D SO-d6) d 11.11 (s, 1H), 10.71 (s, 1H), 9.04-9.07 (tr, 1H, J = 6.0 Hz), 8.92 (br s, 1 H), 7.89-7.91 (d, 2H, J = 8.4 Hz), 7.65-7.67 (d, 2H, J = 8.3 Hz), 7, 54-7.58 (m, 1H), 7.42-7.48 (m, 2H), 7.32-7.34 (d, 2H, J = 8.3 Hz), 4.42-4, 43 (d, 2H, J = 6.0 Hz), 2.47 (s, 3H); 13 C NMR (D SO-d 6) d 167.5, 153.0, 141.8, 132.0, 131.8, 130.7, 128.4, 127.8, 127.7, 127.4, 126 , 3, 41.8. Anal, calculated for C16Hi5 304: C, 61.34; H, 4.83; N, 13.41. Experimental: C, 61.31; H, 4.79; N, 13.38.

Example 7 Preparation of 2- [3- (3-benzoyl-ureido) -phenyl] -N-hydroxy-acetamide Prepared from the corresponding methyl ester. Performance: 7%. White solid substance. Purity by HPLC at 254 nm: 99%; LC-MS (ESI, positive mode) m / z 314 ([M + H] +); ¾ NMR (DMSO-de) d 11.02 (s, 1H), 10.84 (s, 1H), 10.66 (S, 1H), 8.83 (s, 1H), 8.01-8, 03-8.02 (d, 2H, J = 8.5 Hz), 7.64-7.66-7.65. { m, 1H), 7.53-7.57 (m, 2H), 7.49-7.51-7.50 (dd, 1 H, J = 8.1 Hz), 7.44 (s, 1 H), 7.27-7.30 (tr, 1 H, J = 7.8 Hz), 7.00-7.02-7.01 (d, 1 H, J = 7.8 Hz), 3 , 29 (s, 2H).

Example 8 Preparation of 2- [4- (3-benzoyl-ureido) -phenyl] -N-hydroxy-acetamide Prepared from the corresponding methyl ester. Yield: 2%. White solid substance. Purity by HPLC at 254 nm: 98%; LC-MS (ESI, positive mode) m / z 314 ([M + H] +).

Example 9 Preparation of 3-. { 4- [3-benzoyl-1- (3-hydroxy-propyl) -ureidomethyl] -phenyl} -N-hydroxy acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity by HPLC at 254 nm: 97%; LC-MS (ESI, positive mode) m / z 398 ([? +? G). ¾ RM (DMSO-d6) 5 10.69 (1 H, s), 10.27 (1 H, s), 8.97 (s, 1 H), 7.76 (br d, 2 H, J = 6, 4 Hz), 7.54 (t, 1 H, J = 7.3 Hz), 7.49 (d, 2H, J = 8.4 Hz), 7.42 (t, 2H, J = 7.6 Hz), 7.38 (d, 1 H, J = 15.9 Hz), 7.31 (br type d, 2H), 6.39 (d, 1 H, J = 15.8 Hz), 4, 80 (br s, 1 H), 4.51 (s, 2H), 3.25 and 3.32 (each 2H, superimposed with solvent peak), 1.61 (m, 2H).

Example 10 Preparation of 6- (3-benzoyl-ureido) -hexanoic hydroxyamide hydroxyamide Method A; To a solution of 6- (3-benzoyl-ureido) -hexanoic acid (0.0033 g, 0.01 mmol) in DMF (1 mL) was added Py-BOP (0.07 g, 0.013 mmol) and N, N-diisopropylethylamine (0.013 ml, 0.07 mmol). The reaction mixture was stirred for 5 minutes and NH 2 OH-HCl (0.02 g, 0.02 mmol) was added. The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was purified by mass-induced HPLC to give 6- (3-benzoyl-ureido) -hexanoic acid hydroxyamide as a white solid.

Method B: To a solution of 6- (3-benzoyl-ureido) -hexanoic acid methyl ester (0.300 g, 1.03 mmol) in dry MeOH (2.0 mL) was added NH20H-HC1 (0.555 g, , Mmol) followed by 30% NaOMe in MeOH (2.23 ml, 5.38 M, 12.0 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 h, then trifluoroacetic acid (0.3 ml) was added in an ice bath. The solution was extracted with 10% MeOH in dichloromethane. The extract was dried and concentrated. The residue was purified by reverse phase preparative HPLC to give 6- (3-benzoyl-ureido) -hexanoic acid hydroxyamide (0.175 g, 59%) as a white solid substance. HPLC purity at 254 nm: 99.7%, ta = 5.15 min. LC-MS (ESI, positive mode) m / z 293 ([M + H] +). X H NMR (DMSO-d 5) 8 10.63 (1H, s), 10.34 (1H, s), 8.70- 8.60 (1H, bs), 8.65 (1H, t, J = 5 , 7 Hz), 7.95 (2H, dt, J = 7.2, 1.6 Hz), 7.62 (1 H, tt, J = 7.4, 1.2 Hz), 7.50 ( 2H, t, J = 7.9 Hz), 3.22 (2H, q, J = 6.6 Hz, CH2N), 1.96 (2H, t, J = 7.4 Hz, C¾CO), 1, 56-1.46 (4H, m), 1.30-1.24 (2H, m); 13 C NMR (DMS0-d 6) 6 169.1 (CONHOH), 168.2 (PhCO), 153.4 (NHCONH), 132.7 (CH), 132.6 (Cq), 128.4 (CH X 2 ), 128.0 (CH 2), 38.9 (CH 2 N), 32.2 (CH 2 CO), 28.9, 25.9, 24.8. Anal, calculated for C1H19N3O4: C, 57.33; H, 6.53; N, 14.33. Experimental: C, 57.06; H, 6.32; N, 13.88.

Example 11 Preparation of 3- (4-. {3-benzoyl-l- [2- (lH-indol-3-yl) -ethyl] -ureidomethyl}. Phenyl) -N-hydroxy-acrylamide To a cooled solution of 3- (4. {3-benzoyl-l- [2- (lH-indol-3-yl) -ethyl] -ureidomethyl) -phenyl) -acrylic acid methyl ester (crude, 2, 86 g, 5.93 mmol) and hydroxylamine hydrochloride (4.14 g, 59.5 mmol) in dry MeOH (40 mL) was added NaOMe in MeOH (4.37 M, 16.9 mL, 73.9 mmol ) by means of a syringe. The reaction mixture was stirred at room temperature under nitrogen for 1 h, then dry ice powder was added, followed by the addition of water and neutralized with 6 N HCl to pH 6-7. The resulting mixture was concentrated to remove the organic solvent and the residue was filtered and washed with water. The residue was purified by reverse phase preparative HPLC to give 3- (4- [3-benzoyl-1- [2- (1H-indol-3-yl) -ethyl] -ureidomethyl) -phenyl) -N-hydroxy-5-hydroxypropyl ester. acrylamide (0.85 g, 30%) as a pale yellow or white solid substance. LC-MS (ESI, positive mode) m / z 483 (tM + H] +). Purity by HPLC (254 nm) = 97%. aH RM (DMSC ~ d6) 5 10.80 (s, 1H), 10.77 (s, 1H), 10.28 (s, 1 H), 9.05 (br s, 1 H), 7.82 (d, 2H, J = 7.4 Hz), 7.60 (t, 1 H, J = 7.3 Hz), 7.57 (d, 2H, J = 8.3 Hz), 7.50 ( tod, 2H, J = 7.7 Hz), 7.46 (d, 1 H, J = 14.2 Hz), 7.46 -7.34 (br m, 3H), 7.10 (br s, 1 H), 7.02 (t, 1 H, J = 7.4 Hz), 6.9-6.7 (very br s, 1 H), 6.47 (d, 1 H, J = 15, 8 Hz), 4.67 (s, 2H), 3.52 (dt or br type t, 2H, J = 6.7 Hz), 2.96 (br type t, 2H, J = 7.6 Hz); 13C NMR (DMSO-d6) d 166.5, 162.8, 154. 1, 139.0, 138.0 (CH =), 136.1, 133.8, 133.2, 132.2, 128.4, 127.92, 127.88, 127.6, 126.9, 122.9, 120.9, 118.8, 118. 2, 118.0, 111.4, 110.7, 49.4 *, 49.2 *, 24.5 * (* these peaks are weak and wide, identified by ^ - "c HSQC) Anal, calculated for C 28 H 26 N 4 O 4: C, 69.70; H, 5.43; N, 11.61, Experimental: C, 69.43; H, 5.45; N, 11.62.

Example 12 Preparation of 8- (3-benzoyl-ureido) -octanoic acid hydroxyamide To a solution of 8- (3-benzoyl-ureido) -octanoic acid methyl ester (0, 275 g, equals 0.811 mmol) and NH20H-HC1 (0.562 g, 8.09 mmol) was added dry MeOH (5 mL), followed by NaOMe in MeOH (2.30 mL, 4.37 M, 10, 0 mmol). The reaction mixture was stirred at room temperature under nitrogen for 50 min, then neutralized with trifluoroacetic acid (0.80 ml). The mixture was purified by preparative reverse phase HPLC (Ci8, 5 um, 21.2 x 150 mm, 20 ml / min, 5 to 95% CH3CN + 0.05% TFA for 18 min), to give the hydroxyamide 8- (3-benzoyl-ureido) -octanoic acid as a white powder (0.115 g, 44%). LC-MS (ESI, positive mode) m / z 322 ([M + H] +). ¾ MN (DMSO-d6) d 10.64 (1H, s), 10.34 (1 H, s), 8.70-8.60 (1 H, bs), 8.66 (1 H, t, J = 5.1 Hz), 7.96 (2H, d, J = 7.5 Hz), 7.62 (1 H, t, J = 7.0 Hz), 7.50 (2H, t, J = 7.3 Hz), 3.23 (2H, q, J = 6.1 Hz, CH2N, 1.95 (2H, t, J = 7.2 Hz, CH2CO), 1.50-1.48 ( 4H, m), 1.29-1.22 (6H, m); 13 C NMR (DMSO-d 6) d 169.1 (CONHOH), 168.2 (PhCO), 153.5 (NHCONH), 132.7 (CH), 132.6 (Cq), 128.4 (CH X 2 ), 128.1 (CH X 2), 39.0 (camf 32.2 (CH2CO), 29.1, 28.5, 28.4, 26.3, 25, 0.

Example 13 Preparation of 7- (3-benzoyl-ureido) -heptanoic acid hydroxyamide Procedure as described in Example 12 above, but using the appropriate starting materials (7- (3-benzoyl-ureido) -heptanoic acid methyl ester), and the reaction mixture was neutralized with TFA and evaporated to dryness . The residue was washed with water and the compound in the title was obtained as a white solid substance (0.175 g, 67% in two steps). LC- S (ESI, positive mode) m / z 308 ([M + H] +). Purity by HPLC at 254 nm: 98.7% ¾ NMR (D SO-dg) d 10.64 (1 H, s), 10.35 (1 H, s), 8.70-8.60 (1 H , bs), 8.64 (1H, t, J = 5.6 Hz), 7.96 (2H, d, J = 7.4 Hz), 7.62 (1 H, t, J = 7.4) Hz), 7.50 (2H, t, J = 7.7 Hz), 3.22 (2H, q, J = 6.5 Hz, CH2N), 1.95 (2H, t, J = 7.3) Hz, CH2CO), 1.55-1.40 (4H, m), 1.35-1.20 (4H, m); 13 C NMR (DMSO-d 6) 5 169.1 (CONHOH), 168.2 (PhCO), 153.4, 132.7, 132.6 (Cq), 128.4 (CH 2), 128.1 ( CH x 2), 39.0, 32.2, 29.1, 28.2, 26.1, 25.0.

EXAMPLE 14 8- [3- (4-Methylbenzenesulfonyl) -ureido]) -octanoic acid hydroxyamide: Process as described in Example 1 above, but using the appropriate starting materials. LC-MS (ESI, positive mode) m / z 372 ([M + H] +). Purity by HPLC at 254 nm: 100%.

Example 15 7- [3- (4-Methylbenzenesulfonyl) -ureido]) -heptanoic acid hydroxyamide: Process as described in Example 1 above, but using the appropriate starting materials. LC-MS (ESI, positive mode) m / z 358 ([M + H] +). Purity by HPLC at 254 nm: 100%.

Example 16 6- [3- (Benzenesulfonyl) -ureido]) -hexanoic acid hydroxyamide Process as described in Example 1 above, but using the appropriate starting materials. LC- S (ESI, positive mode) m / z 330 ([M + H] +). Purity by HPLC at 254 nm: 100%.

Example 17 Preparation of 6- [3-benzoyl-1- (3-phenyl-propyl) -ureido] -hexanoic acid hydroxyamide Procedure as described in Example 12 above, but using the appropriate starting materials 6- (3-benzoyl-1- (3-phenyl-propyl) -ureido] -hexanoic acid methyl ester, and the reaction mixture is neutralized with TFA and purified by reverse-phase HPLC to give the title compound in the form of gum (15 mg, 32%). LC-MS (ESI, positive mode) m / z 412 ([M + H] +). Purity by HPLC at 254 nm: 98.1 ¾ NMR (DMSO-d6) d 10.34 (1 H, s), 10.08 (1 H, s), 7.81 (2 H, d, J = 7, 1 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.49 (2H, t, J = 7.5 Hz), 7.30-7.10 (5H, m), 3 , 40-3.20 (4H, m), 2.57 (2H, m), 1.93 (2H, to penta type, J = 7.0 Hz), 1.85 (2H, perita, J = 7 , 2 Hz), 1.60-1.40 (4H, m), 1.30-1.10 (2H, m); 13 C NMR (DMSO-d 6) d 169.0, 166.1, 153.5, 133.4, 132.0, 128.4, 128.2, 128.1, 127.8, 125.7, 48, 0 *, 46.4 *, 32.22, 32.17, 29.9 *, 27.9 *, 25.8, 24.8 (*: very weak and broad peaks identified by ^ - "c HSQC).

Example 18 Preparation of hydroxyamide 6- (3-benzoyl thioureido) -hexanoic acid.

Scheme 7 Step 1 Preparation of 6- (3-benzoyl-thioureido) -hexanoic acid (2,4-dimethoxy-benzyloxy) -amide.

To a solution of 6-amino-hexanoic acid (2, 4-dimethoxy-benzyloxy) -amide (0.160 mg, 0.54 mmol) in dichloromethane (DCM, 4 mL) was added triethylamine (0.11 mL, 0. 79 mmol) and benzoyl isothiocyanate (0.11 ml, 0.82 mmol). The reaction was stirred at room temperature overnight and worked up. The residue (0.369 g) was used without further purification. LC-MS: m / z = 460 (M + H).

Step 2: Preparation of 6- (3-benzoyl-ioureido) -hexanoic acid hydroxyamide. To a solution of 6- (3-benzoyl-thioureido) -hexanoic acid (2,4-dimethoxy-benzyloxy) -amide (crude from stage 1, 0.186 g equals 0.27 mmol) and triethylsilane (0.05 ml) in DCM (1.7 ml) was added TFA (0.3 ml) at room temperature with stirring. After 20 min, the solution was evaporated to dryness and diluted with methanol and filtered. The filtrate was concentrated and the residue was purified by preparative HPLC. Hydroxyamide of 6- (3-benzoyl-thioureido) -hexanoic acid was obtained in the form of a white solid substance (cf., 027 g, 32% overall yield). LC-MS (ESI, positive mode) m / z = 310 (M + H). Purity by HPLC (254 nm) 95.4%. ¾ NMR (DMS0-d5) d 11.24 (s, 1H), 10.87 (s, 1H), 10.36 (s, 1H), 8.9-8.4 (very broad, 0.6H ), 7.92 (d, 2H, J = 7.4 Hz), 7.63 (t, 1 H, J = 7.4 Hz), 7.51 (t, 2H, J = 7.7 Hz) , 3.60 (dt or type q, 2H, J = 6.7 and 6.0 Hz), 1.97 (t, 2H, J = 7.3 Hz), 1.54 (penta, 2H, J = 6.0 Hz), 1.54 (penta, 2H, J = 7.4 Hz), 1.32 (m, 2H); 13C R (DMS0-d6) d 179.9, 169.0, 168.0, 132.9, 132.2 (Cq), 128.45, 128.38, 44.6, 32.1, 27.3, 26.0, 24.8.

Example 19 Preparation of 6- (3-benzoyl-l-pyridin-2-ylmethyl-ureido) -hexanoic acid hydroxyamide Scheme 8 Step 1 Preparation of 6- [(pyridin-2-ylmethyl) -amino] -hexanoic acid (2,4-dimethoxy-benzyloxy) -amide Using an analogous method described in Intermediary 13, (2, -dimethoxy- benzyloxy) -amide of 6-amino-hexanoic acid and pyridine-2-carbaldehyde in 6- [(pyridin-2-ylmethyl) -amino] -hexanoic acid (2,4-dimethoxy-benzyloxy) -amide.

Step 2 Preparation of 6- (3-benzoyl-l-pyridin-2-ylmethyl-ureido) -hexanoic acid (2,4-dimethoxy-benzyloxy) -amide Using an analogous method described in Intermediary 14, it was , 6- ((pyridin-2-ylmethyl) -amino] -hexanoic acid-dimethoxy-benzyloxy) -amide in the title compound.

Step 3 Preparation of 6- (3-benzoyl-l-pyridin-2-ylmethyl-ureido) -hexanoic acid hydroxyamide Using an analogous method described in Example 18, step 2, (2,4-dimethoxy-benzyloxy) was deprotected ) - 6- (3-benzoyl-l-pyridin-2-ylmethyl-ureido) -hexanoic acid amide with 15% TFA in DCM and gave 6- (3-benzoyl-l-pyridin-2-ylmethyl) hydroxyamide -ureido) -hexanoic in the form of TFA salt after purification by preparative HPLC. Purity by HPLC at 254 nm: 100%; LC-MS (ESI, positive mode) m / z 385.43 ([M + H] +); aH NMR (CD30D) d 8.63-7.80 (br, m, Ar-H), 7.58-7.44 (m, Ar-H), 4.71-4.54 (d, 2H, N- C¾-py), 3.44-3.40 (t, 2H, N-CH2), 2.02-1.98 (t, 2H, 0 = C- CH2), 1.61-1.50 , 1.27-1.21 (m, 8H, CH2); 13C NMR (CD3OD) 5 170.8, 167.0, 154.4 (C = 0), 148.7, 136.8 (Ar-C), 132.0, 127.9, 127.7, 127, 5, 127.2, 127.1, 126.7, 12.4, 123.1, 122.1 (Ar-CH), 49.8, 31.6, 31.3, 26.6, 25.1 , 24.8, 24.3, 24, O (CH2).

E p e 20 Preparation of 7- (3-benzoyl-l-pyridin-2-ylmethyl-ureido) -heptanoic acid hydroxyamide Process as described in Example 19 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC and obtained as TFA salt. Purity by HPLC at 254 nm: 100%; LC-MS (ESI, positive mode) m / z 399 ([M + H] +); ¾ RM (CD3OD) 5 8.58-7.75 (br, m), 7.58-7.34 (m, Ar-H), 3.40-3.36 (t, 2H), 1.97 -1.93 (t, 2H), 1.52-1.19 (br, m, 8H); 13 C NMR (CD 3 OD) d 131.9, 127.9, 127.1, 31.6, 27.6, Example 21 Preparation of 7- (3-benzoyl-1-benzole-ureido) -heptanoic acid hydroxyamide Method as described in Example 19 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC.

Purity by HPLC at 254 nm: 95%; LC-MS (ESI, positive mode) m / z 398 ([+ H] +); XH NMR (CD3OD) d 7.69-7.17 (br, m, Ar-H), 4.56 (S, 2H), 3.31-3.26 (t, 2H), 1.97-1 , 93 (t, 2H), 1.51-1.21 (m, 8H); 13C NMR (CD3OD) d 170.9, 167.2, 154.2, 136.3, 132.7, 131.7, 128.9, 128.4, 127.8, 127.7, 127.2, 127.0, 126.7, 31.6, 27.7, 27.4, 26.4, 25.3, 24.5, 24.2.

Example 22 Preparation of 6- (3-benzoyl-l-benzole-ureidohexanoic acid hydroxyamide. Process as described in Example 19 above, but using the appropriate starting materials.) The crude compound shown in the title is purified by preparative reverse phase HPLC.

Purity by HPLC at 254 nm: 96%; LC-MS (ESI, positive mode) m / z 384 ([M + H] +); ¾ RM (CD3OD) d 7.68-7.16 (br, m, Ar-H), 4.52 (s, 2H), 3.31-3.27 (t, 2H), 1.98-1 , 95 (t, 2H), 1.55-1.22 (m, 7H, CH2); 13 C NMR (CD3OD) d 136.3, 132.7 (Ar-C), 127.8, 127.7, 127.0, 126.7, 31.6, 25.2, 24.3 (CH2).

Example 23 Preparation of 3- [4- (3-benzoyl-l-phenethyl-ureidomethyl) phenyl] -N-hydroxy-acrylamide Scheme 9 Step 1 Preparation of 3- [4- (phenethylamino-methyl) -phenyl] -acrylic acid methyl ester. To a solution of 3- (4-formyl-phenyl) -acrylic acid methyl ester (4.16 g, 5.17 mmol) in DCM (150 mL) was added phenethylamine (4)., 05 g, 33.4 mmol) and the solution was stirred at room temperature for 1 hour. NaBH (OAc) 3 (9.15 g, 38.9 mmol) was added to the above solution in portions, followed by acetic acid (2 mL, 34.9 mmol), and the mixture was stirred at room temperature for the entire night. The mixture was made alkaline by addition of aqueous NaHCO 3 and extracted with EtOAc (x 3). After working up, the residue was purified by flash chromatography (silica, EtOAc: DC: MeOH = 100: 95: 5) and gave 3- [4- (phenethylamino-methyl) -phenyl] -acrylic acid methyl ester in the form of white solid substance (5.47 g, 86%). LC-MS (ESI, positive mode) m / z = 296 (M + H) Step 2 Preparation of 3- [4- (3-benzoyl-1-phenethyl-ureidomethyl) -phenyl] -acrylic acid methyl ester. To a mixture of 3- [4- (phenethylamino-methyl) -phenyl] -acrylic acid methyl ester (3.01 g, 10.2 mmol) and benzoyl isocyanate (2.43 g, 90% pure, 14, 8 mmol) was added DCM (30 mL), followed by Et3N (1.8 mL, 12.9 mmol).

The solution was stirred at room temperature overnight and evaporated to dryness. The crude solid product can be used for the next reaction step without further purification. LC- S (ESI, positive mode) m / z = 443 (M + H). Step 3: Preparation of 3- [4- (3-benzoyl-l-phenethyl-ureidomethyl) -phenyl] -N-hydroxy-acrylamide. To a cooled solution of 3- [4- (3-benzoyl-1-phenethyl-ureidomethyl) -phenyl] -acrylic acid methyl ester (crude from step 2, 10.2 mmol) and hydroxylamine hydrochloride (7, 08 g, 102 mmol) in MeOH (60 mL) was slowly added sodium methoxide solution in MeOH (4.37 M, 30 mL, 131 mmol) by means of a syringe. The resulting mixture was then stirred at room temperature for about 2 h (controlling progress by LC-MS) and neutralized by adding dry ice powder. Deionized water was added to the cold mixture and the pH was adjusted to 3-4 by adding 4N HCl. The solution was evaporated to remove all of the organic solvent and the residue was washed with water (x 3). The crude product was purified by reverse phase preparative HPLC and gave 3- [4- (3-benzoyl-1-phenethylureidomethyl) -phenyl] -N-hydroxy-acrylamide as white powder / solid substance (0.945 g, 21% of stage 2). Purity by HPLC (254 nm) 97%. LC- S (ESI, positive mode) m / z = 444 (M + H). XH RN (DMSO-d6) d 10.76 (s, 1H), 10.27 (s, 1H), 9.04 (br s, 1H), 7.81 (d, 2H, J = 7.3 25 Hz), 7.60 (t, 1H, J = 7.3 Hz), 7.56 (d, 2H, J = 8.0 Hz), 7.50 (d O t, 2H, J = 7.2 Hz), 7.44 (d, 1 H, J = 16.4 Hz), 7.39 (br d, 2H), 7.26 (t, 2H, J = 7.2 Hz), 7.21- 7.10 (m, 3H), 6.46 (1 H, d, J = 15.8 Hz), 4.60 (s, 2H), 3.48 (t, 2H, J = 7.7 Hz) , 2.84 (t, 2H, J = 7.6 Hz); 13 C NMR (DMSO-d 6) d 166.6, 162.8, 154.0, 139.0, 138.7, 138.0, 133.8, 133.4, 132.2, 128.6, 128, 42, 128.40, 127.90, 127.88, 127.6, 126.3, 118.9, 49.7 *, 49.5 *, 34.2 * (* these peaks are weak and wide, identified by ^ - ^ C HSQC). Anal-calculated for C 26 H 2 S 3 O 4: C, 70.41, H, 5.68, N, 9.47. Experimental: C, 69.95, H, 5.97, N, 9.41.

Example 24 Preparation of 3-. { 4- [3-benzoyl-1- (2-morpholin-4-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC in the form of TFA salt. LC- S (ESI, positive mode) m / z 453 ([M + H] +); XH NMR (CD3OD) d 7.71-7.25 (br, m, Ar-H), 6.40-6.36 (d, 1H, J = 16Hz), 4.64 (s, 2H), 3 , 82-3.71 (br, m, 5H), 3.32-3.25 (br, t, 2H); 13C NMR (CD3OD) 6 167.7, 164.1, 155.1, 137.1, 134.2 (Ar-C), 138.8, 132.2, 132.1, 127.8, 127.5 , 127.2, 117.0, 63.1, 54.2, 51.9, 41.2.

Example 25 Preparation of 3- (4-. {3-benzoyl-l- [2- (4-bromo-phenyl) -ethyl] -ureidomethyl) -phenyl) -N-hydroxy-acrylamide.

Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity or HPLC at 254 nm: 96%; LC-MS (ESI, positive mode) m / z 524 ([M + H] +); ¾ NMR (CD3OD) d 7.67-7.01 (br, m, Ar-H), 6.41-6.37 (d, 1 H, J = 16Hz), 4.56 (s, 2H), 3.54-3.50 (br, t, 2H), 2.81-2.77 (br, t, 2H); 13 C NMR (CD 3 OD) d 169.1, 141.0, 140.0, 134.5, 133.7, 138.3, 132.7, 131.9, 131.7, 131.5, 129.6, 129.4, 129.1, 128.9, 121.3 (CH = CH), 34.6.

Example 26 Preparation of 3- (4-. {3-benzoyl-l- [2- (4-fluoro-phenyl) -ethyl] -ureidomethyl} -phenyl) -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity by HPLC at 254 nm: 91%; LC-MS (ESI, positive mode) m / z 462 ([M + H] +); ¾ NMR (CD30D) d 7.68-7.66 (br, m, Ar-H), 6.41-6.37 (d, 1 H, J = 16Hz), 4.56 (s, 2H), 3.52-3.26 (br t, 2H), 2.82-2.79 (br t, 2H); 13 C NMR (CD30D) d 167.2, 162.4, 159.9, 138.2, 134.0, 132.6, 116.6, 139.1, 131.8, 129.7, 129.6, 114.4, 114.2, 116.6, 32.4.

Example 27 Preparation of 3-. { 4- [3-benzoyl-1- (3-iuidazol-1-yl-propyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC in the form of TFA salt. Purity by HPLC at 254 nm: 98%; LC- S (ESI, positive mode) m / z 448 ([M + H] +); XH NMR (CD30D) d 8.83 (s, 1 H, NH), 7.70-7.26 (b, m, Ar-H), 6.40-6.36 (d, 1H, J = 16Hz ), 4.24 (br s, 2H), 3.40-3.37 (brt, 2H), 2.17-2.10 (br, t, 2H); 13 C NMR (CD3OD) d 138.9, 132.0, 136.2, 127.8, 127.3, 127.1, 121.2, 119.2, 116.9, 45.9, 27.15.

Example 28 Preparation of 3- (4-. {3-benzoyl-l- [2- (lH-imidazol-4-yl) -ethyl] -ureidomethyl) -phenyl) -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC in the form of TFA salt. Purity by HPLC at 254 nm: 100%; LC-MS (ESI, positive mode) m / z 434 ([M + H] +); XH NMR (CD3OD) 8 8.67 (s, 1 H, NH), 7.72-7.24 (b, m, Ar-H), 6.44-6.40 (d, 1 H, J = 16Hz), 4.57 (br, s, 2H), 3.71-3.68 (br, t, 2H), 3.02-2.99 (br, t, 2H); 13 C NMR (CD30D) d 167.3, 164.3, 154.4, 137.9, 133.9, 132.3, 130.2, 139.0, 132.3, 131.9, 127.8, 127.3, 127.1, 116.8, 116.1 (CH = CH), 45.9, 22.0.

Example 29 Preparation of 3-. { 4 ~ [1- (1H-benzoimidazol-2-ylmethyl) -3-benzoyl-ureidomethyl] -phenyl} -N-hydroxy-acrylamide.

Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. LC- S (ESI, positive mode) m / z 470 ([M + H] +); ¾ NMR (CD3OD) d 7.80-7.31 (br, m, Ar-H), 6.41-6.37 (d, 1H, J = 16Hz), 4.81 (s, 2H), 4 70 (s, 2H); 13C NMR (CD3OD) d 166.9, 154.1, 134.0, 133.5, 137.8, 132.4, 128.4, 128.1, 127.7, 124.2, 119.0, 114.5.

EXAMPLE 30 Preparation of 4- (4-benzoylaminocarbonyl-piperazin-1-ylmethyl) -N-idroxy-benzamide Procedure as described in Example 23 (steps 2 and 3) above, but using the appropriate starting material (intermediate 32). The crude compound in the title was purified by reverse phase preparative HPLC and obtained as the TFA salt. LC-MS (ESI, positive mode) m / z 383 ([M + H] +). XH NMR (CD3OD) d 7.83 (d, 2H, J = 7.2 Hz), 7.63 (d, 2H, J = 7.7 Hz), 7.56 (t, 1 H, J = 7.5 Hz), 7.53 (d, 1 H, J = 15.7 Hz), 7.51 (d, 2H, J = 6.4 Hz), 7.45 (t, 2H, J = 7.5 Hz), 4.38 (s, 2H), 4.0-3.2 (very br m, 8H).

Example 31 Preparation of N-. { 4- [4- (2-hydroxycarbamoyl-vinyl) -benzyl] -piperazine-1-carbonyl} -benzamide Procedure as described in Example 23 (steps 2 and 3) above, but using the appropriate starting material (intermediate 33). The crude compound in the title was purified by reverse phase preparative HPLC and was obtained as a free base after basification (23% two-step). LC-MS (ESI, positive mode) m / z 408 ([M + H] +). Purity by HPLC (254 nm) = 94%. ¾ NMR (CD3OD) 5 7.83 (d, 2H, J = 7.3 Hz), 7.80 (d, 2H, J = 8.3 Hz), 7.58 (d, 2H, J = 8, 1 Hz), 7.55 (t, 1 H, J = 7.4 Hz), 7.44 (t, 2H, J = 7.6 Hz), 4.42 (s, 2H), 4.3- 3.3 (very br m, 8H). Example 32 Preparation of 6- [2- (3-benzoyl-ureido) -3- (lH-indol-3-yl) -propionylamino] -hexanoic acid hydroxyamide Scheme 10 Step 1 Preparation of (S) -6- [2- (9H-Fluoren-9-ylmethoxycarbonylamino) -3- (lH-indol-3-yl) -propionylamino] -hexanoic acid methyl ester To a solution of Fmoc-L Trypthan (0.422 g, 0.99 mmol) and HOBt hydrate (0.171 g, 1.13 mmol) in dichloromethane (DCM, 10 mL) was added diisopropyl-carbodiimide (DIC, 0.170 mL, 1.09 mmol). After stirring at room temperature for 1 h, 6-amino-hexanoic acid methyl ester hydrochloride salt (0.201 g, 1.11 mmol) was added to the above solution, followed by diisopropylethylamine (0.210 ml, 1.21 mmol) . The reaction mixture was stirred overnight, worked up and purified by flash chromatography (silica, 50% to 100% EtOAc in hexanes). LC-MS (ESI, positive mode) m / z = 554 (M + H).

Step 2 Preparation of 6- [2-amino-3- (1H-indol-3-yl) -propionylamino] -hexanoic acid methyl ester To a solution of (S) -6- [2- (9H) methyl ester Fluororen-9-ylmethoxycarbonylamino) -3- (1 H -indol-3-yl) -propionylamino] -hexanoic acid (crude, 0.433 g, equals 0.61 mmol) in DCM (4 mL) was added piperidine (1 my) . After stirring at room temperature for 30 min, the solution was evaporated to dryness and the residue was washed with hexanes (x 4) and worked up to give the title compound (0.219 g). LC-MS (ESI, positive mode) m / z = 332 (M + H). Procedure as described in Example 23 (steps 2 and 3) above, but using the appropriate starting material (6- [2-amino-3- (1H-indol-3-yl) -propionylamino] methyl ester] -hexanoic). The crude compound in the title was purified by reverse phase preparative HPLC. LC-MS (ESI, positive mode) m / z 480 ([M + H] +). Purity by HPLC (254 nm) = 94%. ¾ NMR (CD3OD) d 7.79 (δd, 2H, J = 7.2, 1.3 Hz), 7.53 (d, 1H, J = 5.4 Hz), 7.51 (t, 1) H, J = 7.5 Hz), 7.40 (t, 2H, J = 7.7 Hz), 7.23 (d, 1 H, J = 8.1 Hz), 7.09 (s, 1 H), 6.98 (td, 1H, J = 7.0, 0.9 Hz), 6.90 (td, 1H, J = 7.4, 0.7 Hz), 4.51 (t, 1H , J = 6.7 Hz), 3.18 (2H, superimposed by HDO), 3.03 and 2.91 (m, each 1 H), 1.93 (t, 2H, J = 7. 4 Hz), 1.42 (penta, 2H, J = 7.5 Hz), 1.20 (penta, 2H, J = 7. 5 Hz), 1, 04 (m, 2H).

Example 33 Preparation of 3- [4- (3-benzoyl-l-pyridin-3-ylmethyl-ureidomethyl) -phenyl] -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity by HPLC at 254 nm: 99%; LC-MS (ESI, positive mode) m / z 431 ([M + H] +); ¾ NMR (DMSO-ds) d 10.70 (br s, 1 H), 10.40 (s, 1H), 8.52 * (type?, 2H, including 1 H (d, J = 4.0 Hz ) and 1H (s)), 7.87 (br, 1H), 7.74 (d, 2H, J = 7.3 Hz), 7.51 (t, 1H, J = 7.4 Hz), 7 , 49 (superimposed, 1 H), 7.48 * (d, 2H, J = 8.0 Hz), 7.42 (t, 2H, J = 7.8 Hz), 7.38 (d, 1 H) , J = 16.7 Hz), 7.26 * (d, 2H, J = 7.3 Hz), 6.39 (d, 1 H, J = 15.8 Hz), 4.56 (S, 2H ), 4.54 (s, 2H); 13 C NMR (DMSO-d 6) d 166.6, 162.5 *, 154.5, 146.4 (br, CH x 2), 138.3, 137.8, 137.5 *, 134.0, 133 , 1, 132.3, 128.4, 127.9 * (CH x 2 x 2), 124.4, 119.0, 51.9 *, 48.3 * (* these peaks are identified by ^ - ^ C HSQC and HMBC).

Example 34 Preparation of 4- (3-benzoyl-ureido) -N-hydroxy-butyramide.

Process as described in Example 10 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity by HPLC at 254 nm: 98%; LC-MS (ESI, positive mode) m / z 266 ([M + H] +); X H NMR (DMS0-d 6) d 10.60 (s, 1 H), 10.34 (s, 1 H), 8.62 (br, 1 H), 8.61 (t, 1 H, J = 5.7 Hz) , 7.89 (d, 2H, J = 7.4 Hz), 7.55 (t, 1 H, J = 7.4 Hz), 7.44 (t, 2H, J = 7.7 Hz), 3.16 (type g, 2H, J = 6.4 30 Hz), 1.94 (t, 2H, J = 7.5 Hz), 1.66 (penta, 2H, J = 7.3 Hz); 13C NMR (DMSO-d6) 5 168.6, 168.1, 153.5, 132.7, 132.6, 128.5, 128.1, 38.7, 29.8, 25.5.

Example 35 Preparation of 3-. { 4- [3-benzoyl-1- (3-phenyl-propyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. LC-MS (ESI, positive mode) m / z 458 ([M + H] +); ¾ NMR (CD30D) d 7.65 (d, 2H, J = 7.3 Hz), 7.49 (1 H, t, J = 7.4 Hz), 7.47 (1 H, d, J = 15.6 Hz), 7.44 (d, 2H, J = 7.7 Hz), 7.37 (t, 2H, J = 7.7 Hz), 7.27 (br d, 2H), 7, 14 (type t, 1H), 7.05 (m, 2H), 7.02 (m, 2H), 6.37 (d, 1H, J = 15.8 Hz), 4.58 (s, 2H) , 3.28 (m, 2H), 3.15 (type s, 2H), 1.83 (penta, 2H, J = 7.4 Hz).

Example 36 Preparation of 3-methyl ester. { 4- [3-benzoyl-1- (2-phenoxy-ethyl) -ureidomethyl] -phenyl} -N- idroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. LC-MS (ESI, positive mode) m / z 460 ([M + H] +); XH NMR (CD3OD) d 7.74 (br s, 2H), 7.50 (t, 1 H, J = 7.3 Hz), 7.45 (d, 1 H, J = 15.3 Hz), 7.43 (d, 2H, J = 7.3 Hz), 7.37 (t, 2H, J = 7.6 Hz), 7.32 (d, 2H, J = 7.7 Hz), 7, 14 (td, 2H, J = 7.4, 1.2, Hz), 6.85 (t, 1 H, J = 7.4 Hz), 6.75 (d, 2H, J = 7.4 Hz ), 6.35 (d, 1 H, J = 15.8 Hz), 4.69 (s, 2H), 4.08 (t, 2H, J = 4.8 Hz), 3.75 (t, 2H, J = 4.9 Hz). Example 37 Preparation of 4- [3-benzoyl-1- (3-phenyl-propyl) -ureidomethyl] -N-hydroxy-benzamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. LC- S (ESI, positive mode) m / z 432 ([M + H] +); ¾ R (CD3OD) d 7.65 (d, 2H, J = 7.6 Hz), 7.63 (d, 2H, J = 8.3 Hz), 7.50 (t, J = 7.3 Hz) ), 7.38 (t, 2H, J = 7.7 Hz), 7.33 (br d, 2H, J = 6.6 Hz), 7.10-6.88 (m, 5H), 4, 62 (s, 2H), 3.27 (m, 2H), 2.50 (type t, 2H, J = 6.9 Hz), 1.84 (penta, 2H, J = 7.5 Hz).

Example 38 Preparation of 4- (3-benzoyl-l-pyridin-3-ylmethyl-ureidomethyl) -N-idroxy-benzamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity or HPLC at 254 nitl: 98%; LC-MS (ESI, positive mode) m / z 405 (tM + H] +); XH NMR (CD3OD) 5 8.73 (s, 1 H), 8.64 (d, 1 H, J = 5.4 Hz), 8.38 (br d, 1 H, J = 6.9 Hz) , 7.85 (t, 1 H, J 6.8 Hz), 7.76 (d, 2H, J = 8.5 Hz), 7.67 (d, 2H, J = 8.3 Hz), 7 , 55 (tt, 1 H, J = 7.7 Hz), 7.43 (t, 2H, J = 7.7 Hz), 7.34 (d, 2H, J = 8.2 Hz), 4, 79 (s, 2H), 4.73 (s, 2H).

Example 39 Preparation of 4- (3-benzoyl-l-benzole-ureidomethyl) -N-hydroxy-benzamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity by HPLC at 254 nm: 97%; LC-MS (ESI, positive mode) m / z 404 ([M + HD; XH NMR (CD3OD) d 7.638 (d, 2h, J = 7.0 Hz), 7.636 (d, 2, J = 8.4) HZ), 7.48 (tt, 1 H, J = 7.4, 1.2 Hz), 7.36 (t, 2H, J = 7.7 Hz), 7.31 (br type d, 2H) , 7.28-7.17 (m, 5H), 4.58 (s, 2H), 4.53 (s, 2H).

Example 40 Preparation of 4- [3-benzoyl-l-pyridin-2-yl-ethyl) -ureidomethyl] -N-hydroxy-benzamide methyl ester Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. LC-MS (ESI, positive mode) m / z 419 ([M + H] +); X H NMR (CD 3 OD) d 8.54 (br S, 1 H), 8.28 (br s, 1 H), 7.80-7.60 (m, 6H), 7.48 (t, 1 H, J = 7.4 Hz), 7.37 (t, 2H, J = 8.0 Hz), 7.30 (d, 2H, J = 7.6 Hz), 4.62 (s, 2H), 3, 82 (t, J = 6.5 Hz), 3.25 (t, 2H, J = 6.4 Hz).

Example 41 Preparation of 4- [3-benzoyl-1- (3-hydroxy-propyl) -ureidomethyl] -N-hydroxy-benzamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity by HPLC at 254 nm: 97%; LC- S (ESI, positive mode) m / z 372 ([M + H] +); ¾ RM (CD3OD) 57.78 (br m, 2H), 7.65 (d, 2H, J = 8.3 Hz), 7.49 (t, 1 H, J = 7.4 Hz), 7, 41-7.36 (m, 4H), 4.59 (s, 2H), 3.52 (t, 2H, J = 5.8 Hz), 3.48 (t, 2H, J = 6.5 Hz), 1.72 (t, 2H, J = 6, 0 Hz).

Example 42 Preparation of 3- [4- (3-benzoyl-l-benzyl-ureidomethyl) -phenyl] -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity by HPLC at 254 nm: 96%; LC-MS (ESI, positive mode) m / z 430 ([M + HD; ¾ NMR (CD3OD) d 7.67 (dd, 2H, J = 8.5, 1.3 Hz), 7.55-7 , 46 (m, 4H), 7.39 (t, 2H, J = 7.4 Hz), 7.32-7.22 (m, 7H), 6.37 (d, 1H, J = 15.7 Hz), 4.58 (s, 2H), 4.57 (s, 2H).

Example 43 Preparation of 3-. { 4- [3-benzoyl-1- (2-pyridyl-2-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity by HPLC at 254 nm: 96%; LC-MS (ESI, positive mode) m / z 558 ([+ H] +); ¾ NMR (CD30D) d 8.56 (1 H, s), 8.32 (br s, 1 H), 7.83 (br s, 1 H), 7.76 (br S, 1 H), 7.66 ( d, 2H, J = 6.6 Hz), 7.51-7.45 (m, 4H), 7.37 (t, 2H, J = 7.5 Hz), 7.25 (d, 2H, J = 7.4 Hz), 6.39 (d, 1 H, J = 14.7 Hz), 4.58 (s, 2H), 3.82 (t, 2H, J = 8.4 Hz), 3 , 26 (t, 2H, J 6.3 Hz).

Example 44 Preparation of 3-. { 4- [3-benzoyl-1- (2-pyridin-3-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. LC-MS (ESI, positive mode) m / z 445 ([M + H] +); XH NMR (CD3OD) d 8.67-8.39, 7.27 (br m, py-H), 7.84-7.35 (br, m, Ar-H), 6.40-6.36 (d, 1 H, J = 16Hz), 4.58 (s, 2H), 3.73-3.69 (t, 2H), 3.10-3.07 (t, 2H); 13C NMR (CD3OD) 5 167.1, 164.2, 154.4, 137.9, 133.9, 132.3 (Ar-C), 141.8, 138.9, 131.9, 127.8 , 127.3, 127.2, 127.0, 126.0, 116.9, 29.8.

Example 45 Preparation of 3-. { 4- [3-benzoyl-1- (2-pyridin-4-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity by HPLC at 254 nm: 100%; LC-MS (ESI, positive mode) m / z 445 ([M + H] +); ¾ NMR (CD3OD) d 8.66-8.53 and 7.28-7.27 (br m), 7.86-7.35 (br m), 6.41-6.37 (d, 1 H , J = 16Hz), 4.61 (s, 2H), 3.77-3.74 (t, 2H), 3.16-3.15 (t, 2H); 13C NMR (CD3OD) 5 167.1, 164.2, 160.3, 154.4, 138.9, 137.8, 133.9, 132.3, 140.5, 131.9, 127.8, 127.3, 127.3, 127.2, 127.1, 116.9, 33.3.

Example 46 Preparation of 3-. { 4- [3-benzoyl-1- (2-piperidin-1-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity or HPLC at 254 fflti: 100%; LC-MS (ESI, positive mode) m / z 451 (tM + H] +); X H NMR (CD 3 OD) d 7.70-7.32 (m, 11 H), 6.43 (d, 1 H, J = 16 Hz), 4.61 (t, 2 H), 3.77 (t, 2H), 3.56-3.53 (br, 2H), 2.94 (br, 2H), 1.90-1.47 (br, 6H); 13C NMR (CD3OD) d 167. 4, 164.1, 137.2, 134.2, 132.1, 138.8, 132.2, 127.8, 127. 5, 127.2, 117.0, 53.7, 53.1, 51.0, 41.6, 22.3, 20.6.

Example 47 Preparation of 3-. { 4- [3-benzoyl-1- (2-pyrrolidin-1-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide Process as described in Example 23 above, but using the appropriate starting materials. The crude compound in the title was purified by reverse phase preparative HPLC. Purity by HPLC at 254 nm: 97%; LC-MS (ESI, positive mode) m / z 437 ([M + H] +); ¾ NMR (CD3OD) d 7.70 (d, 2H, J = 7.5 Hz), 7.52 (t, 1 H, J = 7.4 Hz), 7.51 (d, 2H, J = 7 , 8 Hz), 7.48 (d, 1 H, J = 18.3 Hz), 7.39 (t, 2H, J = 7.6 Hz), 7.30 (d, 2H, J = 7, 9 Hz), 6.40 (d, 1 H, J = 15.8 Hz), 4.66 (s, 2H), 3.72 (t, 2H, J = 6.3 Hz), 3.67 ( br m, 2H), 3.34 (t, 2H, J = 6.2 Hz) N-CH2), 3.05 (br m, 2H), 2.07 (br m, 2H), 1.96 ( br m, 2H).

Solid phase synthesis of hydroxamates containing acylurea The following protocol was used for the synthesis of solid phase acylurea. Step 1 O- (2,4-dimethoxy-benzyl) -hydroxylamine was attached to the SASRIN aldehyde (super acid-sensitive resin, Katritzky, AR 38: 7849-7850 (1997)) by reductive amination to give the hydroxylamine resin labile protected by acid. Step 2 3- (4-Formyl-phenyl) -acrylic acid was bound to the resin, by treatment with PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) and N, N-diisopropylethylamine (DIEA). Stage 3 Reductive amination with selected variety of amines. Step 4 Formation of acylurea by reaction of the above resin with benzoyl isocyanate. Stage 5 Excision of TFA and subsequent elaboration. Step 6 The crude products were purified by a high performance mass-dependent HPLC purification system. Scheme 11 Table 1. Examples prepared by solid phase synthesis Compo Structure M + H Name 3-. { 4- [3-benzoyl-1- (2-cyclohex-l-enyl-ethyl) -0 L01 HCNX 448 ureidomethyl] -H-phenyl} -N- 0 or idroxi- acrylamide 3-. { 4- [3-benzoyl-1- (2-ethylhexyl) -L02 451 ureidomethyl] -phenyl} -N-hydroxy acrylamide 3-. { 4- [3-benzoyl-1- (3-phenyl-propyl) -L03 458 ureidomethyl] -phenyl} -N-hydroxy acrylamide 3-. { 4- [3-benzoyl- l- (3,3-diphenyl-propyl) -L05 534 ureidomethyl] -phenyl} -N-hydroxy-acrylamide 3-. { 4- [3-benzoyl-1- (2-biphenyl-4-yl-ethyl) - L06 0 520 ureidomethyl] - H phenyl} -N- O 0 hydroxy acrylamide 3-. { 4- [3-benzoyl- 1- (3-phenyl- 0 propyl) - L27 458 ureidomethyl] -H phenyl} -N- 0 or hydroxy acrylamide 3-. { 4- [3-benzoyl- 1- (3, 3-diphenyl-propyl) -0 L28 534 ureidomethyl] -H phenyl} -N- 0 0 hydroxy acrylamide 3- [4- (3-benzoyl- 1-benzyl ureidomethyl) - L36 429 phenyl] -N- 0 0 hydroxy acrylamide By means of methods analogous to those described with priority and varying the starting materials used in the synthesis, a great variety of compounds of the formula (I), including, but not limited to, those of table 2.

Acyl isocyanates could not be prepared commercially available according to the methods published in the bibliography. For example, acetyl isocyanate could be synthesized by reacting Et3SnNCO with acetyl bromide [Chauzov, v. TO.; Baukov, Yu. I. Zhurnal Obshchei Khimii (1972), 42 (8), 1868-9], or by reacting Bu3SnNCO with acetyl chloride [Kodama, H. et al. Jpn. Tokkio oho (1972) JP47009568]. One could prepare acyl isocyanate R'CONCO [R '= Cx-4 alkyl, Ph (substituted), naphthyl] by reaction of R'COX (X = halo) with NaOCN [Caubere, P. et al. Eur Pat. Appl. (1989), EP 334720 Al].

??? OR IT) H O LO H O LD H OR LO H o H BIOLOGICAL TESTS AND ENZYME TESTS Recombinant GST-HDAC1, and Expression and Purification of GST-HDAC8 Proteins A human cDNA library was prepared with cultured SW620 cells. Amplifications of the human HDAC1 and HDAC8 coding regions from this library were cloned separately into the baculovirus expression vectors pDEST20 and pFASTBAC, respectively (GATEWAY Cloning Technology, Invitrogen Pte Ltd). The constructs of pDEST20-HDACl and pFASTBAC ~ HTGST-HDAC8 were confirmed by determination of the DNA sequence. Recombinant baculovirus was prepared by the Bac-To-Bac method, according to the manufacturer's instructions (Invitrogen Pte Ltd). The baculovirus titer was determined by plaque assay at approximately 108 PFu / ml. Expression of GST-HDAC1 or HTGST-HDAC8 was obtained by infection of SF9 cells (Invitrogen Pte Ltd) with baculovirus pDEST20-HDACl or pFASTBAC-GST-HDAC8 at MOI = 1 for 48 h. The soluble cell lysate was incubated with pre-equilibrated Glutathione-Sepharose 4B beads (Amersham) at 4 ° C for 2 h. The beads were washed with PBS buffer 3 times. The GST-HDAC1 protein or the GST-HDAC8 protein was eluted by elution buffer containing 50 iriM Tris, pH 8.0, 150 mM NaCl, 1% Triton X-100 and 10 m or 20 mM reduced glutathione. The purified GST-HDAC1 protein or the purified GST-HDAC8 protein was dialyzed with HDAC stored buffer containing 10 mM Tris, pH 7.5, 100 mM NaCl and 3 mM MgCl2. 20% glycerol was added to the purified protein GST-HDAC1 or the purified protein GST-HDAC8 before storage at -80 ° C.

In vitro HDAC assay for the determination of IC 50 values. The assay was conducted in 96-well format, and the HDAC activity assay based on fluorescent BIOMOL was applied. The reaction mixture comprised a test buffer containing 25 mM Tris pH 7.5, 137 mM NaCl, 2.7 mM KC1, 1 mM MgCl2, 1 mg / ml BSA, the test compounds, 500 nM HDAC8 enzyme or 600 nM of HDAC1 enzyme, 200 μ? of peptide substrate Flur de lys p53 for enzyme HDAC8 or 500 μ? of generic substrate for HDAC1 enzyme, and then incubated at room temperature for 2 h. Flur de lys developer was added and the reaction mixture was incubated for 10 min. Briefly, the deacetylation of the substrate sensitizes the developer, which then generates the fluorophore. The fluorophore is excited with light of 360 nm and the emitted light (460 nm) is detected in a fluorometric plate reader (Tecan Ultra Microplate detection system, Tecan Group Ltd.). The analytical software, Prism 3.0® (GraphPad Software Inc) is used to generate IC50 from a data set. The HDAC enzyme inhibition results of the representative compounds are shown in Table 3.

Table 3. HDAC Enzyme Inhibition Activities of Representative Examples Compound IC50 of HDAC1 (μ?) IC50 of HDAC8 (μ?) Example 1 > 100 0, 79 Example 2 2.61 0, 040 Example 3 1.54 0, 022 Example 4 2, 92 0, 049 Example 5 > 100 0.14 Example 6 0, 13 0, 041 Example 7 > 100 0, 15 Example 8 > 100 0, 072 Example 10 0.056 1.07 Example 11 0.004 0.21 Example 12 0.098 0.40 Example 13 0.15 0.27 Example 14 1, 13 0.051 Example 18 0, 027 0.52 Example 23 0, 012 0.20 Example 30 2, 87 0.46 Example 46 0.048 0.23 Example 47 0.024 0.25 Cell proliferation assay for the determination of IC50 values Human colon cancer cell lines (Colo205) and human breast cancer cell lines (MDA-MB435 and MDA-B231) were obtained by ATCC. Colo205 cells were cultured in RPMI 1640 containing 2 mM L-glutamine, 5% FBS, 1.0 mM Na pyruvate. MDA-MB231 cells were cultured in RPMI 1640 containing 2 mM L-glutamine, 5% FBS. The MDA-MB435 cells were cultured in DMEM containing 2 mM L-glutamine, 5% FBS. Colo205 cells were seeded in a 96-well plate at 5,000 cells per well, respectively. The MDA-MB435 and MDA-MB231 cells were plated in a 96-well plate at 6,000 cells per well. Plates were incubated at 37 ° C, 5% C02 for 24 h. The cells were treated with the compounds in various concentrations for 96 h. Cell development was then monitored by a cyquant cell proliferation assay (Invitrogen Pte Ltd). The dose response curves were plotted to determine IC 50 values for the compounds using XL-fit fit (ID Business Solution, Emeryville, CA). Table 4 shows the results of the cell growth inhibition activity of the representative compounds. These data indicate that the compounds of the present invention are very active inhibitors of the growth of tumor cells. In addition, representative compounds have also demonstrated their ability to inhibit the growth of other types of cancer cell lines, for example lung cancer cell lines (e.g., NCI-H522 and A549), prostate cancer cell lines (eg. example PC3), leukemia cell lines (eg HL-60), lymphoma cell lines (eg Ramos) and pancreatic cancer cell lines (MIAPaCA2) (data not shown).

Table 4. Cellular activities of representative examples Compound GI50 Coló 205 GI50 MDA-MB231 6I50 MDA-MB435 (μ?) (Μ?) (Μ) Example 6 1.91 1.92 1.24 Example 10 1.893.03 1.79 Example 11 0.26 0.26 0.62 Example 12 8, 03 Example 13 2.68 Example 18 2, 67 Example 23 0.15 0.26 Example 25 0.16 Example 46 0.63 Histone acetylation assay H3, H4, H2A and H2B A reference point in The inhibition of histone deacetylase (HDAG) is the increase in the level of histone acetylation. Acetylation of histones, for example H3, H4, H2A and H2B, can be detected by immunoblotting (western blot). Colo205 cells, approximately 1.5 x 106 cells / 10 cm dish were seeded in the medium described above, cultured for 24 h and then treated with HDAC inhibitors with final concentrations of 0.1, 1, 5 and 10. n. After 24 h the cells were harvested and lysed according to the instructions of the Sigma Mammalian Cell Lysis kit. The concentration of proteins was quantified by the BCA method (Sigma Pte Ltd). The protein lysate was separated by 4-12% bis-tris gel SDS-PAGE (Invitrogen Pte Ltd) and transferred to a PVDF membrane (BioRad Pte Ltd). The membrane was processed with different probes by antibodies specific for acetylated H3, acetylated H4 or acetylated H2A (Upstate Pte Ltd). The detection antibody, anti-rabbit rabbit antibody conjugated with horseradish peroxidase (HRP) was used, according to the manufacturer's instructions (Pierce Pte Ltd). After removing the membrane detection antibody, a substrate with increased guimioluminescence was added to detect HRP (Pierce Pte Ltd) on the membrane.

After removing the substrate, the membrane was exposed to an X-ray film (Kodak) for 1 s - 20 min. The X-ray film was revealed by the X-ray film processor. The density of each band observed in the film could be analyzed by UVP Bioimaging software (UVP, Inc., Upland, CA). The values were then normalized with respect to the actin density in the corresponding samples, in order to obtain the expression of the protein. The results of the istone deacetylase assay are shown in Table 5.Table 5. Effects of representative examples on the accumulation of acetylated histone. Compound Acetylation Acetylation Acetylation Histone Histone Histone Histone Histone 3 4 2A 2B Histone Acetylation Example 6 Active Asset Example 10 Asset Active Active Asset Example 11 Asset Active Active Asset Example 13 Active Example 18 Active Example 23 Active Example 46 Active "Active" means accumulation of acetylated histone observed when compared to the control (without compound).

These data demonstrate that the compounds of the present invention inhibit histone deacetylases, which results in the accumulation of acetylated histones.

Apoptosis assays In various therapeutics, such as for proliferative disorders such as cancer, one of the sought approaches is the selective induction of apoptosis in proliferating cells such as tumor cells, and can be mediated by treatment with various antiproliferative compounds [Blagosklonny MV, Oncogene, 23 (16): 2967 (2004); Kaufmann and Earnshaw, Exp Cell Res. 256 (1): 42-9 (2000)]. Programmed cell death or apoptosis is the cellular response to stressors such as DNA damage caused during conventional anticancer treatment. The concerted sequence of events during apoptosis clearly differentiates this pathway from an uncoordinated form of cell death called necrosis. During the course of apoptosis characteristic phenotypic cell changes take place, for example condensation of chromatin, reduction of cell size and, finally, fragmentation of chromosomal DNA. One of the very early changes caused by apoptotic processes takes place in the phospholipid bilayer of the plasma membrane. Phospholipid phosphatidylserine translocates from the internal part to the external part of the plasma membrane, and as a consequence is exposed to the extracellular space. One way to detect early apoptotic cells is to determine the amount of phosphatidylserine in the extracellular face of the plasma membrane that is obtained by the standard flow cytometric method of Annexin V staining. The phospholipid recognition protein Annexin V binds with large affinity to these inverse and exposed phosphatidylserines. The ability of these compounds of the present invention to induce apoptosis was studied in Ramos Burkitt lymphoma cells. This cell line is one of the gold standards of cell lines, often used as a tissue culture model for B lymphoma cells. As indicated below, the representative compounds were added to 80,000 cells per 500 μ? of culture medium (RPMI 1640 medium supplemented with 2 m L-glutamine, 10% heat-inactivated PBS, 1 mM Na pyruvate and 10 mM HEPES) in 24-cavity format at various concentrations. Two days after starting treatment, the cells were recovered and subjected to the Annexin V staining protocol, according to the manufacturer's instructions (BD Biosciences). Through the use of propidium iodide (PI) as a control of viability, it was observed that the cells, which stain positive for Annexin V, but negative for PI, undergo apoptosis. The percentage of cells in late apoptosis after treatment was derived from a standard flow cytometric analysis (FACS) [Steensma et al, ethods Mol Med 85: 323-32 (2003). For example, the percentage of late apoptotic cells 48 h after treatment with 10 μ? it was 84% for the compound of Example 3 (N-hydroxy-3. {3- [3- (4-methyl-benzenesulfonyl) -ureido] -phenyl} -acrylamide). In addition, selected compounds were studied for their ability to induce apoptosis in HL-60 cells, an acute promyelocytic leukemia cell line (data not shown). Accordingly, the compounds described in the present invention can be used to treat cancer such as hematological malignancies (e.g., lymphoma and leukemia).

Study of tumors by xenograft in vivo In data not shown, selected compounds were studied to determine the maximum tolerated dose in normal mice, and it was observed that they were well tolerated in mice, without obvious signs of toxicity or side effects in the dose range requested (may be> 200 mg / kg / day).

Therefore, the efficacy of the compounds of the invention can be determined by xenograft studies in animals in vivo. The xenograft model in animals is one of the most commonly used in vivo cancer models. In these studies, female athymic nude mice (Harían) 12-14 weeks of age were implanted subcutaneously in the flank, 5 x 10 6 cells of HCT116 or 1 x 10 6 cells Colo205 of human colon carcinoma suspended in 50% of Matrigel. When the tumor reaches the size of 100 mm, nude mice are divided with xenograft in pairs with several treatments. Selected HDAC inhibitors are dissolved in suitable vehicles such as 10% DMA / 10% Cremophore / 80% water and administered to nude mice with xenograft intraperitoneally twice a day for 14 days. The dosage volume is 0.2-ml / 20 g of mouse. Paclitaxol is prepared as a positive control for intravenous administration in 10% ethanol / 10% Cremophore / 80% water. The dosage volume for Paclitaxol will be 0.015 ml / g of mouse. The tumor volume is calculated every second day after injection by the formula: tumor volume (mm3) = (w2 xl) / 2, where w = width and 1 = length in mm of a carcinoma HCT116 or Colo205 [Beverly AT, In Tumor Models in Cancer Research, published by Humana Press, New Jersey, pgs. 593-612, 2002]. The compounds of the present invention studied would show significant reduction in tumor volume compared to controls treated only with vehicle. The measured histone deacetylase activity should be reduced, and produces the accumulation of acetylated histone relative to the control group treated with control. Accordingly, the result will indicate that the compounds of the present invention are effective for the treatment of a proliferative disorder, for example cancer. The details of the specific embodiments described in the present invention should not be construed as limitations. Various equivalences and modifications can be made without departing from the essence and scope of the present invention, and it is understood that said equivalent embodiments are part of the present invention.

Claims

CLAIMS 1. Hydroxamates connected to acylurea and sulfonylurea, characterized in that they have the formula

Formula (I) wherein R is a linking moiety; R1 is selected from the group consisting of H, Ci-C6 alkyl and acyl; M is selected from the group consisting of O, S, H, NR4, NOH and ÑOR4; R 2 is selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, haloalkenyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl , arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, phenoxy, benzyloxy, COOR4, CO HR4, HCOR, NHC00R4, NHCONHR4, C (= N0H) R4, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted, or R2 together with the nitrogen to which it is attached and a portion of R form an optionally substituted heterocycloalkyl group; R3 is selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl , arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, phenoxy, benzyloxy, COOR4, CO HR4, NHCOR4, NHC00R4 NHCONHR4, C (= NOH) R4, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted; Q is selected from the group consisting of -S (0) 2-, -C (= 0) - and -C (= S) -; G is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; each R4 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; or one of its pharmaceutically acceptable salts or prodrugs.
2. A compound according to claim 1 characterized in that it has the formula (2)
Formula (2) wherein R1 is selected from the group consisting of H, alkyl QL-C6 and acyl; L is a single bond or is a chain of hydrocarbons QL-C5 which may contain 0 to 2 multiple bonds independently selected from double bonds and triple bonds and wherein the chain may be optionally interrupted by at least one of -O -, -S-, - S (O) - and -S (O) 2- and the chain can be optionally substituted with one or more substituents independently selected from the group consisting of C! -C4 alkyl Z is selected of the group consisting of a single bond, N (R1), 0, S, S (0) and S (0) 2; A is selected from the group consisting of a single bond, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene and optionally substituted heterocycloalkylene;
B is selected from the group consisting of a single bond, optionally substituted aminoacyl, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted arylalkylene, optionally substituted heteroarylalkylene, optionally substituted alkylarylene, optionally substituted alkylheteroarylene, optionally substituted Ci-C3 alkylene, optionally substituted heteroalkylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene and - (CH2) mC (0) -N (R4) (CH2) n-optionally substituted, wherein n is an integer from 0 to 6, m is an integer from 0 to 6; M is selected from the group consisting of O, S, NH, NR4, NOH and ÑOR4; R 2 is selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl , arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, phenoxy, benzyloxy, C00R4, CONHR4, NHCOR4 , NHCOOR4, NHCONHR4, C (= N0H) R4, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted, or R2 together with the nitrogen to which it is attached and a portion of B form an optionally substituted heterocycloalkyl group; R3 is independently selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, ilheteroalquilo heteroa, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, phenoxy, benzyloxy , COOR4, CONHR4, NHCOR4, HC00R4, HCONHR4, C (= N0H) R4f alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminosulfinyl, SR4 and acyl; each of which may be optionally substituted; Q is selected from the group consisting of -S (0) 2-, -C (= C0- and -C (= S) -; G is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, cycloalkyl optionally substituted, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; each R 4 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted, or a pharmaceutically acceptable salt or prodrug thereof 3. A compound according to claim 1 or 2 characterized in that it has the formula (2a)
Formula (2a) wherein R1 is selected from the group consisting of H, Ci-C6 alkyl and acyl; L is a single bond or is a C1-C5 hydrocarbon chain which may contain 0 to 2 multiple bonds independently selected from double bonds and triple bonds and wherein the chain may be optionally interrupted by at least one of -0 -, -S-, -S (O) - and -S (O) 2- and the chain may be optionally substituted with one or more substituents selected, independently, from the group consisting of Ci-C4 alkyl; Z is selected from the group consisting of a single bond, N (RX), O, S, S (O) and S (0) 2; A is selected from the group consisting of a single bond, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene and optionally substituted heterocycloalkylene;
B is selected from the group consisting of a single bond, optionally substituted aminoacyl, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted arylalkylene, optionally substituted heteroarylalkylene, optionally substituted alkylarylene, optionally substituted alkylheteroarylene, optionally substituted Ci-C3 alkylene, optionally substituted heteroalkylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene and - (CH2) mC (O) -N (R4) (C¾) n-optionally substituted, wherein n is an integer from 0 to 6, m is an integer from 0 to 6; M is selected from the group consisting of 0, S, NH, NR4, NOH and OR4; R2 is selected from the group consisting of H, L-CIO alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), arylalkyl (e.g. benzyl), heteroarylalkyl (eg pyridylmethyl), hydroxyl, hydroxyalkyl, alkoxy, amino, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C (0) OR4, - CONHR4, -NHCONHR4, C (= N0H ) R4, and acyl; R3 is selected from the group consisting of H, Ci-Cio alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl (e.g. cyclopropylmethyl), arylalkyl (e.g. benzyl), heteroarylalkyl (for example pyridylmethyl), hydroxyl, hydroxyalkyl, alkoxy, amino, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C (0) 0R4, -CONHR4, -NHCONHR4, C (= NOH) ) R4 and acyl; Q is selected from the group consisting of -S (0) 2-, -C0- and -C (= S) -; G is selected from optionally substituted aryl, optionally substituted heteroaryl, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl, wherein substituents are independently selected from the group consisting of X, Y, R4 , hydroxyl, hydroxyalkyl, alkoxy, amino, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C (0) OR 4, -C (0) OH, -SH, - CONHR 4, -NHCONHR 4 and C (= NOH) R4; R4 is selected from the group consisting of Ci-C4 alkyl / heteroalkyl, aryl, heteroaryl and acyl; X and Y are the same or different and are independently selected from the group consisting of H, halo, C 1 -C 4 alkyl, NO 2, OR 4, SR 4, C (0) R 5, and NR 6 R 7;
R5 is Ci-C4 alkyl; R6 and R7 are the same or different and are independently selected from the group consisting of H, Ci-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl or one of its salts or prodrugs pharmaceutically acceptable 4. A compound according to claim 2 or 3 characterized in that it has the formula (2b)
Formula (2b) or one of its pharmaceutically acceptable salts or prodrugs. 5. A compound according to any of claims 2-4 characterized in that they have the formula (2c)
Formula (2c) or one of its pharmaceutically acceptable salts or prodrugs. 6. A compound according to any of claims 2 to 4, characterized in that A is optionally substituted arylene. 7. A compound according to any of claims 2 to 4, characterized in that A is selected from the group consisting of 1,4-phenylene and 1,3-phenylene. 8. A compound according to any of claims 2 to 4, characterized in that A is 1,4-phenylene. 9. A compound according to any of claims 2 to 8, characterized in that L is selected from the group consisting of a single bond, -CH2-, - (CH2) 2 - and -CH = CH-.
10. A compound according to any of claims 2 to 9, characterized in that L is a bond.
11. A compound according to any of claims 2 to 9, characterized in that L is a group of the formula -CH2-.
12. A compound according to any of claims 2 to 9, characterized in that L is a group of the formula -CH = CH-.
13. A compound according to any of claims 2 to 12, characterized in that B is selected from the group consisting of a single bond, methylene, ethylene, propylene, alkylarylene and heteroalkylene.
14. A compound according to any of claims 2 to 13, characterized in that B is methylene.
15. A compound according to any of claims 2 to 13, characterized in that B is a single bond.
16. A compound according to any of claims 2 to 13, characterized in that B is ethylene.
17. A compound according to any of claims 2 to 13, characterized in that B is propylene.
18. A compound according to claim 2 or 3, characterized in that the BAZL group is a group of the formula - (CH2) n- / wherein n is an integer from 1 to 7.
19. A compound according to claim 2 or 3, characterized in that the BAZ group is a group of the formula - (CH2) -phenyl-.
20. A compound according to claim 2 or 3, characterized in that the BAZL group is selected from the group consisting of it's a simple link
21. A compound according to any of claims 2 to 20, characterized in that R2 and a portion of B, together with the nitrogen to which they are attached, form a heterocycloalkylene.
22. A compound according to claim 21, characterized in that the heterocycloalkylene is 1,4-piperazinylene.
23. A compound according to any of claims 1 to 22, characterized in that R1 = H.
24. A compound according to any of claims 1 to 23, characterized in that M is O.
25. A compound according to any of claims 1 to 23, characterized in that M is S.
26. A compound according to any of claims 1 to 23, characterized in that Q is S (0) 2-
27. A compound according to with any of claims 1 to 23, characterized in that Q is CO.
28. A compound according to any of claims 1 to 27, characterized in that G is optionally substituted aryl.
29. A compound according to any of claims 1 to 28, characterized in that G is phenol.
30. A compound according to any of claims 1 to 28, wherein G is 4-methylphenyl.
31. A compound according to any of claims 1 to 30, characterized in that R2 is selected from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylheteroalkyl, optionally substituted eteroarylalkyl, optionally substituted heteroaryl heteroalkyl, optionally substituted cycloalkylalkyl, and optionally substituted heterocycloalkylalkyl.
32. A compound according to any of claims 1 to 31, characterized in that R2 is selected from the group consisting of H, 2- (lH-indol-3-yl) -ethyl, 2- (2-methyl-lH-indole-3 -yl) -ethyl, pyridin-3-ylmethyl, 3-hydroxy-propyl, 2-pyridin-2-yl-ethyl, 2-pyridin-3-yl-ethyl, pyridin-3-ylmethyl, 2-pyridin-4- il-ethyl, benzyl, 3-phenyl-propyl, 2-phenoxy-ethyl, morpholin-4-yl, pyridin-2-yl, phenethyl, 2- (4-bromo-phenyl) -ethyl, 2- (4-fluoro) phenyl) -ethyl, 3-imidazol-l-yl-propyl, 2- (lH-imidazol-4-yl) -ethyl, lH-benzoimidazol-2-ylmethyl, 2-piperidin-l-yl-ethyl, 2- pyrrolidin-l-yl-ethyl, 2-cyclo-ex-l-enyl-ethyl, 2-ethyl-hexyl, 2-thiophen-2-yl-ethyl, 3, 3-diphenyl-propyl, 2-biphenyl-4-yl -ethyl, 4-phenoxy-phenyl, 2- (3-phenoxy-phenyl) -ethyl, 2- (2,3-dimethoxy) -phenyl, 2- (2,4-dichloro-phenyl) -ethyl, cyclohexylmethyl, hexyl , isobutyl, 3-isopropoxypropyl, 2-phenoxy-ethyl, 2-isopropoxy-ethyl, 3-methoxy-benzyl, 4- [1,2,3] thiadiazol-4-yl-benzyl, 2,4-dichloro-benzyl 2- (2-methoxy-feni) l) -ethyl, 2- (3-fluoro-phenyl) ethyl, 2- (2-fluoro-phenyl) -ethyl, 2,2-diphenyl-ethyl, 2- (4-methoxy-phenyl) -ethyl, 2- ( 3-chloro-phenyl) -ethyl, 4-phenyl butyl, 3-phenyl-propyl, 3,3-diphenyl-propyl, 3- (4-methyl piperazin-1-yl, 3-morpholin-4-yl-propyl, 3- (2-Oxo-pyrrolidin-1-yl) -propyl, 3-pyrrolidin-1-yl-propyl-tetrahydro-furan-2-ylmethyl, 1,5-dimethyl-hexyl, 2-diethylamino-ethyl and 2-dimethylamino-ethyl .
33. A compound according to any of claims 1 to 31, characterized in that R2 is selected from the group consisting of H, 2- (lH-indol-3-yl) -ethyl, 2- (2-methyl-lH-indole-3 -yl) -ethyl, pyridin-3-ylmethyl, 3-hydroxy-propyl, 2-pyridin-2-yl-ethyl, 2-pyridin-3-yl-ethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, 2-pyridin-4-yl-ethyl, benzyl, 3-phenyl-propyl, 2-phenoxy-ethyl, 2-morpholino-ethyl, 2-phenyl-ethyl, 2- (4-bromo-phenyl) -ethyl, 2- (4-fluoro-phenyl) -ethyl, 3-imidazol-1-yl-propyl, 2- (1H-imidazol-4-yl) -ethyl, lH-benzoimidazol-2-ylmethyl, 2-piperidin-1-yl- ethyl and 2-pyrrolidin-1-yl-ethyl.
34. A compound according to any of claims 1 to 31, characterized in that R2 is selected from the group consisting of H, 2- (lH-indol-3-yl) -ethyl, 2- (2-methyl-lH-indole -3-yl) -ethyl, 2-phenyl-ethyl, 2-piperidin-1-yl-ethyl and 2-pyrrolidin-1-yl-ethyl.
35. A compound according to any of claims 1 to 34, characterized in that the optional substituents are selected from the group consisting of halogen, -0, = S, -CN, -N02, -CF3, -0CF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cicloalilalquilo, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocicloalquilalquenilo, arylalkenyl, heteroarylalkenyl, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, arylalkyl, hetero arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -COOH, -COR5, -C (0) OR5 , CONHR5, NHCOR5, NHCOOR5, HCONHR5, C (= NOH) R5, -SH, -SR5, -0R5 and acyl, wherein each R5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted.
36. A compound according to claim 1 characterized in that it is selected from the group consisting of hydroxyamide of 8-enylsulfonyl) -ureido]) -octanoic acid, 7-enzenesulfonyl) -ureido]) -heptanoic acid hydroxyamide of 6-enzenesulfonyl) - ureido]) -hexanoic, 6- [3- (benzenesulfonyl) -ureido]) -hexanoic acid hydroxyamide N-hydroxy-4- [3- (4-methylbenzenesulfonyl) ureido] methyl-benzamide,
N-hydroxy-2-. { 4- [3- (4-methylbenzenesulfonyl) ureido] -phenyl j-acetamide, N-hydroxy-2-. { 3- [3- (4-methylbenzenesulfonyl) -reido] -phenyl} -acetamide,
N-hydroxy-3-. { 4- [3- (4-methylbenzenesulfonyl) ureido] -phenyl} -acylamide,
N-hydroxy-3-. { 3- [3- (4-methylbenzenesulfonyl) ureido] -phenyl) -acrylamide, 6- (3-benzoyl-ureido) -hexanedic acid hydroxyamide 7- (3-benzoyl-ureido) -heptanoic acid hydroxyamide, acid hydroxyamide 8- (3-benzoyl-ureido) -octanoic,
Hydroxyamide of 6- [3-benzoyl-1- (3-phenyl-propyl) -ureido] -hexanoic acid 4- (3-benzoyl-ureidomethyl) -N-hydroxy-benzamide, 2- [4- (3-benzoyl-ureido) -phenyl] -N-hydroxy-acetamide, 2- [3- (3-benzoyl-ureido) -phenyl] -N-hydroxy-acetamide, 3- [4- (3-benzoyl-ureido) -phenyl] -N-hydroxy-acrylamide, 3- (4-. {3-benzoyl-l- [2- (1H-indol-3-yl) -ethyl] -ureidomethyl} -phenyl) -N-hydroxy-acrylamide, 3- [4- (3-benzoyl-l-pyridin-3-ylmethyl-ureidomethyl) -phenyl] -N-hydroxy-acrylamide, 3-. { 4- [3-benzoyl-l- (3-idroxy-propyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide, 4-. { 3-benzoyl-l- [2- (1H-indol-3-yl) -ethyl] -ureidomethyl} -N-hydroxy-benzamide, 4- (3-benzoyl-ureido) -N-hydroxy-N-butyramide, 4- (3-benzoyl-1-benzyl-ureidomethyl) -N-hydroxy-benzamide, 4- [3-benzoyl-l- (2-pyridin-2-yl-ethyl) -ureidomethyl] -N-hydroxy-benzamide, 4- [3-benzoyl-l- (3-hydroxy-propyl) -ureidomethyl] - - hydroxy-benzamide, 3- [4- (3-benzoyl-l-benzyl-ureidomethyl) -phenyl] -N-hydroxy-acrylamide, 3-. { 4- [3-benzoyl-1- (3-phenyl-propyl) -ureidomethyl] -phenyl} -N- idroxy-ac ilamide, 3- . { 4- [3-benzoyl-l- (2-phenoxy-ethyl) -ureidomethyl] -phenyl} -N-hydroxy acrylamide, 4- [3-benzoyl-1- (3-phenyl-propyl) -ureidomethyl] -N-hydroxy-benzamide, 4- (3-benzoyl-l-pyridin-3-ylmethyl-ureidomethyl) -N-hydroxy-benzamide,
(S) -6- [2- (3-Benzoyl-ureido) -3- (lH-indol-3-yl) -propionylamino] -hexanoic acid hydroxyamide, 4- (4-benzoylaminocarbonyl-piperazin-1-ylmethyl) -N-hydroxy-benzamide, 7- (3-benzoyl-1-pyridin-2-ylmethyl-ureido) -heptanoic acid hydroxyamide, 6- (3-benzoyl-l-pyridin-2-ylmethyl-ureido) -hexanoic acid hydroxyamide, 3-. { 4- [3-benzoyl-1- (2-morpholin-4-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide, 7- (3-benzoyl-1-benzylureido) -heptanoic acid hydroxyamide, 6- (3-benzoyl-1-benzylureido) -hexanoic acid hydroxyamide, 3-. { 4- [3-benzoyl-l- (2-pyridin-2-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acyl amide, 3- [4- (3-benzoyl-l-phenethyl-ureidomethyl) -phenyl] -N-hydroxy-acrylamide, 3- (4- { 3-benzoyl-l- [2- (4-bromo-phenyl) -ethyl] -ureidomethyl] -phenyl) -N-idroxy-acrylamide, 3- (4-. 3-benzoyl-l- [2- (4-fluoro-phenyl) -ethyl] -ureidomethyl] -phenyl) -N-hydroxy-acrylamide, N-. { 4- [4- (2-hydroxycarbamoyl-vinyl) -benzyl] -piperazine-1-carbonyl-benzamide,, 3-. { 4- [3-benzoyl-1- (3-imidazol-1-yl-propyl) -ureidomethyl] -phenyl} -N-idroxy-acrylamide, 3- (4- { 3-benzoyl-l- [2- (1H-imidazol-4-yl) -ethyl] -ureidomethyl] -phenyl) -N-hydroxy-acrylamide, hydroxyamide of 6- ( 3-benzoyl-thioureido) -hexanoic, 3-. { 4- [1- (1H-benzoimidazol-2-ylmethyl) -3-benzoyl-ureidomethyl] -phenyl} -N-hydroxy-acrylamide, 3-. { 4- [3-benzoyl-l- (2-pyridin-3-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acyl amide, 3-. { 4- [3-benzoyl-l- (2-pyridin-4-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide, 3-. { 4- [3-benzoyl-1- (2-piperidin-1-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide, 3-. { 4- [3-benzoyl-l- (2-pyrrolidin-1-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide or one of its pharmaceutically acceptable salts or prodrugs. 37. A compound according to claim 1, characterized in that it is selected from the group consisting of 6- (3-benzoyl-ureido) -nexanoic acid idroxyamide, 8- (3-benzoyl-uxeido) -octanoic acid hydroxyamide, 4- (3-benzoyl-ureidomethyl) -N-hydroxy-benzamide, 3- (4-. {3-benzoyl-l- [2- (1H-indol-3-yl) -ethyl] -ureidomethyl} -phenyl) -N-hydroxy-acrylamide, 3- [4- (3-benzoyl-l-phenethyl-ureidomethyl) -phenyl] -N-hydroxy-acrylamide, 6- (3-benzoyl-thioureido) -hexanoic acid hydroxyamide, 3-. { 4- [3-benzoyl-1- (2-piperidin-1-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide, 3-. { 4- [3-benzoyl-l- (2-pyrrolidin-1-yl-ethyl) -ureidomethyl] -phenyl} -N-hydroxy-acrylamide, or one of its pharmaceutically acceptable salts or prodrugs. 38. A pharmaceutical composition characterized by including a compound according to any of claims 1 to 37 and a pharmaceutically acceptable diluent, excipient or carrier. 39. Use of a compound according to any of claims 1 to 37 in the preparation of a medicament for the treatment of a disorder caused by, associated with or accompanied by interruptions of cell proliferation and / or angiogenesis. 40. A use according to claim 39, wherein the disorder is a proliferative disorder. 41. A use according to claim 40, wherein the proliferative disorder is cancer.
42. A use according to claim 41, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, head cancer? neck, kidney cancer, gastric cancer, colon cancer, pancreatic cancer and brain cancer.
43. A method of treating a disorder caused by, associated with or accompanied by interruptions of cell proliferation and / or angiogenesis in a patient, including administration of a therapeutically effective amount of a compound according to any of the claims 1 to 37 to the patient.
44. A method according to claim 43, wherein the disorder is a proliferative disorder.
45. A method according to claim 44, wherein the proliferative disorder is cancer.
46. A method according to claim 45, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, kidney cancer, gastric cancer, colon cancer, pancreatic cancer and brain cancer.
47. Use of a compound according to any of claims 1 to 37 or a pharmaceutical composition according to claim 38 for modifying the activity of deacetylase.
48. A use according to claim 47, wherein the activity of deacetylase is the activity of histone deacetylase.
49. A use according to claim 47, wherein the activity of deacetylase is histone deacetylase class I activity.
50. A use according to claim 48 or 49, wherein the histone deacetylase is HDAC1.
51. A use according to claim 48 or 49, wherein the histone deacetylase is HDAC8.
52. A method for modifying deacetylase activity that includes contacting deacetylase with a compound according to any of claims 1 to 37.
53. A method according to claim 52, wherein the deacetylase activity is the activity of histone deacetylase.
54. A method according to claim 52, wherein the activity of deacetylase is histone deacetylase class I activity.
55. A method according to claim 53 or 54, wherein the histone deacetylase is HDAC1.
56. A method according to claim 53 or 54, wherein the histone deacetylase is HDAC8.
57. A method of treating a disorder that can be treated by inhibiting deacetylase activity in a patient that includes administering a therapeutically effective amount of a compound according to any of claims 1 to 37 to the patient.
58. A method according to claim 57, wherein the activity of deacetylase is the activity of histone deacetylase.
59. A method of treating a disorder that is mediated by histone deacetylase activity in a patient that includes administering a therapeutically effective amount of a compound according to any of claims 1 to 37 to the patient.
60. A method according to any of claims 57 to 59, wherein the disorder is selected from the group consisting of proliferative disorders (eg, cancer); neurodegenerative diseases such as Huntington's disease, polyglutamine diseases, Parkinson's disease, Alzheimer's disease, seizures, degeneration of the black and striated nuclei, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis and dyskinesia, familial tremor, Gilles syndrome Tourette, diffuse disease of Le bodies, progressive supranuclear palsy, Pick disease, intracerebral hemorrhage, primary lateral sclerosis, spinal muscular atrophy, amyotrophic lateral sclerosis, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, ataxia Progressive and Shy-Drager syndrome; metabolic diseases such as type 2 diabetes; degenerative diseases of the eye, including glaucoma, macular degeneration associated with age, rubeotic glaucoma, interstitial keratitis, diabetic retinopathy; inflammatory diseases and / or disorders of the immune system, for example 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; diseases related to angiogenesis, such as cancer, psoriasis, rheumatoid arthritis; psychological disorders such as bipolar diseases, schizophrenia, depression and dementia; cardiovascular diseases such as heart failure, restenosis and arteriosclerosis; fibrotic diseases such as hepatic fibrosis, cystic fibrosis and angiofibroma; infectious diseases such as fungal infections, for example 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 such as thalassemia, anemia and sickle cell anemia.
61. A method for inhibiting cell proliferation, including administering an effective amount of a compound according to any of claims 1 to 37.
62. A method of treating a neurodegenerative disorder in a patient, including administration of a therapeutically effective amount of a compound according to any of claims 1 to 37 to the patient.
63. A method according to claim 62, wherein the neurodegenerative disorder is the disease of Huntington.
64. A method of treating an inflammatory disease and / or immune system disorder in a patient, which includes administering a therapeutically effective amount of a compound according to any of claims 1 to 37 to the patient.
65. A method according to claim 64, wherein the inflammatory disease and / or immune system disorder is rheumatoid arthritis.
66. A method according to claim 64, wherein the inflammatory disease and / or immune system disorder is systemic lupus erythematosus.
67. The use of a compound according to any of claims 1 to 37 in the preparation of a medicament for the treatment of cancer.
68. A use according to claim 67, wherein the cancer is a haematological malignancy.
69. A use according to claim 68, wherein the hematological malignancies are selected from a group consisting of B-cell lymphoma, T-cell lymphoma and leukemia.
70. A use according to claim 67, wherein the cancer is a solid tumor.
71. A use according to claim 70, wherein the tumor solid substance is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, renal cancer, gastric cancer. , colon cancer, pancreatic cancer and brain cancer.
72. A method of treating a proliferative disorder in a patient, including administering a therapeutically effective amount of a compound according to any of claims 1 to 37 to the patient.
73. A method of treating cancer in a patient, which includes administering a therapeutically effective amount of a compound according to any of claims 1 to 37 to the patient.
74. A method according to claim 73, wherein the cancer is a haematological malignancy.
75. A method according to claim 7, wherein the haematological malignancy is selected from the group consisting of B-cell lymphoma, T-cell lymphoma and leukemia.
76. A method according to claim 73, wherein the cancer is a solid tumor.
77. A method according to claim 76, wherein the solid tumor is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, renal cancer, gastric cancer, colon cancer, pancreatic cancer and brain cancer.
78. Use of a compound according to any of claims 1 to 37 in the preparation of a medicament for the induction of apoptosis of tumor cells.
79. A method of induction of apoptosis of a cell, which includes contacting the cell with an effective amount of a compound according to any of claims 1 to 37.