MXPA99002016A - 1,4-heterocyclic metallprotease inhibitors - Google Patents

Abstract

The invention provides compounds of formula (I) as described in the claims, or an optical isomer, diastereomer or enantiomer thereof, or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof are useful as inhibitors of metalloproteases. Also disclosed are pharmaceutical compositions and methods of treating diseases, disorders and conditions characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

Description

INHIBITORS OF METALOPROTEASE 1, 4-HETEROCICLICOS FIELD OF THE INVENTION This invention is directed to compounds that are useful for treating diseases, disorders and conditions associated with the undesirable activity of the metalloprotease. ü BACKGROUND .0 Numerous structurally related metalloproteases (MPs) effect the decomposition of structural proteins. These metalloproteases frequently act on the intercellular matrix, and are thus involved in tissue breakdown and tissue remodeling. These proteins are called metalloproteases or MPs. There are several different families of MPs, classified by sequence homology. Several families of the known MPs as well as examples thereof are described in the art. 20 These MPs include the matrix metalloproteases [MMPs], zinc metalloproteases, many of membrane-bound metalloproteases, enzyme converting enzymes, FNT, angiotensin converting enzymes (ACEs), disintegrins, including ADAMs (See Wolfsberg and co-authors, 131 J. Cell Bio. , 275-78, October 1995) and enkephalinases. Examples of MPs include human skin fibroblast collagenase, human skin fibroblast gelatinase, human sputum collagenase, aggrecase and gelatinase, as well as stromelysin. It is believed that collagenase, stromelysin, aggrecanase and other related enzymes are important in mediating the symptomatology of numerous diseases. The potential therapeutic indications of MP inhibitors have been discussed in the literature. See, for example, U.S. Patent 5,506,242 (Ciba Geigy Corp); U.S. Patent 5,403,952 (Merck and Co.); PCT publication application WO 96/06074 (British Bio Tech Ltd), TCP publication WO 96/00214 (Ciba Geigy); WO 95/35275 (British Bio Tech Ltd); WO 95/35276 (British Bio Tech Ltd); WO 95/33731 (Hoffman-LaRoche); WO 95/33709 (Hoffman-La Roche); WO 95/32944 (British Bio Tech Ltd); WO 9526989 (Merck); WO 9529892 (DuPont Merck); WO 95/24921 (Inst. Opthamo1ogy); WO 95/23790 (Smi-hKline Beechman); WO 95/22966 (Sanofi Winthrop); WO 95/19965 / Glycomed); WO 95/19956 (British Bio Tech Ltd); WO 95/19957 (British Bio Tech Ltd); WO 95/19961 (British Bio Tech Ltd); WO 95/13289 (Chrioscience Ltd); WO 95/12603 (Syntex); WO 95/09633 (Florida State Univ.); WO 95/09620 (Florida State Univ.); WO 95/04033 (Celltech); WO 94/25434 (Celltech); WO 94/25435 (Celltech); WO 93/14112 (Merck); WO 94/0019 (Glaxo); WO 93/21942 (British Bio Tech Ltd); WO 92/22523 (Res. Corp. Tech. Inc.); WO 94/10990 (British Bio Tech Ltd); WO 93/09090 (Yamanouchi) and British patents GB 2282598 (Merck) and GB 2268934 (British Bio Tech Ltd); European patent applications published EP 95/684240 (Hoffman LaRoche); EP 574758 (Hoffman LaRoche); EP 575844 (Hoffman LaRoche); Japanese published applications: JP 08053403 (Fujusows Pharm, Co. Ltd.); JP 7304770 (Kanebo Ltd.); and Bird and co-authors, J. Med. Chem. volume 37, pages 158-69 (1994). Examples of potential therapeutic uses of MP inhibitors include rheumatoid arthritis (Mullins, D.E. and co-authors Biochim, Biophvs. Acta. (1983) 695: 117-214); osteoarthritis (Henderson, B. and coauthors, Drucrs of the Future (1990) 15: 495-508); metastasis of tumor cells (ibidem, Broadhurst, MJ and co-inventors, European patent application 276,436 (published in 1987), Reich, R. and co-authors, 48 Cancer Res. 3307-3312 (19S8), and various ulcerations and ulcerative conditions of the For example, ulcerative conditions can result in the cornea from alkali burns or as a result of infection by Pseudomonas aeruginosa, Acar.thomoeba, Herpes simplex and vaccine viruses Other examples of conditions characterized by undesirable metalloprotease activity include periodontal diseases, bullous epidermolysis, fever, inflammation and scleritis (See DeCicco and co-inventors, WO 95/29892, published November 9, 1995.) In view of the involvement of such metalloproteases in numerous disease conditions, they have been made attempts to prepare inhibitors for these enzymes Numerous inhibitors are described in the literature Examples include the patent is US No. 5,183,900, issued on February 2, 1993 to Galardy; U.S. Patent No. 4,996,358, issued February 26, 1991 to Handa and co-inventors; U.S. Patent No. 4,771,038, issued September 13, 1988 to Wolanin and coauthors; U.S. Patent No. 4,743,587, issued May 10, 1988 to Dickens and co-inventors; European Patent Publication No. 575,844, published on December 29, 1993, Broadhurts and co-inventors; International Patent Publication No. WO 93/09090, published May 13, 1993 by Isomura and co-inventors; World Patent Publication 92/17460, published October 15, 1992 by Markwell and co-inventors; and European Patent Publication No. 498,665, published August 12, 1992 by Beckett and co-inventors. Metalloprotease inhibitors are useful for treating diseases caused, at least in part, by the decomposition of structural proteins. Although a variety of inhibitors have been prepared, there remains a need for potent matrix metalloprotease inhibitors useful in treating such diseases. The applicant has discovered that, surprisingly, the compounds of the present invention are potent metalloprotease inhibitors.

OBJECTIVES OF THE INVENTION Thus, it is an object of the present invention to provide compounds useful for treating conditions and diseases that are characterized by undesirable MP activity. It is also an object of the invention to provide potent inhibitors of metalloproteases. It is another object of the invention to provide pharmaceutical compositions comprising said inhibitors. It is an object of the invention also to provide a method for treating diseases related to metalloprotease.

BRIEF DESCRIPTION OF THE INVENTION The invention provides compounds that are useful as inhibitors of metalloproteases and that are effective to treat conditions characterized by excessive activity of these enzymes. In particular, the present invention relates to a compound having a structure according to the formula wherein: R is H; R2 is hydrogen, alkyl or acyl; Ar is COR3 or SO2R4; and R3 is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; R 4 is alkyl, heteroalkyl, aryl or heteroaryl, substituted or unsubstituted; X is 0, S, SO, SO2 or NR5, wherein R5 is independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S? 2, COR7, CSRg, P0 (Rg) 2 / or can optionally form a ring with W; and Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R7 is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino, - Rg is alkyl, aryl, heteroaryl, heteroalkyl; W is hydrogen or one or more lower alkyl portions, or is an alkylene, arylene or heteroarylene bridge between two adjacent or non-adjacent carbon atoms (thereby forming a molten ring); And it is independently one or more of hydrogen, hydroxy, SR Q, SOR4, SO2 4, alkoxy, amino, where amino is of the formula NR 11 R 12 'en ^ to F-1 * 2 Rll and R 12 are independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S02 g / COR7, CSR8, PO (R9) 2; and R10 is hydrogen, alkyl, aryl, heteroaryl; Z is nothing, a spiro portion or an oxo group substituted on the heterocyclic ring. This structure also includes an optical, diastereomeric or enantiomeric isomer for the formula (I), or a pharmaceutically acceptable salt, or an amide, an ester or an imide of the hydrate, biohydrolyzable. These compounds have the possibility of inhibiting at least one mammalian metalloprotease. Accordingly, in other aspects, the invention is directed to pharmaceutical compositions containing the compounds of the formula (I), and to methods for treating diseases characterized by undesirable metalloprotease activity, using these compounds or the pharmaceutical compositions containing them. Metalloproteases that are active in a particularly undesirable location (eg, an organ or certain types of cells) can form a target by conjugating the compounds of the invention to a specific destination ligand for a marker at that location, at that location, such as an antibody or a fragment thereof, or a receptor ligand. Methods of conjugation are known in the art. The invention is also directed to several other methods that take advantage of the unique properties of these compounds. Thus, in another aspect, the invention is subject to compounds of the formula (I) conjugated with solid supports. These conjugates can be used as affinity reagents for the purification of a desired metalloprotease. In another aspect, the invention is directed to the compounds of formula (I) conjugated to a label. As the compounds of the invention bind to at least one methotloprotease, the tag can be used to detect the presence of relatively high levels of metalloprotease, preferably a matrix metalloprotease in a cell culture in vivo or in vitro. . Additionally, the compounds of the formula (I) can be conjugated to carriers that allow the use of the compounds for immunization protocols in order to prepare antibodies specifically immunoreactive with the compounds of the invention. Typical conjugation methods are known in the art. These antibodies are then useful both in therapy and in the monitoring of the dose of the inhibitors. 20 DETAILED DESCRIPTION The compounds of the present invention are inhibitors of mammalian metalloproteases, preferably matrix metalloproteases. Preferably the compounds are those of the formula (I) or a pharmaceutically acceptable salt or an amide, ester or imide thereof, biohydrolyzable. Throughout this description, reference is made to publications and patents in an effort to fully describe the state of the art. All references cited herein are incorporated herein by reference.

DEFINITIONS AND USE OF TERMS The following is a list of definitions for the terms used here. "Acyl" or "carbonyl" is described as a radical that could be formed by the removal of the hydroxy from a carboxylic acid (i.e., R-C (= 0) -). Preferred acyl groups include (for example) acetyl, formyl and propionyl. "Acyloxy" is an oxy radical having an acyl substituent (i.e., -O-acyl); for example, -O-C (= 0) -alkyl. "Alcoxyacyl" is an acyl radical (-C (= 0) -) having an alkoxy substituent (ie, -O-R), for example, -C (= 0) -0-alkyl. This radical can be termed an ester. "Acylamino" is an amino radical having an acyl substituent (i.e., -N-acyl); for example, -NH-C (= 0I -alkyl. "Alkenyl" is an unsubstituted or substituted hydrocarbon chain radical having from 2 to 15 carbon atoms, preferably from 2 to 10 carbon atoms, more preferably from 2 to 8 carbon atoms, except where indicated The alkenyl substituents have at least one olefinic double bond (including, for example, vinyl, allyl and butenyl). "Alkynyl" is an unsubstituted or substituted hydrocarbon chain radical that it has from 2 to 15 carbon atoms, preferably from 2 to 10 carbon atoms, more preferably from 2 to 8, except when indicated.The chain has at least one triple carbon-to-carbon bonding. "Alkoxy" is a radical oxygen having a hydrocarbon chain substituent, wherein the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl) The preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy. "Alkoxyalkyl" is an unsubstituted alkyl portion substituted or substituted, substituted with an alkoxy moiety (ie, -alkoxy-O-alkyl). It is preferred when the alkyl has from 1 to 6 carbon atoms (more preferably from 1 to 3 carbon atoms) and the alkoxy has from 1 to 6 carbon atoms (more preferably from 1 to 3 carbon atoms). "Alkyl" is a saturated or unsubstituted or substituted hydrocarbon chain radical having from 1 to 15 carbon atoms; more preferably from 1 to 10 carbon atoms, most preferably from 1 to 4; except when indicated. Preferred alkyl groups include (for example) methyl, ethyl, propyl, isopropyl and butyl, substituted or unsubstituted.

When referred to herein as "spiro cycle" or "cyclic spiro" it refers to a cyclic portion that shares a carbon in another ring. Said cyclic portion may be carbocyclic or heterocyclic in nature. Preferred heteroatoms included in the heterocyclic cyclo spire skeleton include oxygen, nitrogen and sulfur. Spiro cycles may be unsubstituted or substituted. Preferred substituents include oxo, hydroxy, alkyl, cycloalkyl, arylalkyl, alkoxy, amino, heteroalkyl, aryloxy, fused rings (eg, benzothiol, cycloalkyl, heterocycloalkyl, benzimidizoles, pyridylthiol, etc., which may also be substituted) and the like. In addition, the heteroatom of the heterocycles may be substituted if the valence permits. Preferred spirocyclic ring sizes include rings of 3 to 7 members. Alkylene refers to alkyl, alkenyl or alkynyl, which is a di-radical instead of a radical. "Heteroalkylene" in the same way, is defined as a (diradical) alkylene, which has a heteroatom in its chain. "Alkylamino" is an amino radical having one substituent (secondary amine) or two substituents (tertiary amine) alkyl (i.e., -N-alkyl). For example, methylamino (-NHCH3), dimethylamino (-N (CH3) 2) methylethylamino (-N (CH CH3). "Aminoacyl" is an acyl radical having an amino substituent (ie, -C (= 0) - N), for example, -C (= 0) - NH2 The amino group of the aminoacyl moiety may be unsubstituted (ie, primary amine) or may be substituted with an alkyl group (secondary amine) or two alkyl groups ( that is, tertiary amine.) "Aryl" is an aromatic carbocyclic ring radical Preferred aryl groups include (for example) phenyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl and flucrenyl These groups may be substituted or unsubstituted. .alpha.0"Arylalkyl" is an alkyl radical substituted with an aryl group Preferred arylalkyl groups include benzyl, phenylethyl and phenylpropyl These groups may be substituted or unsubstituted. "Arylalkylamino" is an amine radical substituted with an arylalkyl group (for example, -NH- 15 benzyl) These groups can be substituted two or not replaced. "Arylamino" is an amine radical substituted with an aryl group (ie, -NH-aryl). Said groups may be substituted or unsubstituted. "Aryloxy" is an oxygen radical having an aryl substituent (i.e., -O-aryl). Said groups may be substituted or unsubstituted. "Carboxylic ring" is a saturated, unsaturated or aromatic hydrocarbon ring radical, unsubstituted or replaced. The carbocyclic rings are monocyclic or are fused, bridged or are polycyclic spiro ring systems. The monocyclic carbocyclic rings generally contain from 4 to 9 atoms, preferably from 4 to 7 atoms. The polycyclic carbocyclic rings contain from 7 to 17 atoms, preferably from 7 to 12 atoms. Preferred polycyclic systems comprise rings of 4, 5, 6 or 7 members fused to 5, 6 or 7 membered rings. "Carbocycloalkyl" is an unsubstituted or substituted alkyl radical substituted with a carbocyclic ring. Unless otherwise specified, the carbocyclic ring is an aryl or cycloalkyl; more preferable, an aril. Preferred carbocycloalkyl groups include benzyl, phenylethyl and phenylpropyl. "Carbocycloheteroalkyl" is an unsubstituted or substituted heteroalkyl radical substituted with a carbocyclic ring. Unless otherwise specified, the carbocyclic ring is preferably an aryl or cycloalkyl; more preferable an aryl. The heteroalkyl is preferably 2-oxa-propyl, 2-oxa-ethyl, 2-thia-propyl or 2-thia-ethyl. "Carboxyalkyl" is an unsubstituted or substituted alkyl radical, substituted with a carboxy moiety (-C (= 0) 0H). for example, -CH2-C (= 0) OH. "Cycloalkyl" is a saturated carbocyclic ring radical. Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl. "Cycloheteroalkyl" is a saturated heterocyclic ring. Preferred cycloheteroalkyl groups include (for example) morpholinyl, piperadinyl, piperazinyl, tetrahydrofuryl and hydrantoinyl. "Fused rings" are rings that are superimposed on each other in such a way that they share two ring atoms. A given ring may be fused to more than one different ring. The fused rings are contemplated in the heteroaryl, aryl and heterocycle radicals or the like. "Heterocycle-alkyl" is an alkyl radical substituted with a heterocyclic ring. The heterocyclic ring is preferably a heteroaryl or a cycloheteroalkyl; more preferable, a heteroaryl. Preferred heteroarylcycloalkyl includes alkyl of 1 to 4 carbon atoms having the preferred heteroaryl attached thereto. More preferred is, for example, pyridylalkyl and the like. "Hetero-cycloheteroalkyl" is an unsubstituted or substituted heteroalkyl radical substituted with a heterocyclic ring. The heterocyclic ring is preferably an aryl or a cycloheteroalkyl; more preferable, an aril. "Heteroatom" is a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms. "Heteroalkenyl" is an unsaturated chain radical, unsubstituted or substituted, having from 3 to 8 members, comprising carbon atoms and one or two heteroatoms. The chain has at least one carbon-carbon double bond.

"Heteroalkyl" is a saturated or unsubstituted or substituted chain radical having from 2 to 8 members, comprising carbon atoms and one or two heteroatoms. "Heterocyclic ring" is a saturated, unsaturated or aromatic ring radical, unsubstituted or substituted, consisting of carbon atoms and one or more heteroatoms in the ring. The heterocyclic rings are monocyclic or are melted, bridged or polycyclic spiro ring systems. The monocyclic heterocyclic rings contain from 3 to 9 torments, preferably from 4 to 7 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms. "Heteroaryl" is a heterocyclic aromatic ring radical, either monocyclic or bicyclic. Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl and tetrazolyl, benzothiazolyl, benzofuryl, indolyl and the like. Said groups may be substituted or unsubstituted. "Halo", "halogen" or "halogenide" is a radical chloro, bromo, fluorine or iodine. The preferred halides are bromine, chlorine and fluorine. In addition, as mentioned herein, a "lower" hydrocarbon portion (eg, "lower" alkyl) is a hydrocarbon chain consisting of 1 to 6, preferably 1 to 4, carbon atoms.

A "pharmaceutically acceptable salt" is a cationic salt formed in any acid group (eg, carboxyl) or an anionic salt formed in any basic group (for example, amino). Many of these salts are known in the technique as described in world patent publication 87/05297, by Johnston and co-inventors, published on September 11, 1987 (incorporated herein by reference). Preferred cationic salts include * alkali metal salts (such as sodium and potassium) and alkaline earth metal salts (such as magnesium and calcium) and organic salts.Preferred anionic salts include halides (such as chloride salts). "Biohydrolyzable amides" are amides of the compounds of the invention that do not interfere with the inhibitory activity of the compound, or that are easily converted in vivo by a mammalian subject to produce an active inhibitor A "biohydrolyzable hydroxyimide" is an amide of a compound of the formula (I) which does not interfere with the metalloprotease inhibitory activity of these compounds, or which is readily converted in vivo by a mammalian subject, to produce an active compound of the formula (I). Said hydroxyimides include those which do not interfere with the biological activity of the compounds of the formula (I). A "biohydrolyzable ester" refers to an ester of A compound of the formula (I) which does not interfere with the metalloprotease inhibitory activity of these compounds, or which is readily converted by an animal to produce an active compound of the formula (I). A "solvate" is a complex formed by the combination of a solute (e.g., a metalloprotease inhibitor) and a solvent (e.g., water). See J. Honig and co-authors, The Van Nostrand Chemist's Dictionary, page 650 (1953). The pharmaceutically acceptable solvents, used in accordance with this invention, include those which do not interfere with the biological activity of the metalloprotease inhibitor (e.g., water, ethanol, acetic acid, N, N-dimethylformamide and others known or which are readily determined by the expert in the field). "Optical isomer", "stereoisomer", "diastereomer", as mentioned herein, have the normal meanings recognized in the art (see Hawley's Condensed Chemical Dictionary, eleventh edition). The illustration of the specific forms and other derivatives of the compounds of the formula (I) is not intended to be limiting. The application of other useful protectants, salt forms, etc., is within the ability of those skilled in the art. As defined above and as used herein, the substituent groups, by themselves, may be substituted. Said substitution can be with one or more substituents. These substituents include those mentioned in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated herein by reference. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halogen, carboxy, alkoxyacetyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (for example, piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof. As used herein, "mammalian metalloprotease" means any metal-containing enzyme, found in mammalian sources, that is capable of catalyzing the decomposition of collagen, gelatin or proteoglycan, under conditions of suitable assays. Appropriate analysis conditions can be found, for example, in U.S. Patent No. 4,743,587, which relates to the procedure of Cawston and coauthors, Anal. Biochem. (1979) 99: 340-345, to the use of a synthetic substrate as described in Weingarten, H. and co-authors Biochem. Biophy. Res. Comm. (1984) 139: 1184-1187. Any normal method to analyze the decomposition of these structural proteins, of course, can be used. The metalloprotease enzymes referred to herein, are all zinc-containing proteases, which are similar in structure, for example, to human stromelysin or skin fibroblast collagenase. The ability of candidate compounds to inhibit metalloprotease activity, of course, can be tested in the analyzes described above. Isolated metalloprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or crude extracts containing the enzyme branch capable of decomposing the tissue can be used.

THE COMPOUNDS The compounds of the invention are described in the brief description of the invention. Preferred compounds of the invention are those in which Z is het roespiroalkylene, preferably having heteroatoms adjacent to the predecessor ring structure, more preferably, said spiroheteroalkylenes having from 4 to 5 members. The preferred heteroatoms are divalent. The invention provides compounds that are useful as inhibitors of metalloproteases, preferably a matrix mets.loprotease, and which are effective to treat conditions characterized by excessive activity of those enzymes. In particular, the present invention relates to a compound having a structure according to the formula in 1 that: R is H; R2 is hydrogen, alkyl or acyl; Ar is C0R3 or SO2 4; and R3 is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamins; R 4 is alkyl, heteroalkyl, aryl or heteroaryl, substituted or unsubstituted; X is O, S, SO, S02 or NR5, wherein R5 is independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S? 2 g # COR7, CSRg, PO (Rg) 2 or can optionally form a ring with W; and Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R7 is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R9 is alkyl, aryl, heteroaryl, heteroalkyl; W is hydrogen or one or more lower alkyl portions, or is an alkylene, arylene or heteroarylene bridge between two adjacent or non-adjacent carbon atoms (thereby forming a molten ring); And it is independently one or more of hydrogen, hydroxy, SRig, SOR4, SO2R4, alkoxy, amino, where amino is of the formula NR11R12 'in I cyn Rll and R12 are independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S02 6, COR7, CSRg, P0 (Rg) 2; and R O is hydrogen, alkyl, aryl, heteroaryl; Z is nothing, a spiro portion or an oxo group substituted on the heterocyclic ring. This structure also includes an optical isomer, diastereomer or enantiomer for formula (I), or a pharmaceutically acceptable salt, or an ester, amine or amide thereof, biohydrolyzable.

PREPARATION OF THE COMPOUND The hydroxamic compounds of the formula (I) can be prepared using a variety of procedures. The general schemes include the following.

PREPARATION OF THE PORTION AND For the manipulation of Y, it is understood that those skilled in the art can select to prepare Y before, after or concurrently with the preparation of the heterocyclic ring. For clarity, the portions W and Z are not shown in the following. More than one Y and Z may be present in the compounds of the formula (I). For compounds where Y is not adjacent to the ring nitrogen, a preferred method of preparing the compound is: SCHEME I When R is a group that can be derivatized or that can be manipulated or substituted, said compounds are known or are prepared by known methods. (A) it is converted to its analogous sultaméster and R is manipulated to give (B) during this step or a subsequent step. And e Z can be added or altered, followed by the appropriate reaction to provide R_. For example, this step may include treatment with hydroxylamine under basic conditions to provide a compound of formula I (C). For the preparation and preparation of the heterocyclic ring it is understood that those skilled in the art can select to prepare Y before, after or concurrently with the preparation of the heterocyclic ring. For clarity, W portions are not shown below, Y e Z. More than one W, Y and Z may be present in the compounds of the formula (I). For compounds where X is nitrogen, the preferred method for handling R5 is shown. In the scheme that follows, L is any acceptable substitutable group and B is a blocking group, as before, Boc is an example of a preferred blocking group, recognized in the art. The experts in the material will recognize that the selection of the blocking group is within what an expert in organic chemistry knows. So, the selection of Boc is not necessary, but it is preferred.

SCHEME II For the compounds containing a sulfur in the heterocyclic ring, the preferred methods for ring formation are shown. For the preparation and preparation of the heterocyclic ring it is understood that the person skilled in the art can select to prepare Y before, after or concurrent with the preparation of the heterocyclic ring. For clarity, the portions W, Y and Z are not shown in the following. More than one W, Y and Z may be present in the compounds of the formula (I).

SCHEME III Another acceptable strategy for preparing the invention having X as sulfur includes the following scheme. The method allows the formation of the sulfaster and the subsequent reaction with a bifunctional portion. Preferably the OH described in the following is a primary hydroxyl. The closure of the ring uses common and current methods. The functionalization and the preparation of the molecule proceed as described above.

SCHEME IV When X is sulfur, further elaboration of the heterocyclic ring can be achieved after the ring has been formed. For example, oxidation of the ring sulfur atom using known methods can provide the corresponding sulfoxides and sulfones, as shown.

ESOUEMA V For compounds containing an oxygen in the heterocyclic ring, preferred methods of ring formation are shown. A bifunctional portion, for example, a halohydroxy species, is reacted with an aziridine, as shown below. The halo portion serves as a substitutable group, useful in ring closure reactions. When the ring is formed, the preparation of the invention provides as described above.

SCHEME VI PREPARATION OF THE Z PORTION Of course, those skilled in the art will recognize that the schemes applicable for the preparation of Y may be useful in the preparation of Z, as noted above. Other preferred methods are provided for the reader. When Z is a ketal or thioketal, the compounds of the invention can be prepared from a compound having a carbonyl in the ring. Such compounds are prepared by well-known methods and many of these methods are known or can be obtained commercially. Thus, those skilled in the art will appreciate that a hydroxy, amino, imino, alkoxy, oxo or any other group can be manipulated in a carbonyl compound. The order of elaboration of the cets.l, Ri or the sultaméster, can change. A preferred method for preparing these spiro compounds of the invention is through a carbonyl compound using the "protecting group" technology known in the art, such as a thioketal or ketal, and the like. Ceta.les, acetals and the like are prepared from carbonyl compounds by methods known in the art. Said carbonyl compounds can be prepared from cyclic hydroxyalkyleneamines by the oxidation of a ketone or lactams, which provide the 2-aminospiro functionality. A variety of compounds can be generated in a similar manner, using the guidance of the above scheme. In the above schemes, when R1 is alkoxy or alkylthio, the corresponding hydroxy or thiol compounds are derived from the final compounds using a normal dealkylation process (Bhatt, and co-authors, "Cleavage of Ethers", Synthesis, 1983, pages 249-281 ). These steps may vary to increase the performance of the desired product. Those skilled in the art will also recognize that the judicious choice of reagents, solvents and temperatures are an important component in satisfactory synthesis. Although the determination of optimum conditions, etc., is routine, it will be understood that a variety of compounds can be generated in a similar manner, using the guides of the above scheme. The starting materials used to prepare the compounds of the invention are shown, or are made by known methods, or are commercially available as starting material. Those skilled in the art of organic chemistry will recognize that common and ordinary manipulations of organic compounds can be easily carried out without additional instructions; that is, it is well within the scope and practice of those skilled in the art to effect such manipulations. These include, but are not limited to, the reduction of the carbonyl compounds to their corresponding alcohols, the oxidations of the hydroxyls and the like; the acylations, aromatic substitutions, both electrophilic and nucleophilic, the etherifications, esterifications and saponification, and the like. Examples of such manipulations are discussed in normal texts, such as March, Advanced Orqanic Chemistry (Wiley), Carey and Sundberg, Advanced Orqanic Chemistry (volume 2) and Keeting, Heterocvclic Chemistrv (all 17 volumes). Those skilled in the art will readily appreciate that certain reactions can be carried out when another functionality is masked or protected in the molecule, thereby avoiding any undesirable side reactions and / or increasing the reaction yield. Frequently experts use protective groups to obtain said increased yields or to avoid undesirable reactions. These reactions are found in the literature and are well within what experts in the field know. Examples of many of these manipulations can be found, for example, in T. Green, Protective Groups in Orqa.nic Synthesis. Of course, the amino acids used as starting materials with reactive side chains are preferably blocked to prevent undesirable side reactions. The compounds of the invention may have one or more chiral centers. As a result, an optical isomer, including a diastereomer or an enantiomer, or even others, for example, chiral starting materials, catalysts or solvents, can be prepared selectively, or both stereoisomers and optical isomers can be prepared, including diastereomers and enantiomers to the once (a racemic mixture). Since the compounds of the invention can exist as racemic mixtures, mixtures of optical isomers, including the diastereomers and enantiomers or stereoisomers, can be separated, using known methods, such as chiral salts, chiral chromatography and the like. Additionally it is recognized that an optical isomer, including a diastereomer and enantiomer, or the stereoisomer, may have favorable properties with respect to others. Thus, when the invention is described and claimed, when a racemic mixture is described, it is clearly contemplated that both optical isomers, including the diastereomers and enantiomers, or the stereoisomers, are also substantially described and claimed, substantially free of the others.

THE METHODS OF USE The metalloproteinases (MPs) found in the body operate, in part, by decomposing the extracellular matrix comprising proteins and extracellular glycoproteins. These proteins and glycoproteins play an important role in the maintenance, size, structure and stability of tissue in the body. Metalloprotease inhibitors are useful for treating diseases caused, at least in part, by the decomposition of said proteins. It is known that MPs are intimately involved in tissue remodeling. As a result of that activity, it has been said that they are active in many disorders that involve: 5"the decomposition of tissues, including degenerative diseases, such as arthritis, multiple sclerosis and the like; metastasis or mobility of tissues in the body; of tissues, including fibrotic diseases, scarring, benign hyperplasia and the like jfl The compounds of the present invention treat disorders, diseases and / or undesirable conditions that are characterized by undesirable or elevated activity of that class of proteases. , the compounds can be used to inhibit proteases that: 15"destroy structural proteins (i.e., the proteins that maintain tissue stability and structure); interfere in inter / intracellular signaling, including those involved in ascending cyccine regulation and / or cytokine processing and / or inflammation, tissue degradation and other diseases [Mohler KM and co-authors, Nature 370 (1994) 218 -220, Gearing AJH and co-authors, Nature 370 (1994) 555-557, McGeehan GM and co-authors, Nature 370 (1994) 558-561] and / or facilitate procedures that are undesirable in the subject 25 being treated, for example , the process of maturation of the sperm, fertilization of the ovule and the like.

As used herein an "MP-related disorder" or an "MP-related disease" is one that involves undesirable or high activity of MP in the biological manifestation of the disease or disorder; in the biological cascade that leads to the disorder, or as a symptom of the disorder. This "implication" of MP includes: the undesirable or high activity of MP as a "cause" of the disorder or biological manifestation, whether the activity is genetically high, by infection, by auto-immunity, by trauma, by biomechanical causes , for the lifestyle (for example, obesity) or for some other cause; MP, as part of the observable manifestation of the disease or disorder. That is, the disease or disorder can be measured in terms of increased MP activity, or from a clinical point of view, undesirable or elevated levels of MP indicate the disease. MPs do not need to be the "visible mark" of the disease or disorder; the undesirable or high activity of MP is part of the biochemical or cellular cascade that results or is related to the disease or disorder. In this sense, the inhibition of MP activity interrupts the cascade and, in that way, controls the disease. Advantageously, many MPs are not evenly distributed throughout the body. Thus, the distribution of MP expressed in various tissues is often specific for these tissues. For example, the distribution of the metalloproteases involved in the decomposition of tissues in the joints is not the same as the distribution of the metalloproteases found in other tissues. Thus, although not essential for activity or efficacy, certain disorders are preferably treated with compounds that act on the specific MPs found in the affected tissues or regions of the body. For example, a compound that exhibits a high degree of affinity or inhibition for an MP that is found in the joints (e.g., chondrocytes), would be preferred for treatment of the disease found there, to other compounds that are less specific. Additionally, certain inhibitors are more bioavailable for certain tissues than others; and it is judicious to select the inhibitor, and that said selectivity described above provides the specific treatment of the disorder, disease or undesirable condition. For example, the compounds of this invention vary in their ability to penetrate the central nervous system. Thus, compounds can be selected to produce mediated effects through MPs found specifically outside the central nervous system. The determination of the specificity of an inhibitor of an MP, of a certain MP, is within what an expert in this field knows. The appropriate analysis conditions can be found in the literature. The analyzes are specifically shown for stromelysin and collagenase. For example, U.S. Patent No. 4,743,587 relates to the Cawston procedure and Anal coauthors. Biochem (1979 = 99: 340-345) The use of a synthetic substrate in an analysis is described by Weingarten, H. and co-authors Biochem. Biophy, Res. Comm. (1984) 139: 1184-1187. analyzing the decomposition of structural proteins by MPs can, of course, be used The ability of the compounds of the invention to inhibit metalloprotease activity can, of course, be tested in the analyzes found in the literature or their Variations The isolated metalloprotease enzymes can be made to confirm the inhibitory activity of the compounds of the invention, or crude extracts can be used which contain the range of enzymes capable of breaking down the tissues. As a result of the inhibitory effect of MP of the compounds of the invention, the compounds of the invention are also useful for treating the following disorders, in by virtue of its metalloprotease activity. The compounds of the invention are also useful for prophylactic or acute treatment. They are administered in any way by the expert in the fields of pharmacology or medicine. It is immediately evident to the experts that the preferred routes of administration will depend on the disease state being treated, and on the dosage form selected. Preferred routes for systemic administration include peroral and parenteral routes of administration. However, the experts will readily appreciate the advantages of directly administering the MP inhibitor to the affected area, for many disorders. For example, it may be advantageous to administer MP inhibitors to the area of the disease or condition, such as in an area affected by surgical trauma (e.g., angioplasty), or an area affected by scarring or burn (e.g., topically). To the skin) . Because bone remodeling involves MPs, the compounds of the invention are useful in preventing prosthetic loosening. It is known in the art that over time the prostheses are loosened and become painful, and can result in additional damage to the bone, which requires its replacement. The need to replace such prostheses includes those that are, for example, in joint replacements (for example, in the hip, knee and shoulder replacements), in dental prostheses, including dentures, bridges and prostheses secured to the maxilla and / or to the jaw. MPs are also active to reshape the cardiovascular system (for example, in congestive heart failure). It has been suggested that one of the reasons why angioplasty has a higher than expected regimen of long-term failures (reclose with time) is that PM activity is not desirable nor is it elevated in response to what is It recognizes by the body as "damage" to the base membrane of the vessel. Thus, the regulation of MP activity in indications such as dilated cardiomyopathy, congestive heart failure, arteriosclerosis, plaque rupture, reperfusion damage, ischemia, chronic obstructive pulmonary diseases, restenosis by angioplasty and aortic aneurysm, may increase long-term success of any other treatment or can be in itself a treatment. IB.0 In skin care, MPs are involved in the remodeling or "change" of the skin. As a result, the regulation of MPs improves the treatment of skin conditions, including, but not limited to, wrinkle repair, regulation and prevention and repair of damage to the skin. skin induced by ultraviolet radiation. Such treatment includes prophylactic treatment or treatment before the physiological manifestations are obvious. For example, MPs can be applied as a pre-exposure treatment to prevent damage by ultraviolet radiation and / or after exposure to prevent or minimize post-exposure damage. Additionally, MPs are involved in skin disorders and skin diseases related to abnormal tissues, which are the result of abnormal change, which include the activity of metalloprotease, such as epidermolysis bullosa, psoriasis, scleroderma and topical dermatitis. The compounds of the invention are also useful for treating the consequences of "normal" skin damage, including scars or "shrinkage" of the tissue, for example, after burns. The inhibition of MP is also useful in surgical procedures involving the skin, to prevent the formation of scarring and the promotion of normal tissue development., which include applications such as repositioning of a limb and refractive surgery (either by laser or by incision). Additionally, MPs are related to disorders that involve irregular remodeling of other tissues, for example, bone in otosclerosis and / or osteoporosis, or to specific organs, such as liver cirrhosis and fibrotic lung diseases. Similarly, in diseases such as multiple sclerosis, MPs can are involved in the irregular remodeling of the blood / brain barrier and / or the myelin sheaths in the nervous tissue. So, regulating MP activity can be > used as a strategy to treat, prevent and control dichcis diseases. 20 It is also believed that MPs are involved in many infections, including cytomegalovirus (CMV), retinitis, HIV and the resulting syndrome, AIDS. MPs may also be involved in extra vascularization, when the surrounding tissue needs to be decomposed to allow new blood vessels, as in an angiofibroma and hemangioma.

Since MPs decompose the extracellular matrix, it is contemplated that inhibitors of these enzymes can be used as birth control agents, for example, to prevent ovulation and to prevent sperm penetration into and through the extracellular medium of the ovule, the implantation of the fertilized ovum and the prevention of sperm maturation. In addition, they are also considered as useful in the prevention or arrest of premature labor and premature birth. As the MPs are involved in the inflammatory response and in the cytokine processing, the compounds are also useful as anti-inflammatories for use in diseases where inflammation is prevalent, including inflammatory bowel disease, Crohn's disease, colitis ulcerative, pancreatitis, diverticulitis, asthma or related lung diseases, rheumatoid arthritis, gout and Reiter's syndrome. When autoimmunity is the cause of the disorder, the immune response often triggers the activity of MP and cytokine. The regulation of MPs in the treatment of said autoimmune disorders is a useful treatment strategy. Thus, MP inhibitors can be used to treat disorders including lupus erythematosus, ankylosing spondylitis and autoimmune keratitis.

Sometimes the side effects of autoimmune therapy result in the exacerbation of other conditions mediated by MPs, here the therapy with MP inhibitor is also effective, for example, in fibrosis induced by • autoimmune tere.pia. Additionally, other fibrotic diseases themselves lead to this type of therapy, including lung diseases, bronchitis, efusema, cystic fibrosis, acute respiratory distress syndrome (especially the acute phase response). When MPs are involved in the undesirable decomposition of tissue by exogenous agents, these can be • treated with MP inhibitors. For example, they are effective as an antidote against rattlesnake bites, as well as antivesics in the treatment of allergic inflammation, septicemia and shock. Additionally, they are useful as antiparasitic (for example, in malaria) and antiinfectors. For example, it is believed that they are useful for treating or preventing viral infections including the infection that would result in • result in herpes, "colds" (for example, renoviral infection), meningitis, hepatitis, HIV infection and AIDS.

It is also believed that MP inhibitors are useful for treating Alzheimer's disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, complications resulting from increased diabetes, especially those involving the loss of tissue viability, coagulation, disease of graft against receptor, leukemia, cachexia, anorexia, proteinuria and perhaps the regulation of hair growth. For some diseases, conditions or disorders, the inhibition of MP is contemplated as a preferred treatment method. Said diseases, conditions or disorders include: arthritis (including osteoarthritis and rheumatoid arthritis), cancer (especially the prevention or det t ntion of tumor growth and metastasis), ocular disorders (especially corneal ulceration), lack of corneal cics.trización, macular degeneration and pterygium), diseases of the gums (especially periodontal diseases and ginc? vitis). Preferred compounds, but not limited to, the treatment of arthritis ((including osteoarthritis and rheumatoid arthritis) are compounds that are selective for metalloproteases and disintegrin metalloproteases.Preferred compounds for the treatment of cancer, although not limited to this (especially for the prevention or arrest of tumor growth and metastasis) are those compounds which preferably inhibit gelatinases or collagenases of type IV.The preferred compounds for the treatment of eye disorders, but without limitation thereto (especially corneal ulceration, lack of corneal scarring, macular degeneration and pterygium), are those compounds that widely inhibit metalloproteases, preferably these compounds are administered topically, more preferably, as a drop or gel. Gum diseases, but without limitation Ion to it (especially periodontal diseases and gingivitis) are those compounds that preferentially inhibit collagenases.

THE COMPOSITIONS The compositions of the present invention comprise: (a) a safe and effective amount of a compound of the formula (I); and (b) a pharmaceutically acceptable carrier. As discussed above, it is known that numerous diseases are mediated by excessive or undesirable metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, inflammation of the skin, ulcerations, particularly of the cornea, reaction to infections, periodontitis and the like. Thus, the compounds of the invention are useful in therapy with respect to conditions involving this undesirable activity. The compounds of the invention, therefore, can be formulated into pharmaceutical compositions for use in the treatment or prophylaxis of those conditions. Common pharmaceutical formulating techniques are used as described in Reminqton's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa, USA, latest edition. A "safe and effective amount" of a compound of the formula (I) is an amount that is effective to inhibit the meteiloproteases at the site or sites of activity, in a mammalian subject, without unduly affecting side effects (such as toxicity, irritation or allergic response), together with a reasonable proportion of benefit / risk when used in the manner of this invention. The specific "safe and effective amount", • obviously it will vary with factors such as the particular condition that is being treated, the physical condition of the patient, the duration of the treatment, the nature of the concurrent therapy (if any), the specific dosage form to be used, the carrier employed, the solubility of the compound of formula (I) herein and the desired dosage regimen for the composition. In addition to the compound herein, the compositions of the present invention contain a carrier pharmaceutically acceptable. The term "pharmaceutically acceptable carrier" as used herein means one or more compatible solid or liquid filler diluents or encapsulating substances that are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition can be mixed with the compound herein, and with each other, such that there is no interaction that substantially reduces the pharmaceutical efficacy of the composition under ordinary use situations. The pharmaceutically acceptable carriers, of course, must be of sufficient purity and toxicity low enough to be suitable for administration to the animal, preferably mammal, being treated. Some examples of substances that can serve as pharmaceutically acceptable carriers or their components are sugars, such as lactose, glucose and sucrose; the almdones, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth, malt, gelatin, talc, solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid, emulsifiers such as TWEEN; wetting agents, such as sodium lauryl sulfate; coloring agents, flavoring agents, tablet-forming agents, stabilizers, antioxidants, preservatives, pyrogen-free water, isotonic saline and phosphate buffer solutions. The selection of a pharmaceutically acceptable carrier to be used in conjunction with the compound herein is determined primarily by the compound to be administered. If you are going to inject the compound of this, the preferred pharmaceutically acceptable carrier is sterile physiological saline, with a compatible suspending agent in the blood, whose pH has been adjusted to approximately 7.4. In particular, pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffers, emulsifiers, salt isotonic and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically acceptable carrier in compositions for parenteral administration comprises at least 90% by weight of the total composition. The compositions of this invention are preferably provided in unit dosage form. As used herein, a "unit dose form" is a composition of this invention that contains an amount of a compound of the formula (I) that is suitable for administration to an animal, preferably a mammalian subject, in a single dose, in accordance with good medical practice. These compositions preferably contain about 5 mg to about 1000 mg, more preferably about 10 mg to 500 mg, most preferably about 10 mg to 300 mg, of a compound of the formula (I). The compositions of this invention can be in any of a variety of forms, suitable (for example) for oral, topical rectal, nasal, ocular or parenteral administration. Depending on the particular administration route desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. These include solid or liquid charges; the diluents, hydrotropes, surfactants and encapsulating substances. Optional pharmaceutically active materials can be included as long as they do not substantially interfere with the inhibitory activity of the compound of formula (I). The amount of carrier employed in conjunction with the compound of formula (I) is sufficient to provide a practical amount of material for administration per unit dose of the compound of formula (I). The techniques and compositions for preparing dosage forms useful in the methods of this invention are described in the following reference, all incorporated herein by reference: Modern Pharmaceutics, chapters 9 and 10 (Banker and Rhodes, editors, 1979); Lieberman and co-authors, Pharmaceutics Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, second edition (1976). In addition to the compound of the present invention, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein, means one or more solid or liquid loading diluents or compatible encapsulating substances, which are suitable for administration to an animal, preferably a mammal. The term "compatible" as used herein, means that the components of the composition are capable of being mixed with the present compound and each other in such a way that there is no interaction that substantially reduces the efficacy of pharmaceutical fefl. of the composition under the conditions of ordinary use. Of course, pharmaceutically acceptable carriers should be of sufficiently high purity and of sufficiently low toxicity to make them suitable for administration to the animal, preferably to the mammal that is being treated. Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and starch Pope; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth, malt, gelatin, talcum, solid lubricants, such as stearic acid and magnesium stearate; Calcium sulfate, vegetable oils such as peanut oil, pomace oil, cotton, sesame oil, olive oil, corn oil and theobroma oil; polyols, such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid, emulsifiers such as TWEEN; wetting agents, such as sodium lauryl sulfate; coloring agents, flavoring agents, tablet-forming agents, stabilizers, antioxidants, preservatives, pyrogen-free water, isotonic saline and phosphate buffer solutions. The solution of a pharmaceutically acceptable carrier to be used in conjunction with the compound herein is basically determined by the route to administer the compound. If the compound of the present invention is to be injected, the preferred pharmaceutically acceptable carrier is sterile physiological saline, with blood-compatible suspending agent, whose pH has been adjusted to approximately 7.4. Various oral dosage forms can be used, including solid forms, such as tablets, capsules, granules and loose powders. These oral forms comprise a safe and effective amount, also at least about 5% and preferably about 25% to 50%, of the compound of the formula (I). May be compressed tablets crushed to tablet, they can be coated with enteric coating, sugar, film or compressed several times, so as to contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and fusion agents. Forms of liquid oral dose include aqueous solutions, emulsions, suspensions, solutions and / or reconstitutions suspensions from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, fusion agents, coloring agents and flavoring agents. The pharmaceutically acceptable carrier, suitable for. the preparation of unit dosage forms for peroral administration are well known in the art. The tablets typically comprise conventional, pharmaceutically compatible adjuvants, such as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose.; agglutinators, such as starch, gelatin and sucrose; disintegrators such as starch, alginic acid and croscaramellose; lubricants, such as magnesium stearate, stearic acid and talc. Slippers, such as silicon dioxide, can be used to improve the flow characteristics of the powder mix. Coloring agents can be added, such as FD &C dyes for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, mint and fruit flavors, are useful adjuvants for chewable tablets. The capsules comprise one or more solid diluents described above. The selection of carrier components depends on secondary considerations such as taste, cost and warehouse stability, which are not critical for the purposes • of the present invention, and which can be easily made by one skilled in the art. Peroral compositions also include liquid solutions, emulsions, suspensions and the like. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Typical components of carriers for syrups, .0 elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methylcellulose, carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; the typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Peroral liquid compositions may also contain one or more • components such as sweeteners, flavoring agents and colorants described above. Said compositions may also be coated by conventional methods, typically with coatings that depend on pH or time such that the compound present in the gastrointestinal tract is released in the vicinity of the desired topical application, or in various moments to prolong the desired action. Said dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes and shellac. The compositions of the present invention may optionally include other drug active substances. Other compositions useful for obtaining the systemic delivery of the compounds of the present invention include sublingual, buccal and nasal dosage forms. Said compositions typically comprise one or more soluble fillers, such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. The glidants, lubricants, sweeteners, colorants, antioxidants and savoring agents described above may also be included. The compositions of this invention can also be administered topically to a subject, for example, by direct application or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally, by means of a "patch". Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1% and preferably about 1% to 5%, of the compound of the formula (I). Carriers suitable for topical administration preferably remain in place on the skin as a continuous film and resist removal by perspiration or immersion in water. Generally, the carrier is of an organic nature and is capable of having the compound of the formula (I) dispersed or dissolved therein. The carrier can include emollients, emulsifiers, thickening agents, solvent and the like.

METHODS OF ADMINISTRATION This invention also provides methods for treating or preventing disorders associated with excessive or undesirable metalloprotease activity in an animal, preferably a mammalian subject, by administering a safe and effective amount of a compound of the formula (I) to said subject. As used herein, a "disorder associated with excessive or undesirable metalloprotease activity" is any disorder characterized by protein degradation. The methods of the invention are useful for treating disorders such as (for example) osteoarthritis, periodontitis, corneal ulceration, tumor invasion and rheumatoid arthritis. The compounds of the formula (I) and the compositions of this invention can be administered, typically or systemically. The systemic application includes any method for introducing the compound of the formula (I) into the tissues of the body, for example, by intra-articular administration (especially in the treatment of rheumatoid arthritis), intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal and oral. The compounds of the formula (I) of the present invention are preferably administered orally. The specific dose of inhibitor to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic, are interdependent. The dose and the treatment regimen will also depend on factors such as the specific compound of the formula (I) used and the indication of the treatment, the indication of the compound of the formula (I) to reach minimal inhibitory concentrations at the site where the metalloprotease will be inhibited, the subject's personal attributes (such as weight), compliance with the treatment regimen and the presence and severity of any side effects of the treatment. Typically, for a human adult (weighing approximately 70 kilograms), about 5 mg to 3000 mg, more preferably about 5 mg to 1000 mg, most preferably about 10 mg to 100 mg of the compound of the formula (I) is administered. ) per day, for systemic administration. It should be understood that these dose scales are only by way of example, and that daily administration can be adjusted depending on the factors mentioned above. A preferred method of administration for the treatment of rheumatoid arthritis is orally or parenterally, by intra-articular injection. As is known and practiced in the art, all formulations for parenteral administration must be sterile. For mammals, especially humans, (assuming an approximate body weight of 70 kg), individual doses of about 10 mg to 1000 mg are preferred. A preferred method for systemic administration is oral. The preferred individual doses are from about 10 mg to 1000 mg, more preferably about 10 mg to 300 mg. Topical administration can be used to administer the compound of formula (I) systemically, or to treat a subject locally. The amounts of the compound of the formula (I) to be administered topically depend on factors such as the sensitivity of the skin, the type and the loosening of the tissue to be treated, the composition and the carrier (if any) that are going to to be administered, the particular compound of the formula (I) to be administered, as well as the particular alteration to be treated and the degree to which the systemic effects are desired (in distinction from the local effects). The inhibitors of the invention can be directed to specific locations in which mete.loprotease accumulates, using target ligands. For example, to target the inhibitors to the mataloprotease contained in a tumor, the inhibitor is conjugated to an antibody or fragment thereof that is immunoreactive with a tumor marker, as generally understood in the preparation of immunotoxins in general. . The target ligand may also be suitable for, a receptor that is in the tumor. Any target ligand that specifically reacts with a marker for the target tissue can be used. The methods for coupling the compound of the invention to the target ligand are well known and are similar to those described below for coupling with the carrier. The conjugates are formulator and administered as described above. For localized conditions, topical administration is preferred. For example, to treat an ulcerated cornea, direct application to the affected eye can be used, using a formulation such as eye drops or ael. For the treatment of the cornea, the compounds of the invention can be formulated as gels, drops or ointments, or they can be incorporated into collagen or a hydrophilic polymeric shield. You can also insert the materials as a contact lens or a deposit, or as a subeconjunctive formulation. For the treatment of inflammation of the skin, the compound is applied locally and topically in a gel, a paste, a plaster or an ointment. The mode of treatment thus reflects the nature of the condition and suitable formulations for any selected route are available in the art. In all of the above, of course, the compounds of the invention can be administered alone or as mixtures, and the compositions can additionally include other drugs or excipients, as appropriate for the indication. Some of the compounds of the invention also inhibit bacterial metalloproteases, although generally at lower levels than those exhibited with respect to mammalian metalloproteases. Some bacterial metalloproteases appear to be less dependent on the stereochemistry of the inhibitor, while substantial differences between diastereomers are found in their ability to inactivate mammalian proteases. Thus, this pattern of activity can be used to distinguish between mammalian and bacterial enzymes.

PREPARATION AND USE OF ANTIBODIES The compounds of the invention can also be used in immunization protocols to obtain immunospecific antisera for the compounds of the invention. Since the compounds of the invention are relatively small, they are advantageously coupled with antigenically neutral carriers, such as conventionally used keyhole limpet hemecyanin (KLH) carriers or serum albumin carriers. For those compounds of the invention having carboxyl functionality, coupling to the carrier can be achieved by methods generally well known in the art. For example, the carboxyl residue can be reduced to an aldehyde and they can be coupled to the carrier by means of a reaction with amino groups of the side chain, in protein-based carriers, optionally followed by reduction of the imino bond formed. The carboxyl residue can also be reacted with side chain amino groups using condensing agents such as dicyclohexylcarbodiimide or other carbodiimide dehydrating agents. Linker compounds can also be used to effect coupling; Both optional and heterobifunctional linkers are available from Pierce Chemical Company, Rockford, Illinois, USA. The resulting immunogenic complex can then be injected into suitable mammalian subjects, such as mice, rabbits and the like. Suitable protocols involve the repeated injection of the immunogen in the presence of adjuvants according to a pattern that increases the production of the antibody in the serum. The immunological serum titers can be easily measured using immunoassay methods that are now normal in the art, using the compounds of the invention as anti-rings. The antisera obtained can be used directly or monoclonal antibodies can be obtained by harvesting the lymphocytes from the peripheral blood or the spleen of the immunized animal and immortalizing the antibody-producing cells, followed by identification of the appropriate antibody producers using common and current immunoassay techniques. . Polyclonal or monoclonal preparations are then useful in surveillance therapy or in prophylaxis regimens involving the compounds of the invention. Suitable samples, such as those derived from blood, serum, urine or saliva, can be tested for the presence of the inhibitor administered during various times during the treatment protocol, using common immunoassay techniques, which employ the antibody preparations. of the invention. The compounds of the invention can also be coupled to labels, such as scintigraphic labels, for example, technetium 99 or 1-131, using common and current coupling methods. Labeled or labeled compounds are administered to subjects to determine the locations of excessive amounts of one or more meta.loproteases, in vivo. The ability of inhibitors to selectively bind to metalloproteases is exploited in this way in order to form the distribution map of these enzymes in itself. The techniques can also be employed in hydrological procedures, and the labeled compounds of the invention can be used in competitive immunoassays. The following non-limiting examples illustrate the compounds, compositions and uses of the present invention.

EXAMPLES Compounds are analyzed using nuclear magnetic resonance analysis with "^ H and with 13C, elemental analysis, mass spectra and / or infrared spectra, where appropriate, typically inert solvents are used, preferably in dry form. distils tetrahydrofuran (THF) of sodium and benzophenone, diisopropylamine is distilled from calcium hydride and all other solvents are • acquired as the appropriate quality. Chromatography is carried out on silica gel (70 to 230 mesh, Aldrich) or (230 to 400 mesh, Merck), as appropriate. Thin-layer chromatography (TLC) analysis is carried out on glass-mounted silica gel plates (200 to 300 mesh, Baker) and visualized with UV or with 5% phosphomolybdic acid in EtOH.

• EXAMPLE 1 SYNTHESIS OF N-HIDROXY-1- [(4-METOXYPENYL) SULFONYL] -4- 20 BENCILOXICARBONYL-PIPERAZINE-2-CARBOXYAMIDE 1a 25 la.- 1- [(4-Methoxyphenyl) sulfonyl] -4- (tert-butoxycarbonyl) -piperazine-2-carboxylic acid To a solution of 3 g (14.8 mmol) of piperazin-2-carboxylic acid dihydrochloride in 30 ml of p-dioxane and 15 ml of water, 1.6 ml (29.6 mmol) of 50% w / w aqueous sodium hydroxide is slowly added, followed by 3.6 g (16.3 mmol) of di-tert-butyl dicarbonate. After 5 hours 4.1 ml (29.6 mmol) of triethylamine, 0.18 g (1.48 mmol) of 4-dimethylaminopyridine and 3.0 g (14.8 mmol) of 4-methoxyphenylsulfonyl chloride are added, and the reaction is stirred overnight. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl. The EtOAc layer is washed with 2 x 100 ml of brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a solid. CI + MS: m / z 418 (M + + NH 4), 401 (M + + H).

Ib.- Methyl ester of l - [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride. To a solution of 19.6 g (48.9 mmol) is added 1N- (4-methoxyphenyl) sulfonyl- 4N- (tert-butoxycarbonyl) -piperazine-2-carboxylic acid in 100 ml of methanol, 36 ml (493 mmol) of Thionyl chloride, dropwise, at room temperature. The reaction mixture is stirred overnight and then concentrated under reduced pressure to a solid residue which is triturated with 5% methanol / hexane to give the title compound as a solid. CI + MS: m / z 315 (M + + H). le- 1- [(4-Methoxyphenyl (sulfonyl-4-benzyloxycarbonyl-piperazine-2-carboxylic acid methyl ester) To a solution of 1.2 g (3.42 mmol) of the methyl ester of the hydrochloride of INN- [(4-methoxyphenyl)] sulfonyl] -piperazine-2-carboxylic acid, 1.42 ml (10.26 mmol) of triethylamine and 41 g (0.34 mmol) of DMAP in 5 ml of water and 5 ml of p-dioxane, 0.67 ml (4.45 mmol) of chloroformate are added. The mixture is stirred overnight at room temperature, the reaction is stirred overnight at room temperature, the reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl, and the EtOAc layer is washed with IN HCl. , with? aOH 1 ?, with water and with brine, dried over magnesium sulfate and concentrated under reduced pressure The crude product was purified by column chromatography (hexane / EtOAc (2: 1)) to give the title compound. title as an oil CI + MS: m / z 466 (M + +? H4), 449 (M + + H). ld. - N-hydroxy-1- [(4-methoxyphenyl) sulfonyl] -4-benzyloxycarbonyl-pipe? Razin-2-carboxyamide 0.58 g (1.29 mmol) of the methyl ester is mixed with 6 ml (10 mmol) of a 1.7 M solution NH2OK in methanol, (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. 1.5 g of silica gel is added to the mixture and the solvent is evaporated. Dry silica is poured on top of a column of rapid silica gel, which is subsequently eluted with 100% EtOAc, followed by 5% methanol / EtOAc to give the title compound as a foamy solid. MS with ionic spray m / z 472 (M + + Na), 450 (M + + H).

EXAMPLE 2 PREPARATION OF N-HIDROXY-1N- (4-METOXYPENYL) SULFONYL-4N-METHYL-P PERAZIN-2 -CARBOXYAMIDE 2a. - Methyl (4-metsxyphenyl) sulfonyl-4N-methyl-piperazine-2-carboxylate To a solution of 1.2 g (3.4 mmol) of the methyl ester of the hydrochloride of IN - [(4-methoxyphenyl) sulfonyl] -piperazine-2-hydrochloride -carboxylic acid, 0.84 g (10.26 mmol) of sodium acetate in 10 ml of ethanol, 0.21 g (6.84 mmol) of paraformaldehyde is added, followed by 0.45 g (6.84 mmol) of sodium cyanoborohydride, slowly, at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and stirred in IN HCl for 30 minutes. The mixture is made basic with? AOH 1? and extracted with 3 x 80 ml of EtOAc in the presence of some solid? aCl. The EtOAc layer is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel using EtOAc as eluent to give the title compound. CI + MS: m / z 329 (M + + H). 2b. -? - Hydroxy-1 - (4-methoxyphenyl) sulfonyl-4? -methylpiperazine-2-carboxyamide 0.45 g (1.37 mmol) of the methyl ester is mixed with 6 ml (10.2 mmol) of a 1.7 M solution of? H2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. 1.5 g of silica is added to the mixture and the solvent is evaporated. The dried silica is poured on top of the fast silica gel column, which is subsequently eluted with methanol / EtOAc (1: 5) to give the desired product as a thick oil. MS with ion spray m / z 352 (M + + Na), 330 (M + + H).

EXAMPLE 3 PREPARATION OF N-HIDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- • MORPHOLINCARBONIL PIPERAZIN-2-CARBOXYAMIDE 3a 3b 3a. - methyl (4-methoxyphenyl) sulfonyl-4N-morpholinecarbonyl-piperazine-2-carboxylate To a solution of 1.2 g (3.42 mmol) of the methyl ester of the hydrochloride of INN- [(4-methoxyphenyl) sulfonyl] - piperazine-2-carboxylic acid lb, 1.42 ml (10.26 mmol) of triethylamine and 41 mg (0.34 mmol) of DMAP in 7 ml of methylene chloride, 4 ml of water and 3 ml of p-dioxane, 0.52 ml is added. (4.45 mmol) of 4-morpholinecarbonyl chloride, dropwise, at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated to The pressure is reduced and partitioned between EtOAc and water. The EtOAc layer is washed with IN HCl, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography (EtOAc) to give the title compound, as an oil. CI + MS: m / z 428 (M + + H). 3b. - N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N-morpholinecarbonyl-piperazine-2-carboxyamide 0.75 g (1.75 mmol) of the methyl ester is mixed with 8.2 ml (14 mmol) of a 1.7 M solution of NH2OK in raetanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. 1.5 g of silica gel is added to the mixture and the solvent is evaporated. Dry silica is poured onto a column of flash silica gel, which is subsequently eluted with 15% methanol / EtOAc to give the title compound. MS with ion spray m / z 451 (M + + Na), 429 (M + + H).

EXAMPLE 4 PREPARATION OF N-HIDROXY-1N- (4-METOXYPENYL) SULFQNIL-4N-BENZYLPIPERAZIN-2 -CARBOXYAMIDE 4b 4a. - methyl (4-methoxyphenyl) sulfonyl-4N-benzylpiperazine-2-carboxylate To a solution of 1.2 g (3.42 mmol) of the methyl ester of the hydrochloride of IN - [(4-methoxyphenyl) sulfonyl] -piperazine-2-hydrochloride -carboxylic Ib and 1.42 ml (10.26 mmol) of triethylamine in 8 ml of water and 8 ml of p-dioxane, 0.5 ml (4.1 mmol) of benzyl bromide is added, dropwise, at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. The EtOAc layer is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography (hexane / EtOAc 1: 1) to give the title compound, as a solid. CI + MS: m / z 405 (M + + H). 4b. - N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N-benzylpiperazine-2-carboxyamide 0.42 g (1.04 mmol) of the methyl ester is mixed with 4.9 ml (8.3 mmol) of a 1.7 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stir overnight at room temperature. 1.5 g of silica gel is added to the mixture and the solvent is evaporated. Dry silica is poured onto a column of rapid silica gel, which is subsequently eluted with hexane / EtOAc (1: 1) to give the desired product. MS with ion spray m / z 428 (M + +? A), 406 (M + + H).

EXAMPLE 5 PREPARATION OF N-HYDROXY-1N- (4-METOXYPHENYL) SULFONYL-4N-NICOTINOILPIPERAZIN-2-CARBOXYAMIDE CHLORHYDRATE Sa 5b 5a.- Methyl 1N- (4-methoxyphenyl) sulfonyl-4N-nicotinoyl-piperazine-2-carboxylate To a solution of 1.2 g (3.4 mmol) of the methyl ester of the hydrochloride of IN - [(4-methoxyphenyl) sulfonyl] -piperazin-2-carboxylic acid, 1.9 ml (13.6 mmol) of triethylamine in 4 ml of water and 3 ml of p-dioxane, 0.73 g (4.1 mmol) of nicotinoyl chloride hydrochloride is added dropwise at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. Wash the EtOAc capei with water and with brine, dry over magnesium sulfate and concentrate under reduced pressure to give the title compound, which is purified by eluting with EtOAc on silica gel to give the title compound. MS: m / z 413 (M + + H). 5b.- N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N-morpholinecarbonyl-piperazine-2-carboxyamide hydrochloride 0.4 g (0.95 mmol) of the methyl ester is mixed with 4.5 ml (7.6 mmol) of a 1.7 M solution. of NH2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature 1.5 g of silica is added to the mixture and the solvent is evaporated. dry over a column of rapid silica gel, which is subsequently eluted with methanol / EtOAc (1: 3) The product is diluted with EtOAc followed by the addition of IN HCl (anhydrous in ether) slowly. to give the desired product MS with ion spray m / z 443 (M + + Na), 421 (M + + H).

EXAMPLE 6 PREPARATION OF N-HIDROXY-1N- (4-METOXYPENYL) SULFONYL-4N-n-HEXANOILPIPERAZIN-2-CARBOXYAMIDE 6a. - Methyl (4-methoxyphenyl) sul-onyl-4N-n-hexanoylpiperazine-2-carboxylate To a solution of 1.2 g (3.42 mmol) of the ester 61 of IN-N- [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride and 1.42 ml (10.26 mmol) of triethylamine in 5 ml of water and 5 ml of p-dioxane, 0.62 ml is added dropwise ( 4.42 mmol) of hexanoyl chloride, at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl. The EtOAc layer is washed with aqueous sodium bicarbonate, with water, with brine, dried over magnesium sulfate and concentrated to give the title compound, as an oil. CI + MS: m / z 413 (M + + H). 6b. -? -hydroxy-1 - (4-methoxyphenyl) sulfonyl-4? -n-hexanoyl-piperazin-2-carboxyamide 0.88 g (2.1 mmol) of the methyl ester is mixed with 10 ml (17.1 mmol) of a 1.7 M solution. of? H2OK in methanol (pre-heated as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. 1.5 g of silica gel is added to the mixture and the solvent is evaporated. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with EtOAc to give the desired product as a solid. MS with ionic spray m / z 436 (M + +? A), 414 (M + + H).

EXAMPLE 7 PREPARATION OF N-HIDROXY-1N- (4-METOX PHENYL) SULFONYL-4N- (3- FENILPRQPIL) -P PERAZIN-2 -CARBOXYAMIDE 7a.- Nitrogen (4-methoxyphenyl) sulfonyl-4N- (3-phenylpropyl) -piperazine-2-carboxylate To a solution of 1.2 g (3.42 mmol) of the methyl ester of the hydrochloride of INN- [(4 - methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid lb. and 1.42 ml (10.26 mmol) of triethylamine in 8 ml of water and 8 ml of p-dioxane, 0.62 ml (4.1 mmol) of l-bromo-3- is added dropwise. phenylpropane, at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and extracted with EtOAc. The EtOAc layer is washed with aqueous sodium bicarbonate, with water, with brine, dried over magnesium sulfate and concentrated to give an oil. The crude product is chromatographed by chromatography on silica gel (EtOAc / hexane, 1: 1) to give the title compound. CI + MS: m / z 433 (M + + H). 7b. - N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (3-phenylpropyl) -piperazine-2-carboxyamide 0.42 g (0.97 mmol) of the methyl ester 7a is mixed with 4.6 ml (7.8 mmol) of a 1.7 solution M NH2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. 1.5 g of silica is added to the mixture and the solvent is evaporated. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with EtOAc / hexane (1: 1) to give the desired product. MS with ion spray m / z 456 (M + + Na), 434 (M + + H).

EXAMPLE 8 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SUT.FQNIL-4N- (n-HEXYLAMINOCARBONYL) -PIPERAZIN-2-CARBOXYAMIDE 8a. - Nitrogen (4-methoxyphenyl) sulfonyl-4N- (n-hexylaminocarbonyl) -piperazine-2-carboxylate To a solution of 2 g (5.7 mmol) of the methyl ester of the hydrochloride of INN- [(4-methoxyphenyl)] sulfonyl] -piperazine-2-carboxylic acid lb and 2.4 ml (17.1 mmol) of triethylamine in 12 ml of dichloroethane, 0.92 ml (6.27 mmol) of n-hexyl isocyanate is added dropwise at room temperature. The reaction is stirred overnight at room temperature. Divide the reaction mixture between EtOAc and IN HCl. The EtOAc layer is washed with 1N HCl, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is chromatographed by chromatography on silica gel (EtOAc / hexane, 1: 1) to give the title compound, as an oil. CI + MS: m / z 442 (M + + H). alO 8b. N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (.}. -hexylaminocarbonyl) -piperazine-2-carboxyamide 0.7 g (1.58 mmol) of the methyl ester 8a is mixed with 10 ml (15.8 mmol) of a 1.7 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. 1.5 g of silica is added to the mixture and the solvent is evaporated. Dry silica is poured onto a column of rapid silica gel, which is subsequently eluted with EtOAc to give the desired product as a white solid. MS with ion spray m / z 465 (M + + Na), 443 (M + + H).

EXAMPLE 9 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULF0NIL-4N- (ADAMANTILAMINOCARBONYL) -PIPERAZIN-2-CARBOXYAMIDE 9a. - Methyl (N-methoxyphenyl) sulforyl-4N- (adamantylcarbonyl) -piperazine-2-carboxylate To a solution of 2 g (5.7 mol) of the methyl ester of 1N- [(4-methoxyphenyl) hydrochloride] sulfonyl] -piperazine-2-carboxylic acid lb in 10 ml of water and 10 ml of p-dioxane, 1.1 g (6.4 mmol) of 1-adamantyl isocyanate is added at room temperature. The reaction is stirred overnight at room temperature. Divide the reaction mixture between EtOAc and IN HCl. The layer of EtOA.c with IN HCl, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure to an oil. The crude product is chromatographed by chromatography on silica gel (EtOAc / hexane, 1: 1) to give the title compound, as a thick oil. CI + MS: m / z 412 (M + + H). 9b. - N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (adamantylaminocarbonyl) -piperazine-2-carboxyamide 1.1 g (2.2 mmol) of methyl ester 9a is mixed with 11 ml (18 mmol) of a 1.7 solution M NH2OK in methanol 5 (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. 3 g of silica gel is added to the mixture and the solvent is evaporated. The dried silica is poured onto a column of flash silica gel, which is subsequently eluted with EtOAc to give the desired product as a white foamy solid. MS with ion spray m / z 515 (M + + NH 4), 493 (M + + H).

EXAMPLE 10 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (2 - 15 FENILETIL) AMINOCARBONYL-PIPERAZIN-2-CARBOXYAMIDE 10a. - Methyl (4-methoxyphenyl) sulfonyl-4N- (2-phenylethyl) aminocarbonyl-prazosrazin-2-carboxylate To a solution of 1.05 g (3 mmol) of the methyl ester 1N- [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid Ib chloride, 1.25 ml (9 mmol) of triethylamine in 5 ml of water and 5 ml of p-dioxane is added dropwise. 0.51 ml (3.59 mmol) of phenylethyl isocyanate, at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl. Wash the EtOAc layer with 1N HCl, with aqueous sodium bicarbonate, with water, with brine, dry over magnesium sulfate and concentrate under reduced pressure to give the title compound, as an oil. CI + MS: m / z 462 (M + + H). 10b. -? -hydroxy-1 - (4-methoxyphenyl) sulfonyl-4? - (2-phenylethyl) -aminocarbonyl-piperazine-2-carboxyamide 0.42 g (0.97 mmol) of the methyl ester 10a is mixed with 4.6 ml (7.8 mmol) of a 1.7 M solution of? H2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. 1.5 g of silica is added to the mixture and the solvent is evaporated. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with EtOAc / hexane (1: 1) to give the desired product. MS with ion spray m / z 485 (M + +? A), 463 (M + + H).

EXAMPLE 11 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (2,6-DICHLOROPYRIDYL-4-AMINOCARBONYL) -PIPERAZIN-2-CARBOXYAMIDE lia - Methyl (1- methoxyphenyl) sulfonyl-4N- (2,6-dichloropyridyl-4-amidocarbonyl) -piperazine-2-carboxylate To a solution of 2 g (5.7 mmol) of the methyl ester 1N- hydrochloride [-] (4-methoxyphenyl) sulfonyl] -piperazine-2-C-carboxylic acid lb, 2.4 ml (17.1 mmol) of triethylamine in 3 ml of water, and 10 ml of p-dioxane, 1.0 g (6.4 mmol) of 2,6-dichloropyridyl 4-isocyanate is added dropwise at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl. The EtOAc layer is washed with IN HCl, with aqueous sodium bicarbonate, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure to an oil. The crude product is chromatographed on silica gel (EtOAc / hexane, 1: 1), to give the title compound, as an oil. CI + MS: m / z 503 (M + + H). 10b.- N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (2,6-dichloropyridyl-4-aminocarbonyl) -piperazine-2-carboxyamide 0.43 g (0.85 mmol) of the methyl ester lia is mixed with 4 ml (6.8 mmol) of a 1.7 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. About 1 g of silica is added to the mixture and the solvent is evaporated. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with EtOAc to give the desired product as a white foamy solid. MS with ionic spray m / z 503.8 (M + + H).

EXAMPLE 12 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N-PHENOXYACETIL-PIPERAZIN-2 -CARBOXYAMIDE 12a. - methyl (4-methoxyphenyl) sulfonyl-4N-phenoxyacet-piperazine-2-carboxylate To a solution of 2 g (5.7 mmol) of the methyl ester 1N- [(4-methoxyphenyl) sulfonyl] - hydrochloride piperazine-2-carboxylic acid lb, 2.4 ml (17.1 mmol) of triethylamine in 3 ml of water and 8 ml of p-dioxane, 1.0 g (7.4 mmol) of phenoxyacetyl chloride is added dropwise at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl. The EtOAc layer is washed with aqueous sodium bicarbonate, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure to an oil. The crude product is chromatographed on silica gel (EtOAc / hexane, 3: 2), to give the title compound, as an oil. CI + MS: m / z 449 (M + + H). 12b. N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N-phenoxyacetyl-piperazine-2-carboxyamide 1 g (2.23 mmol) of the methyl ester 12a is mixed with 13 ml (22.3 mmol) of a 1.7 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stir overnight at room temperature. It is acidified with glacial acetic acid to pH = 5, then approximately 2 g of silica is added to the mixture and the solvent is evaporated. Dry silica is poured onto a column of rapid silica gel, which is subsequently eluted with methanol at % / EtOAc to give the desired product as a white solid.

MS with ion spray m / z 467 (M + + NH 4), 450 (M + + H).

EXAMPLE 13 PREPARATION OF N-HYDROXY-1 N- (4-METOXYPENYL) SULFONYL-4 N- (3-METOXYPHENYLAMINOCARBONYL) -PIPERAZIN-2-CARBOXYAMIDE 13a.- Nitrogen (4-methoxyphenyl) sulfonyl-4N- (3-methoxyphenylaminocarbonyl) -piperazine-2-carboxylate To a solution of 2 g (5.7 mmol) of the methyl ester, the hydrochloride of the acid ÍN- [( 4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid lb, 2.4 ml (17.1 mmol) of triethylamine in 3 ml of water and 8 ml of p-dioxane, 0.98 ml (7.41 mmol) of isocyanate of 3 - methoxyphenyl, at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl. The EtOAc layer is washed with IN HCl, with aqueous sodium bicarbonate, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is chromatographed on silica gel (EtOAc / hexane, 1: 4), to give the title compound, as an oil. CI + MS: m / z 464 (M + + H). 13b. N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (3-methoxyphenyl-aminocarbonyl) -piperazine-2-carboxyamide. 0.91 g (1.96 mmol) of methyl ester 13a is mixed with 5.8 ml (9.8 mmol) of a 1.7 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. The mixture is acidified to pH = 5 with anhydrous IN HCl in Et2, then 1.5 g of silica is added and the solvent is evaporated. Dry silica is poured onto a column of rapid silica gel, which is subsequently eluted with EtOAc to give the desired product as a white solid. MS with ionic spray m / z 482 (M + + Na), 465 (M + + H).

EXAMPLE 14 14a. - Nitrogen (4-methoxyphenyl) sulfonyl-4N- (4-biphenylcarbonyl) -piperazine-2-carboxylate To a solution of 2 g (5.7 mmol) of the methyl ester, the hydrochloride of INN- [(4-methoxyphenyl)] sulfonyl] -piperazine-2-carboxylic acid lb, 2.4 ml (17.1 mmol) of triethylamine in 3 ml of water and 8 ml of p-dioxane, 1.65 g (7.4 mmol) of 4-biphenylcarbonyl chloride are added dropwise to 0 ° C. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl. The EtOAc layer is washed with IN HCl, with aqueous sodium bicarbonate, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is chromatographed on silica gel (EtOAc / hexane, 1: 1), to give the title compound, as an oil. CI + MS: m / z 495 (M + + H). 14b. N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (4-biphenyl-carbonyl) -piperazine-2-carboxyamide 0.85 g (1.72 mmol) of the methyl ester 14a is mixed with 8 ml (13.8 mmol) of a 1.7 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. The mixture is acidified to pH = 5 with anhydrous IN HCl in Et2, then 1.5 g of silica is added and the solvent is evaporated. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with 5% methanol / EtOAc to give the desired product as a white solid. MS with ion spray m / z 518 (M + + Na), 513 (M + + NH 4), 496 (M + + H).

EXAMPLE 15 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (TIOPHENCARBONYL) -PIPERAZIN-2 -CARBOXYAMIDE 15a 15b 15a. - Nitrogen (4-methoxyphenyl) sulfonyl-4N- (thiophenylcarbonyl) -piperazine-2-carboxylate To a solution of 2 g (5.7 mmol) of the methyl ester, the hydrochloride of INN- [(4-methoxyphenyl) sulfonyl]] -piperazin-2-carboxylic Ib, 2.4 ml (17.1 mmol) of triethylamine in 2 ml of water and 8 ml of p-dioxane, 0.82 ml (7.4 mmol) of 2-thiophenylcarbonyl chloride is added at 0 ° C. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl. The EtOAc layer is washed with IN HCl, with aqueous sodium bicarbonate, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is chromatographed on silica gel (EtOAc / hexane, 3: 2), to give the title compound, as an oil. CI + MS: m / z 425 (M + + H). 15b.- N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (thiophenecarbonyl) -piperazine-2-carboxyamide 0.95 g (2.24 mmol) of the methyl ester 15a is mixed with 6.6 ml (11.2 mmol) of a 1.7 solution. M NH2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. 1.5 g of silica is added and the solvent is evaporated. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with 5% methanol / EtOAc to give the desired product as a white solid. MS with ion spray m / z 448 (M + + Na), 443 (M + + NH 4), 426 (M + + H).

EXAMPLE 16 PREPARATION OF N-HIDROXY-1N- (4-METOXYPENYL) SULFONYL-4N-FUROYL-PIPERAZIN-2-CARBOXYAMIDE ißa "b lßa. - methyl (4-methoxyphenyl) sulfonyl-4N-furoyl-piperazine-2-carboxylate To a solution of 4 g (11.4 mmol) of the methyl ester, the hydrochloride of INN- [(4-methoxyphenyl) sulfonyl] -piperazine 2 -carboxylic lb, 4.8 ml (34.2 mmol) of triethylamine and 0.134 g (1.1 mmol) of 4-dimethylaminopyridine in 5 ml of water and 15 ml of p-dioxane, 1.54 ml (14.8 mmol) of sodium chloride are added. - furoylum, at 0 ° C. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl. The EtOAc layer is washed with IN HCl, with aqueous sodium bicarbonate, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is chromatographed on silica gel (EtOAc / hexane, 4: 1), to give the title compound, as an oil. CI + MS: m / z 409 (M + + H). 16b. N-hydroxy-lN- (4-ethoxyphenyl) sulfonyl-4N-furoyl-piperazine-2-carboxyamide 2.3 g (5.63 mmol) of the methyl ester 16a is mixed with 26.5 ml (45 mmol) of a 1.7 M solution of NH2OK in methanol > (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. HE acidifies the mixture at pH = 5 with anhydrous IN HCl in Et2, then adds about 5 g of silica and evaporates the solvent. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with 5% methanol / EtOAc to give the desired product as a white solid. MS with ion spray m / z 432 (M + +? A), 427 (M + +? H4), 410 (M + + H).

EXAMPLE 17 PREPARATION OF N-HIDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (2-AMINO-4-METHYL-5-TIAZOLSULFONYL) -PIPERAZIN-2 -CARBOXYAMIDE 17a. - Methyl (4-methoxyphenyl) sulfonyl-4N- (2 -acetamido-5-methyl-5-thiazolesulfonyl) -piperazine-2-carboxylate To a solution of 2 g (5.7 mmol) of the methyl ester acid chlorhydrate ÍN- [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid lb, 2.4 ml (17.6 mmol) of triethylamine and 70 mg (0.57 mmol) of 4-dimethylaminopyridine in 3 ml of water and 8 ml of p-dioxane, 1.9 ml (7.4 mmol) of 2-acetamido-4-methyl-5-thiazolesulfonyl chloride is added at 0 ° C. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. Wash the EtOAc layer with IN HCl, with aqueous sodium bicarbonate, with water, with brine, dry over magnesium sulfate and concentrate under reduced pressure to give the desired product. CI + MS: m / z 533 (M + + H). 17b.- N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (2-amino-4-methyl-5-thiazolesulfonyl-piperazine-2-carboxy) ida 1.2 g (2.2 mmol) of the methyl ester 17a is mixed with 12 ml (18 mmol) of a 1.7 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred overnight at room temperature, the reaction mixture is concentrated under pressure reduced, then dissolved in 5 ml of methanol and acidified with 37% HCl, about 2 g of silica is added and the solvent is evaporated.The dry silica is poured onto a column of silica gel.

• Rapid, which is subsequently eluted with 5% methanol / EtOAc to give the desired product as a white solid. MS with ion spray m / z 514 (M + + Na), 492 (M + + H).

EXAMPLE 18 PREPARATION OF N-HIDR0XI-1N- (4-METOXYPENYL) SULFONYL-4N-CYCLOHEXANCARBONYL-PIPERAZIN-2 -CARBOXYAMIDE 18a 18b 18. - Methyl (IN-4-methoxyphenyl) sulfonyl-4N-cyclohexanecarbonyl-2-piperazine-2-carboxylate To a solution of 2 g (5.7 mmol) of the methyl ester, the hydrochloride of INN- [(4-methoxyphenyl) sulfonyl] - piperazine-2-carboxylic acid lb, 2.4 ml (17.6 mmol) of triethylamine and 70 mg (0.57 mol) of 4-dimethylaminopyridine in 4 ml of water and 8 ml of pd: oxane, 1.0 ml (7.4 mmol) of chloride are added of 2-furoyl, at 0 ° C. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. Wash the EtOAc layer with IN HCl, with aqueous sodium bicarbonate, with water, with brine, dry over magnesium sulfate and concentrate under reduced pressure to give the desired product. CI + MS: m / z 425 (M + + H). 18b. - N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N-cyclohexane-carbonyl-piperazine-2-carboxyamide 1.3 g (3.0 mmol) of the methyl ester 18a is mixed with 16. 2 ml (24.5 mmol) of a 1.7 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. The HCl mixture is acidified, 2 g of silica is added and the solvent is evaporated. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with 5% methanol / EtOAc to give 0.58 g of the desired product as a white solid. MS: m / z 448 (M + + Na), 443 (M + + NH 4), 426 (M + + H).

EXAMPLE 19 PREPARATION OF N-HIDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (4-METHYL-1,2, 3-THERADYZOL-5-CARBONYL) -PIPERAZIN-2-CARBOXYAMIDE 1st 19a. - 1N- (4-methoxyphenyl) sulfonyl-4N- (4-methyl-1,2-thiadiazole-5-carbonyl) -piperazin-2-methylcarboxylate To a solution of 2 g (5.7 mmol) of the methyl ester the hydrochloride of IN - [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid lb, 2.4 ml (17.6 mmol) of triethylamine and 0.070 g (0.0057 mmol) of 4-dimethylaminopyridine in 2 ml of water and 8 ml of p-dioxane, 1.2 g (7.4 mmol) of 4-methyl-1,2,3-thidiazole-5-carbonyl chloride is added at 0 ° C. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. The EtOAc layer is washed with 1N HCl, with aqueous sodium bicarbonate, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is chromatographed on silica gel (EtOAc / hexane, 3: 2) to give the title compound, as an oil. CI + MS: m / z 458 (M + + NH 4), 441 (M + + H). 19b. - N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (4-methyl-1,2,3-thiadiazole-5-carbonyl) -piperazine-2-carboxyamide 1.1 g (2.49 mmol) of the methyl ester are mixed 19a with 13 ml (20 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. About 2 g of silica is added and the solvent is evaporated. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with 5% methanol / EtOAc to give the desired product as a white solid. MS with ion spray: m / z 459 (M + + NH 4), 442 (M + + H).

EXAMPLE 20 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (5M: STIL-3-FENILISOXAZO-4-CARBONYL) -PIPERAZIN-2-CARBOXYAMIDE a. - 1N- (4-methoxyphenyl) sulfonyl-4N- (5-methyl-3-phenylisoxazole-4-carbonyl) -piperazine-2-carboxylic acid methyl ester To a solution of 2 g (5.7 mmol) of the methyl ester acid chlorhydrate ÍN- [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid lb, 2.4 ml (17.6 mmol) of triethylamine and 0.070 g (0.6 mmol) of 4-dimethylaminopyridine in 2 ml of water and 8 ml of p-dioxane, 1.64 g (7.4 mmol) of 5-methyl-3-phenylisoxazole-4-carbonyl chloride is added at 0 ° C. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl. The EtOAc layer is washed with 1% HCl, with aqueous sodium bicarbonate, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is chromatographed on silica gel (EtOAc / hexane, 1: 1) to (Give the title compound, as an oil CI + MS: m / z 500 (M + + H). 20b.-? -hydroxy-l- (4-methoxyphenyl) sulfoni-1-4? - (5-methyl-3-phenylisoxazole-4-carbonyl) -piperazine-2-carboxyamide. 1.6 g (3.2 mmol) of the ester is mixed. Methyl 20a with ml (25.6 mmol) of a 1.7 M solution of? H2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred overnight at room temperature. The mixture is acidified to pH = 5 with concentrated HCl, then adds about 5 g of silica and the solvent evaporates. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with 2% formic acid / EtOAc to give the desired product as a solid. MS with ion spray: m / z 518 (M + + NH 4), 501 (M + + H). EXAMPLE 21 PREPARATION OF N-HIDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (ISOXAZOL-5-CARBONYL) -PIPERAZIN-2-CARBOXYAMIDE 21a. - Methyl (4-methoxyphenyl) sulfonyl-4N- (isoxazole-5-carbonyl) -piperazine-2-carboxylate To a solution of 2 g (5.7 mmol) of the methyl ester, the hydrochloride of acid methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid lb, 2.4 ml (17.6 mmol) of triethylamine and 0.070 g (0.6 mmol) of 4-dimethylaminopyridine in 2 ml of water and 8 ml of p-dioxane, 0.97 g (7.4 mmol) of isoxazole-5-carbonyl chloride is added at 0 ° C. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. The EtOAc layer is washed with IN HCl, with aqueous sodium bicarbonate, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is chromatographed on silica gel (EtOAc / hexane, 1: 1) to give the title compound, as an oil. Cl + MS: m / z 427 (M + + NH 4), 410 (M + + H). 21b. - N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (isoxazole-5-carbonyl) -piperazine-2-carboxyamide 0.15 g (0.31 mmol) of the methyl ester 21a is mixed with 1.8 ml (2.5 mmol) of a 1.7 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. About 1 g of silica is added and the solvent is evaporated. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with 5% methanol / EtOAc to give the desired product as a white solid. MS with ion spray: m / z 428 (M + + NH 4), 411 (M + + H).

EXAMPLE 22 PREPARATION OF N-HYDROXY-1N- (4-METQXYPENYL) SULFONYL-4N-AMIDO-PIPERAZIN-2 -CARBOXYAMIDE 22a 22b 22a. - methyl (4-methoxyphenyl) sulfonyl-4N-amido-piperazine-2-carboxylate To a solution of 1.5 g (4.3 mmol) of the methyl ester, the hydrochloride of INN- [(4-methoxyphenyl) sulfonyl] -piperazine 2 -carboxylic lb, 1.8 ml (12.7 mmol) of triethylamine and 52 mg (0.43 mmol) of DMAP in 4 ml of water and 8 ml of p-dioxane, 0.89 ml (4.45 mmol) of isocyanate were added dropwise. trimethylsilyl, at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. The EtOAc layer is washed with IN HCl, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is chromatographed on silica gel (EtOAc) to give the title compound. CI + MS: m / z 358 (M + + H). 22b. N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N-amido-piperazine-2-carboxyamide 0.2 g (0.56 mmol) of the methyl ester 22a is mixed with 3.2 ml (4.5 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stir overnight at room temperature. The solvent is removed under reduced pressure. The mixture is then dissolved in 1 ml of methanol, acidified with HCl (4N in dioxane) to pH around 6. The crude product is subsequently eluted with 20% methanol / EtOAc to give the title compound. MS with ion spray: m / z 397 (M + + NH4), 359 (M + + H).

EXAMPLE 23 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (9-FLUORENONE-2 -CARBONYL) -PIPERAZIN-2 -CARBOXYAMIDE 23a.- Methyl- (4-methoxyphenyl) sulfonyl-4N- (9-fluorenone-2-carbonyl) -piperazine-2-carboxylate. 1 ml (11.4 mmol) of oxalyl chloride is added dropwise to a solution of 1.66. g (7.4 mmol) of 9-flucrenone-2-carbonyl chloride in 2 ml of DMF and 20 ml of methylene chloride at 0 ° C. The reaction mixture is stirred for 45 minutes at the temperature before being slowly transferred to a solution of 2 g (5.7 mmol) of methyl ester, the INH- [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride. lb, 5 ml (34.2 mmol) of triethylamine and 70 mg (0.57 mmol) of 4-dimethylaminopyridine in 10 ml of p-dioxane, at 0 ° C. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. Wash the EtOAc layer with IN HCl, with aqueous sodium bicarbonate, with water, with brine, dry over magnesium sulfate and concentrate under reduced pressure to give the desired product. CI + MS: m / z 521 (M + + H). 23b. - N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (9-fluorenone-2-carbonyl) -piperazin-2-carboxyamide 0.42 g (0.807 mmol) of the methyl ester 23a is mixed with 4.6 ml (6.45 mmol) of a 1.7 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. The mixture is acidified to pH = 5 with HCl (4N in dioxane), then about 5 g of silica is added and the solvent is evaporated. The dried silica is poured onto a column of rapid silica gel, which is subsequently eluted with 2% formic acid / EtOAc to give the desired product as a solid. MS with ion spray: m / z 522 (M + + H).

EXAMPLE 24 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N-METANSULFONYL-PIPEERAZIN-2-CARBOXYAMIDE 1 »24a 24b 24a.- Nitrogen (4-methoxyphenyl) sulfonyl-4N-methanesulfonyl-piperazine-2-carboxylate To a solution of 1.5 g (4.3 mmol) of the methyl ester, the hydrochloride of INN- [(4-methoxyphenyl) sulfonyl]] -piperazine-2-carboxylic acid lb, 1.8 ml (12.7 mmol) of triethylamine and 52 mg (0.43 mmol) of DMAP in 2 ml of water and 8 ml of p-dioxane, 0.43 ml (5.56 mmol) of methanesulfonyl chloride is added dropwise at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. Wash the EtOAc layer with 1N HCl, with water, with brine, dry over magnesium sulfate and concentrate under reduced pressure to give the title compound. ESI + MS: m / z 410 (M + NH 4 +), 393 (M + + H). 24b. N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N-methanesulfonyl-piperazine-2-carboxyamide. 0.7 g (1.78 mmol) of the methyl ester 24a is mixed with 10 ml (14.2 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred overnight at room temperature. The reaction mixture is acidified with HCl and 2 g of silica are added, and the solvent is evaporated. The dried silica is poured on top of a column of rapid silica gel, which is subsequently eluted with 5% methanol / EtOAc to give the desired product as a white solid. ESI + MS: m / z 411 (M + + NH 4), 394 (M + + H).

EXAMPLE 25 PREPARATION OF N-HYDROXY-1N-4-METOXYPENYL) SULF0NIL-4N-METANSULFONYL-PIPEERAZIN-2-CARBOXYAMIDE 25a.- Nitrogen (4-methoxyphenyl) sulfonyl-4N-methanesulfonyl-piperazine-2-carboxylate To a solution of 2 g (5.7 mmol) of the methyl ester, the hydrochloride of INN- [(4-methoxyphenyl) sulfonyl]] -piperazine-2-carboxylic acid lb, 3.2 ml (22.8 mmol) of triethylamine and 70 rag (0.57 mmol) of DMAP in 10 ml of p-dioxane, 0.81 ml (8.5 mmol) of acetic anhydride is added dropwise at room temperature. ambient. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. Wash the EtOAc layer with IN HCl, with water, with brine, dry over magnesium sulfate and concentrate under reduced pressure to give the title compound as a mixture of two constituents (2: 1). ESI + MS: m / z 374 (M + NH 4 +), 357 (M + + H). 25b. N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N-methanesulfonyl-piperazine-2-carboxyamide. 1.3 g (3.65 mmol) of the methyl ester 25a is mixed with 21 ml (28.8 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred overnight at room temperature. The reaction mixture is acidified with HCl, silica is added, and the solvent is evaporated. The dried silica is poured on top of a column of rapid silica gel, which is subsequently eluted with EtOAc to 20% methanol / EtOAc to give the desired product as the mixture of two constituents (2: 1). ESI + MS: m / z 375 (M + + NH 4), 358 (M + + H).

EXAMPLE 26 PREPARATION OF N-HYDROXY-1N- (4 -METOXYPENYL) SULFONYL-4N- (3, 5-DIMETILISOXAZQL-4 -SULFONIL) -PIPERAZIN- 2-CARBQXIAMIDE 26a.- Nitrogen (4-methoxyphenyl) sulfonyl-4N- (3,5-dimethylisoxazole-4-sulfonyl) -piperazine-2-carboxylate To a solution of 1.5 g (4.3 mmol) of the methyl ester acid chlorhydrate IN - [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid lb, 1.89 ml (13 mmol) of triethylamine and 53 mg (0.43 mmol) of DMAP in 12 ml of p-dioxane and 2 ml of water, 1.1 g (5.6 mmol) of 3,5-dimethylisoxazole-4-sulfonyl chloride is added dropwise at room temperature. HE • stir the reaction overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. The EtOAc layer is washed with IN HCl, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purify the crude product by column chromatography (hexane / EtOAc, 1: 1 to EtOAc) to give the title compound. ESI + MS: m / z 491 (M +? H4 +), 474 (M + + H). • 26b. ? -hydroxy-1 - (4-methoxyphenyl) sulfonyl-4? - (3,5-dimethyl-isoxazole-4-sulfonyl) -piperazine-2-carboxyamide. 0.32 g (0.68 mmol) of the methyl ester 26a is mixed with 4 ml (5.4 mmol) of a 1.5 M solution of? H2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stir overnight at room temperature. The reaction mixture is acidified with HCl and silica is added, and the solvent is evaporated. Dry silica is poured on top of a column of rapid silica gel, which is subsequently eluted with EtOAc to 5% methanol / EtOAc to give the desired product. ESI + MS: m / z 492 (M + +? H4), 475 (M + + H).

EXAMPLE 27 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (N-METHYLHYLAMINOCARBONYL) -PIPERAZIN-2 -CARBOXYAMIDE 27a. - methyl (4-methoxyphenyl) sulfonyl-4N- (N-methylhexylaminocarbonyl) -piperazine-2-carboxylate To a solution of 17 ml (34 mmol) of 20% phosgene in toluene in 15 ml of dichloroethane , at 0 ° C, 3 g (8.5 mmol) of the methyl ester is added the INH- [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride lb, slowly. The reaction is stirred for 2 hours at 45 ° C and overnight at room temperature. The reaction mixture is concentrated under reduced pressure, dissolved in 15 ml of dichloroethane and a solution of 2.6 ml (17.1 mmol) of N-methylhexylamine, 3.6 ml (12.6 mmol) of triethylamine in 15 ml of 0 ° dichloroethane is added. C, a drop. The mixture is stirred overnight at room temperature. The reaction is diluted by IN HCl and extracted with EtOAc. The EtOAc layer is washed with IN HCl, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The product is purified by column chromatography (hexane / EtOAc, 1: 2) to give the title compound. ESI + MS: m / z 473 (M + + NH 4), 456 (M + + H). 27b. N-hydroxy-lN- (4-methoxyphenyl) sulfoni1-4N- (N-methylhexy1-aminocarbonyl) -piperazine-2-carboxyamide. 0.82 g (1.8 mmol) of the methyl ester 27a is mixed with 10 ml (14.4 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred overnight at room temperature. The reaction mixture is acidified with HCl and silica is added, and the solvent is evaporated. The dried silica is poured on top of a column of rapid silica gel, which is subsequently eluted with EtOAc at 5% methanol / EtOAc to give the desired product. ESI + MS: m / z 479 (M + + Na), 457 (M + + H).

EXAMPLE 28 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- [(4N-METHYL) -PIPERAZIN-1N-CARBONYL] -PIPERAZIN-2-CARBOXYAMIDE 28a.- Nitrogen (4-methoxyphenyl) sulfonyl-4N- [(4N-methyl) piperazine-lN-carbonyl) -piperazine-2-carboxylate To a solution of 14 ml (28.5 mmol) of 20% phosgene in toluene, in 20 ml of dichloroethane, at 0 ° C, 2.5 g (7.1 mmol) of the methyl ester is added the hydrochloride of lN - [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid lb, slowly. 5 The reaction is stirred for 2 hours at 45 ° C and overnight at room temperature. The reaction mixture is concentrated under reduced pressure, dissolved in 20 ml of dichloroethane and a solution of 0.95 ml (8.5 mmol) of 1-methylpiperazine, 3 ml (21 mmol) of triethylamine in 10 ml of 0 ° dichloroethane is added. C, É3L0 drop. The mixture is stirred overnight at room temperature. The reaction is diluted by IN HCl and extracted with EtOAc. Wash the EtOAc layer with IN HCl, with water, with brine, dry over magnesium sulfate and concentrate under reduced pressure to give the title compound. ESI + MS: m / z 441 (M + + H). 28b. N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- [(4N-methyl) -piperazine-lN-carbonyl) -piperazine-2-carboxyamide. 2 g (4.5 mmol) of the methyl ester 28a is mixed with 24 ml (36 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stir overnight at room temperature.

The reaction mixture is acidified with 4N HCl in dioxane and the solvent is evaporated under reduced pressure. The crystal is recrystallized product in EtOAc / methanol to give the desired product. ESI + MS: m / z 480 (M + + K), 442 (M + + H).

EXAMPLE 29 PREPARATION OF N-HIDROXY-1N- (4-METOXYPENYL) SULFONYL-4N-n-HEXIL-PIPERAZIN-2 -CARBOXYAMIDE 29a. - methyl (4-methoxyphenyl) sulfonyl-4N-n-hexyl-piperazine-2-carboxylate To a solution of 2 g (5.7 mmol) of the methyl ester, the hydrochloride of INN- [(4-methoxyphenyl) sulfonyl]] -piperazine-2-carboxylic acid lb, 2.4 ml (17.1 mmol) of triethylamine in 15 ml of p-dioxane and 2 ml of water, 1.95 ml (13.1 mmol) of 1-iodohexane are added dropwise at room temperature. The reaction is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and water. The EtOAc layer is washed with IN HCl, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purify the crude product by column chromatography (hexane to hexane / EtOAc, 1: 1) to give the title compound. ESI + MS: m / z 399 (M + + H). 29b "N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N-n-hexyl-piperazine-2-carboxyamide. 1283 g (3.21 mmol) of methyl ester 29a is mixed with 18 ml (25.7 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred overnight at room temperature. The reaction mixture is acidified with HCl and silica is added, and the solvent is evaporated. The dried silica is poured on top of a column of rapid silica gel, which is subsequently eluted with EtOAc to give the desired product. ESI + MS: m / z 400 (M + + H).

EXAMPLE 30 PREPARATION OF N-HYDROXY-1N- (4-METQXYPENYL) SUI-FONYL-4N- (N-PROPYLCYCLOPROPANOMETHYLAMINOCARBONYL) -PIPERAZIN-2 -CARBOXYAMIDE 30a. - methyl (4-methoxyphenyl) sulfonyl-4N- (N-propylcyclopropane-ethylaminocarbonyl) -piperazine-2-carboxylate To a solution of 56 ml (114 mmol) of 20% phosgene in -oluene in 80 ml of dichloroethane, at 0 ° C, 10 g is added (28.5 mmol) of the methyl ester, the IN - [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride lb, slowly. The reaction is stirred for 2 hours at 55 ° C and overnight at room temperature. The reaction mixture is divided into 5 equivalents and concentrated under reduced pressure. Dissolve a 1.7 g portion (4.5 mmol in theory) in 10 ml of methylene chloride and add to a solution of 0.88 ml (5.85 mmol) of N-propylcyclopropane, 2.5 ml (18 mmol) of triethylamine in 8 ml of dichloroethane, at 0 ° C, dropwise. The mixture is stirred overnight at room temperature. The reaction is diluted with HCl 1? and extracted with EtOAc. The EtOAc layer is washed with 1% HCl, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purify the crude product by column chromatography (hexane to hexane / EtOAc, 2: 1), to give the title compound. ESI + MS: m / z 454 (M + + H). 30b. ? -hydroxy-l? - (4-methoxyphenyl) sulfonyl-4? - (? - propylcyclopropanelaminecarbonyl) -piperazin-2-carboxyamide. 1.1 g (2.4 mmol) of the methyl ester 30a is mixed with 14 ml (19.4 mmol) of a 1.5 M solution of? H2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred during the night at room temperature. The reaction mixture is acidified with HCl and silica is added, and the solvent is evaporated. The dried silica is poured on top of a column of rapid silica gel, which is subsequently eluted with EtOAc to give the desired product. ESI + MS: m / z 455 (M + + H).

EXAMPLE 31 PREPARATION OF N-HIDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (N- PRCPILCICLOPROPANOMETHYLAMINOCARBONYL) -PIPERAZIN-2-CARBOXYAMIDE 31a. - methyl (4-methoxyphenyl) sulfonyl-4N- (N-propylcyclopropane-methylaminocarbonyl) -piperazin-2-carboxylate To a solution of 56 ml (114 mmol) of 20% phosgene in toluene in 80 ml of dichloroethane, at 0 ° C, 10 g (28.5 mmol) of the methyl ester is added the IN - [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride lb, slowly. The reaction is stirred for 2 hours at 55 ° C and overnight at. room temperature. The reaction mixture is divided into 5 equivalents and concentrated under reduced pressure. Dissolve a 2 g portion (5.3 mmol) in 10 ml of methylene chloride and add to a solution of 0.63 ml (6.3 mmol) of 3-pyridinomethanol, 2.9 ml (21 mmol) of triethylamine in 10 ml of Methylene chloride, at 0 ° C, dropwise. The mixture is stirred overnight at room temperature. The reaction is diluted with IN HCl and extracted with EtOAc. The EtOAc layer is washed with IN HCl, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography (hexane / EtOAc, 1: 1 to 1: 4), to give the title compound. ESI + MS: m / z 450 (M + + H). 31b. N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4 N- (N-propylcyclo-propanethylaminocarbonyl) -piperazin-2-carboxyamide. 0.55 g (1.22 mmol) of the methyl ester 31a is mixed with 7 ml (9.76 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred overnight at room temperature. The reaction mixture is cyclized with HCl and the solvent is evaporated. The crude product is purified by reverse phase preparative HPLC (85 A 15 B, A, 95% water, 5% acetonitrile, 0.1% formic acid, B, 80% acetonitrile, 20% water; x 300 mm Waters SymmetryPrep C18) to give the title compound, as a white foamy solid. ESI + MS: m / z 451 (M + + H).

EXAMPLE 32 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (HOMOPIPERIDINYL-N-CARBONYL) -PIPERAZIN-2 -CARBOXYAMIDE 32a. - Methyl (1- methoxyphenyl) sulfonyl-4N- (homopiperidinyl-N-carbonyl) -piperazine-2-carboxylate To a solution of 56 ml (114 mmol) of 20% phosgene in toluene in 80 ml of dichloroethane, at 0 ° C, 10 g (28.5 mmol) of the methyl ester is added the 1N- [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride lb, slowly. The reaction is stirred for 2 hours at 55 ° C and overnight at. room temperature. The reaction mixture is divided into 5 equivalents and concentrated under reduced pressure. Dissolve a portion of 1.7 g (4.5 mmol) in 10 ml of methylene chloride and add to a solution of 0.66 ml (5.87 mmol) of hexamethyleneimine, 2.5 ml (18 mmol) of triethylamine in 5 ml of methylene chloride, at 0 ° C, dropwise. The mixture is stirred overnight at room temperature. The reaction is diluted with IN HCl and extracted with EtOAc. Wash the EtOAc layer with 1N HCl, with water, with brine, dry over magnesium sulfate and concentrate under reduced pressure to give the title compound. ESI + MS: m / z 440 (M + + H). 32b. N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (homopiperidinyl-N-carbonyl) -piperazine-2-carboxyamide. 1.45 g (3.3 mmol) of the methyl ester 32a is mixed with 18.9 ml (26.4 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred overnight at room temperature. The reaction mixture is acidified with HCl and silica is added, and the solvent is evaporated. Dry silica is poured on top of a column of rapid silica gel, which is subsequently eluted with EtOAc / hexane (1: 1) to 100% EtOAc at 5% methanol / EtOAc, to give the desired product. ESI + MS: m / z 441 (M + + H).

EXAMPLE 33 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (3-ETOXY-1-PROPOXICARBONYL) -PIPERAZIN-2-CARBOXYAMIDE 33a. - methyl (4-methoxyphenyl) sulfonyl-4N- (3-ethoxy-1-propoxycarbonyl) -piperazin-2-carboxylate To a solution of 85 ml (171 mmol) of 20% phosgene in toluene, in 150 ml of dichloroethane, at 0 ° C, is added 30 g (85.5 mmol) of the methyl ester, the IN - [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride lb, slowly. The reaction is stirred for 2 hours at 55 ° C and overnight at room temperature. The reaction mixture is concentrated under reduced pressure to give 24 g of the acid chloride. Dissolve a 1.67 g (4.4 mmol) portion of the acid chloride in 8 mL of methylene chloride and add to a solution of 0.66 mL (5.76 mmol) of 3-ethoxy-1-propanol, 2.1 mL (15.5 mmol) of triethylamine in 5 ml of methylene chloride, at 0 ° C, dropwise. The mixture is stirred for 3 days at room temperature. The reaction is diluted with IN HCl and extracted with EtOAc. The EtOAc layer is washed with IN HCl, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography (hexane / EtOAc, 1: 1) to give the title compound. ESI + MS: m / z 462 (M + + NH 4), 445 (M + + H). alO 33b "N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (3-ethoxy-l-propoxycarbonyl) -piperazine-2-carboxyamide. 0.39 g (0.88 mmol) of methyl ester 33a is mixed with 5 ml (7 mmol) of a 1.5 M solution of NH2OK in methanol. (prepared as described in Fieser and Fieser, Volume 1, page 478) and stirred overnight at room temperature. The reaction mixture is acidified with HCl and silica is added, and the solvent is evaporated. Dry silica is poured on top of a column of rapid silica gel, which is subsequently eluted with EtOAc / hexane (3: 2) to give the desired product. ESI + MS: m / z 463 (M + + NH 4), 446 (M + + H).

EXAMPLE 34 PREPARATION OF N-HYDROXY-1N- (4-METOXYPENYL) SULFONYL-4N- (N-BENZYLMETHYLAMINOCARBONYL) -PIPERAZIN-2-CARBOXYAMIDE 34a. - methyl (4-methoxyphenyl) sulfonyl-4N- (N-benzylmethylaminocarbonyl) -piperazin-2-carboxylate To a solution of 85 ml (171 mmol) of 20% phosgene in toluene in 150 ml of dichloroethane , at 0 ° C, 30 g (85.5 mmol) of the methyl ester is added the IN - [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride lb, slowly. The reaction is stirred for 2 hours at 55 ° C and overnight at room temperature. The reaction mixture is concentrated under reduced pressure to give 24 g of the acid chloride. A portion of 1.8 g (4.78 mmol) of the acid chloride is dissolved in 8 ml of methylene chloride and added to a solution of 1.3 ml (9.56 mmol) of N-benzylmethylamine, 2.7 ml (19.1 mmol) of triethylamine in 5 ml. ml of methylene chloride, at 0 ° C, dropwise. The mixture is stirred for 4 hours at room temperature. The reaction is diluted with 1N HCl and extracted with EtOAc. Wash the EtOAc layer with 1N HCl, with water, with brine, dry over magnesium sulfate and concentrate under reduced pressure to give the title compound. ESI + MS: m / z 463 (M + + H). 34b. N-hydroxy-lN- (4-methoxyphenyl) sulfonyl-4N- (N-benzylmethylaminocarbonyl) -piperazin-2-carboxyamide. 1.8 g (3.9 mmol) of the methyl ester 34a is mixed with 10 ml (14 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred overnight at room temperature. The reaction mixture is acidified with HCl and silica is added, and the solvent is evaporated. Dry silica is poured on top of a column of rapid silica gel, which is subsequently eluted with EtOAc / hexane (1: 1) to 100% EtOAc, to give the desired product. ESI + MS: m / z 463 (M + + H).

EXAMPLE 35 PREPARATION OF N-HYDROXY-1N- (4-BROMOFENYL) SULFONYL-4N- (N-METHYLHYLAMINOCARBONYL) PIPERAZIN-2 -CARBOXYAMIDE 35a. INN (4-bromophenyl) sulfonyl-4N- (tert-butoxycarbonyl) -piperazine-2-carboxylic acid To a solution of 10 g (49.2 mmol) of piperazine-2-carboxylic acid dihydrochloride in 70 ml of p-dioxane and 90 ml of water, at 0 ° C, slowly add 5 ml (98.4 mmol) of 50% (w / w) aqueous solution of sodium hydroxide, followed by 11.0 g (49.2 mmol) of di-ter dicarboxylate. -butyl. After 17 hours 23 ml (170 mmol) of triethylamine and 12.6 g (49.2 mmol) of 4-bromophenylsulfonyl chloride are added and the reaction is stirred overnight. The reaction mixture is concentrated under reduced pressure and partitioned between EtOAc and IN HCl. The EtOAc layer is washed with 2 x 100 ml of brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound. ESI + MS: m / z 468, 466 (M + + NH 4), 451, 449 (M + + H). 35b.- ÍN- (4-bromophenyl) sulfonyl-piperazine-2-carboxylic acid hydrochloride 6 is slowly added. 6 ml (90.8 mmol) of thionyl chloride to a solution of the acid 35a in 80 ml of methanol, at 0 ° C. The reaction mixture is stirred overnight. After degassing to remove excess sulfonyl chloride, the solvent is removed under reduced pressure to give the desired product. ESI + MS: m / z 365, 363 (M + + H). 35c. - 1N- (4-bromophenyl) sulfonyl-4N- (N-methylhexylaminocarbonyl) -piperazine-2-carboxylic acid methyl ester To a solution of 15 ml (30 mmol) of 20% phosgene in toluene, in 25 ml of dichloroethane, a 0 ° C, 4 g (10 mmol) of the methyl ester is added slowly to the IN - [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride lb. The reaction is stirred for 2 hours at 55 ° C and overnight at room temperature. The reaction mixture is concentrated under reduced pressure to give 3.6 g of the acid chloride. Dissolve a 1.25 g portion (2.94 mmol) of the acid chloride in 8 ml of methylene chloride and add to a solution of 0.9 ml (5.87 mmol) of N-methylhexylamine.1.65 ml (11.7 mmol) of triethylamine in 5 ml of methylene chloride, at 0 ° C, dropwise. The mixture is stirred overnight at room temperature. The reaction is diluted with IN HCl and extracted with EtOAc. Wash the EtOAc layer with 1N HCl, with water, with brine, dry over magnesium sulfate and concentrate under reduced pressure to give the title compound. ESI + MS: m / z 506 504 (M + + H). 35d. IN- (4-bromophenyl) sulfonyl-4N- (N-methylhexylaminocarbonyl) -piperazine-2-carboxyamide. 1.3 g (2.58 mmol) of the methyl ester 35c is mixed with 9.2 ml (12.8 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred overnight at room temperature. The reaction mixture is acidified with 10% HCl and extracted with EtOAc. The EtOAc layer is dried over magnesium sulfate and the solvent is evaporated. The crude product is purified by preparatory reverse phase HPLC (40 A 60 B, A, 95% water, 5% acetonitrile, 0.1% formic acid, B, 80% acetonitrile, 20% water, column 19 x 300 mm Waters SymmetryPrep C18) to give the title compound as a white foamy solid. ESI + MS: m / z 507, 505 (M + + H).

EXAMPLE 36 • PREPARATION OF N-HYDROXY-1N- (4-BROMOFENIL) SULFONYL-4N- [N-BIS (2-METHODYL) AMINOCHARBONYL -PIPERAZIN-2-CARBOXYAMIDE 36a.- Nitrogen (4-bromophenyl) sulfonyl-4N- [N-bis (2-methoxyethyl) amino-20 carbonyl) -piperazine-2-carboxylate To a solution of 15 ml (30 mmol) of 20% phosgene. % in toluene, in 25 ml of dichloroethane, at 0 ° C, 4 g (10 mmol) of the methyl ester are added the IN - [(4-bromophenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride 35b, slowly. The reaction is stirred for 2 hours at 55 ° C and overnight at room temperature. The reaction mixture is concentrated under reduced pressure to give. 3.6 g of the acid chloride. A portion of 1.2 g (2.8 mmol) of acid chloride is distilled • in 5 ml of methylene chloride and added to a solution of 0.83 ml (5.64 mmol) of bis (2-methoxyethyl) amine, 1.6 ml (11.2 mmol) of triethylamine in 5 ml of methylene chloride, at 0 °. C, a drop. The mixture is stirred overnight at room temperature. The reaction is diluted with 1N HCl and extracted with EtOAc. The? TOAc layer is washed with 1N HCl, with water, with brine, dried over magnesium sulfate and concentrated at reduced pressure. The crude product is purified by column chromatography (hexane / EtOAc, 2: 3) to give the title compound. ESI + MS: m / z 524, 522 (M + + H). 36b. N-hydroxy-lN- (4-bromophenyl) sulfonyl-4N- [N-bis (2-methoxyethyl) aminocarbonyl) -piperazine-2-carboxyamide. Mix 1.0 g (1.91 mmol) of methyl ester 36a with 5.5 ml (7.6 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stir overnight at room temperature.

The reaction mixture is cyclized with 10% HCl and extracted with EtOAc. The EtOAc layer is dried over magnesium sulfate and the solvent is evaporated. The crude product is purified by column chromatography (EtOAc) to give the title compound, as a white foamy solid. ESI + MS: m / z 525, 523 (M + + H).

EXAMPLE 37 PREPARATION OF N-HIDR0XI-1N- (4-BROMOFENIL) SULFONIL-4N- (BENZOXICARBONIL) -PIPERAZIN-2 -CARBOXYAMIDE 37a. - Methyl (4-bromophenyl) sulfonyl-4N- (benzoxycarbonyl) -piperazine-2-carboxylate To a solution of 1.5 g (3.75 mmol) of the methyl ester, the hydrochloride of INN- [(4-bromophenyl) sulfonyl]] -piperazine-2-carboxylic acid 35b, 2.6 ml (18.7 mmol) of triethylamine and 45 mg (0.37 mmol) of DMAP in 10 ml of methylene chloride, 0.85 ml (5.62 mmol) of benzyl chloroformate are added dropwise to the room temperature. The reaction is diluted with IN HCl and extracted with 3 x 50 mL EtOAc. The EtOAc layer is washed with IN HCl, with water, with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography (hexane / EtOAc, 7: 3 to 6: 4) to give the title compound. ESI + MS: m / z 516, 514 (M + + NH 4), 499, 497 (M + + H). 37b, N-hydroxy-lN- (4-bromophenyl) sulfonyl-4N- (benzoxycarbonyl) -piperazin-2-carboxyamide. 1.25 g (2.35 mmol) of the methyl ester 37a is mixed with 6.6 ml (9.2 mmol) of a 1.5 M solution of NH2OK in methanol (prepared as described in Fieser and Fieser, volume 1, page 478) and stirred overnight at room temperature. The reaction mixture is acidified with 10% HCl and extracted with EtOAc. The EtOAc layer is dried over magnesium sulfate and the solvent is evaporated. The crude product is purified by column chromatography (EtOAc / hexane 1: 1) to give the title compound, as a white foamy solid. ESI + MS: m / z 517, 515 (M + + NH 4), 500, 498 (M + + H).

EXAMPLE 38 PREPARATION OF N-HYDROXY-1N- (4-BROMOFENYL) SULFONYL-4N- t (S) - (+) - 2-HYDROXY-3-METHYL-BUTIRIL] -PIPERAZIN-2 -CARBOXYAMIDE 38a. - Methyl (N-methoxyphenyl) sulfonyl-4N- [(S) - (+) -2-hydroxy-3-methyl-butyryl] piperazine-2-carboxylate. 2 g (5.7 mmol) of the methyl ester are mixed. 1N- [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid hydrochloride lb, 1.0 g (8.5 mmol) of (S) - (+) - 2-hydroxy-3-methylbutyric acid, 2.3 g (17.1 mmol) ) of 1-hydroxybenzotriazole hydrate, 1.4 g (7.4 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide in 15 ml of DMF and 2.2 ml (20 mmol) of N-methylmorpholine at 0 ° C, and stirred for 17 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is washed with IN HCl, with water, with INN NaOH and with brine, dried over magnesium sulfate, filtered and evaporated to give an oil which is chromatographed on flash silica with EtOAc to give the desired product. ESI + MS: m / z 415 (M + + H). 38b. - 1-Hydroxy-lN- (4-bromophenyl) sulfonyl-4N- [(S) - (+) - 2-hydroxy-3-methyl-butyryl] piperazine-2-carboxyamide 1.6 g (3.8 mmol) of the ester is mixed methyl 38a with . 8 ml (15.2 mmol) of a 1.5 M solution of NH2OK in methanol and stir overnight at room temperature. The reaction mixture is acidified with 10% HCl and extracted with 3 x 50 ml of EtOAc. The EtOAc layer is dried over magnesium sulfate and the solvent is evaporated. The crude product is purified by column chromatography (EtOAc / 5% methanol) to give the title compound, as a white foamy solid. ESI + MS: m / z 433 (M + +? H4), 416 (M + + H).

EXAMPLE 39 The following compounds are prepared in a similar manner to Example 1. 39a. N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -4- (3-trifluoromethyl-benzenesulfonyl) -piperazine-2-carboxyamide, MS (ESI) 524 (M + H +). 39b. N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -4- (3,4-dimethoxy-benzoyl) -piperazine-2-carboxyamide, MS (ESI) 480 (M + H +), 502 (M + Na +) . 39c. N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -4- (1-methyl-lH-imidazole-4-sulfonyl) -piperazine-2-carboxyamide, MS (ESI) 460 (M + H '). 39d. N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -4- (2-methoxyacetyl) -1-piperazin-2-carboxyamide, MS (ESI) 388 (M + H +), 410 (M + Na +). 39f. N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -4- (benzo [2.1.3] thia-diazole-4-sulfonyl) -piperazine-2-carboxyamide, MS (ESI) 514 (M + H +), 531 (M + NH 4 +). 39g. N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -4- (4-i-propylphenyl) aminocarbonyl) -piperazin-2-carboxyamide, MS (ESI) 477 (M + H +). 39h N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -4- (4 '-octyloxy-4-biphenylcarbonyl) -piperazin-2-carboxyamide, MS (ESI) 625 (M + H +), 642 (M + NH4 + ).

EXAMPLE 40 PREPARATION OF N-HYDROXY-1,4-DI- [(4-METOXYPENYL) SULFONYL] -PIPERAZIN-2 -CARBOXYAMIDE 40a.- 1,4-di [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid To a solution of 2 g (9.85 mmol) of piperazin-2-carboxylic acid dihydrochloride in 10 ml of p-dioxane and 10 ml of water, 9.6 ml (69 mmol) of triethylamine and 0.12 g (1 mmol) of DMAP are added, followed by 5.09 g (24.6 mmol) of 4-methoxyphenylsulfonyl chloride, the resulting mixture is stirred overnight at room temperature and then concentrated under reduced pressure. The residue is partitioned between EtOAc and 1N HCl. The EtOAc layer is washed with 2 x 100 ml of IN HCl, with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound, as a solid. CI + MS: m / z 488 (M + + NH 4), 471 (M + + H). 40b. 1,4-di [(4-methoxyphenyl) sulfonyl] -piperazin-2-carboxyamide To a solution of 0.8 ml (8.5 mmol) of oxalyl chloride in 10 ml of methylene chloride and 0.7 ml of DMF, a l, 4-Di [(4-methoxyphenyl) sulfonyl] -piperazine-2-carboxylic acid solution in 4 ml of DMF, at 0 ° C. After 45 minutes at room temperature the solution at 0 ° C is added dropwise to a mixture of 2.96 g (42.5 mmol) of hydroxylamine hydrochloride and 5.9 ml (42.5 mmol) of triethylamine in 3 ml of water and 16 ml of THF. The reaction is warmed to room temperature and stirred overnight. The reaction mixture is filtered and the organic layer is concentrated under reduced pressure. The residue is dissolved in chloride The mixture is washed with IN HCl, with water, with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (5% EtOAc methanol / EtOAc) to give the title compound, as a solid. MS ion spray: m / z 508 (M + + Na), 503 (M + +? H4), 486 (M + + H).

EXAMPLE 41 PREPARATION OF N-HYDROXY-1- [(4-METOXYPENYL) SULFONYL] -4- (TER-BUTOXICARBONYL) -PIPERAZIN-2 -CARBOXYAMIDE 18 * 1 «41b 25 41A. - 1- [(4-Methoxyphenyl) sulfonyl] -4- (tert-butoxycarbonyl) -piperazine-2-carboxylic acid methyl ester To a solution of 2 g (5.61 mmol) of lN- (4-methoxyphenyl) sulfonyl acid -4N- (tert-butoxycarbonyl) piperazine-2-carboxylic acid in 8 ml of DMF, add 1 g (8.4 mmol) of potassium 5-butoxide at room temperature. After 30 minutes, 0.42 ml (6.73 mmol) of iodomethane is added at 0 ° C, and the reaction is stirred at room temperature overnight. The reaction mixture is quenched with water, partitioned between EtOAc and water. The EtOAc layer is washed with 1N HCl, with fLO? AOH 1 ?, with water and with brine, dried over magnesium sulfate and filtered and concentrated in vacuo. The residue is chromatographed on a silica gel column using hexa.no/EtOAc (4: 1) which produces the title compound as an oil. CI + MS: m / z 432 (M + +? H4), 415 (M + + H). 41b. -? - Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -4- (tert-butoxycarbonyl) -piperazine-2-carboxyamide Take 0.33 g (0.8 mmol) of methyl ester 41a in 1 ml of methanol, with 4 ml (6.8 mmol) of a 1.7 M solution of? H2OK in methanol (prepared as described in Fieser and Fieeer, volume 1, page 478) and stirred for 4 hours. 1.5 ml of silica is added to the mixture and the solvent is evaporated. The dried silica is poured on top of a column of flash silica gel which is subsequently eluted with hexane: EtOAc (4: 1 to 7: 3) to give the desired product as a white foamy solid. MS ion spray: m / z 438 (M + + Na), 433 (M + + NH 4), 416 (M + + H).

EXAMPLE 42 PREPARATION OF THE SALT OF THE TRIFLUOROACTIC ACID OF N-HYDROXY- 1- [(4-METOXYPENYL) SULFONYL] -PIPERAZIN-2-CARBOXYAMIDE 42a.- N-hydroxy-1- (4-methoxyphenyl) sulfonyl-piperazine-2-carboxyamide trifluoroacetic acid To a solution of 95 mg (0.23 mmol) of N-hydroxy-1- [(4-methoxyphenyl) sulfonyl] - 4- (tert-butoxycarbonyl) -piperazine-2-hydroxamic acid 41b in 5 ml of methylene chloride, add 5 ml of trifluoroacetic acid at 0 ° C. The reaction is stirred for 4 hours at room temperature, and then the solvent is removed under reduced pressure. Purify the crude product by flash silica gel column chromatography eluting with methanol / EtOAc (1: 9) to give the desired product as a foamy solid. MS (ES): 338 (M + + Na), 316 (M + + H).

EXAMPLE 43 PREPARATION OF N-HYDROXY-4- [(4-METOXYPENYL) SULFONYL] TIOMORFOLIN-3 -CARBOXYAMIDE I 43b 43c 43a.- Tiomorpholin-3-ethyl carboxylate. 10.1 g (38.8 mmol) of ethyl dibromopropionate in 100 ml of THF are stirred at room temperature and then 16.3 ml (116.7 mmol, 3 equivalents) of triethylamine are slowly added. The resulting heterogeneous solution is stirred at room temperature and then 3.0 g (38.8 mmol) of cysteamine is added. 50 ml of ethanol is added and the resulting mixture is heated at reflux for 12 hours. The reaction mixture is cooled to room temperature and then the solvent is removed to leave a yellow solid. The solid is dissolved in water and extracted with methylene chloride. Dry the combined organic extracts over sodium sulfate and concentrate them to an oil under reduced pressure. No further purification is attempted. 43b, - [(4-methoxyphenyl) sulfonyl] -thiomorpholine-3-ethyl carboxylate 6.1 g (34.8 mmol) of ethyl ester 43a and 12.1 ml (87.0 mmol, 2.5 equivalents) of triethylamine in 75 ml are stirred at room temperature. of 1,4-dioxane, and then 7.91 g (38.3 mmol) of 4-methoxybenzenesulfonyl chloride is added. The resulting solution is stirred at room temperature for 4 hours and then the solution is acidified to pH about 1 with IN HCl. The solution is poured into water and then extracted with methylene chloride. The organic extracts are dried over sodium sulfate and concentrated in an oil. The oil is purified by chromatography using 8/2 hexane / EtOAc as eluent, to give the desired product as a colorless oil.43c, - l-Hydroxy-4- [(4-methoxyphenyl) sulfonyl] -thiomorpholine-3-carboxyamide 0.5 g (1.45 mmol) of sulfonamide 43b are stirred at room temperature in 10 ml of methanol and then 3.3 ml is added (2.90 mmol, 2 equivalents) of a 0.868 M solution of KONH2 in methanol. The resulting solution is stirred at room temperature for 24 hours and then acidified to pH about 2 with 1N HCl. The solution is poured into water and then extracted with methylene chloride. The organic extracts are dried over sodium sulfate and concentrated to a white solid under reduced pressure to give the desired hydroxamic acid. Purification of the solid is achieved by recrystallization from EtOAc / hexane (1 / L) to give the title compound. MS (ESI): 355 (M + + NH 4), 333 (M + + H).

EXAMPLE 44 N-HYDROXY-4- [(4-METOXYPENYL) SULFONYL] -TIOMORFOLIN-S-OX DO-3 -10 CARBOXYAMIDE 44a. - N-hydroxy-4- [(4-methoxyphenyl) sulfonyl] -thiomarpholin-S-oxide-3-carboxyamide. At room temperature, 0.5 g (1.5 mmol) is stirred. of hydroxamic acid 43c in 50 ml of chloroform and then stirred at room temperature and slowly added 0.4 g. (1.50 mmol) of m-chloroperbenzoic acid. The resulting homogeneous solution is stirred at room temperature for 1 hour and then concentrated to a white solid. The Purification of the solid by chromatography (HPLC preparatory reversed phase, using column 40 x 100 mm Waters Nova-Pak C18) and 85/15 water / acetonitrile, as eluent). MS (ESI): 386 (M +? A +), 365 (M + H +).

EXAMPLE 45? -H: CDR0XI-4- [(4-METOXIFE? L) SULFO? IL] -TIOMORFOLI? -S, S-DIOXIDE- 3-CARBOXYAMIDE 46a 45a. -? - Hydroxy-4- [(4-methoxyphenyl) sulfonyl] -thiomorpholin-S, S-dioxide-3-carboxyamide 0.5 g (1.5 mmol) of the hydroxamic acid 43c is stirred at room temperature in 50 ml of chloroform, and 0.86 g (3.01 mmol, 2 equivalents) of m-chloroperbenzoic acid is slowly added. The homogeneous solution is stirred at room temperature for 1 hour and then concentrated to a white solid. Purification of the solid is achieved by reverse phase preparative HPLC chromatography (40 x 100 mm Waters? Ova-Pak C18 column) and 85/15 water / acetonitrile, as eluent. MS (ESI): 386 (M + Na +), 365 (M + H +).

EXAMPLE 46 The following compound is prepared in a manner similar to Example 45. N-Hydroxy-4- [(4-methoxyphenyl) sulfonyl] -2,2-dimethylthiomorpholin-S, S-dioxide-3-carboxyamide EXAMPLE 47 3- (S) -N-HYDROXY-2,2-DIMETHYL-4- [(4-METOXYPENYL) SULFONYL] - TIOMORFOLIN-3 -CARBOXYAMIDE 47a. - N- [(4-methoxyphenyl) sulfonyl] -S- (2-hydroxyethyl) -D-penicillamine methyl. It is stirred at 0 ° C, under an argon atmosphere, 14.9 g (0.1 mol) of D-penicillamine in 65 ml. (0.13 mmol, 1.3 equivalents) of 2N sodium hydroxide. Slowly add, at 0 ° C, 15 g (0.12 mol, 1.2 equivalents) of 2-bromopropanol in 100 ml of ethanol. The resulting solution is stirred overnight at room temperature and the mixture is acidified to pH around 6 with 1N HCl. The solvent is removed under reduced pressure to leave a thick oil. The penicillamine adduct is then dissolved in 200 ml of dioxane and 200 ml of water, and stirred at room temperature. 29.8 g (0.295 mol, 3 equivalents) of triethylamine are then added to the reaction mixture, and then 22.3 g (0.108 mol, 1.1 equivalents) of 4- (flf-methoxybenzenesulfonyl chloride.) The resulting homogeneous solution is stirred to the The solution is poured into water and extracted with methylene chloride, and the organic extracts are dried over magnesium sulfate and dried at room temperature for 18 hours, then the pH is adjusted to about 2 with 1 HCl. concentrate to an oil under reduced pressure. The resulting oil is diluted in 30 ml of methanol and sufficient diazomethane in diethyl ether is added to form a yellow solution. The mixture is concentrated under reduced pressure to leave a colorless oil. The purification of the methyl ester The resulting 20 is achieved by chromatography on silica gel using 1/1 hexane / EtOAc as eluent. The desired product is obtained as a clear, colorless oil. 47b. Methyl 4 - [(4-methoxyphenyl) sulfonyl] -2,2-dimethylthiomorpholin-3-carboxylic acid 10.8 g (28.6 mmol) of the methyl ester 47a are stirred at room temperature in 200 ml of THF, and then stirred at room temperature. add 9.0 g (34.3 mmol, 1.2 equivalents) of triphenylphosphine, followed by 5.48 g (31.5 mmol, 1.1 equivalents) of diethyl azodicarboxylate. The resulting solution is stirred at room temperature for 2 hours. The solvent is removed and then the thick yellow oil is diluted with methylene chloride and 30 g of silica gel is added. The solvent is removed to leave a white powder. This powder is placed on a chromatography column and eluted with 8/2 hexane / EtOAc. The desired product is obtained as a colorless oil. MS (ESI): 360 (M + + H), 377 (M + + NH 4). 47- 4- [(4-Methoxyphenyl) sulfonyl] -2,2-dimethylthiomorpholine-3-carboxylic acid 9.5 g (26.4 mmol) of the methyl ester 47b in 150 ml of pyridine is stirred at room temperature under argon atmosphere. 42.4 g (317 mmol, 12 equivalents) of lithium iodide are added and the resulting solution is heated at reflux for 3 hours. The reaction mixture is cooled to room temperature and then the solution is acidified with IN HCl. The mixture is extracted with methylene chloride and then the organic extracts are dried over sodium sulfate and concentrated to an oil under reduced pressure. The oil is purified by column chromatography using 1 μl of hexane / EtOAc as eluent, to give the desired product as a pale yellow oil. MS (ESI): 346 (M + + H), 363 (M + + NH 4) 47d. - N-Hydroxy-4- [(4-methoxyphenyl) sulfonyl] -2,2-dimethylthio-or olin-3-carboxyamide 4.1 g (11.8 mmol) of the carboxylic acid 47c are stirred at room temperature in 50 ml of dichloromethane and then 3.09 g (24.3 mmol, 2.05 equivalents) of oxalyl chloride and 0.87 g (11.8 mmol) of DMF are added. The resulting solution is stirred at room temperature for 30 minutes. Into a separate flask, 3.3 g (47.5 mmol, 4 equivalent) of hydroxylamine hydrochloride in 50 ml of THF and 10 ml of water are stirred at 0 ° C. 7.16 g (70.8 mmol, 6 equivalents) of triethylamine are added and stir the resulting solution at 0 ° C for 15 minutes. The acid chloride solution is then added to the hydroxylamine solution at 0 ° C, and the resulting mixture is allowed to stir overnight at room temperature. The reaction mixture is acidified with IN HCl and then extracted with dichloromethane. The organic extracts are dried over sodium sulfate and concentrated to a solid under reduced pressure. The solid is recrystallized from acetonitrile / water to give a white powder. MS (ESI): 378 (M + + NH 4), 361 (M + + H).

EXAMPLE 48 N-HYDROXY-1- [(4-METOXYPENYL) SULFONYL] -4- [4- (4-BROMOFENYL) -2- TIAZOLYL] -PIPERAZIN-2-CARBOXYAMIDE 48a. Methyl 1- [(4-methoxyl) sulfonyl] -4- [4- (4-bromophenyl) -2-thiazolyl] -piperazin-2-carboxylate is added to 300 mg (0.86 mmol) of l - [( Methyl 4-methoxyphenyl) sulfonyl] -piperazin-2-carboxylate lb in 50 ml of ethyl alcohol, 220 mg (0.86 mmol) of 4-bromotenacyl thiocyanate and 0.05 ml (0.87 mmol) of acetic acid. The reaction is stirred for 6 hours at room temperature and then triethylamine is added to neutralize the mixture. The ethyl alcohol is removed under reduced pressure. The resulting residue is taken up in 250 ml of diethyl ether and this mixture is washed three times with water. The organic extract is dried over sodium sulfate and concentrated to give the desired product as a light yellow solid, m.p. 68-70 ° C. 48b. - N-hydroxy-1- [(4-methoxyphenyl) sulfonyl] -4- [4- (4-bromophenyl) -2-thiazolyl] -piperazine-2-carboxyamide. It is stirred for 16 hours at room temperature 121 mg (0.22 g. mmol) of the methyl ester 48a in 1.0 ml (1.76 mmol) of a 1.76 M solution of KONH2 in methyl alcohol. The resulting solution is neutralized with ÍM HCl. The volatiles are removed under reduced pressure and the product is purified by chromatography using 7/3 ethyl acetate / hexane, as eluent to give the desired hydroxamic acid as a tan solid. MS (ESI): 553, 555 (M + + H), 575, 577 (M + + Na).

EXAMPLE 49 PREPARATION OF N-HYDROXY-4N-C (4-METOXYPENYL) SULFONYL] -MORFOLIN-3-CARBOXYAMIDE 49a.- Methyl N- [(phenylmethoxy) carbonyl] -aziridine-2-carboxylate. 5.0 g (49.4 mmol) of methyl aziridine-2-carboxylate in 6.87 ml (49.4 mmol) of triethylamine are stirred at 0 [deg.] C. 100 ml of chloroform, in an ice bath, and then 6.30 ml (44.5 mmol) of carbomethoxybenzyl chloride is added. The resulting solution is stirred at room temperature overnight. The resulting solution is washed with 10% citric acid, saturated sodium bicarbonate and water. The organic layer is dried over sodium sulfate and concentrated to an oil. The oil is purified by silica gel column chromatography using 5/1 hexane / ethyl acetate as eluent to give the desired product. MS (ESI): 236 (M + H +), 253 (M + NH 3 +). 49b.- N- [(phenylmethoxy) carbonyl] -O- (2-chloroethyl) serine methyl ester 5.0 g (21.3 mmol) of the 49th methyl ester is dissolved in 50 ml of chloroform, and then 13.7 g (205.6 mmol) is added. ) of 2-chloroethanol and 15 drops of BF3"OEt2 at room temperature.The resulting solution is added overnight.The reaction mixture is washed with water several times and the combined organic extracts are dried over sodium sulfate and they are concentrated to an oil under reduced pressure The oil is purified by silica gel column chromatography using 4/1 hexane / ethyl acetate as eluent to give the desired product MS (ESI): 316, 318 ( M + + H), 333, 335 (M + + NH 4). 49- O- (2-Chloroethyl) serine methyl ester 3.8 g (12.1 mmol) of the protected methyl ester 49b is dissolved in 40 ml of methanol and hydrogenated on a paddy's black (5% by weight) with a flask. of hydrogen during the night. The mixture is filtered through celite and concentrated to an oil under reduced pressure. The residue is taken to the next step without further purification. MS (ESI): 182, 184 (M + + H). 49d.- methyl morpholine-3-carboxylate. 2.1 g (11.6 mmol) of the free methyl ester-amine 49c and 3.2 ml, 23.2 mmol) of triethylamine in 120 ml of methanol are stirred at room temperature. The reaction is then heated to reflux at 65 ° C and stirred overnight. The reaction mixture is cooled to room temperature and concentrated under reduced pressure to form a solid containing some triethylamine salts. The mixture is taken to the next step without further purification. MS (ESI): 146 (M + + H). 49e.- Methyl 4 - [(4-methoxyphenyl) sulfonyl] -morpholin-3-carboxylate. 1.68 g (11.6 mmol) of methyl ester 49d and 3.22 ml (23.2 mmol) of triethylamine are stirred at room temperature at room temperature. 1,4-dioxane and 15 ml of water; then 2.87 g is added (13.9 mmol) of 4-methoxyphenylsulfonyl chloride, The resulting solution is stirred at room temperature overnight, and then the solution is acidified to pH about 1 with HCl IN. The solution is poured into water and then extracted with methylene chloride. Dry the organic extracts over sodium sulfate and concentrate to an oil. The oil is purified by chromatography using 5/1 hexane / EtOAc as eluent, to produce the desired product as a colorless oil. 49f.- N-Hydroxy-4N- [(4-methoxyphenyl) sulfonyl] -morpholine-3-carboxyamide. 1.0 g (3.17 mmol) of methyl ester 49e is dissolved in 3 ml of methanol, and then 8 equivalents of a solution are added. 1.76 M of potassium hydroxylamine. The mixture is stirred to. Room temperature overnight and then acidified to pE around 2 with IN HCl. The solution is poured into water and extracted with ethyl acetate. The organic extracts are dried over magnesium sulfate and concentrated under reduced pressure to an oil. The oil is purified by reverse phase HPLC using 65% (95% water, 5% acetonitrile, 1% formic acid) and 35% (80% acetonitrile, 20% water) to produce a white solid. , crystalline. MS (ESI): 317 (M + + H), 334 (M + + NH 4).

EXAMPLE 50 PREPARATION OF 3 (S) -N-HYDROXY-2, 2-DIMETHYL-4N- [(4-PHENOXYPENYL) SULFONYLl-THIOMORFOLIN-3-CARBOXYAMIDE BropDetapol? < O NaOH 2 > CHIN? Mßo- NH 50a 50b 50c SM 50a.- N- (4-methoxybenzenesulfonyl) -S- (2-hydroxyethyl) -D-penicillamine methyl. It is stirred at 0 ° C under an argon atmosphere, 3.0 g (20.1 mmol) of D-penicillamine in 14.1 ml (28.1 mmol). , 1.4 equivalents) of 2N NaOH. A solution of 3.30 g (26.1 mmol, 1.3 equivalents) of 2-brorr.opropanol in 20 ml of ethanol is slowly added dropwise at 0 ° C. The resulting solution is stirred overnight at room temperature, and then the mixture is acidified to pH about 6 with IN HCl. The solvent is removed under reduced pressure to leave a thick oil. The penicillamine adduct is then dissolved in 25 ml of dioxane and 25 ml of water and stirred at room temperature. Then 6.1 g (60.3 mmol, 3 equivalents) of triethylamine was added to the reaction mixture, followed by 5.4 g (20.1 mmol, 1.0 equivalent, Ref: Cremlyn and co-authors, Aust. J. Chem, 1979, 32, 445-52 ) of 4-phenoxyphenylsulfonyl chloride. The resulting solution is stirred at room temperature for 18 hours and then acidified to pH about 2 with IN HCl. The solution was poured into water and extracted with methylene chloride. The organic extracts were dried over magnesium sulfate and concentrated to an oil under reduced pressure. The resulting oil was diluted in 15 ml of methanol and sufficient diazomethane in diethyl ether was added to form a yellow solution. The mixture was concentrated under reduced pressure to give a colorless oil. Purification of the resulting metal ester was obtained by chromatography on silica gel using 7/3 hexane / EtOAc as eluent. The desired product was obtained as a clear, colorless oil. 50b, 2,2-dimethyl-4N- [(4-phenoxyphenyl) sulfonyl] -thiomorpholine-3-carboxylic acid methyl ester. 4.5 g (10.2 mmol) of the methyl ester in 50 ml of THF were stirred at room temperature. 3.22 g was added (12.3 mmol, 1.2 equivalent) of triphenylphosphine followed by 1. 96 g (11.3 mmol, 1.1 equivalent) of diethyl azodicarboxylate. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed and then the yellow oil was diluted with methylene chloride, and 20 g of silica gel was added. The solvent was removed to give a white powder. This powder was placed on a chromatography column and eluted with 8/2 hexane / EtOAc. The desired product was obtained as a colorless oil. 50- 2, 2-dimethyl-4N- [(4-phenoxyphenyl) sulfonyl] -thiomorpholin-3-carboxylic acid. 3.4 g (8.06 mmol) of the methyl ester in 50 ml of pyridine was stirred at room temperature under argon atmosphere . 12.9 g (96.7 mmol, 2 equivalents) of lithium iodide was added and the resulting solution was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and then the solution was acidified with IN HCl. The mixture was extracted with methylene chloride and then the organic extracts were dried over sodium sulfate and concentrated to an oil under reduced pressure. The oil was purified by column chromatography using 1 μl of hexane / EtOAc as eluent, to give the desired product as a light yellow oil. MS (ESI): 408 (M + + H), 425 (M + +? H4), 430 (M + + Na). 50d.-? -Hydroxy-2,2-dimethyl-4? - [(4-phenoxyphenyl) sulfonyl] thiomorpholine-3-carboxyamide 1.25 g (3.06 mmol) of the carboxylic acid was stirred at room temperature in 20 ml of acetonitrile and then 0.77 g (6.12 mmol, 2.05 equivalents) of oxalyl chloride and 0.22 g (3.06 mmol) of DMF were added. The resulting solution was stirred at room temperature for 30 minutes. Into a separate flask was stirred 0.85 g (12.24 mmol, 4 equivalents) of hydroxylamine hydrochloride in 15 ml of THF and 3 ml of water at 0 ° C. 1.85 g (18.4 mmol, 6 equivalents) of triethylamine was added and the resulting solution was stirred at 0 ° C for 15 minutes. Then the acid chloride solution was added to the hydroxylamine solution at 0 ° C, and the resulting mixture was allowed to stir overnight at room temperature. The reaction mixture was then acidified with IN HCl and extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated to a solid under reduced pressure. The solid was recrystallized from acetonitrile to give the title compound as a white powder. MS (ESI): 423 (M + + H), 440 (M + + NH 4), 445 (M + + Na). These examples give those skilled in the art sufficient guidance to prepare the present invention, and are not limitations in any way.COMPOSITION AND METHOD OF EXAMPLES OF USE The compounds of the invention are useful for preparing compositions for the treatment of diseases and the like. The following examples of composition and method do not limit the invention, but rather give guidance to those skilled in the art to prepare and use the compounds, compositions and methods of the invention. In each case, the compound of the example shown below can be replaced with the compounds of the formula I, with similar results. The exemplified methods of use do not limit the invention but give a guide for the person skilled in the art to use compounds, compositions and methods of the invention, who have practice in the art will appreciate that the examples give guidelines and that they can be varied based on in the condition and in the patient.

IFCLO EXAMPLE A A tablet composition for oral administration is prepared according to the present invention, comprising: Component Quantity Example 9 15 mg Lactose 20 mg Corn starch 70 mg Talc 4 mg 20 Magnesium stearate 1 mg Other compounds having a Structure according to formula (I), with substantially similar results. It is a 60 kg female human subject, who suffers from rheumatoid arthritis, by a method of this invention. Specifically, this subject is administered, for 2 years, a regimen of three tablets a day. At the end of the treatment period, the patient is examined and found to have reduced inflammation and improved mobility, without concomitant pain.

EXAMPLE B A capsule for oral administration is prepared, according to the present invention, comprising. Component Quantity (% by weight / weight) Example 3 15% Polyethylene glycol 85% Other compounds having an acid structure to formula (I) are used, with substantially similar results. It is a male human subject weighing 90 kg who suffers from osteoarthritis, by a method of this invention. Specifically, this subject is administered, for 5 years, a capsule containing 70 mg of Example 3. At the end of the treatment period the patient is examined with orthoscopy and it is found that there is no further advance in the erosion / fibrillation of the articular cartilage .

EXAMPLE C A salt-based composition is prepared for local administration, according to the present invention, comprising: Component Quantity (% by weight / weight) Example 12 5% 5 Polyvinyl alcohol 15% Saline 80% Other compounds having a structure are used according to formula (I), with substantially similar results. He applies a drop to each eye of a patient who has deep corneal abrasion, twice a day. The healing is accelerated, without visual sequels.

EXAMPLE D A topical composition for local administration is prepared according to the present invention, which comprises: Component Quantity (% by weight / vol.) Compound of Example 3 0.20 20 Benzalkonium Chloride 0.02 Thimerosal 0.002 d-Scrbitol 5.00 Glycine 0.35 Aromatics 0.075 25 Purified water q.s. Total = 100.00 Total = 100.00 Any other compound having a structure according to formula (I) is used, with substantially similar results. It applies to a patient suffering from chemical burns the composition in each change of bandages (2 times a day). The formation of a scar is substantially reduced.

EXAMPLE E An aerosol composition for inhalation is prepared, according to the present invention, comprising: Component Quantity (% by weight / vol.) Compound of example 2 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 Saccharin sodium 0.2 Propellant (F12, F114) cs Total = 100.00 Any other compound having a structure according to formula (I) is used, with substantially similar results. A patient suffering from asthma is sprayed with 0.01 ml by means of a pump actuator in the mouth, while inhaling. The symptoms of asthma are reduced.

EXAMPLE F A topical ophthalmic composition according to the present invention is prepared, comprising: Component Quantity (% by weight / vol.) Compound of Example 5 0.10 Benzalkonium Chloride 0.01 EDTA 0.05 Hydroxyethylcellulose (NATROSOL MMR) 0.50 Sodium Metabisulfite 0.10 Sodium Chloride (0.9%) q.s. Total = 100.00 Any other compound having a structure according to formula (I) is used, with substantially similar results. It is a male human subject weighing 90 kg, suffering from corneal ulcerations, by a method of this invention. Specifically, said subject is administered, for 2 months, a saline solution containing 10 mg of Example 5, twice a day. in the affected eye.

EXAMPLE G A composition for parenteral administration is prepared, comprising: Component Quantity Example 4 100 mg / ml carrier Carrier Regulator sodium citrate with (poi: weight percent carrier) Lecithin 0.48% Carboxymethylcellulose 0.53 Povidone 0.50 Meti lparaben 0.11 Propylparaben 0.011 Mix the above ingredients forming a suspension. Approximately 2.0 ml of the suspension is administered by injection to a human subject with a pre-etatic tumor. The site of the injection is juxtaposed with the tumcr. This dosage is repeated twice a day for approximately 30 days. After 30 days the symptoms of age cease and the dose is gradually decreased to maintain the patient. Other compounds having a structure according to formula (I) are used, substantially with similar results.

EXAMPLE H A mouthwash composition is prepared: Component (% by weight / volume) Extract 1 3.00 Alcohol SDA 40 8.00 Flavor 0.08 Emulsifier 0.08 Sodium fluoride 0.05 Glycerin 10.00 Sweetener 0.02 Benzoic acid 0.05 Sodium hydroxide 0.20 Dye 0.04 Water remaining up to 100% A patient with gum disease uses 1 ml of mouthwash three times a day to prevent further oral degeneration. Other compounds having a structure according to formula (I) are used, substantially with similar results.

EXAMPLE I A troche composition is prepared: Component (% by weight / volume) Example 3 0.01 Sorbitol 17.50 Mannitol 17.50 Alm: .don 13.60 Sweetener 1.20 Flavor 11.70 Color 0.10 Corn syrup rest up to 100% One patient uses the trocus to prevent loosening an implant in the maxilla. Other compounds having a structure according to formula (I) are used, substantially with similar results.

EXAMPLE J RUBBER COMPOSITION FOR MASCAR Component (% by weight / volume) Example 1 0.03 Sorbitol crystals 38.44 Paloja-T gum base 20.00 Sorbitol (70% aqueous solution) 22.00 Mannitol 10.00 Glycerin 7.56 Flavor 1.00 A patient chews the gum for prevent loosening of the denture. Other compounds having a structure according to formula (I) are used, substantially with similar results.

EXAMPLE K Component (% by weight / volume) Example 1 2.00 Water. USP 54.656 Methylparaben 0.05 Propylparaben 0.01 Xanthan gum 0.12 Guar gum 0.09 Calcium carbonate 12.38 Defoamer 1.27 Sucrose 15.0 Sorbitol 11.0 Glycerin 5.0 Benzyl alcohol 0.2 Citric acid 0.15 Cooler 0.00888 Flavor 0.0645 Colorant 0.0014 Prepare example K by first mixing 80 kg of glycerin and the totality of the benzyl alcohol and heating to 65 ° C; then methylparaben, propylparaben, water, xanthan gum and guar gum are added slowly and mixed together. Mix these ingredients for about 12 minutes with a Silverson in-line mixer. The following ingredients are slowly mixed in the following order: the rest of the glycerin, sorbitol, antifoam C, calcium carbonate, citric acid and sucrose. Flavors and chillers are combined separately and then added slowly to the other ingredients. Mix for about 40 minutes. 5 The patient takes the formulation to prevent the colitis from widening. All references described herein are incorporated herein by reference. Although it has been described particular modalities of theThe present invention will be obvious to those skilled in the art. - that various changes and modifications can be made to the present invention without departing from the spirit and scope thereof. It is intended to protect, in the appended claims, all modifications that are within the scope of this invention.

Claims (30)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound characterized in that it has a structure according to formula (I): (I) where: Ri is H; R2 is hydrogen, alkyl or acyl; Ar is COR3 or SO2R4; and R3 is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; R 4 is alkyl, heteroalkyl, aryl or heteroaryl, substituted or unsubstituted; X is O, S, SO, SO2 or NR5, wherein R5 is independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2 6 / COR7, CSRg, PO (Rg) 2 / or can optionally form a ring with W; and Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R7 is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diamine; and alkylarylamino; R9 is alkyl, aryl, heteroaryl, heteroalkyl; is hydrogen or one or more lower alkyl portions, or is an alkylene, arylene or heteroarylene bridge between two adjacent or non-adjacent carbon atoms (thereby forming a molten ring); Y is independently one or more of hydrogen, hydroxy, SR Q, SOR4, SO2 4, alkoxy, amino, where amino is of the formula RnRi2 / wherein Rn and R? 2 are independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2 6 COR7, CSRg, P0 (Rg) 2; and io is hydrogen, alkyl, aryl, • LO heteroaryl; Z is nothing, a spiro portion or an oxo group substituted on the heterocyclic ring.

This structure also includes an optical isomer, diastereomer or enantiomer for the formula (I), or a pharmaceutically acceptable salt, or an amide, an ester or an imide thereof, biohydrolyzable. 15 2. - The compound in accordance with the claim 1, further characterized in that X is O, S, SO, SO2 or NR5, where R5 is independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2 7, CORg, CSRg.

3. - The compound in accordance with the claim 20 1, further characterized in that Ar is SÜ2 4 and R4 is alkyl, heteroalkyl, aryl or heteroaryl, substituted or unsubstituted.

4. The compound according to claim 1, further characterized in that Ar is phenyl or substituted phenyl.

5. The compound in accordance with the claim 4, further characterized in that Ar is substituted phenyl and the substitution is with hydroxy, alkoxy, nitro or halogen.

6.- The compound in accordance with the claim 5, further characterized in that Ar is substituted with methoxy, bromine, nitro and butoxy.

7. - The compound in accordance with the claim 6, further characterized in that Ar is substituted in the ortho or para position with respect to the sulfonyl.

8. The compound according to claim 1, further characterized in that W is one or more of hydrogen or alkyl of 1 to 4 carbon atoms.

9. The compound according to claim 1, further characterized in that W is alkyl of 1 to 4 geminal carbon atoms.

10. The compound according to claim 1, further characterized in that Z is an oxo substituted portion in the heterocyclic ring.

11. A pharmaceutical composition, characterized in that it comprises: (a) a safe and effective amount of a compound of claim 1; and (b) a pharmaceutically acceptable carrier.

12. A pharmaceutical composition, characterized in that it comprises: (a) a safe and effective amount of a compound of claim 4; and (b) a pharmaceutically acceptable carrier.

13. A pharmaceutical composition, characterized in that it comprises: (a) a safe and effective amount of a compound of claim 5; and (b) a pharmaceutically acceptable carrier.

14. A pharmaceutical composition, characterized in that it comprises: (a) a safe and effective amount of a compound of claim 9; and (b) a pharmaceutically acceptable carrier.

15. A pharmaceutical composition, characterized in that it comprises: (a) a safe and effective amount of a compound of claim 10; and (b) a pharmaceutically acceptable carrier.

16. The use of a compound of claim 1, for the preparation of a medicament for preventing or treating a disease associated with the undesirable activity of meth = .loprotease in a mammalian subject.

17. The use of a compound of claim 4 for the preparation of a medicament for preventing or treating a disease associated with undesirable metalloprotease activity in a mammalian subject.

18. The use of a compound of claim 5 for the preparation of a medicament for preventing or treating a disease associated with undesirable metalloprotease activity in a mammalian subject.

19. The use of a compound of claim 9, for the preparation of a medicament for preventing or treating a disease associated with undesirable metalloprotease activity in a mammalian subject.

20. The use of a metalloprotease inhibitor according to claim 1 for the preparation of a medicament for preventing or treating a disorder modulated by metalloproteases in a mammal, wherein the disorder is selected from the group comprising arthritis, cancer, cardiovascular disorders, cutaneous disorders, eye disorders, inflammation and gum disease, in a mammal.

21. The use according to claim 20, further characterized in that the disorder is arthritis and is selected from the group comprising osteoarthritis and rheumatoid arthritis.

22. The use according to claim 20, further characterized in that the disorder is cancer and the treatment prevents or stops tumor growth and metastasis.

23. The use according to claim 20, further characterized in that the disorder is a cardiovascular disorder selected from the group comprising dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion damage, ischemia, chronic obstructive pulmonary disease, restenosis due to angioplasty and aneurysm of the aorta.

24. The use according to claim 20, further characterized in that the disorder is an ocular disorder, and is selected from the group comprising corneal ulcerations, lack of corneal scarring, macular degeneration and pterygium.

25. The use according to claim 20, further characterized in that the disorder is a disease of the gums and is selected from the group comprising periodontal diseases and gingivitis.

26. The use according to claim 20, further characterized in that the condition is a cutaneous condition selected from the group comprising repair and prevention of wrinkles, skin damage by ultraviolet radiation, epidermolysis bullosa, psoriasis, sclerodema, atopic dermatitis and scars.

27. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a medicament for preventing loosening of prosthetic devices selected from the group comprising joint replacements and dental prostheses in a mammal.

28. The use according to claim 20, further characterized by the disease is selected from the group comprising inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, inflammation of acne, osteomyelitis, bronchitis, arthritis, asthma.

29. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a medicament for treating multiple sclerosis in a mammal.

30. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a medicament for treating musculoskeletal diseases or cachexia in a mammal.