This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to pharmaceutical compositions useful therefor.

There are a number of enzymes which effect the breakdown of structural proteins and which are structurally related metalloproteases. Matrix-degrading metalloproteinases, such as gelatinase, stromelysin and collagenase, are involved in tissue matrix degradation (e.g. collagen collapse) and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. comeal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease (e.g. Pages disease and osteoporosis), tumor metastasis or invasion, as well as HlV-infection (J. Leuk. Biol., 52 (2): 244248,1992).

Tumor necrosis factor is recognized to be involved in many infectious and auto- immune diseases (W. Fiers, FEBS Letters, 1991, 285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C.E. Spooner et al., Clinical Immunology and Immunoqathology, 1992, 62 S11).

Summarv of the Invention The present invention relates to a compound of the formula or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond; X is carbon, oxygen or sulfur; Y is carbon, oxygen, sulfur, SO, SO2 or nitrogen; R', R2 R3, R4 R5, Re, R7, R8 and R9 are selected from the group consisting of hydrogen, (C1-C6)alkyl optionally substituted by one or two groups selected from (C,- C6)alkylthio, (C1-C6)alkoxy, trifluoromethyl, halo, (C6-C10)aryl, (C5-C9)heteroaryl, (C6- C10)arylamino, (C6-C10)arylthio, (C6-C10)aryloxy, (C5-C9)heteroarylamino, (C5- C))heteroarylthio, (C5-C9)heteroaryloxy, (C6-C10)aryl(C6-C10)aryl, (C3-C6)cycloalkyl, hydroxy, piperazinyl, (C6-C10)aryl(C1-C6)alkoxy, (C5-C9)heteroaryl(C1-C6)alkoxy, (C1- C6)acylamino, (C1-C6)acylthio, (C1-C6)acyloxy, (C1-C6)alkylsufinyl, (C6-C10)arylsulfinyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl, amino, (C1-C6)alkylamino or ((C1.

C6)alkylamino2; (C2-C5)alkenyl, (C5-C10)aryl(C2-C6)alkenyl, (C5-C9)heteroaryl(C2.

C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl(C2-C6)alkynyl, (C5-C9)heteroaryl(C2-C6)alkynyl, (C1-C6)alkylamino, (C1-C6)alkylthio, (C1-C6)alkoxy, perfluoro(C1-C6)alkyl, (C6-C10)aryl, (C5- C9)heteroaryl, (C6-C10)arylamino, (C6-C10)arylthio, (C6-C10)aryloxy, (C5- C9)heteroarylamino, (C6-C9)heteroarylthio, (C5-C9)heteroaryloxy, (C3-C6)cycloalkyl, (C1- C6)alkyl(hydroxymethylene), piperidyl, (C1-C6alkylpiperidyl, (C1-C6)acylamino, (C1- C6)acylthio, (C1-C6)acyloxy, R10(C1-C6)alkyl, wherein R10 is (C1-C6)acylpiperazino, (C6- C10)arylpiperazino, (C5-C9)heteroarylpiperazino (C1-C6)alkylpiperazino, (C6-C10)aryl(C1- C6)alkylpiperazino, (C6-C9)heteroaryl(C1-C6)alkylpiperazino,morpholino,thiomorph olino, pyrrolidino, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C6- C9)heteroarylpiperidyl,(C1-C6)alkylpiperidyl(C1-C6)alkyl(C6- C10)arylpiperidyl(C1-C6)alkyl, (C6-C9)heteroarylpiperidyl(C1-C6)alkyl or (C12-C6)acylpiperidyl; or a group of the formula

wherein n is O to 6; y isO or 1; W is oxygen or NR24 wherein R24 is hydrogen or (C,-Ce)alkyl; Z is OR" or NR24R" wherein R24 is as defined above and R11 is as defined below; azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl or a bridged diazabicycioalkyl ring selected from the group consisting of

wherein r is 1, 2 or 3; m is 1 or 2; p isO or 1; and wherein each heterocyclic group may optionally be substituted by one or two groups selected from hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C10)acyl, (C1-C10)acyloxy, (C6- C10)aryl, (C5-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C5-C9)heteroaryl(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)acyloxy(C1-C6)alkyl, (C1- C6)alkylthio, (C1-C6)alkylthio(C1-C6)alkyl, (C6-C10)arylthio, (C6-C10)arylthio(C1-C6)alkyl, R12R13N, R12R13NSO2, R12R13NCO, R12R13NCO(C1-C6)alkyl wherein R12 and R'3 are each independently hydrogen, (C1-C6)alkyl, (C6-C10)aryl, (C5-C9)heteroaryl, (C6-C10)aryl (C1- Ce)alkyl or (C5-C9)heteroaryl (C1-C6)alkyl or R12 and R'3 may be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl ring; R14SO2, R'4SO2NH wherein R14 is trifluoromethyl, (C1-C6)alkyl, (C6-C10)aryl, (C5-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl or (C5-C9)heteroaryl (C1-C6)alkyl; R15CONR12 wherein R12 is as defined above and R15 is hydrogen, (C,- C6)alkyl, (C1-C6)alkoxy, (C6-C10)aryl, (C5-C9)heteroaryl, (C1-C6)aryl(C1-C6)alkyl(C6- C10)aryl(C1-C6)alkoxy or (C5-C9)heteroaryl(C1-C6)alkyl; R16OOC, R16OOC(C1-C6)alkyl wherein R16 is (C1-C6)alkyl, (C6-C10)aryl, (C5-C9)heteroaryl, (C6-C10)aryl (C1-C6)alkyl, 5- indanyl, CHR17OCOR18 wherein R17 is hydrogen or (C1-C6)alkyl and R18 is (c1-C6)alkyl, (C1-C6)alkoxy or (C6-C10)aryl; CH2CONR'9R2° wherein R'9 and R20 are each independently hydrogen or (C,-Ce)aikyl or may be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or

thiomopholinyl ring; or R21O (C1C6)alkyl wherein R21 is H2N(CHR22)CO wherein R22 is the side chain of a naturai D- or L-amino acid; R11 is hydrogen, (C6-C10)aryl, (C5-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C5- Cg)heteroaryl (C, -Ce)alkyl, (C1-C6)alkyl(C6-C1 O)aryl(Cl -Ce)alkyl, (C, -Ce)alkyl(C5- C9)heteroaryl(C1-C6)alkyl, 5-indanyl, CHR''OCOR'8 or CH2CONR19R20 wherein R'7, R'8, R19 and R20 are as defined above; or R' and R2, or R3 and R4, or R5 and Re may be taken together to form a carbonyl; or R' and R2, or R3 and R4, or R5 and Re, or R7 and Re may be taken together to form a (C3-Ce)cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula wherein R23 is hydrogen, (C,-Ce)acyl, (C,-Ce)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C5- C9)heteroaryl(C1-C6)alkyl or (C1-C6)alkylsulfonyl; and Q is (C1-C10)alkyl, (C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6- C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (C6- C10)aryloxy(C5-C9)heteroaryl, (C5-C9)heteroaryl, (C1-C6)heteroaryl, (C1-C6)alkyl(C6-C10)aryl, (C1- C6)alkoxy(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(C6-C10)aryl, (C5-C9)heteroaryloxy(C6- C10)aryl, (C1-C6)alkyl(C5-C9)heteroaryl, (C1-C6)alkoxy(C5-C9)heteroaryl, (C6-C10)aryl(C1- C6)alkoxy(C5-C9)heteroaryl, (C5-C9)heteroaryloxy(C5-C9)heteroaryl, (C6-C10)aryloxy(C1- C6)alkyl, (C5-C9)heteroaryloxy(C1-C6)alkyl, (C1-C6)alkyl(C6-C10)aryloxy(C6-C10)aryl, (C1- C6)alkyl(C5-C9)heteroaryloxy(C6-C10)aryl, (C1-C6)alkyl(C6-C10)aryloxy(C5-C9)heteroaryl, (C1-C6)alkoxy(C6-C10)aryloxy(C6-C10)aryl, (C1-C6)alkoxy(C5-C9)heteroaryloxy(C6-C10)aryl or (C1 -C6)alkoxy(C6-C10)aryloxy(C5-C9)heteroaryl optionally substituted byfluoro, chloro, (C1-C6)alkyl, (C1-C6)alkyl or perfluoro(C1-C3)alkyl; with the proviso that Z must be substituted when defined as azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, piperazinyl, (C1-C10)acylpiperazinyl, (C1-C6)alkylpiperazinyl, (C6- C10)arylpiperazinyl, (C5-C9)heteroarylpiperazinyl or a bridged diazabicycloalkyl ring;

with the proviso that R7 jS other than hydrogen only when Re is other than hydrogen; with the proviso that Re is other than hydrogen only when R5 iS other than hydrogen; with the proviso that R3 iS other than hydrogen only when R4 iS other than hydrogen; with the proviso that R2 is other than hydrogen only when R' is other than hydrogen; with the provisio that when R', R2 and R9 are a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 2- or 6- positions; with the proviso that when X is nitrogen, R4 jS not present; with the proviso that when X is oxygen, sulfur, SO, SO2 or nitrogen and when one or more of the group consisting of R', R2, R5 and Re, is a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 4- or 6- positions; with the proviso that when Y is oxygen, sulfur, SO, SO2 or nitrogen and when one or more of the group consisting of R3, R4, R7 and R8, are independently a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 3- or 5- positions; with the proviso that when X is oxygen, sulfur, SO or SO2, R3 and R4 are not present; with the proviso that when y is 1 and W is NR24 or oxygen, Z cannot be hydroxy; with the proviso that when Y is oxygen, sulfur, SO or SO29 R5 and Rd are not present; with the proviso that when Y is nitrogen, Re is not present; with the proviso that when the broken line represents a double bond, R4 and Re are not present; with the proviso that when R3 and R5 are independently a substituent comprising a heteroatom when the broken line represents a double bond, the heteroatom cannot be directly bonded to positions X and Y; with the proviso that when either the X or Y position is oxygen, sulfur, SO, SO2 or nitrogen, the other of X or Y is carbon; with the proviso that when X or Y is defined by a heteroatom, the broken line does not represent a double bond;

with the proviso that at least one of R', R2, R3, R4, R5, R6, R7, R8 and R9 must be defined as the group of formula li.

The term "alkly", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.

The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is defined above.

The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, cyano, nitro, trifluoromethyl, (C,-Ce)alkoxy, (Ce-C,O)aryloxy, trifluoromethoxy, difluoromethoxy and (C,-Ce)alkyl.

The term Nheteroaryl', as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents independently selected from the group consisting of fluoro, chloro, trifluoromethyl, (C1- Ce)alkoxy, (Ce-C,O)aryloxy, trifluoromethoxy, difluoromethoxy and (C,-Ce)alkyl.

The term "acyl", as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy (such as methyloxy carbonyl), aryl, arylalkyi or arylalkyloxy and the terms 1alkyl1 or saryll are as defined above.

The term XacyloxyX, as used herein, includes O-acyl groups wherein "acyl" is defined above.

The term D- or L-amino acid', as used herein, unless otherwise indicated, includes glycine, alanine, valine, leucine, isoleucine, phenylalanine, asparagine, glutarnine, tryptophan, proline, serine, threonine, tyrosine, hydroxyproline, cysteine, cystine, methionine, aspartic acid, glutamic acid, lysine, arginine or histidine.

The positions on the ring of formula I, as used herein, are defined as follows:

The preferred conformation of the compound of formula I includes hydroxamic acid axially disposed in the 2-position.

The compound of formula I may have chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.

Preferred compounds of formula I include those wherein Y is carbon.

Other preferred compounds of formula I include those wherein Q is (C,- C6)alkoxy(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(C6-C10)aryl, or (C6-C10)aryl(C1- C6)alkoxy(C1-C6)alkyl wherein each terminal aryl group is optionally substituted by fluoro.

Other preferred compounds of formula I include those wherein R2, R3, R6, R7 and R9 are hydrogen.

More preferred compounds of formula I include those wherein Y is carbon; Q is (C1-C6)alkoxy(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(C6-C10)aryl, or (C6-C10)aryl(C1- C6)alkoxy(C1-C6)alkyl.

Specific preferred compounds of formula I include the following: (2R,4JR-1 -[4-(4-Fluorobenzyloxy)-benzenesulfonyli-2-hydroxycarbamoyl- piperidine4-carboxylic acid; (2R,4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxyc arbamoyl- piperidine4-carboxylic acid methyl ester; (2R,4R)-1 -[3-(4-Fluorophenoxy)-propane-l -sulfonyl]-2-hydroxycarbamoyl- piperidine4-carboxylic acid; (2R,4R)-1-[3-(4-Fluorophenoxy)-propane-1-sulfonyl]-2-hydroxy carbamoyl- piperidine4-carboxylic acid methyl ester; (2R,3S)-{1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxy carbamoyl- piperidin-3-yl}-carbamic acid isopropyl ester;

3-(S)-4-(4'-Fluorobiphenyl-4-sulfonyl)-2,2-dimethyl-thiomorp holine-3-carboxylic acid hydroxyamide; 3-(S)-4-[4-(4-Fluorobenzyloxy)benzenesulfonyl]-2,2-dimethyl- thiomorpholine-3- carboxylic acid hydroxyamide; (2R,4S)- 1- [4-(4-Fluorobenzyloxy)-benzenesulfonyl4-hydrnxy-piperidine-2 - carboxylic acid hydroxyamide; and (2R,4R)-1-(4-Methoxybenzenesulfonyl)-4-(piperazine-1-carbony l)-piperadine-2- carboxylic acid hydroxyamide hydrochloride.

Other compounds of the invention include: (3S)-4-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2, 2-dimethyl- thiomorpholine3-carboxylic acid hydroxyamide; (3S)-2,2-Dimethyl-4-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl ]-thiomorpholine-3- carboxylic acid hydroxyamide; (3O-2,2-Dimethyl+[4-(pyridinXyimethoxy)-benzenesuWonyl] -thiomorpholineO carboxylic acid hydroxyamide; (3S)-4-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2,2-d imethyl- thiomorpholine3carboxylic acid hydroxyamide; (3S)-2,2-Dimethyl-4-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfon yl]-thiomorpholine-3- carboxylic acid hydroxyamide; (3S)-4-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl}-2,2-di methyl- thiomorpholine-3-carboxylic acid hydroxyamide; (3S)-2,2-Dimethyl-4-{4-(5-trifluoromethyl-benzothiazol-2-ylm ethoxy)- benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide; (3S)-2,2-Dimethyl-4-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulf onyl]-thiomorpholine- 3-carboxylic acid hydroxyamide; (2R,3S)-{1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl ]-2- hydroxycarbamoyl-piperidin-3-yl)carbamic acid methyl ester; (2R, 32-{ 2-Hydroxycarbamoyl-1 -[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]- piperidin-3-yl}-carbamic acid methyl ester; (2R,3S)-{2-Hydroxycarbamoyl-1-[4-(pyridin-4-ylmethoxy)-benze nesulfonyl] piperidin-3-yl}-carbamic acid methyl ester; (2R, 3S)-{ 1- [4-(4-Fluorobenzyloxy)-benzenesulfonyl] -2-hyd roxycarbamoyl- piperidin-3-yl}-carbamic acid methyl ester;

(2R,3S)-(1-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2 -hydroxycarbamoyl- piperidin-3-yl)-carbamic acid methyl ester; (2R,3S)-{2-Hydroxycarbamoyl-1-[4-(2-pyridin-4-yl-ethoxy)-ben zenesulfonyl]- piperidin-3-yl}-carbamic acid methyl ester; (2R,3S)-(1-[4-Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2-h ydroxycarbamoyl- piperidin-3-yl} carbamic acid methyl ester; (2R,3S)-{2-Hydroxycarbamoyl-1-[4-(5-trifluoromethyl-benzothi azol-2-ylmethoxy)- benzenesuffonyl]-piperidin3-yi)-carbamic acid methyl ester; (2R,3S)-{2-Hydroxycarbamoyl-1-[4-(1H-tetrazol-5-ylmethoxy)-b enzenesulfonyl]- piperidin-3-yl}carbamic acid methyl ester; (2R,3S)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl] -3-hydroxy- piperidine-2-carboxylic acid hydroxyamide; (2R, 32-3-Hydroxy-1 -(4-(thiazol-5-ylmethoxy)-benzenesuIfonyl-piperidine-2- carboxylic acid hydroxyamide; (2R,3-3-Hydrnxy-1 -{4-(pyridin4-ylmethoxy)-benzenesulfonyl]-piperidine-2- carboxylic acid hydroxyamide; (2R,3S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-3-hydroxy- piperidine-2- carboxylic acid hydroxyamide; (2R,3S)-(1-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-3 -hydroxy-piperidine- 2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfon yl]-piperidine-2- carboxylic acid hydroxyamide; (2R,3S)-1-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-3-h ydroxy-piperidine-2- carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-1-[4-(5-trifluoromethyl-benzothiazol-2-ylm ethoxy)- benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-1-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulf onyl]-piperidine-2- carboxylic acid hydroxyamide; (2R,3S)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl] -3-hydroxy-3-methyl- piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-3-methyl-1-[4-(thiazol-5-ylmethoxy)-benzen esulfonyl]- piperidine-2-carboxylic acid hydroxyamide;

(2R,3S)-3-Hydroxy-3-methyl-1-[4-(pyridin-4-ylmethoxy)-benzen esulfonyl]- piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-3-hydroxy- 3-methyl-piperidine- 2-carboxylic acid hydroxyamide; (2R,3S)-1-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-3- hydroxy-3-methyl- piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-3-methyl-1-[4-(2-pyridin-4-yl-ethoxy)-benz enesulfonyl]- piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-1-{4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-3-h ydroxy-3-methyl- piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-3-methyl-1-[4-(5-trifluoromethyl-benzothia zol-2-ylmethoxy)- benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-3-methyl-1-[4-(1H-tetrazol-5-ylmethoxy)-be nzenesulfonyl]- piperidine-2-carboxylic acid hydroxyamide; (3B)-4- [4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl] -2,2-dimethyl- morpholine-3-carboxylic acid hydroxyamide; (3R)-2,2-Dimethyl-4-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl ]-morpholine-3- carboxylic acid hydroxyamide; (3R)-2,2-Dimethyl-4-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl ]-morpholine-3- carboxylic acid hydroxyamide; (3R)-2,2-Dimethyl-4-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]- 2,2-dimethyl-morpholine-3- carboxylic acid hydroxyamide; (3R)-2,2-Dimethyl-4-{4-[2-(4-Fluorophenyl)-ethoxy]benzenesul fonyl}-2,2-dimethyl-morpholine- 3-carboxylic acid hydroxyamide; (3R)-2,2-Dimethyl-4-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfon yl]-morpholine-3- carboxylic acid hydroxyamide; (3R)-4-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2,3-di methyl-morpholine-3- carboxylic acid hydroxyamide; (3R)-2,2-Dimethyl-4-[4-(5-trifluoromethyl-benzothiazol-2-ylm ethoxy)- benzenesulfonyl]-morpholine-3-carboxylic acid hydroxyamide; (3flR-2,2-Dimethyl(4(1 H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-morpholineo carboxylic acid hydroxyamide;

(2R,4R)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl] -2- hydroxycarbamoyl-piperidine-4-carboxylic acid; (2R,4R)-2-Hydroxycarbamoyl-1-[4-(thiazol-5-ylmethoxy)-benzen esulfonyl]- piperidine4-carboxylic acid; (2R,4R)-2-Hydroxycarbamoyl-1-[4-(pyridin-4-ylmethoxy)-benzen esulfonyl]- piperidine-4-carboxylic acid; (2R,4R)-1-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2- hydroxycarbamoyl- piperidine-4-carboxylic acid; (2R,4R)-2-Hydroxycarbamoyl-1-[4-(2-pyridin-4-yl-ethoxy)-benz enesulfonyl]- piperidine-4-carboxylic acid; (2R,4R)-1-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2-h ydroxycarbamoyl- piperidine-4-carboxylic acid; (2R,4R)-2-Hydroxycarbamoyl-1-[4-(5-trifluoromethyl-benzothia zol-2-ylmethoxy)- benzenesulfonyl]-piperidine-4-carboxylic acid; (2R,4R)-2-Hydroxycarbamoyl-1-[4-(1H-tetrazol-5-ylmethoxy)-be nzenesulfonyl]- piperidine4oarboxylic acid; (3R)-4-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-3- methyl-morpholine-3- carboxylic acid hydroxyamide; (3R)-3-Methyl-4-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-mo rpholine-3-carboxylic acid hydroxyamide; (3R)-3-Methyl-4-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-mo rpholine-3-carboxylic acid hydroxyamide; (3R)-4-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-3-methyl-morp holine-3-carboxylic acid hydroxyamide; (3R)-4-[4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-3-met hyl-morpholine-3- carboxylic acid hydroxyamide; (3O-3-Methyl4-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl] -morpholine-3- carboxylic acid hydroxyamide; (3R)-4-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-3-meth yl-morpholine-3- carboxylic acid hydroxyamide; (3R)-3-Methyl-4-[4-(5-trifluoromethyl-benzothiazol-2-ylmetho xy)-benzenesulfonyl]- morpholine-3-carboxylic acid hydroxyamide;

(3R)-3-Methyl-4-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulfonyl ]-morpholine-3- carboxylic acid hydroxyamide; (2O- 1 (4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl)-2-methyl- 3xo- piperidine-2-carboxylic acid hydroxyamide; (2R)-2-Methyl-3-oxo-1-[4-(thiazol-5-ylmethoxy)-benzenesulfon yl]-piperidine-2- carboxylic acid hydroxyamide; (2R)-2-Methyl-3-oxo-1-[4-(pyridin-4-ylmethoxy)-benzenesulfon yl]-piperidine-2- carboxylic acid hydroxyamide; (2R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-methyl-3-ox o-piperidine-2- carboxylic acid hydroxyamide; (2R)-1-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2-met hyl-3-oxo-piperidine- 2carboxylic acid hydroxyamide; (2R)-2-Methyl-3-oxo-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulf onyl]-piperidine-2- carboxylic acid hydroxyamide; (2R)-1-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2-meth yl-3-oxo-piperidine- 2-carboxylic acid hydroxyamide; (2R)-2-Methyl-3-oxo-1-[4-(5-trifluoromethyl-benzothiazol-2-y lmethoxy)- benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R)-2-Methyl-3-oxo-1-[4-(1H-tetrazol-5-ylmethoxy)-benzenesu lfonyl]-piperidine-2- carboxylic acid hydroxyamide; (2R,42-1 -(4-Benzyloxy-benzenesulfonyl)-4-butylaminomethyl-4-hydroxy- piperidine-2-carboxylic acid hydroxyamide; (2R,4S)-4-Butylaminomethyl-1-[4-(4-fluorobenzyloxy)-benzenes ulfonyl]-4-hydroxy- piperidine-2-carboxylic acid hydroxyamide; (2R,4S)-4-Benzylamino-1-(4-benzyloxy-benzenesulfonyl)-piperi dine-2-carboxylic acid hydroxyamide; (2R,4S)-4-Benzylamino-1-[4-(4-fluorobenzyloxy)-benzenesulfon yl)-piperidine-2- carboxylic acid hydroxyamide; (2R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-oxo-piperid ine-2-carboxylic acid hydroxyamide; (2R,4S)-1-(4-Benzyloxy-benzenesulfonyl)-4-hydroxy-piperidine -2-carboxylicacid hydroxyamide;

(2R,4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-hydroxy- piperidine-2- carboxylic acid hydroxyamide; (2R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-methyl-pipe razine-2-carboxylic acid hydroxyamide; (2R,5S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-5-hydroxy- piperidine-2- carboxylic acid hydroxyamide; (2R,5S)-1-(4-Benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine -2-carboxylicacid hydroxyamide; (2R,5S)-1-(4-Benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine -2-carboxylicacid hydroxyamide; (2R, 5R)- 1- [4-(4-Fluorobenzyloxy)-benzenesulfonyli-6-hydroxy-piperidine -2- carboxylic acid hydroxyamide; (2R,3S)-1-(4-Benzyloxy-benzenesulfonyl)-3-hydroxy-piperidine -2-carboxylicacid hydroxyamide; (2R,4S)-1-(4-Benzyloxy-benzenesulfonyl)-4-hydroxy-piperidine -2-carboxylicacid hydroxyamide; (2R,4S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-hydroxy- piperidine-2- carboxylic acid hydroxyamide; 1-(4-Butoxy-benzenesulfonyl)-3-(morpholine-4-carbonyl)-piper idine-2-carboxylic acid hydroxyamide; 1-[4-(4-Fluoro-benzyloxy)-benzenesulfonyl)-3-(morpholine-4-c arbonyl)-piperidine- 2-carboxylic acid hydroxyamide; 1-[3-(Fluoro-benzyloxy)-propane-1-sulfonyl]-3-(morpholine-4- carbonyl)-piperidine- 2-carboxylic acid hydroxymide; 1-(4-Butoxy-benzenesulfonyl)-3-(pyrrollidine-1-carbonyl)-pip eridine-2-carboxylic acid hydroxyamide; 1-[4-(4-Fluoro-benzyloxy)-benzenesulfonyl)-3-(pyrrollidine-1 -carbonyl)-piperidine-2- carboxylic acid hydroxyamide; 1- -[3-(4-Fluoro-benzyloxy)-propane-1 -sulfonyl)-3-(pyrrolidine-1 -carbonyl)- piperidine-2-carboxylic acid hydroxyamide; and 1-[4-(4-Fluoro-benzyloxy)-benzenesulfonyl]-2-hydroxycarbamoy l-piperidine-4- carboxylic acid.

The present invention also relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, cancer, synergy with cytotoxic anticancer agents, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scieritis, in combination with standard NSAID'S and anaigesics and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (mix) or (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically acceptable carrier.

The present invention also relates to a method for the inhibition of (a) matrix metailoproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method for treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, compounds of formula I may be used in combination with standard NSAICS and analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition.

Detailed Description of the Invention The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated R', R2, R3, R4, R5, Re, R7, R8, R9, n and Ar in the reaction Schemes and the discussion that follow are defined as above.

Preparation 1

Preparation 2

Scheme 1

Scheme 2 Scheme 3

Scheme 4

Scheme 4 continued

Scheme 5

Scheme 5 continued

Preparation 1 refers to the preparation of intermediates of the formula Vl.

Compounds of the formula VI are converted to compounds of the formula I according to the methods of Scheme 1. The starting materials of formula XVI can be prepared according to methods well known to those of ordinary skill in the art.

In reaction 1 of Preparation 1 the compound of formula XVI is converted to the corresponding hydroxy ester compound of formula VI by first reacting XVI with an arylsulfonylhalide in the presence of triethylamine and an aprotic solvent, such as methylene chloride, tetrahydrofuran or dioxane, at a temperature between about 200C to about 300 C, preferably at room temperature. The compound so formed is further reacted with a compound of the formula wherein R25 is carbobenzyloxy, (C-Cf,)aikyi, benzyl, allyl or tert-butyl, in the presence of sodium hexamethyldisilazane and a tetrahydrofuran-dimethylformamide solvent mixture at a temperature between about -200C to about 200 C, preferably about OOC, to form the hydroxy ester compound of formula Vl.

Preparation 2 refers to an altemate method of preparing compounds of the formula VI. The starting materials of formula XVIII can be prepared according to methods well known to those of ordinary skill in the art. In reaction 1 of Preparation 2, the amine compound of formula XVlil, wherein R25 is as defined above, is converted to the corresponding arylsulfonyl amine compound of formula XVII by (1) reacting XVIII with an arylsulfonylhalide in the presence of triethylamine and an aprotic solvent, such as methylene chloride, tetrahydrofuran, or dioxane, at a temperature between about 200C to about 300C, preferably at room temperature, (2) reacting the compound so formed with a compound of the formula in the presence of sodium hexamethyidisilazane and a tetrahydrofuran- dimethylformamide solvent mixture at a temperature between about -200C to about 200 C, preferably about OOC, and (3) further reacting the compound so formed with ozone in a methylene chloridemethanol solution at a temperature between about -90 o C

to about .700 C, preferably about .780 C. The unstable ozonide compound so formed is then reacted with triphenylphosphine to form the arylsulfonyl amine compound formula XVII. In Reaction 2 of Preparation 2, the arylsulfonyl amine compound of formula XVII is converted to the corresponding hydroxy ester compound of formula VI by reacting XVII with a compound of the formula wherein W is lithium, magnesium, copper or chromium.

Scheme 1 refers to the preparation of compounds of the formula II, which are compounds of the formula I, wherein X and Y are carbon; R4, Re and R7 are hydrogen; and the dashed line between X and Y Is absent. In reaction 1 of Scheme 1, the compound of formula VI, wherein the Rm protecting group is carbobenzyloxy, (C,-C,) alkyl, benzyl, allyl or tert-butyl, is converted to the corresponding morpholinone compound of formula V by lactonization and subsequent Claisen rearrangement of the compound of formula Vl. The reaction is facilitated by the removal of the R25 protecting group from the compound of formula VI and is carried out under conditions appropriate for that particular R26 protecting group in use. Such conditions include: (a) treatment with hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, where R25 is carbobenzyloxy, (b) saponification where R25 is lower alkyl, (c) hydrogenolysis where R25 is benzyl, (d) treatment with a strong acid, such as trifluoroacetic acid or hydrochloric acid, where R25 is tert-butyl, or (e) treatment with tributyltinhydride and acetic acid in the presence of catalytic bis(triphenylphosphine) palladium (II) chloride where R25 is allyl.

In reaction 2 of Scheme 1, the morpholinone compound of formula V is converted to the carboxylic acid compound of formula IV by reacting V with lithium hexamethyldisilazane in an aprotic solvent, such as tetrahydrofuran, at a temperature between about -900C to about .700 C, preferably about .780 C. Trimethylsilyl chloride is then added to the reaction mixture and the solvent, tetrahydrofuran, is removed in vacuo and replaced with toluene. The resuling reaction mixture is heated to a temperature between about 1000C to about 1200C, preferably about 1100C, and treated with hydrochloric acid to form the carboxylic acid compound of formula IV.

In reaction 3 of Scheme 1, the carboxylic acid compound of formula IV Is converted to the corresponding hydroxamic acid compound of formula lil by treating IV with 1 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenztriazole in a polar solvent, such as dimethylformamide, followed by the addition of hydroxylamine to the reaction mixture after a time period between about 15 minutes to about 1 hour, preferably about 30 minutes. The hydroxylamine is preferably generated in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as N-methylmorpholine. Alternatively, a protected derivative of hydroxylamine or its salt form, where the hydroxyl group is protected as a tert-butyl, benzyl or allyl ether, may be used in the presence of (benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexafluorphosphate and a base, such as N-methylmorpholine. Removal of the hydroxylamine protecting group is carried out by hydrogenolysis for a benzyl protecting group or treatment with a strong acid, such as trifluoroacetic add, for a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyltinhydride and acetic acid In the presence of catalytic bls(triphenylphosphine) palladium (II) chloride. N,O-bis(4methoxybenzyl)hydroxylamine may also be used as the protected hydroxylamine derivative where deprotection is achieved using a mixture of methanesulfonic add and trifluoroacetic add.

In reaction 4 of Scheme 1, the hydroxamic acid compound of formula lil is converted, if desired, to the corresponding piperidine compound of formula II by treating Ill with hydrogen and a hydrogenation catayst, such a 10% palladium on carbon.

Scheme 2 refers to the preparation of compounds of the formula Vll, which are compound of the formula I wherein Y is nitrogen; X Is carbon; R1, R2, R3, R4, R7 and Re are hydrogen, and Re is absent. The starting materials of formula IX can be prepared according to methods well known to those of ordinary skill in the art. In reaction 1 of Scheme 2, the arylsulfonylpiperazine compound of formula IX, wherein R2e is carbobenzyloxy, benzyl or carbotertbutyloxy, is converted to the compound of formula Vlil by reacting IX with a protected derivative of hydroxylamine of the formula R27ONH2oHCl wherein R27 is tertbutyl, benzyl or allyl, In the presence of dicyclohexylcarbodiimide, dimethylaminopyridine and an aprotic solvent, such as methylene chloride. The R2d protecting group is chosen such that it may be selectively removed in the presence of an without loss of the R27 protecting group, therefore, Rlb cannot be the same e as R27

Removal of the R2e protecting group from the compound of formula IX is carried out under conditions appropriate for that particular R20 protecting group in use. Such conditions include; (a) treatment with a hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, where R20 is carbobenzyloxy, (b) hydrogenolysis' where R26 is benzyl or (c) treatment with a strong acid, such as trifluoroacetic acid or hydrochloric acid where R20 is carbotertbutyloxy.

In reaction 2 of Scheme 2 the compound of formula VIII is converted to the corresponding hydroxamic acid compound of formula VII, wherein R5 is hydrogen or (C,-C,)alkyl, by reacting, if desired, VIII with an alkylhalide when R5 is (C,-Ce)alkyi.

Subsequent removal of the R27 hydroxylamine protecting group is carried out by hydrogenolysis for a benzyl protecting group or treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyitinhydride and acetic acid in the presence of catalytic bis(triphenylphosphine) palladium (Il) chloride.

Scheme 3 refers to the preparation of compounds of the formula X, which are compounds of the formula I wherein Y Is nitrogen; X Is carbon; R21 R7, Ra and R0 are hydrogen; R3 and R4 taken together are carbonyl; R5 is hydrogen, and Rd Is absent.

In reaction 1 of Scheme 3, the arylsuffonylamine compound of formula XII, wherein R25 is as defined above, is converted to the corresponding piperazine compound of formula Xl by reacting XII with a carbodiimide and a base, such as triethylamine. The compound of formula Xl is further reacted to give the hydroxamic acid compound of formula X according to the procedure described above in reaction 3 of Scheme 1.

Scheme 4 refers to the preparation of compounds of the formula XIII. The starting materials of formula XVIII can be prepared according to methods well known to those of ordinary skill in the art. Compounds of the formula XIII are compounds of the formula I wherein X is carbon, and the dotted line between X and Y is absent. In reaction 1 of Scheme 4, removal of the R28 protecting group and subsequent reductive amination of the compound of formula XXII, wherein Y Is oxygen, sulfur or carbon, to give the corresponding imine compound of formula XXI Is carried out under conditions appropriate for that particular R28 protecting group in use. Such conditions inciude those used above for removal of the R protecting group in reaction 1 of Scheme 2.

In reaction 2 of Scheme 4, the imine compound of formula XXI is converted to the corresponding piperidine compound of formula XX by reacting XXI with a nucleophile of the formula R2M wherein M is lithium, magnesium halide or cerium

halide. The reaction is carried out in ether solvents, such as diethyl ether or tetrahydrofuran, at a temperature between about -780C to about 0°C, preferably about -70°C.

In reaction 3 of Scheme 4, the sulfonation of the piperidine compound of formula XX to given the corresponding arylsulfonylpiperidine compound of formula XIX is carried out by reacting XX with an arylsulfonyihalide in the presence of triethylamine and an aprotic solvent, such as methylene chloride, tetrahydrofuran or dioxane, at a temperature between about 20°C to about 300C, preferably at room temperature.

In reaction 4 of Scheme 4, the arylsulfonylpiperidine compound of formula XIX is converted to the hydroxamic acid compound of formula XIII according to the procedure described above in reaction 3 of Scheme 1.

Scheme 5 refers to the preparation of compounds of the formula XIV, which are compounds of formula I wherein Y is nitrogen, X is carbon, the dotted line between X and Y is absent, R5 is hydrogen and Rd Is absent. In reaction 1 of Scheme 5, the compound of formula XXVI, wherein the R2st and R3l protecting groups are each independently selected from the group consisting of carbobenzyloxy, benzyl and carbotertbutyloxy and R30 is carbobenzyloxy, (Cl-Ce)aiicyl, benzyl, allyl or tert-butyl, is converted to the corresponding imine compound of formula XXV by the removal of the R29 protecting group and subsequent reductive amination of the compound of formula XXVI. The R29 protecting group is chosen such that it may be selectively removed in the presence of and without loss of the R31 protecting group. Removal of the R29 protecting group from the compound of formula XXVI is carried out under conditions appropriate for that particular R29 protecting group in use which will not affect the R31 protecting group. Such conditions include; (a) treatment with hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, where R20 is carbobenzyloxy and R31 is tert-butyl, (b) saponification where R29 is (C1-C6)alkyl and R31 is tert-butyl, (c) hydrogenolysis where R29 is benzyl and R3' is (C,-Ce) alkyl or tert-butyl, (d) treatment with a strong acid such as trifluoroacetic acid or hydrochloric acid where R29 is tert-butyl and R3t is (C1-C6)alkyl, benzyl or allyl, or (e) treatment with tributyitinhydride and acetic acid in the presence of catalytic bis(triphenylphosphine) palladium (II) chloride where R29 is allyl and R31 is (C,-Ce)aikyi, benzyl or tert-butyl. The R30 protective group may be selected such that it is removed in the same reaction step as the R29 protecting group.

In reaction 2 of Scheme 5 the imine compound of formula XXV is converted to the corresponding compound of formula XXIV by reacting XXV with a nucleophile of the formula R2M wherein M is lithium, magnesium halide or calcium halide. The reaction is carried out in ether solvents, such as diethyl ether or tetrahydrofuran, at a temperature between about -780C to about OOC, preferably about -700C. in reaction 3 of Scheme 5 the sulfonation of the piperidine compound of formula XXIV to give the corresponding arylsuffonylpiperidine compound of formula Ill is carried out according to the procedure described above in reaction 3 of Scheme 4.

In reaction 4 of Scheme 5, the arylsuffonylpiperidine compound of formula XXIII is converted to the hydroxamic acid compound of formula XIV by (1) removing the R30, if needed, and R3l protecting groups from XXIII followed by (2) reacting XXIII according to the procedure described above in reaction 3 of Scheme 1. Removal of the R30 and R3l protecting groups from the compound of formula XXIII is carried out under conditions appropriate for that particular R30 and R3' protecting group in use. Such conditions include those used above for removal of the R25 protecting group in reaction 1 of Scheme 1.

Pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal saits, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium slats, such as ammonium, trimethyl-ammonium, diethylammonium, and tris- (hydroxymethyl)-methylammonium salts.

Similarly acid addition saits, such as of mineral acids, organic carboxylic and organic sulfonic acids e.g. hydrochloric acid, methanesuffonic acid, maieic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.

The ability of the compounds of formula I or their pharmaceutically acceptable saits (the compounds of the invention) to inhibit matrix metalloproteinases or the production of tumor necrosis factor (TNF) and, consequently, demonstrate their effectiveness for treating diseases characterized by matrix metalloproteinase or the production of tumor necrosis factor is shown by the following In vitro assay tests.

Bioloaical Assay Inhibition of Human Collaaenase (MMP-1) Human recombinant collagenase is activated with trypsin using the following ratio: 10 pg trypsin per 100 pg of collagenase. The trypsin and collagenase are incubated at room temperature for 10 minutes then a five fold excess (50 µg/10 pg trypsin) of soybean trypsin inhibitor is added.

10 mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then diluted using the following Scheme: 10 mM ------> 120 µM ------> 12 µM ------> 1.2 µM ------> 0.12 µM Twenty-five microliters of each concentration is then added in triplicate to appropriate wells of a 96 well microfluor plate. The final concentration of inhibitor will be a 1:4 dilution after addition of enzyme and substrate. Positive controls (enzyme, no inhibitor) are set up in wells D1-D6 and blanks (no enzyme, no inhibitors) are set in wells D7-D12.

Collagenase is diluted to 400 ng/ml and 25 pl is then added to appropriate wells of the microfluor plate. Final concentration of collagenase in the assay is 100 ng/ml.

Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is made as a5 mM stock in dimethyl sulfoxide and then diluted to 20 pM in assay buffer. The assay is initiated by the addition of 50 pl substrate per well of the microfluor plate to give a final concentration of 10 pM.

Fluorescence readings (360 nM excitation, 460 nm emission) were taken at time 0 and then at 20 minute intervals. The assay is conducted at room temperature with a typical assay time of 3 hours.

Fluorescence vs time is then plotted for both the blank and collagenase containing samples (data from triplicate determinations is averaged). A time point that provides a good signal (the blank) and that is on a linear part of the curve (usually around 120 minutes) is chosen to determine IC50 values. The zero time is used as a blank for each compound at each concentration and these values are subtracted from the 120 minute data. Data is plotted as inhibitor concentration vs % control (inhibitor fluorescence divided by fluorescence of collagenase alone x 100). IC5o's are determined from the concentration of inhibitor that gives a signal that is 50% of the control.

If lC0,s are reported to be <0.03 pM then the inhibitors are assayed at concentrations of 0.3 pM, 0.03 pM, 0.03 pM and 0.003 pM.

Inhibition of Gelatinase (MMP-2) Inhibition of gelatinase activity is assayed using the Dnp-Pro-Cha-Gly-Cys(Me)- His-Ala-Lys(NMA)-NH2 substrate (10 pM) under the same conditions as inhibition of human collagenase (MMP-1).

72kD gelatinase is activated with 1 mM APMA (p.aminophenyl mercuric acetate) for 15 hours at 4°C and is diluted to give a final concentration in the assay of 100 mg/ml. Inhibitors are diluted as for inhibition of human collagenase (MMP-1) to give final concentrations in the assay of 30 pM, 3 pM, 0.3 pM and 0.03 pM. Each concentration is done in triplicate.

Fluorescence readings (360 nm excitation, 460 emission) are taken at time zero and then at 20 minutes intervals for 4 hours. iC50's are determined as per inhibition of human collagenase (MMP-1). If IC,ds are reported to be less than 0.03 pM, then the inhibitors are assayed at final concentrations of 0.3 pM, 0.03 pM, 0.003 pM and 0.003 pM.

Inhibition of Stromelysin Activitv (MMP-3) Inhibition of stromelysin activity is based on a modified spectrophotometric assay described by Weingarten and Feder (Weingarten, H. and Feder, J., Spectrophotometric Assay for Vertebrate Collagenase, Anal. Biochem. 147, 437-440 (1985)). Hydrolysis of the thio peptolide substrate [Ac-Pro-Leu-Gly- SCH[CH2CH(CH3)2]CO-Leu-Gly-OC2H5] yields a mercaptan fragment that can be monitored in the presence of Ellman's reagent.

Human recombinant prostromelysin is activated with trypsin using a ratio of 1 µl of a 10 mg/ml trypsin stock per 26 pg of stromelysin. The trypsin and stromeiysin are incubated at 370C for 15 minutes followed by 10 p1 of 10 mg/ml soybean trypsin inhibitor for 10 minutes at 37°C for 10 minutes at 37°C to quench trypsin activity.

Assays are conducted in a total volume of 250 p1 of assay buffer (200 mM sodium chloride, 50 mM MES, and 10 mM calcium chloride, pH 6.0) in 96-well microliter plates. Activated stromelysin is diluted in assay buffer to 25 yg/ml. Ellman's reagent (3-Carboxy-4-nitrophenyl disulfide) is made as a 1 M stock in dimethyl formamide and diluted to 5 mM in assay buffer with 50 pi per well yielding at 1 mM final concentration.

10 mM stock solutions of inhibitors are made in dimethyl sulfoxide and diluted serially in assay buffer such that addition of 50 pL to the appropriate wells yields final

concentrations of 3 pM, 0.3 pM, 0.003 pM, and 0.0003 pM. All conditions are completed in triplicate.

A 300 mM dimethyl suffoxide stock solution of the peptide substrate is diluted to 15 mM in assay buffer and the assay is initiated by addition of 50 111 to each well to give a final concentration of 3 mM substrate. Blanks consist of the peptide substrate and Ellman's reagent without the enzyme. Product formation was monitored at 405 nm with a Molecular Devices Wmax plate reader.

IC50 values were determined in the same manner as for collagenase.

Inhibition of MMP-13 Human recombinant MMP-13 Is activated with 2mM APMA (p-aminophenyl mercuric acetate) for 1.5 hours, at 370C and is diluted to 400 mg/ml in assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5mM calcium chloride, 20pM zinc chloride, 0.02% brij). Twenty-five microliters of diluted enzyme is added per well of a 96 well microfluor plate. The enzyme is then diluted in a 1:4 ratio in the assay by the addition of inhibitor and substrate to give a final concentration in the assay of 100 mg/ml.

10 mM stock solutions of inhibitors are made up in dimethyl sutfoxide and then diluted in assay buffer as per the inhibitor dilution scheme for inhibition of human collagenase (MMP-1): Twenty-five microliters of each concentration is added in triplicate to the microfluor plate. The final concentrations in the assay are 30 pM, 3pM, 0.3 pM, and 0.03 pM.

Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is prepared as for inhibition of human collagenase (MMP-1) and 50 p is added to each well to give a final assay concentration of 10 IJM. Fluorescence readings (360 nM excitation; 450 emission) are taken at time 0 and every 5 minutes for 1 hour.

Positive controls consist of enzyme and substrate with no inhibitor and blanks consist of substrate only.

IC50's are determined as per inhibition of human collagenase (MMP-1). If IC50,s are reported to be less than 0.03 pM, inhibitors are then assayed at final concentrations of 0.3 pM, 0.03 pM, 0.003 pM and 0.0003 HM.

Inhibition of TNF Production The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating diseases involving the production of TNF is shown by the following in vitro assay:

Human mononuclear cells were isolated from anticoagulated human blood using a one-step Ficoll-hypaque separation technique. (2) The mononuclear cells were washed three times in Hanks balanced sait solution (HBSS) with divalent cations and resuspended to a density of 2 x 1 0e /ml in HBSS containing 1% BSA. Differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that monocytes ranged from 17 to 24% of the total cells in these preparations.

1 8or of the cell suspension was aliquoted into ftate bottom 96 well plates (Costar). Additions of compounds and US (1 00ng/ml final concentration) gave a final volume of 200,us. All conditions were performed in triplicate. After a four hour incubation at 370C in an humidified CO2 incubator, plates were removed and centrifuged (10 minutes at approximately 250 x g) and the supematants removed and assayed for TNFa using the R&D EUSA Kit.

For administration to mammals, including humans, for the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF), a variety of conventional routes may be used including orally, parenteraily and topically. In general, the compound of the invention will be administered oraily or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

The compounds of the invention can be administered in a wide variety of different dosage forms. In general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably com, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinyipyrrolidone, sucrose, gelation and acacia.

Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight

polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying andlor suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. In the case of animals, they are advantageously contained in an animal feed or drinking water in a concentration of 5- 5000 ppm, preferably 25 to 500 ppm.

For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile injectable solution of the active ingredient is usually prepared.

Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable intravenous injection purposes. The oiiy solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. In the case of animals, compounds can be administered intramusculariy or subcutaneously at dosage levels of about 0.1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to 3 divided doses.

The present invention is illustrated by the following examples, but it is not limited to the details thereof.

EXAMPLE 1 (2R, 4R)-1-(4-Methoxy-benzenesulfonyl)-4-(piperazine-1-carbonyl)- piperidine-2- carboxylic acid hvdroxvamlde hydrochloride (a) To a stirred, cold (-78 OC) solution of (2I9)-2-benzyioxycarbonyiamino- pentanedioic acid 1-tert-butyl ester dimethyl ester (5.69, 15.9 mmol), prepared as described in J. Org. Chem., 55, 1711-1721 (1990) and J. Med. Chem., 39, 73-85 (1996), in 30 mL of tetrahydrofuran was added lithium bis(trimethylsilyl)amide (40 mL, 1 M in tetrahydrofuran, 39.8 mmol). The resulting mixture was stirred for 1 hour at45 OC and then recooled to -78 OC. Allyl bromide (5.2 ml, 63.7 mmol) was then added. After 2 hours the reaction was quenched by the addition of 1 M aqueous hydrogen chloride at -78 OC. The mixture was then extracted with diethyl ether. The combined ethereal

extracts were washed with brine and the mixture was dried over sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by silica gel chromatography (elution with 1:5 ethyl acetate/hexanes) to provide (2R,4R)-4-allyl-2- benzyloxycarbonylamino-pentanedioic acid 1 -tert-butyl ester 5-methyl ester.

(b) Ozone gas was bubbled through a stirred, cold (-78 °C) solution of (2B,4B)+ allyl-2-benzyloxycarbonylamino-pentanedioic acid 1-tert-butyl ester 5-methyl ester (5.0 g, 12.8 mmol) in 100 mL of 10:1 methanol/methyiene chloride, and 0.73 mL of acetic acid until a blue color persisted. Nitrogen gas was then bubbled through the solution until the blue color dissipated. The mixture was warmed to ambient temperature and dimethyl sulfide (2.8 mL, 3.83 mmol) was added. The mixture was stirred for 48 hours, diluted with methylene chloride, and washed with 10% aqueous sodium carbonate, brine, and the mixture was dried over sodium sulfate. Filtration and concentration of the filtrate provided (2R,4)-6-methoxygiperidine-l ,2,4-tricarboxylic acid 1-benzyi ester 2-tert-butyl ester 4methyl ester as a clear oil, which was used in the subsequent step without purification.

(c) A mixture of (2R,4S)-6-methoxy-piperidine-1 ,2,4-tricarboxylic acid 1 benzyl ester 2-tert-butyl ester 4methyl ester (4.85 g, 11.9 mmol) and 10% palladium on carbon (500 mg) in 100 mL of ethanol was shaken under a 45 psi atmosphere of hydrogen gas for 1.5 hours. The mixture was filtered through nylon and the filtrate was concentrated to provide (2R,4R)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester as light yellow oil, which was used in the subsequent step without further purification.

(d) To a stirred, cold (0 °C) solution of (2R,4R)-piperidine-2,4-dicarboxylic acid 2- tert-butyl ester 4-methyl ester (2.7 g, 11.1 mmol) and triethylamine (4.6 ml, 33.3 mmol) in 30 mL of methylene chloride was added 4-methoxy-benzenesuffonyl chloride (2.3 g, 11.1 mmol). The mixture was warmed to ambient temperature and stirred for 4 hours.

The reaction was quenched by the addition of aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, and the organic mixture was dried over sodium sulfate. After filtration and concentration of the filtrate, the resulting crude product was purified by silica gel chromatography (elution with 3:8 ethyl acetate/hexanes) to provide (2Ii,4B)-1-(4- methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic acid 2-tert-butyi ester 4 methyl ester.

(e) To a stirred, cold (0 °C) solution of (2R,4R)-1-(4-methoxy-benzenesulfonyl)- piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester (4.4 9, 10.6 mmol) in 30 mL of methylene chloride was added 10 mL of trifluoroacetic acid dropwise. The mixture was stirred for 1 hour at 0 °C and for 8 hours at ambient temperature.

Concentration provided (2R,4O-1-(Smethoxy-benzenesulfonyl)-piperidine-2,4* dicarboxylic acid 4-methyl ester, which was used in the subsequent step without purification. <BR> <BR> <BR> <BR> <BR> <P>(f) To a stirred solution of (2R,4B) 1-(4-methoxy-benzenesulfonyl)-piperidine-2,4- dicarboxylic acid dimethyl ester (4.4 9, 12.3 mmol), O-benzylhydroxylamine hydrochloride (2.15 g, 13.5 mmol), and triethylamine (5.15 mL, 36.9 mmol) was added benzotriazol-1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (6.09, 12.3 mmol) at ambient temperature. The resulting mixture was stirred for 24 hours. The mixture was diluted with ethyl acetate and washed with 1 M aqueous hydrogen chloride, aqueous sodium bicarbonate, and brine. The organic mixture was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (elution with 5% methanol in methylene chloride) to provide (2B,4-2-benzyloxyciarbamoyl.1 -(4-methoxy-benzenesulfonyl)-piperidine- 4 carboxylic acid methyl ester as a coloriess solid.

(g) To a stirred cold (0 OC) solution of (2R,4R)-2-benzyloxycarbamoyl-1 -(4methoxy- benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (4.0 g, 8.6 mmol) in 10 mL of 9:1 methanol/water was added lithium hydroxide monohydrate (1.8 g, 43 mmol). The mixture was stirred for 2 hours before Amberiite IR-120 resin (96 g) was added. After 15 minutes, the mixture was filtered and the filtrate was concentrated to give (2R,4R)-2- benzyloxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-piperidine- 4-carboxylicacid,which was used in the subsequent reaction without purification.

(h) To a stirred solution of (2R,4R)-2-benzyloxycarbamoyl-1-(4-methoxy- benzenesulfonyl)-piperidine-4-carboxylic add (500 mg, 1.11 mmol), tert- butyloxycarbonyl piperazine (226 mg, 1.21 mmol), and triethylamine (0.47 mL, 3.33 mmol) was added benzotriazol-1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (535 mg, 1.21 mmol) at ambient temperature. The resulting mixture was stirred for 24 hours. The mixture was diluted with ethyl acetate and washed with 1 M aqueous hydrogen chloride, aqueous sodium bicarbonate, and brine.

The organic mixture was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (elution with 2% methanol in methylene chloride) to provide (2R,4R)-4-[2-benzyloxycarbamoyl-1- (4-methoxy-benzenesulfonyl)-piperidinecarbonyl]piperazlne-1 carboxylic acid tert- butyl ester as a coloriess solid.

(i) A mixture of (2R,4R)-4-[2-benzyloxycarbamoyl-1 -(4-methoxy-benzene- sulfonyl)- piperidine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 0.81 mmol) and 5% palladium on barium sulfate (250 mg) in 10 mL of methanol was shaken under a 40 psi atmosphere of hydrogen gas for 1.5 hours. Filtration through nylon and concentration of the filtrate provided (2R,4R)-4-[2-hydroxycarbamoyl-1-(4-methoxy- benzenesulfonyl)-piperidine-4-carbonyl]-piperazine-1 -carboxylic acid tert-butyl ester as a colorless solid, which was used in the subsequent step without purification.

(j) Hydrogen chloride gas was bubbled through a cold (0°C) solution of (2R,4B)4 [2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-piperidine -4-carbonyl]-piperazine-1- carboxylic acid tert-butyl ester (420 mg, 0.8 mmol) for 10 minutes. After an additional 20 minutes the mixture was concentrated to provide (2R, 4R)-1-(4-methoxy- benzenesultonyl)(piperazlne-1 -carbonyl)-piperidine-2-carboxylic acid hydroxyamide hydrochloride as a colorless solid: Mass spectrum (atmospheric pressure chemical ionization; basic mode) only (M+H) 427, 366; 'H NMR (dimethyl sulfoxide-d5, 5, 400 MHz, ppm) 6 10.70 (bd, 1 H, J = 2.7 Hz), 9.06 (bs, 2 H), 8.84 (bs, 1 H), 7.70 (dd, 2 H, J = 8.9, 2.9 Hz), 7.06 (dd, 2 H, J = 8.9, 2.9 Hz), 4.42 (bs, 1 H), 3.80 (s, 3 H), 3.8o3.20 (m, <BR> <BR> <BR> <BR> 6 H), 3.04 (m, 4 H), 2.76 (m, 1 H), 1.79 (bd, 1 H, J = 13.5 Hz), 1.52 (bd, 1 H, J = 12.6 Hz), 1.32 (m, 1 H) 1.14 (m 1H).

Example 2 (2R,4R)-1-[3-(4-Fluorophenoxy)-propane-1-sulfonyl]-2-hydroxy carbamoyl- piperidine-4-carboxylic acid methvl ester (a) To astirred solution of (2R,4R)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester (920 mg, 3.78 mmol) and triethylamine (1.58ml, 11.3 mmol) in 10 mL of methylene chloride was added a solution of 3(4fluorophenoxy)-propane-1 - sulfonyl chloride (1.05 g, 4.16 mmol) in 2 mL of methylene chloride under a nitrogen atmosphere. The mixture was stirred for 16 hours at ambient temperature (22 °C), then

diluted with 20 mL of 1 N hydrochloric acid and 20 mL of methylene chloride. The organic layer was removed and washed with brine and dried over sodium sulfate.

Filtration and concentration of the filtrate gave 2.8 g of a yellow oil, which was purified by flash chromatography (3:2 hexanes/ethyl acetate elution) to give 1.15 g (2R,4R)-1-[3- (4-fiuoro-phenoxy)-propane-1 -sulfonyl]-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester of as a yellow oil.

(b) To a stirred, cold (0 °C) solution of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1- sulfonyl]-piperidine-2,4dicarboxylic acid 2-tert-butyl ester ethyl ester (1.15 g, 2.5 mmol) in 10 mL of methylene chloride was added 10 mL of trifluroacetic acid. The mixture was allowed warm to ambient temperature (22 °C) over 16 hours. The mixture was concentrated in vacuo to give 970 mg of crude (2R,4E-1 -I3-(4-fluorophenoxy)- propane-1-sulfonyl]-piperidine-2,4-dicarboxylic acid 4-methyl ester as a orange solid.

(c) To a stirred solution of (2R,4R-1-[3-(4-fluorophenoxy)-propane-1-sulfonyl]- piperidine-2,4-dicarboxylic acid 4methyl ester (970 mg, 2.4 mmol) in 5 mL of methylene chloride was added triethylamine (1.0 ml, 7.2 mmol) and O-benzylhydroxylamine hydrochloride (410 mg, 2.64 mmol) at ambient temperature (22 °C). To the resulting solution was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.17 g, 2.64 mmol) and the mixture was stirred for 16 hours under a nitrogen atmosphere. The mixture was diluted with 25 mL of 1 N hydrochloric acid and 25 mL of ethyl acetate. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (2 x). The combined organic layers were washed with saturated aqueous sodium carbonate (1 x) and brine (1 x). The organic layer was dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo. Purification of the viscous yellow residue by flash chromatography (eluting with 1:1 ethyl acetate/hexanes) gave 810 mg of (2R,4R)-2-benzyloxycarbamoyl-1-[3-(4-fluorophenoxy)-propane- 1- sulfonyl]-piperidineXcarboxylic acid methyl ester as a dear oil.

(d) A mixture of (2R,4f)-2-benzyloxycarbamoyl-1 -!(4-fluornphenoxy')-prnpane-I - sulfonyl]-piperidine-4-carboxylic acid methyl ester (800 mg, 1.57 mmol) and 200 mg of 5% palladium on barium sulfate in 15 mL of methanol was shaken in a Parr apparatus under a 40 psi hydrogen gas atmosphere for 2 hours. The catalyst was removed by passage of the mixture through a 0.45 pm nylon filter and the filtrate was concentrated to give 650 mg of (2R,4B)-1-[3-(4-fluorophenoxy)-propane-1-sulfonyl]-2-

hydroxycarbamoyl-piperidine4-carboxylic acid methyl ester as a white foam: MS (atmospheric pressure chemical ionization) acidic mode, 417 (M-1); 1H NMR (400 MHz, CDCl3) 6 6.946.97 (m, 2 £i), 6.80-6.83 (m, 2 JH, 4.56 (s, 1 j:j), 4.03 (t, 2 H, J = 5.3 Hz), 3.83 (d, 1 H, J = 12.9Hz), 3.68 (s, 3 H), 3.15-3.28 (m, 3 O, 2.76 (t, 1 H, J = 11.5 Hz), <BR> <BR> <BR> 2.54 (d 1 H J = 13.5 Hz), 2.26 (d, 2 H, J = 5.9 Hz),2.02 (m, 1 H,J = 13.0Hz), 1.73- 1.78 (m, 1H), 1.56-1.62 (m, 1 H).

Example 3 (2R,4R)-1-[3-(4-Fluorophenoxy)-propane-1-sulfonyl]-2-hydroxy carbamoyl- piperidine-4-carboxylic acid To a stirred, cold (0 °C) solution of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1- sulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester (400 mg, 0.96 mmol) in 5 mL of a methanol/water mixture (10:1) was added lithium hydroxide monohydrate (120 mg, 2.88 mmol). After 3 hours at 0 OC, prerinsed (methanol) Amberlite resin (4.19) was added. The mixture was filtered and the filtrate was concentrated to give 370 mg of (2B,4B)-1-[3-(4-fluorophenoxy)-propane-1-sulfonyi]-2- hydroxycarbamoyl-piperidine-4-carboxylic acid as a white foam: MS (atmospheric pressure chemical ionization) acidic mode, 403 (M-1).

Example 4 (2R,4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydrocar bamoyl- piperidine-4-carboxylic acid methyl ester 4-(4-Fluoro-benzyloxy)-benzenesufonyl chloride. MS: 465 (M-1).

The titled compound of example 4 was prepared by a method analogous to that described in example 2 using the reagents.

Example 5 (2R,4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxyc arbamoyl- piperidine-4-carboxylic acid. MS: 451 (M-1).

The titled compound of example 5 was prepared by a method analogous to that described in example 3 starting with 1-[4-(4-Fluoro-benzyloxy)-benzenesulfonyl]- 2-hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester.

Example 6 2R,3S-{1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxyca rbamoyl- piperidin-3-yl}-carbamic acid Isocrocyl ester (a) To a stirred, cold (0 °C) solution of the known (Agami, C.; Hamon, L; Kadouri-Puchot, C.; Le Guen, V J. Ora. Chem. 1996, 61, 5736-5742) [4S-4a,9a,9aa1- 1-oxo-4-phenyl-octahydro-pyrido[2,1-c][1,4]oxazine-9-carboxy lic acid methyl ester (8.28 g, 2.86 mmol) in 100 mL of tetrahydrofuran was added 2.39 mL of concentrated hydrochloric acid. After 5 minutes the mixture was concentrated to dryness. The resulting solid was suspended in ethyl acetate and the mixture was stirred for an hour. The solids were collected by filtration, rinsed with ethyl acetate, and dried to give 9.04 g of a white solid.

Two grams of this solid was dissolved in 26 mL of 6 N hydrochloric acid and heated at reflux for 6 hours. The mixture was cooled to 0 °C and neutralized with 3 N sodium hydroxide and concentrated in vacuo. The resulting solids were suspended in chloroform and passed through a 45 jim nylon filter. The filtrate was concentrated to a yellow oil which was purified by flash chromatography (eluting with 2:1 hexanes/ethyl acetate with 1% acetic acid) to give 802 mg of [4S- 4a,9a,9aa] 1 -oxo-4-phenyl-octahydro-pyrido[2,1-c][1,4]oxazine-9-carboxyl ic acid as white solid.

(b) To a stirred solution of [4S-4α,9α,9aα]1-oxo-4-4-phenyl-octahydro- pyrido[2,1-c][1,4]oxazine-9-carboxylic acid (568 mg, 2.06 mmol) in 15 mL of benzene was added triethylamine (0.28 mL, 2.06 mmol) and diphenylphosphoryl azide (0.44 mL, 2.06 mmol) at 22 °C under a nitrogen atmosphere. The mixture was stirred at 22 OC for 45 minutes and at reflux for 50 minutes before 2-propanol (3.2 ml, 41.2 mmol) was added. After an additional 20 hours at reflux the mixture was cooled to 22 °C and concentrated in vacuo. The residue was taken up in ethyl acetate and the resulting solution was washed with 5% citric acid, water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo. The yellow residue was purified by flash chromatrography (eluting with 3:1 hexanes/ethyl acetate) to give 402 mg of [4S-4α,9α,9aα](1-oxo-4-phenyl-octahydro-pyrido[2,1-c][1,4 ]oxazin-9-yl)- carbamic acid isopropyl ester as white solid.

(c) A mixture of [4S4a,9a,9aa](l sxo4-phenylsctahydro-pyrido [2,1- g1[1,4]oxazin-9-yl)-carbamic acid isopropyl ester (900 mg , 2.71 mmol) and 20% palladium hydroxide on carbon (920 mg) in 77 mL of ethanol/water (10:1) was shaken in a Parr apparatus under a 45 psi hydrogen gas atmosphere for 72 hours.

The catalyst was removed by passage of the mixture through a 0.45 pm nylon filter and the filtrate was concentrated to give 610 mg of 2R,3S-3- isopropoxycarbonylamino-piperidine-2-carboxylic acid as white solid. MS: 229 (M-1).

(d) To a stirred solution of 2R,3S-3-isopropoxycarbonylamino-piperidine-2- carboxylic acid (320 mg, 1.39 mmol) in 5 mL of methylene chloride was added triethylamine (0.58 ml, 4.17 mmol) followed by Q-(4-fluorobenzyloxy)- benzenesulfonyl chloride (460 mg, 1.53 mmol). After 16 hours at 22 °C the mixture was partioned between 1 N hydrochloric acid and ethyl acetate. The organic layer was removed and washed with brine and dried over sodium sulfate. Filtration and concentration of the filtrate gave 480 mg of crude 2R,3S-1 -I4-(4-Ruorobenzyloxy)- benzenesulfonyl]-isopropoxycarbonylamino-piperidine-2-carbox ylic acid as a light yellow solid.

(e) To a stirred, cold (0 °C) solution of cnrde 2R 35-1-(4-(4 fluorobenzyloxy)enzenesulfonyl]3rAsoprnpoxycarbonylamino-pip eridine-2 carboxylic acid (380 mg, 0.77 mmol) in 5 mL of methylene chloride was added triethylamine (0.32 mL, 2.31 mmol) followed by benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (510 mg, 1.15 mmol). The resulting solution was stirred for 2 minutes at 0 °C under a nitrogen atmosphere before O-(trimethylsilylethyl)hydroxylamine hydrochloride (195 mg, 1.15 mmol) was added. The mixture was allowed to warm slowly to 22 °C over 14 hours. The mixture was concentrated in vacuo and the residue was diluted with water and extracted with ethyl acetate/diethyl ether (1:1; 3 x). The combined organic extracts were washed with saturated aqueous carbonate (2 x), water (2 x), and brine (1 x).

The organic layer was dried (magnesium sulfate), filtered, and the filtrate was concentrated in vacuo. The yellow residue was purified by flash chromatography (eluting with 65:35 hexanes/ethyl acetate) to give 300 mg of 2R,3S-[1-[4-(4- fluorobenzyloxy)-benzenesulfonyl]-2-(2-trimethylsilanyl-etho xycarbamoyl)-piperidin-3- yl]-carbamic acid isopropyl ester as a white foam. MS: 610 (M+1).

(f) To a stirred, cold (0 °C) solution of 2R,3S-I1- I4-(4-fluorobenryloxy)- benzenesulfonyl]-2-(2-trimethylsilanyl-ethoxycarbamoyl)-pipe ridin-3-yl]-carbamic acid isopropyl ester (265 mg, 0.44 mmol) in 4 mL of methylene chloride was added 3 mL of trifluoroacetic acid. The resulting coloriess solution was allowed to warm to 23 °C over 2 hours and was stirred for an additional 28 hours. The mixture was concentrated in vacuo to a solid/foam, which was suspended in ethyl acetate hexanes (1:6) and stirred for 10 hours. The white solids were collected by flitration, rinsed with hexanes, and purified further by flash chromatography (eluting with 7:3 ethyl acetate/hexanes with 1% acetic acid) to give 130 mg of 2R,3S-1-l4-(4- fluorobenzyloxy)benzenesulfonyl]-2-hydroxycarbamoyl-piperidi n-3-yl}-carbamic acid isopropyl ester as a white solid/foam. MS: 510 (M+1).

Example 7 3-(S)-4-(4'-Fluorobiphenyl-4-sulfonyl)-2,2-dimethyl-thiomorp holine-3- carboxylic acid hydroxyamide (a) To a stirred solution of the known (PCT Publication WO 97/20824) 3- (S)-dimethylthexylsilyl-2,2-dimethyl-tetrahydro-2H-1,4-thiaz ine-3-carboxylate (1.17 g, 3.70 mmol) in 6 mL of methylene chloride was added triethylamine (1.02 ml, 7.40 mmol) followed by 4'-fluorobiphenylsulfonyi chloride (1.0 g, 3.70 mmol). The resulting solution was stirred for 56 hours at 23 OC. The reaction mixture was diluted with methylene chloride and washed with water. The organic layer was concentrated in vacuo; the residue was dissolved in methanol, and the mixture was heated at reflux for 6 hours. The mixture was cooled to 23 °C and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 3:7 ethyl acetate/hexanes with 0.1% acetic acid) to give 670 mg of 3-(S)-4-(4'-fluorobiphenyl-4-sulfonyl)-2,2- dimethyl-thiomorpholine-3-carboxylic acid as a white foam/solid. MS: 427 (M+NH4).

(b) To a stirred, cold (0 °C) solution of 3-(24(4'-fluorobiphenylX sulfonyl)-2,2-dimethyl-thiomorpholinefficarboxylic acid (605 mg, 1.48 mmol) in 5 mL of methylene chloride was added triethylamine (0.62 mL, 4.43 mmol) under a nitrogen atmosphere. Benzotriazol-I -yloxy-trls(dimethylamino)phosphonium hexafluorophosphate (980 mg, 2.22 mmol) was added and the resulting solution was stirred for 5 minutes before O-(trimethylsilyfethyi)hydroxylamine hydrochloride (376 mg, 2.22 mmol) was added. The ice bath was removed and the mixture was

stirred for 20 hours at 23 OC. The mixture was diluted with aqueous ammonium chloride and extracted with 1:1 ethyl acetate/diethyl ether (3 x). The combined organic extracts were washed with saturated aqueous sodium carbonate (2 x), water (1 x), and brine (1 x). The organic layer was dried (magnesium sulfate), filtered, and the filtrate was concentrated in vacuo. The residual yellow oil was purified by flash chromatography (eluting with 3:7 ethyl acetate/hexanes) to give 650 mg of 3-(O (4'-fluorobiphenyl-4-sulfonyl)-2,2-dimethyl-thiomorpholine-3 -carboxylic acid (2- trimethylsilanylthoxy)9mide as a white foam. MS: 523 (M-1).

(c) A solution of 3-(S)-4-(4'-fluorobiphenyl-4-sulfonyl)-2,2-dimethyl- thiomorpholincarboxylic acid (2-trimethylsilanyl-ethoxy)-amide (650 mg, 1.24 mmol) in 8 mL of trifluoroacetic acid was stirred for at 22 °C for 16 hours. The mixture was concentrated in vacuo and the residue was triturated with methylene chloride and diethyl ether. The solvent was removed to give 550 mg of a tan solid.

The solid was suspended in 1:1 diethyl ether/hexanes and stirred gently for 20 hours. The solids were collected by filtration (1:1 diethyl ether/hexanes rinsing) and dried to give 470 mg of 3-(S)-4-(4'-fluorobiphenyl-4-sulfonyl)-2,2-dimethyl) thiomorpholine-3-carboxylic acid hydroxyamide as white solid. MS: 423 (M-1).

Examole 8 3-(S)-4-[4-(4-Fluorobenzyloxy)benzenesulfonyl]-2,2-dimethyl- thlomornholine-3 -carboxylic acid hydroxyamide (a) To a stirred, cold (0 °C) solution of the known (Belgian Patent Publication BE 893025) 2,2-dimethyl-thiomorpholine-3-carboxylic acid (600 mg, 3.42 mmol) in 10 mL of 1:1 water/dioxane was added 6 N sodium hydroxide (1.2 mL, 7.1 mmol). To the resulting solution 4-(4-fluorobenzyloxy)benzenesulfonyl chloride (1.08 g, 3.77 mmol) was added. After 30 and 60 minutes an additional 1 gram of 4(4- fluorobenzyloxy)benzenesulfonyl chloride and 1.2 mL of 6 N sodium hydroxide was added. The mixture (pH ca. 12) was diluted with water and extracted with diethyl ether (1 x). The ethereal layer was washed with 1 N sodium hydroxide; the combined basic aqueous layers were acidified to pH 3 using concentrated hydrochloric acid, and the acidic mixture was extracted with ethyl acetate (3 x). The combined organic extracts were dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo to give 820 mg of 3-(S)-4-[4-(4-

fluorobenzyloxy)benzenesulfonyl]-2,2-dimethyl-thiomorpholine -3-carboxylic acid as a white solid. MS: 438 (M-1).

(b) To a stirred, cold (0 °C) solution of 3-(S)-4-[4-(4-fluorobenzyloxy)- benzenesulfonyl]-2,2siimethyl-thiomorpholineAboxyzic acid (820 mg, 1.87 mmol) in 5 mL of methylene chloride was added triethylamine (0.52 mL, 3.74 mmol) under a nitrogen atmosphere. Benzotriazol-l -yloxy-trls (dimethylamino) phosphonium hexafluorophosphate (1.24 g, 2.81 mmol) was added and the resulting solution was stirred for 5 minutes before O-(t-butyldimethylsilyl)hydroxyl amine (550 mg, 3.74 mmol) was added.The ice bath was removed and the mixture was stirred for 16 hours at 23 OC. The mixture was diluted with aqueous ammonium chloride and extracted with ethyl acetate (3 x). The combined organic extracts were washed with water, brine, and dried over sodium sulfate. Filtration and concentration of the filtrate gave a viscous yellow oil, which was purified by flash chromatography (eluting with 1:3 ethyl acetate/hexanes) to give 270 mg of 3-(S)-4-[4-(4- fluorobenzyloxy)benzenesulfonyl]-2,2-dimethyl-thiomorpholine -3-carboxylic acid (tert- butyldimethylsiloxy)-amide as a white foam. MS: 569 (M+1).

(c) To a stirred, cold (0 °C) solution of 3-(S)-4-[4-(4-fluorobenzyloxy)- benzenesulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid (tert- butyldimethylsiloxy)-amide (270 mg, 0.47 mmol) in 10 mL of tetrahydrofuran was added two drops of concentrated hydrochloric add. After 30 minutes the mixture was diluted with 15 mL of tetrahydrofuran and the mixture was concentrated in vacuo to a volume of ca. 5 mL The volume was adjusted to ca. 25 mL with tetranyrofuran and the mixture was concentrated again to ca. 5 mL This process was repeated twice more before the mixture was finally concentrated to dryness.

The resulting solids were suspended in a mixture of hexanes and diethyl ether and the mixture was stirred for 16 hours. The solid were collected by filtration, rinsed with diethyl ether,and dried to give 180 mg of 3-(S)-4-[4-(4- fluorobenzyloxy)benzenesulfonyl]-2,2-dimethyl-thiomorpholine -3 -carboxylic acid hydroxyarnide as a white solid. MS: 453 (M-1). 1H NMR (400 MHz, dmso-d5) 6 10.63 (s, 1 H), 8.80 (bs, 1 H) 7.59-7.61 (m, 2 JH, 7.46-7.50 (m, 2 flH, 7.17-7-21 (m, 2 O.

7.09-7.12 (m, 2 O. 5.12 (s, 2 O. 3.99 (s, 1 H), 3.87-3.93 (m, 1 H), 3.69 (d, 1 tj J = 12.7 Hz), 2.78-2.86 (m, 1 H), 2.44-2.50 (m, 1 H), 1.35 (s, 3 H), 1.12 (s, 3H).

Preparation 1 4-(4-Fluorobenzvloxv)benzenbsuifonvl chloride To a stirred solution of 4-hydroxybenzenesutfonic acid sodium sait dihydrate (5.13 g, 22.1 mmol) in 23 mL of 1 N sodium hydroxide was added a solution of 4- fluorobenzyl bromide (3.3 mL, 26.5 mmol) in 20 mL of ethanol. The mixture was heated at reflux for two days, then cooled to ambient temperature (22 °C), whereupon a white precipitate formed. The flaky white solids were collected by filtration, rinsed with ethyl acetate and diethyl ether, and dried to give 4. 95 g of 4-(4- fluoro-benzyloxy)-benzenesulfonic acid sodium salt. A stirred solution of 4-(4-fluoro- benzyloxy)-benzenesulfonic acid sodium salt (13.0 g, 42.7 mmol) in 50 mL of thionyl chloride and two drops of dimethylformamide was heated at a gentle reflux for 8 hours. The mixture was concentrated to a yellow solid which was suspended in ethyl acetate and filtered. The filtrate was concentrated to 11.2 g of 4-(4- fiuorobenzyloxy)benzenesutfonyl chloride as a light yellow solid: 1H NMR (400 MHz, CDCl3) a 7.95-7.98 (m, 2 JH, 7.38 7.41 (m, 2 JH, 7.0&7.12 (m, 4 O. 5.12 (s, 2 U).

Preparation 2 3-(4-Fluorophenoxy)-propane-1-sulfonyl chloride To a stirred solution of 4-fluorophenol (5.0 g, 44.6 mmol) in 50 mL of toluene was added sodium hydride (60% dispersion in mineral oil, 1.78 g, 44.6 mmol) at ambient temperature (22 °C). After 20 minutes, a solution of 1,3-propane sulfone (3.9 mL, 44.6 mmol) in toluene was added slowly and the mixture was stirred for 16 hours. The reaction was quenched by the addition of methanol and the mixture was concentrated in vacuo to an off-white solid. This solid was suspended in ethyl acetate, filtered, and the solids were collected and dried to give 10.9 g of 3-(4- fluorophenoxy)-propanv1-sulfonic acid sodium salt as an off-white powder. A stirred solution of 3-(4fluorophenoxy)-propane-1-sulfonic acid sodium salt (2.0 g, 7.8 mmol) in 10 mL of thionyl chloride and one drops of dimethylformamide was heated at reflux for 16 hours. The mixture was then cooled to 0 oC, diluted with 25 mL of diethyl ether, and the reaction was quenched by the slow addition of water. The organic layer was removed and the aqueous layer was extracted with 25 mL of diethyl ether. The combined organic layers were washed with brine and dried over

sodium sulfate. Filtration and concentration gave 1.75 g of 3-(4-fluoro-phenoxy)- propane-1-sulfonyl chloride as a yellow oil: 'H NMR (400 MHz, CDCI3) 6 6.9S7.00 (m, 2 H), 6.80-6.84 (m, 2 H), 4.10 (t, 2 H, J = 5.5 Hz), 3.91 (t, 2 H, J = 7.5 Hz) 2.47- 2.54 (m, 2 O.

PreparatIon 3 41uoroblchenvlsulfonvl chloride Chlorosuifonic acid (8.7 ml, 0.13 mole) was added dropwise to stirred cold (0 °C) 4-fluorobiphenyl (10.2 g, 59 mmol). After 30 minutes at O °C the reaction mixture was poured onto ice. The resulting white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water, brine, dried over magnesium sulfate, and concentrated to afford a white solid.

The desired 4'-fluorobiphenylsulfonyl chloride (4.3 g), was separated from 4'- fluorobiphenylsulfonic acid by crystallization of the latter from ethyl acetate and crystallization of the remaining material from hexanes.