ES2365731T3 - HYDROXAMIC ACID DERIVATIVES AS METALOPROTEINASE INHIBITORS. - Google Patents

Abstract

A compound of formula (I) or an enantiomer or diastereomer thereof or a salt, hydrate or solvate thereof: wherein Ar represents an aryl, heteroaryl, C3-C8 cycloalkyl or optionally substituted heterocycloalkyl group; R represents hydrogen or C1-C6 alkyl, or C3-C6 cycloalkyl; Alq represents a divalent C1-C5 alkylene or C2-C5 and R1 and R2 alkenylene radical taken together with the nitrogen atom to which they are attached form a first heterocycloalkyl ring that is optionally fused to a second C3-C8 cycloalkyl or heterocycloalkyl ring, being optionally substituted said first and second ring with at least one group of formula (II): in which m, pyn are independently 0 or 1; Z represents hydrogen or an optionally substituted carbocyclic or heterocyclic ring of 5 to 7 ring atoms that is optionally fused to another optionally substituted carbocyclic or heterocyclic ring of 5 to 7 ring atoms; Alq 1 and Alq 2 independently represent optionally substituted divalent C1-C3 alkylene radicals; X represents -0-, -S-, -S (0) -, -S (02) -, -C (= 0) -, -NH-, -NR3-, -S (02) NH-, -S (02) NR3-, -NHS (02) - or -NR3S (02) -, where R3 is C1-C3 alkyl.

Description

The present invention relates to therapeutically active hydroxamic acid derivatives, processes for their preparation, pharmaceutical compositions containing them and the use of such compounds in medicine. In particular, the compounds are inhibitors of matrix metalloproteinases.

Background of the invention

Matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that can cleave large biomolecules such as collagen, proteoglycans and gelatins. The imbalance between active MMPs and endogenous inhibitors, leads to excessive tissue rupture. The three main groups of MMPs are collagenases, gelatinases and stromelysins. Collagenases include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8) and collagenase 3 (MMP-13). Gelatinases include 72 kDa gelatinase (gelatinase A; MMP-2) and 92 kDa gelatinase (gelatinase B; MMP-9). Stromelysins include stromelysin 1 (MMP-3), stromelysin 2 (MMP-10) and matrilysin (MMP-7). However, there are MMPs that do not fully conform to the above groups, for example metalloelastase (MMP-12), membrane type MMPs (MT-MMP or MMP-14) and stromelysin 3 (MMP-11).

Overexpression and activation of MMPs have been associated with a wide range of diseases such as cancer; rheumatoid arthritis; osteoarthritis; chronic inflammatory disorders, such as asthma, bronchitis and emphysema; cardiovascular disorders, such as atherosclerosis; ulceration of the cornea; dental diseases such as gingivitis and periodontal disease; neurological disorders, such as multiple sclerosis and restenosis. For example, MMP-12 is required for the development of tobacco smoke-induced emphysema in mice, Science, 277, 2002 (1997). The inhibition of MMPs is therefore a strategy for the treatment of such pathological conditions. However, there is evidence that non-selective inhibition of matrix metalloproteinase activity may affect the normal physiological process that leads to dose-limiting side effects. It is believed that selective inhibition of MMP-12 and / or MMP-9 is a particularly relevant strategy for intervention in inflammatory conditions.

Some MMPs can hydrolyse the membrane-bound precursor of tumor necrosis factor α from proinflammatory cytokines (TNF-α). This cleavage produces mature soluble TNF-α and some MMP inhibitors can block TNF-α production both in vitro and in vivo. This pharmacological action probably contributes to the anti-inflammatory action of this class of compounds.

For a recent review of MMP inhibition as reflected in the patent literature, see Doherty et. to the. Therapeutic Developments in Matrix Metalloproteinase Inhibition; Expert Opinions on Therapeutic Patents, 2.002, 12, 665-707.

Many of the prior art MMP inhibitors have a hydroxamic acid metal binding group (-CONHOH). Examples include US Pat. No. 5,703,092, European Patent No. 0684240 and International Patent Application No. 03/070711. none of these last three publications describes selective MMP-12 inhibitors concerning collagenases and stromelysins.

Brief Description of the Invention

The present invention provides a class of compounds that in general are selective MMP-12 inhibitors relating to collagenases and stromelysins. In addition, the compounds of the invention may exhibit selective activity towards MMP-9. The compounds of the invention are therefore indicated for the treatment of diseases mediated primarily by MMP-12 and / or MMP-9, especially inflammatory conditions such as multiple sclerosis and fibrosis.

Detailed description of the invention

According to the invention, there is provided a compound of formula (1) or an enantiomer or diastereomer thereof or a salt, hydrate or solvate thereof:

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in which: Ar represents an aryl, heteroaryl, C3-C8 cycloalkyl or optionally substituted heterocycloalkyl group; R represents hydrogen or C1-C6 alkyl or C3-C6 cycloalkyl; Alq represents a divalent C1-C5 alkylene or C2-C5 alkenylene radical and R1 and R2 taken together with the nitrogen atom to which they are attached form a first heterocycloalkyl ring that

is optionally condensed with a second C3-C8 cycloalkyl or heterocycloalkyl ring, being

optionally substituted said first and second ring with at least one group of formula (II):

image 1

in which

m, p and n are independently 0 or 1;

Z represents hydrogen or an optionally substituted carbocyclic or heterocyclic ring of 5 to 7 ring atoms that is optionally fused to another optionally substituted carbocyclic or heterocyclic ring of 5 to 7 ring atoms;

Alq1 and Alq2 independently represent optionally substituted divalent C1-C3 alkylene radicals;

X represents -0-, -S-, -S (0) -, -S (02) -, -C (= 0) -, -NH-, -NR3-,

-S (02) NH-, -S (02) NR3-, -NHS (02) - or -NR3S (02) -, where R3 is C1-C3 alkyl.

As used herein the term "alkyl (Ca-Cb)" where a and b are whole numbers refer to a straight or branched chain alkyl moiety having carbon atoms, including, for example, methyl, ethyl, n -propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl and n-hexyl, depending on the values of a and

b.

As used herein the term "divalent alkylene radical (Ca-Cb)" where a and b are integers refers to a saturated hydrocarbon chain having a to b carbon atoms and two unsaturated valences.

As used herein the term "alkenyl (Ca-Cb)" where a and b are integers refers to a linear or branched chain alkenyl moiety having carbon atoms with at least one stereochemistry double bond or E or Z where it can be applied. The terminology includes, for example, vinyl, allyl, 1-and 2-butenyl and 2-methyl-2-propenyl, depending on the values of a and b.

As used herein the term "divalent alkenylene radical (Ca-Cb)" refers to a hydrocarbon chain having from a to b carbon atoms, at least one double bond and two unsaturated valences.

As used herein the unqualified terminology "carbocyclyl" or "carbocyclic" refers to a ring

or ring system of 3 to 14 ring atoms that are all carbon and includes "aryl", "cycloalkyl" and "cycloalkenyl" as defined below.

As used herein, the unqualified "cycloalkyl" terminology refers to a saturated alicyclic moiety having 3-8 carbon atoms consisting of a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornil). The preferred cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl and the like.

As used herein, the unqualified "cycloalkenyl" terminology refers to an unsaturated alicyclic moiety having 3-8 carbon atoms and includes, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. In the case of cycloalkenyl rings of 5-8 carbon atoms, the ring may contain more than one double bond.

As used herein the unqualified "aryl" terminology refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring or multiple condensed rings and two monocyclic carbocyclic aromatic groups linked by covalent bonds. Examples of aryl include phenyl, biphenyl and the like.

As used herein the unqualified terminology "heterocyclyl" or "heterocyclic" refers to a ring or ring system whose ring members include one or more heteroatoms selected from O, S, and N and the terminology includes "heteroaryl "and" heterocycloalkyl "as defined below.

As used herein, the unqualified "heterocycloalkyl" terminology refers to a cycloalkyl group as defined above, in which up to 3 ring carbon atoms are replaced by heteroatoms selected from O, S, and N. the preferred heterocycloalkyl. includes pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine and the like.

As used herein the unqualified "heteroaryl" terminology refers to a condensed monocyclic or bicyclic or tricyclic aromatic ring or system containing one or more heteroatoms selected from O, S and N and to groups consisting of two rings monocyclic aromatics linked by covalent bonds containing one or more such heteroatoms and to groups consisting of a monocyclic carbocyclic aromatic group attached to a monocyclic aromatic ring containing one or more heteroatoms. Particular examples of heteroaromatic groups include pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4oxadiazolyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro] benzofuryl , isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1,2, -c] pyridyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolyl, naphthyridinyl, pyrido [3, 4-c] pyridyl, pyrido [3,2c] pyridyl, pyrido [3,4,3-c] pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, Purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl, optionally substituted.

Unless otherwise specified in the context in which it takes place, the term "substituted" when applied to any remainder herein means substituted, for example, with at least one substituent selected from (C1-C6) alkyl , (C1-C6) alkoxy, hydroxy, hydroxyalkyl (C1-C6), mercapto, mercaptoalkyl (C1-C6), alkylthio (C1-C6), halo (including fluorine and chlorine), trifluoromethyl, trifluoromethoxy, nitro, nitrile (- CN), oxo, phenyl, -COOH, -COORA, -CORA, -S02RA, -CONH2, -S02NH2, -CONHRA, -S02NHRA, -CONRARB, -S02NRARB, -NH2, -NHRA, -NRARB, OCONH2, -OCONHRA , -OCONRARB, -NHCORA, -NHCOORA, -NRBCOORA, -NHS02ORA, -NRBS02ORA, -NHCONH2, NRACONH2, -NHCONHR8 -NRACONHRB, -NHCONRARB or -NRACONRARB in which RA and RB are independently a C6-group6 or phenyl.

As used herein the term "salt" includes base addition, acid addition and quaternary salts. Compounds of the invention that are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, for example, sodium and potassium hydroxides; alkaline earth metal hydroxides for example, calcium, barium and magnesium hydroxides; with organic bases for example, N-methyl-D-glucamine, choline tris (hydroxymethyl) amino-methane, L-arginine, L-lysine, N-ethylpiperidine, dibenzylamine and the like. These compounds (I) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, for example, with hydrochloric acids such as hydrochloric or hydrobromic acids, sulfuric acid, nitric acid or phosphoric acid and the like, and with organic acids for example , with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulfonic, ptoluenesulfonic, benzoic, benzenesunphonic, glutamic, lactic and mandelic acids and the like.

For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2.002).

The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is used when said solvent is water.

The compounds referred to in the invention that may exist in one or more stereoisomeric forms, due to the presence of asymmetric atoms or rotational restrictions, may exist as a series of stereoisomers with stereochemistry R or S in each chiral center or as atropisomers with stereochemistry R or S in each chiral axis. The invention includes all those enantiomers and diastereomers and mixtures thereof. In particular, the invention includes compounds having the stereochemical configuration (AI):

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The compounds of the invention include compounds of formula (I) as defined above, including all polymorphs and crystalline habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined hereafter. and compounds of formula (I) labeled isotopically.

The Ar group

Ar may be, for example, a monocyclic 5- or 6-membered aryl or heteroaryl ring, which is optionally substituted, for example in position 4 in the case of a 6-member ring or in position 2 and / or 3 in the case of a 5-membered ring, for at least one substituent selected from (C1-C3) alkyl, (C1-C3) alkoxy, hydroxy, hydroxyalkyl (C1-C3), mercapto, mercaptoalkyl (C1-C3), alkylthio (C1 -C3), halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), -COOH, -COORA, -CORA, -S02RA, -CONH2, -SO2NH2, -CONHRA, -S02NHRA, -CONRARB, -S02H2AR-, , -NHRA, -NRARB, -OCONH2, -OCONHRA, -OCONRARB, -NHCORA, -NHCOORA, -NRBCOORA, -NHS02ORA, NRBS02ORA, -NHCONH2, -NRACONH2, -NHCONHRB, -NRACONHRB, -NHCACRBR-oHCNRB-oHCNBB-oHC-RB-NBACNRB RA and RB are independently (C1-C3) alkyl, phenyl or a 5- or 6-membered aryl or heteroaryl ring.

Ar may be, for example, phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl or 2- or 3-furanyl, optionally substituted as specified above in relation to formula (I). Preferably, the substituent may be, for example, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl, hydroxyl, mercapto, fluorine, chlorine or bromine. At present, he prefers that Ar be 4- (C1-C3 alkoxy) phenyl and ethoxyphenyl is most preferred.

The R group

In one embodiment of the invention R is hydrogen.

In another embodiment of the invention R is (C1-C6) alkyl, for example ethyl, n-propyl, isopropyl, n-, sec or tert-butyl. In a preferred embodiment, R is methyl.

In yet another embodiment R is cycloalkyl (C3-C6), for example cyclopropyl or cyclopentyl.

The radical Alq

Alq can be, for example, -CH2-, -CH2CH2-, -CH2CH (CH3) -, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH = CH-, CH2CH = CH-, -CH2CH = CHCH2-or -CH = CHCH = CH-. At present, he prefers that Alq be -CH2CH2CH2-.

The group -NR1R2

This group is a first saturated heterocyclic ring of 5 to 7 atoms that is optionally condensed to a second carbocyclic or heterocyclic ring, saturated or unsaturated, of 5 to 7 atoms. (Said first and / or second ring may be optionally substituted by a group of formula (II), discussed below). One of the heteroatoms of the group -NR1R2 is of course the nitrogen shown, and it may be the only heteroatom in the ring system or they may be other nitrogen, oxygen or sulfur atoms.

The group -NR1R2 may be unsubstituted or substituted by at least one group (II):

image 1

It will be noted that since an optional substituent at or Alq1 or Alq2 may be oxo, a carbonyl group may be located adjacent to element X, for example formed combinations such as amide, inverted amide and carboxy linkages.

In one embodiment of the invention, R1 and R2 taken together with the nitrogen atom to which they are attached form a

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morpholyl group, optionally substituted by at least one group of formula (II).

In another embodiment of the invention, R1 and R2 taken together with the nitrogen atom to which they are attached form a thiomorpholyl group, optionally substituted by at least one group of formula (II).

In another embodiment of the invention, R1 and R2 taken together with the nitrogen atom to which they are attached form a piperidinyl group, optionally substituted by at least one group of formula (II).

In another embodiment of the invention, R1 and R2 taken together with the nitrogen atom to which they are attached form a pyrrolidinyl group, optionally substituted by at least one group of formula (II).

In another embodiment of the invention, R1 and R2 taken together with the nitrogen atom to which they are attached form a piperazinyl group, optionally substituted by at least one group of formula (II).

In a particular embodiment of the invention, group (II) is such that p is 0, Z is hydrogen and at least one of n and m is 1. In this subclass group (II) is optionally substituted C1-C6 alkyl, which may be attached to a ring carbon or a ring nitrogen of the group -NR1R2. For example, when -NR1R2 is piperidinyl or piperazinyl, the C-4 in the former) and the N-4 (in the latter) can be substituted by methyl, ethyl or n- or iso-propyl.

In a second particular embodiment of the invention, the group (II) is such that m, n and p are all 0 and Z is a carbocyclic or heterocyclic ring directly attached to a ring carbon or ring nitrogen of the group -NR1R2. Examples of such directly attached Z rings include cyclopentyl and cyclohexyl and (preferably) aryl rings

or heteroaryls such as phenyl, pyridyl, thienyl, furanyl and pyrimidinyl. These directly bonded rings may be substituted by optional substituents, for example methoxy, ethoxy, n- or iso-propoxy, trifluoromethoxy, methylenedioxy, ethylenedioxy, methyl, ethyl, n- or isopropyl, trifluoromethyl, fluorine, chlorine, bromine, methylsulfonyl, phenylsulfonyl or mono- or dialkylamino (C1-C3).

In a third particular embodiment of the invention, the group (II) is such that p is 0, at least one of myn is 1, and Z is a carbocyclic or heterocyclic ring bonded to a carbon of the ring or nitrogen of the group ring - NR1R2 via a C1-C6 alkylene linker between Z and the -NR1R2 ring. In this case, the Z ring may be any of these optionally substituted Z rings discussed and preferred above in the case of the second subclass of groups (II), but here Z is attached to the -NR1R2 ring via a C1-alkylene linker radical C6, such as a radical -CH2- or CH2CH2-.

In a fourth particular embodiment of the invention, the group (II) is such that p is 1, so that the group (II) contains the heteroatom X. Clearly, when m is 0, X is directly attached to the -NR1R2 ring; when m and n are both 1 X interrupts a C1-C6 alkylene linker, between Z and the -NR1R2 ring; and when one of m and n is 1 and the other 0, group (II) represents a variety of substituents containing O, S- or N directly attached to the NR1R2 ring; or linked by a C1-C3 alkylene linker.

A particular embodiment of the invention comprises compounds of formula (IB) or (IC) and salts, hydrates and solvates thereof, especially compounds having the stereo configuration shown in formula (IA above):

image 1

wherein R is hydrogen or methyl, R3 is trifluoromethyl, trifluoromethoxyalkoxy C1-C3, hydroxy or halo; R4 is (i) -SO2R5 or -COR5 in which R5 is C1-C6 alkyl or phenyl or monocyclic heteroaryl with 5 or 6 ring atoms, optionally substituted by (C1-C3) alkyl, (C1-C3) alkoxy, hydroxy , hydroxyalkyl (C1-C3), mercapto, mercaptoalkyl (C1-C3), alkylthio (C1-C3), halo, trifluoromethyl, trifluoromethoxy or (ii) phenyl or monocyclic heteroaryl with 5 or 6 ring atoms; optionally substituted by (C1-C3) alkyl, (C1-C3) alkoxy, hydroxy, hydroxyalkyl (C1-C3), mercapto, mercaptoalkyl (C1-C3), alkylthio (C1-C3), halo, trifluoromethyl, trifluoromethoxy). Examples of heteroaryl rings that are part of R4 in this embodiment include pyridyl, pyrimidinyl, triazinyl, thienyl and furanyl.

Specific embodiments of the invention are compounds selected from the group consisting of the following: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (pyrrolidin-1-carbonyl) -hexanoic acid hydroxyamide. 3R- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (3-methoxy-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-methoxy-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-4-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (2RS-methyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (2,6-RS-dimethyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (thiomorphIin-4-carbonyl) -hexanoic acid hydroxyamide. 3R- (4-Benzyl-piperidin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-Benzo [1,3] dioxol-5-ylmethyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-4-ylmethyl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-benzylpiperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyrimidin-2-i-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethyl-pyrimidin-2-yl) -piperazin-1-carbonyl] hydroxyamide

hexanoic 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-chloro-pyrimidin-2-yl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 3R- [4- (4,6-Dimethoxy- [1,3,5] triazin-2-yl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxy acid hydroxyamide

hexanoic 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 3R- [4- (Acetyl-methyl-amino) -piperidin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (methyl-propyl-amino) -piperidin-1-carbonyl] -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (3S-benzyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (3S-isobutyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (3S-phenyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 3R- (4-benzyl-3RS-methyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (3S, 4-dibenzyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-benzyl-3RS-phenyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 4- (4-benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -2S, N-dihydroxy-4-oxo-3R- (4-trifluoromethoxy-benzyl) -butyramide. 3R-benzyl-2S, N-dihydroxy-4-morpholin-4-yl-4-oxo-butyramide. 3R- (4-Benzyloxy-benzyl) -2S, N-dihydroxy-4-oxo-4-piperidin-1-yl-butyramide. 2S, N-dihydroxy-3R- (4-hydroxy-benzyl) -4-oxo-4-piperidin-1-yl-butyramide. 4- (4-benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -3R- (4-benzyloxy-benzyl) -2S, N-dihydroxy-4-oxo-butyramide. 6- (3,5-bis-trifluorometiI-phenyl) -2S-hydroxy-3R- (morpholin-4-carbonyl) -hexanoic acid hydroxyamide.

3R- (4-Benzyl-piperidin-1-carbonyl) -6- (3,5-bis-trifluoromethyl-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (3,5-Bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (3,5-bis-trifluoromethyl-phenyl) -3R- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-carbonyl) -2S hydroxyamide

hydroxy-hexanoic. 6- (3,5-bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (pyrrolidin-1-carbonyl) -hexanoic acid hydroxyamide 3R- (2S-benzyl-4-methyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazin-1-carbonyl] hydroxyamide

hexanoic 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (toluene-4-sulfonyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 3R- [4- (5-Bromo-thiophene-2-sulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- [4- (5-Benzenesulfonyl-thiophene-2-sulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxy acid hydroxyamide

hexanoic 3R- [4- (4-Butoxy-benzenesulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-methoxy-2,3,6-trimethyl-benzenesulfonyl) -piperazin-1 acid hydroxyamide

carbonyl] -hexanoic.

3R- [4- (3,4-Dimethoxy-benzenesulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxyhexanoic acid hydroxyamide. 6- (4-Methoxy-phenyl) -2S-hydroxy-3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 6- (4-Methoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Fluoro-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Fluoro-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 3R- (4-Benzyl-2S-methyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-Benzyl-2S-methyl-piperazin-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-Benzyl-2S-i-butyl-piperazin-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-Benzyl-2S-methyl-piperazin-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-Benzyl-2S-i-butyl-piperazin-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 4- [5- (4-Ethoxy-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-methyl-piperazin-1 acid tert-butyl ester

carboxylic.

4- [5- (4-Ethoxy-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-i-butyl-piperazine-1-carboxylic acid tert-butyl ester. 4- [5- (4-Methoxy-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-methyl-piperazin acid tert-butyl ester

1-carboxylic.

4- [5- (4-Methoxy-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-i-butyl-piperazin-1-carboxylic acid tert-butyl ester. 4- [5- (4-Fluoro-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-methyl-piperazin acid tert-butyl ester

1-carboxylic.

4- [5- (4-Fluoro-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-i-butyl-piperazin-1-carboxylic acid tert-butyl ester. 6- (4-Ethoxy-phenyl) -2S-methoxy-3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. As mentioned above, the present compounds are useful in human or veterinary medicine since

which are active as MMP inhibitors, in particular as selective MMP-12 inhibitors (and / or MMP-9) referring to MMP-1 and other collagenases and stromelysins. According to this in another aspect, this invention is refers to the use of a compound of formula (I) defined above in the preparation of an agent for the

5

10

fifteen

twenty

25

30

35

40

Four. Five

treatment of diseases and conditions responsible for the inhibition of MMP-12 and / or MMP-9, selected from fibrotic disease, for example, fibrosis after radiotherapy, carotid scarring, liver fibrosis and cystic fibrosis; inflammatory multiple sclerosis; emphysema; bronchitis and asthma

In a further aspect of the invention there is provided a pharmaceutical or veterinary composition comprising a compound of formula (I) defined above together with a pharmaceutically or veterinarily excipient or carrier.

It will be understood that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, administration time, route of administration, excretion rate. , combination of drugs and the importance of the particular disease being treated. Optimum dose levels and frequency of administration will be determined by clinical study.

The compounds referred to in the invention can be with their pharmacokinetic properties. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, tablets, liquid or gel preparations, such as sterile oral, topical or parenteral solutions or suspensions. Tablets and capsules for oral administration may be in the form of a single dose and may contain conventional excipients such as binding agents, for example, syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tablet lubricant, magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to the methods known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, syrup emulsions or elixirs or may be present as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methylcellulose, glucose syrup, hydrogenated edible gelatin fats, for example, lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid and if desired conventional flavoring or coloring agents.

For topical application on the skin, the drug can be manufactured in cream, lotion or ointment. Cream or ointment formulations that can be used for the drug are conventional formulations known in the art, for example as described in the classic textbooks of pharmaceutical products such as the British Pharmacopoeia.

For topical application in the eye, the drug can be manufactured in a solution or suspension in an aqueous vehicle

or suitable sterile non-aqueous. Additives may also be included, for example buffers such as sodium metabisulfite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl acetate or mercuric nitrate, benzalkonium chloride or chlorhexidine and thickening agents such as hypromellose.

The active ingredient can also be administered parenterally in a sterile medium. Depending on the vehicle and the concentration used, the drug may or may be suspended or dissolved in the vehicle. Advantageously, preservatives and buffering agents can be dissolved in the vehicle.

Compounds of formula (I) can be prepared by classical literature methods, as illustrated in the Examples herein. In general, compounds in which R is hydrogen can be prepared by coupling a dioxolane protected dicarboxylic acid of formula (III) with the desired cyclic amine HNR1R2:

image 1

wherein R1, R2: Ar and Alq are as defined in relation to formula (I), to form the intermediate compound (IIIA)

image 1

then react the intermediate compound (IIIA) with hydroxylamine. Methods of coupling amines with carboxylic acids to form amides are known, for example from the peptide synthesis technique. Thus, the invention also includes:

(vi) a compound of formula (IIIB) in which R1, R2, Ar and Alq are as defined in relation to formula (I)

(vii) a process for the preparation of a compound of formula (I) defined above, comprising deprotection and / or transformation of a compound of formula (IIIA) as defined above,) in which R1, R2, Ar and Alq are as defined in relation to formula (I)

(viii) a process for the preparation of a compound of formula (IIIA) comprising the step of reacting a compound of formula (III) with a cyclic amine HNR1R2, in which R1, R2: Ar and Alq are as defined in relation to formula (I),

The following preparative Examples describe the preparation of useful compounds according to the invention. The following abbreviations have been used in the examples: AcOEt -Ethyl acetate CH3CN -Acetonitrile DMF -N, N-Dimethylformamide HOBT - 1-Hydroxybenzotriazole HOAT- 1-Hydroxyazobenzotriazole MgS04 - Magnesium sulfate Pfp-Pentafluorophene-N-hydrochloride 3-Dimethylaminopropyl) -N'-ethylcarbodiimide HCl - Hydrochloric acid P (O-Tol) 3 -Tri-O-tolylphosphine THF -Tetrahydrofuran TFA - Trifluoroacetic acid Z-Benzyloxycarbonyl Example 1: 6- (4-ethoxy-phenyl-hydroxyamide ) -2S-hydroxy-3R- (pyrrolidin-1-carbonyl) -hexanoic

image2

Reagents and conditions. A: LiHMDS, AIIBr, THF, -78C to TA; B: ArBr, P (o-Tol) 3, Pd (OAc) 2, NEt3, CH3CN; C: 10% Pd / C, H2, MeOH; D: LiOH, MeOH, H20; E: CuCI2, dimethoxypropane, acetone; F: pentafluorophenol, WSCDI, HOAt, CH2CI2; G: pyrrolidine, NEt3, CH2CI2, H: acNH2OH, iPrOH

5 Scheme 1

Example 1 was prepared as indicated in general in Scheme 1 using the procedures described below.

To a cold solution (-78C) of 2S-hydroxy-succinic acid diisopropyl ester (19.70 ml, 95 mmol) in THF (35

10 ml) LiHMDS (200 ml, 0.2 mol, 2.1 eq.) Was added dropwise. The reaction mixture was stirred at -78C for two hours and then at -30 ° C for 30 min. The reaction mixture was then cooled to -78 ° C and allyl bromide (12.36 ml, 0.14 mol, 1.5 eq.) Was added dropwise. It was left after the reaction mixture was heated at RT overnight. It was poured into a saturated solution of NH4CI / ice (200 ml). Extraction with AcOEt (3 X 200 ml) followed by washing with water (50 ml) and brine (50 ml) provided a yellow oil after

15 solvent removal in vacuo. Purification by flash chromatography gave 2R-allyl-3S-hydroxy-succinic acid diisopropyl ester as a colorless oil (7.76 g, = 80%, 40% yield).

1 H NMR; Delta (CDCI3): 5.77-5.88 (1H, m), 4.98-5.21 (4H, m), 4.22 (1H, sa), 3.18 (1H, sa), 2 , 87-2.94 (1H, m), 2,562.65 (1H, m), 2.40-2.48 (1H, m), 1.29 (6H, d, J = 6.3 Hz), 1.22 (6H, d, J = 6.3 Hz). LRMS: + see ion 281 (M + Na).

Stage B: 2R- [3- (4-ethoxy-phenyl) -alyl] -3S-hydroxy-succinic acid diisopropyl ester.

To a solution of 2R-allyl-3S-hydroxy-succinic acid diisopropyl ester (4.79 g, 18.5 mmol), 4-bromo phenethol (3.19 ml, 22.2 mmol, 1.2 eq. ) and NEt3 (6.22 ml, 44.6 mmol, 2.4 eq.) in CH3CN (40 ml), an ultrasonic suspension (for 2 min) of P (0-Tol) 3 (0, 57 g, 2.22 mmol, 0.1 eq.) And Pd (OAc) 2 (209 mg, 5%) in CH3CN (5 ml). The reaction mixture was heated to boil under reflux for 2 h. CH3CN was removed in vacuo. The crude was extracted with AcOEt (3 X 200 ml), washed with water (50 ml) and with brine (50 ml). Purification by flash chromatography gave the desired diisopropyl ester of 2R- [3- (4-ethoxy-phenyl) -alyl] -3S-hydroxy-succinic acid (5.92 g, 84% yield).

1 H NMR; Delta (CDCI3): 7.28 (2H, d, J = 8.8 Hz), 6.83 (2H, d, J = 8.8), 6.46 (1H, d, J = 15.7 Hz ), 6.02-6.12 (1H, m), 4,985.13 (2H, m), 4.26 (1H, dd, J = 7.1; 3.0 Hz), 4.02 (2H, c, J = 7.0 Hz): 3.23 (1H, d, J = 7.1 Hz), 2.92-2.97 (1H, m), 2,682.79 (1H, m), 2, 49-2.62 (1H, m), 1.41 (3H, t, J = 7.0 Hz), 1.19-1.30 (12H, m). LRMS: + see ion 401 (M + Na).

Stage C: 2R- [3- (4-ethoxy-phenyl) -propyl] -3S-hydroxy-succinic acid diisopropyl ester.

To a solution of diisopropyl ester of 2R- [3- (4-ethoxy-phenyl) -alyl] -3S-hydroxy-succinic acid (129 mg, 0.34 mmol) in MeOH (10 ml) in an inert atmosphere, added 10% Pd / C (13 mg). H2 was bubbled through the resulting suspension for 30 min. The reaction mixture was then stirred in 1.01105 Pa (1 atmosphere) of H2 for 16 h. Pd / C was filtered off and the solvent was removed under reduced pressure to give 2R- [3- (4-ethoxy-phenyl) -propyl] -3S-hydroxy-succinic acid diisopropyl ester (115 mg, 88% yield ).

1 H NMR; Delta (CDCI3): 7.08 (2H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.6), 4.97-5.14 (2H, m), 4 , 20 (1H, dd, J = 7.3; 3.5 Hz), 4.01 (2H, c, J = 7.0 Hz), 3.18 (1H, d, J = 7.3 Hz) , 2.77-2.83 (1H, m), 2.55-2.62 (2H, m), 1.45-1.94 (4H, m), 1.40 (3H, t, J = 7.0 Hz), 1.12-1.30 (12H, m). LRMS: + see xx ion (M + Na).

Stage D: 2R- [3- (4-ethoxy-phenyl) -propyl] -3S-hydroxy-succinic acid. To a solution of 2R [3- (4-ethoxy-phenyl) -propyl] -3S-hydroxy-succinic acid diisopropyl ester (4.78 g, 12.6 mmol) in THF / water (3: 1, 120 ml ) NaOH (1.66 g, 41.5 mmol, 5.5 eq.) was added. The reaction mixture was then stirred for 16 h at RT. The mixture was concentrated under reduced pressure and acidified to pH = 3 by the addition of 1N HCl. The hydroxyacid was extracted with AcOEt. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give 2R- [3- (4-ethoxy-phenyl) -propyl] 3S-hydroxy-succinic acid (3.66 g, 85% yield) .

1 H NMR; Delta (MeOD): 7.07 (2H, d, J = 8.6 Hz), 6.79 (2H, d, J = 8.6), 4.23 (1H, d, J = 5.8 Hz ), 3.98 (2H, c, J = 7.0 Hz), 2.76-2.81 (1H, m), 2.53-2.59 (2H, m), 1.55-1, 72 (4H, m), 1.35 (3H, t, J = 7.0 Hz). LRMS: + ve ion 319 (M + Na); -ve ion 295 (M-H).

Stage E: 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid.

To a solution of 2R- [3- (4-ethoxy-phenyl) -propyl] -3S-hydroxy-succinic acid (3.66 g, 12.3 mmol) in acetone (50 ml) in an inert atmosphere added dimethoxypropane ( 2.58 ml, 21 mmol, 1.7 eq.) And copper chloride (165 mg, 1.2 mmol, 0.1 eq.). The reaction mixture was stirred at RT for 16 h. The solvent was then removed in vacuo to give 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid (4.03 g, 97% yield).

1 H NMR; Delta (CDCI3): 7.08 (2H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5), 4.48 (1H, d, J = 4.8 Hz ), 4.01 (2H, c, J = 7.0 Hz), 2.91-2.98 (1H, m), 2.54-2.64 (3H, m), 1.23-2, 20 (4H, m), 1.58 (3H, s), 1.53 (3H, s), 1.40 (3H, t, J = 7.0 Hz). LRMS: + see 359 ion (M + Na); -ve ion 335 (M-H).

Step F. 2R- (2,2-Dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid pentafluorophenyl ester.

To a cold solution (0C) of 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid (4.03 g , 12 mmol) and pentafluorophenol (2.43 g, 13.2 mmol, 1.1 eq.) In CH2CI2 (50 ml) WSC (2.54 g, 13.2 mmol, 1.1 eq.) Was added. The reaction mixture was allowed to warm to RT overnight. CH2CI2 was removed in vacuo and the resulting crude reaction mixture was dissolved in AcOEt (200 ml). The organic layer was washed with water (50 ml), sat. NaHC03 (20 ml) and finally with brine (20 ml). The solvent was removed under reduced pressure to give an oil that was purified by flash chromatography to provide the pentafluorophenyl ester of 2R- (2,2-dimethyl-5oxo- [1,3] dioxolan-4S-yl) -5- ( 4-ethoxy-phenyl) -pentanoic acid (3.94 g, 65% yield).

1 H NMR; delta (CDCI3): 7.09 (2H, d, J = 8.4 Hz), 6.83 (2H, d, J = 8.4 Hz), 4.56 (1H, d, J = 6.0 Hz), 4.01 (2H, c, J = 7.0 Hz), 3.20-3.28 (1H, m), 2.64 (2H, t, J = 7.6 Hz), 1, 98-2.08 (2H, m), 1.70-1.86 (2H, m), 1.62 (3H, s), 1.57 (3H, s), 1.40 (3H, t, J = 7.0 Hz).

Step G. 5- (4-Ethoxy-phenyl) -2R - [(2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl)] - 1 -pyrrolidin-1-yl-pentan- 1 -one.

To a solution of 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) pentanoic acid pentafluorophenyl ester (150 mg, 0.30 mmol) in CH2CI2 (10 ml) pyrrolidine (30 µl, 0.36 mmol, 1.2 eq.) was added. The reaction mixture was stirred for 16 h and the solvent was removed in vacuo. The crude was absorbed in AcOEt (70 ml) and washed with water (10 ml), then with NaHCO3sat (10 ml) and finally with brine (10 ml). The solvent was dried over MgSO4 and removed under reduced pressure to give 5- (4-Ethoxy-phenyl) -2R - [(2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) ] -1 pyrrolidin-1-yl-pentan-1-one (116 mg, quant.).

1 H NMR; delta (CDCI3): 7.05 (2H, d, J = 8.6 Hz), 6.8 (2H, d, J = 8.6 Hz), 4.55 (1H, d, J = 8.4 Hz), 3.99 (2H, m), 3.8-3.3 (10 H, m), 3.05 (1H, m), 2.55 (2H, t, J = 7.6 Hz) , 2.1-1.7 (2H, m), 1.6 (3H, s), 1.5 (3H, s), 1.4 (3H, t, J = 7.0 Hz). LRMS: + ve ion 405 (M + H), 428 (M + Na).

Stage H. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (pyrrolidin-1-carbonyl) -hexanoic acid hydroxyamide

To a solution of 5- (4-Ethoxy-phenyl) -2R - [(2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl)] - 1-pyrrolidin-1-yl-pentan -1-one (116 mg, 0.30 mmol) in i-PrOH (5 ml), an aqueous solution of hydroxylamine (50%, 99 µl, 1.5 mmol, 5 eq.) Was added. The reaction mixture was allowed to stir at RT for 16 h. The solvent was removed under reduced pressure to

5 to provide an oil that was purified by preparative reverse phase chromatography to give the required product.

1 H NMR; Delta (CD3OD): 7.05 (2H, d, J = 8.6 Hz), 6.8 (2H, d, J = 8.6 Hz), 4.0 (4H, m), 3.85 ( 1H, m), 3.7 (1H, m), 3.4 (2H, m), 3.1 (1H, m), 2.55 (2H, m), 1.9-1.5 (7H , m), 1.35 (3H, t, J = 7.0 Hz). LRMS: + ve ion 387 (M + Na); -ve ion 363 (M-H)

The compounds of Examples 2-20 were prepared by the method of Example 1 by parallel synthesis, using the appropriate 10 amine in Step G. The products were purified by preparative HPLC.

Example 2: 3R- (6,7-Dimethoxy-3,4-dihydro-1 H-isoquinolin-2-carbonyl) -6- (4-ethoxy-phenyl) -2-Hydroxy-hexanoic acid hydroxyamide.

image 1

LRMS: + ve ion 487 (M + H), 509 (M + Na); -ve ion 485 (M-H). Example 3: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (3-methoxy-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide.

image 1

LRMS: + ve ion 486 (M + H), 508 (M + Na); -ve ion 484 (M-H). Example 4: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-methoxy-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide.

image 1

20 LRMS: + ve ion 486 (M + H), 508 (M + Na); -ve ion 484 (M-H). Example 5: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide.

image 1

1 H NMR; delta (CD3OD): 8.1 (1H, d, J = 1.4Hz), 7.55 (1H, m), 7.05 (2H, d, J = 8.7Hz), 6.9-6, 6 (4H, m), 3.95 (1H, d, J = 7.0 Hz), 3.55 (4H, m), 2.55 (1H, m), 1.8-1.5 (6H , m), 1.35 (3H, m). LRMS: + ve ion 457 (M + H); -ve ion 455 (M-H). Example 6: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-4-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide.

image 1

image3

1 H NMR; Delta (CD3OD): 7.05 (2H, d, J = 8.6Hz), 6.8 (2H, d, J = 8.6 Hz), 4.05-3.90 (3H, m), 3 , 8-3.4 (8H, m), 2.55 (2H, t, J = 6.7 Hz), 1.75-1.4 (4H, m), 1.35 (3H, t, J = 7.0 Hz). LRMS: + ve ion 403 (M + Na); -ve ion 379 (M-H).

Example 8: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (2RS-methyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide.

image 1

10 LRMS: + see ion 417 (M + Na), 395 (M + H); -ve ion 393 (M-H). Example 9: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (2,6-RS-dimethyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide.

image 1

LRMS: + ve ion 431 (M + Na), 409 (M + H); -ve ion 407 (M-H). Example 10: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (thiomorpholin-4-carbonyl) -hexanoic acid hydroxyamide.

image 1

1 H NMR; Delta (CD3OD): 7.05 (2H, d), 6.8 (2H, d), 4.0 (5H, m), 3.8-3.5 (2H, m), 2.9-2 , 4 (7H, m), 1.55 (4H, m) and 1.3

(3H, t). LRMS: + see ion 419 (M + Na). 397 (M + H); -ve ion 395 (M-H). Example 11: 3R- (4-Benzyl-piperidin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

image 1

1 H NMR; delta (CD3OD): 7.3-7.0 (8H, m), 6.8 (2H, m), 4.55 (1H, d, J = 12.4 Hz), 4.05 (2H, dd , J = 2.0 Hz), 3.9 (2H, m), 2.9 (1H, m), 2.6-2.4 (5H, m), 1.84 (1H, d, J = 2.9 Hz), 1.7-1.5 (6H, m), 1.35 (3H, t, J = 7.0 Hz). LRMS: + see ion 491 (M + Na); -ve ion 467 (M-H).

Example 12: 3R- (4-Benzo [1,3] dioxol-5-ylomethyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2-Hydroxy-hexanoic acid hydroxyamide.

image 1

10 LRMS: + ve ion 514 (M + H); - 512 ion (M-H). Example 13: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-4-ylmethyl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide.

image 1

LRMS: + see ion 471 (M + H); -ve ion 469 (M-H). Example 14: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-benzylpiperazin-1-carbonyl) -hexanoic acid hydroxyamide.

image 1

LRMS: + see ion 471 (M + H); -ve ion 469 (M-H). Example 15: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyrimidin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide.

image4

LRMS: + see ion 458 (M + H); -ve ion 456 (M-H).

image 1

LRMS: + ve ion 526 (M + H), 548 (M + Na); -ve ion 524 (M-H).

Example 17: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-chloro-pyrimidin-2-yl) -piperazin-1-carbonyl] hexanoic acid hydroxyamide.

image 1

10 LRMS: + see ion 492 (M + H); -ve ion 490 (M-H).

Example 18: 3R- [4- (4,6-Dimethoxy- [1,3,5] triazin-2-yl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2Shydroxy acid hydroxyamide -hexanoic.

image 1

LRMS: + ve ion 519 (M + H); -ve ion 517 (M-H).

Example 19: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] hexanoic acid hydroxyamide.

image 1

LRMS: + ve ion 524 (M + H); -ve ion 522 (M-H). Example 20: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide.

image 1

5 LRMS: + ion 474 (M + H); -ve ion 472 (M-H).

Example 21: 3R- [4- (Acetyl-methyl-amino) -piperidin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxyhexanoic acid hydroxyamide. The compound of Example 21 was prepared as indicated in general in Scheme 2, using the

procedures described below. 10

image5

Reagents and conditions: A: H2, Pd / C, MeOH; B: AcCI, NEt3, CH2Cl2; C: TFA / CH2CI2; D: PFP ester, NEt3; E: NH2OH, iPrOH

Scheme 2

To a solution of 4- (benzyloxycarbonyl-methyl-amino) -piperidine-1-carboxylic acid tert-butyl ester (5 g, 0.014 mmol) in MeOH (30 ml) was added in an inert atmosphere 10% Pd / C (500 mg) H2 was bubbled through the resulting suspension for 2 h. The reaction mixture was then stirred at 1.01105 Pa (1 atm) of H2 for 2 h. Pd / C was filtered off and the solvent was removed under reduced pressure to give the 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (3.08 g, quant.).

Stage B: 4- (Acetyl-methyl-amino) -piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-methylamino-piperidin-1-carboxylic acid tert-butyl ester (616 mg, 2.9 mmol) in CH2CI2 (25 mL), acetyl chloride (215 µl, 3.02 mmol, 1.05 eq.) drop by drop. The reaction mixture was stirred at RT for 16 h. The crude reaction mixture was extracted with CH2CI2 (2 X 50 ml) and washed with water (10 ml) and with brine (10 ml). The solvent was removed under reduced pressure to give the expected 4- (Acetyl-methyl-amino) -piperidine-1-carboxylic acid tert-butyl ester (708 mg, 96% yield).

1 H NMR; Delta (CDCI3): 4.7-4.5 (1H, m), 4.1 (2H, da, J = 12.7 Hz), 2.8 (5H, m), 2.1 (5H, m ), 1.6 (2H, m), 1.5 (9H, s). LRMS: + see ion 215 (M + H).

Stage C: N-methyl-N-piperidin-4-yl-acetamide.

To a solution of 4- (acetyl-methyl-amino) -piperidine-1-carboxylic acid tert-butyl ester (525 mg, 2.05 mmol) in AcOEt (5 ml) was added 3N HCI (4 ml). The reaction mixture was stirred at RT for 16 h. Solvent was removed under reduced pressure to give the expected N-methyl-N-piperidin-4-yl-acetamide as its hydrochloride salt (395 mg, quant.).

1 H NMR; Delta (CD3OD): 4.6 (1H, m), 3.5 (2H, da, J = 12.8 Hz), 3.2-3.1 (2H, m), 3.0-2.85 (3H, s), 2.2 (3H, s), 2.1-1.8 (4H, m). LRMS: + see ion 157 (M + H).

Stage D: N- {1- [2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoyl] -piperidin-4 -il} -N-methyl-acetamide.

To a solution of pentafluorophenyl ester of 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl)

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Pentanoic acid (230 mg, 0.46 mmol) in CH2CI2 (5 ml) was added N-Methyl-N-piperidin-4-yl-acetamide (137 mg, 0.6 mmol, 1.3 eq.) followed by NEt3 ( 257 μl, 1.83 mmol, 4 eq.). The reaction mixture was stirred at RT for 16 h. The reaction mixture was extracted with CH2CI2 (2 X 20 ml) and washed with water (10 ml), NaHC03 sat (5 ml) and finally with brine (10 ml). The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give the N- {1- [2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5 - (4-Ethoxy-phenyl) -pentanoyl] -piperidin-4-yl} -N-methyl-acetamide expected in quantitative yield. It is the compound used in the next step without further purification.

1 H NMR; Delta (CDCI3): 7.05 (2H, d, J = 7.2 Hz), 6.7 (2H, d, J = 7.2 Hz), 4.75 (2H, m), 4.55 ( 1H, d, J = 7.9 Hz), 4.0 (3H, m), 3.05 (1H, m), 2.8 (1H, m), 2.7-2.5 (4H, m ), 2.1 (3H, s), 1.85 (3H, m), 1.75-1.5 (4H, m), 1.65 (3H, s), 1.55 (3H, s) , 1.4 (3H, t, J = 7.0 Hz), 0.8 (3H, t, J = 7.2 Hz). LRMS: + see ion 475 (M + H).

Step E: 3R- [4- (Acetyl-methyl-amino) -piperidin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxyhexanoic acid hydroxyamide.

To a solution of N- {1- [2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoyl] -piperidin- 4-yl} -N-methylacetamide (135 mg, 0.28 mmol) in i-PrOH (5 ml) was added an aqueous solution of hydroxylamine (50%, 94 µl, 1.43 mmol, 5 eq.). The reaction mixture was allowed to stir at RT for 16 h. The solvent was removed under reduced pressure to provide an oil that was purified by preparative reverse phase chromatography to give the hydroxyamide of 3R- [4- (acetyl-methyl-amino) -piperidin-1-carbonyl] -6- (4 -ethoxy-phenyl) -2S-hydroxy-hexanoic.

LRMS: + see ion (M + Na); -ve ion (M-H)

Example 22: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (methyl-propyl-amino) -piperidin-1-carbonyl] hexanoic acid hydroxyamide.

image 1

Example 22 was prepared as indicated in general in Scheme 3 using the procedures described below.

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Reagents and conditions: A: methylpropylamine; B: TFA / CH2CI2; C: PFP ester, NEt3; D: NH2OH, iPrOH

Scheme 3

Stage A: 4- (Methyl-propyl-amino) -piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.5 mmol) in MeOH (5 mL) was added NaBH3CN (32 mg, 0.5 mmol, 1 eq.). The pH of the reaction mixture was adjusted to 5.5 by the addition of 5N HCl and stirred for 48 h at RT under an inert atmosphere. The solvent was removed under reduced pressure and the crude was absorbed in AcOEt (150 ml). The organic layer was washed with NaHC03 (10 ml) and with brine (10 ml) and dried over MgSO4. The solvent was removed in vacuo to give the 4- (methyl-propyl-amino) -piperidine-1-carboxylic acid tert-butyl ester (106 mg, 82% yield).

1 H NMR; delta (CDCI3): 4.14 (1H, da, J = 12.2 Hz), 3.8 (1H, m), 3.0 (1H, m), 2.8-2.35 (5H, m ), 2.2 (3H, s), 1.9-1.7 (3H, m), 1.5 (11H, s), 0.9 (3H, t, J = 3.4 Hz).

LRMS: + see ion 257 (M + H).

Stage B: methyl-piperidin-4-yl-propyl-amine.

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To a solution of 4- (methyl-propyl-amino) -piperidine-1-carboxylic acid tert-butyl ester (106 mg, 0.41 mmol) in AcOEt (10 ml) was added 3N HCl (4 ml). The reaction mixture was stirred for 16 h at RT. The solvent was removed under reduced pressure to give the desired methyl-piperidin-4-yl-propyl amine (87 mg, 92% yield).

1 H NMR; delta (CD3OD): 3.95 (1H, m), 3.6 (2H, d, J = 13.9 Hz), 2.3 (2H, d, J = 11.3 Hz), 2.05 ( 4H, m), 1.85 (4H, m), 1.05 (3H, t, J = 7.3 Hz). LRMS: + see ion 157 (M + H).

Step C: 5S- {4- (4-Ethoxy-phenyl) -1 R- [4- (methyl-propyl-amino) -piperidin-1-carbonyl] -butyl} -2,2-dimethyl- [1,3 ] dioxolan-4-one.

To a solution of 2R- (2,2-dimethyl-5-oxo- [1,3] dioxoIan-4S-yl) -5- (4-ethoxy-phenyl) pentanoic acid pentafluorophenyl ester (175 mg, 0.35 mmol) in CH2CI2 (5 mL) methyl-piperidin-4-yl-propyl amine (87 mg, 0.45 mmol, 1.3 eq.) was added followed by NEt3 (197 µl, 1.39 mmol, 4 eq .). The reaction mixture was stirred for 16 h and the solvent was removed in vacuo. The crude was absorbed in AcOEt (70 ml) and washed with water (10 ml), then with NaHC03 sat (10 ml) and finally with brine (10 ml). The organic layer was dried over MgSO4 and removed under reduced pressure. Purification on silica gel provided 5S- {4- (4-Ethoxy-phenyl) -1R- [4- (methyl-propyl-amino) -piperidin-1-carbonyl] butyl} -2,2-dimethyl- [ 1,3] dioxolan-4-one. (82 mg, 50% yield).

1 H NMR; Delta (CDCI3): 7.0 (2H, d, J = 8.3 Hz), 6.7 (2H, d, J = 8.3 Hz), 4.65 (1H, m), 4.5 ( 1H, m), 3.9 (2H, m), 3.05 (1H, m), 2.9 (1H, m), 2.5 (4H, d, J = 7.7 Hz), 2, 3 (2H, m), 2.15 (3H, dd, J = 4.0, 13.8 Hz), 1.7 (4H, t, J = 7.0 Hz), 1.55 (3H, s ), 1.5 (3H, s), 1.45-1.3 (7H, m), 1.3 (3H, t, J = 7.0 Hz), 0.8 (3H, t, J = 7.2 Hz). LRMS: + see ion 475 (M + H).

Stage D: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (methyl-propyl-amino) -piperidin-1-carbonyl] hexanoic acid hydroxyamide.

To a solution of 5S- {4- (4-ethoxy-phenyl) -1R- [4- (methyl-propyl-amino) -piperidin-1-carbonyl] -butyl} -2,2-dimethyl [1,3] dioxolan-4-one (82 mg, 0.17 mmol) in i-PrOH (3 ml), an aqueous solution of hydroxylamine (50%, 57 µl, 0.87 mmol, 5 eq.) was added. The reaction mixture was allowed to stir at RT for 16 h. The solvent was removed under reduced pressure to provide an oil that was purified by preparative reverse phase chromatography to give the required product.

1 H NMR; delta (CH3OD): 7.1 (2H, d), 6.8 (2H, d), 4.6 (1H, d), 4.1 (1H, d), 4.0 (2H, m), 3.35 (1H, m), 2.9-2.35 (8H, m), 2.3-2.2 (3H, s), 2.0-1.4 (10H, m), 1, 35 (3H, t) and 0.9 (3H, t).

LRMS: + ion 450 (M + H); -ve ion 448 (M-H)

Example 23: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (3S-benzyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide.

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The compound of Example 23-25 was prepared by the method of Example 1 according to scheme 1, and using the appropriate amine (synthesized according to the procedures described in Tetrahedron, 36, 409-415, 1980 and Journal of Organic Chemistry, 61, 4,990 -4.998, 1996), in Step A. The products were purified by preparative HPLC.

LRMS: + see ion 471 (M + H); -ve ion 469 (M-H)

Example 24: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (3S-isobutyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide.

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LRMS: + ve ion 437 (M + H); -ve ion 435 (M-H) Example 25: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (3S-phenyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide.

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LRMS: + ve ion 457 (M + H), 479 (M + Na); -ve ion 455 (M-H)

Example 26: 3R- (4-Benzyl-3RS-methyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxyhexanoic acid hydroxyamide.

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The compound of example 26-28 was prepared by the method of example 1 according to scheme 1 and using the appropriate piperazines (synthesized according to the procedure described in Tetrahedron: Asymmetry, 12, 3,319-3,324,

10 2,001 and Org. Prep. Proced. Int., 22, (6), 761-768, 1990, in Step A. The products were purified by preparative HPLC.

LRMS: + see ion 484 (M + H).

Example 27: 3R- (3S, 4-dibenzyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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15 LRMS: + ve ion 560 (M + H).

Example 28: 3R- (4-Benzyl-3RS-phenyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxyhexanoic acid hydroxyamide.

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LRMS: + see ion 546 (M + H).

Example 29: 4- (4-benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -2S, N-dihydroxy-4-oxo-3R- (4-trifluoromethoxy-benzyl) butyramide.

Example 29 was prepared as indicated in general in Scheme 4 using procedures described below.

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Reagents and conditions. A: LiHMDS, 4-OCF3-C6H4-CH2Br, THF, -78 to TA; B: NaOH, THF, H20; C: CuCI2, dimethoxyacetone, acetone; D: pentafluorophenol, WSC, HOAt, CH2CI2; E: RNH2, NEt3CH2CI2; F: HONH2ac, iPrOH

Scheme 4

To a cold solution (-78C) of 2S-hydroxy-succinic acid dimethyl ester (3.0 g, 18.5 mmol) in THF (100 ml), a 1 N solution of LiHMDS (40.7 ml,) was added 40.7 mmol, 2.2 eq.) Drop by drop. The reaction mixture was stirred at -78C for 30 min and then at -30C for 1 h. The temperature was lowered to -78C and 1-bromomethyl4-trifluoromethoxybenzene (3.11 ml, 19.4 mmol, 1.05 eq.) Was added dropwise. The reaction mixture was allowed to warm to RT overnight and then poured into NH4Clsat (50 ml). THF was removed in vacuo and the crude was absorbed in AcOEt (150 ml). The organic layer was washed with water (2 X 20 ml) and with brine (20 ml) before it was dried over MgSO4. The solvent was removed under reduced pressure to give an oil that was purified by flash chromatography on silica gel. The dimethyl ester of 2S-hydroxy-3R- (4-trifluoromethoxy-benzyl) -succinic acid in 24% yield (1.50 g).

1 H NMR; Delta (CDCI3): 7.31 (2H, d, J = 8.5 Hz), 7.15 (2H, d, J = 8.4 Hz), 4.12 (1H, d, J = 6.5 Hz), 3.75 (3H, s), 3.69 (3H, s), 3.20 (2H, m), 3.01 (1H, m). LRMS: + see 358 ion (M + Na).

Stage B: 2S-hydroxy-3R- (4-trifluoromethoxy-benzyl) -succinic acid.

To a cold solution (0C) dimethyl ester of 2S-hydroxy-3R- (4-trifluoromethoxy-benzyl) succinic acid (1.50 g, 4.45 mmol) in MeOH / water (3: 1, 28 ml) Lithium hydroxide (617 mg, 14.7 mmol, 3.3 eq.) was added. The reaction mixture was stirred at RT for 16 h. The reaction was rapidly cooled by the addition of 1N HCl (5 ml) and MeOH was removed under reduced pressure. Extraction was performed with AcOEt (10 ml). The organic layer was washed with 1N HCl (10 ml), water (10 ml) and finally with brine (10 ml). The organic layer was dried over MgSO4. The solvent was removed under reduced pressure to give the expected 2S-hydroxy-3R- (4-trifluoromethoxy-benzyl) succinic acid as a clear oil (1.36 g, 99% yield).

1 H NMR; Delta (CDCI3): 7.32 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.4 Hz), 4.08 (1H, d, J = 6.5 Hz), 3.25 (2H, m), 3.05

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(1H, m). LRMS: + ve ion 331 (M + Na), -ve ion 307 (M-H).

Stage C: 2R- (2,2-Dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -3- (4-trifluoromethoxy-phenyl) -propionic acid.

To a solution of 2S-hydroxy-3R- (4-trifluoromethoxy-benzyl) -succinic acid (1.36 g, 4.4 mmol) in acetone (10 ml) in an inert atmosphere was added dimethoxypropane (923 μl, 7, 5 mmol, 1.7 eq.) And copper chloride (59 mg, 0.44 mmol, 0.1 eq.). The reaction mixture was stirred at RT for 16 h. Solvent was then removed in vacuo to give 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -3- (4-trifluoromethoxy-phenyl) -propionic acid (1.08 g , 70% yield).

1 H NMR; Delta (CDCI3): 7.29 (2H, d, J = 8.7 Hz), 7.14 (2H, d, J = 8.4 Hz), 4.30 (1H, d, J = 6.2 Hz), 3.21 (2H, m), 3.0 (1H, m), 1.61 (3H, s), 1.52 (3H, s). LRMS: + ve ion 371 (M + Na), -ve ion 347 (M-H).

Stage D: 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -3- (4-trifluoromethoxy-phenyl) propionic acid pentafluorophenyl ester.

To a cold solution (0C) of 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -3- (4-trifluoromethoxy-phenyl) -propionic acid (1.08 g , 3.1 mmol) and pentafluorophenol (685 mg, 3.7 mmol, 1.2 eq.) In CH2CI2 (10 mL) WSC (714 mg, 3.7 mmol, 1.2 eq.) Was added. The reaction mixture was allowed to warm to RT overnight. CH2CI2 was removed in vacuo and the resulting crude reaction mixture was dissolved in AcOEt (80 ml). The organic layer was washed with water (20 ml), NaHC03sat (10 ml) and finally with brine (10 ml). The solvent was removed under reduced pressure to give an oil that was purified by flash chromatography to provide the pentafluorophenyl ester of 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -3- ( 4-trifluoromethoxy-phenyl) -propionic (254 mg, 16% yield).

1 H NMR; Delta (CDCI3): 7.29 (2H, da, J = 9.3 Hz), 7.21 (2H, da, J = 8.7 Hz), 4.45 (1H, d, J = 6.2 Hz), 3.51 (1H, m), 3.3 (2H, m), 1.65 (3H, s), 1.58 (1H, s). LRMS: + ve ion 537 (M + Na).

Stage E: 5S- [2- (4-benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -2-oxo-1R- (4-trifluoromethoxy-benzyl) -ethyl] -2,2 -dimethyl [1,3] dioxolan-4-one

To a solution of 2- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -3R- (4-trifluoromethoxyphenyl) -propionic acid pentafluorophenyl ester (59 mg, 0.11 mmol) ) in CH2CI2 (10 ml) 1-benzo [1,3] dioxol-5-ylmethyl-piperazine (28 mg, 0.13 mmol, 1.1 eq.) was added. The reaction mixture was stirred for 16 h and the solvent was removed in vacuo. The crude was absorbed in AcOEt (50 ml) and washed with water (10 ml), then with NaHC03sat (10 ml) and finally with brine (10 ml). The solvent was dried over MgSO4 and removed under reduced pressure to give an oil that was purified by preparative reverse phase chromatography to provide 5S- [2- (4-benzo [1,3] dioxol-5-ylmethyl-piperazine- 1-yl) -2oxo-1R- (4-trifluoromethoxy-benzyl) -ethyl] -2,2-dimethyl- [1,3] dioxolan-4-one expected.

1 H NMR; Delta (CD3OD): 7.27-7.12 (4H, m), 6.78-6.62 (3H, m), 5.93 (2H, s), 4.57 (1H, d, J = 6.6 Hz), 3.85-2.9 (10H, m), 2.44-2.21 (2H, m), 2.05-1.91 (1H, m), 1.69-1 , 42 (6H, m). LRMS: + see ion 551 (M + H).

Stage F: 4- (4-benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -2S, N-dihydroxy-4-oxo-3R- (4-trifluoromethoxy-benzyl) -butyramide.

To a solution of 5S- [2- (4-benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -2-oxo-1R- (4-trifluoromethoxy-benzyl) -ethyl] -2, 2-dimethyl- [1,3] dioxolan-4-one (26 mg, 0.047 mmol) in i-PrOH (2 ml), an aqueous solution of hydroxylamine (50%, 16 µl, 0.24 mmol, 5 eq. ). The reaction mixture was allowed to stir at RT for 16 h. The solvent was removed under reduced pressure to provide an oil that was purified by preparative reverse phase chromatography to give 4- (4-Benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -2S, N -dihydroxy-4-oxo-3R- (4-trifluoromethoxybenzyl) -butyramide required.

1 H NMR; Delta (CD3OD): 7.32-7.15 (4H), 6.79-6.65 (4H, m), 5.90 (2H, s), 4.13 (1H, d, J = 6, 8 Hz), 3.75-3.35 (4H, m), 3.30 (2H, s), 3.0-2.8 (4H, m), 2.5-2.25 (2H, m ), 1.90 (1H, m).

LRMS: + ion 526 (M + H); -ve ion 524 (M-H).

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The compound of example 30 was prepared by the method of example 29 according to scheme 4 and using the benzyl bromide in step A and morpholine in step E.

1 H NMR; Delta (CD3OD): 7.32-7.18 (5H, m), 4.16 (1H, d, J = 6.7 Hz), 3.59-2.67 (11H, m). LRMS: + ion 331 (M + Na); -ve ion 307 (M-H). Example 31: 3R- (4-Benzyloxy-benzyl) -2S, N-dihydroxy-4-oxo-4-piperidin-1-yl-butyramide.

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The compound of example 31 was prepared by the method of example 29 according to scheme 4 and using 1-benzyloxy4-bromomethyl-benzene in step A and piperidine in step E.

1 H NMR; delta (MeOD): 7.41-7.26 (5H, m), 7.10-6.87 (4H, m), 5.05 (2H, s), 4.11 (1H, d, J = J 6.1 Hz), 3.57-3.48 (2H, m), 3.24-3.09 (3H, m), 2.89-2.69 (2H, m), 1.41- 1.17 (5H, m) and 0.72-0.67 (1H, m). LRMS: + ve ion 435 (M + Na); -ve ion 411 (M-H).

Example 32: 2S, N-dihydroxy-3R- (4-hydroxy-benzyl) -4-oxo-4-piperidin-1-yl-butyramide.

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15 Reagents and conditions: A: H2, Pd / C, MeOH

Scheme 5

Stage A: 2S, N-dihydroxy-3R- (4-hydroxy-benzyl) -4-oxo-4-piperidin-1-yl-butyramide.

To a solution of 2S, N-dihydroxy-3R- (4-hydroxy-benzyl) -4-oxo-4-piperidin-1-yl-butyramide (14 mg, 3.5.10-5 moles) in MeOH (5 ml) under an inert atmosphere, 10% Pd / C (1 mg) was added. H2 was then bubbled through the suspension

20 resulting for 2 h. Pd / C was filtered off and the solvent was removed under reduced pressure to give 2S, Ndihydroxy-3R- (4-hydroxy-benzyl) -4-oxo-4-piperidin-1-yl-butyramide (10 mg, quant. ).

1 H NMR; Delta (MeOD): 7.02-6.67 (4H, 2d, J = 8.4 Hz and J 8.4 Hz), 4.12 (1H, d, J = 6.0 Hz), 3.65 -3.48 (2H, m), 3.27-3.12 (3H, m), 2.87-2.68 (2H, m), 1.47-1.26 (5H, m) and 0 , 83-0.78 (1H, m). LRMS: + ion 345 (M + Na); -ve ion 321 (M-H).

Example 33: 4- (4-benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -3R- (4-benzyloxy-benzyl) -2S, N-dihydroxy-4-oxo-butyramide.

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The compound of example 33 was prepared by the method of example 29 according to scheme 4 and using 1-benzyloxy4-bromomethyl-benzene in step A.

1 H NMR; Delta (DMSO): 9.80 (1H, s), 8.88 (1H, s), 7.48-7.31 (5H, m), 7.04-6.90 (4H, m), 6 , 82-6.77 (2H, m), 6.67-6.62 5 (1H, m), 5.98 (2H, s), 5.45 (1H, d), 5.09 (2H, s), 3.91 (1H, m), 3.56-3.44 (2H, m), 3.20-3.08 (6H, m), 2.78-2.60 (1H, m) , 2.30-2.08 (2H, m), 1.92-1.83 (1H, m) and 1.42-1.30 (1H, m). LRMS: + ve ion 548 (M + H); -ve ion 546 (M-H).

Example 34: 6- (3,5-Bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (morpholin-4-carbonyl) -hexanoic acid hydroxyamide.

The compounds of Examples 34-38 were prepared by the method of Example 1 according to scheme 1, where ArBr in Step B was 1-bromomethyl-3,5-bis-trifluoromethyl-benzene by parallel synthesis and using the appropriate amine in The 10 Stage G. The products were purified by preparative HPLC.

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1 H NMR; Delta (CD3OD): 7.79 (2H, s), 7.77 (1H, s), 4.07 (1H, d, J = 6.8 Hz), 3.19-3.76 (9H, m ), 2.73-2.98 (2H, m), 1.52-1.88 (4H, m). LRMS: + ion 473 (M + H), 495 (M + Na); -ve ion 471 (M-H).

Example 35: 3R- (4-Benzyl-piperidin-1-carbonyl) -6- (3,5-bis-trifluoromethyl-phenyl) -2S-hydroxy15 hexanoic acid hydroxyamide.

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LRMS: + ion 561 (M + H), 583 (M + Na); -ve ion 559 (M-H).

Example 36: 6- (3,5-bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) hexanoic acid hydroxyamide.

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LRMS: + ve ion 549 (M + H); -ve ion 547 (M-H).

Example 37: 6- (3,5-Bis-trifluoromethyl-phenyl) -3R- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-carbonyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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LRMS: + ve ion 601 (M + Na); -ve ion 577 (M-H). Example 38: 6- (3,5-Bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (pyrrolidin-1-carbonyl) -hexanoic acid hydroxyamide.

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1 H NMR; delta (CD3OD): 7.84 (2H, s), 7.79 (1H, s), 4.06 (1H, d, J = 6.6 Hz), 3.71-3.81 (1H, m ), 3.10-3.54 (5H, m), 2.75-2.83 (1H, m), 1.51-1.98 (7H, m). LRMS: + see ion 479 (M + Na); -ve ion 455 (M-H).

Example 39: 3R- (2S-Benzyl-4-methyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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The compound of Example 39 was prepared by the method of Example 1 according to Scheme 1 and using the appropriate piperazine 10 (synthesized according to the procedure described in J. Heterocyclic Chem, 28, 1.219-1.224, 1991; in Step

A. The product was purified by preparative HPLC.

LRMS: + see ion 484 (M + H).

Example 40: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazin-1 carbonyl] -hexanoic acid hydroxyamide.

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Reagents and conditions: A: RS02Cl 1.2 eq., NEt31.4 eq., CH2CI2, B: TFA / CH2CI2; C: LHS, EDAC, HOAt, CH2CI2; D: H2NOH ac., IPrOH

Scheme 6

Example 40 was prepared as indicated in general in Scheme 6 using the procedures described below.

Stage A: 4- (4-Trifluoromethoxybenzenesulfonyl) -piperazin-1-carboxylic acid tert-butyl ester.

To a solution of piperazin-1-carboxylic acid tert-butyl ester (521 mg, 2.8 mmol) in DCM (6 ml) was added NEt3 (547μl, 3.92 mmol, 1.4 eq.) And chloride of 4-trifluoromethoxybenzenesulfonyl (880 mg, 3.36 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 12 h. The excess sulfonyl chloride was cooled rapidly by the addition of trisamine resin (150 mg) and with subsequent stirring for 2 h. The resin was then filtered off and satd NaHC03 (5 ml) was added. Filtration of the resulting mixture by hydrophobic cartridge and subsequent removal of the solvent under reduced pressure provided the 4- (4-trifluoromethoxy-benzenesulfonyl) -piperazin-1-carboxylic acid tert-butyl ester in quantitative yield.

Stage B: 1- (4-Trifluoromethoxy-benzenesulfonyl) -piperazine. To a cold solution (0 C) of 4 (4-trifluoromethoxybenzenesulfonyl) -piperazin-1-carboxylic acid tert-butyl ester (1.15 g, 2.8 mmol) in DCM (3 ml) was added TFA ( 2 ml) The resulting solution was stirred for 1 h. Then the solvent was removed under reduced pressure. The crude solid was absorbed in AcOEt (15 ml) and washed with NaHCO3sat (2X5 ml), water (5 ml) and finally with brine (5 ml). The organic layer was dried over MgSO4 and the solvent removed in vacuo to provide the desired 1- (4-trifluoromethoxybenzenesulfonyl) -piperazine as a white solid (753 mg, 87% yield).

1 H NMR; Delta (CDCI3): 7.80 (2H, m), 7.38 (2H, m), 3.01 (8H, m). LRMS: + see ion 311 (M + H).

Stage C: 5- {4- (4-ethoxy-phenyl) -1- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazin-1-carbonyl] -butyl} -2,2-dimethyl [1,3] dioxolan -4-one.

To a cold solution (0 C) of 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid (91 mg, 0.27 mmol), 1- (4-Trifluoromethoxy-benzenesulfonyl) -piperazine (100 mg, 0.325 mmol, 1.2 eq.) In DCM (6 mL), WSCDI (62 mg, 0.325 mmol, 1.2 eq.) and HOAt (cat). The reaction mixture was stirred for 16 h allowing the temperature to rise to 20 C. Then DCM was removed under reduced pressure and the resulting reaction mixture was absorbed in AcOEt (30 ml). The organic layer was washed with water (2X10 ml) and with brine (10 ml). The organic layer was dried over MgSO4 and the solvent removed in vacuo to provide 5- {4- (4-ethoxy-phenyl) -1- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazin-1-carbonyl] -butyl} Desired -2,2-dimethyl- [1,3] dioxolan-4-one (170 mg, quant.).

LRMS: + ion 629 (M + H), 651 (M + Na).

Stage D: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazin-1 carbonyl] -hexanoic acid hydroxyamide.

To a solution of 5- {4- (4-ethoxy-phenyl) -1- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazin-1-carbonyl] -butyl} -2,2-dimethyl- [1,3] dioxolan -4-one (170 mg, 0.27 mmol) in iPrOH (5 ml) H2NHOH ac (90 μl, 1.35 mmol, 5 eq.) Was added. The reaction mixture was stirred for 12 h and the solvent was removed in vacuo. The crude reaction mixture was purified by preparative HPLC to give the 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethoxybenzenesulfonyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide .

1 H NMR; Delta (CDCI3): 7.79 (2H, m), 7.38 (2H, m), 7.01 (2H, m), 6.80 (2H, m), 4.06 (2H, c), 3.90 (1H, m), 3.64 (1H, m), 3.43-3.20 (3H, m), 3.19-3.00 (2H, t), 2.91-2, 70 (2H, dt), 2.5 (2H, t), 1.8-1.5 (2H, m), 1.41 (3H, t). LRMS: + ve ion 604 (M + H), 651 (M + Na), -ve ion (602 (M-H).

Example 41: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (toluene-4-sulfonyl) -piperazin-1-carbonyl] hexanoic acid hydroxyamide.

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The compound of example 41-46 was prepared by the method of example 40 according to scheme 6 and using the appropriate sulfonyl chloride in step A.

LRMS: + ve ion 534 (M + H), -ve ion 532 (M-H).

Example 42: 3R - [4- (5-Bromo-thiophene-2-sulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2-Hydroxy-hexanoic acid hydroxyamide.

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10 LRMS: + ve ion 605 (M + H), -ve ion 603 (M-H).

Example 43: 3R - [4- (5-Benzenesulfonyl-thiophene-2-sulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxyphenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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LRMS: + ve ion 666 (M + H), -ve ion 664 (M-H).

Example 44: 3R- [4- (4-Butoxy-benzenesulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2-Hydroxy-hexanoic acid hydroxyamide.

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LRMS: + ve ion 592 (M + H), -ve ion 590 (M-H).

Example 45: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-methoxy-2,3,6-trimethyl-benzenesulfonyl) 20 piperazin-1-carbonyl] -hexanoic acid hydroxyamide.

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LRMS: + ve ion 592 (M + H), -ve ion 590 (M-H).

Example 46: 3R - [4- (3,4-Dimethoxy-benzenesulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2-Hydroxy-hexanoic acid hydroxyamide.

5

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LRMS: + ve ion 580 (M + H), -ve ion 578 (M-H).

The compounds of Examples 47-50 were prepared by the method of Example 1 by parallel synthesis, using the appropriate aryl bromide in Step B and the appropriate amine in Step G. The products were purified by preparative HPLC.

Example 47: 6- (4-Methoxy-phenyl) -2S-hydroxy-3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] hexanoic acid hydroxyamide.

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1 H NMR; Delta (MeOD): 7.20-7.00 (6H, m), 6.85 (2H, m), 4.15-4.10 (1H, m), 3.95-3.70 (6H, m), 3.45-3.35 (4H, m), 3.20-2.95 (3H, m), 2.65-2.55 (2H, m), 1.80-1.55 ( 3H, m). 15 LRMS: + see ion 460 (M + H); -ve ion 458 (M-H). Example 48: 6- (4-Methoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide.

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1 H NMR; Delta (MeOD): 8.15-8.10 (1H, m), 7.65-7.55 (1H, m), 7.15-7.05 (2H, m), 6.90-6, 80 (3H, m), 6.80-6.70 (1H, m), 4.20-4.10 (1H, m), 3.95-3.35 (13H, m), 2.65- 2.55 (2H, m), 1.80-1.55 (3H, m). LRMS: + see ion 443 (M + H).

Example 49: 6- (4-Fluoro-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-hydroxyhexanoic acid hydroxyamide.

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1 H NMR; Delta (MeOD): 7.2-6.9 (8H, m), 4.05 (1H, d), 3.9-3.6 (4H, m), 3.35 (2H, m), 3 , 1-2.9 (3H, m), 2.55 (2H, t), 1.81.5 (3H, m), 1.15 (1H, t). LRMS: + see ion 448 (M + H).

Example 50: 6- (4-Fluoro-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide.

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1 H NMR; delta (MeOD): 8.1 (1H, d), 7.55 (1H, t), 7.15 (2H, m), 6.9 (2H, m), 6.8 (1H, d), 6.7 (1H, m), 4.05 (1H, d), 3.85 (2H, m), 3.7-3.3 (6H, m), 3.05 (1H, t), 2 , 55 (2H, t), 1.8 (4H, m), 1.15 (1H, t). LRMS: + see ion 431 (M + H).

Example 51: 3R- (4-Benzyl-2S-methyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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10 Example 51 was prepared as indicated in general in Scheme 7 using the procedures described below.

The piperazine intermediates used in step A of scheme 7 were prepared according to the procedures described in the Journal of Organic Chemistry, 60, 4,177-4,183, 1995.

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Reagents and conditions: Stage A: 1-benzyl-3S-methyl-piperazine, WSC, HOAt, CH2CI2; Stage B: H2NOHac, iPrOH

Scheme 7

Stage A: 5S- [1- (4-benzyl-2S-methy-piperazin-1-carbonyl) -4R- (4-ethoxy-phenyl) -butyl] -2,2-dimethyl- [1,3] dioxolan- 4-one

To a cold (0C) mixture of 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid (80 mg, 2 , 38.10-4 moles) and 1-benzyl-3S-methyl-piperazine (54 mg, 2.84-10-4 moles, 1.2 eq), WSC (55 mg, 2.84-10-4) was added

20 moles, 1.2 eq) and HOAt (cat). The reaction mixture was then stirred at RT for 16 h before it was diluted by adding 5 ml of CH2CI2. The organic layer was washed with water (3 ml) and then dried over MgSO4. The solvent was removed under reduced pressure to provide 5S- [1- (4-benzyl-2S-methyl-piperazin-1-carbonyl) -4R- (4-ethoxy-phenyl) butyl] -2,2-dimethyl- [ 1,3] desired dioxolan-4-one that was used in the next step without further purification.

Stage B: 3R- (4-Benzyl-2S-methyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

To a cold solution (0C) of 5S- [1- (4-benzyl-2S-methyl-piperazin-1-carbonyl) -4R- (4-ethoxy-phenyl) -butyl] -2,2-dimethyl [1, 3] dioxolan-4-one (120 mg, 2.38.10-4 mol) in iPrOH (4 ml), H2NOH (100 ml, 1.19 10-3 mol, 5 eq) was added. The reaction mixture was stirred at RT for 5 h and the solvent was removed under reduced pressure. The crude oil was purified by prep HPLC. to provide 3R- (4-benzyl-2S-methyl-piperazin-1-carbonyl) -6- (4-ethoxy acid hydroxyamide

5 phenyl) -2S-hydroxy-hexanoic expected as a white solid.

LRMS: + see ion 484 (M + H).

The compound of example 52-61 was prepared by the method of example 51 according to scheme 7 and using the appropriate piperazines.

Example 52: 3R- (4-Benzyl-2S-methyl-piperazin-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxy10 hexanoic acid hydroxyamide.

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LRMS: + see ion 470 (M + H).

Example 53: 3R- (4-Benzyl-2S-i-butyl-piperazin-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxyhexanoic acid hydroxyamide.

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LRMS: + 512 ion (M + H).

Example 54: 3R- (4-Benzyl-2S-methyl-piperazin-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxyhexanoic acid hydroxyamide.

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20 LRMS: + ion 458 (M + H).

Example 55: 3R- (4-Benzyl-2S-i-butyl-piperazin-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxyhexanoic acid hydroxyamide.

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LRMS: + see ion 500 (M + H).

Example 56: 4- [5- (4-Ethoxy-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-methylpiperazin-1-carboxylic acid tert-butyl ester.

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LRMS: + see ion 494 (M + H).

Example 57: 4- [5- (4-Ethoxy-phenyl) -2R- (1 S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-ibyl-piperazin-1-carboxylic acid tert-butyl ester.

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LRMS: + see ion 536 (M + H).

Example 58: 4- [5- (4-Methoxy-phenyl) -2R- (1 S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S10 methyl-piperazin-1-carboxylic acid tert-butyl ester.

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LRMS: + ion 480 (M + H).

Example 59: 4- [5- (4-Methoxy-phenyl) -2R- (1 S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-ibutyl-piperazin-1-carboxylic acid tert-butyl ester.

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LRMS: + see ion 522 (M + H).

Example 60: 4- [5- (4-Fluoro-phenyl) -2R- (1 S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2Smethyl-piperazin-1-carboxylic acid tert-butyl ester.

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LRMS: + see ion 468 (M + H).

Example 61: 4- [5- (4-Fluoro-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-ibyl-piperazin-1-carboxylic acid tert-butyl ester.

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LRMS: + see ion 510 (M + H). Example 62: 6- (4-Ethoxy-phenyl) -2S-methoxy-3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide.

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Reagents and conditions. A: LiHMDS, AIIBr, THF, -78C to TA; B: ArBr, P (o-Tol) 3, Pd (OAc) 2, NEt3, CH3CN; C: 10% Pd / C, H2, MeOH; D: LiOH, MeOH, H20; E: CuCI2, dimethoxypropane, acetone; F: pentafluorophenol, WSCDI, HOAt, 5 CH2CI2; G: 1- (2-fluoro-phenyl) -piperazine, NEt3, CH2CI2; H: thionyl chloride, methanol; I: NaH, methyl iodide, DMF; J: NaOH, MeOH, water; K: BnONH2, WSC, HOBt, DMF; L: H2, Pd / C, ethanol

Scheme 1

The compound of this Example 62 was prepared as indicated in general in Scheme 1 using the procedures described below.

Stage A: 2R-allyl-3S-hydroxy-succinic acid diisopropyl ester. To a cold solution (-78C) of 2S-hydroxy-succinic acid diisopropyl ester (19.70 ml, 95 mmol) in THF (35 ml) was added LiHMDS (200 ml, 0.2 mol, 2.1 eq. ) drop by drop. The reaction mixture was stirred at -78C for two hours and then at 30C for 30 min. The reaction mixture was then cooled to -78C and allyl bromide (12.36 ml, 0.14 mol, 1.5 eq.) Was added dropwise. It was left after the reaction mixture was heated at RT overnight. Poured into a

15 saturated NH4CI / ice solution (200 ml). Extraction with AcOEt (3 X 200 ml) followed by washing with water (50 ml) and with brine (50 ml) provided a yellow oil after removal of the solvents in vacuo. Purification by flash chromatography provided 2R-allyl-3S-hydroxy-succinic acid diisopropyl ester as a colorless oil (7.76 g, = 80%, 40% yield).

1 H NMR; Delta (CDCI3): 5.77-5.88 (1H, m), 4.98-5.21 (4H, m), 4.22 (1H, sa), 3.18 (1H, sa), 2 , 87-2.94 (1H, m), 2.5620 2.65 (1H, m), 2.40-2.48 (1H, m), 1.29 (6H, d, J = 6.3 Hz), 1.22 (6H, d, J = 6.3 Hz). LRMS: + see ion 281 (M + Na).

Stage B: 2R- [3- (4-Ethoxy-phenyl) -alyl] -3S-hydroxy-succinic acid diisopropyl ester.

To a solution of 2R-allyl-3S-hydroxy-succinic acid diisopropyl ester (4.79 g, 18.5 mmol), 4-bromo phenethol (3.19 ml, 22.2 mmol, 1.2 eq.) and NEt3 (6.22 ml, 44.6 mmol, 2.4 eq.) in CH3CN (40 ml), an ultrasonic suspension (for 2 min) of P (0-Tol) 3 (0.57) was added g, 2.22 mmol, 0.1 eq.) and Pd (OAc) 2 (209 mg, 5%) in CH3CN (5 ml). The reaction mixture was heated to boil under reflux for 2 h. CH3CN was removed in vacuo. The crude was extracted with AcOEt (3 X 200 ml), washed with water (50 ml) and with brine (50 ml). Purification by flash chromatography gave the diisopropyl ester of 2R- [3- (4-ethoxy-phenyl) -alyl] -3S-hydroxy-succinic acid (5.92 g, 84% yield).

1 H NMR; Delta (CDCI3): 7.28 (2H, d, J = 8.8 Hz), 6.83 (2H, d, J = 8.8), 6.46 (1H, d, J = 15.7 Hz ), 6.02-6.12 (1H, m), 4,985.13 (2H, m), 4.26 (1H, dd, J = 7.1; 3.0 Hz), 4.02 (2H, c, J = 7.0 Hz): 3.23 (1H, d, J = 7.1 Hz), 2.92-2.97 (1H, m), 2,682.79 (1H, m), 2, 49-2.62 (1H, m), 1.41 (3H, t, J = 7.0 Hz), 1.19-1.30 (12H, m). LRMS: + see ion 401 (M + Na).

Stage C: 2R- [3- (4-Ethoxy-phenyl) -propyl] -3S-hydroxy-succinic acid diisopropyl ester.

To a solution of diisopropyl ester of 2R- [3- (4-ethoxy-phenyl) -alyl] -3S-hydroxy-succinic acid (129 mg, 0.34 mmol) in MeOH (10 ml) in an inert atmosphere, added 10% Pd / C (13 mg). H2 was bubbled through the resulting suspension for 30 min. The reaction mixture was then stirred at 1.01105 Pa (1 atmosphere) of H2 for 16 h. Pd / C was filtered off and the solvent was removed under reduced pressure to give 2R- [3- (4-ethoxy-phenyl) -propyl] -3S-hydroxy-succinic acid diisopropyl ester (115 mg, 88% yield ).

1 H NMR; Delta (CDCI3): 7.08 (2H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.6), 4.97-5.14 (2H, m), 4 , 20 (1H, dd, J = 7.3; 3.5 Hz), 4.01 (2H, c, J = 7.0 Hz), 3.18 (1H, d, J = 7.3 Hz) , 2.77-2.83 (1H, m), 2.55-2.62 (2H, m), 1.45-1.94 (4H, m), 1.40 (3H, t, J = 7.0 Hz), 1.12-1.30 (12H, m). LRMS: + see xx ion (M + Na).

Stage D: 2R- [3- (4-Ethoxy-phenyl) -propyl] -3S-hydroxy-succinic acid. To a solution of 2R- [3- (4-ethoxy-phenyl) -propyl] -3S-hydroxy-succinic acid diisopropyl ester (4.78 g, 12.6 mmol) in THF / water (3: 1, 120 ml) NaOH (1.66 g, 41.5 mmol, 5.5 eq.) was added. The reaction mixture was then stirred for 16 h at RT. The mixture was concentrated under reduced pressure and acidified to pH = 3 by the addition of 1 N HCl. The hydroxyacid was extracted with AcOEt. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give the desired 2R- [3- (4-ethoxy-phenyl) -propyl] 3S-hydroxy-succinic acid (3.66 g, 85% yield ).

1 H NMR; Delta (MeOD): 7.07 (2H, d, J = 8.6 Hz), 6.79 (2H, d, J = 8.6), 4.23 (1H, d, J = 5.8 Hz ), 3.98 (2H, c, J = 7.0 Hz), 2.76-2.81 (1H, m), 2.53-2.59 (2H, m), 1.55-1, 72 (4H, m), 1.35 (3H, t, J = 7.0 Hz). LRMS: + ve ion 319 (M + Na); -ve ion 295 (M-H).

Stage E: 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid.

To a solution of 2R- [3- (4-ethoxy-phenyl) -propyl] -3S-hydroxy-succinic acid (3.66 g, 12.3 mmol) in acetone (50 ml) in an inert atmosphere was added dimethoxypropane (2.58 ml, 21 mmol, 1.7 eq.) And copper chloride (165 mg, 1.2 mmol, 0.1 eq.). The reaction mixture was stirred at RT for 16 h. The solvent was then removed in vacuo to give 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid (4.03 g, 97% yield).

1 H NMR; Delta (CDCI3): 7.08 (2H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5), 4.48 (1H, d, J = 4.8 Hz ), 4.01 (2H, c, J = 7.0 Hz), 2.91-2.98 (1H, m), 2.54-2.64 (3H, m), 1.23-2, 20 (4H, m), 1.58 (3H, s), 1.53 (3H, s), 1.40 (3H, t, J = 7.0 Hz). LRMS: + see 359 ion (M + Na); -ve ion 335 (M-H).

Step F. 2R- (2,2-Dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid pentafluorophenyl ester.

To a cold solution (0C) of 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid (4.03 g , 12 mmol) and pentafluorophenol (2.43 g, 13.2 mmol, 1.1 eq.) In CH2CI2 (50 ml) WSC (2.54 g, 13.2 mmol, 1.1 eq.) Was added. The reaction mixture was allowed to warm to RT overnight. CH2CI2 was removed in vacuo and the resulting crude reaction mixture was dissolved in AcOEt (200 ml). The organic layer was washed with water (50 ml), NaHCO3sat (20 ml) and finally with brine (20 ml). The solvent was removed under reduced pressure to give an oil that was purified by flash chromatography to provide the pentafluorophenyl ester of 2R- (2,2-dimethyl-5oxo- [1,3] dioxolan-4S-yl) -5- ( Expected 4-ethoxy-phenyl) -pentanoic acid (3.94 g, 65% yield).

1 H NMR; delta (CDCI3): 7.09 (2H, d, J = 8.4 Hz), 6.83 (2H, d, J = 8.4 Hz), 4.56 (1H, d, J = 6.0 Hz), 4.01 (2H, c, J = 7.0 Hz), 3.20-3.28 (1H, m), 2.64 (2H, t, J = 7.6 Hz), 1, 98-2.08 (2H, m), 1.70-1.86 (2H, m), 1.62 (3H, s), 1.57 (3H, s), 1.40 (3H, t, J = 7.0 Hz).

Stage G. 5- {4- (4-Ethoxy-phenyl) -1 - [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -butyl} -2,2-dimethyl- [1,3] dioxolan-4-one

To a solution of 2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -5- (4-ethoxy-phenyl) pentanoic acid pentafluorophenyl ester (150 mg, 0.30 mmol) in CH2CI2 (10 ml) 1- (2-fluorophenyl) -4-piperazine (65 mg, 0.36 mmol,

1.2 eq.). The reaction mixture was stirred for 16 h and the solvent was removed in vacuo. The crude was absorbed in AcOEt (70 ml) and washed with water (10 ml), then with NaHCO3sat (10 ml) and finally with brine (10 ml). The solvent was dried over MgSO4 and removed under reduced pressure to give 5- {4- (4-Ethoxy-phenyl) -1- [4- (2-fluoro-phenyl) -piperazin-1carbonyl] -butyl} -2 , 2-dimethyl- [1,3] dioxolan-4-one (97 mg, 65% yield.). 1 H NMR; Delta (CDCI3):

Step H: 6- (4-Ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-hydroxy-hexanoic acid methyl ester.

To a cold solution (0C) of 5- {4- (4-ethoxy-phenyl) -1- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -butyl} -2,2-dimethyl [ 1,3] dioxolan-4-one (482 mg, 0.95 mmol) in methanol (5 ml) thionyl chloride (0.078 ml, 1.06 mmol, 1.1 eq.) Was added dropwise. The reaction mixture was stirred at room temperature and then heated to boil under reflux for 3 hours. The reaction mixture was then cooled to room temperature and evaporated under reduced pressure. The reaction crude was extracted with AcOEt (2 x 50 ml) and washed with 1 M Na2CO3 (50 ml) and brine (50 ml). The organic layer was dried over MgSO4 and purification by flash chromatography provided the 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S methyl ester -hydroxy-hexanoic acid as a colorless oil (200 mg, 44% yield).

1 H NMR; Delta (CDCI3): 7.12 (2H, d, J = 6.5 Hz), 7.08 (4H, m), 6.81 (2H, d, J = 6.3 Hz), 5.00 ( 1H, d, J = 6.1 Hz), 3.98 (2H, c, 5.3; 8.9 Hz), 3.75 (3H, s), 3.40-3.65 (4H, m ), 3.21 (1H, m), 2.99 (4H, ma), 2.64 (2H, m), 1.90-1.65 (4H, m), 1.45 (3H, m) .

LRMS: + see ion 473 (M + H).

Stage I: 6- (4-Ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-methoxy-hexanoic acid methyl ester. To a cold solution (0C) of 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2Shydroxy-hexanoic acid methyl ester (200 mg, 0 , 44 mmol) in anhydrous DMF sodium hydride (20 mg, 0.48 mmol, 1.1 eq, 60% dispersion) was added The reaction mixture was stirred for 30 minutes before dropwise addition of iodide of methyl (0.04 ml, 0.60 mmol, 1.2 eq). The reaction mixture was heated to room temperature and stirred for 16 hours. The reaction crude was evaporated under reduced pressure and extracted with AcOEt (2 x 50 ml) and washed with water and brine (50 ml). Purification by flash chromatography provided the 6- (4-ethoxy-phenyl) 3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-methoxy-hexanoic acid methyl ester as a colorless oil ( 125 mg, 61% yield).

1 H NMR; Delta (CDCI3): 7.12 (2H, d, J = 6.5 Hz), 7.08 (4H, m), 6.81 (2H, d, J = 6.3 Hz), 5.00 ( 1H, d, J = 6.1 Hz), 3.98 (2H, c, 5.3; 8.9 Hz), 3.75 (3H, s), 3.40-3.65 (4H, m ), 3.30 (3H, s), 3.21 (1H, m), 3.05 (4H, ma), 2.64 (2H, m), 1,801.65 (4H, m), 1.39 (3H, t, J = 7.0 Hz). LRMS: + see ion 487 (M + H).

Step J: 6- (4-Ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-methoxy-hexanoic acid.

To a solution of 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-methoxyhexanoic acid methyl ester (125 mg, 0.26 mmol) in methanol / water (3: 1.10 ml) NaOH (11 mg, 0.28 mmol, 1.1 eq.) was added. The reaction mixture was then stirred for 16 h at RT. The mixture was concentrated under reduced pressure and acidified to pH = 3 by the addition of 1 N HCI. Methoxy acid was extracted with AcOEt. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2Smethoxy acid -hexanoic desired (101 mg, 83% yield).

1 H NMR; Delta (CDCI3): 7.12 (2H, d, J = 6.5 Hz), 7.08 (4H, m), 6.81 (2H, d, J = 6.3 Hz), 4.01 ( 1H, d, J = 6.5 Hz), 3.98 (2H, m), 3.45 (3H, s), 3.30-2.85 (8H, m), 2.64 (2H, m ), 1.80-1.65 (4H, m), 1.39 (3H, t, J = 7.0 Hz). LRMS: + see ion 473.2 (M + H).

Step K: 6- (4-Ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-hydroxy-hexanoic acid benzyloxy-amide.

To a cold solution (0C) of 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-methoxy-hexanoic acid (101 mg, 0.21 mmol) in DMF (2 ml) benzylhydroxylamine (39 mg, 0.32 mmol), WSC (49 mg, 0.26 mmol) and finally HOBt (2 mg, 0.043 mmol) were added. The mixture was then allowed to warm to room temperature and stirred for 16 h. The solvent was removed under reduced pressure. The reaction crude was absorbed in AcOEt (30 ml) and washed with water (10 ml), then with NaHCO3sat (10 ml) and finally with brine (10 ml). The solvent was dried over MgSO4 and removed under reduced pressure before purification by column chromatography to give the benzyloxy-amide of the acid 6- (4-Ethoxy-phenyl) -3- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2-hydroxy-hexanoic acid as a white solid (38 mg, 31% yield). LRMS: + see ion 578.2 (M + H).

Stage L: 6- (4-Ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-methoxy-hexanoic acid hydroxyamide.

To a solution of benzyloxyamide of 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-hydroxyhexanoic acid (38 mg, 0.007 mmol) in MeOH ( 10 ml) in an inert atmosphere, 10% Pd / C (5 mg) was added. H2 was bubbled through the resulting suspension for 30 min. The reaction mixture was then stirred under 1.013 N / s.m (1 atmosphere) of H2 for 3 h. Pd / C was filtered off and the solvent was removed under reduced pressure. Purification by preparative HPLC provided 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-methoxy-hexanoic acid hydroxyamide as a white solid (5 mg, 40% yield).

Biological Results

A. Enzyme Inhibition Assays

Its activities as inhibitors of MMP9, MMP12 and MMP-1 were tested in the compounds of the invention.

MMP9 Test Protocol

Inhibitory activity against 92 kDa gelatinase (MMP9) was tested in a compound using a coumarin labeled peptide substrate, (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu- ( 3- [2,4-Dinitrophenyl] -L-2,3-diaminopropionyl) -Ala-Arg-NH2 (McaPLGLDpaAR) (Knight et al, FEBS Lett. 1992; 263-266).

Standard solutions were prepared as follows:

Assay buffer: 100 mM Tris-HCI pH 7.6 containing 100 mM NaCI, 10 mM CaCI2 and 0.05% Brij 35

Substrate: 0.4 mM McaPLGLDpaAR standard solution (from Bachem) (0.437 mg / ml) in 100% DMSO (stored at 20 ° C). Dilute to 8 μM in assay buffer.

Enzyme: Recombinant human 92 kDa gelatinase (MMP-9; APMA (4-aminophenylmercuric acetate) - activated if necessary) diluted appropriately in assay buffer.

The test compounds were initially prepared as a solution of 10 mM compound in 100% DMSO, diluted to 1 mM in 100% DMSO, then serially diluted 3 times in 100% DMSO by 1-10 columns of a plate of 96 well microtiter. The test concentration range, 100 μM (column 1) to 5.1 nM (column 10)

The test was performed in a total volume of 100 μl per well in 96 well microtiter plates. Activated enzyme (20 μI) was added to the wells followed by 20 μl of assay buffer. Appropriate concentrations of the test compounds dissolved in 10 μl of DMSO were then added followed by 50 μl of McaPLGLDpaAR (8 μM, prepared by dilution of standard DMSO in assay buffer). Ten concentrations of test compounds were examined in duplicate for each test. Control wells contained neither enzyme nor test compound. The reactions were incubated at 37 ° C for 2 hours. Fluorescence was measured immediately at 405 nm with an SLT Fluostar fluorimeter (SLT Labinstruments GmbH, Grödig, Austria) using excitation at 320 nm, without stopping the reaction.

The effect of the test compound was determined from the dose response curve by the 10 concentrations in duplicate inhibitor. The IC50 (the concentration of compound required to give a 50% decrease in enzyme activity) was obtained by adjusting the data to the equation, Y = a + ((b -a) / (1 + (c / X) d )). (Y = inhibition achieved for a particular dose; X = the dose in nM; a = minimum and or zero% inhibition; b = maximum and or 100% inhibition; c = is the IC50; d = is the slope). The result was rounded to a significant figure.

MMP12 Test Protocol

Inhibitory activity against metalloelastase (MMP12) was tested in a compound using a coumarin labeled peptide substrate, (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu- (3- [ 2,4-dinitrophenyl] -L-2,3-diaminopropionyl) -Ala-Arg-NH2 (McaPLGLDpaAR) (Knight et al, FEBS Lett. 1992; 263-266). The protocol for this assay was as described for the previous MMP9 assay.

MMP1 Test Protocol

Inhibitory activity against collagenase (MMP1) in a test using a coumarin labeled peptide substrate, (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu- (3-) was tested in the compounds of the invention [2,4-dinitrophenyl] -L-2,3-diaminopropionyl) -Ala-Arg-NH2 (McaPLGLDpaAR) (Knight et al, FEBS Lett. 1992; 263-266). The protocol for this assay was as described for the previous MMP9 assay.

Results:

Key for test data

Interval

TO <100nM

B

100-1,000 nM

C

1,000-10,000 nM

D

> 10,000 nM

For example the inhibitory activities of some of the compounds of the examples against MMP-12, MMP-9,

MMP-2 and MMP-1 are shown in the following table:

Example Number

 MMP-9 (nM) MMP-2 (nM) MMP-1 (nM) MMP-12 (nM)

4

TO TO D TO

5

TO TO D TO

6

B B D TO

12

TO TO D TO

13

TO TO D TO

14

TO TO D TO

20 62

To To D d To

B. Biological Assay: IL2-induced peritoneal regeneration in mice

Protocol

5 C3H mice (Elevage Janvier) (8 weeks, n = 6) received IL2 (SPRI, 20 μg / kg, 40 ml / kg, ip) 15 min after administration of the test molecules. Twenty-four hours later, the animals were sacrificed and the peritoneal cavity was washed using 3 x 5 ml of 1 mM PBS-AEDT (+ 4 ° C). After centrifugation (10 min at 314 rad / s (3,000 rpm)), the granule was resuspended in 1 ml of PBS. Peritoneal cells were counted using a Beckman / Coulter counter. IL2 was solubilized in saline. The solubilized or suspended

10 test compounds of the invention in 0.5% carboxymethylcellulose (CMC) / 0.25% Tween-20 and administered orally. Dexamethasone (0.1 mg / kg, po) was used as the reference compound.

For example, using the compounds of the specified examples, the inhibition of peritoneal regeneration induced by IL-2 was as explained in the following table:

Peritoneal regeneration induced by IL-2

 Dose (mg / kg)

Route  % Inhibition

Example 4

3 po 3. 4%

Example 5

3 po fifty%

Example 6

3 po 33%

Example 13

3 po 47%

Example 14

3 po 30%

Example 20

3 po 57%

Dexamethasone

one sc 76%

5

10

fifteen

twenty

25

30

35

Claims (26)

1. A compound of formula (I) or an enantiomer or diastereomer thereof or a salt, hydrate or solvate thereof: image 1 wherein Ar represents an aryl, heteroaryl, C3-C8 cycloalkyl or optionally substituted heterocycloalkyl group; R represents hydrogen or C1-C6 alkyl, or C3-C6 cycloalkyl; Alq represents a divalent C1-C5 alkylene or C2-C5 and R1 and R2 alkenylene radical taken together with the nitrogen atom to which they are attached form a first heterocycloalkyl ring that is optionally condensed with a second C3-C8 cycloalkyl or heterocycloalkyl ring, said first and second ring being optionally substituted by at least one group of formula (II): image 1 in which m, p and n are independently 0 or 1; Z represents hydrogen or an optionally substituted carbocyclic or heterocyclic ring of 5 to 7 ring atoms which is optionally condensed with another optionally substituted carbocyclic or heterocyclic ring of 5 to 7 ring atoms; Alq1 and Alq2 independently represent optionally substituted divalent C1-C3 alkylene radicals; X represents -0-, -S-, -S (0) -, -S (02) -, -C (= 0) -, -NH-, -NR3-, -S (02) NH-, -S (02) NR3-, -NHS (02) - or -NR3S (02) -, where R3 is C1-C3 alkyl.

2.

 A compound according to claim 1 wherein R is hydrogen.

3.

 A compound according to claim 1 wherein R is methyl.

Four.

 A compound according to claim 1 wherein R is ethyl, n-propyl, isopropyl, n-, sec- or tert-butyl, cyclopropyl

or cyclopentyl.

5.

 A compound according to any of the preceding claims wherein Ar is a 5 or 6 membered monocyclic aryl or heteroaryl ring, which is optionally substituted by at least one substituent selected from: (C1-C3) alkyl, (C 1-C3) alkoxy ), hydroxy, hydroxyalkyl (C1-C3), mercapto, mercaptoalkyl (C1-C3), alkylthio (C1-C3), halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), -COOH, -COORA, -CORA, -S02RA, -CONH2, -SO2NH2, -CONHRA, -S02NHRA, -CONRARB, -S02NRARB, -NH2, -NHRA, -NRARB, -OCONH2, -OCONHRA, -OCONRARB, -NHCORA, -NHCOORA, -NHCOORA-- , -NRBS02ORA, -NHCONH2, -NRACONH2, -NHCONHRB, -NRACONHRB, -NHCONRARB or -NRACONRARB in which RA and RB are independently alkyl (C1-C3), phenyl or a 5 or 6 membered monocyclic aryl or heteroaryl ring.

6.

 A compound according to claim 5 wherein an optional substituent is in the 4 position in the case of a 6 member ring or in the 2 and / or 3 position in the case of a 5 member ring.

7.

A compound according to any of the preceding claims wherein Ar is phenyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl or 2-or 3-furanyl optionally substituted.

8.

 A compound according to any one of the preceding claims wherein the optional substituents in Ar 39

5 10 fifteen twenty 25 30 they are selected from methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl, hydroxyl, mercapto, fluoro, chloro and bromo.

9.

 A compound according to claim 5 wherein Ar is 4- (C1C3 alkoxy) phenyl.

10.

 A compound according to claim 5 wherein Ar is 4-ethoxyphenyl

eleven.

 A compound according to any of the preceding claims wherein Alq is -CH2-, -CH2CH2-, CH2CH (CH3) -, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH = CH-, -CH2CH = CH-, -CH2CH = CHCH2- or -CH = CHCH = CH-.

12.

A compound according to any one of the preceding claims wherein -NR1R2 forms a pyrrolidinyl, morphyl or thiomorphyl ring.

13.

 A compound according to any one of claims 1 to 11 wherein -NR1R2 forms a piperidinyl or piperazinyl ring.

14.

 A compound according to any one of the preceding claims wherein in group (II), when present, p is 0, Z is hydrogen and at least one of n and m is 1.

fifteen.

 A compound according to any one of claims 1 to 13 wherein in group (II), when present, m, n and p are all 0 and Z is a carbocyclic or heterocyclic ring directly attached to a carbon of the ring or nitrogen of the ring of the group -NR1R2.

16.

 A compound according to any one of claims 1 to 13 wherein in group (II), when present, p is 0, at least one of myn is 1, and Z is a carbocyclic or heterocyclic ring attached to a ring carbon or ring-group nitrogen -NR1R2 via a C1-C6 alkylene linker between Z and the -NR1R2 ring.

17.

 A compound according to any one of claims 1 to 13 wherein in group (II), when present, p is 1.

18.

 A compound according to claim 1 of formula (IB) or (IC) or an enantiomer or diastereomer thereof or a salt, hydrate or solvate thereof:

image 1 wherein R is hydrogen or methoxy, R3 is trifluoromethyl, trifluoromethoxyalkoxy C1-C3, hydroxy or halo; R4 is (i) -SO2R5 or -COR5 in which R5 is C1-C6 alkyl or phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, optionally substituted by (C1-C3) alkyl, (C1-C3) alkoxy, hydroxy, hydroxyalkyl (C1-C3), mercapto, mercaptoalkyl (C1-C3), alkylthio (C1-C3), halo, trifluoromethyl, trifluoromethoxy or (ii) phenyl or monocyclic heteroaryl having 5 or 6 ring atoms; optionally substituted by (C1-C3) alkyl, (C1-C3) alkoxy, hydroxy, hydroxyalkyl (C1-C3), mercapto, mercaptoalkyl (C1-C3), alkylthio (C1-C3), halo, trifluoromethyl, trifluoromethoxy.

19.

 A compound according to claim 18 wherein a heteroaryl ring that is part of R4 is pyridyl, pyrimidinyl, triazinyl, thienyl or furanyl.

twenty.

 A compound according to any of the preceding claims, which has the stereochemical configuration shown in formula (IA):

twenty-one.

A compound according to claim 1, which is selected from the group consisting of: 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (pyrrolidin-1-carbonyl) -hexanoic acid hydroxyamide. 3R- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (3-methoxy-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-methoxy-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-4-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (2RS-methyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (2,6-RS-dimethyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (thiomorpholin-4-carbonyl) -hexanoic acid hydroxyamide. 3R- (4-Benzyl-piperidin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-Benzo [1,3] dioxol-5-ylmethyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-4-ylmethyl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-benzylpiperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (4-pyrimidin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethyl-pyrimidin-2-yl) -piperazin-1-carbonyl] hydroxyamide

image 1 hexanoic 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-chloro-pyrimidin-2-yl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 3R- [4- (4,6-Dimethoxy- [1,3,5] triazin-2-yl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxy acid hydroxyamide hexanoic 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 3R- [4- (Acetyl-methyl-amino) -piperidin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (methyl-propyl-amino) -piperidin-1-carbonyl] -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (3S-benzyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (3S-isobutyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- (3S-phenyl-morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 3R- (4-Benzyl-3RS-methyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (3S, 4-dibenzyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-Benzyl-3RS-phenyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 4- (4-benzo [1,3] dioxol-5-ylmethyl-piperazin-1-iI) -2S, N-dihydroxy-4-oxo-3R- (4-trifluoromethoxy-benzyl) -butyramide. 3R-benzyl-2S, N-dihydroxy-4-morpholin-4-yl-4-oxo-butyramide. 3R- (4-Benzyloxy-benzyl) -2S, N-dihydroxy-4-oxo-4-piperidin-1-yl-butyramide. 2S, N-dihydroxy-3R- (4-hydroxy-benzyl) -4-oxo-4-piperidin-1-yl-butyramide. 4- (4-benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -3R- (4-benzyloxy-benzyl) -2S, N-dihydroxy-4-oxo-butyramide. 6- (3,5-Bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (morpholin-4-carbonyl) -hexanoic acid hydroxyamide. 3R- (4-Benzyl-piperidin-1-carbonyl) -6- (3,5-bis-trifluoromethyl-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (3,5-Bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (3,5-Bis-Trifluoromethyl-phenyl) -3R- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-carbonyl) -2S hydroxyamide hydroxy-hexanoic. 6- (3,5-Bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (pyrrolidin-1-carbonyl) -hexanoic acid hydroxyamide. 3R- (2S-Benzyl-4-methyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazin-1-carbonyl acid hydroxyamide] hexanoic 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (toluene-4-sulfonyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 3R- [4- (5-Bromo-thiophene-2-sulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxy acid hydroxyamide hexanoic 3R- [4- (5-Benzenesulfonyl-thiophene-2-sulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxyhexanoic acid hydroxyamide. 3R- [4- (4-Butoxy-benzenesulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-methoxy-2,3,6-trimethyl-benzenesulfonyl) -piperazin-1 acid hydroxyamide carbonyl] -hexanoic. 3R- [4- (3,4-Dimethoxy-benzenesulfonyl) -piperazin-1-carbonyl] -6- (4-ethoxy-phenyl) -2S-hydroxyhexanoic acid hydroxyamide. 6- (4-Methoxy-phenyl) -2S-hydroxy-3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide. 6- (4-Methoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 6- (4-Fluoro-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -2S-hydroxy-hexanoic acid hydroxyamide. 6- (4-Fluoro-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazin-1-carbonyl) -hexanoic acid hydroxyamide. 3R- (4-Benzyl-2S-methyl-piperazin-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-Benzyl-2S-methyl-piperazin-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-Benzyl-2S-i-butyl-piperazin-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-Benzyl-2S-methyl-piperazin-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 3R- (4-Benzyl-2S-i-butyl-piperazin-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide. 4- [5- (4-Ethoxy-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-methyl-piperazin-1 acid tert-butyl ester carboxylic. 4- [5- (4-Ethoxy-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-i-butyl-piperazine-1-carboxylic acid tert-butyl ester. 4- [5- (4-Methoxy-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-methyl-piperazin acid tert-butyl ester 1-carboxylic. 4- [5- (4-Methoxy-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-i-butyl-piperazin acid tert-butyl ester 1-carboxylic. 4- [5- (4-Fluoro-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-methyl-piperazine-1-carboxylic acid tert-butyl ester. 4- [5- (4-Fluoro-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl] -2S-i-butyl-piperazin acid tert-butyl ester 5 1-carboxylic. 6- (4-Ethoxy-phenyl) -2S-methoxy-3R- [4- (2-fluoro-phenyl) -piperazin-1-carbonyl] -hexanoic acid hydroxyamide.

22

 A pharmaceutical composition comprising a compound according to any of the preceding claims, together with a pharmaceutically acceptable carrier.

2. 3.

The use of a compound according to any one of claims 1 to 21 in the preparation of an agent for the

10 treatment or prophylaxis of diseases or conditions responsible for the inhibition of MMP-12 and / or MMP-9, selected from fibrotic disease, multiple sclerosis, emphysema, bronchitis and asthma. 24. A method for preparing metalloproteinase inhibitors of formula (IA) according to any one of claims 1 to 21, wherein R is hydrogen, comprising the deprotection and / or transformation step of: image 1 Wherein Ar, Alq, R1 and R2 are as defined in any one of claims 1 to 16. 25. A compound of formula (IIIB) image 1 wherein Ar, Alq, R1 and R2 are as defined in any one of claims 1 to 19. 26. A process for the preparation of a compound according to claim 25, comprising the step of reacting a compound according to formula (III) image 1 with a cyclic amine HNR1R2, wherein Ar, Alq, R1 and R2 are as defined in any one of claims 1 to 19.