HK1104925B

HK1104925B - Derivatives of hydroxamic acid as metalloproteinase inhibitors

Info

Publication number: HK1104925B
Application number: HK07110022.4A
Authority: HK
Inventors: G.佩恩; S.J.戴维斯; A．邦布伦
Original assignee: 弗奈利斯(牛津)公司; 雪兰诺实验室有限公司
Priority date: 2003-08-23
Filing date: 2004-08-18
Publication date: 2012-05-25

Description

Hydroximic acid derivatives as metalloproteinase inhibitors

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

Background

Matrix Metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that are capable of cleaving large biomolecules such as collagen, proteoglycans and gelatin. An imbalance between active MMPs and endogenous inhibitors leads to excessive tissue destruction. The three main groups of MMPs are collagenase, gelatinase and stromelysin. The collagenases include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), and collagenase 3 (MMP-13). Gelatinases include 72kDa gelatinase (gelatinase A; MMP-2) and 92kDa gelatinase (gelatinase B; MMP-9). The stromelysins include stromelysin 1(MMP-3), stromelysin 2(MMP-10) and stromelysin protein (MMP-7). However, some MMPs are not well suited to be divided into the above-mentioned groups, such as metalloelastase (MMP-12), membrane-type MMPs (MT-MMP or MMP-14), and stromelysin 3 (MMP-11).

Overexpression and activation of MMPs are associated with various diseases, such as cancer; rheumatoid arthritis; osteoarthritis; chronic inflammation, such as asthma, bronchitis, and emphysema; cardiovascular diseases, such as atherosclerosis; corneal ulceration; dental diseases such as gingivitis and periodontal disease; neurological diseases such as multiple sclerosis and restenosis. For example, MMP-12, Science, 277, 2002(1997) is required for the development of tobacco smoke-induced emphysema in mice. Thus, inhibition of MMPs is a therapeutic approach to these conditions. However, there is evidence that non-selective inhibition of matrix metalloproteinase activity may affect normal physiological processes, causing dose-limiting side effects. Selective inhibition of MMP-12 and/or MMP-9 is considered to be a particularly relevant approach to intervention in inflammation.

Some MMPs can hydrolyze membrane-bound precursors of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). This cleavage produces mature soluble TNF- α, which some MMP inhibitors can block in vitro and in vivo. This pharmacological effect may contribute to the anti-inflammatory effect of such compounds.

For a recent review of MMP inhibition reflected in this patent document, see Doherty et al, Therapeutic development of Matrix metalloproteinase inhibition (Therapeutic Developments in Matrix metalloproteinases inhibition); expert Opinions on Therapeutic documents, 2002, 12, 665-.

Many MMP inhibitors in the prior art have a hydroxamic acid metal binding group (-CONHOH).

Summary of The Invention

The present invention provides a class of compounds that are, in general, selective inhibitors of MMP-12 relative to collagenase and stromelysin.

In addition, the compounds of the present invention may exhibit selective activity for MMP-9. Thus, the compounds of the present invention are indicated to be useful in the treatment of diseases mediated primarily by MMP-12 and/or MMP-9, particularly inflammation such as multiple sclerosis and fibrosis.

Detailed Description

The present invention provides a compound of formula (I), or an enantiomer or diastereomer thereof, or a salt, hydrate or solvate thereof:

wherein

Ar represents optionally substituted aryl, heteroaryl, C₃-C₈Cycloalkyl or heterocycloalkyl;

r represents hydrogen or C₁-C₆Alkyl, or C₃-C₆A cycloalkyl group;

alk represents divalent C₁-C₅Alkylene or C₂-C₅An alkenylene group; and

R₁and R₂Together with the nitrogen atom to which they are attached form an optionally fused second C₃-C₈A first heterocycloalkyl group of cycloalkyl or heterocycloalkyl, said first and second rings being optionally substituted with at least one group of formula (II):

wherein

m, p and n are independently 0 or 1;

z represents hydrogen, or an optionally substituted 5-7 membered carbocyclic or heterocyclic ring optionally fused to another optionally substituted 5-7 membered carbocyclic or heterocyclic ring;

Alk¹and Alk²Independently represents optionally substituted divalent C₁-C₃An alkylene group;

x represents-O-, -S (O)₂)-、-C(＝O)-、-NH-、-NR₃-、-S(O₂)NH-、-S(O₂)NR₃-、-NHS(O₂) -or-NR₃S(O₂) -, wherein R₃Is C₁-C₃An alkyl group.

The term "(C) as used herein_a-C_b) Alkyl ", wherein a and b are integers, refers to straight or branched alkyl moieties having a to b 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.

The term "divalent (C) as used herein_a-C_b) Alkylene group "Wherein a and b are integers, means a saturated hydrocarbon chain having a to b carbon atoms and two unsaturated valences.

The term "(C) as used herein_a-C_b) Alkenyl ", wherein a and b are integers, refers to straight or branched chain alkenyl moieties having a to b carbon atoms with at least one applicable double bond of E or Z stereochemistry. The term includes, for example: vinyl, allyl, 1-and 2-butenyl and 2-methyl-2-propenyl, depending on the values of a and b.

The term "divalent (C) as used herein_a-C_b) Alkenylene "refers to a hydrocarbon chain having a-b carbon atoms, at least one double bond, and two unsaturated valencies.

The unlimited term "carbocyclyl" or "carbocycle" as used herein refers to a 3-14 membered ring or ring system wherein each is carbon, including "aryl", "cycloalkyl" and "cycloalkenyl" as defined below.

The unlimited term "cycloalkyl" as used herein refers to a saturated alicyclic moiety having 3 to 8 carbon atoms containing a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). Preferred cycloalkyl groups include cyclopentyl, cyclohexyl, norbornyl, and the like.

As used herein, the unlimited term "cycloalkenyl" refers to unsaturated alicyclic moieties having 3 to 8 carbon atoms, including for example: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. In the case of cycloalkenyl of 5 to 8 carbon atoms, the ring may contain more than one double bond.

The unlimited term "aryl" as used herein refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring or multiple condensed rings and to two covalently linked monocyclic carbocyclic aromatic groups. Examples of aryl groups include phenyl, biphenyl, and the like.

As used herein, the unlimited term "heterocyclyl" or "heterocycle" refers to a ring or ring system in which the ring members include one or more heteroatoms selected from O, S and N, and this term includes "heteroaryl" and "heterocycloalkyl" as defined below.

The unlimited term "heterocycloalkyl" as used herein refers to a cycloalkyl group as defined above, wherein up to 3 ring carbon atoms are substituted with a heteroatom selected from O, S and N. Preferred heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, 1-methylpiperazinyl, morpholinyl and the like.

The unlimited term "heteroaryl" as used herein refers to a monocyclic, or fused bicyclic or tricyclic aromatic ring or ring system containing one or more heteroatoms selected from O, S and N, and to a group containing two covalently linked monocyclic aromatic rings containing one or more such heteroatoms; and refers to groups containing a monocyclic aromatic group covalently linked to a monocyclic aromatic ring containing one or more heteroatoms. Specific examples of heteroaryl groups include: optionally substituted pyridyl, pyrimidinyl, pyrrolyl, furanyl, 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, 4-oxadiazolyl, 1, 2, 4-triazinyl, 1, 2, 3-triazinyl, benzofuranyl, [2, 3-dihydro ] benzofuranyl, isobenzofuranyl, benzothiophenyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1, 2, -c ] pyridyl, benzothiazolyl, benzoxazolyl, quinazolinyl, M-naphthyridinyl, 2, 3-naphthyridinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido [3, 4-c ] pyridyl, pyrido [3, 2-c ] 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.

Unless otherwise specified where the context appears, the term "substituted" as used herein in any part refers, for example, to substitution with at least one substituent selected from the group consisting of: (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, hydroxy (C)₁-C₆) Alkyl, mercapto (C)₁-C₆) Alkyl, (C)₁-C₆) Alkylthio, halogen (including fluoro and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, phenyl, -COOH, -COOR^A、-COR^A、-SO₂R^A、-CONH₂、-SO₂NH₂、-CONHR^A、-SO₂NHR^A、-CONR^AR^B、-SO₂NR^AR^B、-NH₂、-NHR^A、-NR^AR^B、-OCONH₂、-OCONHR^A、-OCONR^AR^B、-NHCOR^A、-NHCOOR^A、-NR^BCOOR^A、-NHSO₂OR^A、-NR^BSO₂OR^A、-NHCONH₂、-NR^ACONH₂、-NHCONHR^B、-NR^ACONHR^B、-NHCONR^AR^Bor-NR^ACONR^AR^BWherein R is^AAnd R^BIndependently is (C)₁-C₆) Alkyl or phenyl.

The term "salt" as used herein includes base adducts, acid adducts and quaternary salts. The acidic compounds of the present invention can be reacted with a base, for example, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide, barium hydroxide and magnesium hydroxide; organic bases such as N-methyl-D-glucamine, choline tris (hydroxymethyl) amino-methane, L-arginine, L-lysine, N-ethylpiperidine, dibenzylamine and the like form salts, including pharmaceutically acceptable salts. Those basic compounds (I) can form salts, including pharmaceutically acceptable salts, with inorganic acids, for example with hydrohalic acids such as hydrochloric or hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, and the like, and with organic acids, for example with acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, benzenesulfonic acid, glutamic acid, lactic acid and mandelic acid, and the like.

For a review of suitable salts see Stahl and Wermuth, handbook of pharmaceutical salts: properties, Selection and uses (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) (Wiley-VCH, Weinheim, Germany, 2002).

The term "solvate" as used herein describes a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol. When the solvent is water, the term "hydrate" is used.

The compounds to which the present invention relates may exist in one or more stereoisomeric forms which, due to the presence of asymmetric atoms or rotational constraints, may exist as a plurality of stereoisomers having R or S stereochemistry at each chiral center, or as atropisomers having R or S stereochemistry at each chiral axis. The present invention includes all such enantiomers and diastereomers and mixtures thereof. Specifically included in the present invention are compounds (IA) having the following stereochemical configuration:

the compounds of the present invention include compounds of formula (I) as described above, including all polymorphs and crystal habit thereof, prodrugs and isomers (including optical isomers, geometric isomers and tautomers) thereof as described above and isotopically-labeled compounds of formula (I).

Group Ar

Ar may be, for example, a 5-or 6-membered monocyclic aryl or heteroaryl ring, which is optionally substituted, for example at the 4-position in the case of a 6-membered ring, or at the 2-and/or 3-position in the case of a 5-membered ring, with at least one substituent selected from: (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, hydroxy (C)₁-C₃) Alkyl, mercapto (C)₁-C₃) Alkyl, (C)₁-C₃) Alkylthio, halogen, trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), -COOH, -COOR^A、-COR^A、-SO₂R^A、-CONH₂、-SO₂NH₂、-CONHR^A、-SO₂NHR^A、-CONR^AR^B、-SO₂NR^AR^B、-NH₂、-NHR^A、-NR^AR^B、-OCONH₂、-OCONHR^A、-OCONR^AR^B、-NHCOR^A、-NHCOOR^A、-NR^BCOOR^A、-NHSO₂OR^A、-NR^BSO₂OR^A、-NHCONH₂、-NR^ACONH₂、-NHCONHR^B、-NR^ACONHR^B、-NHCONR^AR^Bor-NR^ACONR^AR^BWherein R is^AAnd R^BIndependently is C₁-C₃Alkyl, phenyl, or a 5-or 6-membered monocyclic aryl or heteroaryl ring.

Ar may be, for example, phenyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl, or 2-or 3-furyl, which may be optionally substituted as described above with respect to formula (I). The substituents may preferably be, for example: methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl, hydroxy, mercapto, fluoro, chloro or bromo. Here, Ar is preferably 4- (C)₁-C₃Alkoxy) phenyl, most preferably ethoxyphenyl.

Radical R

In one embodiment of the invention, R is hydrogen.

In another embodiment of the invention, R is (C)₁-C₆) Alkyl radicals, such as the ethyl, n-propyl, isopropyl, n-, sec-or tert-butyl radical. In a preferred embodiment, R is methyl.

In yet another embodiment, R is C₃-C₆Cycloalkyl radicals, e.g. cyclopropyl orA cyclopentyl group.

Alk radical

Alk may be, for example, -CH₂-、-CH₂CH₂-、-CH₂CH(CH₃)-、-CH₂CH₂CH₂-、-CH₂CH₂CH₂CH₂-、-CH＝CH-、-CH₂CH＝CH-、-CH₂CH＝CHCH₂-or-CH ═ CHCH ═ CH-. Alk herein is preferably-CH₂CH₂CH₂-。

group-NR ₁ R ₂

The group is a first ring having 5 to 7 atoms as a saturated heterocyclic ring optionally fused to a second ring having 5 to 7 atoms as a saturated or unsaturated carbocyclic or heterocyclic ring. (the first and/or second ring may be optionally substituted with a group of formula (II), discussed below). group-NR₁R₂One of the heteroatoms of (a) is of course the nitrogen shown, it may be the only heteroatom in the ring system, or there may be other nitrogen, oxygen or sulphur atoms in the ring.

The radical-NR may be unsubstituted or substituted by at least one radical (II)₁R₂：

It should be noted that since Alk¹Or Alk²The optional substituent in (a) may be oxo, so the carbonyl group may be located in the vicinity of the X element, forming, for example, a combination such as an amide, a reverse amide, and a carboxyl linkage.

In one embodiment of the invention, R₁And R₂Together with the nitrogen atom to which they are attached form a morpholinyl radical, areAt least one group of formula (II) is optionally substituted.

In another embodiment of the invention, R₁And R₂Together with the nitrogen atom to which they are attached form a thiomorpholinyl group, optionally substituted by at least one group of formula (II).

In another embodiment of the invention, R₁And R₂Together with the nitrogen atom to which they are attached form a piperidinyl group, optionally substituted with at least one group of formula (II).

In another embodiment of the invention, R₁And R₂Together with the nitrogen atom to which they are attached form a pyrrolidinyl group, optionally substituted with at least one group of formula (II).

In another embodiment of the invention, R₁And R₂Together with the nitrogen atom to which they are attached form a piperazinyl group, optionally substituted with at least one group of formula (II).

In one embodiment of the invention, p in the radical (II) is 0, Z is hydrogen and at least one of n and m is 1. In this subclass, the group (II) is optionally substituted C₁-C₆Alkyl, it being possible to link the radical (II) to-NR₁R₂A ring carbon or ring nitrogen of the group. For example when-NR₁R₂When it is piperidinyl or piperazinyl, 4-C (in the former) and 4-N (in the latter) may be substituted with methyl, ethyl, or N-propyl or isopropyl.

In a second embodiment of the invention, m, n and p in the radical (II) are all 0 and Z is directly linked to-NR₁R₂A carbocyclic or heterocyclic ring on a ring carbon or ring nitrogen of the group. Examples of such directly attached rings Z include cyclopentyl and cyclyl, (preferably) aryl or heteroaryl rings such as phenyl, pyridyl, thienyl, furyl and pyrimidinyl. The directly linked rings may themselves be substituted by optional substituents, for example methoxy, ethoxy, n-or isopropoxy, trifluoromethoxy, methylenedioxy, ethylenedioxy, methyl, ethyl, n-propyl or isopropylA group, trifluoromethyl, fluorine, chlorine, bromine, methylsulfonyl, phenylsulfonyl, or mono (C)₁-C₃) Alkylamino or di (C)₁-C₃) An alkylamino group.

In a third embodiment of the invention, p in the radical (II) is 0, at least one of m and n is 1, Z is defined by Z and-NR₁R₂C between rings₁-C₆The alkylene linker (linker) is directly attached to-NR₁R₂A carbocyclic or heterocyclic ring on a ring carbon or ring nitrogen of the group. In this case, ring Z may be any of the optionally substituted Z rings discussed and preferred above in the context of the second subclass of group (II), but here Z is taken to be via optionally substituted C₁-C₆Alkylene linking groups, e.g. -CH₂-or-CH₂CH₂The radical-being linked to the radical-NR₁R₂And (4) a ring.

In a fourth embodiment of the invention, p in the radical (II) is 1, so that the radical (II) contains the X heteroatom. It is clear that when m is 0, X is directly linked to-NR₁R₂A ring; when m and n are both 1, X interrupts Z and-NR₁R₂C between rings₁-C₆An alkylene linker; when one of m and n is 1 and the other is 0, the group (II) represents a direct link to-NR₁R₂Ring, or through C₁-C₃Various O, S or N-containing substituents attached to the alkylene linker.

One embodiment of the present invention includes compounds of formula (IB) or (IC) and salts, hydrates and solvates thereof, particularly compounds having the stereoconfiguration of formula (IA above):

(C₁-C₃) Alkylthio, halogen, trifluoromethyl, trifluoromethoxy optionally substituted, or (ii) phenyl or a monocyclic ring having 5-6 ring atomsA heteroaryl group; quilt (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, hydroxy (C)₁-C₃) Alkyl, mercapto (C)₁-C₃) Alkyl, (C)₁-C₃) Alkylthio, halogen, trifluoromethyl, trifluoromethoxy are optionally substituted. In this embodiment, examples of heteroaryl rings forming part R4 include pyridyl, pyrimidinyl, triazinyl, thienyl and furanyl.

Particular embodiments of the present invention are compounds selected from the group consisting of:

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (pyrrolidine-1-carbonyl) -hexanoic acid hydroxyamide.

3R- (6, 7-dimethoxy-3, 4-dihydro-1H-isoquinoline-2-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (3-methoxy-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-methoxy-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-4-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (2 RS-methyl-morpholine-4-carbonyl) -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (2, 6-RS-dimethyl-morpholine-4-carbonyl) -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (thiomorpholine-4-carbonyl) -hexanoic acid hydroxyamide.

3R- (4-benzyl-piperidine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

3R- (4-benzo [1, 3] dioxol-5-ylmethyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-4-ylmethyl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-benzylpiperazine-1-carbonyl) -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-pyrimidin-2-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethyl-pyrimidin-2-yl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-chloro-pyrimidin-2-yl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

3R- [4- (4, 6-dimethoxy- [1, 3, 5] triazin-2-yl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

3R- [4- (acetyl-methyl-amino) -piperidine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (methyl-propyl-amino) -piperidine-1-carbonyl ] -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (3S-benzyl-morpholine-4-carbonyl) -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (3S-isobutyl-morpholine-4-carbonyl) -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (3S-phenyl-morpholine-4-carbonyl) -hexanoic acid hydroxyamide.

3R- (4-benzyl-3 RS-methyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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

3R- (4-benzyl-3 RS-phenyl-piperazine-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-trifluoromethyl-phenyl) -2S-hydroxy-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide.

3R- (4-benzyl-piperidine-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-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

6- (3, 5-bis-trifluoromethyl-phenyl) -3R- (6, 7-dimethoxy-3, 4-dihydro-1H-isoquinoline-2-carbonyl) -2S-hydroxy-hexanoic acid hydroxyamide.

6- (3, 5-bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (pyrrolidine-1-carbonyl) -hexanoic acid hydroxyamide.

3R- (2S-benzyl-4-methyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (toluene-4-sulfonyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

3R- [4- (5-bromo-thiophene-2-sulfonyl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

3R- [4- (5-benzenesulfonyl-thiophene-2-sulfonyl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

3R- [4- (4-butoxy-benzenesulfonyl) -piperazine-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) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

3R- [4- (3, 4-dimethoxy-benzenesulfonyl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

6- (4-methoxy-phenyl) -2S-hydroxy-3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

6- (4-methoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

6- (4-fluoro-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -2S-hydroxy-hexanoic acid hydroxyamide.

6- (4-fluoro-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

3R- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

3R- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

3R- (4-benzyl-2S-isobutyl-piperazine-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

3R- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

3R- (4-benzyl-2S-isobutyl-piperazine-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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

4- [5- (4-ethoxy-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl ] -2S-isobutyl-piperazine-1-carboxylic acid tert-butyl ester.

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

4- [5- (4-methoxy-phenyl) -2R- (1S-hydroxy-hydroxycarbamoyl-methyl) -pentanoyl ] -2S-isobutyl-piperazine-1-carboxylic acid tert-butyl ester.

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-isobutyl-piperazine-1-carboxylic acid tert-butyl ester.

6- (4-ethoxy-phenyl) -2S-methoxy-3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

As noted above, the compounds of the invention are useful in human or veterinary medicine because they have MMP inhibitory activity, and in particular are selective inhibitors of MMP-12 (and/or MMP-9) over MMP-1 and other collagenases and stromelysins. Thus, in another aspect, the invention relates to:

(i) a method of treatment (meaning treatment or prophylaxis) of a disease or condition which is responsive to inhibition of MMP-12 and/or MMP-9 in a mammal, especially a human, which comprises administering to the mammal an effective amount of a compound of formula (I) as hereinbefore described, or a pharmaceutically acceptable salt thereof; and

(ii) the compounds of formula (I) above are useful in human or veterinary medicine, particularly in the treatment (meaning treatment or prevention) of diseases or conditions responsive to MMP-12 and/or MMP-9 inhibition. (diseases or conditions responsive to inhibition of MMP-12 and/or MMP-9 include bone resorption, tumor growth or secondary metastatic invasion; rheumatoid arthritis, septic arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, cardiac hypertrophy, acute respiratory distress syndrome, neuroinflammatory disorders such as multiple sclerosis, restenosis, emphysema, fibrotic disorders such as postradiation fibrosis, corneal scarring (kerotid scaring), hepatic fibrosis and cystic fibrosis; chronic obstructive pulmonary disease; bronchitis; asthma; autoimmune diseases; graft rejection (such as graft versus host disease; cystic fibrosis; psoriasis; psoriatic arthritis; degenerative cartilage loss; inflammatory stomach disorders such as Crohn's disease, inflammatory bowel disease and ulcerative colitis; atopic dermatitis, epidermolysis bullosa; epidermal ulcers; neuropathy or nephropathies such as interstitial nephritis; psoriasis; atopic dermatitis, secondary metastatic invasion; inflammatory diseases such as rheumatoid arthritis, septic arthritis, inflammatory bowel disease and ulcerative colitis; atopic dermatitis, epidermolysis bullosa; atopic dermatitis; neuropathy or nephrosis, such as interstitial nephritis, Glomerulonephritis or renal failure; inflammation of the eye; cirrhosis, Sjoegren syndrome; or inflammation of the nervous system; and

(iii) use of a compound of formula (I) as a medicament; and

(iv) the use of a compound of formula (I) as defined above for the manufacture of a medicament (agent) for the treatment (meaning treatment or prevention) of a disease or condition responsive to MMP-12 and/or MMP-9 inhibition; and

(v) the use of a compound of formula (I) for the preparation of a medicament for the prevention and treatment of a disease selected from the group consisting of: inflammatory diseases include multiple sclerosis, emphysema, bronchitis, asthma, and MMP-12 and/or MMP-9 related diseases.

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

It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. The optimal dose level and dosing frequency are determined by clinical trials.

The compounds of the invention may be prepared so that they can be administered by any route consistent with their pharmacokinetic properties. Orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel dosage forms such as oral, topical or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be presented in unit dose form and may contain conventional excipients such as binding agents, for example syrup, gum arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, such as magnesium stearate, talc, polyethylene glycol or silica; a disintegrant such as potato starch or an acceptable wetting agent such as sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid dosage forms may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid dosage forms may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifiers, such as lecithin, sorbitan monooleate or gum arabic; non-aqueous media (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerol, propylene glycol or ethanol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, may, if desired, also contain conventional flavouring or colouring agents.

For topical application to the skin, the medicament may be formulated as a cream, lotion or ointment. Cream or ointment formulations which may be used for the medicament are conventional formulations well known in the art, as described in standard textbooks of pharmacy, such as the british pharmacopoeia.

For topical administration to the eye, the drug may be formulated as a solution or suspension in a suitable sterile aqueous or nonaqueous medium. Additives may also be included, for example buffers such as sodium metabisulphite or edetate disodium; preservatives include bactericides and fungicides, such as phenylmercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickeners such as hydrolysed cellulose (hypromellose).

The active ingredient may also be administered parenterally, dissolved in a sterile medium. Depending on the medium and concentration used, the drug may be suspended or dissolved in the medium. Adjuvants such as local anesthetics, preservatives and buffering agents are preferably dissolved in the medium.

The compounds of formula (I) can be prepared by standard literature methods, as shown in the examples herein. In general, by reacting the dioxolane-protected dicarboxylic acid form of the formula (III) with the desired cyclic amine HNR₁R₂Coupling to prepare a compound wherein R is hydrogen:

wherein R is₁、R₂Ar and Alk are as defined in formula (I) to form intermediate (IIIA)

Intermediate (IIIA) is then reacted with hydroxylamine.

Methods for coupling amines with carboxylic acids to form amides are, for example, well known in the art of peptide synthesis.

Accordingly, the present invention also includes

(vi) A compound of formula (IIIB), wherein R₁、R₂Ar and Alk are as defined in formula (I),

(vii) a process for the preparation of a compound of formula (I) as described above, comprising deprotecting and/or converting a compound of formula (IIIA) as described above, wherein R₁、R₂Ar and Alk are as defined in formula (I),

(viii) a process for the preparation of a compound of formula (IIIA) comprising reacting a compound of formula (III) with a cyclic amine HNR₁R₂Step of reaction wherein R₁、R₂Ar and Alk are as defined in formula (I),

the following preparation examples describe the preparation of the compounds used in the present invention.

The following abbreviations are used in the examples:

AcOEt-acetic acid ethyl ester

CH₃CN-acetonitrile

DMF-N, N-dimethylformamide

HOBT-1-hydroxybenzotriazole

HOAT-1-HYDROXYAZO BENZOTRIAZOLES

MgSO₄Magnesium sulfate

Pfp-pentafluorophenol

WSCDI-N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride

HCl-hydrochloric acid

P(O-Tol)₃-tri-o-tolylphosphine

THF-tetrahydrofuran

TFA-trifluoroacetic acid

Z-benzyloxycarbonyl

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

Reagents and conditions: a: LiHMDS, AllBr, THF, -78 deg.C-room temperature; b: ArBr, P (o-Tol)₃，Pd(OAc)₂，NEt₃，CH₃CN；C：10％Pd/C，H₂，MeOH；D：LiOH，MeOH，H₂O；E：CuCl₂Dimethoxypropane, acetone; f: pentafluorophenol, WSCDI, HOAt, CH₂Cl₂(ii) a G: pyrrolidine, NEt₃，CH₂Cl₂，H：_aqNH₂OH，iPrOH

Scheme 1

Example 1 was prepared as briefly described in scheme 1 using the following procedure.

Step A: 2R-allyl-3S-hydroxy-succinic acid diisopropyl ester.

LiHMDS (200ml, 0.2mol, 2.1 equiv.) was added dropwise to a cold (-78 ℃ C.) solution of 2S-hydroxy-succinic acid diisopropyl ester (19.70ml, 95mmol) in THF (35 ml). The reaction mixture was stirred at-78 ℃ for two hours and then at-30 ℃ for 30 minutes. The reaction mixture was then cooled to-78 ℃ and allyl bromide (12.36ml, 0.14mol, 1.5 eq.) was added dropwise. The reaction mixture was then allowed to warm to room temperature overnight. It is poured into NH₄Cl/ice (200ml) in saturated solution. Extraction with AcOEt (3X 200ml) followed by washing with water (50ml) and brine (50ml)Removal of the solvent under vacuum gave a yellow oil. Purification by flash chromatography gave 2R-allyl-3S-hydroxy-succinic acid diisopropyl ester as a colorless oil (7.76g, de 80%, 40% yield).

¹H-NMR；δ(CDCl₃)：5.77-5.88(1H，m)，4.98-5.21(4H，m)，4.22(1H，brs)，3.18(1H，brs)，2.87-2.94(1H，m)，2.56-2.65(1H，m)，2.40-2.48(1H，m)，1.29(6H，d，J＝6.3Hz)，1.22(6H，d，J＝6.3Hz)。

LRMS: + ve ion 281(M + Na).

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

Sonicated (2 min) P (O-Tol)₃(0.57g, 2.22mmol, 0.1 equiv.) and Pd (OAc)₂(209mg, 5%) of CH₃CN (5ml) suspension was added 2R-allyl-3S-hydroxy-succinic acid diisopropyl ester (4.79g, 18.5mmol), 4-bromophene (3.19ml, 22.2mmol, 1.2 equiv.) and NEt3(6.22ml, 44.6mmol, 2.4 equiv.) in CH₃CN (40ml) solution. The reaction mixture was heated to reflux for 2 hours. Removal of CH under vacuum₃And (C) CN. The crude product was extracted with AcOEt (3X 200ml) and washed with water (50ml) and brine (50 ml). Purification by flash chromatography gave the desired 2R- [3- (4-ethoxy-phenyl) -allyl]diisopropyl-3S-hydroxy-succinate (5.92g, 84% yield).

¹H-NMR；δ(CDCl₃)：7.28(2H，d，J＝8.8Hz)，6.83(2H，d，J＝8.8)，6.46(1H，d，J＝15.7Hz)，6.02-6.12(1H，m)，4.98-5.13(2H，m)，4.26(1H，dd，J＝7.1，3.0Hz)，4.02(2H，q，J＝7.0Hz)：3.23(1H，d，J＝7.1Hz)，2.92-2.97(1H，m)，2.68-2.79(1H，m)，2.49-2.62(1H，m)，1.41(3H，t，J＝7.0Hz)，1.19-1.30(12H，m)。

LRMS: + ve ion 401(M + Na).

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

Add 10% Pd/C (13mg) to 2R- [3- (4-ethoxy-phenyl) -allyl under inert atmosphere]-3S-hydroxy-succinic acid diisopropyl ester (129mg, 0.34mmol) in MeOH (10 ml). By H₂The resulting suspension was bubbled for 30 minutes. Then H at 1 atm₂The reaction mixture was stirred under atmosphere for 16 hours. Pd/C was filtered off and the solvent was removed under reduced pressure to give 2R- [3- (4-ethoxy-phenyl) -propyl]Diisopropyl (3S-hydroxy-succinate (115mg, 88% yield).

¹H-NMR；δ(CDCl₃)：7.08(2H，d，J＝8.6Hz)，6.81(2H，d，J＝8.6)，4.97-5.14(2H，m)，4.20(1H，dd，J＝7.3，3.5Hz)，4.01(2H，q，J＝7.0Hz)，3.18(1H，d，J＝7.3Hz)，2.77-2.83(1H，m)，2.55-2.62(2H，m)，1.45-1.94(4H，m)，1.40(3H，t，J＝7.0Hz)，1.12-1.30(12H，m)。

LRMS: + ve ion xx (M + Na).

Step D: 2R- [3- (4-ethoxy-phenyl) -propyl ] -3S-hydroxy-succinic acid.

NaOH (1.66g, 41.5mmol, 5.5 equiv.) was added to 2R- [3- (4-ethoxy-phenyl) -propyl]-3S-hydroxy-succinic acid diisopropyl ester (4.78g, 12.6mmol) in THF/water (3: 1, 120 ml). The reaction mixture was then stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and acidified to pH 3 by addition of 1N hydrochloric acid. The hydroxy diacid was extracted with AcOEt. With MgSO₄Drying the organic layer and removing the solvent under reduced pressure to yield the desired 2R- [3- (4-ethoxy-phenyl) -propyl]-3S-hydroxy-succinic acid (3.66g, 85% yield).

¹H-NMR；δ(MeOD)：7.07(2H，d，J＝8.6Hz)，6.79(2H，d，J＝8.6)，4.23(1H，d，J＝5.8Hz)，3.98(2H，q，J＝7.0Hz)，2.76-2.81(1H，m)，2.53-2.59(2H，m)，1.55-1.72(4H，m)，1.35(3H，t，J＝7.0Hz)。

LRMS: + ve ion 319(M + Na); ve ion 295 (M-H).

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

Dimethoxypropane (2.58ml, 21mmol, 1.7 equiv.) and copper chloride (165mg, 1.2mmol, 0.1 equiv.) were added to a solution of 2R- [3- (4-ethoxy-phenyl) -propyl ] -3S-hydroxy-succinic acid (3.66g, 12.3mmol) in acetone (50ml) under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 hours. 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 (4.03g, 97% yield).

¹H-NMR；δ(CDCl₃)：7.08(2H，d，J＝8.5Hz)，6.82(2H，d，J＝8.5)，4.48(1H，d，J＝4.8Hz)，4.01(2H，q，J＝7.0Hz)，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＝7.0Hz)。

LRMS: + ve ion 359(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.

WSC (2.54g, 13.2mmol, 1.1 equiv.) was added to cold (0 ℃ C.) 2R- (2, 2-dimethyl-5-oxo- [1, 3]]Dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid (4.03g, 12mmol) and pentafluorophenol (2.43g, 13.2mmol, 1.1 equiv.) in CH₂Cl₂(50ml) in solution. The reaction mixture was allowed to warm to room temperature overnight. Removal of CH under vacuum₂Cl₂The resulting crude reaction mixture was dissolved in AcOEt (200 ml). With water (50ml), NaHCO_{3 saturation}(20ml) and finally the organic layer was washed with brine (20 ml). Removal of the solvent under reduced pressure gave an oil which, after purification by flash chromatography, provided the desired 2R- (2, 2-dimethyl-5-oxo- [1, 3)]Dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid pentafluorophenyl ester (3.94g, 65% yield).

¹H-NMR；δ(CDCl₃)：7.09(2H，d，J＝8.4Hz)，6.83(2H，d，J＝8.4Hz)，4.56(1H，d，J＝6.0Hz)，4.01(2H，q，J＝7.0Hz)，3.20-3.28(1H，m)，2.64(2H，t，J＝7.6Hz)，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＝7.0Hz)。

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

Pyrrolidine (30. mu.l, 0.36mmol, 1.2 eq) was added to 2R- (2, 2-dimethyl-5-oxo- [1, 3)]Dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid pentafluorophenyl ester (150mg, 0.30mmol) in CH₂Cl₂(10ml) in solution. The reaction mixture was stirred for 16 hours and the solvent was removed in vacuo. The crude product was dissolved in AcOEt (70ml), washed with water (10ml) and then with NaHCO_{3 saturation}(10ml) and finally washed with brine (10 ml). With MgSO₄Drying the solvent and removing the solvent under reduced pressure to yield the desired 5- (4-ethoxy-phenyl) -2R- [ (2, 2-dimethyl-5-oxo- [1, 3)]dioxolane-4S-yl group)]-1-pyrrolidin-1-yl-pentan-1-one (116mg, quantitative).

¹H-NMR；δ(CDCl₃)：7.05(2H，d，J＝8.6Hz)，6.8(2H，d，J＝8.6Hz)，4.55(1H，d，J＝8.4Hz)，3.99(2H，m)，3.8-3.3(10H，m)，3.05(1H，m)，2.55(2H，t，J＝7.6Hz)，2.1-1.7(2H，m)，1.6(3H，s)，1.5(3H，s)，1.4(3H，t，J＝7.0Hz)。

LRMS: + ve ions 405(M + H), 428(M + Na).

Step H: 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (pyrrolidine-1-carbonyl) -hexanoic acid hydroxyamide an aqueous solution of hydroxylamine (50%, 99. mu.l, 1.5mmol, 5 equiv.) was added 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 (116mg, 0.30mmol) in i-PrOH (5 ml). The reaction mixture was stirred at room temperature for 16 hours. Removal of the solvent under reduced pressure gave an oil which was purified by preparative reverse phase chromatography to give the desired product.

¹H-NMR；δ(CD₃OD)：7.05(2H，d，J＝8.6Hz)，6.8(2H，d，J＝8.6Hz)，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＝7.0Hz)。

LRMS: + ve ion 387(M + Na); ve ion 363 (M-H).

The compounds of examples 2-20 were prepared by parallel synthesis using the procedure of example 1, using the appropriate amine in step G. The product was purified by preparative HPLC.

Example 2: 3R- (6, 7-dimethoxy-3, 4-dihydro-1H-isoquinoline-2-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

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) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

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-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

¹H-NMR；δ(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＝7.0Hz)，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-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

Example 7: 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide.

¹H-NMR；δ(CD₃OD)：7.05(2H，d，J＝8.6Hz)，6.8(2H，d，J＝8.6Hz)，4.05-3.90(3H，m)，3.8-3.4(8H，m)，2.55(2H，t，J＝6.7Hz)，1.75-1.4(4H，m)，1.35(3H，t，J＝7.0Hz)。

LRMS: + ve ion 403(M + Na); ve ion 379 (M-H).

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

LRMS: + ve 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-morpholine-4-carbonyl) -hexanoic acid hydroxyamide.

LRMS: + ve ion 431(M + Na), 409(M + H); ve ion 407 (M-H).

Example 10: 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (thiomorpholine-4-carbonyl) -hexanoic acid hydroxyamide.

¹H-NMR；δ(CD₃₀D) The method comprises the following steps 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: + ve ion 419(M + Na), 397(M + H); ve ion 395 (M-H).

Example 11: 3R- (4-benzyl-piperidine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

¹H-NMR；δ(CD₃OD)：7.3-7.0(8H，m)，6.8(2H，m)，4.55(1H，d，J＝12.4Hz)，4.05(2H，dd，J＝2.0Hz)，3.9(2H，m)，2.9(1H，m)，2.6-2.4(5H，m)，1.84(1H，d， J＝2.9Hz)，1.7-1.5(6H，m)，1.35(3H，t，J＝7.0Hz)。

LRMS: + ve ion 491(M + Na); ve ion 467 (M-H).

Example 12: 3R- (4-benzo [1, 3] dioxol-5-ylmethyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

LRMS: + ve ion 514(M + H); ve ion 512 (M-H).

Example 13: 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-4-ylmethyl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

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

Example 14: 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-benzylpiperazine-1-carbonyl) -hexanoic acid hydroxyamide.

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

Example 15: 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-pyrimidin-2-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

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

Example 16: 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethyl-pyrimidin-2-yl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

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) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

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

Example 18: 3R- [4- (4, 6-dimethoxy- [1, 3, 5] triazin-2-yl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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

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

LRMS: + ve ion 524(M + H); ve ion 522 (M-H).

Example 20: 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

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

Example 21: 3R- [4- (acetyl-methyl-amino) -piperidine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

The compound of example 21 was prepared as briefly described in scheme 2 using the following procedure.

Reagents and conditions: a: h₂，Pd/C，MeOH；B：AcCl，NEt₃，CH₂Cl₂；C：TFA/CH₂Cl₂(ii) a D: PFP esters, NEt₃；E：NH₂OH，iPrOH

Scheme 2

Step A: 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester.

10% Pd/C (500mg) was added under an inert atmosphere to a solution of tert-butyl 4- (benzyloxycarbonyl-methyl-amino) -piperidine-1-carboxylate (5g, 0.014mmol) in MeOH (30 ml). By H₂The resulting suspension was bubbled for 2 hours. Then H at 1 atm₂The reaction mixture was stirred under atmosphere for 2 hours. Pd/C was filtered off and the solvent was removed under reduced pressure to give the desired tert-butyl 4-methylamino-piperidine-1-carboxylate (3.08g, quantitative).

And B: 4- (acetyl-methyl-amino) -piperidine-1-carboxylic acid tert-butyl ester.

Acetyl chloride (215. mu.l, 3.02mmol, 1.05 equiv.) is added dropwise to 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (616mg, 2.9mmol) in CH₂Cl₂(25ml) in solution. The reaction mixture was stirred at room temperature for 16 hours. By CH₂Cl₂The crude reaction mixture was extracted (2X 50ml) and washed with water (10ml) and brine (10 ml). The solvent was removed under reduced pressure to give the desired 4- (acetyl-methyl-amino) -piperidine-1-carboxylic acid tert-butyl ester (708mg, 96% yield).

¹H-NMR；δ(CDCl₃)：4.7-4.5(1H，m)，4.1(2H，brd，J＝12.7Hz)，2.8(5H，m)，2.1(5H，m)，1.6(2H，m)，1.5(9H，s)。

LRMS: + ve ion 215(M + H).

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

3N HCl (4ml) was added to a solution of tert-butyl 4- (acetyl-methyl-amino) -piperidine-1-carboxylate (525mg, 2.05mmol) in AcOEt (5 ml). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to give the desired N-methyl-N-piperidin-4-yl-acetamide (395mg, quantitative) as its hydrochloride salt.

¹H-NMR；δ(CD₃OD)：4.6(1H，m)，3.5(2H，brd，J＝12.8Hz)，3.2-3.1(2H，m)，3.0-2.85(3H，s)，2.2(3H，s)，2.1-1.8(4H，m)。

LRMS: + ve ion 157(M + H).

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

N-methyl-N-piperidin-4-yl-acetamide (137mg, 0.6mmol, 1.3 equiv.) was added 2R- (2, 2-dimethyl-5-oxo- [1, 3%]Dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid pentafluorophenyl ester (230mg, 0.46mmol) in CH₂Cl₂(5ml) solution, then NEt was added₃(257 microliters, 1.83mmol, 4 equivalents). The reaction mixture was stirred at room temperature for 16 hours. By CH₂Cl₂(2X 20ml) the reaction mixture was extracted with water (10ml), NaHCO_{3 saturation}(5ml) and finally washed with brine (10 ml). With MgSO₄The organic layer was dried and the solvent removed under reduced pressure to yield the desired N- {1- [2R- (2, 2-dimethyl-5-oxo- [1, 3] in quantitative yield]Dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoyl]-piperidin-4-yl } -N-methyl-acetamide. This compound was used in the next step without any further purification.

¹H-NMR；δ(CDCl₃)：7.05(2H，d，J＝7.2Hz)，6.7(2H，d，J＝7.2Hz)，4.75(2H，m)，4.55(1H，d，J＝7.9Hz)，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＝7.0Hz)，0.8(3H，t，J＝7.2Hz)。

LRMS: + ve ion 475(M + H).

Step E: 3R- [4- (acetyl-methyl-amino) -piperidine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

An aqueous hydroxylamine solution (50%, 94. mu.l, 1.43mmol, 5 eq.) was added 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-methyl-acetamide (135mg, 0.28mmol) in i-PrOH (5 ml). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to give an oil which was purified by preparative reverse phase chromatography to give the desired 3R- [4- (acetyl-methyl-amino) -piperidine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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

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

Example 22 was prepared as outlined in scheme 3 using the following procedure.

Reagents and conditions: a: methylpropylamine; b: TFA/CH₂Cl₂(ii) a C: PFP esters, NEt₃；D：NH₂OH，iPrOH

Scheme 3

Step A: 4- (methyl-propyl-amino) -piperidine-1-carboxylic acid tert-butyl ester.

Reacting NaBH₃CN (32mg, 0.5mmol, 1 equiv.) is added to a solution of tert-butyl 4-oxo-piperidine-1-carboxylate (100mg, 0.5mmol) in MeOH (5 ml). The reaction mixture was adjusted to pH 5.5 by addition of 5N HCl and stirred at room temperature under an inert gas atmosphere for 48 hours. The solvent was removed under reduced pressure and the crude product was dissolved in AcOEt (150 ml). With NaHCO₃The organic layer was washed (10ml) with brine (10ml), MgSO₄The organic layer was dried. The solvent was removed in vacuo to give the desired tert-butyl 4- (methyl-propyl-amino) -piperidine-1-carboxylate (106mg, 82% yield).

¹H-NMR；δ(CDCl₃)：4.14(1H，brd，J＝12.2Hz)，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＝3.4Hz)。

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

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

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

¹H-NMR；δ(CD₃OD)：3.95(1H，m)，3.6(2H，d，J＝13.9Hz)，2.3(2H，d，J＝11.3Hz)，2.05(4H，m)，1.85(4H，m)，1.05(3H，t，J＝7.3Hz)。

LRMS: + ve ion 157(M + H).

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

Methyl-piperidin-4-yl-propyl-amine (87mg, 0.45mmol, 1.3 equiv.) is added to 2R- (2, 2-dimethyl-5-oxo- [1, 3%]Dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid pentafluorophenyl ester (175mg, 0.35mmol) in CH₂Cl₂(5ml) solution, then NEt was added₃(197 microliters, 1.39mmol, 4 equivalents). The reaction mixture was stirred for 16 hours and the solvent was removed in vacuo. The crude product was dissolved in AcOEt (70ml), washed with water (10ml) and then with NaHCO_{3 saturation}(10ml) and finally washed with brine (10 ml). With MgSO₄The organic layer was dried and removed under reduced pressure. Purification on silica gel yielded the desired 5S- {4- (4-ethoxy-phenyl) -1R- [4- (methyl-propyl-amino) -piperidine-1-carbonyl]-butyl } -2, 2-dimethyl- [1, 3]Dioxolan-4-one (82mg, 50% yield).

¹H-NMR；δ(CDCl₃)：7.0(2H，d，J＝8.3Hz)，6.7(2H，d，J＝8.3Hz)，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＝7.7Hz)，2.3(2H，m)，2.15(3H，dd，J＝4.0，13.8Hz)，1.7(4H，t，J＝7.0Hz)，1.55(3H，s)，1.5(3H，s)，1.45-1.3(7H，m).1.3(3H，t，J＝7.0Hz)，0.8(3H，t，J＝7.2Hz)。

LRMS: + ve ion 475(M + H).

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

An aqueous solution of hydroxylamine (50%, 57. mu.l, 0.87mmol, 5 equiv.) was added to a solution of 5S- {4- (4-ethoxy-phenyl) -1R- [4- (methyl-propyl-amino) -piperidine-1-carbonyl ] -butyl } -2, 2-dimethyl- [1, 3] dioxolan-4-one (82mg, 0.17mmol) in i-PrOH (3 ml). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to give an oil. Purification by preparative reverse phase chromatography gave the desired product.

¹H-NMR；δ(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: + ve ion 450(M + H); ve ion 448(M-H)

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

The compounds of examples 23-25 were prepared by the method of example 1 in scheme 1, using the appropriate amine in step A (synthesized according to the methods described in Tetrahedron, 36, 409-415, 1980 and Journal of Organic Chemistry, 61, 4990-4998, 1996). The product was purified by preparative HPLC.

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

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

LRMS: + ve ion 437(M + H); ve ion 435(M-H)

Example 25: 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (3S-phenyl-morpholine-4-carbonyl) -hexanoic acid hydroxyamide.

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

Example 26: 3R- (4-benzyl-3 RS-methyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

The compounds of examples 26-28 were prepared by the method of example 1 in scheme 1, using the appropriate piperazine in step A (synthesized according to the method described in Tetrahedron: Asymmetry, 12, 3319-promoted 3324, 2001 and org. Prep. proced. int, 22, (6), 761-768, 1990). The product was purified by preparative HPLC.

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

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

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

Example 28: 3R- (4-benzyl-3 RS-phenyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

LRMS: + ve 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 outlined in scheme 4 using the following procedure.

Reagents and conditions: a: LiHMDS, 4-OCF₃-C₆H₄-CH₂Br, THF, -78-room temperature; b: NaOH, THF, H₂O；C：CuCl₂Dimethoxyacetone, acetone; d: pentafluorophenol, WSC, HOAt, CH₂Cl₂；E：RNH₂，NEt₃，CH₂Cl₂；F：HONH₂Aqueous solution, iPrOH

Scheme 4

Step A: 2S-hydroxy-3R- (4-trifluoromethoxy-benzyl) -succinic acid dimethyl ester.

1N LiHMDS (40.7ml, 40.7mmol, 2.2 equiv.) was dissolvedThe solution was added dropwise to a cold (-78 ℃ C.) solution of dimethyl 2S-hydroxy-succinate (3.0g, 18.5mmol) in THF (100 ml). The reaction mixture was stirred at-78 ℃ for 30 minutes and then at-30 ℃ for 1 hour. The temperature was lowered to-78 ℃ and 1-bromomethyl-4-trifluoromethoxy-benzene (3.11ml, 19.4mmol, 1.05 equiv.) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight and then poured into NH₄Cl_{Saturation of}(50 ml). THF was removed under vacuum and the crude product was dissolved in AcOEt (150 ml). The organic layer was washed with water (2X 20ml) and brine (20ml) and then MgSO₄And (5) drying. The solvent was removed under reduced pressure to give an oil which was purified by flash chromatography on silica gel. The desired 2S-hydroxy-3R- (4-trifluoromethoxy-benzyl) -succinic acid dimethyl ester was obtained in 24% yield (1.50 g).

¹H-NMR；δ(CDCl₃)：7.31(2H，d，J＝8.5Hz)，7.15(2H，d，J＝8.4Hz)，4.12(1H，d，J＝6.5Hz)，3.75(3H，s)，3.69(3H，s)，3.20(2H，m)，3.01(1H，m)。

LRMS: + ve ion 358(M + Na).

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

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

¹H-NMR；δ(CDCl₃)：7.32(2H，d，J＝8.4Hz)，7.19(2H，d，J＝8.4Hz)，4.08(1H，d，J＝6.5Hz)，3.25(2H，m)，3.05(1H，m)。

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

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

Dimethoxypropane (923 microliters, 7.5mmol, 1.7 equivalents) and copper chloride (59mg, 0.44mmol, 0.1 equivalents) were added to a solution of 2S-hydroxy-3R- (4-trifluoromethoxy-benzyl) -succinic acid (1.36g, 4.4mmol) in acetone (10ml) under an inert gas atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The 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 (1.08g, 70% yield).

¹H-NMR；δ(CDCl₃)：7.29(2H，d，J＝8.7Hz)，7.14(2H，d，J＝8.4Hz)，4.30(1H，d，J＝6.2Hz)，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).

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

WSC (714mg, 3.7mmol, 1.2 equiv.) was added to ice-cold (0 ℃ C.) 2R- (2, 2-dimethyl-5-oxo- [1, 3)]Dioxolan-4S-yl) -3- (4-trifluoromethoxy-phenyl) -propionic acid (1.08g, 3.1mmol) and pentafluorophenol (685mg, 3.7mmol, 1.2 equivalents) in CH₂Cl₂(10ml) in solution. The reaction mixture was allowed to warm to room temperature overnight. Removal of CH under vacuum₂Cl₂The resulting crude reaction mixture was dissolved in AcOEt (80 ml). With water (20ml), NaHCO_{3 saturation}(10ml) and finally the organic layer was washed with brine (10 ml). Removal of the solvent under reduced pressure gave an oil which, after purification by flash chromatography, provided the desired 2R- (2, 2-dimethyl-5-oxo- [1, 3)]dioxolan-4S-yl) -3- (4-trifluoromethoxy-phenyl) -propionic acid pentafluorophenyl ester (254mg, 16% yield).

¹H-NMR：δ(CDCl₃)：7.29(2H，bd，J＝9.3Hz)，7.21(2H，bd，J＝8.7Hz)，4.45(1H，d，J＝6.2Hz)，3.51(1H，m)，3.3(2H，m)，1.65(3H，s)，1.58(1H，s)。

LRMS: + ve ion 537(M + Na).

Step 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.

1-benzo [1, 3]]Dioxol-5-ylmethyl-piperazine (28mg, 0.13mmol, 1.1 equiv.) was added 2- (2, 2-dimethyl-5-oxo- [1, 3)]Dioxolan-4S-yl) -3R- (4-trifluoromethoxy-phenyl) -propionic acid pentafluorophenyl ester (59mg, 0.11mmol) in CH₂Cl₂(10ml) in solution. The reaction mixture was stirred for 16 hours and the solvent was removed in vacuo. The crude product was dissolved in AcOEt (50ml), washed with water (10ml) and then with NaHCO₃Saturated (10ml) and finally washed with brine (10 ml). With MgSO₄Drying the solvent, removing the solvent under reduced pressure to give an oil, and purifying the oil by preparative reverse phase chromatography to give the desired 5S- [2- (4-benzo [1, 3] b]Dioxo-5-ylmethyl-piperazin-1-yl) -2-oxo-1R- (4-trifluoromethoxy-benzyl) -ethyl]-2, 2-dimethyl- [1, 3]Dioxolan-4-one.

¹H-NMR；δ(CD₃OD)：7.27-7.12(4H，m)，6.78-6.62(3H，m)，5.93(2H，s)，4.57(1H，d，J＝6.6Hz)，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: + ve ion 551(M + H).

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

An aqueous hydroxylamine solution (50%, 16 μ l, 0.24mmol, 5 eq) was added to a solution of 5S- [2- (4-benzo [1, 3] dioxo-5-ylmethyl-piperazin-1-yl) -2-oxo-1R- (4-trifluoromethoxy-benzyl) -ethyl ] -2, 2-dimethyl- [1, 3] dioxolan-4-one (26mg, 0.047mmol) in i-PrOH (2 ml). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to give an oil which was purified by preparative reverse phase chromatography to give the desired 4- (4-benzo [1, 3] dioxol-5-ylmethyl-piperazin-1-yl) -2S, N-dihydroxy-4-oxo-3R- (4-trifluoromethoxy-benzyl) -butyramide.

¹H-NMR；δ(CD₃OD)：7.32-7.15(4H)，6.79-6.65(4H，m)，5.90(2H，s)，4.13(1H，d，J＝6.8Hz)，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: + ve ion 526(M + H); ve ion 524 (M-H).

Example 30: 3R-benzyl-2S, N-dihydroxy-4-morpholin-4-yl-4-oxo-butyramide.

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

¹H-NMR；δ(CD₃OD)：7.32-7.18(5H，m)，4.16(1H，d，J＝6.7Hz)，3.59-2.67(11H，m)。

LRMS: + ve ion 331(M + Na); ve ions 307 (M-H).

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

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

¹H-NMR; δ (MeOD): 7.41-7.26(5H, m), 7.10-6.87(4H, m), 5.05(2H, s), 4.11(1H, d, J ═ j6.1hz), 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.

Example 32 was prepared as briefly described in scheme 5 using the following procedure.

Reagents and conditions: a: h₂，Pd/C，MeOH

Scheme 5

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

Add 10% Pd/C (1mg) to 2S, N-dihydroxy-3R- (4-hydroxy-benzyl) -4-oxo-4-piperidin-1-yl-butyramide (14mg, 3.5X 10) under inert gas atmosphere^-5mol) in MeOH (5 ml). By H₂The resulting suspension was bubbled for 2 hours. Pd/C was filtered off and the solvent was removed under reduced pressure to give 2S, N-bis-hydroxy-3R- (4-hydroxy-benzyl) -4-oxo-4-piperidin-1-yl-butyramide (10mg, quant.).

¹H-NMR; δ (MeOD): 7.02-6.67(4H, 2d, J-8.4 Hz and J8.4Hz), 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: + ve 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.

The compound of example 33 was prepared by the method of example 29 in scheme 4, using 1-benzyloxy-4-bromomethyl-benzene in step A.

¹H-NMR; δ (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(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- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide.

The compounds of examples 34-38 were prepared by parallel synthesis using the procedure of example 1 in scheme 1, with ArBr being 1-bromomethyl-3, 5-bis-trifluoromethyl-benzene in step B and the appropriate amine used in step G. The product was purified by preparative HPLC.

¹H-NMR；δ(CD₃OD)：7.79(2H，s)，7.77(1H，s)，4.07(1H，d，J＝6.8Hz)，3.19-3.76(9H，m)，2.73-2.98(2H，m)，1.52-1.88(4H，m)。

LRMS: + ve ion 473(M + H), 495(M + Na); ve ion 471 (M-H).

Example 35: 3R- (4-benzyl-piperidine-1-carbonyl) -6- (3, 5-bis-trifluoromethyl-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

LRMS: + ve ions 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-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

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-isoquinoline-2-carbonyl) -2S-hydroxy-hexanoic acid hydroxyamide.

LRMS: + ve ion 601(M + Na); ve ions 577 (M-H).

Example 38: 6- (3, 5-bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (pyrrolidine-1-carbonyl) -hexanoic acid hydroxyamide.

¹H-NMR；δ(CD₃OD)：7.84(2H，s)，7.79(1H，s)，4.06(1H，d，J＝6.6Hz)，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: + ve ion 479(M + Na); ve ion 455 (M-H).

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

The compound of example 39 was prepared by the method of example 1 in scheme 1, using the appropriate piperazine in step A (synthesized according to the method described in J.heterocyclic Chem, 28, 1219-. The product was purified by preparative HPLC.

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

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

Reagents and conditions: a: RSO₂Cl 1.2 when heavy, NEt₃1.4 when heavy, CH₂Cl₂，B：TFA/CH₂Cl₂；C：LHS，EDAC，HOAt，CH₂Cl₂；D：H₂Aqueous NOH solution, iPrOH

Scheme 6

The compound of example 40 was prepared as briefly described in scheme 6 using the following procedure.

Step A: 4- (4-trifluoromethoxy-benzenesulfonyl) -piperazine-1-carboxylic acid tert-butyl ester.

Will NEt₃(547 microliters, 3.92mmol, 1.4 equivalents) and 4-trifluoromethoxy-benzenesulfonyl chloride (880mg, 3.36mmol, 1.2 equivalents) were added to a solution of piperazine-1-carboxylic acid tert-butyl ester (521mg, 2.8mmol) in DCM (6 ml). The reaction mixture was stirred at room temperature for 12 hours. Excess sulfonyl chloride was quenched by addition of triamine resin (150mg) and then stirred for 2 hours. The resin was then filtered off and NaHCO was added_{3 saturation}(5 ml). The resulting mixture was filtered through a hydrophobic cartridge and then the solvent was removed under reduced pressure to yield the desired 4- (4-trifluoromethoxy-benzenesulfonyl) -piperazine-1-carboxylic acid tert-butyl ester in quantitative yield.

And B: 1- (4-trifluoromethoxy-benzenesulfonyl) -piperazine.

TFA (2ml) was added to an ice-cold (0 ℃) solution of 4- (4-trifluoromethoxy-benzenesulfonyl) -piperazine-1-carboxylic acid tert-butyl ester (1.15g, 2.8mmol) in DCM (3 ml). The resulting solution was stirred for 1 hour. The solvent was then removed under reduced pressure. The solid crude product was dissolved in AcOEt (15ml) and NaHCO was used_{3 saturation}(2X 5ml), water (5ml) and finally washed with brine (5 ml). With MgSO₄The organic layer was dried and the solvent removed in vacuo to yield the desired 1- (4-trifluoromethoxy-benzenesulfonyl) -piperazine as a white solid (753mg, 87% yield).

¹H-NMR；δ(CDCl₃)：7.80(2H，m)，7.38(2H，m)，3.01(8H，m)。

LRMS: + ve ion 311(M + H).

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

WSCDI (62mg, 0.325mmol, 1.2 equiv.) and HOAt (catalytic amount) were added to ice-cold (0 ℃ C.) 2R- (2, 2-dimethyl-5-oxo- [1, 3)]dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid (91mg, 0.27mmol), 1- (4-trifluoromethoxy-benzenesulfonyl) -piperazine (100mg, 0.325mmol, 1.2 eq) in DCM (6 ml). The reaction mixture was stirred for 16 hours and the temperature was allowed to rise to 20 ℃. DCM was then removed under reduced pressure and the resulting crude reaction mixture was dissolved in AcOEt (30 ml). The organic layer was washed with water (2X 10ml) and brine (10 ml). With MgSO₄The organic layer was dried and the solvent removed in vacuo to yield the desired 5- {4- (4-ethoxy-phenyl) -1- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazine-1-carbonyl]-butyl } -2, 2-dimethyl- [1, 3]Dioxolan-4-one (170mg, quantitative).

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

Step D: 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

H is to be₂NHOH_{Aqueous solution}(90 μ l, 1.35mmol, 5 equiv.) 5- {4- (4-ethoxy-phenyl) -1- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazine-1-carbonyl was added]-butyl } -2, 2-dimethyl- [1, 3]Dioxolan-4-one (170mg, 0.27mmol) in iPrOH (5 ml). The reaction mixture was stirred for 12 hours and the solvent was removed in vacuo. Purification of the crude reaction mixture by preparative HPLC gave the desired 6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazine-1-carbonyl]-hexanoic acid hydroxyamide.

¹H-NMR；δ(CDCl₃)：7.79(2H，m)，7.38(2H，m)，7.01(2H，m)，6.80(2H，m)，4.06(2H，q)，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) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

The compounds of examples 41-46 were prepared by the method of example 40 in scheme 6, using the appropriate sulfonyl chloride in step A.

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

Example 42: 3R- [4- (5-bromo-thiophene-2-sulfonyl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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

Example 43: 3R- [4- (5-benzenesulfonyl-thiophene-2-sulfonyl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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

Example 44: 3R- [4- (4-butoxy-benzenesulfonyl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

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

Example 46: 3R- [4- (3, 4-dimethoxy-benzenesulfonyl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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

The compounds of examples 47-50 were prepared by parallel synthesis using the procedure of example 1, using the appropriate aryl bromide in step B and the appropriate amine in step G. The product was purified by preparative HPLC.

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

¹H-NMR；δ(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)。

LRMS: + ve ion 460(M + H); ve ion 458 (M-H).

Example 48: 6- (4-methoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide.

¹H-NMR；δ(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: + ve ion 443(M + H).

Example 49: 6- (4-fluoro-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -2S-hydroxy-hexanoic acid hydroxyamide.

¹H-NMR；δ(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)，1.8-1.5(3H，m)，1.15(1H，t)。

LRMS: + ve ion 448(M + H).

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

¹H-NMR；δ(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: + ve ion 431(M + H).

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

Example 51 was prepared as described briefly in scheme 7 using the following procedure.

The piperazine intermediates used in step A in scheme 7 were prepared according to the method described in Journal of Organic Chemistry, 60, 4177-4183, 1995.

Reagents and conditions: step A: 1-benzyl-3S-methyl-piperazine, WSC, HOAt, CH₂Cl₂(ii) a And B: h₂Aqueous NOH solution, iProH

Scheme 7

Step A: 5S- [1- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -4R- (4-ethoxy-phenyl) -butyl ] -2, 2-dimethyl- [1, 3] dioxolan-4-one.

WSC (55mg, 2.84X 10)^-4mol, 1.2 eq) and HOAt (catalytic amount) were added ice cold (0 ℃ C.) 2R- (2, 2-dimethyl-5-oxo- [1, 3)]Dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid (80mg, 2.38X 10)^-4mol) and 1-benzyl-3S-methyl-piperazine (54mg, 2.84X 10)^-4mol, 1.2 equivalents) of the reaction mixture. The reaction mixture was then stirred at room temperature for 16 hours, then purified by addition of 5ml of CH₂Cl₂And (6) diluting. The organic layer was washed with water (3ml) and then MgSO₄And (5) drying. The solvent was removed under reduced pressure to give the desired 5S- [1- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -4R- (4-ethoxy-phenyl) -butyl]-2, 2-dimethyl- [1, 3]Dioxolan-4-one, which compound can be used in the next step without any further purification.

And B: 3R- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

H is to be₂NOH(100ml，1.19×10^-3mol, 5 equivalents) was added ice-cold (0 ℃)5S- [1- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -4R- (4-ethoxy-phenyl) -butyl]-2, 2-dimethyl- [1, 3]Dioxolan-4-one (120mg, 2.38X 10)^-4mol) in iPrOH (4 ml). The reaction mixture was stirred at room temperature for 5 hours and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to give the desired 3R- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide as a white solid.

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

The compounds of examples 52-61 were prepared by the method of example 51 in scheme 7, using the appropriate piperazine.

Example 52: 3R- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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

Example 53: 3R- (4-benzyl-2S-isobutyl-piperazine-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

LRMS: + ve ion 512(M + H).

Example 54: 3R- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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

Example 55: 3R- (4-benzyl-2S-isobutyl-piperazine-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide.

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

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

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

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

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

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

LRMS: + ve ion 480(M + H).

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

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

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

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

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

LRMS: + ve ion 510(M + H).

Example 62: 6- (4-ethoxy-phenyl) -2S-methoxy-3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide.

Reagents and conditions: a: LiHMDS, AllBr, THF, -78 deg.C-room temperature; b: ArBr, P (o-Tol)₃，Pd(OAc)₂，NEt₃，CH₃CN；C：10％Pd/C，H₂，MeOH；D：LiOH，MeOH，H₂O；E：CuCl₂Dimethoxypropane, acetone; f: pentafluorophenol, WSCDI, HOAt, CH₂Cl₂(ii) a G: 1- (2-fluoro-phenyl) -piperazine, NEt₃，CH₂Cl₂(ii) a H: thionyl chloride, methanol; i: NaH, methyl iodide, DMF; j: NaOH, MeOH, water; k: BnONH₂，WSC，HOBt，DMF；L：H₂Pd/C, ethanol.

Scheme 1

The compound of example 62 was prepared as briefly described in scheme 1 using the following procedure.

Step A: 2R-allyl-3S-hydroxy-succinic acid diisopropyl ester.

LiHMDS (200ml, 0.2mol, 2.1 equiv.) was added dropwise to a cold (-78 ℃ C.) solution of 2S-hydroxy-succinic acid diisopropyl ester (19.70ml, 95mmol) in THF (35 ml). The reaction mixture was stirred at-78 ℃ for two hours and then at-30 ℃ for 30 minutes. The reaction mixture was then cooled to-78 ℃ and allyl bromide (12.36ml, 0.14mol, 1.5 eq.) was added dropwise. The reaction mixture was then allowed to warm to room temperature overnight. It was poured into a saturated solution of NH4 Cl/ice (200 ml). Extraction with AcOEt (3X 200ml) followed by washing with water (50ml) and brine (50ml) gave a yellow oil after removal of the solvent in vacuo. Purification by flash chromatography gave 2R-allyl-3S-hydroxy-succinic acid diisopropyl ester as a colorless oil (7.76g, de 80%, 40% yield).

LRMS: + ve ion 281(M + Na).

LRMS: + ve ion 401(M + Na).

LRMS: + ve ion xx (M + Na).

Step D: 2R- [3- (4-ethoxy-phenyl) -propyl ] -3S-hydroxy-succinic acid.

LRMS: + ve ion 319(M + Na); ve ion 295 (M-H).

LRMS: + ve ion 359(M + Na); ve ion 335 (M-H).

WSC (2.54g, 13.2mmol, 1.1 equiv.) was added to ice cold (0 ℃ C.) 2R- (2, 2-dimethyl-5-oxo- [1, 3)]Dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid (4.03g, 12mmol) and pentafluorophenol (2.43g, 13.2mmol, 1.1 equiv.) in CH₂Cl₂(50ml) in solution. The reaction mixture was allowed to warm to room temperature overnight. Removal of CH under vacuum₂Cl₂The resulting crude reaction mixture was dissolved in AcOEt (200 ml). Using water (50ml), NaHC0_{3 saturation}(20ml) and finally the organic layer was washed with brine (20 ml). Removal of the solvent under reduced pressure gave an oil which, after purification by flash chromatography, provided the desired 2R- (2, 2-dimethyl-5-oxo- [1, 3)]Dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid pentafluorophenyl ester (3.94g, 65% yield).

Step G: 5- {4- (4-ethoxy-phenyl) -1- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -butyl } -2, 2-dimethyl- [1, 3] dioxolan-4-one

1- (2-fluorophenyl) -4-piperazine (65mg, 0.36mmol, 1.2 equiv.) was added to 2R- (2, 2-dimethyl-5-oxo- [1, 3]Dioxolan-4S-yl) -5- (4-ethoxy-phenyl) -pentanoic acid pentafluorophenyl ester (150mg, 0.30mmol) in CH₂Cl₂(10ml) solution. The reaction mixture was stirred for 16 hours and the solvent was removed in vacuo. The crude product was dissolved in AcOEt (70ml), washed with water (10ml) and then with NaHCO_{3 saturation}(10ml) and finally washed with brine (10 ml). With MgSO₄The solvent was dried and removed under reduced pressure to give the desired 5- {4- (4-ethoxy-phenyl) -1- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl]-butyl } -2, 2-dimethyl- [1, 3]Dioxolan-4-one (97mg, 65% yield).

¹H-NMR；δ(CDCl₃)：

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

Thionyl chloride (0.078ml, 1.06mmol, 1.1 equiv.) was added dropwise to ice-cold (0 ℃)5- {4- (4-ethoxy-phenyl) -1- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl]-butyl } -2, 2-dimethyl- [1, 3]Dioxolan-4-one (482mg, 0.95mmol) in methanol (5 ml). The reaction mixture was stirred at room temperature and then heated under reflux for 3 hours. The reaction mixture was then allowed to cool to room temperature and evaporated under reduced pressure. The crude reaction was extracted with AcOEt (2X 50ml) and 1M Na₂CO₃(50ml) and brine (50 ml). The organic layer was dried over MgSO4 and purified by flash chromatography to give 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl as a colorless oil]-2S-hydroxy-hexanoic acid methyl ester (200mg, 44% yield).

¹H-NMR；δ(CDCl₃)：7.12(2H，d，J＝6.5Hz)，7.08(4H，m)，6.81(2H，d，J＝6.3Hz)，5.00(1H，d，J＝6，1Hz)，3.98(2H，q，5.3，8.9Hz)，3.75(3H，s)，3.40-3.65(4H，m)，3.21(1H，m)，2.99(4H，bm)，2.64(2H，m)，1.90-1.65(4H，m)，1.45(3H，m)。

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

Step I: 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -2S-methoxy-hexanoic acid methyl ester.

Sodium hydride (20mg, 0.48mmol, 1.1 equiv., 60% dispersion) was added to an ice-cold (0 ℃) solution of 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -2S-hydroxy-hexanoic acid methyl ester (200mg, 0.44mmol) in anhydrous DMF. The reaction mixture was stirred for 30 minutes, then methyl iodide (0.04ml, 0.60mmol, 1.2 equiv.) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for more than 16 hours. The crude reaction mixture was evaporated under reduced pressure, extracted with AcOEt (2X 50ml), washed with water and brine (50 ml). Purification by flash chromatography gave the desired methyl 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -2S-methoxy-hexanoate as a colorless oil (125mg, 61% yield).

¹H-NMR；δ(CDCl₃)：7.12(2H，d，J＝6.5Hz)，7.08(4H，m)，6.81(2H，d，J＝6.3Hz)，5.00(1H，d，J＝6.1Hz)，3.98(2H，q，5.3，8.9Hz)，3.75(3H，s)，3.40-3.65(4H，m)，3.30(3H，s)，3.21(1H，m)，3.05(4H，bm)，2.64(2H，m)，1.80-1.65(4H，m)，1.39(3H，t，J＝7.0Hz)。

LRMS: + ve ion 487(M + H).

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

NaOH (11mg, 0.28mmol, 1.1 equiv.) was added to 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl]-2S-methoxy-hexanoic acidMethyl ester (125mg, 0.26mmol) in methanol/water (3: 1, 10 ml). The reaction mixture was then stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and acidified to pH 3 by addition of 1 NHCl. Methoxy acid was extracted with AcOEt. With MgSO₄Drying the organic layer and removing the solvent under reduced pressure to yield the desired 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl]-2S-methoxy-hexanoic acid (101mg, 83% yield).

¹H-NMR；δ(CDCl₃)：7.12(2H，d，J＝6.5Hz)，7.08(4H，m)，6.81(2H，d，J＝6.3Hz)，4.01(1H，d，J＝6.5Hz)，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＝7.0Hz)。

LRMS: + ve ion 473.2(M + H).

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

Benzylhydroxylamine (39mg, 0.32mmol), WSC (49mg, 0.26mmol), and finally HOBt (2mg, 0.043 mmol) were added to ice-cold 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl]-2S-methoxy-hexanoic acid (101mg, 0.21mmol) in DMF (2 ml). The reaction mixture was then allowed to warm to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure. The crude reaction mixture was dissolved in AcOEt (30ml), washed with water (10ml) and then with NaHCO_{3 saturation}(10ml) and finally washed with brine (10 ml). With MgSO₄Drying the solvent, removing the solvent under reduced pressure, and purifying by column chromatography to give the desired 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl as a white solid]-2S-hydroxy-hexanoic acid benzyloxy-amide (38mg, 31% yield).

LRMS: + ve ion 578.2(M + H).

Step L: 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -2S-methoxy-hexanoic acid hydroxyamide.

Add 10% Pd/C (5mg) to 6- (4-ethoxy-phenyl) -3R under inert gas atmosphere- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl]-2S-hydroxy-hexanoic acid benzyloxy-amide (38mg, 0.007mmol) in MeOH (10 ml). By H₂The resulting suspension was bubbled for 30 minutes. Then H at 1 atm₂The reaction mixture was stirred under atmosphere for 3 hours. Pd/C was filtered off, the solvent was removed under reduced pressure, and purification by preparative HPLC gave 6- (4-ethoxy-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl as a white solid]-2S-methoxy-hexanoic acid hydroxyamide (5mg, 40% yield).

Biological results

A. Enzyme inhibition assay

The compounds of the present invention were tested and evaluated for their activity as MMP9, MMP12 and MMP-1 inhibitors.

MMP9 determination method

In the case of 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-NH₂The inhibitory activity of the compounds of the invention against 92kDa gelatinase (MMP9) was tested in an assay (McAPLGLDpaAR) (Knight et al, FEBS Lett.1992; 263-266).

The stock solution consisted of:

determination of buffer: containing 100mM NaCl, 10mM CaCl₂And 0.05% Brij 35 in 100mM Tris-HCl pH7.6

Substrate: 0.4mM McAPLGLDpaAR (from Bachem) (0.437mg/ml) stock solution in 100% DMSO (stored at-20 ℃). Diluted to 8 μ M in assay buffer.

Enzyme: recombinant human 92kDa gelatinase (MMP-9; APMA (Mercury 4-aminophenylacetate) — activated if necessary), suitably diluted in assay buffer.

First, test compounds were prepared as 10mM compound solutions in 100% DMSO, diluted to 1mM with 100% DMSO, and then serially diluted 3-fold with 100% DMSO in columns 1-10 of a 96-well microtiter plate. The concentration range determined was 100. mu.M (column 1) -5.1nM (column 10)

The assay was performed in 96-well microtiter plates in a total volume of 100 microliters per well. Activated enzyme (20. mu.l) was added to the wells followed by 20. mu.l of assay buffer. Test compounds at appropriate concentrations dissolved in 10 μ l DMSO were then added followed by 50 μ l mcaplldpaar (8 μ M, prepared by diluting DMSO stock solutions with assay buffer). For each assay, ten concentrations of test compound were tested in duplicate. Control wells lack either enzyme or test compound. The reaction was incubated at 37 ℃ for 2 hours. The reaction was promptly run on a SLT Fluostar fluorimeter (SLT Labinstruments GmbH,austria) measured fluorescence at 405nm with 320nm excitation.

The effect of the test compound was determined from the dose response curve generated with 10 replicate concentrations of inhibitor. By making the data satisfy the equation Y ═ a + ((b-a)/(1+ (c/X)^d) To obtain an IC₅₀(concentration of compound required to reduce enzyme activity by 50%). (specific doses of Y give inhibition; doses of X in nM; a-min Y inhibition or 0% inhibition; b-max Y inhibition or 100% inhibition; c is IC₅₀(ii) a d ═ slope). The result is to retain a valid number.

MMP12 determination method

In the case of 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-NH₂The inhibitory activity of the compounds of the invention against metalloelastase (MMP12) was tested in an assay (McaPLGLDpaAR) (Knight et al, FEBS Lett.1992; 263-266). This measurement method is the same as the MMP9 measurement described above.

MMP1 determination method

In the presence of coumarinLabeled peptide substrate, (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu- (3- [2, 4-dinitrophenyl)]-L-2, 3-diaminopropionyl) -Ala-Arg-NH₂The inhibitory activity of the compounds of the invention against collagenase (MMP1) was tested in an assay (McAPLGLDpaAR) (Knight et al, FEBS Lett.1992; 263-266). This measurement method is the same as the MMP9 measurement described above.

As a result:

key assay data

The range A < 100nM

B100-1000nM

C1000-10,000nM

D＞10,000nM

For example, the inhibitory activity of some of the compounds of the examples on MMP-12, MMP-9, MMP-2, and MMP-1 is set forth in the following table:

example numbering	MMP-9 (nM)	MMP-2 (nM)	MMP-1 (nM)	MMP-12 (nM)
					4	A	A	D	A
5	A	A	D	A
					6	B	B	D	A
12	A	A	D	A
					13	A	A	D	A
14	A	A	D	A
					20 62	A A	A A	D D	A A

B. Biological assay: IL2 induces peritoneal aggregation of lymphocytes in mice

Method of producing a composite material

C3H mice (elevoge Janvier) (8 weeks old, n ═ 6) were given test molecules 15 minutes later and then received IL2(SPRI, 20, μ g/kg, 40 ml/kg, ip). After 24 hours, the animals were sacrificed and the peritoneal cavity was irrigated with 3X 5ml PBS-1mM EDTA (+4 ℃). After centrifugation (3000rpm, 10 min), the pellet was resuspended in 1ml PBS. Peritoneal cells were counted using a Beckman/Coulter counter. IL2 was dissolved in saline. Test compounds of the invention were dissolved or suspended in 0.5% carboxymethylcellulose (CMC)/0.25% tween-20 and administered orally. Dexamethasone (0.1 mg/kg, po) was used as reference compound.

For example, the inhibition of IL-2 induced peritoneal aggregation with the compounds of the specific examples is listed in the following table:

IL-2 induced peritoneal aggregation

	Dosage (mg/kg)	Route of administration	% inhibition
				Example 4	3	po	34％
Example 5	3	po	50％
				Example 6	3	po	33％
Example 13	3	po	47％
				Example 14	3	po	30％
Example 20	3	po	57％
				Dexamethasone	1	sc	76％

Claims

1. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof:

wherein

Ar represents optionally substituted phenyl;

r represents hydrogen or C₁-C₆Alkyl or C₃-C₆A cycloalkyl group;

alk represents divalent C₁-C₅An alkylene group; and

R₁and R₂Together with the nitrogen atom to which they are attached form a pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidine ring or piperazine ring, said ring being optionally substituted with at least one group of formula (II):

wherein

m, p and n are independently 0 or 1;

z represents hydrogen, optionally substituted phenyl, pyridyl, pyrimidinyl, thienyl, the optional substituents being methoxy, ethoxy, n-or isopropoxy, trifluoromethoxy, methylenedioxy, ethylenedioxy, methyl, ethyl, n-or isopropyl, trifluoromethyl, fluoro, chloro, bromo, methanesulfonyl, benzenesulfonyl, or mono (C1-C3) alkylamino or di (C1-C3) alkylamino;

x represents-S (O)₂)，

Wherein Ar and Alk¹And Alk²Wherein said optional substituents are selected from (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, hydroxy (C)₁-C₆) Alkyl, mercapto (C)₁-C₆) Alkyl, (C)₁-C₆) Alkylthio, halogen, trifluoromethyl, trifluoromethoxy, nitro, -CN, oxo, phenyl, -COOH, -COOR^A，-COR^A，-SO₂R^A，-CONH₂，-SO₂NH₂，-CONHR^A，-SO₂NHR^A，-CONR^AR^B，-SO₂NR^AR^B，-NH₂，-NHR^A，-NR^AR^B，-OCONH₂，-OCONHR^A，-OCONR^AR^B，-NHCOR^A，-NHCOOR^A，-NR^BCOOR^A，-NHSO₂OR^A，-NR^BSO₂OR^A，-NHCONH₂，-NR^ACONH₂，-NHCONHR^B，-NR^ACONHR^B，-NHCONR^AR^Bor-NR^ACONR^AR^BWherein R is^AAnd R^BIndependently is (C)₁-C₆) Alkyl or phenyl.

2. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein R is hydrogen.

3. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein R is methyl.

4. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein R is ethyl, n-propyl, isopropyl, n-, sec-or tert-butyl, cyclopropyl or cyclopentyl.

5. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein the optional substituent of Ar is at the 4-position.

6. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein the optional substituents in Ar are selected from methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl, hydroxy, mercapto, fluoro, chloro and bromo.

7. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein in ArThe optionally substituted phenyl group being 4- (C)₁-C₃Alkoxy) phenyl.

8. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein the optionally substituted phenyl in Ar is 4-ethoxyphenyl.

9. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein Alk is-CH₂-、-CH₂CH₂-、-CH₂CH(CH₃)-、-CH₂CH₂CH₂-、-CH₂CH₂CH₂CH₂-。

10. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein-NR is₁R₂Forming a pyrrolidinyl, morpholinyl, or thiomorpholinyl ring.

11. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein-NR is₁R₂Forming a piperidinyl or piperazinyl ring.

12. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein in group (II), when present, p is 0, Z is hydrogen and at least one of n and m is 1.

13. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein in group (II), when present, m, n and p are all 0, Z is directly linked to-NR₁R₂Optionally substituted phenyl on a ring carbon or ring nitrogen of a radicalPyridyl, pyrimidinyl, thienyl, optionally substituted with methoxy, ethoxy, n-or isopropoxy, trifluoromethoxy, methylenedioxy, ethylenedioxy, methyl, ethyl, n-or isopropyl, trifluoromethyl, fluoro, chloro, bromo, methylsulfonyl, phenylsulfonyl, or mono (C1-C3) alkylamino or di (C1-C3) alkylamino.

14. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein in group (II), when present, p is 0, at least one of m and n is 1, Z is optionally substituted phenyl, pyridyl, pyrimidinyl, thienyl, the optional substituent is methoxy, ethoxy, n-or iso-propoxy, trifluoromethoxy, methylenedioxy, ethylenedioxy, methyl, ethyl, n-or iso-propyl, trifluoromethyl, fluoro, chloro, bromo, methanesulfonyl, benzenesulfonyl, or mono (C1-C3) alkylamino or di (C1-C3) alkylamino.

15. A compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein in group (II), when present, p is 1.

16. A compound having formula (IB) or (IC), or an enantiomer or diastereomer thereof, or a salt thereof:

wherein R is hydrogen or methyl, R₃Is trifluoromethyl, trifluoromethoxy, C₁-C₃Alkoxy, hydroxy or halogen; r₄Is (i) -SO₂R₅or-COR₅Wherein R is₅Is C₁-C₆Alkyl or phenyl or pyridyl, pyrimidinyl, triazinyl, thienyl or furanyl, with (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, hydroxy (C)₁-C₃) Alkyl, mercapto (C)₁-C₃) Alkyl, (C)₁-C₃) Alkylthio, halogen, trifluoromethyl, trifluoromethoxy optionally substituted or (ii) phenyl or pyridyl, pyrimidinyl, triazinyl, thienyl or furanyl; quilt (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, hydroxy (C)₁-C₃) Alkyl, mercapto (C)₁-C₃) Alkyl, (C)₁-C₃) Alkylthio, halogen, trifluoromethyl, trifluoromethoxy are optionally substituted.

17. A compound of formula (I) as claimed in claim 1, or an enantiomer or diastereomer thereof, or a salt thereof, having the stereochemical configuration shown in formula (IA):

18. a compound of formula (I), or an enantiomer or diastereomer thereof, or a salt thereof, as claimed in claim 1, wherein the compound is selected from:

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (pyrrolidine-1-carbonyl) -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (3-methoxy-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-methoxy-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-4-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (2 RS-methyl-morpholine-4-carbonyl) -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (2, 6-RS-dimethyl-morpholine-4-carbonyl) -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (thiomorpholine-4-carbonyl) -hexanoic acid hydroxyamide;

3R- (4-benzyl-piperidine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

3R- (4-benzo [1, 3] dioxol-5-ylmethyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-4-ylmethyl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-benzylpiperazine-1-carbonyl) -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (4-pyrimidin-2-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethyl-pyrimidin-2-yl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-chloro-pyrimidin-2-yl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (methyl-propyl-amino) -piperidine-1-carbonyl ] -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (3S-benzyl-morpholine-4-carbonyl) -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (3S-isobutyl-morpholine-4-carbonyl) -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- (3S-phenyl-morpholine-4-carbonyl) -hexanoic acid hydroxyamide;

3R- (4-benzyl-3 RS-methyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

3R- (3S, 4-dibenzyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

3R- (4-benzyl-3 RS-phenyl-piperazine-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;

6- (3, 5-bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide;

3R- (4-benzyl-piperidine-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-piperazine-1-carbonyl) -hexanoic acid hydroxyamide;

6- (3, 5-bis-trifluoromethyl-phenyl) -2S-hydroxy-3R- (pyrrolidine-1-carbonyl) -hexanoic acid hydroxyamide;

3R- (2S-benzyl-4-methyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (4-trifluoromethoxy-benzenesulfonyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide;

6- (4-ethoxy-phenyl) -2S-hydroxy-3R- [4- (toluene-4-sulfonyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide;

3R- [4- (5-bromo-thiophene-2-sulfonyl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

3R- [4- (5-benzenesulfonyl-thiophene-2-sulfonyl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

3R- [4- (4-butoxy-benzenesulfonyl) -piperazine-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) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide;

3R- [4- (3, 4-dimethoxy-benzenesulfonyl) -piperazine-1-carbonyl ] -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

6- (4-methoxy-phenyl) -2S-hydroxy-3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -hexanoic acid hydroxyamide;

6- (4-methoxy-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide;

6- (4-fluoro-phenyl) -3R- [4- (2-fluoro-phenyl) -piperazine-1-carbonyl ] -2S-hydroxy-hexanoic acid hydroxyamide;

6- (4-fluoro-phenyl) -2S-hydroxy-3R- (4-pyridin-2-yl-piperazine-1-carbonyl) -hexanoic acid hydroxyamide;

3R- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -6- (4-ethoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

3R- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

3R- (4-benzyl-2S-isobutyl-piperazine-1-carbonyl) -6- (4-methoxy-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

3R- (4-benzyl-2S-methyl-piperazine-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

3R- (4-benzyl-2S-isobutyl-piperazine-1-carbonyl) -6- (4-fluoro-phenyl) -2S-hydroxy-hexanoic acid hydroxyamide;

19. A pharmaceutical composition comprising a compound of any one of claims 1-18, and a pharmaceutically acceptable carrier.

20. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for the treatment or prevention of a disease or condition responsive to inhibition of matrix metalloproteinase-12 and/or matrix metalloproteinase-9.

21. The use of claim 20, wherein the disease or condition is bone resorption, tumor growth, or secondary metastatic invasion; rheumatoid arthritis, septic arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, cardiac hypertrophy, acute respiratory distress syndrome, neuroinflammatory disorders; restenosis; emphysema; fibrosis; chronic obstructive pulmonary disease; bronchitis; asthma; (ii) an autoimmune disease; graft rejection; psoriasis; psoriatic arthritis; degenerative cartilage loss; inflammatory gastric diseases; crohn's disease; inflammatory bowel disease; ulcerative colitis; atopic dermatitis; epidermolysis bullosa; an epidermal ulcer; neuropathy or nephropathy; inflammation of the eye; cirrhosis or sjogren's syndrome.

22. The use of claim 21, wherein the inflammatory bowel disease is ulcerative colitis.

23. The use of claim 21, wherein the renal disease is interstitial nephritis, glomerulonephritis, or renal failure.

24. The use of claim 21, wherein the neuroinflammatory disorder is multiple sclerosis.

25. The use of claim 21, wherein the fibrotic disease is post-radiation fibrosis, corneal scarring, liver fibrosis, and cystic fibrosis.

26. The use of claim 21, wherein the graft rejection is graft versus host disease.

27. The use of claim 20, wherein the disease or condition is a fibrotic disease, multiple sclerosis, emphysema, bronchitis, or asthma.

28. A process for the preparation of a compound of formula (IA), said process comprising the following deprotection and/or conversion steps:

wherein Ar, Alk, R₁And R₂As defined in any one of claims 1 to 15.

29. A compound of formula (IIIB)

Wherein Ar, Alk, R₁And R₂As defined in any one of claims 1 to 15.

30. A process for preparing a compound of claim 29, comprising reacting a compound of formula (III)

With cyclic amines HNR₁R₂Step of reaction, wherein Ar, Alk, R₁And R₂As defined in any one of claims 1 to 15.