AP958A - Arylsulfonyl hydroxamic acid derivatives. - Google Patents

Arylsulfonyl hydroxamic acid derivatives.

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Publication number
AP958A
AP958A AP9801179A AP9801179A AP958A AP 958 A AP958 A AP 958A AP 9801179 A AP9801179 A AP 9801179A AP 9801179 A AP9801179 A AP 9801179A AP 958 A AP958 A AP 958A
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ARIPO
Prior art keywords
c6
alkyl
c10
c1
c2
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AP9801179A
Inventor
Kim Francis Mcclure
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Pfizer
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D265/00Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/281,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/301,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96Sulfur atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D279/00Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/101,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/121,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings

Abstract

"A compound of the formula R5 R6 wherein R1, R2 R3, R4 R5, R??, R7, R', R' and Q are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue Liberation, macular degeneration, restenosis, perio"

Description

£P 00958-1-

ARYLSULFONYL HYDROXAMIC ACID DERIVATIVES

Background of the Invention

The present invention relates to aryisuffonyl hydroxamic acid derivatives whichare inhibitors of matrix metalloproteinases or the production of tumor necrosis factor 10 (TNF) and as such are useful in the treatment of a condition selected from the groupconsisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease,epidermolysis bullosa, sderitis and other diseases characterized by matrixmetalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving theproduction of TNF. In addition, the compounds of the present invention may be used 15 in combination therapy with standard non-steroidal anti-inflammatory drugs (hereinafterNSAIDS) and analgesics for the treatment of arthritis, and in combination with cytotoxicdrugs such as adriamycin, daunomydn, cis-platinum, etoposide, taxol, taxotere andalkaloids, such as vincristine, in the treatment of cancer.

This invention also relates to a method of using such compounds in the 20 treatment of the above diseases in mammals, especially humans, and topharmaceutical compositions useful therefor.

There are a number of enzymes which effect the breakdown of structuralproteins and which are structurally related metalloproteases. Matrix-degradingmetalloproteinases, such as gelatinase, stromelysin and collagenase, are involved in 25 tissue matrix degradation (e.g. collagen collapse) and have been implicated in manypathological conditions involving abnormal connective tissue and basement membranematrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissueulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing,periodontal disease, bone disease (e.g. Pagefs disease and osteoporosis), tumor 30 metastasis or invasion, as well as HIV-infection (J. Leuk. Biol., 52 (2): 244-248, 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 beenshown that TNF is the prime mediator of the inflammatory response seen in sepsis andseptic shock (C.E. Spooner et al., Clinical Immunology and Immunopathology, 1992, 35 62S11).

6 L I 10/86 /d/dV -- *.··>( a·'. -2-

Summary of the Invention

The present invention relates to a compound of the formula R5 R6

R

7 9

OH Ή S02

Q 10 15 or the pharmaceutically acceptable salt thereof, wherein the broken line represents anoptional double bond; X is carbon, oxygen or sulfur; Y is carbon, oxygen, sulfur, SO, SO2 or nitrogen; R\ R2 R3, R* R5, R®, R7, R® and R® are selected from the group consisting ofhydrogen, (C,-Ce)alkyl optionally substituted by one or two groups selected from (0,-Ce)alkylthio, (0,-0,,) alkoxy, trifiuoro methyl, halo, (Ce-C10)aryl, (C5-C9)heteroaryl, (Ce- 20 C10)arylamino, (CB-C10)arylthio, (Ce-C10)aryloxy, (C5-C9)heteroarylamino, (C5-Cg)heteroarytthio, (C5-C9)heteroaryloxy, (Ce-C10)aryl(Ce-C10)aryl, (C3-Ce)cydoalkyl,hydroxy, piperazinyl, (C9-C10)aryl(C1-Ce)alkoxy, (Cg-C^heteroaryliCTCgJalkoxy, (0,-Ce)acylamino, (C^C^acylthio, (C1-Ce)acyioxy, (C1-Ce)alkylsutfinyl, (Ce-C10)arylsulfinyl,(C^C^alkyisulfonyl, (Ce-C10)arylsulfonyl, amino, (C,-Ce)alkyiamino or ((0,- 25 Ce)alkylamino)2; (C2-Cfl)alkenyl, (Ce-C10)aryl(C2-Ce)alkenyl, (C5-C9)heteroaryl(C2-Ce)alkenyl, (C2-Ce)alkynyl, (Ce-C10)aryl(C2-Ce)alkynyl, (C5-C9)heteroaryi(C2-Ce)aJkynyl,(C,-C6)alkylamino,(C1-Ce)alkytthio,(C1-Ce)alkoxy,perfluoro(C1-Ce)alkyl,(Ce-C10)aryl,(Cs-C9) heteroaryl, (Ce-C10)arylamino, (Ce-C,o)arylthio, (Ce-C10)aryloxy, (C5-C9)heteroarytamino, (Cs-C9)heteroarylthio, (C5-C8)heteroaryloxy, (C3-Ce)cycloalkyl, (0,- 30 Ce)alkyl(hydroxymethylene), piperidyl, (C,-Ce)aikyipiperidyi, (C,-Ce)acylamino, (0,-C„)acylthio, (C,-C„)acyloxy, R’°(C1-Ce)alkyl wherein R10 is (C,-Ce)acyipiperazino, (Ce-C10)arylpiperazino, (Cs-C9)heteroaryipiperazino, (C,-Ce)alkylpipera2ino, (Ce-C10)aryl(C,-Ce)alkylpiperazino,(C5-C9)heteroaryl(C,-Ce)aJkyJpiperazino,morpholino,lhiomorpholino, AP/PZ 9 8/01 179 10 AP 00958 -3- pyrrolidino, piperidyl, (C,-Ce)alkylpiperidyl, (Ce-C10)arylpiperidyl, (C5-C9)heteroarylpiperidyl^C1-Ce)alkylpiperidyl(C1-Ce)alky1/Ce-C,0)arylpiperidyl(C1-Ce)aJkyl,(Cj-CgJheteroarylpiperidyliC^CeJalkyl or (C^-CeJacylpiperidyi; or a group of the formula (U),

II (CH2)n -<ΎΛΖ\_τ- wherein n is 0 to 6;yisOorl; 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 R” is as defined 15 below; azetidinyl, pyrrolidinyl, piperidinyi, piperazinyl, morpholinyl, thiomorpholinyl,indolinyl, isoindolinyl, tetrahydroquinolinyi, tetrahydroisoquinolinyi or a bridgeddiazabicycloalkyl ring selected from the group consisting of 20

APZPZ 9 8/01179 25

Η Η H 30 AP 00958

d e 10 wherein r is 1, 2 or 3;m is 1 or 2;p is 0 or 1; and wherein each heterocyclic group may optionally be substituted by one or two groups15 selected from hydroxy, (C^-C^aJkyl, (C,-Ce)aJkoxy, (C^^Jacyi, (C,-C10)acyloxy, (Ce- C10)ary1, (C5-C9)heteroaryl, (Ce-C50)aryi(C1-Ce)alkyi, (Cj-CgJheteroaryliC^jJalkyi,hydroxy(C,-Ce)alkyl, (C,-Ce)aikoxy(C ,-Ce) alkyl, (C^^acyloxyiC^gJalkyl, (C,-Ce)alkytthio, (C^C^alkytthiofC^^alkyi, (Ce-C10)aryithio, (Ce-C, Jarylthiof^-CJalkyl,R12R13N, R12R’3NSO2, R12R,3NCO, R12R13NCO(C1-Ce)aikyl wherein R12 and R13 are each 20 independently hydrogen, (C,-Ce)alkyl, (Ce-C10)ary1, (C5-C9)heteroary1, (Ce-C10}aryl (C,-

Ce)alkyf or (C5-C9)heteroaryl (C^CjJalkyi or R12 and R13 may be taken together with thenitrogen to which they are attached to form an azetidinyi, pyrrolidinyi, piperidinyl,morpholinyl or thiomorpholinyl ring; R’*SO2, R14S02NH wherein R’4 is trifluoromethyl,(C,-Ce)alky1, (Ce-C10)aryl, (C5-C9)heteroaryl, (Cs-C^aryl^-C^alkyl or (Cj-CaJheteroaryl 25 (C,-Ce)alkyt; R16CONR’2 wherein R12 is as defined above and R15 is hydrogen, (C,- C„)alkyl, (C^-C^alkoxy, (Ce-C,0)aryl, (C5-Ci)heteroaryi, (C,-Ce)aryl(C,-Ce)alkyl(Ce-C10)aryl(C,-Ce)alkoxy or (C5-C9)heteroarylf^-C^alky!; R’eOOC, R^OOCfC^-CjJalkylwherein R16 is (C^-C^alkyl, (Ce-C10)aryi, (C5-C9)heteroaryl, (Ce-Cw)ary1 (C,-Ce)alkyl, 5-indanyi, CHR17OCOR18 wherein R17 is hydrogen or (C.,-Ce)aJkyl and R18 is (C,-Ce)aJkyl, 30 (C^C^alkoxy or (Ce-C10)aryt; CH2CONR”R2<’ wherein R1’ and R20 are eachindependently hydrogen or (C^eJalkyi or may be taken together with the nitrogen towhich they are attached to form an azetidinyi, pyrrolidinyi, piperidinyl, morpholinyl or AP/P/ 9 8/01 179 AP 00958 -5- thiomopholinyl ring; or R21O (C,CB)alkyi wherein R2’ is H2N(CHR22)CO wherein R22 isthe side chain of a natural D- or L-amino acid; R” is hydrogen, (Ce-C,0)aryl, (C6-C9)heteroaryl, (Ce-C^aryl^-C^alkyl, (C6-C9)heteroaryl(C,-CB)alkyl, (Cl-CB)alkyl(CB-Cl0)aryl(C1-CB)alkyl, (C.-C^alkyl^-C9)heteroaryi(C,-CB)aJky1, 5-indanyl, CHR’OCOR” or CH2CONR19R20 wherein R”, R”,R19 and R20 are as defined above; or R’ and R2, or R3 and R4, or R5 and R® may be taken together to form acarbonyl; or R’ and R2, or R3 and R4, or R6 and Re, or R7 and R8 may be taken togetherto form a (C3-Ce)cycloalky1, oxacydohexyl, thiocydohexyi, indanyl or tetralinyl ring ora group of the formula N‘ wherein R23 is hydrogen, (C,-C9)acyi, (C,-Ce)alkyl, (CB-C,0)aryl(C,-CB)alkyl, (C,-CgJheteroaryliC^-C^alkyl or (C,-CB)alkylsulfonyl; and Q is (C,-C10)alkyl, (Ce-C10)aryl, (Ce-C10)aryloxy(Ce-C10)aryi, (Ce-C10)aryi(Ce- C10)aryl, (Ce-C10)aryi(Cs-C10)aryl(C1-CB)aJkyl, (C^Jaryi^-C^alkoxytCVC^alkyl, (CB- AP/P/ 9 8/01179 C10)aryloxy(C5-C9)heteroaryi, (C5-C9)heteroaryi, (C,-CB)alkyl(CB-C10)aryl, (C,- CB)alkoxy(CB-C,0)aryl, (CB-C10)aryl(C,-CB)alkoxy(CB-C10)aryl, (C5-C9)heteroaryloxy(CB-C10)aryi, (C,-Ce)alky1(C5-C9)heteroaryl, (C1-C9)aJkoxy(C5-C9)heteroaryl, (Ce-C,0)aryl(Cr

Ce)alkoxy(C5-C9)heteroaryi, (C5-C9}heteroaryloxy(C5-Ce)heteroaryl, (CB-C, 0)aryloxy{C, -CB)alkyl, (C5-C9)heteroaryloxy(C,-Ce)aIkyl, (C,-CB)alkyl(CB-C10)aryloxy(CB-C,0)aryl, (CrCB)alkyl(C5-C9)heteroaryioxy(CB-C,0)aryl, (C,-Ce)alky1(Ce-C10)aryloxy(C5-Cg)heteroaryi,(Cl-CB)alkoxy(CB-C10)aryloxy(CB-Cl0)aryl,(C1-CB)alkoxy(C5-C9)heteroaryloxy(CB-C10)arylor (C, -C,)alkoxy(Ce-C10)aryloxy(C5-C9)heteroaryl optionally substituted by fluoro, chloro,(C,-CB)alkyl, {C,-CB)alkoxy or perfluorofC^CjJalkyl; with the proviso that Z must be substituted when defined as azetidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyf, isoindolinyi, tetrahydroquinolinyi,tetrahydroisoquinolinyi, piperazinyl, (C^-C^acyipiperazinyl, (C,-CB)aIkylpiperazinyl, (CB-C10)arylpiperazinyl, (C5-C9)heteroaryipiperazinyl or a bridged diazabicydoalkyl ring; βρ Ο Ο 9 5 θ with the proviso that R7 is other than hydrogen only when R8 is other thanhydrogen; with the proviso that R® is other than hydrogen only when R5 is other thanhydrogen; 5 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 R1 is other thanhydrogen; with the provisio that when R1, R2 and R8 are a substituent comprising a10 heteroatom, the heteroatom cannot be directly bonded to the 2- or 6- positions; with the proviso that when X is nitrogen, R4 is 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 R1, R2, R5 and R®, is a substituent comprisinga heteroatom, the heteroatom cannot be directly bonded to the 4- or 6- positions; 15 with the proviso that when Y is oxygen, sulfur, SO, SO2 or nitrogen and when one or more of the group consisting of R3, R*, R7 and R8, are independently asubstituent 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 20 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 SO2, R5 and R® are not present; with the proviso that when Y is nitrogen, R® is not present; 25 with the proviso that when the broken line represents a double bond, R4 and R® are not present; with the proviso that when R3 and R9 are independently a substituent comprisinga heteroatom when the broken line represents a double bond, the heteroatom cannotbe directly bonded to positions X and Y; 30 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 linedoes not represent a double bond; AP/PZ 9 8/01 179 AP 00958 -7- with the proviso that at least one of R’, R2, R3, R4, R5, R®, R7, R® and RB must bedefined as the group of formula II.

The term "alkyl", as used herein, unless otherwise indicated, includes saturatedmonovalent hydrocarbon radicals having straight, branched or cyclic moieties or 5 combinations thereof.

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

The term "aryl", as used herein, unless otherwise indicated, includes an organicradical derived from an aromatic hydrocarbon by removal of one hydrogen, such as 10 phenyl or naphthyl, optionally substituted by 1 to 3 substituents independently selectedfrom the group consisting of fluoro, chloro, cyano, nitro, trifluoromethyl, (C,-Ce)alkoxy,(Ce-C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C,-Ce)alkyl:

The term "heteroaryl", as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic heterocyclic compound by removal of one 15 hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl,tetrazolyl, pyrazinyl, pyrimidyi, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl,benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl,oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituentsindependently selected from the group consisting of fluoro, chloro, trifluoromethyl, (C,- 20 Ce)alkoxy, (Ce-C,0)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, arylalkyl or arylalkyloxy and tine terms ’alkyl’ or "aryl" are as defined above.

The term "acyloxy", as used herein, includes O-acyl groups wherein "acyl" is 25 defined above.

The term "D- or L-amino add", as used herein, unless otherwise indicated,includes glycine, alanine, valine, leucine, isoleucine, phenylalanine, asparagine,glutamine, tryptophan, proline, serine, threonine, tyrosine, hydroxyproline, cysteine,cystine, methionine, aspartic add, glutamic add, lysine, arginine or histidine. 30 The positions on the ring of formula I, as used herein, are defined as follows: AP/P/ 9 0/01 179 AP 00958 -8-

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

The compound of formula I may have chiral centers and therefore exist in10 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,-

Ce)alkoxy(Ce-C10)aryl, (Ce-C^JaryliC^eJalkoxyiCg-C^Jaryl, or (Ce-Cw)aryl(C,-15 Ce)alkoxy(C,-Ce)alkyl wherein each terminal aryl group is optionally substituted by fluoro.

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

More preferred compounds of formula I include those wherein Y is carbon; Q20 is (C,-Ce)alkoxy(Ce-C10)aryl, (Ce-C10)aryl(C,-Ce)alkoxy(Ce-C10)aryl, or (Cg-C^aryHC,-

Ce)alkoxy(C,-CB)alkyl.

Specific preferred compounds of formula I include the following:(2R,4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoyi- piperidine-4-carboxylic add; 25 (2R,4R)-1-[4-(4-Fluorobenzy!oxy)-benzenesulfonyl]-2-hydroxycarbamoyl- piperidine-4-carboxylic add methyl ester; (2R,4R)-1-[3-(4-Fluorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic add; (2R,4R)-1-[3-{4-FIuorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoyl-30 piperidine-4-carboxylic add methyl ester; (2R,3S)-{1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidin-3-yl}-carbamic add isopropyl ester; AP/P/ 9 8/01179 AP 00958 -9- 3-(S)-4-(4'-F1uorobiphenyl-4-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide; 3-(S)-4-[4-(4-Fluorobenzyloxy)benzenesulfonyi]-2,2-dimethyl-thiomorpholine-3-carboxylic add hydroxyamide; 5 (2R,4S)*1-l4*(4-Fluorobenzyloxy)-benzenesulfonyl]-4-hydroxy-piperidine-2- carboxylic add hydroxyamide; and (2R, 4R)-1 -(4-Methoxybenzenesutfonyl)-4-{piperazine-1 -carbonyt)-piperidine-2-carboxylic add hydroxyamide hydrochloride.

Other compounds of the invention indude: 10 (3S)-4-(4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2,2-dimethyl- thiomorpholine-3-carboxylic add hydroxyamide; (3S)-2,2-Dimethyl-4-[4-(thiazol-5-ylmethoxy)-benzenesuifonyf|-thiomorpholine-3-carboxylic add hydroxyamide; (3S)-2,2-Dimethyl-4-[4-(pyridin-4-ylmethoxy)-benzenesulfonyi]-thiomorpholine-3-15 carboxylic add hydroxyamide; (3S)-4-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2,2-dimethyl-thiomorpholine-3-carboxylic add hydroxyamide; {3S)-2,2«Dimethyl-4-[4-{2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic add hydroxyamide; 20 (3S)-4-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2,2-dimethyl- thiomorpholine-3-carboxylic acid hydroxyamide; (3S)-2,2-Dimethyl-4-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesuifony1]-thiomorpholine-3-carboxylic add hydroxyamide; (3S)-2,2-Oimethyi-4-[4-(1H-tetrazol-5-ylmethoxy}-benzenesulfony1]-thiomorpholine-25 3-carboxyiic add hydroxyamide; (2R,3S}-{1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidin-3-yl}-carbamic add methyl ester; (2R,3S)-{2-Hydroxycarbamoyl-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidin-3-yl}-carbamic add methyl ester, 30 (2R,3S)-{2-HydroxycarbamoyI-1 -[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]· piperidin-3-yl}-carbamic add methyl ester; (2R,3S)-{1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidin-3-yl}-carbamic add methyl ester, AP/P/ 9 8/01 179 AP 00958 -10- (2R,3S)-(1-(4-[2-(4-Fluorophenyl)-ethoxyl-benzenesulfonyl}-2-hydroxycarbamoyl-piperidin-3-yl)-carbamic add methyl ester; (2R,3S)-(2-Hydroxycarbamoyl-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-piperidin-3-yl}-carbamic add methyl ester, 5 (2R,3S)-{1 -[^Benzothiazoka-ylmethoxyl-benzenesutfonyll-S-hydroxycarbamoyl- piperidin-3-yI}-carbamic add methyl ester, (2R,3S)-{2-Hydroxycarbarnoyi-1-[4-{5-trifluoromethyi-benzothiazol-2-yirnethoxy)-benzenesulfonyl]-piperidin-3-yl}-carbamic add methyl ester; (2R,3S)-{2-Hydroxycarbamoyi-1 -(4-(1 H-tetrazol-5-ylmethoxy}-benzenesulfonyll-10 piperidin-3-yl}-carbamic add methyl ester; (2R,3S)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzene$ulfonyl]-3-hydroxy-piperidine-2-carboxylic add hydroxyamide; (2R,3S)-3-Hydroxy-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic add hydroxyamide; 15 (2R,3S)-3-Hydroxy-1 -[4-(pyridin-4-ylmethoxy)-benzenesulfonyi]-piperidine-2- carboxylic add hydroxyamide; (2R,3S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-3-hydroxy-piperidine-2-carboxylic add hydroxyamide; (2R,3S)-1 -{4-(2-(4-Ruorophenyl}-ethoxy]-benzenesuffonyl}>3-hydroxy-piperidine-20 2-carboxylic add hydroxyamide; (2R,3S)-3-Hydroxy-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-piperidine-2-carboxylic add hydroxyamide; (2R,3S)-1-[4-(Benzothiazol-2-ylmethoxy}-benzenesulfonyl]-3-hydroxy-piperidine-2-carboxylic add hydroxyamide; 25 (2R,3SJ-3-Hydroxy-1-[4-(5-trifIuoromethyl-benzothiazol-2-ylmethoxy)- benzenesuffonyl]-piperidine-2-carboxylic add hydroxyamide; (2R,3S)-3-Hydroxy-1 -(4-(1 H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic add hydroxyamide; (2R,3S)-1 -[4-(2-Chloro-thiazol-5-ylmethoxy}-benzenesu[fonyf]-3-hydroxy-3-methyl-30 piperidine-2-oarboxyiic add hydroxyamide; (2R,3S)-3-Hydroxy-3-methyl-1-(4-(thiazoi-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic add hydroxyamide; AP/P/ 9 8/01 179 AP 00958 -11- (2R,3S)-3-Hydroxy-3-methyl-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic add hydroxyamide; (2R,3S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperldine- 2- carboxyiic add hydroxyamide; 5 (2R,3S)-1 -{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-3-hydroxy-3-methyl- piperidine-2-carboxylic add hydroxyamide; (2R,3S)-3-Hydroxy-3-methyl-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-piperidine-2-carboxylic add hydroxyamide; (2R ,3S)-1 - [4-(Benzothiazoi'2-yimethoxy)-benzenesutfonyi] -3-hydroxy-3-methyl-10 piperidine-2-carboxylic add hydroxyamide; (2R,3S}-3-Hydroxy-3-methyl-1-[4-{5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyi]-piperidine-2-carboxylic add hydroxyamide; (2R,3S)-3-Hydroxy-3-methyl-1 -[4-(1 H-tetrazo!-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic add hydroxyamide; 15 (3R)-4-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2,2-dimethyl- morphoiine-3-carboxyiic add hydroxyamide; (3R)-2,2-Dimethyl-4-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-morpholine-3-carboxylic add hydroxyamide; (3R)-2,2-Dimethyl-4-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-morpholine-3-20 carboxylic add hydroxyamide; (3R)-4-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2,2-dimethyi-morpholine-3-carboxylic add hydroxyamide; (3R)-4-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesutfonyl}-2,2-dim6thyl-morpholine- 3- carboxylic add hydroxyamide; 25 (3R)-2,2-Dimethyl-4-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-morpholine-3- carboxylic add hydroxyamide; (3R)-4-[4-(BenzothiazoP2-ylmethoxy)-benzenesuifonyl]-2^-dimethyl-morpholine-3-carboxylic add hydroxyamide; (3R)-2,2-Dimethyl-4-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-30 benzenesulfonyl]-morpholine-3-carboxylic add hydroxyamide; (3R)-2,2-DimethyM-[4-{1H-tetrazol-5-ylmethoxy}-benzenesutfonyl]-morpholine-3-carboxylic add hydroxyamide; AP/P/ 9 8/01179 AP 00958 -12- (2R,4R)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxyiic acid; (2R,4R)-2-Hydroxycarbamoyl-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-4-carboxyiic add; 5 (2R,4R)-2-Hydroxycarbamoyl-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]- piperidine-4-carboxyiic add; (2R,4R)-1-{4-I2-{4-nuorophenyi)-ethoxy}-benzenesulfonyl}-2-hydroxycarbamoyl-piperidine-4-carboxyiic add; (2R,4R)-2-Hydroxycarbamoyl-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesuffonyi]-10 piperidine-4-carboxyiic add; (2R,4R)-1-[4-{Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2-hydroxycarbamoyi-piperidine-4-carboxylic add; (2R,4R)-2-Hydroxycarbamoyl-1-[4-(5-trifluoromethyi-benzothiazol-2-ylmethoxy)-benzenesulfonyi]-piperidine-4-carboxylic add; 15 (2R,4R)-2-Hydroxycarbamoyl-1 -[4-{1 H-tetrazol-5-ylmethoxy)-benzenesutfony1]- piperidine-4-carboxyiic add; (3R)-4-[4-(2-Chloro-thiazol-5-yimethoxy}-benzenesuifonyi]-3-methy1-morpho6ne-3-carboxylic add hydroxyamide; (3R)-3-Methyl-4-[4-{1hiazol-5-ylmethoxy}-benzenesutionyi]-morphoIine-3-carboxyiic20 add hydroxyamide; (3R)-3-Methyt-4-[4^yridin-4-ylrnethoxy}-benzenesutfonyr]-morphoiine-3-carboxyficadd hydroxyamide; (3R)-4-[4-(4-FIuorobenzyioxy)-benzenesutfonyf]-3-methyi-morphoCne-3-carboxyiicadd hydroxyamide; 25 (3RM44-[2-{4-Ruorophenyi)-ethoxy]-benzenesuifonyl}-3-methyi-morphofine-3- carboxylic add hydroxyamide; (3R)-3-Methyl-4-[4-(2-pyridin-4-yl-ethoxy)-benzenesuifonyl]-morpholine-3-carboxyiic add hydroxyamide; (3R)-4-[4-(Benzothiazol-2-yimethoxy)-benzenesulfonyi]-3-methyf-morphoiine-3-30 carboxylic add hydroxyamide; (3R)-3-Methyi-4-[4-(54rifluoromethyi-benzothiazoi-2-ylmethoxy}-benzenesutfonyl]-morpholine-3-carboxylic add hydroxyamide; AP/P/ 9 8/01 179 AP 00958 -13- (3R)-3-Methyl-4-[4-{1H-tetrazol-5-ylmethoxy)-benzenesulionyl]-morpholine-3-carboxylic acid hydroxyamide; (2R)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2-methyl-3-oxo-piperidine-2-carboxyiic add hydroxyamide; 5 (2R)-2-Methyl-3-oxo-1-[4-{thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2- carboxylic add hydroxyamide; (2R)-2-Methyl-3-oxo-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic add hydroxyamide; (2R)-1-[4-(4-Fiuorobenzyloxy)-benzenesulfonyl]-2-methyl-3-oxo-piperidine-2-10 carboxylic acid hydroxyamide; (2R)-1-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2-methyl-3-oxo-piperidine·2-carboxylic add hydroxyamide; (2R)-2-Methyl-3-oxo-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; 15 (2R)-1 -[4-{Benzothiazol-2-y1methoxy)-benzenesulfonyn-2-methyi-3-oxo-piperidine- 2-carboxylic add hydroxyamide; (2R)-2-Methyl-3-oxo-1-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyi]-piperidine-2-carboxylic add hydroxyamide; (2R)-2-Methyl-3-oxo-1-[4-(1H-tetrazol-5-ylmethoxy}-benzenesulfonyl]-piperidine-2-20 carboxylic add hydroxyamide; (2R,4S)-1-(4-Benzyloxy-benzenesulfonyl)-4-butylaminomethyl-4-hydroxy-piperidine-2-carboxylic add hydroxyamide; (2R,4S)-4-Butylaminomethyl-1-{4-{44luorobenzyloxy)-benzenesulfonyl]-4-hydroxy-piperidine-2-carboxylic add hydroxyamide; 25 (2R,4S)-4-Benzy1amino-1 -(4-benzyloxy-benzenesulfonyl)-piperidine-2-carboxyiic add hydroxyamide; (2R,4S)-4-Benzylamino-1-[4-{44iuorobenzyloxy)-benzenesulfonyl]-piperidine-2-carboxyiic acid hydroxyamide; (2R)-1 -[4-{4-nuorobenzyloxy}-benzenesutfonyl]-4-oxo-piperidine-2-carboxylic add30 hydroxyamide; (2R,4R)-1-(4-Benzyloxy-benzenesulfonyl)-4-hydroxy-piperidine-2-carboxylicadd hydroxyamide; AP/P/ 9 8/01 179 AP 00958 -14- (2Rl4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R)-1-[4-{4-Fluoroben2yioxy)-benzenesuifonyi]-4-methy1-piperazine-2-carboxyiicadd hydroxyamide; 5 (2R,5S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-5-hydroxy-piperidine-2- carboxylic add hydroxyamide; (2R,5S)-i-{4-Benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxylicadd hydroxyamide; (2E,5R)-1-(4-Benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxylicadd10 hydroxyamide; (2R,5R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-5-hydroxy-piperidine-2-carboxyiic add hydroxyamide; (2R,3S)-1-(4-Benzyloxy-benzenesulfonyl)-3-hydroxy-piperidine-2-carboxylicadd hydroxyamide; 15 (2R,4S)-1 -(4-Benzyloxy-benzenesulfony1)-4-hydroxyLpiperidine-2-carboxyiicadd hydroxyamide; (2R,4S)-1-[4-(4-Fluorobenzyioxy)-benzenesulfonyi]-4-hydroxy-piperidine-2-carboxylic add hydroxyamide; 1-{4-Butoxy-benzenesutfonyl)-3-(morpholine-4-carbonyt)-piperidine-2-carboxylic20 add hydroxyamide; 1-[4-(4-Fluoro-benzyloxy)-benzenesutfonyl)-3-{morphofine-4-carbonyi)-piperidine-2-carboxylic add hydroxyamide; 1-[3-(Fluoro-benzyloxy)-propane-1-sulfonyl]-3-{morphoiine-4-cartx5nyl)-piperidine-2-carboxylic add hydroxymide; 25 1 -(4-Butoxy-benzenesulfonyl)-3-(pyrrolidine-1 -carbonyl)-piperidine-2-carboxylic acid hydroxyamide; 1 -[4-(4-Fluoro-benzy1oxy}-benzenesuffonyi}-3-(pyrroiidine-1 -carbonyl)-piperidine-2-carboxylic acid hydroxyamide; 1 -[3-(4-Fluoro-benzyloxy)-propane-1 -sulfonyl)-3-(pyrrolidine-1 -carbonyl)-30 piperidine-2-carboxylic add hydroxyamide; and 1-[4-(4-Fluoro-benzyloxy)-benzenes uffon yl]-2-hydroxycarbamoyl-pi peridine-4-carboxylic add. AP/P/ 9 8/01 179 1 AP 00958 -15-

The present invention also relates to a pharmaceutical composition for (a) thetreatment of a condition selected from the group consisting of arthritis, cancer, synergywith cytotoxic anticancer agents, tissue ulceration, macular degeneration, restenosis,periodontal disease, epidermolysis bullosa, sderitis, in combination with standard 5 NSAIDS and analgesics and other diseases characterized by matrix metalloproteinaseactivity, AIDS, sepsis, septic shock and other diseases involving the production oftumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinases or theproduction of tumor necrosis factor (TNF) in a mammal, including a human, comprisingan amount of a compound of formula I or a pharmaceutically acceptable salt thereof 10 effective in such treatments and a pharmaceutically acceptable carrier.

The present invention also relates to a method for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal,including a human, comprising administering to said mammal an effective amount ofa compound of formula I or a pharmaceutically acceptable salt thereof. 15 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, sderitis, compounds of formulaI may be used in combination with standard NSAID'S and analgesics and incombination with cytotoxic anticancer agents, and other diseases characterized by 20 matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseasesinvolving the production of tumor necrosis factor (TNF) in a mammal, induding ahuman, comprising administering to said mammal an amount of a compound offormula I or a pharmaceutically acceptable salt thereof effective in treating such acondition. AP/P/ 9 8/01179 25 AP 00958 -16-

Detailed Description of the Invention

The following reaction Schemes illustrate the preparation of the compounds ofthe present invention. Unless otherwise indicated R’, R2, R3, R*, R6, Re, R7, R8, R8, nand Ar in the reaction Schemes and the discussion that follow are defined as above. 5 Preparation 1

AP/PZ 98/01179

VI 30 AP 00958 10 15 20 25 -17-

Preparation 2R\ /C02R25

NHS xviii 1

VI cn r·*.

GO σ»

CL a < 30 AP 00958-18·

Scheme 1

30 AP 00958 -19-

Scheme 2 R26

VII AP/P/ 9 8/01 179 AP 00958 10 15 20 25 -20-

Scheme 3

XII

61110/86 /d/dV

X 30 AP 00958-21-

2 AP/P/ 9 8/01179

30

XX AP 00958 -22-

Scheme 4 continued

XX

AP/P/ 9 8/01179

30

XIII 10 15 20 25 AP 00958 -23-

XXVI 1

6 L I 10/86 /d/dV

30

XXIV AP 00958 -24-

Scheme 5 continued

XXIV 3

AP/P/ 9 8/01 179 25

XIV AP 00958 -25-

Preparation 1 refers to the preparation of intermediates of the formula VI.Compounds of the formula VI are converted to compounds of the formula I accordingto the methods of Scheme 1. The starting materials of formula XVI can be preparedaccording to methods well known to those of ordinary skill in the art. 5 In reaction 1 of Preparation i, the compound of formula XVI is converted to the corresponding hydroxy ester compound of formula VI by first reacting XVI with anaryisulfonylhalide in the presence of triethyiamine and an aprotic solvent, such asmethylene chloride, tetrahydrofuran or dioxane, at a temperature between about 20°Cto about 30°C, preferably at room temperature. The compound so formed is further 10 reacted with a compound of the formula R9 C02R25

Y

Br 15 wherein R25 is carbobenzyloxy, (^-C^alkyl, benzyl, allyl or tert-butyl, in the presenceof sodium hexamethyldisilazane and a tetrahydrofuran-dimethylformamide solventmixture at a temperature between about -20°C to about 20°C, preferably about 0°C,to form the hydroxy ester compound of formula VI.

Preparation 2 refers to an alternate method of preparing compounds of the 20 formula VI. The starting materials of formula XVIII can be prepared according tomethods well known to those of ordinary skill in the art. In reaction 1 of Preparation2, the amine compound of formula XVIII, wherein R25 is as defined above, is convertedto the corresponding arylsulfonyi amine compound of formula XVII by (1) reacting XVIIIwith an aryisulfonylhalide in the presence of triethyiamine and an aprotic solvent, such 25 as methylene chloride, tetrahydrofuran, or dioxane, at a temperature between about20°C to about 30°C, preferably at room temperature, (2) reacting the compound soformed with a compound of the formula

AP/P/ 9 8/01 179 30

in the presence of sodium hexamethyldisilazane and a tetrahydrofuran-dimethyfformamide solvent mixture at a temperature between about -20°C to about20°C, preferably about 0°C, and (3) further reacting the compound so formed withozone in a methylene chloride-methanol solution at a temperature between about -90°C AP 00958 -26-

to about -70°C, preferably about -78°C. The unstable ozonide compound so formedis then reacted with triphenylphosphlne to form the arylsulfonyl _amine compoundformula XVII. In Reaction 2 of Preparation 2, the arylsulfonyl amine compound offormula XVII is converted to the corresponding hydroxy ester compound of formula VI 5 by reacting XVII with a compound of the formula 10 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; R*. R® and R7 are hydrogen;and the dashed line between X and Y is absent. In reaction Ϊ of Scheme i, thecompound of formula VI, wherein the R* protecting group is carbobenzyloxy, (C,-Ce) 15 alkyl, benzyl, allyl or tert-butyl, is converted to the corresponding morpholinonecompound of formula V by lactonization and subsequent Claisen rearrangement of thecompound of formula VI. The reaction is facilitated by the removal of the R25 protectinggroup from the compound of formula VI and is carried out under conditions appropriatefor that particular R25 protecting group in use. Such conditions indude: (a) treatment 20 with hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, whereR25 is carbobenzyloxy, (b) saponification where R” is lower alkyl, (c) hydrogenolysiswhere R25 is benzyl, (d) treatment with a strong add, such as trifluoroacetic add orhydrochloric acid, where R25 is tert-butyl, or (e) treatment with tributyltinhydride andacetic add in the presence of catalytic bis(triphenyiphosphine) palladium (II) chloride 25 where R25 is allyl.

In reaction 2 of Scheme χ the morpholinone compound of formula V Isconverted to the carboxylic add compound of formula IV by reacting V with lithiumhexamethyldisilazane in an aprotic solvent, such as tetrahydrofuran, at a temperaturebetween about -90°C to about -70°C, preferably about -78°C. Trimethylsilyl chloride 30 is then added to the reaction mixture and the solvent, tetrahydrofuran, is removed invacuo and replaced with toluene. The resuling reaction mixture is heated to atemperature between about 100°C to about 120°C, preferably about 110°C, andtreated with hydrochloric add to form the carboxylic add compound of formula IV. AP/P/ 9 8/01 179 AP 00958 -27- ln reaction 3 of Scheme i, the carboxylic add compound of formula IV isconverted to the corresponding hydroxamic acid compound of formula III by treatingIV with 1-(3-dimethylaminopropyl)-3-ethylcarbodi»mide and 1-hydroxybenztrlazole in apolar solvent, such as dimethyiformamide, followed by the addition of hydroxylamine 5 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 froma salt form, such as hydroxylamine hydrochloride, in the presence of a base, such asN-methylmorpholine. Alternatively, a protected derivative of hydroxylamine or its saltform, where the hydroxyl group is protected as a tert-butyl, benzyl or allyl ether, may 10 be used in the presence of (benzotriazol-l-yioxy)tris(dimethylamino) phosphoniumhexafluorphosphate and a base, such as N-methylmorpholine. Removal of thehydroxylamine protecting group is carried out by hydrogenolysis for a benzyl protectinggroup or treatment with a strong acid, such as trifluoroacetic add, for a tert-butylprotecting group. The allyl protecting group may be removed by treatment with 15 tributyitinhydride and acetic add in the presence of catalytic bis(triphenylphosphine)palladium (II) chloride. N,0-bis(4-methoxybenzyi)hydroxylamine may also be used asthe protected hydroxylamine derivative where deprotection is achieved using a mixtureof methanesuifonic add and trifluoroacetic add. in reaction 4 of Scheme 1, the hydroxamic add compound of formula III is 20 converted, if desired, to the corresponding piperidine compound of formula II bytreating III with hydrogen and a hydrogenation catayst, such a 10% palladium oncarbon.

Scheme 2 refers to the preparation of compounds of the formula Vll, which arecompound of the formula I wherein Y is nitrogen; X Is carbon; R1, R2, R3, R*, R7 and R® 25 are hydrogen, and R® is absent. The starting materials of formula IX can be preparedaccording to methods well known to those of ordinary skill in the art. In reaction 1 ofScheme 2, the arylsuifonylpiperazine compound of formula IX, wherein R2® iscarbobenzyloxy, benzyl or carbotertbutyioxy, is converted to the compound of formulaVIII by reacting IX with a protected derivative of hydroxylamine of the formula 30 R^ONH^HCi wherein R27 is tertbutyl, benzyl or allyl, in the presence of dicydohexylcarbodumide,dimethylaminopyridine and an aprotic solvent, such as methylene chloride. The R2®protecting group is chosen such that it may be selectively removed in the presence ofan without loss of the R27 protecting group, therefore, R2® cannot be the same as R27. AP/P/ 9 8/01 179 AP 00958 -28-

Removal of the R2e protecting group from the compound of formula IX is earned outunder conditions appropriate for that particular RM protecting group in use. Suchconditions include; (a) treatment with a hydrogen and a hydrogenation catalyst, suchas 10% palladium on carbon, where R” Is carbobenzyloxy, (b) hydrogenolysis where 5 R2® is benzyl or (c) treatment with a strong add, such as trifluoroacetic add or hydrochloric add where R” is carbotertbutyloxy.

In reaction 2 of Scheme 2, the compound of formula VIII is converted to thecorresponding hydroxamic add compound of formula VII, wherein Rs is hydrogen or(C^C^alkyl, by reacting, if desired, VIII with an alkylhaiide when Rs is (C^-C^aJkyl. 10 Subsequent removal of the R27 hydroxylamine protecting group is carried out byhydrogenolysis for a benzyl protecting group or treatment with a strong add, such astrifluoroacetic add, for a tert-butyl protecting group. The allyl protecting group may beremoved by treatment with tributyttinhydride and acetic add in the presence of catalyticbis(triphenylphosphine) palladium (II) chloride. 15 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; R2, R7, R“ and R* arehydrogen; R3 and R* taken together are carbonyl; R® is hydrogen, and R® is absent.In reaction 1 of Scheme 3, the arylsutfonyiamine compound of formula XII, wherein R26is as defined above, is converted to the corresponding piperazine compound of formula 20 XI by reacting XII with a carbodiimide and a base, such as triethylamine. Thecompound of formula XI is further reacted to give the hydroxamic add compound offormula 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. Thestarting materials of formula XVIII can be prepared according to methods wefl known 25 to those of ordinary skill in the art. Compounds of the formula XIII are compounds ofthe formula I wherein X is carbon, and the dotted line between X and Y is absent. Inreaction 1 of Scheme 4, removal of the R” protecting group and subsequent reductiveamination of the compound of formula XXII, wherein Y is oxygen, sulfur or carbon, togive the corresponding imine compound of formula XXI is carried out under conditions 30 appropriate for that particular R28 protecting group in use. Such conditions includethose used above for removal of the R2® protecting group in reaction 1 of Scheme 2.

In reaction 2 of Scheme 4, the imine compound of formula XXI is converted tothe corresponding piperidine compound of formula XX by reacting XXI with a nucleophile of the formula R2M wher^ M ^ lftfiium, rnagnetium· halide or cerium

PATENTS 1 ; • -··,· · > r.-, -. ; CY 1 ' AP/P/ 9 8/01 179 AP 00958 -29- halide. The reaction is carried out in ether solvents, such as diethyl ether ortetrahydrofuran, at a temperature between about -78°C to about 0°C, preferably about-70° C. in reaction 3 of Scheme 4, the sulfonation of the piperidine compound of 5 formula XX to given the corresponding arytsulfonyipiperidine compound of formula XIXis carried out by reacting XX with an aryisuifonylhalide in the presence of triethylamineand an aprotic solvent, such as methylene chloride, tetrahydrofuran or dioxane, at atemperature between about 20°C to about 30°C, preferably at room temperature.

In reaction 4 of Scheme 4, the aryisulfonylpiperidine compound of formula XIX 10 is converted to the hydroxamic add compound of formula XIII according to theprocedure described above in reaction 3 of Scheme 1-

Scheme 5 refers to the preparation of compounds of the formula XIV, which arecompounds of formula I wherein Y is nitrogen, X is carbon, the dotted line between Xand Y is absent, Ft5 is hydrogen and R® is absent. In reaction 1 of Scheme 5, the 15 compound of formula XXVI, wherein the R29 and R3' protecting groups are eachindependently selected from the group consisting of carbobenzyloxy, benzyl andcarbotertbutyloxy and R30 is carbobenzyloxy, (C,-Ce)alkyl, benzyl, allyl or tert-butyl, isconverted to the corresponding imine compound of formula XXV by the removal of theR29 protecting group and subsequent reductive amination of the compound of formula 20 XXVI. The R29 protecting group is chosen such that it may be selectively removed inthe presence of and without loss of the R31 protecting group. Removal of the R”protecting group from the compound of formula XXVI is carried out under conditionsappropriate for that particular R29 protecting group in use which will not affect the R3’protecting group. Such conditions include; (a) treatment with hydrogen and a 25 hydrogenation catalyst, such as 10% palladium on carbon, where R29 is carbobenzyloxyand R31 is tert-butyl, (b) saponification where R29 is (C.,-Ce) alkyl and R31 is tert-butyl, (c)hydrogenolysis where R29 is benzyl and R31 is (C,-Ce) alkyl or tert-butyl, (d) treatmentwith a strong add such as trifluoroacetic add or hydrochloric add where R29 is tert-butyland R31 is (C^eJalkyl, benzyl or allyl, or (e) treatment with tributyttinhydride and acetic 30 add in the presence of catalytic bis(triphenylphosphine) palladium (11) chloride whereR29 is allyl and R31 is (C,-Ce)alkyl, benzyl or tert-butyl. The R30 protective group maybe selected such that it is removed in the same reaction step as the R29 protectinggroup. AP/P/ 9 8/01 179 AP 00958 -30- ln reaction 2 of Scheme 5, the imine compound of formula XXV is converted tothe corresponding compound of formula XXIV by reacting XXV with a nucleophile ofthe formula R3M wherein M is lithium, magnesium halide or calcium halide. Thereaction is carried out in ether solvents, such as diethyl ether or tetrahydrofuran, at a 5 temperature between about -78°C to about 0°C, preferably about -70°C.

In reaction 3 of Scheme 5, the sulfonation of the piperidine compound offormula XXIV to give the corresponding arylsulfonylpiperidine compound of formula IIIis carried out according to the procedure described above in reaction 3 of Scheme 4.

In reaction 4 of Scheme 5, the aryisulfonyipiperidine compound of formula XXIII10 is converted to the hydroxamic add compound of formula XIV by (1) removing the R30,if needed, and R31 protecting groups from XXIII followed by (2) reacting XXIII accordingto the procedure described above in reaction 3 of Scheme 1.. Removal of the R30 andR31 protecting groups from the compound of formula XXIII is carried out underconditions appropriate for that particular R30 and R31 protecting group in use. Such 15 conditions indude those used above for removal of the R25 protecting group in reaction1 of Scheme 1..

Pharmaceutically acceptable salts of the addic compounds of the invention aresalts formed with bases, namely cationic salts such as alkali and alkaline earth metalsalts, such as sodium, lithium, potassium, caldum, magnesium, as well as ammonium 20 slats, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyiammonium salts.

Similarly acid addition salts, such as of mineral adds, organic carboxylic andorganic sulfonic adds e.g. hydrochloric add, methanesutfonic add, maleic add, arealso possible provided a basic group, such as pyridyl, constitutes part of the structure. 25 The ability of the compounds of formula I or their pharmaceutically acceptable salts (the compounds of the invention) to inhibit matrix metalloproteinases or theproduction of tumor necrosis factor (TNF) and, consequently, demonstrate theireffectiveness for treating diseases characterized by matrix metalloproteinase or theproduction of tumor necrosis factor is shown by the following in vitro assay tests. AP/P/ 9 8/01 179 AP 00958 -31-

Bioloqical Assay

Inhibition of Human Collagenase (MMP-1) _

Human recombinant collagenase is activated with trypsin using the following ratio: 10 pg trypsin per 100 ^g of coiiagenase. The trypsin and collagenase are 5 incubated at room temperature for 10 minutes then a five fold excess (50 pg/10 pgtrypsin) of soybean trypsin inhibitor is added. 10 mM stock solutions of inhibitors are made up in dimethyl sulfoxide and thendiluted using the following Scheme: 10 mM-> 120 μΜ -—> 12μΜ-> 1.2 μΜ-> 0.12μΜ 10 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 willbe a 1:4 dilution after addition of enzyme and substrate. Positive controls (enzyme, noinhibitor) are set up in wells D1-O6 and blanks (no enzyme, no inhibitors) are set inwells D7-D12. 15 Collagenase is diluted to 400 ng/ml and 25 μ! 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 mMstock in dimethyl sulfoxide and then diluted to 20 μΜ in assay buffer. The assay isinitiated by the addition of 50 μΙ substrate per well of the microfluor plate to give a final 20 concentration of 10 μΜ.

Fluorescence readings (360 nM excitation, 460 nm emission) were taken at time0 and then at 20 minute intervals. The assay is conducted at room temperature witha typical assay time of 3 hours.

Fluorescence vs time is then plotted for both the blank and collagenase25 containing samples (data from triplicate determinations is averaged). A time point thatprovides a good signal (the blank) and that is on a linear part of the curve (usuallyaround 120 minutes) is chosen to determine IC^ values. The zero time is used as ablank for each compound at each concentration and these values are subtracted fromthe 120 minute data. Data is plotted as inhibitor concentration vs % control (inhibitor 30 fluorescence divided by fluorescence of collagenase alone x 100). ICjo's aredetermined from the concentration of inhibitor that gives a signal that is 50% of thecontrol. AP/P/ 9 8/01 179 AP 00958 -32-

If IC50's are reported to be <0.03 μΜ then the inhibitors are assayed atconcentrations of 0.3 μΜ, 0.03 μΜ, 0.03 μΜ and 0.003 μΜ.

Inhibition of Geiatinase (MMP-2)

Inhibition of geiatinase activity is assayed using the Dnp-Pro-Cha-Gly-Cys(Me)- 5 His-Ala-Lys(NMA)-NH2 substrate (10 μΜ) under the same conditions as inhibition ofhuman coiiagenase (MMP-1). 72kD geiatinase is activated with 1 mM ΑΡΜΑ (p-aminophenyl mercuric acetate)for 15 hours at 4°C and is diluted to give a final concentration in the assay of 100mg/ml. Inhibitors are diluted as for inhibition of human coiiagenase (MMP-1) to give 10 final concentrations in the assay of 30 μΜ, 3 μΜ, 0.3 μΜ and 0.03 μΜ. Eachconcentration is done in triplicate.

Fluorescence readings (360 nm excitation, 460 emission) are taken at time zeroand then at 20 minutes intervals for 4 hours. ICS0‘s are determined as per inhibition of human coiiagenase (MMP-1). If IC^'s15 are reported to be less than 0.03 μΜ, then the inhibitors are assayed at final concentrations of 0.3 μΜ, 0.03 μΜ, 0.003 μΜ and 0.003 μΜ. inhibition of Stromeiysin Activity (MMP-31

Inhibition of stromeiysin activity is based on a modified spectrophotometricassay described by Weingarten and Feder (Weingarten, H. and Feder, J., 20 Spectrophotometric Assay for Vertebrate Coiiagenase, Anal. Biochem. 147, 437-440(1985)). Hydrolysis of the thio peptoiide substrate [Ac-Pro-Leu-Gly-SCH[CH2CH(CH3)2]CO-Leu-Gly-OC2l-y yields a mercaptan fragment that can bemonitored in the presence of Eliman's reagent.

Human recombinant prostromeiysin is activated with trypsin using a ratio of 1 /A 25 of a 10 mg/ml trypsin stock per 26 pg of stromeiysin. The trypsin and stromeiysin areincubated at 37°C for 15 minutes followed by 10 /A of 10 mg/ml soybean trypsininhibitor 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 μ! of assay buffer (200 mMsodium chloride, 50 mM MES, and 10 mM calcium chloride, pH 6.0) in 96-well microliter 30 plates. Activated stromeiysin is diluted in assay buffer to 25 μο/πΑ. Slman's reagent(3-Carboxy-4-nitrophenyi disulfide) is made as a 1M stock in dimethyl formamide anddiluted to 5 mM in assay buffer with 50 μ! per well yielding at 1 mM final concentration. 10 mM stock solutions of inhibitors are made in dimethyl sulfoxide and dilutedserially in assay buffer such that addition of 50 μί to the appropriate wells yields final AP/P/ 9 8/01 179 AP 00958 -33- concentrations of 3 μΜ, 0.3 μΜ, 0.003 μΜ, and 0.0003 μΜ. All conditions arecompleted in triplicate. A 300 mM dimethyl sulfoxide stock solution of the peptide substrate is dilutedto 15 mM in assay buffer and the assay is initiated by addition of 50 μΙ to each well to 5 give a final concentration of 3 mM substrate. Blanks consist of the peptide substrateand Ellman's reagent without the enzyme. Product formation was monitored at 405 nmwith a Molecular Devices UVmax plate reader. IC50 values were determined in the same manner as for collagenase.

Inhibition of MMP-13 10 Human recombinant MMP-13 is activated with 2mM ΑΡΜΑ (p-aminophenyl mercuric acetate) for 1.5 hours, at 37°C and is diluted to 400 mg/ml in assay buffer (50mM Tris, pH 7.5, 200 mM sodium chloride, 5mM calcium chloride, 20μΜ zinc chloride,0.02% brij). Twenty-five microGters of diluted enzyme is added per well of a 96 wellmicrofluor plate. The enzyme is then diluted in a 1:4 ratio in the assay by the addition 15 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 sulfoxide and then diluted in assay buffer as per the inhibitor dilution scheme for inhibition of humancollagenase (MMP-1): Twenty-five microliters of each concentration is added intriplicate to the microfluor plate. The final concentrations in the assay are 30 μΜ, 3μΜ, 20 0.3 μΜ, and 0.03 μΜ.

Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is prepared as forinhibition of human collagenase (MMP-1) and 50 μ! is added to each well to give a finalassay concentration of 10 μΜ. Fluorescence readings (360 nM excitation; 450emission) are taken at time 0 and every 5 minutes for 1 hour. 25 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 IC^'sare reported to be less than 0.03 μΜ, inhibitors are then assayed affinal concentrationsof 0.3 μΜ, 0.03 μΜ, 0.003 μΜ and 0.0003 μΜ. 30 Inhibition of TNF Production

The ability of the compounds or the pharmaceutically acceptable salts thereofto inhibit the production of TNF and, consequently, demonstrate their effectiveness fortreating diseases involving the production of TNF is shown by the following in vitroassay: AP/PZ 9 8/01 179 AP 00958 -34-

Human mononuclear cells were isolated from anti-coagulated human bloodusing a one-step Ficoll-hypaque separation technique. (2) The mononuclear ceils werewashed three times in Hanks balanced salt solution (HBSS) with divalent cations andresuspended to a density of 2 x 10® /ml in HBSS containing 1% BSA. Differentialcounts determined using the Abbott Cell Dyn 3500 analyzer indicated that monocytesranged from 17 to 24% of the total cells in these preparations. 180μ of the cell suspension was aliquoted Into flate bottom 96 well plates(Costar). Additions of compounds and LPS (100ng/ml final concentration) gave a finalvolume of 200μ1. All conditions were performed in triplicate. After a four hourincubation at 37°C in an humidified CO2 incubator, plates were removed andcentrifuged (10 minutes at approximately 250 x g) and the supernatants removed andassayed for TNFe using the R&amp;D EUSA Wt

For administration to mammals, including humans, for the inhibition of matrixmetalloproteinases or the production of tumor necrosis factor (TNF), a variety ofconventional routes may be used including orally, parenterally and topically. In general,the compound of the invention will be administered orally or parenterally at dosagesbetween 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 willnecessarily occur depending on the condition of the subject being treated. The personresponsible for administration will, in any event, determine the appropriate dose for theindividual subject.

The compounds of the invention can be administered in a wide variety ofdifferent dosage forms. In general, the therapeutically effective compounds of thisinvention are present in such dosage forms at concentration levels ranging from about5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate andglycine may be employed along with various disintegrants such as starch (andpreferably com, potato or tapioca starch), alginic add and certain complex silicates,together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia.Additionally, lubricating agents such as magnesium stearate, sodium lauryi sulfate andtalc are often very useful for tabletting purposes. Solid compositions of a similar typemay also be employed as fillers in gelatin capsules; preferred materials in thisconnection also include lactose or milk sugar as well as high molecular weight AP/PZ 9 8/01179 AP 00958 -35- polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient may be combined with various sweetening orflavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/orsuspending agents as well, together with such diluents as water, ethanol, propylene 5 glycol, glycerin and various like combinations thereof. In the case of animals, they areadvantageously 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 andintravenous use) a sterile injectable solution of the active ingredient is usually prepared. 10 Solutions of a therapeutic compound of the present invention in either sesame orpeanut oil or in aqueous propylene glycol may be employed. The aqueous solutionsshould be suitably adjusted and buffered, preferably at a pH of greater than 8, ifnecessary and the liquid diluent first rendered isotonic. These aqueous solutions aresuitable intravenous injection purposes. The oily solutions are suitable for intraarticular, 15 intramuscular and subcutaneous injection purposes. The preparation of all thesesolutions under sterile conditions is readily accomplished by standard pharmaceuticaltechniques well known to those skilled in the art. In the case of animals, compoundscan be administered intramuscularly or subcutaneously at dosage levels of about 0.1to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to 20 3 divided doses.

The present invention is illustrated by the following examples, but it is not limitedto the details thereof. EXAMPLE 1 (2R, 4RM -(4-Methoxy-benzenesulfonvl>-4-(plperazine-1 -carbonyl)-oiperidine-2- 25 carboxylic acid hvdroxvamlde hydrochloride (a) To a stirred, cold (-78 °C) solution of (2R)-2-benzyloxycarbonylamino-pentanedioic add 1-tert-butyl ester 5-methyl ester (5.6g, 15.9 mmol), prepared asdescribed 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(trimethy1silyl)amide (40 mL, 1 M in 30 tetrahydrofuran, 39.8 mmol). The resulting mixture was stirred for 1 hour at-45 °C andthen recooled to -78 °C. Allyl bromide (5.2 mL, 63.7 mmol) was then added. After 2hours the reaction was quenched by the addition of 1 M aqueous hydrogen chlorideat -78 °C. The mixture was then extracted with diethyl ether. The combined ethereal AP/P/ 9 8/01 179 -36- extracts were washed with brine and the mixture was dried over sodium sulfate. Afterfiltration and concentration of the filtrate, the crude product was purified by silica gelchromatography (elution with 1:5 ethyl acetate/hexanes) to provide (2R,4R)-4-allyi-2-benzyloxycarbonylamino-pentanedioic add 1-tert-butyf ester 5-methyl ester. 5 (b) Ozone gas was bubbled through a stirred, cold (-78 °C) solution of (2R,4R)-4- ailyl-2-benzyloxycarbonytamino-pentanedioic add 1-tert-butyl ester 5-methyl ester (5.0g, 12.8 mmol) in 100 mL of 10:1 methanoi/methylene chloride, and 0.73 mL of aceticadd until a blue color persisted. Nitrogen gas was then bubbled through the solutionuntil the blue color dissipated. The mixture was warmed to ambient temperature and 10 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 ofthe filtrate provided (2R,4S)-6-methoxy-piperidine-1,2,4-tricarboxylic add 1-benzyl ester2-tert-butyl ester 4-methyl ester as a dear oil, which was used in the subsequent step 15 without purification. (c) A mixture of (2R,4S)-6-methoxy-piperidine-1,2,4-tricarboxylic add 1 -benzyl ester2-tert-butyl ester 4-methyl ester (4.85 g, 11.9 mmol) and 10% palladium on carbon (500mg) 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 20 provide (2R,4R)-piperidine-2,4-dicarboxylic add 2-tert-butyl ester 4-methyl ester as tightyellow 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 add 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-benzenesulfonyi chloride (2.3 g, 25 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 themixture was extracted with ethyl acetate. The combined organic extracts were washedwith brine, and the organic mixture was dried over sodium sulfate. After filtration andconcentration of the filtrate, the resulting crude product was purified by silica gel 30 chromatography (elution with 3:8 ethyl acetate/hexanes) to provide (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic add 2-tert-butyl ester 4-methylester. AP/P/ »8/01 179 AP 00958 -37- (e) To a stirred, cold (0 °C) solution of (2R,4R)-1-(4-methoxy-benzenesuffonyl)-piperidine-2,4-dicarboxylic add 2-tert-butyl ester 4-methyl ester (4.4 g, 10.6 mmol) In 30mL of methylene chloride was added 10 mL of trifluoroacetic add dropwise. Themixture was stirred for 1 hour at 0 °C and for 8 hours at ambient temperature. 5 Concentration provided (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic add 4-methyi ester, which was used in the subsequent step withoutpurification. (f) To a stirred solution of (2R,4R)-1-{4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic add 4-methyi ester (4.4 g, 12.3 mmol), O-benzylhydroxyiamine 10 hydrochloride (2.15 g, 13.5 mmol), and triethyiamine (5.15 mL, 36.9 mmol) was addedbenzotriazol-1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (6.0 g, 12.3mmol) at ambient temperature. The resulting mixture was stirred for 24 hours. Themixture was diluted with ethyl acetate and washed with 1 M aqueous hydrogenchloride, aqueous sodium bicarbonate, and brine. The organic mixture was dried over 15 magnesium sulfate, filtered, and the filtrate was concentrated. The crude residue waspurified by silica gel chromatography (elution with 5% methanol in methylene chloride)to provide (2R,4R)-2-benzyloxycarbamoyf-1-(4-methoxy-benzenesulfonyl)-piperidine- 4-carboxylic acid methyl ester as a colorless solid. (g) To a stirred cold (0 °C) solution of (2R,4R)-2-benzyloxycarbamoyl-1 -(4-methoxy-

20 benzenesulfonyl}-piperidine-4-carboxyiic add 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). Themixture was stirred for 2 hours before Amberiite IR-120 resin (96 g) was added. After15 minutes, the mixture was filtered and the filtrate was concentrated to give (2R,4R)-2-benzyloxycarbamoyi-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicadd,which 25 was used in the subsequent reaction without purification. (h) To a stirred solution of (2R,4R)-2-benzyioxycarbamoyi-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxyiic add (500 mg, 1.11 mmol), tert-butyioxycarbonyl piperazine (226 mg, 1.21 mmol), and triethyiamine (0.47 mL, 3.33mmol) was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium 30 hexafluorophosphate (535 mg, 1.21 mmol) at ambient temperature. The resultingmixture was stirred for 24 hours. The mixture was diluted with ethyl acetate andwashed with 1 M aqueous hydrogen chloride, aqueous sodium bicarbonate, and brine. AP/F/ 9 8/01179 AP 00958 -38-

The organic mixture was dried over magnesium sulfate, filtered, and the filtrate wasconcentrated. The crude residue was purified by silica gel chromatography (elutionwith 2% methanol in methylene chloride) to provide (2R,4R)-4-[2-benzyloxycarbamoyl-1 -(4-methoxy-benzenesuifonyi)-piperidine-4-carbonyl]-piperazine-1-carboxylic add tert-butyl ester as a colorless solid. (i) A mixture of (2R,4R)-4-[2-benzyloxycarbamoyl-1-(4-methoxy-benzene- sulfonyl)-piperidine-4-carbonyl]-piperazine-1 -carboxylic add tert-butyl ester (500 mg, 0.81 mmol)and 5% palladium on barium sulfate (250 mg) in 10 mL of methanol was shaken undera 40 psi atmosphere of hydrogen gas for 1.5 hours, nitration through nylon andconcentration of the filtrate provided (2R,4R)-4-[2-hydroxycarbamoyl-1-(4-methoxy-benzenesuifonyl)-piperidine-4-carbonyl]-piperazine-1-carboxylic add tert-butyl ester asa 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,4R)-4-[2-hydroxy carbamoyl-1 -{4-methoxy-benzenesulfbnyl)-piperidine-4-carbonyl]-piperazvie-1 -carboxylic add tert-butyl ester (420 mg, 0.8 mmol) for 10 minutes. After an additional20 minutes the mixture was concentrated to provide (2R, 4R)-1-(4-methoxy-benzenesulfonyl)-4-(piperazine-1-carbonyt)-piperidine-2-carboxylic add hydroxyamidehydrochloride as a colorless solid: Mass spectrum (atmospheric pressure chemicalionization: basic mode) m/z (M+H) 427,366; Ή NMR (dimethyl sulfoxide-d,, 400 MHz,ppm) δ 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), 3.80-3.20 (m,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 = 12.6Hz), 1.32 (m, 1 H) 1.14 (m 1H). AP/PZ 9 8/01179

Example 2 (2R.4R)-1-f3-(4-Fluorophenoxy}-propane-1-gulfonvH-2-hvdroxvcarbamovl- piperidine-4-carboxylic acid methyl eater (a) To astirred solution of (2R,4R)-piperidine-2,4-dicarboxylic add 2-tert-butyl ester 4-methyl ester (920 mg, 3.78 mmol) and triethylamine (1.58ml, 11.3 mmol) in 10mL of methylene chloride was added a solution of 3-(4-fiuorophenoxy)-propane-1-sulfonyl chloride (1.05 g, 4.16 mmol) in 2 mL of methylene chloride under a nitrogenatmosphere. The mixture was stirred for 16 hours at ambient temperature (22 °C), then AP 00958 -39- diluted with 20 mL of 1 N hydrochloric acid and 20 mL of methylene chloride. Theorganic 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 purifiedby flash chromatography (3:2 hexanes/ethyl acetate elution) to give 1.15 g (2R,4R)-1 -(3- 5 (4-fluoro-phenoxy)-propane-1 -sutfonyi]-piperidine-2,4-dicarboxylic acid 2-tert-butvl 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-2,4-dicarboxyiic add 2-tert-butvl ester 4-methyl ester (1.15 g, 2.5mmol) in 10 mL of methylene chloride was added 10 mL of trifluroacetic add. The 10 mixture was allowed warm to ambient temperature (22 °C) over 16 hours. The mixturewas concentrated in vacuo to give 970 mg of crude (2R,4R)-1-(3-(4-fluorophenoxy)-propane-1-sulfonyi]-piperidine-2,4-dicarboxylic add 4-methyl ester as a orange solid. (c) To a stirred solution of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1-suifonyf]-piperidine-2,4-dicarboxylic add 4-methyl ester (970 mg, 2.4 mmol) in 5 mL of methylene 15 chloride was added triethylamine (1.0 ml_ 7.2 mmol) and O-benzyihydroxyiaminehydrochloride (410 mg, 2.64 mmol) at ambient temperature (22 °C). To the resultingsolution was added benzotriazol-1-yloxy-tris(dimethyiamino)phosphoniumhexafluorophosphate (1.17 g, 2.64 mmol) and the mixture was stirred for 16 hoursunder a nitrogen atmosphere. The mixture was diluted with 25 mL of 1 N hydrochloric 20 acid and 25 mL of ethyl acetate. The organic layer was removed and the aqueous layerwas extracted with ethyl acetate (2 x). The combined organic layers were washed withsaturated 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 theviscous yellow residue by flash chromatography (eluting with 1:1 ethyl acetate/hexanes) 25 gave 810 mg of (2R,4R)-2-benzy1oxycarbamoy1-1-[3-(4-fiuorophenoxy)-propane-1-sulfonyl]-piperidine-4-carboxylic acid methyl ester as a clear oil. (d) A mixture of (2R,4R)-2-benzy1oxycarbamoyl-1-[3-(4-fiuorophenoxy)-propane-1-sulfonyl]-piperidine-4-carboxyiic add methyl ester (800 mg, 1.57 mmol) and 200 mg of5% palladium on barium sulfate in 15 mL of methanol was shaken in a Parr apparatus 30 under a 40 psi hydrogen gas atmosphere for 2 hours. The catalyst was removed bypassage of the mixture through a 0.45 μτη nylon filter and the filtrate was concentratedto give 650 mg of (2R,4R)-1-(3-(4-fluorophenoxy)-propane-1-sulfonyl]-2- AP/P/ 9 8/01 179 AP 00958 -40- hydroxycarbamoyl-piperidine-4-carboxylic add methyl ester as a white foam: MS(atmospheric pressure chemical ionization) addic mode, 417 (M-1);_’H NMR (400 MHz,CDCI3) 6 6.94-6.97 (m, 2 H), 6.80-6.83 (m, 2 H), 4.66 (s, 1 H), 4.03 (t, 2 H, J = 5.3 Hz),3.83 (d, 1 H, J = 12.9 Hz), 3.68 (s„ 3 H), 3.15-3.28 (m, 3 H), 2.76 (t, 1 H, J = 11.5 Hz), 5 2.54 (d, 1 H, J = 13.5 Hz), 2.26 (d, 2 H , J = 5.9 Hz), 2.02 (m, 1 Η» J = 13.0 Hz), 1.73-1.78 (m, 1 H), 1.56-1.62 (m, 1 H).

Example 3 (2R.4R)-1-r3-(4-Fluorophenoxv)-propane-1-8ulfonvH-2-hvdroxvcarbamovl- piperidine-4-cart>oxvHc acid 10 To a stirred, cold (0 °C) solution of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1- sulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic add methyl ester (400 mg, 0.96mmol) in 5 mL of a methanol/water mixture (10:1) was added lithium hydroxidemonohydrate (120 mg, 2.88 mmol). After 3 hours at 0 °C, prerinsed (methanol)Amberirte resin (4.1g) was added. The mixture was filtered and the filtrate was 15 concentrated to give 370 mg of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1-suifonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic add as a white foam: MS (atmosphericpressure chemical ionization) addic mode, 403 (M-1).

Example 4 (2R.4R)-1-f4-(4-Fiuorobenzvloxv1-benzenoulfonvri-2-hvdroxvcarbamovl- 20 plperidlne-4-carboxvHc acid methyl ester 4-(4-Fluoro-benzyloxy)-benzenesulfonyl chloride. MS: 465 (M-1).

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

Example 5 25 (2R,4R)-1-f4-(4-Ruorobenzyloxv)-benzenesulfonvn-2-hvdroxvcarbamovl- piperidine-4-carboxvllc acid. MS: 451 (M-1).

The titled compound of example 5 was prepared by a method analogous tothat described in example 3 starting with 1-[4-{4-Fluoro-benzyloxy)-benzenesutfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic add methyl ester. AP/P/ 9 8/01 179 AP 00958 -41-

Example 6 2R.3S~f1-f444-Fluorobenzyloxv>benzeneeulfonvn-2-hvdrbxvcarbamoYl- piperidin-e-vlT-carbamlc acid Isopropyl ««ter (a) To a stirred, cold (0 °C) solution of the known (Agami, C.; Hamon, L; 5 Kadouri-Puchot, C.; Le Guen, V J. Orq, Chem. 1996, 61, 5736-5742) [4S-4o,9o,9ao]-1-oxo-4-phenyi-octahydro-pyrido[2,1-c][1,4]oxazine-9-carboxyiic add methyl ester(8.28 g, 2.86 mmol) in 100 mL of tetrahydrofuran was added 2.39 mL ofconcentrated hydrochloric add. After 5 minutes the mixture was concentrated todryness. The resulting solid was suspended in ethyl acetate and the mixture was 10 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 add andheated at reflux for 6 hours. The mixture was cooled to 0 °C and neutralized with 3N sodium hydroxide and concentrated in vacuo. The resulting solids were 15 suspended in chloroform and passed through a 45 /jm nylon filter. The filtrate wasconcentrated to a yellow oil which was purified by flash chromatography (elutingwith 2:1 hexanes/ethyl acetate with 1% acetic add) to give 802 mg of [4S-4o,9o,9aa]1-oxo-4-phenyl-octahydro-pyrido[2,1-c][1,4]oxazine-9-carboxylic add aswhite solid. 20 (b) Toastirredsolutionof[4S-4cr,9o,9ao]1-oxo-4-phenyl-octahydro- pyrido[2,1-c][1,4]oxazine-9-carboxyiic add (568 mg, 2.06 mmol) in 15 mL ofbenzene was added triethyiamine (0.28 mL, 2.06 mmol) and diphenyiphosphoryiazide (0.44 ml_ 2.06 mmol) at 22 °C under a nitrogen atmosphere. The mixture wasstirred at 22 °C for 45 minutes and at reflux for 50 minutes before 2-propanol (3.2 25 mL, 41.2 mmol) was added. After an additional 20 hours at reflux the mixture wascooled to 22 °C and concentrated in vacuo. The residue was taken up in ethylacetate and the resulting solution was washed with 5% citric add, water, saturatedaqueous sodium bicarbonate, and brine. The organic layer was dried (sodiumsulfate), filtered, and the filtrate was concentrated in vacuo. The yellow residue was 30 purified by flash chromatrography (eluting with 3:1 hexanes/ethyl acetate) to give402 mg of [4S-4CT,9c,9az7](1-oxo-4-phenyf-octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)-carbamic acid isopropyl ester as white solid. AP/PZ 9 8/01179 j.-, «"'ί

Air* -42- (c) A mixture of [4S-4o,9a,9ao](1-oxo-4-phenyl-octahydro-pyrido[2,1- c] [1,4]oxazin-9-yl)-carbamic add isopropyl ester (900 mg , 2.71 mmol) and 20%palladium hydroxide on carbon (920 mg) in 77 mL of ethanol/water (10:1) wasshaken 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 filterand the filtrate was concentrated to give 610 mg of 2R.3S-3- isopropoxycarbonylamino-piperidine-2-carboxylic add as white solid. MS: 229 (M-1). (d) To a stirred solution of 2R,3S-3-isopropoxycarbonylamino-piperidine-2-carboxyiic add (320 mg, 1.39 mmol) in 5 mL of methylene chloride was addedtriethylamine (0.58 mL, 4.17 mmol) followed by 4-(4-fluorobenzyloxy)-benzenesulfonyi chloride (460 mg, 1.53 mmol). After 16 hours at 22 °C the mixturewas partioned between 1 N hydrochloric add and ethyl acetate. The organic layerwas removed and washed with brine and dried over sodium sulfate. Filtration andconcentration of the filtrate gave 480 mg of crude 2R,3S-1-[4-(4-fluorobenzyloxy)-benzenesulfonyl]-3-isopropoxycarbonylamino-piperidine-2-carboxyiic add as a lightyellow solid. (e) To a stirred, cold (0 °C) solution of crude 2R.3S-1-(4-(4-fluorobenzyloxy)-benzenesulfonyl]-3-isopropoxycarbonylamino-piperidine-2-carboxyiic add (380 mg, 0.77 mmol) in 5 mL of methylene chloride was addedtriethylamine (0.32 mL, 2.31 mmol) followed by benzotriazol-1-yloxy-tris(dimethyiamino)phosphonium hexafluorophosphate (510 mg, 1.15 mmol). Theresulting solution was stirred for 2 minutes at 0 °C under a nitrogen atmospherebefore O-(trimethylsilylethyl)hydroxylamine hydrochloride (195 mg, 1.15 mmol) wasadded. The mixture was allowed to warm slowly to 22 °C over 14 hours. Themixture was concentrated in vacuo and the residue was diluted with water andextracted with ethyl acetate/diethyl ether (1:1; 3 x). The combined organic extractswere 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 wasconcentrated 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-ethoxycarbamoyl)-piperidin-3-yl]-carbamic add isopropyl ester as a white foam. MS: 610 (M+1). AP/P/ 9 8/01 179 AP 00958 -43-

(f) To a stirred, cold (0 °C) solution of 2R,3S-[1-[4-(4-fluorobenzyioxy)-benzenesutfonyl]-2-(2-trimethyisilanyl-ethoxycarbamoyl)-piperidin-3-yl]-carbamic acidisopropyl ester (265 mg, 0.44 mmol) in 4 mL of methylene chloride was added 3 mLof trifiuoroacetic add. The resulting colorless solution was allowed to warm to 23 °C 5 over 2 hours and was stirred for an additional 28 hours. The mixture wasconcentrated in vacuo to a solid/foam, which was suspended in ethyl acetatehexanes (1:6) and stirred for 10 hours. The white solids were collected by filtration,rinsed with hexanes, and purified further by flash chromatography (eluting with 7:3ethyl acetate/hexanes with 1% acetic add) to give 130 mg of 2R,3S-1-[4-{4- 10 fluorobenzyioxy)benzenesulfonyl]-2-hydroxycarbamoyl-piperidin-3-yl}-carbamic addisopropyl ester as a white solid/foam. MS: 510 (M+1).

Example 7 3-(S)-4-f4'-Ruoroblphenvf-4-eulfonvl)-2^-dimethvl-thlomorphoHne-3- carboxvlic acid hydroxvamide 15 (a) To a stirred solution of the known (PCT Publication WO 97/20824) 3- (S)-dimethyithex)dsilyi-2,2-dimethyi-tetrahydro-2H*1,4-thiazine-3-carboxyiaie (1.17 g,3.70 mmol) in 6 mL of methylene chloride was added triethylamine (1.02 ml_ 7.40mmol) followed by 4'-fluorobiphenylsulfonyl chloride (1.0 g, 3.70 mmol). Theresulting solution was stirred for 56 hours at 23 °C. The reaction mixture was diluted 20 with methylene chloride and washed with water. The organic layer was concentratedin vacuo; the residue was dissolved in methanol, and the mixture was heated atreflux for 6 hours. The mixture was cooled to 23 °C and concentrated in vacuo. Theresidue was purified by flash chromatography (eluting with 3:7 ethyl acetate/hexaneswith 0.1% acetic acid) to give 670 mg of 3-(S)-4-{4,-fluorobipheny{-4-sulfonyl}-2,2- 25 dimethyl-thiomorpholine-3-carboxylic add as a white foam/solid. MS: 427 (M+NH4). (b) To a stirred, cold (0 °C) solution of 3-(S)-4-(4'-fluorobiphenyl-4-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic add (605 mg, 1.48 mmol) in 5 mLof methylene chloride was added triethylamine (0.62 mL, 4.43 mmol) under anitrogen atmosphere. BenzotriazoH-yloxy-tris(dimethylamino)phosphonium 30 hexafluorophosphate (980 mg, 2.22 mmol) was added and the resulting solutionwas stirred for 5 minutes before O-{trimethyisilylethyl)hydroxylamine hydrochloride(376 mg, 2.22 mmol) was added. The ice bath was removed and the mixture was AP/P/ 9 8/01 179 AP 0 0 9 5 8 -44- stirred for 20 hours at 23 °C. The mixture was diluted with aqueous ammoniumchloride and extracted with 1:1 ethyl acetate/diethyl ether (3 x). The_combinedorganic 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 5 the filtrate was concentrated in vacuo. The residual yellow oil was purified by flashchromatography (eiuting with 3:7 ethyl acetate/hexanes) to give 650 mg of 3-(S}-4-(4'-fluorobiphenyl-4-sulfonyi)-2,2-dimethyl-thiomorpholine-3-carboxy1ic add (2-trimethylsilany1-ethoxy}-amide as a white foam. MS: 523 (M-1). (c) A solution of 3-(S)-4-(4-fluorobiphenyl-4-sulfonyl)-2,2<limethyl- 10 thiomorpholine-3-carboxyiic add (2-trimethylsilanyl-ethoxy)-amide (650 mg, 1.24mmol) in 8 ml_ of trifluoroacetic add was stirred for at 22 °C for 16 hours. Themixture was concentrated in vacuo and the residue was triturated with methylenechloride 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 15 hours. The solids were collected by filtration (1:1 diethyl ether/hexanes rinsing) anddried to give 470 mg of 3-(S)-4-(4,-fluorobiphenyl-4-sutfonyl)-2,2'dimethyl-thiomorpholine-3-carboxylic add hydroxyamide as white solid. MS: 423 (M-1).

Example 8 3-(S>-4-f4-(4-F1uorobenzvloxv)banzena8Ulfonvl1-2.2-dlmethvl- 20 thlomorphoHne-3 -carboxylic acid hvdroxvamide (a) To a stirred, cold (0 °C) solution of the known (Belgian PatentPublication BE 893025) 2,2-dimethy1-thiomorpholine-3-carboxylic add (600 mg, 3.42mmol) in 10 mL of 1:1 water/dioxane was added 6 N sodium hydroxide (1.2 mL, 7.1mmol). To the resulting solution 4-{4-fiuorobenzyloxy)benzenesulfonyl chloride (1.08 25 g, 3.77 mmol) was added. After 30 and 60 minutes an additional 1 gram of 4-(4-fluorobenzyloxy)benzenesuifonyi chloride and 1.2 mL of 6 N sodium hydroxide wasadded. The mixture (pH ca. 12) was diluted with water and extracted with diethylether (1 x). The ethereal layer was washed with 1 N sodium hydroxide; thecombined basic aqueous layers were acidified to pH 3 using concentrated 30 hydrochloric add, and the acidic mixture was extracted with ethyl acetate (3 x). Thecombined organic extracts were dried (sodium suifate), filtered, and the filtrate wasconcentrated in vacuo to give 820 mg of 3-{S}-4-[4-{4- AP/P/ 9 8/01 179 AP 00958 -45- fluorobenzyloxy)benzenesulfonyl]-2,2-dimettiyl-thiomorpholine-3-carboxylic add as awhite solid. MS: 438 (M-1). (b) To a stirred, cold (0 °C) solution of 3-{S)-4-{4-(4-fluorobenzyloxy)-benzenesulfonyl]-2,2-dimethyi-thiomorphoiin6-3-carboxyiic add (820 mg, 1.87 mmol) 5 in 5 mL of methylene chloride was added triethylamine (0.52 mL 3.74 mmol) undera nitrogen atmosphere. Benzotriazol-1-yioxy-tris(dimethylamino)phosphoniumhexafluorophosphate (1.24 g, 2.81 mmol) was added and the resulting solution wasstirred for 5 minutes before O-{tert-butykJlmethyisilyl)hydroxylamine (550 mg, 3.74mmol) was added.The ice bath was removed and the mixture was stirred for 16 10 hours at 23 °C. The mixture was diluted with aqueous ammonium chloride andextracted with ethyl acetate (3 x). The combined organic extracts were washed withwater, brine, and dried over sodium sulfate. Filtration and concentration of the filtrategave a viscous yellow oil, which was purified by flash chromatography (eluting with1:3 ethyl acetate/hexanes) to give 270 mg of 3-(S)-4-[4-(4- 15 fluorobenzyloxy)benzenesulfonyi]-2,2-dimethyl-thiomorpholine-3-carboxylic add (tert-butyldimethyisiloxy)-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-carboxyiic add (tert-butyldimethylsiloxy)*amide (270 mg, 0.47 mmol) in 10 mL of tetrahydrofuran was 20 added two drops of concentrated hydrochloric add. After 30 minutes the mixturewas diluted with 15 mL of tetrahydrofuran and the mixture was concentrated invacuo to a volume of ca. 5 mL The volume was adjusted to ca. 25 mL withtetrahyrofuran and the mixture was concentrated again to ca. 5 mL This processwas repeated twice more before the mixture was finally concentrated to dryness. 25 The resulting solids were suspended in a mixture of hexanes and diethyl ether andthe mixture was stirred for 16 hours. The solid were collected by filtration, rinsed withdiethyl ether,and dried to give 180 mg of 3-(S)-4-[4-{4- fluorobenzyioxy)benzenesuffonyl]-2,2-dimethyl4hiomorpholine-3 -carboxylic addhydroxyamide as a white solid. MS: 453 (M-1). Ή NMR (400 MHz, dmso-df) δ 10.63 30 (s, 1 H), 8.80 (bs, 1 H) 7.59-7.61 (m, 2 H), 7.46-7.50 (m, 2 H), 7.17-7.21 (m, 2 H), 7.09-7.12 (m, 2 H), 5.12 (s, 2 H), 3.99 (s, 1 H), 3.87-3.93 (m, 1 H), 3.69 (d, 1 H, 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). AP/P/ 9 8/01 179 AP 00958 -46-

Preparatlon 1 4-(4-ffuorobenzvloxy)benzeneaulfonYl chloride

To a stirred solution of 4-bydroxybenzenesulfonic acid sodium salt dihydrate(5.13 g, 22.1 mmol) in 23 mL of 1 N sodium hydroxide was added a solution of 4- 5 fluorobenzyl bromide (3.3 mL, 26.5 mmol) in 20 mL of ethanol. The mixture washeated at reflux for two days, then cooled to ambient temperature (22 °C),whereupon a white precipitate formed. The flaky white solids were collected byfiltration, 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- 10 benzyioxy)-benzenesulfonic acid sodium salt (13.0 g, 42.7 mmol) in 50 mL of thionylchloride and two drops of dimethytformamide was heated at a gentle reflux for 8hours. The mixture was concentrated to a yellow solid which was suspended in ethylacetate and filtered. The filtrate was concentrated to 11.2 g of 4-(4-fluorobenzyioxy)benzenesulfonyl chloride as a light yellow solid: 1H NMR (400 MHz, 15 CDCI3) δ 7.95-7.98 (m, 2 H), 7.38-7.41 (m, 2 H), 7.08-7.12 (m, 4 H), 5.12 (s, 2 H).

Preparation 2 3-(4-Fluorophenoxv)-propane-1 -sulfonyl chloride

To a stirred solution of 4-fluorophenol (5.0 g, 44.6 mmol) in 50 mL of toluenewas added sodium hydride (60% dispersion in mineral oil, 1.78 g, 44.6 mmol) at 20 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 16hours. The reaction was quenched by the addition of methanol and the mixture wasconcentrated in vacuo to an off-white solid. This solid was suspended in ethylacetate, filtered, and the solids were collected and dried to give 10.9 g of 3-(4- 25 fluorophenoxy)-propane-1 -sulfonic add sodium salt as an off-white powder. A stirredsolution of 3-(4-fluorophenoxy)-propane-1 -sulfonic add sodium salt (2.0 g, 7.8 mmol)in 10 mL of thionyl chloride and one drops of dimethytformamide was heated atreflux for 16 hours. The mixture was then cooled to 0 °C, diluted with 25 mL ofdiethyl ether, and the reaction was quenched by the slow addition of water. The 30 organic layer was removed and the aqueous layer was extracted with 25 mL ofdiethyl ether. The combined organic layers were washed with brine and dried over

6 L I 10/86 /d/dV AP 00958 -47- 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) δ 6.96-7.00(m, 2 H), 6.80-6.84 (m, 2 H), 4.10 (t,2H, J = 5.5 Hz), 3.91 (t, 2 H, J = 7.5 Hz) 2.47- 2.54 (m, 2 H). 5 Preparation 3 4*-Ruoroblphenviaulfonvl chloride

Chlorosuffonic add (8.7 mL, 0.13 mole) was added dropwise to stirred cold(0 °C) 4-fiuorobiphenyl (10.2 g, 59 mmol). After 30 minutes at 0 °C the reactionmixture was poured onto ice. The resulting white predpitate was collected by 10 filtration and dissolved in chloroform. The chloroform solution was washed withwater, brine, dried over magnesium sulfate, and concentrated to afford a white solid.The desired 4'-fluorobiphenylsulfonyi chloride (4.3 g), was separated from 4-fluorobiphenylsulfonic add by crystallization of the latter from ethyl acetate andcrystallization of the remaining material from hexanes. AP/P/ 9 8/01 179 z-iTW—-

PATENT AGENT FOR THE APPLICANT

Claims (15)

  1. AP q80 9 5 8
    or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optionaldouble bond; X is carbon; Y is carbon; R1, R2, R3, R4, Rs, Rs, R7, R8 and R9 are selected from the group consisting of hydrogen,hydroxy, (C.,-C6)alkyl optionally substituted by one or two groups selected from (Q-C6)alkylthio, (C^C^alkoxy, trifluoromethyl, halo, (C^-C10)aryl, (C2-C9)heteroaryl, (C6-C10)arylamino, (C6-C10)arylthio, (C6-C10)aryloxy, (C2-C9)heteroarylamino, (Cz-C^heteroarylthio,(C2-C9)heteroaryloxy, (C6-C10)aryl(C6-C10)aryl, (C3-C6)cycloalkyl, hydroxy, piperazinyl, (Cb-CicOaryKC^C^alkoxy, (C2-C9)heteroaryl(C1-C6)aIkoxy, (C^C^acylamino, (C^CgJacylthio, (CrC6)acyloxy, (C^CJalkylsuifinyl, (C6-C10)arylsulfinyl, (CrC^alkylsulfonyl, (C6-C10)arylsulfonyl,amino, (C^CJalkylamino or ((C^-C^alkyl^mino; (C2-C6)alkenyl, (C6-C10)aryl(C2-C6)alkenyl,(C2-C9)heteroaryl(C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl(C2-C6)alkynyl, (C2-C9)heteroaryl(C2-CJalkynyl, (C^C^alkylamino, (CrC^alkylthio, (C1-C6)alkoxy, perfluoro^-C^alkyl, (C6-C10)aryl,(C2-C9)heteroaryl, (C6-C10)arylamino, (C6-C10)arylthio, (C6-C10)aryloxy, (C2-C9)heteroarylamino,(C2-C9)heteroarylthio, (QrC^heteroaryloxy, (C3-C6)cycloalkyl, (C^C^alkyKhydroxymethylene),piperidyl, (C1-C6)alkylpiperidyl, (C1-C6)acylamino, (C.,-C6)acylthio, (C^-C^acyloxy, R^C,-C6)alkyl or a group of the formula AP/PZ 9 8/01 179 USERS\DOCS\LA21952\LPGXB\33CGO11.DOC /144304 / PC9596A. la USOA on Merits ) 0 9 5 8 49
    <w>. II <ch2)„ wherein n is 0 to 6;y is 0 or 1; W is oxygen or >NR24; Z is -OR11, -NR24R11, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl or a bridgeddiazabicycioalkyl ring selected from the group consisting of
    m
    <CH2)r^N· V σ> rx o •x. oo u Cl <
    wherein r is 1,2 or 3;m is 1 or 2;p is 0 or 1; and USERS\DOCS\LA21952\LPGXB\33CGOH.DOC / 144304 / PC9596A.1S USOA on Merits Λ Ο Π 9 5 8 5 0 V is hydrogen, (CrCgJalkyl, (CrC^alkyl^O)-, (C^Cg) alkoxy(C=O)-, (C6-C10)aryl(C=O)-, (C6-Ci0)aryloxy(C=O)-, (Cg-Ci0)aryl(Ci-Cg)alkyl(C=O)-, (Cg-C-^aryl^CpC6)alkoxy(C=O)-, or (C1-C6)alkoxy(C=O)-O-; wherein each heterocyclic group may optionally be independently substituted by one ortwo groups selected from hydroxy, (C,-C6)alkyl, (C1-C6)alkoxy, (CpC^acyl, (C1-C10)acyloxy,(C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl,hydroxy^-C^alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)acyloxy(C1-C6)alkyl, (C1-C6)alkylthio, (CrCeialkylthioCCrC^alkyl, (C6-C10)arylthio, (C6-C10)arylthio(CrC6)alkyl, R12R13N-, R12R13NSO2-,R12R13N(C=O)-, R12R13N(C=O)-(C1-C6)alkyl, R14SO2-, R14SO2NH-, R15(C=O)-[N(R12)]-, R16O(C=O)-, or R16O(C=O)-(CrC6)alkyl; wherein R10 is (CrC6)acylpiperazinyl, (Cs-C10)arylpiperazinyl, (C2-C9)heteroarylpiperazinyl, (CrC6)alkylpiperazinyl, (C6-C10)aryl(C1-C6)alkylpiperazinyl, (C2-C9)heteroaryl(C1-C6)alkylpiperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidyl, (C,-Cs)alkylpiperidyl, (C6-C10)arylpiperidyl, (C2-C9)heteroarylpiperidyl, (CrC^alkylpiperidyKCcC6)alkyl, (C6-C10)arylpiperidyl(CrC6)alkyl, (C2-Ce)heteroaryl-piperidyl-(C1-C6)alkyl or (CrC6)acyipiperidyl; R11 is hydrogen, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C^heteroaryKC^C^alkyl, (C^^alkyKCg-C^aryl^-C^alkyl, (C1-C6)alkyl(C2-C9)heteroaryl(C1-C6)alkyl, 5-indanyl, -CHR17O-(C=O)-R18 or -CH^OJ-NR^R20; R12 and R13 are each independently hydrogen, (Q-^alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (Cg-C^aryliCrCJalkyl or (C2-C9)heteroaryl(C1-C6)alkyl or R12 and R13 may betaken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl or thiomorpholinyl ring; R14 is trifluoromethyl, (C,-C6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (Cg-C^ary^C,-C6)alkyl or (Cz-C^heteroaryKC^CgJalkyl; R15 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C6-C10)aryl, (C^-C^heteroaryl, (CrCg)aryl(Ci-Cg)alkyl(Cg-C-io)aryl(Ci-Cg)alkoxy or (C2-C9)heteroaryl(C.j-Cg)alkyl; R16 is (CrCgJalkyl, {C6-C10)aryl, (C2-C9)heteroaryl, (Cg-C10)aryl(C.,-C6)alkyl, 5-indanyl, -[CH(R17)]O-(C=O)-R18, -CH^O-NR^R20, or R21O(C1-C6)alkyl; R17 is hydrogen or (CrCgJalkyl; R1S is (CrC6)alkyl, (C1-C6)alkoxy or (C6-C10)aryl; R19 and R20 are each independently hydrogen or (Q-Cgjalkyl or may be taken togetherwith the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl or thiomopholinyl ring; 6 L I !· 0 / 8 6 Zd/dV USERS\DOCS\LA21952\LPGXB\33CGOH.DOC / 144304 / PC9396A. la USOA on Merits ftp Ο Ο 9 5 8 51 R21 is H2N(CHR22)(C=O)-; R22 is the side chain of a natural D- or L-amino acid; R23 is hydrogen, ((^-C^acyl, (CrCgJalkyl, (C6-C10)aryl(C1-C6)alkyl, (Cz-CgJheteroaryKC!-C6)alkyl or (C^CgJalkylsulfonyl; R24 wherever it occurs is independently hydrogen or (C,-C6)alkyl; or R1 and R2, or R3 and R4, or R5 and R6 may be taken together to form a carbonyl; or R1 and R2, or R3 and R4, or R5 and R6, or R7 and R8 may be taken together to form a (C3-C6)cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula Q is (C6-C10)aryl(C6-C10)aryl, (C6<: Jaryl^-CJalkoxyiCg-C^aryl or (C,-Cg)heteroaryl(C.,-C6)alkoxy(C6-C.,0)aryl optionally substituted by fluoro, chloro, (C,-CJalkyl, (C.,-C6)alkoxy or perfluoro^-C^alkyl; with the proviso that when R1, R2, R3, R4, R5, R®, R7, R®, and R® are ail defined byhydrogen or (C.,-C6)alkyl, the broken line represents a double bond; with the proviso that when R1, R2 and R9 are a substituent comprising a heteroatom, theheteroatom cannot be directly bonded to the 2- or 6- positions of the ring; with the proviso that when y is 1 and W is NF?4 or oxygen, Z cannot be hydroxy;with the proviso that when the broken line represents a double bond, Rf and R6 are not present; with the proviso that when R3 and R5 are independently a substituent comprising aheteroatom when the broken line represents a double bond, the heteroatom cannot be directlybonded to positions X and Y. -
  2. 2 , A compound of the formula AP/P/9 8/0 1 179 USERS\DOCS\LA21952\LPGXB\33CG01I.DOC 1144304 / PC9596A. 1st USOA on Merits AP 00958 .52
    or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optionaldouble bond; X is carbon; Y is carbon; R1, R2, R3, R4, R5, R6, R7, R8 and R9 are selected from the group consisting of hydrogen,hydroxy, (CrC6)alkyl optionally substituted by one or two groups selected from (Q-C6)alkylthio, (C^CJalkoxy, trifluoromethyl, halo, (Q-C10)aryl, (C2-C9)heteroaryl, (C6-C10)arylamino, (C6-C10)arylthio, (C6-C10)aryloxy, (C2-C9)heteroarylamino, (Cz-C^heteroarylthio,(C2-C9)heteroaryloxy, (C6-C10)aryl(C6-C10)aryl, (C3-C6)cycloalkyl, hydroxy, piperazinyl, (Ce-C10)aryl(Ci-C6)alkoxy, (C2-C9)heteroaryl(C1-C6)alkoxy, (C1-C6)acylamino, (C.,-C6)acylthio, (C,-C6)acyloxy, (C1-C6)alkylsulfinyl, (C6-C10)arylsulfinyl, (C.,-Ce)alky!sulfonyl, (C6-C10)arylsulfonyl,amino, (CrCeJalkylamino or ((C1-C6)alkyl)2amino; (Cj-C^alkenyl, (C6-G10)aryl(G2-C6)alkenyl,(C2-C9)heteroaryl(C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl(C2-C6)alkynyl, (C2-C9)heteroaryl(C2-C6)alkynyl, (C^C^alkyiamino, (C^CJalkylthio, (C.,-C6)alkoxy, perfluoro^-C^alkyl, (C6-C10)aryl,(C2-C9)heteroaryl, (C6-C10)arylamino, (C6-C10)arylthio, (C6-C10)aryloxy, (C2-C9)heteroarylamino,(C2-C9)heteroarylthio, (Cz-C^heteroaryloxy, (CrC^cycloalkyl, (C^C^alkyKhydroxymethylene),piperidyl, (C-,-C6)alkylpiperidyl, (C1-C6)acylamino, (C1-C6)acylthio, (C^CJacyloxy, R10(C.,-Cs)alkyl or a group of the formula AP/P/ 9 8/01 179 OSERS\DOCS\LA21952\LPGXB\3JCG01!.DOC / 1443« / PC9596A.1S USOA on Merils AP 00958 53
    <u>y 11 -a/Lu- 5 wherein n is 0 to 6;y is 0 or 1; W is oxygen or >NR24; Z is -OR11, -NR24R11, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyi, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyi or a bridgeddiazabicycloalkyl ring selected from the group consisting of
    (CH2)r^N' V
    GO σ> £ Ct < d e wherein r is 1, 2 or 3; m is 1 or 2; p is 0 or 1; and USEKS\DOCS\LA21932\LPGXB\33CG01i.DOC / 144304 / PC9596A.lst USOA on Merits AP 00958 54 V is hydrogen, (CrCsJalkyl, (C1-C6)alkyl(C=O)-, (C^Ce) alkoxy(C=O)-, (C6-Cio)aryl(C=0)-, (C6-C10)aryloxy(C=O)-, (Ce-Ci9)aryl(Ci-Cg)aIkyl(C:=O)-, (06-0^)3^1-(0^C6)alkoxy(C=O)-, or (C1-C6)alkoxy(C=O)-O-; wherein each heterocyclic group may optionally be independently substituted by one ortwo groups selected from hydroxy, (C,-C6)alkyl, (C.,-C6)alkoxy, (C^C^Jacyl, (CpC^acyloxy,(C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)aikyl, (C2-C9)heteroaryl(C1-C6)alkyl,hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)acyloxy(C1-C6)alkyl, (C^CeJalkylthio, (CrC6)alkylthio(C1-C6)alkyl, (C6-C10)arylthio, ((VC10)arylthio(CrC6)alkyl, R12R13N-, R12R13NSO2-,R12R13N(C=O)-, R12R13N(C=O)-(C1-C6)alkyl, R14SO2-, R14SO2NH-, R15(C=O)-[N(R12)]-, R16O(C=O)-, or R16O(C=O)-(C1-C6)alkyl; wherein R10 is (C1-C6)acylpiperazinyl, (C6-C10)arylpiperazinyl, (C2-C9)heteroarylpiperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)aryl(C1-C6)alkylpiperazinyI, (C2-C9)heteroaryl(C1-C6)alkylpiperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidyl, (0,-C5)alkylpiperidyl, (C6-C10)arylpiperidyl, (C2-C9)heteroarylpiperidyl, (C1-C6)alkylpiperidyl(C1-C6)alkyl, (Cs-C10)arylpiperidyl(Cl-C6)alkyl, (C2-C9)heteroaryl-piperidyl-(Ci-C6)alkyl or (CrC6)acylpiperidyl; R11 is hydrogen, (C6-C10)aryl, (C2-C9)heteroaryl, (Cs-C^JaryKCrC^alkyl, (C2-CgJheteroaryKCpCgJalkyl, (CrCgJalkyKCs-C^JaryKCrC^alkyl, (C1-C6)alkyl(C2-C9)heteroaryl(C1-C6)alkyl, 5-indanyl, -CHR17O-(C=O)-R18 or -CH^OJ-NR^R20; R12 and R13 are each independently hydrogen, (C,-C6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl or (Cg-CgJheteroaryKC^CgJalkyl or R12 and R13 may betaken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl or thiomorpholinyl ring; R14 is trifluoromethyl, (C,-C6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (Cg-C^aryKC.,-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl; R15 is hydrogen, (CrC6)alkyl, (C1-C6)alkoxy, (C6-C10)aryl, (C2-C9)heteroaryl, (0,-C6)aryl(C1-C6)alkyl(C6-O10)aryl(C1-C6)alkoxy or (C2-C9)heteroaryl(C1-C6)alkyl; R16 is (CrCgJalkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, 5-indanyl, -[CH(R17)]O-(C=O)-R18, -CH2(C=O)-NR19R20, or R2O(C1-C6)alkyl; R17 is hydrogen or (C^-C^alkyl; R18 is (C.,-C6)alkyl, (C^-C^alkoxy or (C6-C10)aryl; R19 and R20 are each independently hydrogen or (C1-C6)alkyl or may be taken togetherwith the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl or thiomopholinyl ring; AP/P/ 9 8/01 179 USERS\DOCS\LA21952\LPGXB\33CGOH.DOC Z 144304 / PC9596A. 1st USOA on Merits AP 00958 55 R21 is H2N(CHR22)(C=O)-; R22 is the side chain of a natural D- or L-amino acid; R23 is hydrogen, (CrC^acyl, (C^C^alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl or (C,-C6)alkyisu;;or;y'; R24 wherever it occurs is independently hydrogen or (C,-C6)alkyl; or R1 and R2, or R3 and R4, or R5 and R6 may be taken together to form a carbonyl; or R1 and R2, or R3 and R4, or R5 and R6, or R7 and R8 may be taken together to form a (C3-C6)cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of theformula
    >23 Q is (Ce-C10)aryl(Ce-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(Ce-C10)aryl or (CrC9)heteroaryl(C1-Ce)alkoxy(C6-C10)aryl optionally substituted by fluoro, chloro, (C,-C6)alkyl, (C^C^alkoxy or perfluoro(C1-C3)aIkyl; with the proviso that when R1, R2, R3, R4, R5, R®, R7, R®, and R® are all defined byhydrogen or (C.,-C,)alkyl, the broken line represents a double bond; with the proviso that R7 is other than hydrogen only when R® is other than hydrogen;with the proviso that R6 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 R1 is other than hydrogen;with the proviso that when R1, R2 and R9 are a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 2- or 6- positions of the ring; with the proviso that when y is 1 and W is NR24 or oxygen, Z cannot be hydroxy;with the proviso that when the broken line represents a double bond.R4 and R6 are not present; with the proviso that when R3 and R5 are independently a substituent comprising aheteroatom when the broken line represents a double bond, the heteroatom cannot bedirectly bonded to positions X and Y.
  3. — 3. " A compound of the formula ΑΡ/Γ/9 8/0 1 179 USERS\DOCS\LA21952\LPGXB\33Qj01I.DOC / 144304 / PC9596A. 1st USOA on Merits AP 00958 5b
    or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optionaldouble bond; X is carbon; Y is carbon; R1, R2, R3, R4, R5, R6, R7, R8 and R9 are selected from the group consisting of hydrogen,hydroxy, (C,-C6)alkyl optionally substituted by one or two groups selected from (C,-C6)alkylthio, (C^CJalkoxy, trifluoromethyl, halo, (Q-C10)aryl, (C2-C9)heteroaryl, (C6-C10)arylamino, (C6-C10)arylthio, (C6-C10)aryloxy, (C2-C9)heteroarylamino, (Cz-Cgjheteroarylthio,(C2-C9)heteroaryloxy, (C6-C10)aryl(C6-C10)aryl, (C3-C6)cycloalkyl, hydroxy, piperazinyl, (Cg-Ci0)aryI(Ci-C6)alkoxy, (C2-C9)heteroaryl(C1-C6)alkoxy, (C-rC^acylamino, (CrCgJacylthio, (CrC6)acyloxy, (CrC6)alkylsulfinyl, (C6-C10)arylsulfinyl, (CrCJalkylsulfonyl, (C6-C10)arylsulfonyi,amino, (CVC^alkylamino or ((CrC^alkyl^mino; (C2-C6)alkenyl, (C6-C10)aryl(C2-C6)alkenyl,(C2-C9)heteroaryl(C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl(C2-C6)alkynyl, (C2-C9)heteroaryl(C2-C6)alkynyl, (C.,-C6)alkylamino, (C^CJalkylthio, (C1-C6)alkoxy, perfluoro(C1-C6)alkyl, (C6-C10)aryl,(C2-C9)heteroaryl, (C6-C10)arylamino, (C6-C10)arylthio, (C6-C10)aryloxy, (C2-C9)heteroarylamino,(C2-C9)heteroarylthio, (C2-C9)heteroaryloxy, (C3-C6)cycloalkyl, (C1-C6)alkyl(hydroxymethylene),piperidyl, (C^C^alkylpiperidyl, (C^CJacylamino, (CrCJacylthio, (C^-C^acyloxy, R10(CrC6)alkyl or a group of the formula AP/P/9 8/0 1 179 USERS\DOCS\LA21952\LPGXB\33CG01I.DOC / 144304 / PC9596A.1S USOA on Merits AP 00958 57 0. ϊ <w>y 11<(L>n wherein n is 0 to 6;y is 0 or 1; W is oxygen or >NR24; Z is -OR11, -NR24R11, azetidinyl, pyrroiidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl or a bridgeddiazabicycloalkyl ring selected from the group consisting of
    m
    (CH2)r V AP/P/ 9 8/01 179
    d e wherein r is 1,2 or 3; m is 1 or 2; p is 0 or 1; and USERS\1X)CS\LA21952\LPGXBO3CC»1!.DOC/ 144304 7PC9396A.1S USOA on Merits AP 00958 58 V is hydrogen, (CrC3)alkyl, (C^C^alkyKOO)-, (C^-Cg) alkoxy(C=O)-, (C6-Cio)aryl(C=0)-, (Cg-Ci0)aryloxy(C=O)-, (C6-C10)aryl(C1-C6)alkyl(C=O)-, (C6-Cio)aryl-(Ci-C6)alkoxy(C=0)-, or (C1-C6)alkoxy(C=O)-O-; wherein each heterocyclic group may optionally be independently substituted by one ortwo groups selected from hydroxy, (C,-C6)aikyl, (C1-C6)alkoxy, (C1-C10)acyl, (C1-C10)acyloxy,(C6-C10)aryl, (C2-C9)heteroaryl, (Ce-C^JaryliCrCgJalkyl, (C2-C9)heteroaryl(C1-C6)alkyl,hydroxy^-CJalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)acyloxy(C1-C6)alkyl, (C^C^alkylthio, (CrC6)alkylthio(CrC6)alkyl, (C6-C10)arylthio, (C6-C10)arylthio(C1-C6)alkyl, R12R13N-, R12R13NSO2-,R12R13N(C=O)-, R^N^OMCrCeJalkyl, R14SO2-, R14SO2NH-, R15(C=O)-[N(R12)]-,R16O(C=O)-, or R16O(C=O)-(C1-C6)alkyl; wherein R10 is (C1-C6)acyipiperazinyl, (C6-C10)arylpiperazinyl, (C2-C9)heteroarylpiperazinyl, (C^-C^alkylpiperazinyl, (C6-C10)aryl(C1-C6)alkylpiperazinyl, (C2-C9)heteroaryl(C1-C6)alkylpiperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidyl, (C,-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C2-C9)heteroarylpiperidyl, (C1-C6)alkylpiperidyl(C1-C6)alkyl, (C6-C10)arylpiperidyl(C1-C6)alkyl, (Cs-CgJheteroaryl-piperidyKC^CgJalkyl or (C-,-C6)acylpiperidyl; R11 is hydrogen, (Ce-C10)aryl, (C2-C9)heteroaryl, (Cg-C^aryltCVCJalkyl, (C2-CgJheteroarykCi-CJalkyl, (C1-C6)alkyl(C6-C10)aryl(C1-C6)alkyl, (CrC^alkyKCz-CgJheteroaryKCrC6)alkyl, 5-indanyl, -CHR17O-(C=O)-R18 or-CH^C^-NR^R20; R12 and R13 are each independently hydrogen, (CrC6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C.,-C6)alkyl or (C2-C9)heteroaryl(C.,-C6)alkyl or R12 and R13 may betaken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl or thiomorpholinyl ring; R14 is trifluoromethyl, (C,-C6)alkyl. (C6-C10)aryl, (C2-C9)heteroafyl, (Cg-C^aryKCrC6)alkyl or (C2-C9)heteroaryl(C1-Cs)alkyl; R15 is hydrogen, (C^CgJalkyl, (C^C^aIkoxy, (C6-C10)aryl, (C2-C9)heteroaryl, (CrC6)aryl(C1-C6)alkyl(C6-C10)aryl(C1-C6)alkoxy or (C2-C9)heteroaryl(C1-C6)alkyl; R16 is (CpCeJalkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (Cg-C^JaryKC^CgJalkyl, 5-indanyl, -[CH(R17)]O-(C=O)-R18, -CH2(C=O)-NR19R20, or R21O(CrC6)alkyl; R17 is hydrogen or (C^^alkyl; R18 is (CrCeJalkyl, (C^CJalkoxy or (C6-C10)aryl; R19 and R20 are each independently hydrogen or (CpCgJalkyl or may be taken togetherwith the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl or thiomopholinyl ring; AP/P/ 9 8/01 179 USERS\DOCS\LA21932yj>GXB\33CG011.DOC/ 144304 /PC9596A. 1st USOA on Merits 0 0 9 5 8 59 R21 is H2N(CHR22)(C=O)-; R22 is the side chain of a natural D- or L-amino acid; R23 is hydrogen, (C^C^acyl, (CrC6)alkyl, (C6-C10)aryl(CrC6)alkyl, (C2-Cg)heteroaryl(C1-C6)alkyl or (C^-C^alkylsulfonyl; R24 wherever it occurs is independently hydrogen or (C,-C6)alkyl; or R1 and R2, or R3 and R4, or R5 and R6 may be taken together to form a carbonyl; or R1 and R2, or R3 and R4, or R5 and R6, or R7 and R8 may be taken together to form a (C3-C6)cycloalkyl, oxacyclohexyl, thiocyclohexyl, indariyl or tetralinyl ring or a group of theformula Ν'
    Q is (C6-C10)aryl(C1-Ce)alkoxy(Ce-C10)aryI optionally substituted by fluoro, chloro,(CrCgJalkyl, (C1-Ce)alkoxy or perfluoro(C1-C3)alkyI; with the proviso that when R1, R2, R3, R4, R5, Re, R7, R8, and R9 are all defined byhydrogen or (C^-CjJalkyl, the broken line represents a double bond; with the proviso that when R1, R2 and R9 are a substituent comprising a heteroatom, theheteroatom cannot be directly bonded to the 2- or 6- positions of the ring; with the proviso that when y is 1 and W is NF?4 or oxygen, Z cannot be hydroxy;with the proviso that when the broken line represents a double bond, R4 and R6 are not present; with the proviso that when R3 and R5 are independently a substituent comprising aheteroatom when the broken line represents a double bond, the heteroatom cannot be directlybonded to positions X and Y. - Please amend the following claims: 6 L I 10/86 /d/dV
  4. - 4. A compound according to claim and R9 are hydrogen. -
  5. 5 . A compound according to claim R7-R9 is other than hydrogen.
  6. - 6. '· - A compound according to claim R7-R9 is (CrC6)alkyl. - [1], wherein R2, R3, R6, R7 [1], wherein at least one of [1], wherein at least one of USERS\DOCS\LA21952\LPGXB\33CGOH.DOC /144304 / PC9396A.la USOA on Merits 60
  7. 7 · A compound according to claim [1], wherein at least one of R7-R9 is methyl.
  8. — 8 · A compound according to claim [1], wherein R7 and R8 are taken together to form a carbonyl and R is (C^C^alkyl.
  9. -9 . A compound according to claim [1], wherein R7 and R8 are each methyl.
  10. — 10 . A compound according to claim [1], wherein R7 and R8 are taken together to form a (Q-C6)cycloalkyl group.
  11. - 11. A compound according to claim f wherein R7 and R8 are taken together to form a (C3-C8)cycloalkyl group.
  12. 12. . A compound according to claim [1], wherein said compound is selected from the group consisting of: (2R,4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid; (2R, 4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxy carbamoyl-pipe ridine-4-carboxylic acid methyl ester; (2R,4R)-1-[3-(4-Fluorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid; (2R,4R)-1-[3-(4-Fluorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester; (2/?,3S)-{1 -[4-(4-Fluorobenzyloxy)-benzenesulfonyi]-2-hydroxycarbamoyl-piperidin-3-yi}-carbamic acid isopropyl ester; [3-(S)“4-(4'-Fluorobiphenyl>4-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide; 3-(S)-4-[4-(4-Fluorobenzyloxy)benzenesulfonyl]-2,2-dimethyl-thiomorpholine-3 -carboxylic acid hydroxyamide;] (2/?,4S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-hydroxy-piperidine-2-carboxylicacid hydroxyamide; and (2R,4R)-1-(4-Methoxybenzenesulfonyl)-4-(piperazine-1-carbonyl)-piperidine-2-carboxylic acid hydroxyamide hydrochloride. -
  13. 13. A pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration,restenosis, periodontal disease, epidermolysis bullosa, scleritis, in combination with standardNSAID’s and analgesics and in combination with cytotoxic anticancer agents, and otherdiseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock andother diseases involving the production of tumor necrosis factor (TNF) or (b) the inhibition of AP/P/ 9 8/01 179 USERS\DOCS\LA21952UPGXB\33CGOU.DOC 1144304 APC9396A. 1st USOA on Merits AP 00958 61 matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a mammal,including a human, comprising an amount of a compound of claim [1] effective in suchtreatment and a pharmaceutically acceptable carrier.
  14. — 14 · ' . ·.' A method for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including a human, comprisingadministering to said mammal an effective amount of a compound of claim [1].
  15. -15. ·. ·· A method for treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontaldisease, epidermolysis bullosa, scleritis, compounds of formula I may be used in combinationwith standard NSAID’s and analgesics and in combination with cytotoxic anticancer agents,and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septicshock 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 ofclaim ; 2- effective in treating such a condition. - AP/P/9 8/0 1 1 79
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