AP958A - Arylsulfonyl hydroxamic acid derivatives. - Google Patents

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, periodontal disease, epidermolysis bullosa, sderitis, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (NSAID'S) and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.

Description

ARYLSULFONYL HYDROXAMIC ACID DERIVATIVES

Background of the Invention

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

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

There are a number of enzymes which effect the breakdown of structural proteins and which are structurally related metalloproteases. Matrix-degrading metalloproteinases, such as gelatinase, stromelysin and coilagenase, are involved in tissue matrix degradation (e.g. collagen collapse) and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease (e.g. Pagefs disease and osteoporosis), tumor 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 autoimmune diseases (W. Fiers, FEBS Letters, 1991, 285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C.E. Spooner et al., Clinical Immunology and Immunopathology, 1992,

62S11).

L I 10/86 /d/dV

-2Summary of the Invention

The present invention relates to a compound ot the formula

R⁵ R⁶

R

OH

Ή

S0₂

Q or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond;

X is carbon, oxygen or sulfur;

Y is carbon, oxygen, sulfur, SO, SO₂ or nitrogen;

R\ R² R³, R* R⁵, R®, R⁷, R® and R® are selected from the group consisting of hydrogen, (C,-Ce)alkyl optionally substituted by one or two groups selected from (0,Ce)alkylthio, (C,-Ce)alkoxy, trifiuoromethyl, halo, (Ce-C10)aryl, (C5-C9)heteroaryl, (Ce20 C10)arylamino, (CB-C10)arylthio, (Ce-C10)aryloxy, (C5-C9)heteroarylamino, (C5Cg)heteroarytthio, (C5-C9)heteroaryloxy, (Ce-C10)aryl(Ce-C10)aryl, (C3-Ce)cydoalkyl, hydroxy, piperazinyl, (C9-C10)aryl(C1-Ce)alkoxy, (Cg-CjJheteroaryliCTCgJalkoxy, (0,Ce)acylamino, (C^CgJacytthio, (C1-Ce)acyioxy, (C,-Ce)alkylsulfinyl, (Ce-C10)arylsulfinyl, (C^Cgjalkyisulfonyl, (Ce-C10)arylsulfonyl, amino, (C,-Ce)alkyiamino or ((0,25 Ce)alkylamino)2; (C2-Cfl)alkenyl, (Ce-C10)aryl(C2-Ce)alkenyi, (C5-C9)heteroaryl(C2Ce)alkenyl, (C2-Ce)alkynyl, (Ce-C,0)aryi(C2-Ce)alkynyi, (C5-C9)heteroaryi(C2-Ce)alkynyl, (C,-C6)alkylamino,(C,-Ce)alkytthio,(C,-Ce)alkoxy,perfluoro(C,-Ce)alkyl,(Ce-C,0)aryl,(CsC9) heteroaryl, (Ce-C10)arylamino, (Ce-C,o)arylthio, (Ce-C10)aryloxy, (C5C9)heteroarytamino, (Cs-C9)heteroarytthio, (C5-C8)heteroaryloxy, (C3-Ce)cycloalkyl, (0,30 Ce)alkyl(hydroxymethylene), piperidyl, (C,-Ce)alkylpiperidyl, (C,-CB)acylamino, (0,C„)acylthio, (Ο,-Ο^βογΙοχγ, R’⁰(C,-Ce)alkyl wherein R¹⁰ is (C,-C_e)acylpiperazino, (C_eC₁₀)arylpiperazino, (C_s-C₉)heteroaryipiperazino, (C,-C_e)alkylpiperazino, (C_e-C,₀)aryi(C,C_e)alkylpiperazino,(C₅-C₉)hetefoaryi(C,-C_e)alkylpiperazino,morpholino,lhiomorpholino,

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-3pyrrolidino, piperidyl, (C,-C_e)alkylpiperidyl, (C_e-C₁₀)arylpiperidyl, (C₅C₉)heteroarylpiperidyUC₁-C_e)alkylpiperidyi(C_rC_e)alkyiXC_e-C,₀)arylpiperidyl(C,-C_e)alkyl, (Cj-CgJheteroarylpiperidykC^CeJalkyl or (C^-CeJacylpiperidyi;

or a group of the fonnula (U),

II (CH₂)_n

-<ΎΛΖ\_τwherein n is 0 to 6; yisOorl;

W is oxygen or NR²⁴ wherein R²⁴ is hydrogen or (C,-C_e)alkyl;

Z is OR” or NR²⁴R” wherein R²⁴ is as defined above and R” is as defined below; azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl or a bridged diazabicycloalkyl ring selected from the group consisting of

Η Η H

AP/P/ 9 8/01179

AP 00958

d e 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 groups 15 selected from hydroxy, (Ck-C^aJkyl, (C,-C_e)aJkoxy, (C^oJacyi, (C,-C₁₀)acyloxy, (C_eC₁₀)aryi, (C₅-C₉)heteroaryl, (Ce-C^aryl^-CeJalkyl, (C^-C^heteroaryliC^-CeJalkyt, hydroxy(C,-C_e)alkyl, (C^-C^alkoxy^-C,,) alkyl, (C^ejacyloxyiC^Jalkyl, (C,C_e)alkytthio, (C^C^alkytthiofC^^alkyl, (C_e-C₁₀)arylthlo, (C_e-C, Jarylthio^-CJalkyl, R¹²R¹³N, R¹²R’³NSO2, R¹²R^,3NCO, R¹²R¹³NCO(C1-C_e)alkyl wherein R¹² and R¹³ are each independently hydrogen, (C,-C_e)alkyi, (C_e-C₁₀)ary1, (C₅-C₉)heteroaryl, (C_e-C₁₀}aryl (C,C_e)alkyt or (C₅-C₉)heteroaryl (C^C^alkyi or R¹² and R¹³ may be taken together with the nitrogen to which they are attached to form an azetidinyi, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl ring; R’*SO2, R¹⁴S02NH wherein R¹⁴ is trifluoromethyl, (C,-C_e)alkyl, (C_e-C₁₀)aryl, (C₅-C₉)heteroaryl, (Ce-C^Jaryl^-CeJalkyl or (Cs-C^heteroaryl (C,-C_e)alkyt; R¹⁶CONR’² wherein R¹² is as defined above and R¹⁵ is hydrogen, (C,C„)alkyl, (C^-C^alkoxy, (Ce-C,0)aryl, (Cj-Cj)heteroaryl, (C,-Ce)aryl(C,-Ce)aIkyl(CeC10)aryl(C,-Ce)alkoxy or (C5-C9)heteroarylf^-C^alkyl; R’^eOOC, R’^eOOC(C1-C_e)alkyl wherein R¹⁶ is (C^-C^alky!, (Ce-C10)aryi, (C5-C9)heteroaryl, (Ce-Cw)aryi (C,-Ce)alkyl, 5indanyl, CHR¹⁷OCOR¹⁸ wherein R¹⁷ is hydrogen or (C,-Ce)aJkyl and R¹⁸ is (C,-C_e)aJkyl, (C^Cjjalkoxy or (C_e-C₁₀)aryi; CH₂CONR”R^2<’ wherein R¹’ and R²⁰ are each independently hydrogen or (C^-Cg) alkyl or may be taken together with the nitrogen to which they are attached to form an azetidinyi, pyrrolidinyl, piperidinyl, morpholinyl or

AP/P/ 9 8/01 179

AP 00958 •5thiomopholinyl ring; or R²¹O (C,CB)alkyl wherein R²’ is H2N(CHR²²)CO wherein R²² is the side chain of a natural D- or L-amino acid;

R” is hydrogen, (C_e-C,₀)aryl, (C₆-C₉)heteroaryi, (Ce-C^aryKC^CgJalkyt, (C₆C₉)heteroaryl(C,-C_e)alkyl, (C_l-C_B)alkyl(C_B-C_l0)aryl(C₁-C_B)alkyl, (C.-C^alkyKCgC₉)heteroaryi(C,-C_B)aJkyl, 5-indanyi, 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 a carbonyl;

or R’ and R², or R³ and R⁴, or R⁶ and R^e, or R⁷ and R⁸ may be taken together to form a (C₃-C_e)cycloalky1, oxacydohexyl, thiocydohexyi, indanyl or tetralinyl ring or a group of the formula

N‘ wherein R²³ is hydrogen, (C,-C₉)acyl, (C,-C_e)alkyl, (C_B-C,₀)aryl(C,-C_B)alkyl, (C,CgJheteroaryliC^C^alkyl or (C,-C_B)alkylsulfonyl; and

Q is (C,-C₁₀)alkyl, (C_e-C₁₀)aryl, (C_e-C₁₀)aryloxy(C_e-C₁₀)aryl, (C_B-C₁₀)aryf(C_eC₁₀)aryl, (C_e-C₁₀)aryl(C_s-C₁₀)aryl(C₁-C_B)alkyl, (Ca-C^arylCC^C^alkoxyiC^C^alkyl, (C_BAP/P/ 9 8/01179

C₁₀)aryloxy(C₅-C₉)heteroaryl, (C₅-C₉)heteroaryt, (C,-C_B)alkyl(C_B-C₁₀)aryl, (C,C_B)alkoxy(C_B-C,₀)aryl, (C_B-C₁₀)aryl(C,-C_B)alkoxy(C_B-C₁₀)aryl, (C₅-C₉)heteroaryloxy(C_BC₁₀)aryi, (C,-C_e)alkyl(C₅-C₉)heteroaryl, (C^-CJaJkoxyiCs-C^heteroaryl, (Cj-C^aryKC,C_e)alkoxy(C₅-C₉)heteroaryl, (C₅-C₉)heteroaryloxy(C5-C₉)heteroaryl, (C_B-C, ₀)aryloxy{C, C_B)aIkyl, (C₅-C₉)heteroary1oxy(C,-C_e)aIky1, (C,-C_B)alkyl(C_B-C₁₀)aryloxy(C_B-C,₀)aryl, (C_r C_B)alkyl(C₅-C₉)heteroaryioxy(C_B-C_w)aryl, (C,-C_B)dky1(C_e-C₁₀)aryioxy(C^-C_g)heteroaryl, (C_l-C_B)alkoxy(C_B-C₁₀)aryloxy(C_B-C,₀)aryl,(C₁-C_B)alkoxy(C₅-C_e)heteroaryloxy(C_B-C₁₀)aryl or (C, -C,)alkoxy(C_e-C_{1 0})aryloxy(C₅-C₉)heteroaryl optionally substituted by fluoro, chloro, (C,-C₆)alkyl, (C,-C_B)alkoxy or perfluorofC^CjJaJkyl;

with the proviso that Z must be substituted when defined as azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyi, isoindolinyl, tetrahydroquinolinyi, tetrahydroisoquinolinyl, piperazinyl, (C^Jacyipiperazinyf, (C,-C_B)aIkylpiperazinyl, (C_BC₁₀)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 than hydrogen;

with the proviso that R® 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 provisio that when R¹, R² and R⁸ are a substituent comprising a 10 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 comprising a heteroatom, the heteroatom cannot be directly bonded to the 4- or 6- positions;

with the proviso that when Y is oxygen, sulfur, SO, SO₂ or nitrogen and when one or more of the group consisting of R³, R*, R⁷ and R⁸, are independently a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the

3- or 5- positions;

with the proviso that when X is oxygen, sulfur, SO or SO₂, R³ and R⁴ are not present;

with the proviso that when y is 1 and W is NR²⁴ or oxygen, Z cannot be hydroxy; with the proviso that when Y is oxygen, suifur, SO or SO₂, R⁵ and R® are not present;

with the proviso that when Y is nitrogen, R® is not present;

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 comprising a heteroatom when the broken line represents a double bond, the heteroatom cannot be directly bonded to positions X and Y;

with the proviso that when either the X or Y position is oxygen, suifur, SO, SO₂ or nitrogen, the other of X or Y is carbon;

with the proviso that when X or Y is defined by a heteroatom, the broken line does not represent a double bond;

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-7with the proviso that at least one of R’, R², R³, R⁴, R⁵, R®, R⁷, R® and R^B must be defined as the group of formula II.

The temn ’alkyl*, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.

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

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

The term ’heteroaryl’, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyi, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents independently selected from the group consisting of fluoro, chloro, trifluoromethyl, (C,20 C_e)alkoxy, (C_e-C,₀)aryloxy, trifluoromethoxy, difluoromethoxy and (C,-C_e)alkyl.

The temn ’acyl’, as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy (such as methyloxy carbonyl), aryl, arylalkyi or arylalkyioxy and tine terms ’alkyl’ or ’aryl* are as defined above.

The term ’acyioxy*, as used herein, includes O-acyi groups wherein *acyi* is 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.

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

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

The compound of formula I may have chiral centers and therefore exist in 10 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 indude those wherein Q is (C,C_e)alkoxy(C_e-C₁₀)aryl, (Ce-C^aryl^-CJalkoxytCe-C^aryl, or (C_e-C_w)aryl(C,15 C_e)alkoxy(C,-C_e)alkyl wherein each terminal aryl group is optionally substituted by fluoro.

Other preferred compounds of formula I indude those wherein R², R³, R®, R⁷ and

R⁹ are hydrogen.

More preferred compounds of formula I indude those wherein Y is carbon; Q 20 is (C,-C_e)alkoxy(C_e-C₁₀)aryl, (C_e-C₁₀)aryl(C,-C_e)alkoxy(C_e-C₁₀)aryl, or (Cg-C^aryifC,C_e)alkoxy(C,-C_B)alkyl.

Specific preferred compounds of formula I indude the following: (2R,4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoyipiperidine-4-carboxylic add;

(2R,4R)-1-[4-(4-Fluorobenzy!oxy)-benzenesulfonyl]-2-hydroxycarbamoylpiperidine-4-carboxylic add methyl ester;

(2R,4R)-1-[3-(4-Fluorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoylpiperidine-4-carboxylic add;

(2R,4R)-1-[3-{4-Fluorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoyl30 piperidine-4-carboxylic add methyl ester;

(2R,3S)-{1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoylpiperidin-3-yl}-carbamic add isopropyl ester;

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AP 00958

-93-(S)-4-(4’-nuorobiphenyl«4-sulfonyl)-2,2-dimethyl-thiomorpholine^-carboxylic acid hydroxyamide;

3-(S)-4-[4-(4-Fluorobenzyloxy)benzenesulfonyi]-2,2-dimethyl-thiomorpholine-3carboxylic add hydroxyamide;

(2R,4S)-1-[4-(4-Fluorobenzyloxy)-benzenesuifonyl]-4-hydroxy-piperidine-2carboxylic add hydroxyamide; and (2R,4R)-1 -(4-Methoxybenzenesutfonyl)-4-(piperazine-1 -carbonyt)-piperidine-2carboxyfic add hydroxyamide hydrochloride.

Other compounds of the invention indude:

(3S)-4-(4-(2-Chloro-thiazol-5-yimethoxy)-benzenesulfonyl]-2,2-dimethylthiomorpholine-3-carboxylic add hydroxyamide;

(3S)-2,2-Dimethyl-4-[4-(thiazol-5-ylmethoxy)-benzenesuifonyf|-thiomorpholine-3carboxylic add hydroxyamide;

(3S)-2,2-Dimethyl-4-[4-(pyridin-4-yimethoxy)-benzenesulfonyi]-thiomorpholine-315 carboxylic add hydroxyamide;

(3S)-4-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-2,2-dimethylthiomorpholine-3-carboxylic add hydroxyamide;

(3S)-2,2«Dimethyl-4-[4-{2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-thiomorpholine-3carboxylic add hydroxyamide;

(3S)-4-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2,2-dimethylthiomorpholine-3-carboxylic add hydroxyamide;

(3S)-2,2-Dimethyl-4>[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)> benzenesulfony1]-thiomorpholine-3-carboxyiic add hydroxyamide;

(3S)-2,2-Dimethyi-4-[4-(1H-tetrazol-5-ylmethoxy}-benzenesuifony1]-thiomorpholine25 3-carboxyiic add hydroxyamide;

(2R,3S)-{1-(4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2hydroxycarbamoyl-piperidin-3-yl}-carbamic add methyl ester;

(2R,3S)-{2-Hydroxycarbamoyl-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]piperidin-3-yl}-carbamic add methyl ester, (2R,3S)-{2-Hydroxycarbamoyl-1 -[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]piperidin-3-yl}-carbamic add methyi ester;

(2R,3S)-{1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoylpiperidin-3-yl}-carbamic add methyl ester,

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-10(2R,3S)-(1-{4-[2-(4-Fluorophenyl)-ethoxyl-benzenesulfonyl}-2-hydroxycarbamoylpiperidin-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, (2R,3S)-{1 -[^BenzothiazokS-ylmethoxyl-benzenesulfonylj-S-hydroxycarbamoylpiperidin-3-yI}-carbamic add methyl ester, (2R,3S)-{2-Hydroxycarbamoyl-1-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)benzenesulfonyl]-piperidin-3-yl}-carbamic add methyl ester;

(2R,3S)-{2-Hydroxycarbamoyi-1 - [4-(1 H-tetrazol-5-ylmethoxy}-benzenesulfonyll10 piperidin-3-yl}-carbamic add methyl ester;

(2R,3S)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzene$ulfonyl]-3-hydroxypiperidine-2-carboxylic add hydroxyamide;

(2R,3S)-3-Hydroxy-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonylJ-piperidine-2carboxylic add hydroxyamide;

(2R,3S)-3-Hydroxy-1 -[4-(pyridin-4-ylmethoxy)-benzenesulfonyi]-piperidine-2carboxylic add hydroxyamide;

(2R,3S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-3-hydroxy-piperidine-2carboxylic add hydroxyamide;

(2R,3S)-1 -{4-[2-(4-Ruorophenyl}-ethoxy]-benzenesuffonyl}>3-hydroxy-piperidine20 2-carboxylic add hydroxyamide;

(2R,3S)-3-Hydroxy-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-piperidine-2carboxylic add hydroxyamide;

(2R,3S)-1-[4-(Benzothiazol-2-ylmethoxy}-benzenesulfonyl]-3-hydroxy-piperidine-2carboxylic add hydroxyamide;

(2R,3SJ-3-Hydroxy-1-[4-(5-trifIuoromethyl-benzothiazol-2-ylmethoxy)benzenesulfonyi]-piperidine-2-carboxyiic add hydroxyamide;

(2R,3S)-3-Hydroxy-1 -(4-(1 H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2carboxylic add hydroxyamide;

(2R,3S)-1 -[4-(2-Chloro-thiazol-5-ylmeihoxy}-benzenesulfonyO-3-hydroxy-3-methyi30 piperidine-2-carboxyiic add hydroxyamide;

(2R,3S)-3-Hydroxy-3-methyl-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]piperidine-2-carboxylic add hydroxyamide;

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-11(2R,3S)-3-Hydroxy-3-methyl-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]piperidine-2-carboxyiic add hydroxyamide;

(2R,3S)-1-[4-(4-F1uorobenzyloxy)-benzenesutfonyi]-3-hydroxy-3-methyl-piperidine2- carboxyiic add hydroxyamide;

⁵ (2R,3S)-1 -{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyi}-3-hydroxy-3-methyipiperidine-2-carboxylic add hydroxyamide;

(2R,3S)-3-Hydroxy-3-methyl-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]piperidine-2-carboxytic add hydroxyamide;

(2R ,3S)-1 - [4-(Benzothiazoi'2-yimethoxy)-benzenesutfonyi] -3-hydroxy-3-methyl10 piperidine-2-carboxylic add hydroxyamide;

(2R,3S}-3-Hydroxy-3-methyl-1-[4-{5-trifluoromethyl-benzothiazol-2-ylmethoxy)benzenesulfonyl]-piperidine-2-carboxylic add hydroxyamide;

(2R,3S)-3-Hydroxy-3-methyl-1 -[4-(1 H-tetrazo!-5-ylmethoxy)-benzenesulfonyl]piperidine-2-carboxylic add hydroxyamide;

(3R)-4-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2,2-dimethylmorphoiine-3-carboxyiic add hydroxyamide;

(3R)-2,2-Dimethyl-4-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-morpholine-3carboxylic add hydroxyamide;

(3R)-2,2-Dimethyl-4-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-morpholine-320 carboxylic add hydroxyamide;

(3R)-4-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2,2-dimethyl-morpholine-3carboxylic add hydroxyamide;

(3R)-4-{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesutfonyl}-2,2-dim6thyl-morpholine3- carboxylic add hydroxyamide;

(3R)-2,2-Dimethyl-4-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-morpholine-3carboxylic add hydroxyamide;

(3R)-4-[4-(BenzothiazoP2-ylmethoxy)-benzenesulfonyl]-2^-dimethyl-morpholine-3carboxylic add hydroxyamide;

(3R)-2,2-Dimethyl-4-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)30 benzenesutfonyl]-morpholine~3-carboxytic add hydroxyamide;

(3R)-2,2-DimethyM-[4-{1H-tetrazol-5-ylmethoxy}-benzenesutfonyl]-morpholine-3carboxylic add hydroxyamide;

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AP 00958

-12(2R,4R)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2hydroxycarbamoyl-piperidine-4-carboxylic acid;

(2R,4R)-2-Hydroxycarbamoyl-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]piperidine-4-carboxylic add;

(2R,4R)-2-Hydroxycarbamoyl-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]piperidine-4-carboxylic add;

(2R,4R)-1-{4-{2-{4-nuorophenyl)-ethoxy}-benzenesulfonyl}-2-hydroxycarbamoylpiperidine-4-carboxyiic add;

(2R,4R)-2-Hydroxycarbamoyl-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfony1]10 piperidine-4-carboxylic add;

(2R,4R)-1-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-2-hydroxycarbamoy1piperidine-4-carboxylic add;

(2R,4R)-2-HydroxycarbamoyH-[4-(54rifluoromethyl-benzothiazol-2-ylmethoxy)benzenesulfonyt]-piperidine-4-carboxylic add;

(2R,4R)-2-Hydroxycarbamoyl-1 -[4-{1 H-tetrazol-5-yimethoxy)-benzenesutfony1]piperidine-4-carboxylic add;

(3R)-4-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-3-methyl-morpho6ne-3carboxylic add hydroxyamide;

(3R)-3-Methyl-4-[4-{1hiazol-5-ylmethoxy)-benzenesutionyf]-morphoIine-3-carboxylic 20 add hydroxyamide;

(3R)-3-Methyt-4-[4-{pyridin-4-ylrnethoxy}-benzenesutfonyf]-morphoCne-3-carboxyfic add hydroxyamide;

(3R)-4-[4-(4-FIuorobenzyioxy)-benzenesutfonyf]-3-methyl-morphoiine-3-carboxyiic add hydroxyamide;

²⁵ (3RM44-[2-(4-Ruorophenyi)-ethoxy]-benzenesuifonyl}-3-methyi-morphofine-3carboxylic add hydroxyamide;

(3R)-3-Methyl-4-[4-(2-pyridin-4-yl-ethoxy)-benzenesuifonyl]-morpholine-3carboxylic add hydroxyamide;

(3R)-4-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-3-meithyf-morpholine-330 carboxylic add hydroxyamide;

(3R)-3-Methy1-4-[4-(54rifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesutfonyl]morpholine-3-carboxylic add hydroxyamide;

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-13(3R)-3-Methyl-4-[4-{1H-tetrazol-5-ylmethoxy)-benzenesulionyl]-morpholine-3carboxylic acid hydroxyamide;

(2R)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-2-methyt-3-oxopiperidine-2-carboxyiic add hydroxyamide;

(2R)-2-Methyi-3-oxo-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2carboxylic add hydroxyamide;

(2R)-2-Methyi-3-oxo-1-[4-(pyridin-4-yimethoxy)-benzenesulfonyl]-piperidine-2carboxylic add hydroxyamide;

(2R)-1-[4-(4-Fluorobenzyioxy)-benzenesulfonyl]-2-methyl-3-oxo-piperidine-210 carboxylic acid hydroxyamide;

(2R)-1-{4-[2-(4-Fluorophenyi)-ethoxy]-benzenesuifonyi}-2-methyi-3-oxo-piperidine·

2-carboxylic add hydroxyamide;

(2R)-2-Methyl-3-oxo-1-[4-(2-pyridin-4-yJ-ethoxy)-benzenesulfonyi]-piperidine-2carboxylic acid hydroxyamide;

(2R)-1 -[4-{Benzothiazol-2-ylmethoxy)-benzenesuifonyn-2-methy1-3-oxo-piperidine2-carboxylic add hydroxyamide;

(2R)-2-Methyl-3-oxo-1-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)benzenesulfonyl]-piperidine-2-carboxy!ic add hydroxyamide;

(2R)-2-Methyl-3oxo-1-[4-(1H-tetrazol-5-ylmethoxy)-benzenesuifonyl]-piperidine-220 carboxylic add hydroxyamide;

(2R,4S)-1-(4-Benzyloxy-benzenesulfonyl)-4-butylaminomethyl-4-hydroxypiperidine-2-carboxylic add hydroxyamide;

(2R,4S)-4-Butylaminomethyl-1-{4-{44luorobenzyloxy)-benzenesulfonyl]-4-hydroxypiperidine-2-carboxylic add hydroxyamide;

(2R,4S)-4-Benzy1amino-1 -(4-benzyloxy-benzenesulfonyl)-piperidine-2-carboxylic add hydroxyamide;

(2R,4S)-4-Benzylamino-1-(4-{44luorobenzyloxy)-benzenesulfonyl]-piperidine-2carboxylic add hydroxyamide;

(2R)-1 -[4^4-nuorobenzytoxy)-benzenesutfony0-4-oxo-piperidine-2-carboxylic add 30 hydroxyamide;

(2R,4R)-1-(4-Benzyloxy-benzenesulfonyl)-4-hydroxy-piperidine-2-carboxylicadd hydroxyamide;

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-14(2R_l4R)-1-[4-(4-Fluorobenzyioxy)-benzenesulfonyl]-4-hydroxy-piperidine-2carboxylic acid hydroxyamide;

(2R)-1-[4-(4-Fluorobenzyioxy)-benzenesuifonyi]-4-methy1-piperazine-2-carboxy1ic add hydroxyamide;

(2R,5S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyi]-5-hydroxy-piperidine-2carboxyiic add hydroxyamide;

(2R,5S)-i-{4-Benzyloxy-benzenesuifonyI)-5-hydroxy-piperidine-2-carboxylicadd hydroxyamide;

(2E,5R)-1-(4-Benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxyiicadd 10 hydroxyamide;

(2R,5R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-5-hydroxy-piperidine-2carboxyiic add hydroxyamide;

(2R,3S)-1-(4-Benzyloxy-benzenesuifonyl)-3-hydroxy-piperidine-2-carboxyiicadd hydroxyamide;

(2R,4S)-1 -(4-Benzyloxy-benzenesutfony1)-4-hydroxyⁱpiperidine-2-carboxyiicadd hydroxyamide;

(2R,4S)-1-[4-(4-Fluorobenzyioxy)-benzenesulfonyi]-4-hydroxy-piperidine-2carboxylic add hydroxyamide;

1-(4-Butoxy-benzenesulfony1)-3-(morpholine-4-carbonyi)-piperidine-2-carboxylic 20 add hydroxyamide;

1-[4-(4-Fluoro-benzyioxy)-benzenesutfonyl)-34morphofine-4-carbonyi)-piperfcfine2-carboxyiic add hydroxyamide;

1-[3-(Fluoro-benzyloxy)-propane-1-suifonyi]-3-{morphoiine-4-cartx5nyi)-piperidine2-carboxylic add hydroxymide;

1 -(4-Butoxy-benzenesulfonyl)-3-(pyrrolidine-1 -carbonyl)-piperidine-2-carboxyiic add hydroxyamide;

-[4-(4-Fluoro-benzy1oxy}-benzenesuffonyi)-3-(pyrroiidine-1 -carbonyf)-piperidine-2carboxylic acid hydroxyamide;

-[3-(4-Fluoro-benzyloxy)-propane-1 -sulfonyi)-3-(pyrrolidine-1 -carbonyl)30 piperidine-2-carboxyiic add hydroxyamide; and

1-[4-(4-Fluoro-benzyloxy)-benzenes uffon yl]-2-hydroxycarbamoyl-pi peridine-4carboxylic add.

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AP 00958

-15The present invention also relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, cancer, synergy with cytotoxic anticancer agents, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, sderitis, in combination with standard

NSAID*S and analgesics and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically acceptable carrier.

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

The present invention aiso 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 formula I may be used in combination with standard NSAID'S and analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) In a mammal, induding a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition.

AP/P/ 9 8/01179

AP 00958

-16Detailed Description of the Invention

The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated R’, R², R³, R*, R⁶, R^e, R⁷, R⁸, R⁸, n and Ar in the reaction Schemes and the discussion that follow are defined as above.

Preparation 1

AP/P/ 98/01179

VI

AP 00958

-17Preparation 2 ^R\ /C0₂R²⁵

NH₂ xviii

VI cn r·*.

co σ»

CL a

<

AP 00958

-18·

Scheme 1

AP 00958

-19Scheme 2 _R26

AP/P/ 9 8/01 179

VII

AP 00958

-20Scheme 3

XII

61110/86 /d/dV

X

AP 00958 -21-

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XX

AP 00958

-22Scheme 4 continued

XX

AP/P/ 9 8/01179

XIII

AP 00958

XXVI

Z l 10/86 /d/dV

XXIV

AP 00958

-24Scheme 5 continued

XXIV

AP/P/ 9 8/01 179

XIV

AP 00958

-25Preparation 1 refers to the preparation of intermediates of the formula VI. Compounds of the formula VI are converted to compounds of the formula I according to the methods of Scheme 1. The starting materials of formula XVI can be prepared according to methods well known to those of ordinary skill in the art.

In reaction 1 of Preparation i, the compound of formula XVI is converted to the corresponding hydroxy ester compound of formula VI by first reacting XVI with an aryisuffonylhalide in the presence of triethylamine and an aprotic solvent, such as methylene chloride, tetrahydrofuran or dioxane, at a temperature between about 20°C to about 30°C, preferably at room temperature. The compound so formed is further reacted with a compound of the formula

R⁹ C0₂R²⁵

Y

Br wherein R²⁵ is carbobenzyloxy, (^-C^alkyf, benzyl, allyl or tert-butyl, in the presence of sodium hexamethyldisilazane and a tetrahydrofuran-dimethytformamide solvent mixture 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 formula VI. The starting materials of formula XVIII can be prepared according to methods well known to those of ordinary skill in the art. In reaction 1 of Preparation 2, the amine compound of formula XVIII, wherein R²⁵ is as defined above, is converted to the corresponding arylsulfonyi amine compound of formula XVII by (1) reacting XVIII with an arylsulfonylhalide in the presence of triethylamine and an aprotic solvent, such as methylene chloride, tetrahydrofuran, or dioxane, at a temperature between about 20°C to about 30°C, preferably at room temperature, (2) reacting the compound so formed with a compound of the formula

AP/P/ 9 8/01 17»

³⁰ in the presence of sodium hexamethyldisilazane and a tetrahydrofurandimethyfformamide solvent mixture at a temperature between about -20°C to about 20°C, preferably about 0°C, and (3) further reacting the compound so formed with ozone in a methylene chloride-methanol solution at a temperature between about -90°C

AP 00958

-26to about -70°C, preferably about -78°C. The unstable ozonide compound so formed is then reacted with triphenylphosphine to form the arylsulfonyl _amine compound formula XVII. In Reaction 2 of Preparation 2, the arylsulfonyl amine compound of formula XVII is converted to the corresponding hydroxy ester compound of formula VI by reading XVII with a compound of the formula wherein W is lithium, magnesium, copper or chromium.

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

In reaction 2 of Scheme χ the morpholinone compound of formula V Is converted to the carboxylic add compound of formula IV by reacting V with lithium hexamethyldisiiazane in an aprotic solvent, such as tetrahydrofuran, at a temperature between about -90°C to about -70°C, preferably about -78°C. Trimethylsilyl chloride is then added to the reaction mixture and the solvent, tetrahydrofuran, is removed in vacuo and replaced with toluene. The resuling reaction mixture is heated to a temperature between about 100°C to about 120°C, preferably about 110°C, and treated with hydrochloric add to form the carboxylic add compound of formula IV.

AP/P/ 9 8/01 179

AP 00958

-27In reaction 3 of Scheme i, the carboxylic add compound of formula IV is converted to the corresponding hydroxamic acid compound of formula III by treating IV with 1-(3-dimethylaminopropyi)-3-ethyicarbodiimide and 1-hydroxybenztriazoie in a polar solvent, such as dimethylformamide, followed by the addition of hydroxylamine to the reaction mixture after a time period between about 15 minutes to about 1 hour, preferably about 30 minutes. The hydroxylamine is preferably generated in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as N-methyimorpholine. Alternatively, a protected derivative of hydroxylamine or its salt form, where the hydroxyl group is protected as a tert-butyl, benzyl or allyl ether, may be used in the presence of (benzotriazol-l-yioxy)tris(dimethylamino) phosphonium hexafluorphosphate and a base, such as N-methylmorphoiine. Removal of the hydroxylamine protecting group is carried out by hydrogenolysis for a benzyl protecting group or treatment with a strong acid, such as trifluoroacetic add, for a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyitinhydride and acetic add in the presence of catalytic bis(triphenyiphosphine) palladium (II) chloride. N,0-bis(4-methoxybenzyi)hydroxyiamine may also be used as the protected hydroxylamine derivative where deprotection is achieved using a mixture of methanesuifonic add and trifluoroacetic add.

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

Scheme 2 refers to the preparation of compounds of the formula Vil, which are compound of the formula I wherein Y is nitrogen; X is carbon; R¹, R², R³, R*, R⁷ and R· are hydrogen, and R® is absent. The starting materials of formula IX can be prepared according to methods well known to those of ordinary skill in the art. In reaction 1 of Scheme 2, the aryisuifonyipiperazine compound of formula IX, wherein R²® is carbobenzytoxy, benzyl or carbotertbutyioxy, is converted to the compound of formula VIII by reacting IX with a protected derivative of hydroxylamine of the formula

R’ONH^Ha 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 of an without loss of the R²⁷ protecting group, therefore, R²® cannot be the same as R²⁷.

AP/P/ 9 8/01 179

AP 00958

-28Removal of the R²⁰ protecting group from the compound of formula IX is earned out under conditions appropriate for that particular R²⁰ protecting group in use. Such conditions include; (a) treatment with a hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, where R²⁰ Is carbobenzyloxy, (b) hydrogenolysis where

R^2S is benzyl or (c) treatment with a strong add, such as trifluoroacetic add or hydrochloric add where R²⁰ is carbotertbutyloxy.

In reaction 2 of Scheme 2, the compound of formula VIII is converted to the corresponding hydroxamic add compound of formula VII, wherein R^s is hydrogen or (C^C^alkyl, by reacting, if desired, VIII with an alkylhaiide when R^s is (C^-C^alky!.

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

Scheme 3 refers to the preparation of compounds of the formula X, which are compounds of the formula I wherein Y is nitrogen; X is carbon; R², R⁷, R“ and R* are hydrogen; 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 R²® is as defined above, is converted to the corresponding piperazine compound of formula

XI by reacting XII with a carbodiimide and a base, such as triethyiamine. The compound of formula XI is further reacted to give the hydroxamic add compound of formula X according to the procedure described above in reaction 3 of Scheme 1.

Scheme 4 refers to the preparation of compounds of the formula XIII. The starting materials of formula XVIII can be prepared according to methods wefl known to those of ordinary skill in the art. Compounds of the formula XIII are compounds of the formula I wherein X is carbon, and the dotted line between X and Y is absent, in reaction 1 of Scheme 4, removal of the R” protecting group and subsequent reductive amination of the compound of formula XXII, wherein Y is oxygen, sulfur or carbon, to give the corresponding imine compound of formula XXI Is carried out under conditions appropriate for that particular R²⁸ protecting group in use. Such conditions include those used above for removal of the R²⁰ protecting group in reaction 1 of Scheme 2.

In reaction 2 of Scheme 4, the imine compound of formula XXI is converted to the corresponding piperidine compound of formula XX by reacting XXI with a nucleophile of the formula R²M whereW* M^Wiium, rnagno^urn- halide or cerium

PATENTS ;

• -··,· ·: >

r.-, -. ; CY ¹

AP/P/ 9 8/01 179

AP 00958

-29halide. The reaction is carried out in ether solvents, such as diethyl ether or tetrahydrofuran, 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 formula XX to given the corresponding aryfsulfonylpiperidine compound of formula XIX is carried out by reacting XX with an aryisuifonythalide in the presence of triethylamine and an aprotic solvent, such as methylene chloride, tetrahydrofuran or dioxane, at a temperature between about 20°C to about 30°C, preferably at room temperature.

in reaction 4 of Scheme 4, the aryisuifonylpiperidine compound of formula XIX is converted to the hydroxamic add compound of formula XIII according to the procedure described above in reaction 3 of Scheme 1Scheme 5 refers to the preparation of compounds of the formula XIV, which are compounds of formula I wherein Y is nitrogen, X is carbon, the dotted line between X and Y is absent, R⁵ is hydrogen and R® is absent. In reaction 1 of Scheme 5, the compound of formula XXVI, wherein the R” and R³' protecting groups are each independently selected from the group consisting of carbobenzyloxy, benzyl and carbotertbutyloxy and R³⁰ Is carbobenzyloxy, (C,-C_e)alkyl, benzyl, allyl or tert-butyl, Is converted to the corresponding imine compound of formula XXV by the removal of the R²⁹ protecting group and subsequent reductive amination of the compound of formula

XXVI. The R²⁹ protecting group is chosen such that it may be selectively removed in the presence of and without loss of the R³¹ protecting group. Removal of the R” protecting group from the compound of formula XXVI is carried out under conditions appropriate for that particular R²⁹ protecting group in use which will not affect the R³’ protecting group. Such conditions include; (a) treatment with hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, where R²⁹ is carbobenzyloxy and R³¹ is tert-butyl, (b) saponification where R²⁹ is (0,-0(,)aikyl and R³¹ is tert-butyl, (c) hydrogenolysis where R²⁹ is benzyl and R³¹ is (C,-Ce) alkyl or tert-butyl, (d) treatment with a strong add such as trifluoroacetic add or hydrochloric add where R²⁹ is tert-butyl and R³¹ is (C,-Ce)aikyl, benzyl or allyl, or (e) treatment with tributyttinhydride and acetic add in the presence of catalytic bis(triphenylphosphine) palladium (11) chloride where R²⁹ is allyl and R³¹ is (C,-C_e)alkyl, benzyl or tert-butyl. The R³⁰ protective group may be selected such that it is removed in the same reaction step as the R²⁹ protecting group.

AP/P/ 9 8/01 179

AP 00958

-30ln reaction 2 of Scheme 5, the imine compound of formula XXV is converted to the corresponding compound of formula XXIV by reacting XXV with a nucleophile of the formula R³M wherein M is lithium, magnesium halide or calcium halide. The reaction is carried out in ether solvents, such as diethyl ether or tetrahydrofuran, at a temperature between about -78°C to about 0°C, preferably about -70°C.

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

In reaction 4 of Scheme 5, the aryisuifonyipiperidine compound of formula XXIII 10 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 according to the procedure described above in reaction 3 of Scheme T Removal of the R³⁰ and R³¹ protecting groups from the compound of formula XXIII Is carried out under conditions appropriate for that particular R³⁰ and R³¹ protecting group in use. Such conditions indude those used above for removal of the R²⁵ protecting group in reaction 1 of Scheme 1..

Pharmaceutically acceptable salts of the addic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium slats, such as ammonium, trimethyl-ammonium, diethyiammonium, and tris(hydroxymethyf)-methyiammonium salts.

Similarly acid addition salts, such as of mineral adds, organic carboxylic and organic sulfonic adds e.g. hydrochloric add, methanesutfonic add, maleic add, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.

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

AP/P/ 9 8/01 179

AP 00958

-31Bloloqlcal Assay

Inhibition of Human Coilagenase (MMP-1) _

Human recombinant coilagenase is activated with trypsin using the following ratio: 10 pg trypsin per 100 pg of coilagenase. The trypsin and coilagenase are incubated at room temperature for 10 minutes then a five fold excess (50 pg/10 pg trypsin) of soybean trypsin inhibitor is added.

mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then diluted using the following Scheme:

mM-> 120 μΜ -—> 12/zM-> 1.2 μΜ-> 0.12μΜ

Twenty-five microliters of each concentration is then added in triplicate to appropriate wells of a 96 well microfluor plate. The final concentration of inhibitor will be a 1:4 dilution after addition of enzyme and substrate. Positive controls (enzyme, no inhibitor) are set up in wells D1-O6 and blanks (no enzyme, no inhibitors) are set in wells D7-D12.

Coilagenase is diluted to 400 ng/ml and 25 μ! is then added to appropriate wells of the microfluor plate. Final concentration of coilagenase in the assay is 100 ng/ml.

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

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

Fluorescence vs time is then plotted for both the blank and coilagenase 25 containing samples (data from triplicate determinations is averaged). A time point that provides a good signal (the blank) and that is on a linear part of the curve (usually around 120 minutes) is chosen to determine IC^ values. The zero time is used as a blank for each compound at each concentration and these values are subtracted from the 120 minute data. Data is plotted as inhibitor concentration vs % control (inhibitor fluorescence divided by fluorescence of coilagenase alone x 100). ICjo's are determined from the concentration of Inhibitor that gives a signal that is 50% of the control.

AP/PZ 9 8/01 179

AP 00958

-32If IC₅₀'s are reported to be <0.03 μΜ then the inhibitors are assayed at concentrations 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 of human collagenase (MMP-1).

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

Fluorescence readings (360 nm excitation, 460 emission) are taken at time zero and then at 20 minutes intervals for 4 hours.

IC_S0‘s are determined as per inhibition of human collagenase (MMP-1). If IC^'s 15 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 Strometysin Activity (MMP-3)

Inhibition of stromelysin activity is based on a modified spectrophotometric assay described by Weingarten and Feder (Weingarten, H. and Feder, J.,

Spectrophotometric Assay for Vertebrate Collagenase, Anal. Biochem. 147, 437-440 (1985)). Hydrolysis of the thio peptoiide substrate [Ac-Pro-Leu-GlySCH[CH₂CH(CH₃)₂]CO-Leu-Gly-OC₂l-y yields a mercaptan fragment that can be monitored in the presence of Eliman's reagent.

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

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

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

AP/P/ 9 8/01 179

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-33concentrations of 3 μΜ, 0.3 μΜ, 0.003 μΜ, and 0.0003 μΜ. All conditions are completed in triplicate.

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

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

Inhibition of MMP-13

Human recombinant MMP-13 is activated with 2mM ΑΡΜΑ (p-aminophenyl mercuric acetate) for 1.5 hours, at 37°C and is diluted to 400 mg/ml in assay buffer (50 mM 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 well microfiuor plate. The enzyme is then diluted in a 1:4 ratio in the assay by the addition of inhibitor and substrate to give a final concentration in the assay of 100 mg/ml.

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 human collagenase (MMP-1): Twenty-five microiiters of each concentration is added in triplicate to the microfiuor plate. The final concentrations in the assay are 30 μΜ, 3μΜ,

0.3 μΜ, and 0.03 μΜ.

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

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

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

Inhibition of TNF Production

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

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-34Human mononuclear cells were isolated from anti-coagulated human blood using a one-step Ficoll-hypaque separation technique. (2) The mononuclear ceils were washed three times in Hanks balanced salt solution (HBSS) with divalent cations and resuspended to a density of 2 x 10® /ml In HBSS containing 1% BSA. Differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that monocytes ranged from 17 to 24% of the total cells in these preparations.

180// of the cell suspension was aliquoted into fiate bottom 96 well plates (Costar). Additions of compounds and LPS (100ng/ml final concentration) gave a final volume of 200/4. All conditions were performed in triplicate. After a four hour incubation at 37°C in an humidified CO₂ incubator, plates were removed and centrifuged (10 minutes at approximately 250 x g) and the supernatants removed and assayed for TNFc using the R&D EUSA Wt

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

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

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably com, potato or tapioca starch), alginic add and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also indude lactose or milk sugar as well as high molecular weight

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-35polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. In the case of animals, they are advantageously contained in an animal feed or drinking water in a concentration of 55000 ppm, preferably 25 to 500 ppm.

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

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

3 divided doses.

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

EXAMPLE 1 (2R, 4R)-1 -(4-Methoxy-benzeneauIfonvl>-4-(plperazine-1 -carbonyl)-oiperidine-225 carboxylic acid hvdroxvamlde hydrochloride (a) To a stirred, cold (-78 °C) solution of (2R)-2-benzyloxycarbonylaminopentanedioic acid 1-tert-butyl ester 5-methyl ester (5.6g, 15.9 mmol), prepared as described in J. Org. Chem., 55,1711-1721 (1990) and J. Med. Chem., 39,73-85 (1996), in 30 mL of tetrahydrofuran was added lithium bis(trimethylsiiyl)amide (40 mL, 1 M in tetrahydrofuran, 39.8 mmol). The resulting mixture was stirred for 1 hour at-45 °C and then recooled to -78 °C. Allyl bromide (5.2 ml_ 63.7 mmol) was then added. After 2 hours the reaction was quenched by the addition of 1 M aqueous hydrogen chloride at -78 °C. The mixture was then extracted with diethyl ether. The combined ethereal

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-36extracts were washed with brine and the mixture was dried over sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by silica gel chromatography (elution with 1:5 ethyl acetate/hexanes) to provide (2R,4R)-4-allyl-2benzyloxycarbonylamino-pentanedioic add 1-tert-butyl ester 5-methyi ester.

(b) Ozone gas was bubbled through a stirred, cold (-78 °C) solution of (2R,4R)-4ailyl-2-benzyloxycarbonytamino-pentanedioic add 1-tert-butyl ester 5-methyl ester (5.0 g, 12.8 mmol) in 100 mL of 10:1 methanoi/methylene chloride, and 0.73 mL of acetic add until a blue color persisted. Nitrogen gas was then bubbled through the solution until the blue color dissipated. The mixture was warmed to ambient temperature and dimethyl sulfide (2.8 mL, 3.83 mmol) was added. The mixture was stirred for 48 hours, diluted with methylene chloride, and washed with 10% aqueous sodium carbonate, brine, and the mixture was dried over sodium sulfate. Filtration and concentration of the filtrate provided (2R,4S)-6-methoxy-piperidine-1,2,44ricarboxylic add 1-benzyl ester 2-tert-butyl ester 4-methyi ester as a dear oil, which was used in the subsequent step without purification.

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

(d) To a stirred, cold (0 °C) solution of (2R,4R)-piperidine-2,4-dicarboxylic add 2tert-butyi 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,

11.1 mmol). The mixture was warmed to ambient temperature and stirred for 4 hours.

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

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-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 30 mL of methylene chloride was added 10 mL of trifluoroacetic add dropwise. The mixture was stirred for 1 hour at 0 °C and for 8 hours at ambient temperature.

Concentration provided (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4dicarboxylic add 4-methyl ester, which was used in the subsequent step without purification.

(f) To a stirred solution of (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidlne-2,4dicarboxylic add 4-methyl ester (4.4 g, 12.3 mmol), O-benzylhydroxylamine hydrochloride (2.15 g, 13.5 mmol), and triethylamine (5.15 mL, 36.9 mmoi) was added benzotriazol-1 -y1oxy-tris(dimethyiamino)phosphonium hexafluorophosphate (6.0 g, 12.3 mmoi) at ambient temperature. The resulting mixture was stirred for 24 hours. The mixture was diluted with ethyl acetate and washed with 1 M aqueous hydrogen chloride, aqueous sodium bicarbonate, and brine. The organic mixture was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (elution with 5% methanol in methylene chloride) to provide (2R,4R)-2-benzyloxycarbamoyf-1-(4-methoxy-benzenesulfonyl)-piperidine4-carboxylic add methyl ester as a colorless solid.

(g) To a stirred cold (0 °C) solution of (2R,4R)-2-benzyioxycarbamoyl-1 -(4-methoxy20 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). The mixture was stirred for 2 hours before Amberiite IR-120 resin (96 g) was added. After 15 minutes, the mixture was filtered and the filtrate was concentrated to give (2R,4R)-2benzyloxycarbamoyi-1-(4-methoxy-benzenesulfonyi)-piperidine-4-carboxyiicadd,which was used in the subsequent reaction without purification.

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

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-38The organic mixture was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (elution with 2% methanol in methylene chloride) to provide (2R,4R)-4-[2-benzyioxycarbamoyl-1 (4-methoxy-benzenesulfonyi)-piperidine-4-carbonyl]-piperazine-1 -carboxylic add tertbutyl 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 under a 40 psi atmosphere of hydrogen gas for 1.5 hours, nitration through nylon and concentration of the filtrate provided (2R,4R)-4-[2-hydroxycarbamoyl-1-(4-methoxybenzenesuifonyl)-piperidine-4-carbonyi]-piperazine-1 -carboxylic add tert-butyl ester as a colorless solid, which was used in the subsequent step without purification.

(j) Hydrogen chloride gas was bubbled through a cold (0°C) solution of (2R,4R)-4[2-hydroxy carbamoyl-1 -{4-methoxy-benzer>esulfonyl)-piperidine-4-ccirbonyl]-piperazine-1 carboxylic add tert-butyl ester (420 mg, 0.8 mmol) for 10 minutes. After an additional 20 minutes the mixture was concentrated to provide (2R, 4R)-1-(4-methoxybenzenesulfonyl)-4-(piperazine-1-carbonyt)-piperidine-2-carboxylic add hydroxyamide hydrochloride as a colorless solid: Mass spectrum (atmospheric pressure chemical ionization: basic mode) m/z (M+H) 427,366; Ή NMR (dimethyl sutfoxide-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, 5 H), 3.04 (m, 4 H), 2.76 (m, 1 H), 1.79 (bd, 1 H, J = 13.5 Hz), 1.52 (bd, 1 H, J = 12.6 Hz), 1.32 (m, 1 H) 1.14 (m 1H).

AP/P/ 9 8/01179

Example 2 (2R.4R)-1-f3-(4-Fluorophenoxv)-propane-1-sulfonvn-2-hvdroxvcarbamovlpiperidine-4-carboxylic acid methvl 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 10 mL of methylene chloride was added a solution of 3-(4-fiuorophenoxy)-propane-1sulfonyl chloride (1.05 g, 4.16 mmol) in 2 mL of methylene chloride under a nitrogen atmosphere. The mixture was stirred for 16 hours at ambient temperature (22 °C), then

AP 00958

-39diluted with 20 mL of 1 N hydrochloric add and 20 mL of methylene chloride. The organic layer was removed and washed with brine and dried over sodium sulfate. Filtration and concentration of the filtrate gave 2.8 g of a yellow oil, which was purified by flash chromatography (3:2 hexanes/ethyf acetate elution) to give 1.15 g (2R,4R)-1 -(35 (4-fluoro-phenoxy)-propane-1 -sulfonyl]-piperidine-2,4-dicarboxyiic add 2-tert-butyl ester

4-methyi ester of as a yellow oil.

(b) To a stirred, cold (0 °C) solution of (2R_J4R)-1-(3-(4-fluorophenoxy)-propane-1sulfonyi]-piperidine-2,4-dicarboxyiic add 2-tert-butvl ester 4-methyl ester (1.15 g, 2.5 mmol) in 10 mL of methylene chloride was added 10 mL of trifluroacetic add. The mixture was allowed warm to ambient temperature (22 °C) over 16 hours. The mixture was concentrated in vacuo to give 970 mg of crude (2R,4R)-1-(3-(4-fluorophenoxy)propane-1-suifonyi]-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-suifonyl]piperidine-2,4-dicarboxyiic add 4-methyl ester (970 mg, 2.4 mmol) in 5 mL of methylene chloride was added triethylamine (1.0 ml_ 7.2 mmol) and O-benzyihydroxyiamine hydrochloride (410 mg, 2.64 mmol) at ambient temperature (22 °C). To the resulting solution was added benzotriazol-1-yloxy-tris(dimethyiamino)phosphonium hexafiuorophosphate (1.17 g, 2.64 mmol) and the mixture was stirred for 16 hours under a nitrogen atmosphere. The mixture was diluted with 25 mL of 1 N hydrochloric acid and 25 mL of ethyl acetate. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (2 x). The combined organic layers were washed with saturated aqueous sodium carbonate (1 x) and brine (1 x). The organic layer was dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo. Purification of the viscous yellow residue by flash chromatography (eluting with 1:1 ethyl acetate/hexanes) gave 810 mg of (2R,4R)-2-benzy1oxycarbamoy1-1-[3-(4-fiuorophenoxy)-propane-1sulfonyi]-piperidine-4-carboxyiic acid methyl ester as a clear oil.

(d) A mixture of (2R,4R)-2-benzy1oxycarbamoyl-1-[3-(4-fluorophenoxy)-propane-1suifonyl]-piperidine-4-oarboxyiic add methyl ester (800 mg, 1.57 mmol) and 200 mg of 5% palladium on barium sulfate in 15 mL of methanol was shaken in a Parr apparatus under a 40 psi hydrogen gas atmosphere for 2 hours. The catalyst was removed by passage of the mixture through a 0.45 μτη nylon filter and the filtrate was concentrated to give 650 mg of (2R,4R)-1-(3-(4-fluorophenoxy)-propane-1-sulfonyl]-2AP/P/ 9 8/01 179

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-40hydroxycarbamoyl-piperidine-4-carboxyiic add methyl ester as a white foam: MS (atmospheric pressure chemical ionization) addic mode, 417 (M-1);_’H NMR (400 MHz, CDCI₃) δ 6.94-6.97 (m, 2 H), 6.80-6.83 (m, 2 H), 4.66 («, 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), 3.1543.28 (m, 3 H), 2.76 (t, 1 H, J = 11.5 Hz),

2.54 (d, 1 H, J = 13.5 Hz), 2.26 (d,2H, J = 5.9 Hz), 2.02 (m, 1 Η» J = 13.0 Hz), 1.731.78 (m, 1 H), 1.56-1.62 (m, 1 H).

Example 3 (2R.4R)-1-r3-(4-Fiuorophenoxv)-propane-1-8ulfonvn-2-hvdroxycarbamovlpiperidine-4-carboxvHc add

To a stirred, cold (0 °C) solution of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1sulfonyl]-2-hydroxycarbamoyi-piperidine-4-carboxyiic add methyl ester (400 mg, 0.96 mmol) in 5 mL of a methanol/water mixture (10:1) was added lithium hydroxide monohydrate (120 mg, 2.88 mmol). After 3 hours at 0 °C, prerinsed (methanol) Amberirte resin (4.1g) was added. The mixture was filtered and the filtrate was concentrated to give 370 mg of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1-suffonyi]-2hydroxycarbamoyl-piperidine-4-carboxyiic add as a white foam: MS (atmospheric pressure chemical ionization) addic mode, 403 (M-1).

Example 4 (2R.4R)-1-f4-(4-Fluorobenzvloxv>-benzenoulfonvri-2-hvdroxvcarbamovi20 piperidlnc-4-carboxvlic add methyl ester

4-(4-Fluoro-benzy1oxy)-benzenesuifonyl chloride. MS: 465 (M-1).

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

Example 5 (2R.4R)-1-f4-(4-Ruorobenzvloxv)-benzenesulfonvl1-2-hvdroxvcarbamovfpiperidine-4-carboxvlic acid. MS: 451 (M-1).

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

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-41Example 6

2R.3S~f1-f444-Fiuorobenzyioxy>benzenetilfonvn-2-hvdrbxvcarbamoYipiperidin-3-vll-orbamlc acid Isopropyl ««ter (a) To a stirred, cold (0 °C) solution of the known (Agaml, C.; Hamon, L;

Kadouri-Puchot, C.; Le Guen, V J. Org, Chem. 1996, 61, 5736-5742) [4S-4o,9o,9aa]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 of concentrated hydrochloric add. After 5 minutes the mixture was concentrated to dryness. The resulting solid was suspended in ethyl acetate and the mixture was stirred for an hour. The solids were collected by filtration, rinsed with ethyl acetate, and dried to give 9.04 g of a white solid.

Two grams of this solid was dissolved in 26 mL of 6 N hydrochloric add and heated at reflux for 6 hours. The mixture was cooled to 0 °C and neutralized with 3 N sodium hydroxide and concentrated in vacuo. The resulting solids were suspended in chloroform and passed through a 45 /jm nylon filter. The filtrate was concentrated to a yellow oil which was purified by flash chromatography (eluting with 2:1 hexanes/ethyi acetate with 1% acetic add) to give 802 mg of [4S4o,9o,9aa]1-oxo-4-phenyi-octahydro-pyrido[2,1-g][1,4]oxazine-9-carboxyiic add as white solid.

(b) Toastirredsolutionof[4S-4cr,9o,9ao]1-oxo-4-phenyi-octahydropyrido[2,1-c][1,4]oxazine-9-carboxyiic add (568 mg, 2.06 mmol) in 15 mL of benzene was added triethylamine (0.28 mL, 2.06 mmol) and diphenyiphosphoryi azide (0.44 ml_ 2.06 mmol) at 22 °C under a nitrogen atmosphere. The mixture was stirred at 22 °C for 45 minutes and at reflux for 50 minutes before 2-propanol (3.2 mL, 41.2 mmol) was added. After an additional 20 hours at reflux the mixture was cooled to 22 °C and concentrated in vacuo. The residue was taken up in ethyl acetate and the resulting solution was washed with 5% citric add, water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo. The yellow residue was purified by flash chromatrography (eluting with 3:1 hexanes/ethyi acetate) to give

402 mg of [4S-4o,9c,9az7](1-oxo-4-phenyi-octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)carbamic acid isopropyl ester as white solid.

AP/P/ 9 8/01179

-42ι.-, «'ί

Air* (c) A mixture of [4S-4o,9ff,9aar](1-oxo-4-phenyl-octahydro-pyrido[2,1c] [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) was shaken in a Parr apparatus under a 45 psi hydrogen gas atmosphere for 72 hours. The catalyst was removed by passage of the mixture through a 0.45 pm nylon filter and the filtrate was concentrated to give 610 mg of 2R.3S-3isopropoxycarbonyiamino-piperidine-2-carboxylic add as white solid. MS: 229 (M-1).

(d) To a stirred solution of 2R₁3S-34sopropoxycarbonylamino-piperidine-2carboxyiic add (320 mg, 1.39 mmol) in 5 mL of methylene chloride was added triethylamine (0.58 mL, 4.17 mmol) followed by 4-(4-fluorobenzyloxy)benzenesulfonyl chloride (460 mg, 1.53 mmol). After 16 hours at 22 °C the mixture was partioned between 1 N hydrochloric add and ethyl acetate. The organic layer was removed and washed with brine and dried over sodium sulfate. Filtration and concentration of the filtrate gave 480 mg of crude 2R,3S-1-[4-(4-fluorobenzy!oxy)benzenesulfonyl]-3-isopropoxycarbonylamino-piperidine*2-carboxyiic add as a light yellow solid.

(e) To a stirred, cold (0 °C) solution of crude 2R.3S-1-(4-(4fluorobenzyloxy)-benzenesulfonyl]-3-isopropoxycarbonylamino-piperidine-2carboxyiic add (380 mg, 0.77 mmol) in 5 mL of methylene chloride was added triethylamine (0.32 mL, 2.31 mmol) followed by benzotriazol-1-yloxytris(dimethyiamino)phosphonium hexafluorophosphate (510 mg, 1.15 mmol). The resulting solution was stirred for 2 minutes at 0 °C under a nitrogen atmosphere before O-(trimethylsilylethyl)hydroxylamine hydrochloride (195 mg, 1.15 mmol) was added. The mixture was allowed to warm slowly to 22 °C over 14 hours. The mixture was concentrated in vacuo and the residue was diluted with water and extracted with ethyl acetate/diethyl ether (1:1; 3 x). The combined organic extracts were washed with saturated aqueous carbonate (2 x), water (2 x), and brine (1 x). The organic layer was dried (magnesium sulfate), filtered, and the filtrate was concentrated in vacuo. The yellow residue was purified by flash chromatography (eluting with 65:35 hexanes/ethyl acetate) to give 300 mg of 2R,3S-[1-(4-(4fiuorobenzyloxy)-benzenesulfony1]-2-(2-trimethy1silanyi-ethoxycarbamoy1}-piperidin-3yl]-carbamic add isopropyl ester as a white foam. MS: 610 (M+1).

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-43(f) To a stirred, cold (0 °C) solution of 2R,3S-[1-[4-(4-fluorobenzyioxy)benzenesulfonyt]-2-(2-trimethyisilanyl-ethoxycarbamoyl)-piperidin-3-yl]-carbamic acid isopropyl ester (265 mg, 0.44 mmol) in 4 mL of methylene chloride was added 3 mL of trifluoroacetic add. The resulting colorless solution was allowed to warm to 23 °C over 2 hours and was stirred for an additional 28 hours. The mixture was concentrated in vacuo to a solid/Toam, which was suspended in ethyl acetate hexanes (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 7:3 ethyl acetate/hexanes with 1% acetic add) to give 130 mg of 2R,3S-1-[4-{410 fluorobenzyloxy)benzenesulfonyl]-2-hydroxycarbamoyl-piperidin-3-yl}-carbamic add isopropyl ester as a white solid/fbam. MS: 510 (M+1).

Example 7

3-(S)-4-f4^l-Fluorobiphenvl-4-eulfonyl)-2.2-dlmethvl-thlomorphoHne-3carboxvlic acid hydroxvamide (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-carboxytate (1.17 g, 3.70 mmol) in 6 mL of methylene chloride was added triethylamine (1.02 ml_ 7.40 mmol) followed by 4'-fiuorobiphenyisutfonyl chloride (1.0 g, 3.70 mmol). The resulting solution was stirred for 56 hours at 23 °C. The reaction mixture was diluted with methylene chloride and washed with water. The organic layer was concentrated in vacuo; the residue was dissolved in methanol, and the mixture was heated at reflux for 6 hours. The mixture was cooled to 23 °C and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 3:7 ethyl acetate/hexanes with 0.1% acetic acid) to give 670 mg of 3-(S)-4-{4^,-fluorobipheny{-4-sulfonyl}-2,225 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-4suifonyl)-2,2-dimethyi-thiomorpholine-3-carboxylic add (605 mg, 1.48 mmol) in 5 mL of methylene chloride was added triethylamine (0.62 mL, 4.43 mmol) under a nitrogen atmosphere. BenzotriazoH-yloxy-tris(dimethyJamino)phosphonium hexafluorophosphate (980 mg, 2122 mmol) was added and the resulting solution was stirred for 5 minutes before O-(trimethyisilylethyi)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

-44stirred for 20 hours at 23 °C. The mixture was diluted with aqueous ammonium chloride and extracted with 1:1 ethyl acetate/diethyi ether (3 x). The_combined organic extracts were washed with saturated aqueous sodium carbonate (2 x), water (1 x), and brine (1 x). The organic layer was dried (magnesium sulfate), filtered, and the filtrate was concentrated in vacuo. The residual yellow oil was purified by flash chromatography (eluting with 3:7 ethyl acetate/hexanes) to give 650 mg of 3-(S}-4(4'-fluorobiphenyl-4-sulfonyi)-2,2-dimethyl-thiomorpholine-3-carboxy1ic add (2trimethylsilanyi-ethoxy)-amide as a white foam. MS: 523 (M-1).

(c) A solution of 3-(S)-4-(4'-fluorobiphenyi-4-suifonyi)-2,2<limethyi10 thiomorpholine-3-carboxylic add (2-trimethytsilanyl-ethoxy)-amide (650 mg, 1.24 mmol) in 8 mL of trifluoroacetic add was stirred for at 22 °C for 16 hours. The mixture was concentrated in vacuo and the residue was triturated with methylene chloride and diethyl ether. The solvent was removed to give 550 mg of a tan solid. The solid was suspended in 1:1 diethyl ether/hexanes and stirred gently for 20 hours. The solids were collected by filtration (1:1 diethyl ether/hexanes rinsing) and dried to give 470 mg of 3-(S)-4-(4^,-fluorobiphenyi-4-sutfonyi)-2,2'dimethylthiomorpholine-3-carboxyiic add hydroxyamide as white solid. MS: 423 (M-1).

Example 8

3-(S)-4-i4-(4-F1uorobenzvloxv)benzene8Ulfonvi1-2.2-dimethv120 thlomorphoUne-3 -carboxylic acid hvdroxvamlde (a) To a stirred, cold (0 °C) solution of the known (Belgian Patent Publication BE 893025) 2,2-dimethy1-thiomorpholine-3-carboxyiic add (600 mg, 3.42 mmol) in 10 mL of 1:1 water/dioxane was added 6 N sodium hydroxide (1.2 mL 7.1 mmol). To the resulting solution 4-{4-fiuorobenzyioxy)benzenesulfonyi chloride (1.08 g, 3.77 mmol) was added. After 30 and 60 minutes an additional 1 gram of 4-(4fiuorobenzyloxy)benzenesuifonyi chloride and 1.2 mL of 6 N sodium hydroxide was added. The mixture (pH ca. 12) was diluted with water and extracted with diethyl ether (1 x). The ethereal layer was washed with 1 N sodium hydroxide; the combined basic aqueous layers were acidified to pH 3 using concentrated hydrochloric add, and the acidic mixture was extracted with ethyl acetate (3 x). The combined organic extracts were dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo to give 820 mg of 3-(S}-4-[4-(4AP/P/ 9 8/01 179

AP 00958

-45fluorobenzyloxy)benzenesulfonyl]-2,2-dimetiiyl-thiomorpholine-3-carboxylic add as a white solid. MS: 438 (M-1).

(b) To a stirred, cold (0 °C) solution of 3-{S)-4-(4-(4-fluorobenzyloxy)benzenesulfonyl]-2,2-dimethy1-thiomorphoiine-3-carboxyiic add (820 mg, 1.87 mmol) in 5 mL of methylene chloride was added triethylamine (0.52 mL, 3.74 mmol) under a nitrogen atmosphere. Benzotriazol-1-yioxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.24 g, 2.81 mmol) was added and the resulting solution was stirred for 5 minutes before O-(tert-butvkflmethvlsilvhhvdroxvlamine (550 mg, 3.74 mmol) was added.The ice bath was removed and the mixture was stirred for 16 hours at 23 °C. The mixture was diluted with aqueous ammonium chloride and extracted with ethyl acetate (3 x). The combined organic extracts were washed with water, brine, and dried over sodium sulfate. Filtration and concentration of the filtrate gave a viscous yellow oil, which was purified by flash chromatography (eluting with 1:3 ethyl acetate/hexanes) to give 270 mg of 3-(S)-4-[4-(415 fluorobenzyloxy)benzenesulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxyiic add (tertbutyldimethyisiloxy)-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-dimethyi-thiomorpholine-3-carboxyiic add (tertbutyidimethylsiloxy)*amide (270 mg, 0.47 mmol) In 10 mL of tetrahydrofuran was added two drops of concentrated hydrochloric add. After 30 minutes the mixture was diluted with 15 mL of tetrahydrofuran and the mixture was concentrated in vacuo to a volume of ca. 5 mL The volume was adjusted to ca. 25 mL with tetrahyrofuran and the mixture was concentrated again to ca. 5 mL This process was repeated twice more before the mixture was finally concentrated to dryness.

The resulting solids were suspended in a mixture of hexanes and diethyl ether and the mixture was stirred for 16 hours. The solid were collected by filtration, rinsed with diethyl ether,and dried to give 180 mg of 3-(S)-4-[4-(4fluorobenzyioxy)benzenesuffonyl]-2,2-dimethyl4hiomorpholine-3 -carboxylic add hydroxyamide as a white solid. MS: 453 (M-1). Ή NMR (400 MHz, dmso-d_f) δ 10.63 (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/F/ 9 8/01 179

AP 00958

-46Preparatlon 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 45 fluorobenzyl bromide (3.3 mL, 26.5 mmol) in 20 mL of ethanol. The mixture was heated at reflux for two days, then cooled to ambient temperature (22 °C), whereupon a white precipitate formed. The flaky white solids were collected by filtration, rinsed with ethyl acetate and diethyl ether, and dried to give 4. 95 g of 4-(4fluoro-benzyloxy)-benzenesulfonic acid sodium salt. A stirred solution of 4-(4-fluoro10 benzyioxy)-benzenesulfonic acid sodium salt (13.0 g, 42.7 mmol) in 50 mL of thionyl chloride and two drops of dimethylformamide was heated at a gentle reflux for 8 hours. The mixture was concentrated to a yellow solid which was suspended in ethyl acetate and filtered. The filtrate was concentrated to 11.2 g of 4-(4fluorobenzyioxy)benzenesulfonyl chloride as a light yellow solid: ¹H NMR (400 MHz,

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 ($, 2 ϋ).

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 toluene was added sodium hydride (60% dispersion in mineral oil, 1.78 g, 44.6 mmol) at ambient temperature (22 °C). After 20 minutes, a solution of 1,3-propane sulfone (3.9 mL, 44.6 mmol) in toluene was added slowly and the mixture was stirred for 16 hours. The reaction was quenched by the addition of methanol and the mixture was concentrated in vacuo to an off-white solid. This solid was suspended in ethyl acetate, filtered, and the solids were collected and dried to give 10.9 g of 3-(425 fluorophenoxy)-propane-1 -sulfonic add sodium salt as an off-white powder. A stirred solution 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 dimethylformamide was heated at reflux for 16 hours. The mixture was then cooled to 0 °C, diluted with 25 mL of diethyl ether, and the reaction was quenched by the slow addition of water. The organic layer was removed and the aqueous layer was extracted with 25 mL of diethyl ether. The combined organic layers were washed with brine and dried over

L I 10/86 /d/dV

AP 00958

-47sodium 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) 2.472.54 (m, 2 H).

Preparation 3

4*-Ruoroblphenviaulfonvl chloride

Chiorosulfonic 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 reaction mixture was poured onto ice. The resulting white predpitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water, brine, dried over magnesium sulfate, and concentrated to afford a white solid. The desired 4'-fluorobiphenylsulfonyl chloride (4.3 g), was separated from 4fluorobiphenylsulfonic add by crystallization of the latter from ethyl acetate and crystallization of the remaining material from hexanes.

Claims (3)

1. or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond;

   X is carbon;

   Y is carbon;

   R¹, R², R³, R⁴, R^s, R^s, 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 (QC₆)alkylthio, (C^CgJalkoxy, trifluoromethyl, halo, (C^-C₁₀)aryl, (C₂-C₉)heteroaryl, (C₆C₁₀)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, piperazinyi, (CgCio)aryl(Ci-C₆)alkoxy, (C₂-C₉)heteroaryl(C₁-C₆)aIkoxy, (C^Cgjacylamino, (C^Cgjacyithio, (C_r C₆)acyloxy, (C^CJalkylsulfinyl, (C₆-C₁₀)arylsulfinyl, (CrCgjalkylsulfonyl, (C₆-C₁₀)arylsulfonyl, amino, (C^CJalkylamino or ((Cq-C^alkyl^mino; (C^-Cgjalkenyl, (C₆-C₁₀)aryl(C₂-C₆)alkenyl, (C₂-C₉)heteroaryl(C₂-C₆)alkenyl, (C₂-C₆)alkynyi, (C₆-C₁₀)aryl(C₂-C₆)alkynyl, (C₂-C₉)heteroaryl(C₂CJalkynyl, (CYC^alkylamino, (C^CJalkylthio, (Q-Cgjalkoxy, perfluoro/C^Cgjalkyl, (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.,-C₆)alkyl(hydroxymethylene), piperidyl, (C-,-C₆)aikylpiperidyI, (C^Cgjacylamino, (C.,-C₆)acylthio, (C^Cgjacyloxy, R^C,C₆)alkyl or a group of the formula

   AP/P/ 9 8/01 179

   USERS\DOCS\LA21952\LPGXB\33CGO11.DOC /144304 / PC9596A. la USOA on Merits <w>.

   II <tL>_n

   -'ύΑγότ- ’ 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 bridged diazabicycloalkyl ring selected from the group consisting of m

   <CH₂)_r ^N·

   V cn rx o

   •x.

   OO u

   Cl <

   wherein r is 1,
2. (2/?,3S)-{1 -[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxycarbamoyl-piperidin-3yl}-carbamic acid isopropyl ester;

   [3-(S)4-(4’-Fluorobiphenyl>4-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;

   2 or 3; m is 1 or 2; p is 0 or 1; and

   USERS\DOCS\LA21952\LPGXB\33CGOH.DOC / 144304 / PC9596A.lst USOA on Merits

   Λ Ο Π 9 5 8

   5 0

   V is hydrogen, (CrCajalkyl, (C₁-C₆)alkyl(C=O)-, (C^Cg) alkoxy(C=O)-, (C₆Cio)aryl(C=0)-, (C₆-C₁₀)aryloxy(C=O)-, (C₆-C₁₀)aryl(C₁-C₆)alkyl(C^:=O)-, (C₆-C₁₀)aryl-(C₁C₆)alkoxy(C=O)-, or (C₁-C₆)alkoxy(C=O)-O-;

   wherein each heterocyclic group may optionally be independently substituted by one or two groups selected from hydroxy, (C,-C₆)alkyl, (C^Cgjalkoxy, (CpC^acyl, (CrC^jacyloxy, (C₆-C₁₀)aryl, (C₂-C₉)heteroaryl, (Cg-C^jaryKC^Cgjalkyl, (Cz-CgJheteroaryKC^CJalkyl, hydroxy^-C^alkyl, (CrCgjalkoxy^-CJalkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, (CrCgjalkylthio, (C_r C₆)alkylthio(C.,-C₆)alkyl, (C₆-C₁₀)arylthio, (C₆-C₁₀)arylthio(C_rC₆)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)-(C_rC₆)alkyl;

   wherein R¹⁰ is (C_rC₆)acylpiperazinyl, (C_s-C₁₀)arylpiperazinyl, (C₂C₉)heteroarylpiperazinyl, (C_rC₆)alkylpiperazinyl, (Cg-C^aryKC^-Cgjalkylpiperazinyl, (C₂CgjheteroaryKC^Cgjalkylpiperazinyi, morpholinyl, thiomorphoiinyl, pyrrolidinyl, piperidyl, (C,C_s)alkylpiperidyl, (C₆-C₁₀)arylpiperidyl, (C₂-C₉)heteroarylpiperidyl, (CrCgJalkylpiperidyKCr C₆)alkyl, (Cg-C^arylpiperidyKCrCgjalkyl, (C₂-C_e)heteroaryl-piperidyl-(C₁-C₆)alkyl or (0,C₆)acyipiperidyl;

   R¹¹ is hydrogen, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C.,-C6)alkyl, (C2CgjheteroaryKCrCgjaikyl, (CrCgjalkyKCg-C^aryl^-Cgjalkyl, (CrCgjalkyKCz-CgjheteroaryKC·,C6)alkyl, 5-indanyl, -CHR¹⁷O-(C=O)-R¹⁸ or -CH2(C=O)-NR¹⁹R²⁰;

   R¹² and R¹³ are each independently hydrogen, (Q-Cgjalkyl, (C₆-C₁₀)aryl, (C₂C₉)heteroaryl, (Cg-C^ary^CrCJalkyl or (Cz-CgJheteroaryKC^Cgjalkyl or R¹² and R¹³ may be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorphoiinyl ring;

   R¹⁴ is trifluoromethyl, (Q-Cgjalkyl, (C₆-C₁₀)aryl, (C₂-C₉)heteroaryl, (Cg-C^aryKC,C₆)alkyl or (Q>-C₉)heteroaryl(C₁-C₆)alkyl;

   R¹⁵ is hydrogen, (CcCgJalkyl, (C^Cgjalkoxy, (C₆-C₁₀)aryl, (C₂-C₉)heteroaryl, (C_r C₆)aryl(Ci-C6)alkyl(C6“C-io)aryl(Ci-Cg)alkoxy or (C₂-C₉)heteroaryl(C.)-Cg)alkyl;

   R¹⁶ is (CrCgjalkyl, {Cg-C10)aryl, (C2-C9)heteroaryl, (Cg-C^jaryKC^Cgjalkyl, 5-indanyl, [CH(R¹⁷)]O-(C=O)-R¹⁸, -CH^Oj-NR^R²⁰, or R²¹O(C1-C₆)alkyl;

   R¹⁷ is hydrogen or (CrCgJalkyl;

   R^1S is (CrQalkyl, (C_rC₆)alkoxy or (C₆-C₁₀)aryl;

   R¹⁹ and R²⁰ are each independently hydrogen or (Q-Cgjalkyl or may be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomopholinyl ring;

   USERS\DOCS\LA21952\LPGXB\33CGOH.DOC / 144304 / PC9596A. la USOA on Merits

   AP Ο Ο 9 5 θ

   R²¹ is H₂N(CHR²²)(C=O)-;

   R²² is the side chain of a natural D- or L-amino acid;

   R²³ is hydrogen, ((^-C^acyl, (C^CJalkyl, (Cg-CmjaryKC^Cejalkyl, (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-C JarylfC^CJalkoxyfCg-C^aryl or (CqC_g)heteroaryl(C.,-C₆)alkoxy(C₆-C.,₀)aryl optionally substituted by fluoro, chloro, (C,CJalkyl, (C.,-C₆)alkoxy or perfluoroiC^CaJalkyl;

   with the proviso that when R¹, R², R³, R⁴, R⁵, R®, R⁷, R®, and R® are ail defined by hydrogen 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, 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 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 a heteroatom when the broken line represents a double bond, the heteroatom cannot be directly bonded to positions X and Y. 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 optional double 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 (C,C6)alkylthio, (C^-CJalkoxy, trifluoromethyl, halo, (Q-C10)aryl, (C2-C9)heteroaryl, (C6C10)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, (CgC10)aryl(Ci-C6)alkoxy, (C2-C9)heteroaryl(C.,-C6)alkoxy, (C^Cgjacylamino, (C.,-C6)acylthio, (C,C6)acyloxy, (C^C^alkylsulfinyl, (C6-C10)arylsulfinyl, (C.,-C6)alky!sulfonyl, (C6-C10)arylsulfonyl, amino, (C.|-C6)alkylaminoor ((CrCgjalkyl^amino; (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(C2C6)alkynyl, (C^Cgjalkyiamino, (C^CJalkylthio, (C.,-C6)alkoxy, perfluoroCCrCsjalkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)arylamino, (C6-C10)arylthio, (C6-C10)aryloxy, (C2-C9)heteroarylamino, (C2-C9)heteroarylthio, (C2-C9)heteroaryloxy, (Cj-CJcycloalkyl, (C^CgjalkyKhydroxymethylene), piperidyl, (C^Cgjalkylpiperidyl, (C^Cgjacylamino, (C^Cgjacylthio, (CpCgjacyloxy, 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 <u>_y ¹¹ <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 bridged diazabicycloalkyl ring selected from the group consisting of (CH₂)_r ^N'

   V oo 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

   V is hydrogen, (CrCsJalkyl, (C₁-C₆)alkyl(C=O)-, (C^Cg) alkoxy(C=O)-, (C₆Cio)3iyl(C⁼0)-, (C6-C10)aryloxy(C=O)-, (C6-C1Q)aryl(C1-Cs)alkyl(C⁼O)-, (Cg-C19)aryi-(C₁C₆)alkoxy(C=O)-, or (C₁-C₆)alkoxy(C=O)-O-;

   wherein each heterocyclic group may optionally be independently substituted by one or two groups selected from hydroxy, (C,-C₆)alkyl, (C.,-C₆)alkoxy, (C^C^Jacyl, (CpC^acyloxy, (C₆-C₁₀)aryl, (C₂-C₉)heteroaryl, (Cg-C^aryKCrCgjaikyl, (Cj.-C^heteroarykCrCgjalkyl, hydroxyfC^Cgjalkyl, (C^CgJalkoxyiCpCgjalkyl, (C^CgJacyloxyiCrCgjalkyl, (C^CgJalkylthio, (C_r C₆)alkylthio(C₁-C₆)alkyl, (C₆-C₁₀)arylthio, ((VC₁₀)arylthio(C,-C₆)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 (CrCJacylpiperazinyl, (C₆-C₁₀)arylpiperazinyl, (C₂C₉)heteroarylpiperazinyl, (C₁-Og)alkylpiperazinyl, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperazinyl, (C₂C₉)heteroaryl(C₁-C₆)alkylpiperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidyl, (C,C₅)alkylpiperidyl, (Cg-C₁₀)arylpiperidyl, (C₂-C₉)heteroarylpiperidyl, (C^CgjalkylpiperidylfC!C₆)alkyl, (Cs-C^jarylpiperidyl/C^Cgjalkyl, (C₂-C₉)heteroaryl-piperidyl-(Ci-C₆)aIkyl or (C_r C₆)acylpiperidyl;

   R¹¹ is hydrogen, (C₆-C₁₀)aryl, (C₂-C₉)heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₂CgJheteroarylfCpCgjalkyl, (C^CgJalkykCg-C^JarykC^Cgjalkyl, (CrCeJalkyKCj-CgJheteroaryKCc C₆)alkyl, 5-indanyl, -CHR¹⁷O-(C=O)-R¹⁸ or-CH^C^-NR^R²⁰;

   R¹² and R¹³ are each independently hydrogen, (C,-C₆)alkyl, (C₆-C₁₀)aryl, (C₂C₉)heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl or (Cg-CgjheteroarykC^Cgjalkyl or R¹² and R¹³ may be taken 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 (C₂-C₉)heteroaryl(C₁-C₆)alkyl;

   R¹⁵ is hydrogen, (C^Cgjalkyl, (C.,-C₆)alkoxy, (C₆-C₁₀)aryl, (C₂-C₉)heteroaryl, (C,C₆)aryl(C₁-Cg)alkyl(C6-G₁₀)aryl(C₁-Cg)alkoxy or (Cz-CgjheteroarylfC^C^alkyi;

   R¹⁶ is (CrCgJalkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C.,-C6)alkyl, 5-indanyl, [CH(R¹⁷)]O-(C=O)-R¹⁸, -CH2(C=O)-NR¹⁹R²⁰, or R²O(C₁-C₆)alkyl;

   R¹⁷ is hydrogen or (C^CgJalkyl;

   R¹⁸ is (C^Cgjalkyl, (C^Cgjalkoxy or (C₆-C₁₀)aryl;

   R¹⁹ and R²⁰ are each independently hydrogen or (C^Cgjalkyl or may be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomopholinyl ring;

   AP/P/ 9 8/01 179

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   AP 00958

   R²¹ is H₂N(CHR²²)(C=O)-;

   R²² is the side chain of a natural D- or L-amino acid;

   R²³ is hydrogen, ((VC^acyl, (Ch-C^alkyl, (Cg-C^jaryKCrCeJalkyl, (C₂-C9)heteroaryl(C_r

   C₆)alkyl or (C_rC₆)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 the formula >23

   Q is (C_e-C₁₀)aryl(C_e-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₆)alkoxy(C_e-C₁₀)aryl or (C_r C₉)heteroaryl(C₁-C_e)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 by hydrogen or (Cj-CeJalkyl, 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 a heteroatom when the broken line represents a double bond, the heteroatom cannot be directly bonded to positions X and Y. —

   3. A compound of the formula

   AP/P/9 8/0 1 179

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   AP 00958

   5b or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double 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^Cgjalkyl optionally substituted by one or two groups selected from (C,C6)alkylthio, (C^-CJalkoxy, trifluoromethyl, halo, (Q-C10)aryl, (C2-C9)heteroaryl, (C6C10)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, (CgCuOaryKCrC^alkoxy, (C2-C9)heteroaryl(C.|-C6)alkoxy, (C-rC^acylamino, (CrCgJacylthio, (Cr C6)acyloxy, (CrC6)alkylsulfinyl, (C6-C10)arylsulfinyl, (CrCJalkylsulfonyl, (C6-C10)arylsulfonyi, amino, (CVC^alkylamino or ((Cq-CgjalkyOzamino; (Cj-C^alkenyl, (C6-C10)aryl(C2-C6)alkenyi, (C2-C9)heteroaryl(C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl(C2-C6)alkynyl, (C2-C9)heteroaryl(C2C6)alkynyl, (C.,-C6)alkylamino, (C^CJalkylthio, (CrC6)aikoxy, perfluoro(C.,-C6)a[kyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryiamino, (C6-C10)arylthio, (C6-C10)aryloxy, (C2-C9)heteroarylamino, (C2-C9)heteroarylthio, (Cz-Cgjheteroaryloxy, (C3-C6)cycloalkyl, (C^Cgjalky I (hydroxy methylene), piperidyl, (CrC^alkylpiperidyl, (C^CJacylamino, (CrCJacylthio, (C^-Cgjacyloxy, R¹⁰(Cr C₆)alkyl or a group of the formula

   AP/P/9 8/0 1 179

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   AP 00958

   0- z <_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, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl or a bridged diazabicycloalkyl 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

   USERSMXXSU>21952UJ>CXB\33CG011.DOC/ 144304 7PC9396A.la USOA on Merits

   AP 0 Q 9 5 8

   V is hydrogen, (C_rC₃)alkyl, (C^CgjalkyKOO)-, (C^Cg) alkoxy(C=O)-, (C₆Cio)^aryl(C⁼0)-, (C6-C10)aryloxy(C=O)-, (C6-C10)aryl(C1-C6)alkyl(C⁼O)-, (Cg-C-,o)aryl-(CiC6)alkoxy(C=0)-, or (C₁-C₆)alkoxy(C=O)-O-;

   wherein each heterocyclic group may optionally be independently substituted by one or two groups selected from hydroxy, (C,-C₆)aikyl, (CrC^alkoxy, (C^Cmjacyl, (C^C^jacyloxy, (C₆-C₁₀)aryl, (C₂-C₉)heteroaryl, (Cg-C^aryKCrCgJalkyl, (Cz-CgjheteroaryKCpCgJalkyl, hydroxy^-CJalkyl, (C^Cejalkoxy/CrC^alkyl, (C^Cgjacyloxy/C^Cgjalkyl, (Q-CJalkylthio, (C_r CejalkylthioiCrCejalkyl, (C₆-C₁₀)arylthio, (Cg-C^arylthioCCrCgJalkyl, 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 (C^Cgjacyipiperazinyl, (C₆-C₁₀)arylpiperazinyl, (C₂C₉)heteroarylpiperazinyl, (C^-Cgjalkylpiperazinyl, (Cg-Cmjaryl/C^Cejalkylpiperazinyl, (C₂Cgjheteroaryl/Ci-CfOalkylpiperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidyl, (C,C₆)alkylpiperidyl, (C₆-C₁₀)arylpiperidyl, (C₂-Cg)heteroarylpiperidyl, (C.,-C₆)alkylpiperidyl(C.|C₆)alkyl, (C₆-C₁₀)arylpiperidyl(C.,-C₆)alkyl, (Cz-Cgjheteroaryl-piperidyKC^CgJalkyl or (C-,C₆)acylpiperidyl;

   R¹¹ is hydrogen, (Ce-C₁₀)aryl, (C₂-C₉)heteroaryl, (Cg-C^aryl/CVCJalkyl, (C₂CgJheteroaryl/Ci-CJalkyl, (C₁-C₆)alkyi(C₆-C₁₀)aryl(C₁-C₆)alkyl, (CrC^alkyKCz-CgJheteroaryKCr C₆)alkyl, 5-indanyl, -CHR¹⁷O-(G=O)-R¹⁸ or-CH^C^-NR^R²⁰;

   R¹² and R¹³ are each independently hydrogen, (C_rC₆)alkyl, (C₆-C₁₀)aryl, (C₂C₉)heteroaryl, (C₆-C₁₀)aryl(C.,-C₆)alkyl or (C₂-C₉)heteroaryl(C₁-Cg)alkyl or R¹² and R¹³ may be taken 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)aryi, (C₂-C₉)heteroafyl, (Cg-C^aryKCc C₆)alkyl or (Cz-CgJheteroaryKCrCgJalkyl;

   R¹⁵ is hydrogen, (C^CgJalkyl, (CVCJalkoxy, (C₆-C₁₀)aryl, (C₂-C₉)heteroaryl, (C_r C₆)aryl(C₁-C₆)alkyl(C₆-C₁₀)aryl(C₁-C₆)alkoxy or (Cz-CgjheteroaryKC^Cgjalkyl;

   R¹⁶ is (CpCgJalkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (Ce-C^aryl^-C^alkyl, 5-indanyl, [CH(R¹⁷)]O-(C=O)-R¹⁸, -CH2(C=O)-NR¹⁹R²⁰, or R²¹O(C_rC₆)alkyl;

   R¹⁷ is hydrogen or (C^Cgjalkyl;

   R¹⁸ is (CrCeJalkyl, (C^CJalkoxy or (C₆-C₁₀)aryl;

   R¹⁹ and R²⁰ are each independently hydrogen or (CpCgJalkyl or may be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomopholinyl ring;

   ΑΡΠΝ 9 8/01 179

   USERS\DOCS\LA21932yj>GXB\33CG011.DOC/ 144304 /PC9596A. 1st USOA on Merits

   0 0 9 5 8

   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, (C_rC₆)alkyl, (C₆-C₁₀)aryl(C_rC₆)alkyI, (Cz-CgjheteroarykC^ C₆)alky! or ((/-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 the formula

   Ν'

   Q is (Cg-C^JarylfC^CeJalkoxyfCg-Cmjaryl optionally substituted by fluoro, chloro, (CrCgJalkyl, (C^C^alkoxy or perfluoro(C₁-C₃)alkyI;

   with the proviso that when R¹, R², R³, R⁴, R⁵, R^e, R⁷, R⁸, and R⁹ are all defined by hydrogen 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, 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 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 a heteroatom when the broken line represents a double bond, the heteroatom cannot be directly bonded to positions X and Y. Please amend the following claims:

   6 L I 10/86 /d/dV

   - 4. A compound according to claim and R⁹ are hydrogen. 5 . A compound according to claim

   R⁷-R⁹ is other than hydrogen. 6. - A compound according to claim

   R⁷-R⁹ is (CrCeJalkyl. [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

   ⁷ · A compound according to claim [1], wherein at least one of R⁷-R⁹ is methyl. — 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 . A compound according to claim [1], wherein R⁷ and R⁸ are each methyl. — 10 . A compound according to claim [1], wherein R⁷ and R⁸ are taken together to form a (Q-C₆)cycloalkyl group. - 11. A compound according to claim f wherein R⁷ and R⁸ are taken together to form a (C₃-C₈)cycloalkyl group. 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-4carboxylic acid;

   (2R, 4/?)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-2-hydroxy carbamoyl-pipe ridine-4carboxylic acid methyl ester;

   (2R,4R)-1-[3-(4-Fluorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoyl-piperidine-4carboxylic acid;

   (2R,4R)-1-[3-(4-Fluorophenoxy)-propane-1-sulfonyI]-2-hydroxy carbamoyl-piperidine-4carboxylic acid methyl ester;
3. 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-carboxylic acid hydroxyamide; and (2R,4R)-1-(4-Methoxybenzenesulfonyl)-4-(piperazine-1-carbonyl)-piperidine-2carboxylic acid hydroxyamide hydrochloride. 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 standard NSAID’s and analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) or (b) the inhibition of

   AP/P/ 9 8/01 179

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   AP 00958 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 such treatment and a pharmaceutically acceptable carrier. — 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, comprising administering to said mammal an effective amount of a compound of claim [1]. 15. ·. ·· A method for treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, compounds of formula I may be used in combination with standard NSAID’s and analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim _; T effective in treating such a condition. -