OA12529A

OA12529A - Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors.

Info

Publication number: OA12529A
Application number: OA1200300123A
Authority: OA
Inventors: Brian Scott Bronk; Mark Carl Noe; Martin James Wythes
Original assignee: Pfizer Prod Inc
Priority date: 2000-10-26
Filing date: 2001-10-23
Publication date: 2006-06-02
Also published as: WO2002034753A2; GT200100213A; WO2002034753A3; ECSP034567A; KR20040004412A; EA005762B1; HN2001000244A; MXPA03003735A; BR0114913A; CN1501937A; SK4972003A3; IS6762A; IL154948A0; SV2003000705A; HRP20030332A2; AP2001002318A0; EE200300196A; EP1332146A2; HUP0301577A3; HUP0301577A2

Abstract

The present invention relates to 5-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors of the formula wherein said "A" is a 5-7 membered heterocyclic ring as defined in the specification and to pharmaceutical compositions and methods of treating inflammation, cancer and othter disorders.

Description

4 0125 29

SPIRO-PYRtMtDINE-2.4,6-TR10NE METALLOPROTEINASE INHIBITQRS

Backqround of the Invention

The présent invention relates to 5-spiro-pyrimidine-2,4,6-trione metalloproteinaseinhibitors and to pharmaceutical compositions and methods of treatment of inflammation, 5 cancer and other disorders.

The compounds of the présent invention are inhibitors of zinc metalloendopeptidases,especially those belonging to the class of matrix metalloproteinases (also called MMP ormatrixin).

The MMP subfamily of enzymes, currently contains seventeen members (MMP-1,10 MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14,MMP-15, MMP-16, MMP-17, MMP-18, MMP-19, MMP-20). The MMP's are most well knownfor their rôle in reguiating the turn-over of extraceliular matrix proteins and as such playimportant rôles in normal physiotogical processes such as reproduction, development anddifférentiation. In addition, the MMP's are expressed in many pathological situations in which 15 abnormal connective tissue turnover is occurring. For example, MMP-13 an enzyme withpotent activity at degrading type II coilagen (the principal coîiagen in cartilage), has beendemonstrated to be overexpressed in osteoarthritic cartilage (Mitcheli, et al., J. Clin, invest.,97, 761 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are alsooverexpressed in osteoarthritic' cartilage and inhibition of some or ail of these MMP's is 20 expected to slow or block the accelerated loss of cartilage typical of joint diseases such asosteoarthritis orrheumatoid arthritîs.

Il is recognized that different combinations of MMP's are expressed in differentpathological situations. As such, inhibitors with spécifie seiectivities for individua! MMP's maybe preferred for individual diseases. 25 Matrix metalloproteinase inhibitors are well known in the literature. Hydroxamic acid MMP inhibitors are exempiified in European Patent Publication 606,046, published July 13,1994. Several pyrimidine-2,4,6-trione MMP inhibitors are referred to in PCT publication WO98/58925, published December 30, 1998. PCT publication WO 00/47565, published August17, 2000 refers to certain aryl substituted pyrimidine-2,4,6-trione MMP inhibitors. United 30 States Non-provisional application 09/635156, filed August 9, 2000 (which daims priority toUnited States Provisionai application 60/148547 filed August 12, 1999) refers to heteroarylsubstituted pyrimidine-2,4,6-trione MMP inhibitors. United States Provisionai Applicationentitled “Pyrimidine-2,4,6-trione Metalloproteinase Inhibitors", filed October 26, 2000, refers tocertain pyrimidine-2,4,6-triones. Barbituric acids and methods for their préparation are well 35 known in the art, see for example Goodman and Gilman's, "The Phamacolooical Basis ofTherapeutics," 345-382 (Eighth Edition, McGraw Hill, 1990). Each of the above referencedpublications and applications is hereby incorporated by référencé in its entirety. 012529 -2-

Summarv of the Invention

The présent invention relates to compounds of the formula:

wherein said *A" is a 5-7 membered heterocyclic ring selected from the group consisting of:

012529 -3-

R2, R3, R4, R5, R6, R7, R8, Rs, R10, R11, R’2 and R13 isindependentiy selected from the group consisting of hydrogen, (Ci-C4)alkyl, (C1-C4)aikenyl,(CrC4)alkynyi, (Cs-C10)aryl, (C1-C10)heteroaryl, (C3-C8)cycloalkyl and (C,-C10)heterocyclyl;wherein each of said (CrC4)alkyl, (C5-C10)aryl, (CrC)0)heteroaryl, (C3-C8)cycloalkyi and (C,-C10)heterocyclyl may be optionatly substituted on any of the ring carbon atoms capable offorming an additional bond with 1-3 substituents per ring independentiy selected from halo,(CrC4)alkylt (C,-C4)alkoxy, -CN, -OH and -NH2; X is (C5-C10)aryl or (C-rC^heteroaryl; Y is selected from the group consisting of a bond, oxygen, sulfur, >C=O, >SO2, >S=O,-CHr> -CH2O-, -0{CH2)n-. -CH2S-, -S(CH2)„-, -CH2SO-, -CH2SO2-, -SO(CH2)n-, -SO2(CH2)n-, -NR’4, -NR14<CH2)„-, -CH2[N(R14)]-, -CH2(CH2)n-, -CH=CH-, -CsC-, -[N(R,4)]-SOrand -SO2[N(R14)]-; n is an integer from one to four; R14 is hydrogen or (C,-C4)aikyi; Z is selected from the group consisting of (C6-C10)aryl, (C3-C8)cycloalkyi, (CrC10)heterocyclyl and (CpCwJheteroaryl; wherein one or two carbon-carbon single bonds ofsaid (C3-C8)cycioalkyl or (Ci-Ci0)heterocyclyl may optionally be replaced by carbon-carbondouble bonds; wherein each of said X or Z may be independentiy optionally substituted on any of thering carbon atoms capable of forming an additional bond by one or two substituents per ringindependentiy selected from F, Cl, Br, CN, OH, (Ci-C4>alkyl, (C1-C4)perfiuoroalky!, (C-i-C4)perfluoroalkoxy, (C1-C4)alkoxy and (C3-CB)cycloalkyloxy; G is R15-(CR1SR17)P-; wherein G is a substituent on any ring carbon atom of Z capableof forming an additional bond and is oriented at a position other than alpha to the point ofattachment of the Z ring to Y; p is an integer from 0 to 4; R15 is independentiy selected from the group consisting of halo, -CN, -NO2, OH, (CrC4)aikenyl, (Ci-C4)aîkynyl, (C1-C4)perfluoroalkyl, perfluoro(C,-C4)alkoxy. R18-, R18-O-, R18-(C,-C„)alkyi-O-, R18-(C=O)-, R18-(C=O)-O-, R,8-O-(C=O)- R18-S-, R22-{S=O)-, R18-(SO2)-, R22-(SO2)-(NR2>, R3S-(C=O)-(NR2')-, R22-O-(C=O)-(NR2a)-, (RasR2ü)N-, (R19R2û)N-(SO2)-, (R19R20)N-(C=O)-; (R18R20)N-(C=OMNR21)- and (R18R20)N-(C=O)-O-; each of R18 and R17 is independentiy selected from hydrogen and (Ct-C4)alkyi; 012529 -4- or R16 and R17 may optionally be taken together with the carbon to which they areattached to form a 5 to 10-membered carbocyclic ring; R18, R19, R20 and R21 are independently seiected from the group consisting ofhydrogen, (CrC4)alkyi, (C6-C,o)aryi, (C3-C8)cycloalkyl, (CrC10)heteroary| and (CrC10)heterocyclyl; wherein said (Ce-Cio)aryl, (C3-C8)cycloalkyl, (CrC10)heteroaryl and {C,-Cl0)heterocyclyl moieties may be optionally substituted on any of the ring carbon atomscapable of forming an additions! bond by one to three substituants per ring independentlyseiected from F, Cl, Br, CN, OH, (CrC4)alkyl, (CrC4)perfiuoroalkyl, (C^C^perfluoroalkoxy,(C4-C4)alkoxy, amino, (CrC4)alky!-NH-, [(CrC4)alkyl]2-N- and (C3-C8)cycloalkyioxy; whereinsaid (C3-C8)cycloalkyi and (CrC10)heterocyclyl moieties may also optionally be substituted byoxo; wherein said (C,-Cw)heteroaryl and (CrCi0)heterocyclyi moieties may optionally besubstituted on any ring nitrogen atom able to support an additions! substituent by one to twosubstituents per ring independently seiected from the group consisting of (Ci-C4)alk'yl and (CrC4)alkyl-(C=O)-; or R19 and R2Û may optionally be taken together with the nitrogen to which they areattached to form a 3 to β-membered heterocyclic ring; or R19 and R21 may optionally be taken together with the nitrogen, the carbon or theoxygen to which they are attached to form a 3 to 8-membered heterocyclic ring; R22 is seiected from the group consisting of (C1-C4)alky1, (C6-C10)aryl, (C3-C8)cycloalkyl, (CrCw)heteroaryl and (C,-Cio)heterocyclyl; wherein said (C6-C10)aryl, (C3-C8)cycloalkyi, (Ci-C,o)heteroaryl and (Ci-Cw)heterocyclyl moieties may be optionallysubstituted on any of the ring carbon atoms capable of forming an additional bond by one tothree substituents per ring independently seiected from F, Cl, Br, CN, OH, (CrC4)alkyi, (CrC4)perfluoroalkyl, (C,-C4)perfluoroalkoxy, (CrC4)alkoxy, amino, (C,-C4)alkyl-NH-, [(C,-C4)alkyl]2-N- and (C3-C8)cycloalkyloxy; wherein said (C3-C8)cycloalky! and (CrC10)heterocyclyImoieties may also optionally be substituted by oxo; wherein said (Ci-C10)heteroaryl and (C,-C10)heterocyclyl moieties may optionally be substituted on any ring nitrogen atom able tosupport an additional substituent by one to two substituents per ring independently seiectedfrom the group consisting of (CrC4)alkyl and (CrC4)alkyl-(C=O)-; or R21 and R22 may optionally be taken together with the nitrogen, the oxygen or thesulfur to which they are attached to form a 3 to 8-membered heterocyclic ring; or the pharmaceutically acceptable salts thereof.

The présent invention also relates to the pharmaceutically acceptable acid additionsalts of compounds of the formula I. The acids which are used to préparé thepharmaceutically acceptable acid addition salts of the aforementioned base compounds of thisinvention are those which form non-toxic acid addition salts, Le., salts containingpharmacologicaliy acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, 012529 -5- tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate,methanesulfonate, ethanesulfonate, benzenesuifonate, para-toluenesulfonate and pamoate[i.e., 1,T-methylene-bis-(2-hydroxy-3- naphthoate)]salts.

The invention aiso relates to base addition salts of formula l. The Chemical bases thatmay be used as reagents to préparé pharmaceuticaliy acceptable base salts of thosecompounds of formula l that are acidic in nature are those that form non-toxic base saits withsuch compounds. Such non-toxic base salts include, but are not limited to those derived fromsuch pharmacologically acceptable cations such as alkali métal cations (e.g., potassium andsodium) and alkaline earth métal cations (e.g., calcium and rriagnesium), ammonium or water-soiuble amine addition salts such as N-methylglucamine (meglumine) and the loweralkanolammonium and other base salts of pharmaceuticaliy acceptable organic amines.

The term “a bond”, as used herein in the group Y, means that the groups X and Z aredirectly connected through a carbon-carbon bond so as to form pendent aryi rings such asdiphenyi.

The dashed Fines as used in each of the heterocyclic ring “A” of formulae a), b), c), g),h), i), k) and i) refer to optional double bonds. The exact positions of the optional doublebonds for each of the heterocyclic ring “A" of formulae a), b), c), g), h), i), k) and I) are asdefined in the spécification. Whenever the dashed line extends over two carbon atoms, oneskilled in the art will understand that two carbons are tetravalent and that the extrasubstituent(s) (Le., any of R1, R2, R3, R4, R5, R6, R7, R8, R10, R11, R12, or R13) may be absent.

The term "alkyl", as used herein, unless otherwise indicated, includes saturatedmonovalent hydrocarbon radicals having straight, branched moieties, or combinations thereof.Alkyl groups, wherever they occur, may be optionally substituted by a suitabie substituent.

The term "alkenyl", as used herein, unless otherwise indicated, includes hydrocarbonradicals containing at least one olefin linkage and having straight, branched moieties, orcombinations thereof.

The term "alkynyl", as used herein, unless otherwise indicated, includes hydrocarbonradicals containing at ieast one carbon-carbon triple bond linkage and having straight, branchedmoieties or combinations thereof.

The term "cyçioalkyl", as used herein, unless otherwise indicated, includes a mono orbicyclic carbocyciic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyciohexyl, cycloheptyl,cyclooctyl, cyciononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl,bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally containing 1or2 double bondsand optionally substituted by 1 to 3 suitabie substituents as defined below such as fluoro,chloro, trifluoromethyl, (CrC„)alkoxy, (Ce-C10)ary!oxy, trifluoromethoxy, difluoromethoxy or(C,-C4)alkyl, more preferably fluoro, chloro, methyl, ethyi and methoxy. 012529 -6-

The term "aikoxy", as used heretn, includes O-alkyl groups wherein "alkyl" is as defîned above.

The term "halo", as used herein, unless otherwise indicated, includes fluorine, chlorine,bromine or iodine, preferabty fluorine or chlorine. 5 The term “aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removai of one or more hydrogens, such as phenyl ornaphthyl, optionally substituted by1 ίο 3 suitable substituents such as fiuoro, chloro, cyano, nitro,trifluoromethyl, (CrC6}alkoxy, (Cs-CwJaryloxy, (C3-C8)cycloalkyloxy, trifluoromethoxy,difluoromethoxy, or (CrC6)alkyl. 10 The term “heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of ’one or morehydrogens, such as benzimidazolyl, benzofuranyt, benzofurazanyl, 2H-1-benzopyranyl,benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, ben2oxa2Olyl, chromanyl,cinnolinyl," furazanyi, furopyridinyl, furyl, imidazoiyl, indazolyl, indolinyl, indolizinyl, indofyl, 3H- 15 indoiyl, isoindolyl, isoquinoiinyl, isothtazolyl, isoxazolyl, naphthyridinyi, oxadiazolyl, oxazolyf,phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyi, pyrazolyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxaiinyt, tetrazolyl, thiazolyi, thiadiazolyi, thienyl, triazinyl andtriazolyl, 'wherein said (Cj-Ci0)heteToaryl is optionally substituted on any of the ring carbonatoms capable of forming an additional bond by one ar two substituents independently 20 selected from F, Cl, Br, CN, OH, (CrC^alkyi, (C^-C^perfluaroalkyl, (CrC^perfluoroalkoxy,(CrC4)alkoxy and (Cj-C8)cycloalkyloxy. The foregoing groups, can be C-attached or N-attached where such is possible. For instance, pyrrolyl can be pyrro!-1-y! (N-attached) orpyrrol-3-yl (C-attached).

The term "heterocyclyl", as used herein, unless otherwise indicated, includes an organic 25 radical derived from a non-aromatic heterocyclic compound by removal of one or morehydrogens, such as 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]-heptanyl, azetidinyl,dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1,3-dioxolanyi, 1,4-dithianyi,hexahydroazepinyi, hexahydropyrimidine, imidazolidinyl, imidazolinyl, isoxazolidinyi,morpholinyl, oxazolidinyl, piperazinyl, piperidinyi, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, 30 pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,6-tetrahydropyridiny!, tetrahydrothienyl, tetrahydrothiopyranyl,thiomorpholinyl, thioxanyl and trithianyl. The foregoing groups, can be C-attached or N-attachedwhere such is possible. For example, piperidinyi can be piperidin-1 -y) (N-attached) or piperidin-4-yl (C-attached). The foregoing groups, as derived from the compounds listed above, can be 35 optionally substituted where such is possible by a suitable substituent, such as oxo, F, Cl, Br,CN, OH, (CrC^alkyl, (C,-C4)perfluoroalkyl, {CrC4)perfluorpalkoxy, (CrC4)alkoxy, or (C3-Ce)cycloalkyioxy. 012529

The phrase "a suitable substituent" is intended to mean a chemicaliy andpharmaceutically acceptable functional group i.e., a moiety that does not negate the inhibitoryactivity of the inventive compounds. Such suitable substituents may be ro'utinely selected bythose skilled in the art. Illustrative exampies of suitable substituents inciude, but are not lïmitedto halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, hydroxy groups, oxogroups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryi groups, aryloxy orheteroaryloxy groups, araîkyi or heteroaralkyl groups, aralkoxy or heteroaralkoxy groups, carboxygroups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups,alkoxycarbonyi groups, alkyiaminocarbonyl groups dialkylamino carbonyl groups, aryicarbonyigroups, aryloxycarbonyl groups, alkylsulfonyl groups, an aryisulfonyl groups and the like.

The phrase "at a position other than alpha to the point of attachment of the Z ring toY", as used herein, unless otherwise indicated, is intended to mean a chemicaliy andpharmaceutically acceptable orientation of the bond connecting group Z to G (Z-G bond)relative to the bond connecting group Y to Z (Y-Z bond). Such relative orientation may bemeta, wherein the Z-G bond is in the 1,3 position relative to the Y-Z bond. Another relativeorientation may be para, wherein the Z-G bond is in the 1,4 position relative to the Y-Z bond.

Some compounds of formula I contain chiral centers and therefore exist in differentenantiomeric forms. This invention relates to ail opticai isomers, enantiomers, diastereomersand stereoisomers of the compounds of formula I and mixtures thereof. The compounds ofthe invention also exist in different tautomeric forms. This invention relates to ail tautomers offormula I. Those skilled in the art are well aware that the pyrimidine-2,4,6-trione nucieusexists as a mixture of tautomers in solution. The various ratios of the tautomers in solid andliquid form is dépendent on the various substituents on the molécule as well as the particuiarcrystallization technique used to isolate a compound. in one embodiment of the invention, the heterocyclic ring “A” of the compounds of theformula I is selected from the formulae a) or b): y.Y.7.n

X-Y-Z-G wherein X is (C6-Cto)aryl, preferably phenyl. Within this embodiment, Y is selected from thegroup consisting of a bond, oxygen, >C=O, -CH2-, -CH2O-, -O(CH2)n-, -CH2CH2-, -CH=CH-and -C=C-; wherein n is 1or 2; preferably Y is selected from the group consisting of oxygen,-OCH2- and -CH2O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A" has the formulae a)or b), wherein X is (Ce-C10)aryl, preferably phenyl. Within this embodiment, V is selected from 012529 -8- the group consisting of suifur, >SO2, >S=O, -CH2S-, -S(CH2)n-, -CH2SO-, -CH2SO2-, -SOCH2-and -SO2(CH2)n-; wherein n is 1 or 2; preferably Y is suifur or >SO2.

In another embodiment of the invention, the heterocyciic ring “A” has the formulae a)or b), wherein X is (C6-Ci0)aryl, preferably phenyl. Within this embodiment, Y is selected fromthe group consisting of CH2[N(R14)]-, >NR14, -NR14(CH2)n-, -SO2fN(R14)]- and -[N(R14)]-SO2-,wherein R14 is hydrogen or methyl; and n is 1 or 2.

In another embodiment of the invention, the heterocyciic ring “A" has the formulae a)or b), wherein X is (C,-Cio)heteroaryl selected from the group consisting of benzimidazoiyl,benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl,benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl,furyi, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinoiinyi,isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl,pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrroiyl, quinazolinyi, quinoiinyl,quinoxalinyi, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (CrC10)heteroaryl is optionally sübstituted on any of the ring carbon atoms capable of forming anadditional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (CrC4)alkyl, (C5-C4)perfluoroalkyl, (CrC4)perfluoroaikoxy, (C,-C4)alkoxy and (C3-C8)cycloalkyioxy;preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferablyX is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within thisembodiment, Y is a bond, oxygen, suifur, -CH2-, >SO2, -OCH2- or -CH2O-; preferably Y isoxygen, -OCH2- or -CH2O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyciic ring “A" has the formulae a)or b), wherein X is (C,-C,0)heteroaryl selected from the group consisting of benzimidazoiyl,benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl,benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl,· furazanyl, furopyridinyl,furyi, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyI, isoindolyl, isoquinoiinyi,isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl,pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrroiyl, quinazolinyi, quinoiinyl,quinoxalinyi, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (CrC10)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming anadditional bond by one or two substituents independently selected from F, CI, Br, CN, OH, (C-rC4)alkyl, (Ci-C4)perfluoroalkyl, (C1-C4)perfluoroalkoxy, (CrC4)alkoxy and (C3-C3)cycloalkyloxy;preferably X is seiected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferablyX is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within thisembodiment, Y is selected from the group consisting of suifur, >SO2l >S=O, -CH2S-, -S(CH2)n- 012529 -9- , -CH2SO-, -CH2SO2-, -SOCH2- and -SO2(CH2)ft-; wherein n is 1 or 2; preferably Y is suifur or>SO2.

In another embodiment of the invention, the heterocyclic ring “A” has the formulae a)or b), wherein X is (C,-C50)heteroaryl selected from the group consisting of benzimidazolyl, 5 benzofuranyi, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl,benzothiazolyl, benzothiophenyl, benzoxazolyi, chromanyl, cinnolinyl, furazanyi, furopyridinyl,furyl, imidazolyl, indazolyl, indoiinyl, indoiizinyl, Indolyi, 3H-indolyl, isoindolyl, isoquinolinyl,isothiazolyi, isoxazolyi, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl,pyrazinyi, pyridazinyi, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyi, quinazoiinyl, quinoiinyl, 10 quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (C,-C10jheteroaryi is optionaliy substituted on any of the ring carbon atoms capable of forming anadditional bond by one ortwo substituents independently selected from F, Cl, Br, CN, OH, (CrC4)alkyl, (CrC^perfiuoroalkyl, (CrC4)perfluoroalkoxy, (CrC4)alkoxy and (C3-CB)cycioalkyloxy;preferably X is selected from the group consisting of imidazolyl, isothiazolyi, isoxazolyi, 15 oxadiazolyl, oxazolyl, pyrazinyi, pyridazinyi, pyridinyl, pyrimidinyl and pyrazolyl; more preferablyX is pyrazinyi, pyridazinyi, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within thisembodiment Y is selected from the group consisting of CH2[N(R14)}-, >NR14, -NRu(CH2)n-, -SO2[N(R14)]- and -(N(R14)]-SO2-, wherein R14 is hydrogen or methyf; and n is 1 or 2.

In another embodiment of the invention, the heterocyclic ring "A” has the formula a), 20 wherein X is (CrC10)heteroaryl selected from the group consisting of benzimidazolyl,benzofuranyi, benzofurazanyl, 2H-1-benzopyranyi, benzothiadiazine, benzothiazinyl,benzothiazolyl, benzothiophenyl, benzoxazolyi, chromanyl, cinnolinyl, furazanyi, furopyridinyl,furyl, imidazolyl, indazolyl, indoiinyl, indoiizinyl, indolyi, 3H-indolyl, isoindolyl, isoquinoiinyl,isothiazolyi, isoxazolyi, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, 25 pyrazinyi, pyridazinyi, pyridinyl, pyrimidinyi, pyrazolyl, pyrrolyi, quinazoiinyl, quinoiinyl,quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (CrC10)heteroaryl is optionaliy substituted on any of the ring carbon atoms capable of forming anadditional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (CrC4)alkyl, (CrC^perfluoroalkyl, (C,-C4)perfluoroalkoxy, (Ci-C4)alkoxy and (C3-C8)cycloalkyloxy; 30 preferably X is selected from the group consisting of imidazolyl, isothiazolyi, isoxazolyi,oxadiazolyl, oxazolyl, pyrazinyi, pyridazinyi, pyridinyl, pyrimidinyl and pyrazolyl; more preferablyX is pyrazinyi, pyridazinyi, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within thisembodiment, Y is selected from the group consisting of a bond, oxygen, suifur, -CH2-, >SO2,-OCH2- and -CH2O-; preferably Y-is oxygen, -OCH2- or -CH2O-; more preferably Y is oxygen. 35 In another embodiment of the invention, the heterocyclic ring “A” has the formula a), as defined in the aforesaid paragraph, wherein in the heterocyclic ring “A" the dashed line is adouble bond. 012529 1 -10- 10 15 20

In another embodiment of the invention, the heterocyclic ring “A" has The formula b),wherein X is (C,-Ci0)heteroaryi selected from the group consisting of benzimidazolyl,benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl,benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyi, furopyridinyl,furyl, imîdazolyi, indazolyi, indolinyi, indolizinyl, indolyl, 3H-indolyI, isoindoiyt, isoquinolinyl,isothiazoiyi, isoxazolyl, naphthyridinyl, oxadiazôlyl, oxazolyi, phthalazinyi, pteridinyl, purinyl,pyrazinyl, pyridazinyl, pyridinyi, pyrimidinyi, pyrazolyl, pyrroiyl, quinazolinyl, quinolinÿl,quinoxalinyl, tetrazolyl, thiazolyi, thiadiazolyl, thienyi, triazinyl and triazoiyi, wherein said (CrCio)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming anadditional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (CrC4)alkyi, (CrC4)perfluoroalkyl, (C1-C4)perfluoroa!koxy, (CrC4)alkoxy and (C3-CB)cycloalkyloxy;preferably X is selected from the group consisting of imidazolyi, isothiazoiyi, isoxazolyl,oxadiazolyl, oxazolyi, pyrazinyl, pyridazinyl, pyridinyi, pyrimidinyi and pyrazolyl; more preferablyX is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyi; most preferably X is pyridinyi. Within thisembodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CHz-, >SO2,-OCH2- and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A" has the formula b),as defined in the aforesaid paragraph, wherein in the heterocyclic ring “A" the dashed line is adouble bond.

In another embodiment of the invention, the heterocyclic ring “A” has the formula c):

25 wherein X is {C,-C10)heteroaryl selected from the group consisting of imidazolyi, isothiazoiyi,isoxazolyl, oxadiazolyl, oxazolyi, pyrazinyl, pyridazinyl, pyridinyi, pyrimidinyi and pyrazolyl;preferably X is selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl andpyrimidinyi; more preferably X is pyridinyi. Within this embodiment, Y is selected from thegroup consisting of a bond, oxygen, sulfur, -CHr, >SO2, -OCH2- and -CH2O-; preferably Y isoxygen, -OCH2- or -CH2O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A" has the formula c),wherein in the heterocyclic ring "A" the dashed line is a double bond, such that theheterocyclic ring “A" of formula c is selected from the group consisting of: 30 012529 -11-

X-Y-Z-G

R1 R2 Rs R

In another embodiment of the invention, the heterocyclic ring “A" has the formula d):

wherein X is (CrCio)heteroaryi selected from the group consisting of imidazolyl, isothiazolyl,5 isoxàzolyl·, oxadîazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl;preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.

Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur,-CH2-, >SO2, -OCH2- and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferablyY is oxygen. 10 In another embodiment of the invention, the heterocyclic ring “A" has the formula e):

wherein X is {C-,-Cw)heteroaryl selected from the group consisting of imidazolyl, isothiazolyl,isoxàzolyl, oxadiazolyi, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl;preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl. 15 Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CK2-, >SO2, -OCH2- and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferablyY is oxygen.

In another embodiment of the invention, the heterocyclic ring “A" has the formula f):

012529 -12- wherein X is (CrC10)heteroaryl seiected from the group consisting of imidazolyl, isothiazolyl,isoxazolyl, oxadiazolyi, oxazolyi, pyrazinyl, pyridaziny!, pyridinyl, pyrimidinyl and pyrazolyl;preferably X is pyrazinyl, pyridazinyl, pyridyi and pyrimidinyl; more preferabiy X is pyridinyl.Within this embodiment, Y is seiected from the group consisting of a bond, oxygen, sulfur,-CH2-, >SO2, -OCH2- and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferabiyY is oxygen.

In another embodiment of the invention, the heterocyciic ring “A" has the formula g):

wherein X is (C,-Cio)heteroaryl seiected from the group consisting of imidazolyl, isothiazolyl,isoxazolyl, oxadiazolyi, oxazolyi, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl;preferably X is pyrazinyl, pyridazinyl, pyridyi and pyrimidinyl; more preferably X is pyridinyl.Within this embodiment, Y is seiected from the group consisting of a bond, oxygen, sulfur,-CH2-, >SO2, -OCH2- and -CHZO-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferablyY is oxygen.

In another embodiment of the invention, the heterocyciic ring “A" has the formula g),as defined in the aforesaid paragraph, wherein in the heterocyciic ring “A” the dashed line is adouble bond.

In another embodiment of the invention, the heterocyciic ring “A" has the formula h):

wherein X is (CrCio)heteroaryl seiected from the group consisting of imidazolyl, isothiazolyl,isoxazolyl, oxadiazolyi, oxazolyi, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl;preferably X is pyrazinyl, pyridazinyl, pyridyi and pyrimidinyi; more preferably X is pyridinyl.Within this embodiment, Y is seiected from the group consisting of a bond, oxygen, sulfur,-CH2-, >SO2, -OCH2- and -CH2O-; preferably Y is oxygen, -OCHZ- or -CH2O-; more preferablyY is oxygen.

In another embodiment of the invention, the heterocyciic ring "A" has the formula h),as defined in the aforesaid paragraph, wherein in the heterocyciic ring "A" the dashed fine is adouble bond. 012529 -13- ln another embodiment of the invention, the heterocyciic ring “A" has the formula i):

wherein X is (CrC1o)heteroaryl seiected from the group consisting of imidazolyl, isothïazolyi,isoxazolyl, oxadiazolyf, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyi and pyrazolyl;preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyi; more preferably X is pyridinyl.Within this embodiment, Y is seiected from the group consisting of a bond, oxygen, sulfur,-CH2-, >SO2, -OCH2- and -CH2O-; preferably Y is oxygen, -OCH2- or -CH20-; more preferablyY is oxygen. in another embodiment of the invention, the heterocyciic ring “A" has the formula i),wherein in the heterocyciic ring “A" the dashed line is a double bond, such that theheterocyciic ring “A” of formula i) is seiected from the group consisting of:

and

In a preferred embodiment of the invention, the heterocyciic ring “A" has the formulaseiected from the group consisting of

wherein X is (C,-C10)heteroaryl seiected from the group consisting of imidazolyl,isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyi andpyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyi; more preferably X ispyridinyl. Within this embodiment, Y is seiected from the group consisting of a bond, oxygen,sulfur, -CH2-, >SO2, -OCH2- and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; morepreferably Y is oxygen.

In another embodiment of the invention, the heterocyciic ring “A” has the formula j): 012529 -14-

wherein X is (Ci-Cio)heteroaryl selected from the group consisting of imidazolyl, isothiazolyl,isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl;preferably X is pyrazinyl, pyridazinyl, pyridyi and pyrimidinyl; more preferably X is pyridinyl.Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur,-CH2-, >SO2, -OCH2- and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferablyY is oxygen.

In another embodiment of the invention, the heterocyclic ring "A” has the formula k):

wherein X is (Ci-Ci0)heteroaryl selected from the group consisting of imidazolyl, isothiazolyl,isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl;preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur,-CH2-, >SO2, -OCHr and -CH2O-; preferably Y is oxygen, -OCHr or -CH2O-; more preferablyY is oxygen.

In another embodiment of the invention, the heterocyclic ring “A" has the formula k),as defined in the aforesaid paragraph, wherein in the heterocyclic ring "A" the dashed line is adouble bond.

In another embodiment of the invention, the heterocyclic ring "A" has the formula I):

wherein X is (Ci-C,Q)heteroaryi selected from the group consisting of imidazolyl, isothiazolyl,isoxazolyl, oxadiazolyl, · oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; 012529 -15- preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur,-CH2-, >SO2, -OCH2- and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferablyY is oxygen.

In another embodiment of the invention, the heterocyclic ring “A" has the formula l),wherein in the heterocyciic ring "A" the dashed line is a double bond, such that theheterocyclic ring “A” of formula I is selected from the group consisting of:

In another embodiment of the invention, the heterocyclic ring “A" has the formula m):

wherein X is (C,-Cw)heieroaryl selected from the group consisting of imidazolyi, isothiazoiyl,isoxazoiyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl;preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur,-CH2-, >SO2, -OCH2- and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferablyY is oxygen.

In another embodiment of the invention, the heterocyclic ring "A" has the formula n):

wherein X is (CrCw)heteroaryl selected from the group consisting of imidazolyi, isothiazoiyl,isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl;preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl.Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur,-CH2-, >SO2, -OCH2- and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferablyY is oxygen. 012529 -16- ln another embodiment of the invention, the heterocyclic ring “A" has the formula o):

wherein X is (C,-Ci0)heteroaryl selected from the group consisting of imidazolyl, isothiazolyl,isoxazoiyl, oxadiazolyl, oxazolyl, pyrazinyi, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyi;preferably X is pyrazinyi, pyridazinyl, pyridyf and pyrimidinyl; more preferably X is pyridinyl.Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur,-CH2-, >SO2, -OCH2- and -CH2O-; preferably Y is oxygen, -OCHZ- or -CH2O-; more preferablyY is oxygen.

In another embodiment of the invention, each of R1, R2, R3, R4, R10, R11, R12 and R13is selected from the group consisting of hydrogen, (CrC4)alkyl, (CrC4)alkenyl, (CrC4)alkynyl,(C6-Cio)aryl, (C5-Cio)heteroaryl, (C3-C8)cycloalkyl and (C,-C,0)heterocyclyl; and wherein eachof said (C,-C4)alkyl, (C6-Cw)aryl, (CrC10)heteroaryl, (C3-C8)cycloalkyl and (C,-Ci0)heterocyclylmay be optionally substituted on any of the ring carbon atoms capable of forming an additionatbond with 1-3 substituents independently selected from halo, (CrC4)aikyi, (C]-C4)alkoxy, -CN,-OH and -NH2. A generic or sub-generic embodiment of each of the foregoing embodiments arethose compounds wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 isselected from the group consisting of hydrogen, (C,-C4)alky|, (CB-Cio)aryl, {Ci-Ci0)heteroaryl,and (C3-C8)cycloalkyl. A preferred generic or sub-generic embodiment is directed to. those foregoingembodiments wherein each of R1, R2, R3, R4, R5. R6, R7, R8, R9, R10, R11, R12 and R13 isselected from hydrogen and (CrC4)alkyl, such as methyl.

In another embodiment of the invention, each of R5, R6, R7 and R8 is selected from thegroup consisting of hydrogen, (C,-C4)alkyl, (CrC4)alkenyl, (CrC4)alkynyl, (C6-C10)ary|, (CrC50)heteroaryl, (C3-C8)cycloalkyl and (Ci-C10)heterocyclyl; and wherein each of said {CrC4)alky(, (Cs-Cw)ary(, (CA-Cw)heteroary!, (C3-CB)cycloafkyl and (C1-C1Q)heterocyclyl may beoptionally substituted on any of the ring carbon atoms capable of forming an additionai bondwith 1-3 substituents independently selected from halo, (CrC4)alkyi, (C1-C4)alkoxy, -CN, -OHand -NH2.

In another embodiment of the invention, one or two of R5, R6, R7 and R8 is/are a groupother than hydrogen.

In another embodiment of the invention, R9 is independently selected from hydrogen,(Ci-C4)alkyl, (C6-C«)aryt, (CrC10)heteroary|, (C3-C8)cycloalkyl and (C1-C,0)heterocyciyl. 012529 -17-

In another embodiment of the invention, R9 is independentiy selected from hydrogenand (C,-C4)alkyl, such as methyl. in another embodiment of the invention, Z is a (C3-C8)cycloalkyl or a (C,-C10)heterocyciyl, selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, tetrahydrofuranyi, tetrahydropyranyi, N-methy!-3-azetidinyI, piperazinyl, piperidinyi, 1.3- oxazolidin-4-on-5-yI, 1,3-oxazolidin-2,4-dion'5-yl, 4,5-dihydro-1,2-oxazolidin-3-on-4-yl, 1,3-thiazolidin-4-on-5-yl, 1,3-thiazolidin-2,4-dion-5-yl, 1,3-imidazoIidin-4-on-5-yl, 1,3-imidazoiidin- 2.4- dion-5-yl, 1,2-pyrazoiidin-3-on-4-yi, tetrahydro-1,3-oxazin-4-on-5-yl, tetrahydro-1,3-oxazin- 2.4- dion-5-yl, morpholinyl, morpholin-3-on-2-yi, morpho!in-3,5-dion-2-yl, 2,3-dihydro-1,4-oxazin-3-on-2-yi, tetrahydro-1,3-thiazin-4-on-5-yl, tetrahydro-1,3-thiazin-2,4-dion-5-yl,thiomorpholinyi. thiomorpholin-3-on-2‘yi, thiomorpholin-3,5-dion-2-yl, 2,3-dihydro-l ,4-thiazin-3-on-2-yl, hexahydro-1,2-diazin-3-on-4-yl, 4,5-dihydro-2H-pyridazin-3-on-4-yl, hexahydro-1,3-diàzin-2,4-dion-5-yl, piperazin-2-on-3-yi, piperazin-2,6-dion-3-yl, tetrahydro-1,3,4-thiadiazin-5-on-6-yl, 5,6-dihydro-1,3,4-thiadiazin-5-on-6-yl, 1,3,4-oxadiazin-5-on-6-yl, 5,6-dihydro-1,2,4-oxadiazin-5-on-6-yl, tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 1,2,4-triazin-5-on-6-y|, tetrahydro- 1.2.4- oxadiazin-5-on-6-yi, 5,6-dihydro-1-2,4-oxadiazin-5-on-6-yl, 1,2,4-oxadiazin-3,5-dion-6-ytand 1,2,4-triazin-6-on-5-yI. Within this embodiment, preferablyZ is selected from the groupconsisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyi,tetrahydropyranyi, N-methyl-3-azetidinyl, piperazinyi, piperidinyi, N-methylpiperidinyl andmorpholinyl. Within this embodiment, more preferably Z is selected from the group consistingof cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyi and tetrahydropyranyi.Within this embodiment, most preferably Z is selected from the group consisting ofcyclopentyl, cyclohexyl, tetrahydrofuranyi and tetrahydropyranyi.

In another embodiment of the invention, Z is a (Ci-C10)heteroaryl selected from thegroup consisting of benzimidazotyi, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl,benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyi, benzoxazolyi, chromanyl,cinnolinyl, furazanyl, furopyridïnyl, furyl, imidazolyi, indazolyl, indolinyl, indolizinyl, indolyi, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazoiyl, naphthyridinyl, oxadiazoiyl, oxazolyi,phthalazinyl, pteridinyl, purinyl, pyrazinyi, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyi, pyrrolyl,quinazotinyl, quinolinyl, quinoxalinyl, tetrazolyi, thiazolyl, thiadiazolyi, thienyl, triazinyl andtriazolyl, more preferably pyridinyl, pyrazinyi, pyridazinyl and pyrazolyi, wherein said (C,-C10)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming anadditional bond by one or two substituents independentiy selected from F, Cl, Br, CN, OH, (CrC4)alkyl, (C1-C4)perfiuoroalkyl, (C^C^perfluoroaikoxy, (CrC4)aikoxy and (C3-C8)cycioaikyloxy.

In another embodiment of the invention, either X or Z is substituted on any of the ringcarbon atoms capable of forming an additional bond by one or two substituents independentiyselected from F, Cl, Br, CN, ΌΗ, (CrC4)alkyl, (C1-C4)perfluoroalkyl, (Ci-C4)perfluoroalkoxy,(Ci-C4)alkoxy and (C3-C8)cycloalkyloxy. 012529 -18-

In another embodiment of the invention, both X and Z are substituted on any of thering carbon atoms capable of forming an additional bond by one or two substituentsindependentiy selected from F, Cl, Br, CN, OH, (CrC4)aikyl, (C1-C4)perfluoroalkyl, (CrC4)perfluoroaikoxy, (CrC4)alkoxy and (C3-C8)cycloalky!oxy.

In another embodiment of the invention, G is R1S-(CR16R17)P-; wherein p is 0; R1s isselected from the group consistïng of halo, -CN, and R18; wherein said R18 Is selected from thegroup consisting hydrogen, (CrC4)alkyl, (C6-C10)aryl, (C3-C8)cycloalkyl, (CrCio)heteroaryl and(Ci-Cw)heterocyclyl; wherein said (C6-Ci0)aryl, (C3-C8)cycloalky{, (C5-C10)heteroaryi and (CrC,0)heterocyciyl moieties may be optîonally substituted on any of the ring carbon atomscapable of forming an additional bond by one to three substituents per ring independentiyselected from F, Cl, Br, CN, OH, (CrC4)alkyl, (CrOOperfluoroalkyl, (Ci-C4)perfluoroalkoxy,(CrC4)alkoxy, amino, (CrC4}alkyl-NH-, [(CrC4)alkyl]2-N- and (C3-C8)cydoalkyloxy whereinsaid (C3-Cs)cycloalkyl and (CrCio)heterocyclyl moieties may also optîonally be substituted byoxo, wherein said (CrC^Jheteroaryl and (Ci-Ci0)heterocyclyl moieties may optîonally besubstituted on any ring nitrogen atom able to support an additional substituent by one to twosubstituents per ring independentiy selected from the group consisting of (C,-C4)alkyl and (C,-C4)alkyl-(C=O}-.

In another embodiment of the invention, G is R15-(CRieR17)p-; wherein p is 0 to 4,preferabiy 1 to 2; R15 is selected from the group consisting of halo, -CN, -NO2, OH, (CrC4)alkenyl, (C,-C4)alkynyl, (C1-C4)perfluoroalkyl, perfluoro(CrC4)alkoxy, R18-, R1®-0-, R18-(CrC4)alkyl-O-, R18-(C=O)-, R18-(C=O)-O-, R18-O-(C=O)- R18-S-, R22-(S=O)-, R18-(SO2)-, R22-(SO2)-(NR21)-, R1b-(C=O)-(NR21)-, Rz2-O-(C=O)-(NR21)-, (R1sR20)N-, (R18R20)N-(SO2)-, (R1sR2D)N-(C=O)-; (R,9R20)N-(C=O)-(NR21)- and (R^R^N-fCsOK); each of R16 and R17 isindependentiy hydrogen or (Ct-C4)alkyl; R18 is selected from the group consisting hydrogen,(C,-C4)alkyl, (C6-C10)aryi, (C3-C8)cycloalkyl, (C,-Cio)heteroaryl and (Ci-Cio)heterocycly!;wherein said (C6-Cw)aryl, (C3-Ca)cycloalkyl, (CrC10)heteroaryl and (C,-C10)’neterocyclylmoieties may be optîonally substituted on any of the ring carbon atoms capable of forming anadditional bond by one to three substituents per ring independentiy selected from F, Cl, Br, CN,OH, {Ci-C4)alkyl, (CrC4)perfluoroaikyl, (Ct-C4)perfluoroalkoxy, (C,-C4)alkoxy, amino, (CrC4)aikyl-NH-, [(CrC4)aiky!]2-N- and (C3-C8)cycioalkyloxy; wherein said (C3-CB)cycloaIkyl and(Cî-C 10)heterocyclyl moieties may also optîonally be substituted by oxo; wherein said (CfC5û)heteroaryi and (CrCio)heterocyclyl moieties may optîonally be substituted on any ringnitrogen atom abte to support an additional substituent by one to two substituents per ringindependentiy selected from the group consisting of (CrC4)alkyi and (Ci-C4)aikyl-(C=O)-.

In another embodiment of the invention, G is R1S-{CR16R17)P-; wherein p is 1; R15 is(R19Rz0)N-; each of R16 or R17 is independentiy hydrogen; and each of R10 and R20 is hydrogenor (CrC10)heteroaryl, such as 2-oxazoiyl, 2-pyrazolyl, or 3-pyrazolyl. 012529 -19- in another embodiment of the invention, G is R1S-(CR16R17)P-; wherein p is 1; R15 is(R1SR2°)N-(C=O)-(NR21)-; each of R15 or R17 is independentiy hydrogen; each of R19 and R20 is(C,-C4)alkyl and are taken together with the nitrogen to which they are attached to form a 3 to 8-membered ring; and wherein R23 is selected from the group consisting of hydrogen and (Cj-C4)alkyl. in another embodiment of the invention, G is R1S-(CR16R17)P-; wherein p is 1; R15 isR22-O-{C=O)-(NR21)-; each of R16 or R17 is independentiy hydrogen; R21 is selected from thegroup consisting of hydrogen and (CrC4)aikyI; and wherein R22 is selected from the groupconsisting of (CrC4)alkyl and (C3-C8)cycloalky!, such as methyl, ethyl, propyl, butyi orcyclobutyi. in another embodiment of the invention G is R15-(CR1SR17)P-; wherein p is 1; R15 isR1S-(C=O)-(NR21}; each of R16 and R17 is independentiy hydrogen or (C,-C4)atkyl; R19 and R21are taken together with the carbon or the nitrogen to which they are attached to form a 3 to 8membere'd heterocyclic ring.

In another embodiment of the invention, G is R15-(CR16R17)P-; wherein p is 1; R15 is(R1SR2°)N-(C=O)-(NR21); each of R16 and R17 is independentiy hydrogen or (C,-C4)alkyl; R1Sand R21 are taken together with the nitrogen to which they are attached to form a 3 to 8membered heterocyclic ring.

In another embodiment of the invention, G is R15-(CR16R17)P-; wherein p is 1; R15 isR22-O-(C=O)-(NR21)-; each of R15 and R17 is independentiy hydrogen or (C5-C4)alkyi; R21 andR22 are taken together with the nitrogen or the oxygen to which they are attached to form a 3to 8 membered heterocyclic ring. in another embodiment of the invention, G is R15-(CR16R17)P-; wherein p is 1 to 4,preferably 1; R15 is selected from the group consisting of halo, -CN and R18; each of R16 andR17 is independentiy hydrogen or (CrC4)alkyl; said R18 is selected from the group consisting ofhydrogen, (CrC4)alkyi, (C6-C10)aryl, (C3-Cs)cycloalkyl, (C,-Ci0)heteroaryl and (CrC10)heterocyciyl; wherein said (C6-C,0)aryl, (C3-C8)cycioalkyl, (CrC^Jheteroaryl and (CrCi0)heterocyciyl moieties may be optionally substituted on any of the ring carbon atomscapable of forming an additional bond by one to three substituents per ring independentiyselected from F, Cl, Br, CN, OH, (C1-C4)alkyll (C,-C4)perfluoroalkyi, (Ci-C4)perfluoroalkoxy,(CrC4)alkoxy, amino, (C1-C4)alkyi-NH-, [{CrC4)alkyI3rN- and (C3-C8)cycloalkyloxy; whereinsaid (C3-CB)cycloaikyl and (Ci-C,0)heterocyclyl moieties may also optionally be substituted byoxo; wherein said (C(-Cio)heteroaryi and (CrCw)heterocyciyl moieties may optionally besubstituted on any ring nitrogen atom abie to support an additional substituent by one to twosubstituents per ring independentiy selected from the group consisting of (C(-C4)alkyl and (C4-C4)alkyl-(C=O)-.

In another embodiment of the invention, G is R15-(CR16R17}P‘; wherein p is 1 to 4,preferably 1; R15 is selected from the group consisting of R18; each of R'6 and R17 is 012529 -20- independently hydrogen or (Ci-C4)afkyl; wherein said R18 is selected from the group consistingof hydrogen and (CrC4)alkyl.

In another embodiment of frie invention, G is R15-(CR16R17)P-; wherein p is 1 to 4,preferably 1; R15 is selected from the group consisting of (R1SR2O)N-, (R1SRZ°)N-(C=O),(R19R20)N-(SO2); (R19R20)N-(C=O)-(NR2’)- and (R1sR20)N-(C=O)-O; each of R16 and R17 isindependently hydrogen or (C5-C4)alkyi; and wherein R19 and R20 are taken together with thenitrogen to which they are attached to form a 3 to 8-membered heterocyciic ring.

In another embodiment of the invention, G is R15-(CR16R17}P-; wherein p is 1 to 4,preferably 1; R1sis selected from the group consisting of R19-(C=O)-(NR21)-, (R19R20)N-(C=O>-(NR21), -NR19R2Q, (R18R20)N-(C=O)-(NR21)-; R22(S=O)-; R22(SO2)-(NR21)-; R^-O-fC^HNR21)-and (R'9R2q)N-(C=O)-O-; each of R16 and R17 is independently hydrogen or (CrC4)alkyl;wherein each of R19, R20 and R2· is independently selected from the group consisting ofhydrogen, (CvC4)aikyl, (C6-C10)aryi, (C3-C8)cycioaikyi, (CrC,Q)heteroaryl and (CrC10)heterôcyclyl; wherein the (C6-C10)aryl, (C3-C8)cycloalkyl, (C5-C10)heteroaryl and (CrCio)heterocyclyi moieties may be optionally substituted on any of the ring carbon atomscapable of forming an additional bond by 1-3 substituents independently selected from F, Ci,Br, CN, OH, (CrC4)alkyl, (C,-C4)perfluoroalkyi, (CrC4)perfluoroalkoxy, (C,-C4)alkoxy, amino,(C1-C4)alkyi-NH-, l(CrC4)alkyi]2-N- and (C3-C8)cycloalkyioxy; wherein said (C3-C8)cycloalkyiand (Ci-Cio)heterocyclyl moieties may also optionally be substituted by oxo; wherein said (CrC,Q)heteroaryl and (Ci-Cio)heterocyclyl moieties may optionally be substituted on any ringnitrogen atom able to support an additional substituent by one to two substituents per ringindependently selected from the group consisting of (Ci-C4)alkyi and (Ci-C4)alkyl-(C=O)-; andwherein R22 is selected from the group consisting of (CrC4)alkyl, (C6-C10)aryl, (C3-C8)cycloalkyi, (C,-Ci0)heteroaryl and (CrC10)heterocyclyi; wherein the (C6-Cio)aryi, (C3-C8)cycloalkyi, (CpC^heteroaryl and (C,-C10)heterocyclyl moieties may be optionallysubstituted on any of the ring carbon atoms capable of forming an additional bond by 1-3substituents independently selected from F, Cl, Br, CN, OH, (CrC4)alkyl, (C-i-C.Operfiuoroaikyi,(CrC4)perfluoroalkoxy, (CrC4)alkoxy, amino, (CrCJalkyl-NH-, [(CrC4)aIkyi]2-N- and (C3-C8)cycioalkyioxy; wherein said (C3-C8)cycloalkyl and (Ci-C10)heterocyc!yl moieties may alsooptionally be substituted by oxo; wherein said (C-|-Cw)heteroaryl and (CrC,0)heterocyciylmoieties may optionally be substituted on any ring nitrogen atom able to support an additionalsubstituent by one to two substituents per ring independently selected from the groupconsisting of (C-|-C4)alkyl and (CrC4)alkyl-{C=O)-. in another embodiment of the invention, G is R15-(CR16R17)P-; wherein p is 1 to 4,preferably 1; R15 is selected from the group consisting of R19-(C=O)-(NR21}-, R19-O-(C=O)-(NR21)- and (R18R20)N-(C=O)-(NR21); each of R16 and R17 is independently hydrogen or (CrC4)alkyl; wherein R19 and R21 are taken together with the nitrogen, the carbon or the oxygen towhich they are attached to form a 3 to 8 membered heterocyciic ring. i 012529 -21- 10 10 15 15 20 20 25 25

In another embodiment of the invention, G is R15-(CR16R17)„-; wherein p is 0; and G isoriented at a position other than alpha to the point of attachment of the Z ring to Y.

In another embodiment of the invention, G is R15-(CR16R17)P-; wherein p is 0; and G isoriented at a position mefa to the point of attachment of the Z ring to Y.

In another embodiment of the invention, G is R15-(CR16R17)P-; wherein p is 1 to 4,preferabiy 1; and G is oriented at a position other than aipha to the point of attachment of theZ ring to Y. in another embodiment of the invention, G is R15-(CR16R17)P-; wherein p is 1 to 4,preferabiy 1 ; and G is oriented at a position meta to the point of attachment of the Z ring to Y.

In another preferred embodiment of the invention, one or two of R1, R2, R3, R4, R10,R11, R12 and R13 is a group other than hydrogen.

In a more preferred embodiment of the invention, each of R1, R2, R3, R4, R5, R6, R7,R8, R9, R10, R1', R12 and R13 is hydrogen.

In another preferred embodiment of the invention, either X or Z is not substituted by ·any optional substituents.

In another preferred embodiment of the invention, both X and Z are not substituted byany optional substituents.

In another preferred embodiment of the invention, G is R15-{CR16R17)P-; wherein p is 0;R1S is selected from the group consisting of halo, -CN and (CrCiQ)heteroaryl. More preferabiy,R,5is bromo, fiuoro, -CN or oxadiazolyl, preferabiy [1,3,4] oxadiazoi-2-yi.

In another preferred embodiment of the invention, G is R15-(CR16R17)P-; wherein p is 0or 1 ; R15 is R18; each of R’6 and R17 is hydrogen; and R18 is independentiy hydrogen or (CrC^aikyl; preferabiy methyl.

In another preferred embodiment of the invention, G is R15-(CR16R17)p-; wherein p is 0or 1 ; wherein G is oriented at a position para to the point of attachment of the Z ring to Y.

In another preferred embodiment of the invention, G is R15-{CRieR17)p-·, wherein p is 1 ;R1S is R19-(C=O)-(NR21)-; each of R16 or R’7 is independentiy hydrogen; R1S is (CrC4)alkyl,more preferabiy methyl, ethyl, or butyl; or (C3-C6)cycloalkyî, more preferabiy cyclobutyl; andR21 is hydrogen.

In another preferred embodiment of the invention, G is R15-{CR1bR17)p-; wherein p is 1 ;R1S is (Ci-C10)heteroaryi, such as 2-pyrazolyl; and wherein each of R16 and R17 isindependentiy hydrogen.

In another preferred embodiment of the invention, the heterocyclic ring “A” has theformula a) or b):

X-Y-Z-G b)

X-Y-Z-G 012529 -22’ wherein X is (CrCio)heteroaryi selected from the group consisting of pyrazinyl, pyridazinyl,pyridyl and pyrimidinyi; more preferabty X is pyridinyl; and Y is selected from the groupconsisting of a bond, oxygen, sulfur, -CH2-, >SO2, -OCH2- and -CH2O-; more preferably Y isoxygen, -OCH2- or -CH2O-; most preferably Y is oxygen.

Other preferred compounds of the invention include compounds of formula I, whereinthe heterocyclic ring “A" has the formula a) or b), as defined above; X is (CrC10)heteroarylselected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and pyrimidinyi; morepreferably X is pyridinyl; most preferably wherein the pyridinyl together with the “A" ring andthe group Y-Z-G has the formula:

wherein Y is a bond, oxygen, sulfur, -CH2-, >SO2, -OCH2- or -CH2O-; preferably Y is oxygen,-OCH2- or -CH2O-; more preferably Y is oxygen.

Other preferred compounds of the invention include compounds of formula I, whereinthe heterocyclic ring “A” has the formula a) or b), as defined above; X is pyridinyl, mostpreferably wherein the pyridinyl together with the “A” ring and the group Y-Z-G has the formulaa") or b") as defined above; Y is oxygen; Z is (C5-Cio)aryi, preferably phenyl; G is R’5-(CR16R17)P-; wherein p is 1; R15is {Ci-C,0)heteroaryl, such as 2-pyrazolyl; each of R16 and R17is independently hydrogen or (CrC4)alkyl, such as methyl, preferably hydragen; and whereinG is oriented at a position para to the point of attachment of the Z ring to Y.

Most preferred compounds of the invention include compounds of formula i, whereinthe heterocyclic ring "A” has the formula a) or b), as defined above; X is pyridinyl, mostpreferably wherein the pyridinyl together with the "A" ring and the group Y-Z-G has the formulaa") or b”) as defined above; Y is oxygen; Z is (C6-C10)aryI, preferably phenyl; G is R15-(CR,6R’7)p-; wherein p is 0; R15 is seiected from the group consisting of hydrogen, -CN, haloand oxadiazolyl; and wherein G is oriented at a position para to the point of attachment of theZ ring to Y.

Other most preferred compounds of the invention include compounds of formula I,wherein the heterocyclic ring “A" has the formula a) or b), as defined above; X is pyridinyl,most preferably wherein the pyridinyl together with the “A” ring and the group Y-Z-G has theformula a") or b”) as defined above; Y is oxygen; Z is (G6-C10)aryl, preferably phenyl; G is R15-{CR16R17)P-; wherein p is 1; R15 is R1®-(C=O)-(NR21)-; each of R16 and R17 is independently 012529 -23- hydrogen; R19 is selected from the group consisting of (CrC^aikyl and (C3-C8)cycloalky|, suchas methyl, ethyl, propyl, fautyl, or cyciobutyl; R21 is selected from the group consisting ofhydrogen or (Ci-C^alkyl; and wherein G is oriented at a position para to the point ofattachment of the Z ring to Y.

Other compounds of the invention are selected from the group consisting of: 1 -(6-(4-(1 ,3,4]Oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1 ,8,10-triaza-spiro(5.5]undecane- 2,7,9,11-tetraone; 1 -(6-(4-(1,3,4]Oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,3,7,9-tetraaza-spiro(4.5]decane- 2.6.8.10- tetraone; 1 -(6-(4-(1,3,4]Oxadiazoi-2-yl-phenoxy)-pyridin-3-yl]-1,3,8,10-tetraaza-spiro(5,5]undecane-2,7,9,11-tetraone; 4-(6-(4-(1,3,4JOxadiazoI-2-yl-phenoxy)-pyridin-3-yi]-1,1 -dioxo-1 A6-thia-2,4,7,9-tetraaza-spiro[4.5]decane-3,6,8,10-tetraone; 1 -(6-(4-(1,3,4]Oxadiazoi-2-yl-phenoxy)-pyridin-3-ylJ-1,3,7,9-tetraaza-spiro[4.5]decane- · 2.4.6.8.10- pentaone; 1-(6-(4-(1,3,4)Oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-2,2-dioxo-2À6-thia-1,7,9-triaza-5piro(4.5)decane-6,8,10-trione; 1-(6-(4-(1,3,4]OxadïazoS-2-yl-phenoxy)-pyridin-3-yl]-2,2-dioxo-2Ae-thia-1,8,10-triaza-spiro[5.5]undecane-7,8,11-trione; 1-(6-(4-(1,3,4}Oxadiazol-2-yl-pbenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro(4.5]decane- 6.8.10- trione; 1-(6-(4-CycIobutylmethoxymethyi-phenoxy)-pyridin-3-yiJ-1,7,9-triaza-spiro[4.5Jdecane- 2.6.8.10- tetraone; 1 -f6-[4-(2-Oxo-pyrroÎid!rt-1 -yimethyl)-phenoxy]-pyridin-3-yl}-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraone; 1 -(6-(1 H-lndazol-5-yioxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraone; 1 -[6-(4-Fluoro-phenoxy)-pyridin-3-yl3-3-methy!-1,7,9-triaza-spiro(4.5]decane-2,6,8,10- tetraone; 1-[6-(3-Fluoro-phenoxy)-pyridin-3-yi]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraone;4-(5-(2,7,9,11 -Tetraoxo-1,8,10-triaza-spiro(5.5]undec-1 -yi}-pyridin-2-yioxy3- benzonitrile; 1-(6-(4-Ethyl-phenoxy)-pyridin-3-yÎJ-1,8,10-triaza-spiro(5.5]undecane-2,7,9,11-tetraone; N-{4-[5-(2,7,9,11-Tetraoxo-1,8l10-triaza-spiro(5.5]undec-1-/)-pyridin-2-yloxy]-benzyi}- acetamide;

Azetidine-1-carboxylic acid 4-(5-(2,7,9,11-teiraoxo-1,8,10-triaza-spiro[5.5]undec-1-yl)-pyridin-2-yloxy}-benzy!amide; 012529 -24- 1-(6-(4-Pyrazol-1-yimethyl-phenoxy)-pyridin-3-yi3-1,8,10-triaza-spÎro(5.5]ijndecane- 2,7,9,11-tetraone; 1-[6-(4-Fiuoro-phenoxy)-pyridin-3-yl]-1,8,10-triaza-spÎro[5.53undecane-2,7,9,11- tetraone; l-ie^-Fluoro-phenoxyJ-pyridin-S-ylj-I.SJ.S-tetraaza-spiro^.Sjdecane^.e.SJO- tetraone; ? 1 -[6-(4-Ethyl-phenoxy)-pyridin-3-yl]-1,3,7,9-tetraaza-spiro[4.5}decane-2,6,8,10-tetraone; 4-(5-(2,6,8,10-Tetraoxo-1,3,7,9-teiraaza-spiro(4.53dec-1-yl)-pyridin-2-yloxy3-benzonitrile; N-{4-[5-(2,6,8,10-Tetraoxo-1,3,7,9-tetraaza-spiro(4.5jdec-1-yl)-pyridin-2-yloxy]- benzylj-acetamide;

Azetidine-1-carboxylic acid 4-(5-(2,6,8,10-tetraoxo-1,3,7,9-tetraaza-spiro[4.5]dec-1-yl)-pyridin-2-ÿloxy3-benzylamide; 1 -[6-(4-Pyrazol-1 -y!methyl-phenoxy)-pyridin-3-yl3-1,3,7,9-tetraaza-spiro[4,5Jdecane- 2,6,8,10-tetraone; 1-[6-(4-Fluoro-phenoxy)-pyridin-3-yf3-1,3,8,10-tetraaza-spiro(5.53undecane-2,7,9,11-tetraone; 1-[6-(4-Ethyl-phenoxy}-pyridin-3-yl]-1,3,8,10-tetraaza-spiro[5.5]undecane-2,7,9,11-tetraone; 4-(5-(2,7,9,11 -Tetraoxo-1,3,8,10-tetraaza-spiro(5.5Jundec-1 -yl)-pyridin-2-yloxy3-benzonitrile; N-(4-(5-(2,7,9,11-Tetraoxo-1,3,8,10-tetraaza-spiro(5.53undec-1-yl)-pyridin-2-yloxy]-benzyl}-acetamide;

Azetidine-1-carboxylic acid 4-(5-(2,7,9,11-tetraoxo-1,3,8,10-tetraaza-spiro[5.53undec-1 -yl)-pyridin-2-yloxy]-benzylamide; 1-[6-(4-Pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl}-1,3,8,10-tetraaza-spiro[5.53undecane-2,7,9,11-tetraone; 4-{e-(4-Fluoro-phenoxy)-pyridin-3-yl]-1,1-dioxo-1À6-thia-2,4,7,9-tetraaza-spiro[4.53decane-3,6,8,10-tetraone; 4-[5-(4-Ethyi-phenoxy)-pyridin-3-yl]-1l1-dioxo-1À6-thia-2t4l7,9-tetraaza- spiro[4.5Jdecane-3,6,8,10-tetraone; 4-(5-(1,1,3,6,8,10-Hexaoxo-1À6-thia-2,4,7,9-tetraaza-spiro(4.5jdec-4-yi)-pyridin-2-yloxyj-benzonitrile; N-{4-(5-(1l1l3,6,8,10-Hexaoxo-1À6-thia-2,4(7,9-tetraaza-spiro(4.53dÊc-4-yi)-pyridin-2- yioxy3-benzyl}-acetamide;

Azetidine-1-carboxyiic acid 4-(5-(1,1,3,6,8,10-hexaoxo-1À6-thia-2,4,7,9-tetraaza- spiro[4.5]dec-4-yl)-pyridin-2-yloxy3-benzylamlde; 012529 -25- 1.1- Dioxo-4-[6-(4-pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yî]-1A6-thia-2,4,7I9-tetraaza-spiro(4.5]decane-3,6,8,10-tetraone; 1-(6-(4-Fluoro-phenoxy)-pyridin-3-yi]-1,3,7,9-tetraaza-spiro{4.5]decane-2,4,6,8,10-pentaone; 4-[5-(2,4,6,8l10-Pentaoxo-1,3,7,9-tetraaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy3- benzonitrile; N-{4-[5-(2,4,6,8,10-Pentaoxo-1,3,7,9-tetraaza-spiro(4.5]dec-1 -yl)-pyridin-2-yloxyj-benzylj-acetamide;

Azetidine-1-carboxylic acid 4-[5-{2,4,6,8,10-pentaoxo-1,3,7,9-tetraaza-spiro(4.5]dec-1yl)-pyridin-2-yloxy]-benzyiamide; -l-[6-(4-Pyrazo!-1-yImethy!-phenoxy)-pyridir)-3-yl]-1,3,7,9-tetraaza-spiro{4.53decane- 2.4.6.8.10- pentaone; 1 -[6-(4-Ethyt-phenoxy)-pyridin-3-yl]-1,3,7,9-tetraaza-spiro[4.5jdecane-2,4,6,8,10-pentaone; 1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-2,2-dioxo-2A6-thia-1,7,9-triaza-spiro(4.5]decane- 6.8.10- trione; 1-(6-(4-Ethyl-phenoxy)-pyridin-3-yIJ-2,2-diûxo-2A6-thia-1,7,9-triaza-spiro{4.5]decane- 6,8,10-trione; 4-(5-(2,2,6,8,10-Pentaoxo-2A6-thia-1,7,9-iriaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-benzonitriie; N-{4-[5-(2,2,6,8,1 Q-Pentaoxo-2A6-thia-1,7,9-triaza-spiro(4.5]dec-1 -yl)-pyridin-2-yioxyj-benzyl}-acetamide;

Azetidine-1-carboxylic acid 4-(5-(2,2,6,8,10-pentaoxo-2A6-thia-1,7,9-triazaspiro[4.5]dec-1-yl)-pyridin-2-yioxy]-benzyiamide; 2.2- Dioxo-1-[6-(4-pyrazol-1-ylmethyi-phenoxy)-pyridin-3-yI]-2A6-thia-1,7,9-triaza-spiro(4.5]decane-6,8,10-trione; 1 -[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-2,2-dioxo-2A6-thia-1,8,10-triaza-spiro(5.5}undecane-7,9,11 -trione; 1-(6-(4-Ethy!-phenoxy)-pyridin-3-yI}-2,2-dioxo-2A6-thia-1,8,10-triaza- spiro[5.5]undecane-7,9,11-trione; 4-(5-(2,2,7,9,11-Pentaoxo-2A6-thia-1,8,10-triaza-spiro[5.5]undec-1-yl)-pyridin-2-y!oxyJ-benzonitrile; N-{4-[5-(2,2,7,9,11-Pentaoxo-2A6-thia-1,8,10-triaza-spiro[5.5}undec-1 -yl)-pyridin-2-yloxy]-benzy!}-acetamide;

Azetidine-1-carboxylic acid 4-(5-(2,2,7,9,11-pentaoxo-2A6-thia-1,8,10-triazaspiro(5.5]undec-1 -yl)-pyridin-2-y!oxyJ-benzyiamide; 2.2- Dioxo-1-[6-(4-pyrazo!-1-ylmethyl-phenaxy)-pyridin-3-yÎJ-2A6-thia-1,8,10-triaza-spiro[5.5}undecane-7,9,11-trione; 012529 -26- 1-[6-(4-Ethyl-phenoxy)-pyridin-3-yi]-1,7,9-triaza-spiro[4.5]decane-6,8,10-trione;1-[6-(4-Fiuoro-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro(4.5]decane-6,8,10-trione;4-(5-(6,8,10-Trioxo-1,7,9-triaza-spiro(4.5]dec-1-yi)-pyridtn-2-yloxy}-benzonitrile;N-{4-(5-(6,8,10-Trioxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-benzyl}- acetamide;

Azetidine-1-carboxylic acid 4-(5-(6,8,10-trioxo-1,7,9-triaza-spiro[4.5]dec-1-yi)-pyridin2-yloxy]-benzylamide; 1 -(6-(4-Pyrazol-1 -ylmethyl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4,5]decane-6,8,10- trione; 1-[6-(3-Fluoro-4-[1 ,3,4}oxadiazo!-2-yi-phenoxy)-pyridin-3-yl]-1,8,10-triaza-spiro(5.5]undecane-2,7,9,11-tetraone; 1 -[6-(2-Fluoro-4-[1,3,4]oxadiazoI-2-yi-phenoxy}-pyridin-3-yi]-1,8,10-triaza-spiro[5.5]undecane-2,7,9,11-tetraone; 1-(6-(3-Methyl-4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,8,10-triaza-spiro[5.5jundecane-2,7,9,11-tetraone; 1 -(4-(4-(1,3,4]Oxadiazol-2-yi-phenoxy)-phenyl]-1,8,10-triaza-spiro[5.5]undecane- 2,7,9,11-tetraone; 1-[6-(Pyridin-4-yioxy)-pyridin-3-yl]-1,8,10-triaza-spiro[5.5]undecane-2,7,9,11-tetraone;1-[5-(Pyridin-4-yloxy)-pyridin-2-yl]-1,8,10-triaza-spiro(5.5]undecane-2,7,9,11-tetraone;1 -[4-(Pyridin-4-yloxy)-phenyl]-1,8,10-triaza-spiro(5.5]undecane-2,7,9,11-tetraone; 1 -(4-(Pyridin-4-yloxy)-phenyi]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraone;Azetidine-1-carboxyiic acid 4-(5-(2,6,8,10-tetraoxo-1,7,9-triaza-spiro[4.5]dec-1 -y!) pyridin-2-yioxy]-benzylamide; and the pharmaceuticaliy acceptable salts thereof.

Spécifie preferred compounds of formula I are selected from the group consistïng of:1-(6-(4-Fiuoro-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro(4.5]decane-2,6,8,10-tetraone;1-(6-(4-Fluoro-phenoxy)-pyridin-3-yi]-1,8,10-triaza-spiro[5.5]undecane-2,7,9,11- telraone; 4-(5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-benzonitrile; 1 -(6-(4-(1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane- 2,6,8,10-tetraone; 1 -[6-(4-Ethyl-phenoxy)-pyridin-3-yi]-1,7,9-triaza-spiro(4.5]decane-2,6,8,10-tetraone;N-{4-(5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro(4.5]dec-1-y!)-pyrÎdin-2-yloxy]-benzyl}- acetamide; N-(4-(5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro(4.5]dec-1-yI)-pyridin-2-yloxy]-benzyi}- propionamide; . N-(4-(5-(2,6,8,10-T etraoxo-1,7,9-triaza-spiro[4.5]dec-1 -yI)-pyridin-2-yloxy]-benzyl}-butyramide; 012529 -27-

Pentanoic acid 4-(5-(2,6,8,1Q-tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-benzyiamide;

Cyclobutanecarboxyiic acid 4-(5-(2,6,8,10-tetraoxo-1,7,9-triaza-spiro(4.5]dec-1-yi)-pyridin-2-yloxy]-benzylamide; 1-(6-(4-Bromo-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro(4,5]decane-2,6,8,10-tetraone; 1-[6-(4-pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane- 2,6,8,10-tetraone; and the pharmaceuticaily acceptable salts thereof.

The présent invention also relates to a pharmaceutical composition for the treatment ofa condition selected from the group consisting of connective tissue disorders, inflammatorydisorders, immunology/ailergy disorders, infectious diseases, respiratory diseases,cardiovascular diseases, eye diseases, metaboiic diseases, central nervous System (CNS)disorders, liver/kidney diseases, reproductive heaith disorders, gastric disorders, skindisorders'and cancers and other diseases characterized by metalloproteinase activity in amammal, including a human, comprising an amount of a compound of formula I or apharmaceuticaily acceptable sait thereof effective in such treatments and a pharmaceuticailyacceptable carrier.

The présent invention also relates to a pharmaceutical composition for the inhibition ofmatrix metalloproteinases or other metalloproteinases involved in matrix dégradation, in amammal, inciuding a human, comprising an effective amount of a compound of formula I or apharmaceuticaily acceptable sait thereof.

The présent invention also relates to a method for treating a condition seiected from thegroup consisting of connective tissue disorders, inflammatory disorders, immunology/ailergydisorders, infectious diseases, respiratory diseases, cardiovascuiar diseases, eye diseases,metaboiic diseases, central nervous System (CNS) disorders, liver/kidney diseases,reproductive heaith disorders, gastric disorders, skin disorders and cancers and otherdiseases characterized by matrix metalloproteinase activity in a mammal, including a human,comprising administering to said mammal an amount of a compound of formula 1 or apharmaceuticaily acceptable sait thereof effective in treating such a condition.

The présent invention also relates to a method for the inhibition of matrixmetalloproteinases or other metalloproteinases involved in matrix dégradation, in a mammal,inciuding a human, comprising administering to said mammal an effective amount of acompound of formula I or a pharmaceuticaily acceptable sait thereof.

The présent inventors hâve also discovered that it is possible to identify inhibitors offormula 1 with differential metalloprotease activity (preferabiy MMP-13 inhibitory activity). Onegroup of preferred inhibitors of formula I the inventors hâve been able to identify inciude thosewhich selectiveiy inhibit MMP-13 preferentially over MMP-1. The compounds of the invention 012529 -28- also possess selectïvity over a reîated group of enzymes known as reprolysins, such as TACEand aggrecanase. Another group of preferred inhibitors of formula I the inventors hâve beenable to identify include those which selectively inhibit MMP-13 preferentialiy over MMP-1 andMMP-14. Another group of preferred Inhibitors of formula I the inventors hâve been able to 5 identify include those which selectively inhibit MMP-13 preferentialiy over MMP-1 and 12.Another group of preferred inhibitors of formula I the inventors hâve been able to identify includethose which selectively inhibit MMP-13 preferentialiy over MMP-1,12 and 14. Another group ofpreferred inhibitors of formula I the inventors hâve been able to identify include those whichselectively inhibit MMP-13 preferentialiy over MMP-1, 2, 3, 7, 9 and 14. Most preferred 10 compounds of the invention seiectively inhibit MMP-13 preferentialiy over MMP-1, 2, 3, 7, 9,12and 14 and mammalian reprolysins.

The terni “treating", as used herein, refers to reversing, alleviating, inhibiting theprogress of, or preventing the disorder or condition to which such term appiies, or one or moresymptoms of such disorder or condition. The term “treatment”, as used herein, refera to the act 15 of treating, as “treating" is defined immediately above. "Connective tissue disorders’ as used herein refera to disorders such as degenerativecartilage loss foliowing traumatic joint injury, osteoarthritis, osteoporosis, Paget's disease,loosening of artificial joint implants, periodontal disease and gingivitis. “Destruction of articuler cartilage” as used herein refera to connective tissue disorders20 resulting in articular cartilage destruction, preferably joint injury, reactive atthritis, acutepyrophosphate arthritis (pseudogout), psoriatic arthritis, or juvénile rheumatoid arthritis, more preferably osteoarthritis. “inflammatory disorders" as used herein refera to disorders such as rheumatoidarthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, goût, 25 inflammatory bowe! disease, ulcerative coiitis, Crohn's disease and cachexia. “Immunology/allergy disorders" as used herein refera to disorders such as organtransplant toxicity, allergie reactions, allergie contact hypersensitivity, autoimmune disorderssuch as those disorders associated with granuiomatous inflammation/tissue remodeling (suchas asthma), immunosuppression and sarcoid. 30 “Infectious diseases," including those mediated by viruses, bacteria, fungi or mycobacteriai infection, as used herein refers to disorders such as septic arthritis, AIDS,fever; Prion diseases, myasthénie gravis, Malaria, sepsis, hémodynamie shock and septicshock. "Respiratory diseases" as used herein refers to disorders such as chronic obstructive 35 puimonary disease (including emphysema), acute respiratory distress syndrome, asthma,hyperoxic alveolar injury and idiopathic puimonary fibrosis and other fibrotic lung diseases. <312529 -29- “Cardiovascular diseases" as used herein refers to disorders such as atherosclerosisincluding atherosclerotic plaque rupture; aortic aneurysm including abdominal aortic aneurysmand brain aortic aneurysm; congestive heart failure; myocardial and cérébral infarction; stroke;cérébral ischemia; coagulation and acute phase response; left ventricular dilation; post 5 ischémie reperfusion injury, angiofibromas; hemangiomas; and restenosis. "Eye diseases" as used herein refers to disorders such as aberrant angiogenesis,ocular angiogenesis, ocular inflammation, keratoconus, Sjogren’s syndrome, myopia, oculartumors, corneal grafi rejection, corneal injury, neovascular giaucoma, corneal ulcération,corneal scarring, macular degeneration (including “Age Related Macular Degeneration 10 (ARMD) including both wet and dry forms), proiiferative vitreoretinopathy and retinopathy ofprematurity. “Metabolic diseases” as used herein refers to disorders such as diabètes (includingnon-insulin dépendent diabètes mellitus, diabetic retinopathy, insulin résistance, diabeticulcération). 15 "Central Nervous System” (CNS) disorders as used herein refers to disorders such as head trauma, spinal cord injury, Inflammatory diseases of the central nervous System, neuro-degenerative disorders (acute and chronic), Alzheimer's disease, demyelinating diseases ofthe nervous System, Huntington's disease, Parkinson's disease, peripheral neuropathy, pain,cérébral amyloid angiopathy, nootropic or cognition enhancement, amyotrophie latéral 20 sclerosis, multiple sclerosis, migraine, dépréssion and anorexia. “Liver/Kidney diseases" as used herein refers to disorders such as nephrotic syndromes such as glomerulonephritis and glomerular disease of the kidney, proteinuria,cirrhosis of the liver and interstitial nephritis. "Reproductive Health disorders" as used herein refers to disorders such as 25 endometriosis, contraception (male/female), dysménorrhée, dysfunctional uterine bleeding,prématuré rupture of fêtai membranes and abortifactant. “Gastric disorders” as used herein refers to disorders such as colonie anastomosisand gastric ulcers. “Skin disorders" as used herein refers to disorders such as skin aging, pressure 30 sores, psoriasis, eczema, dermatitis, radiation damage, tissue ulcération, decubital ulcers,epidermolysis builosa, abnormal wound heaiing (topical and oral formulations), burns andscleritis. “Cancers" as used herein refers to disorders such as solid tumor cancer includingcolon cancer, breast cancer, lung cancer and prostrate cancer, tumor invasion, tumor growth 35 tumor metastasis, cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx),esophagus, stomach, smail intestine, large intestine, rectum, liver and biliary passages,pancréas, larynx, lung, bone, connective tissue, skin, cervix uteri, corpus endometrium, ovary,teslis, bladder, kidney and other urinary tissues, eye brain and central nervous system, thyroid 012529 -30- and other endocrine gland, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myelomaand hematopoieiïc maiïgnancies including leukemias and lymphomas includlng lymphocytic,granulocytic and monocytic.

The subject invention also includes isotopically-labelled compounds, which are

5 identical to those recited in Formula I, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomic mass or massnumber usually found in nature. Exemples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as *H, 3K, 13C, 14C, 1SN, 18O, 170,31P, 32P, “s, UF 10 and 3SCi, respectively. Compounds of the présent invention, prodrugs thereof. andpharmaceutically acceptable salts of sald compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are within the scope of thisinvention. Certain isotopically-labelled compounds of the présent invention, for example thoseinto which radioactive isotopes such as 3H and ’4C are incorporated, are useful in drug and/or 15 substrate tïssue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., ’4C, isotopes areparticularly preferred for their ease of préparation and detectability. Further, substitution withheavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances. Isotopicaliy- 20 labelled compounds of Formula I of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Préparations below, by substituting a readiiy available isotopically-labelled reagent for a l· non-isotopically-labelled reagent.

This invention also encompasses pharmaceutical compositions containing prodrugs of 25 compounds of the formula I. This invention also encompasses methods of treating or preventingdisorders that can be treated or prevented by the inhibition of matrix metalloproteinases or theinhibition of mammaiian reprolysin comprising administering prodrugs of compounds of theformula I. Compounds of formula I having free amino, amïdo, hydroxy, sulfonamide or carboxyiicgroups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid 30 residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residueswhich are covalently joined through peptide bonds to free amido, amino, hydroxy or carboxyiicacid groups of compounds of formula I. The amino acid residues include the 20 naturallyoccurring amino acids commonly designated by three ietter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methyihistidine, norvalin, beta-alanine, 35 gamma-aminobutyric acid, citruiiine, homocystéine, homoserine, omithine and méthioninesulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyt 012529 -31- esters, which are covaientiy, bonded to the above substituants of formula I through the carbonylcarbon prodrug sidechain. Prodrugs also include dimers of compounds of formula I.

One of ordinary skill in the art will appreciate that the compounds of the invention areusefui- in treating a diverse array of diseases. One of ordinary skill in the art wiil alsoappreciate that when using the compounds of the invention in the treatment of a spécifiedîsease that the compounds of the invention may be combined with various existingtherapeutic agents used for that disease.

For the treatment of rheumatoid arthritis, the compounds of the invention may becombined with agents such as TNF-α inhibitors such as anti-TNF. monoclonal antibodies(such as ïnfliximab, D2E7 and CDP-870) and TNF receptor immunoglobuiin molécules (suchas etanercept), ICE inhibitors, MEKK1 inhibitors, COX-2 inhibitors such as celecoxib,rofecoxib, valdecoxib and etoricoxib; low dose methotrexate, lefunimide, steroids,glucosamines, chondrosamlnesZ sulfates, gabapentin, A-agonists, IL-1 process and releaseinhibitors, IL-1 receptor antagonists such as Kineret®, CCR-1 antagonists,hydroxychioroquine, d-penicilamine, auranofin or parentéral or oral goid.

The compounds of the invention can aiso be used in combination with existingtherapeutic agents for the treatment of osteoarthritis. Suitable agents to be used incombination include standard non-steroidal anti-inflammatory agents (hereinafter NSAlD’s)such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, suiindac,apazone, pyrazolones such as phenyibutazone, saiieylates such as aspirin, COX-2 inhibitorssuch as celecoxib, valdecoxib, paracoxïb, etoricoxib and rofecoxib, analgésies, steroids,glucosamines, chondrosamines/ sulfates, gabapentin, A-agonists, IL-1 process and releaseinhibitors, CCR-1 antagonists, LTD-4, LTB-4 and 5-LO inhibitors, p38 kinase inhibitors andintraarticular thérapies such as corticosteroids and hyaluronic acids such as hyalgan andsynvisc.

The compounds of the présent invention may aiso be used in combination withanticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin,daunomycin, cis-platinum, etoposide, paciitaxei, docetaxel and aikaloids, such as vincristineand antimetaboliles such as methotrexate.

The compounds of the présent invention may aiso be used in combination withcardiovascular agents such as calcium channel btockers (such as amlodipine and nifedipine),lipid lowering agents such as statins (such as lovastatin, atorvastatin, pravastatin andsimvastatin), adrenergics such as doxazosin and terazosin; fibrates, beta-blockers, Aceinhibitors (such as captopril, lisinopril, fosinopril, enalapri! and quinaprill), Angiotensin-2receptor antagonists such as losartan and irbesartan; nitrates, CCB's, diureiics such asdigitalis and plateiet aggregation inhibitors. The compounds of the présent invention may aiso 012529 -32- be used in combination with plaque rupture preventitive agents such as statins, zithromax,NSAIDs including aspirin, heparin, urarfarin, abciximab, TPA and platelet inhibitors. Thecompounds of the présent invention may aiso be used in combination with stroke treatmentagents such as NIF, NHEI’s and CCRIR antagoniste.

5 The compounds of the présent invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such asdeprenyi, carbadopa, L-dopa, dopamine receptor agonists such as ropiniroie, pergolide andpramipexole; MAOB inhibitors such as selegiline and rasagiline, catechol-O-methyltrasferaseinhibitors such as tolcapone, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagoniste, 10 Nicotine agonists, NK-1 inhibitors, dopamine agonists and inhibitors of neuronal nitric oxidesynthase) and anti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors,propentofyliine or metryfonate.

The compounds of the présent invention may also be used in combination withosteoporosis agents such as roloxifene, droloxifene, lasofoxifene or fosomax and 15 immunosuppressant agente such as FK-506 and rapamycin.

The compounds of the présent invention may also be used in combination with agents for the treatment of respiratory diseases such as PDE-IV inhibitors, steroidals such asfluticasone, triamcinoione, budesonide, budesonide and beclomethasone, antichoiinergicssuch as ipratropium, sympathomimetics such as salmeteroi, aibuteroi and Xopenex, 20 decongestants such as fexofenadine, loratadine and cetirizine; leukotriene antagoniste suchas zafirlukast and motelukast; and mast celi stabilizers such as zileuton.

The compounds of the présent invention may also be used in combination with agentefor the treatment of skin disorders such as tretinoin, isotretinoin, steroids such as cortisoneand mometasone, antibiotics such as tétracycline, antifungals such as clotrimazole, 25 rniconazole and fiuconazole and PDE-IV inhibitors.

The compounds of the présent invention may also be used in combination with agentsfor the treatment of diabètes such as insulin, including human or humanized insulin andihhaied insulin, aldose reductase inhibitors, sorbitoi dehydrogenase inhibitors, antidiabeticagents such as biguanides such as metformin; giitazones, glycosidase inhibitors such as 30 acarbose, sulfonylureas such as glimepiride and giipizide; and thiazoiidinediones such aspioglitazone, rosigiitazone and trogiiazone. Preferred combinations are usefui for treating theside effects of diabètes such as retinapathy, nephropathy and neuropathy, preferablyretinopathy.

Detailed Description of the Invention 3E The foilowing reaction Schemes illustrate the préparation of the compounds of the présent invention. Unless otherwise indicated each of X, Y, Z, G, R1, Rz, R3, R4, R5, R6, R7,R8, R9, Rw, R11, R12, R13, R14, R15, Ri6, R17, R18, R19. R20, R21 and R22 in the reaction Schemesand the discussion that foitows is defined as above. 012529 -33-

SCHEME1H,N—X-Y-Z-G

O

N

,0 X-Y-Z-G 012529 -34-

SCHEME2H2N—X-Y-Z-G

X-Y-Z-G

012529 -35- SCHEME 3 no2- X—L7 N02-X—Y—2—G Vlîl

H2N

X-Y—-2—G 012529 -36-

Scheme 1 refers to the préparation of compounds of the formula I. Referring to Scheme1, compounds of formula I, wherein the heterocyclic ring “A" has the formuiae a-n (i.e., acompound of the formuiae la-in, respectively):

can be prepared by reacting a compound of the formuiae llla-llln, respectively: 012529 -37-

X-Y-Z-G O R® .ο I ji ZR.N-%1 R”tt

' ’R

lllg lllj p'-Z-GP N-SO,

Hlf ;

R1 R2 R5 RX-Y-Z-G îili ;

X-Y-Z-G .0 and L2— lllrn

lllk llln

R ' SR6R- RsR

Illl ; wherein L1 and L2 are leaving groups such as alkoxy, preferably methoxy, ethoxy or benzyloxy,more preferably methoxy or ethoxy, with a urea of formula 11 (i.e., H2N-(CO)-NH2) in thepresence of a suitable base in a polar solvent. Suitable bases include alkoxide bases, such assodium methoxide, sodium ethoxide, or potassium ferf-butoxide, preferably sodium ethoxide.Suitable solvents include tetrahydrofuran, dimethylformamide, or alcohols (such as ethanoi),preferably tetrahydrofuran or dimethylformamide. The aforesaid reaction is conducted at a 012529 température of about 20°C to about 90°C, preferabiy about 50°C to about 80°C, for a timeperiod of about 5 minutes to about 8 hours. A compound of formulae IIIa-IIH, respectively, can be prepared by reacting acompound of formulae IVa-IVI, respectively:

X-Y-Z-G

IVg ;

X-Y-Z-G

IVj .

X-Y-Z-G

10 wherein L1 and l2 are Ieaving groups such as alkoxy, preferabiy methoxy, etboxy or benzyloxy,more preferabiy methoxy or ethoxy and wherein L3 is a suitable ieaving group, such as halo,para-tolylsulfonyloxy (OTs), or methyisulfonyloxy (OMs), preferabiy halo, such as bromo oriodo, with a suitable base in a polar solvent. Suitable bases include tertiary amines, ,such astriethylamine. Other suitable bases include a strongly basic macro-reticuiar resin or gel typeresin, such as Amberlyst 400® resin (hydroxide form). Suitable solvents include alcoholicsolvents, preferabiy éthanol. The aforesaid reaction can be conducted at a température ofabout -10 °C to about 50 °C, preferabiy about 20 °C, for a period of about 6 to about 35 hours. 012529 -39- A compound of formulae Illm-llln, respectively, can be prepared by reacting acompound of formulae tVm-IVn, respectively:

and

IVm IVn 10 wherein L3 is a suitable leaving group, with a suïtable' base in a polar solvent according tomethods analogous to the préparation of the compounds of formulae Hla-lHi in the foregoingparagraph. Suitable leaving groups of the formula L3 include halo, para-tolylsulfonyloxy (OTs),or methylsulfonyloxy (OMs). Preferablÿ L3 is halo, such as chloro. The aforesaid reaction canbe conducted at a température of about O’C to about 50°C, preferablÿ about 20 °C, for aperiod of about 1 hour to about 4 hours. Suitable solvents include tetrahydrofuran,dimethylformamide and aicohol. A compound of formulae IVa-IVi, respectively, can be prepared by reacting acompound of formula VI with a compound of general formula L3-( A' )-L4 ’ (V) (i.e., a compound of formulae Va-Vi, respectively): 15

012529 -40- wherein each of 1? and L4 is a suitable leaving group, such as halo, para-tolylsulfonyloxy (OTs), or methylsulfonyloxy (OMs). Preferably L3 is halo, such as bromo, chioro or iodo.Preferabfy L4 is chioro or fluoro. Optionally, the aforementioned reaction' may be conducted inthe presence of a tertiary amine base, such as /V,N-dlmethylaniiine or pyridine, in the presenceof a suitable solvent, such as a hydrocarbon solvent (benzene or toluene), tetrahydrofuran ormethylene chioride. The aforementioned reaction is conducted at a température of about 20°Cto about 90°C, preferably about 50’C to about 80°C, for a time period of about 30 minutes toabout 6 hours.

Preferably, the aforementioned réaction is conducted in an aromatic hydrocarbonsolvent, such as benzene or toluene, in the absence of the aforementioned base. A compound of formulae IVj-IVI, respectively, can be prepared by reacting acompound of formula VI with a compound of formula: L3-( A')-L4 (i.e., a compound of formulae Vj-VI, respectively): (V) R R'

L'

Vj

R

and

wherein each of L3 and L4 is a suitable leaving group, such as halo, para-tolylsulfonyloxy (OTs)or methylsulfonyloxy (OMs), according to the methods analogous to those described in the préparation of the compounds of formulae IVa-IVi in the foregoing paragraph. Preferably L3 is chioro, bromo, or iodo. Preferably L4 is chioro, bromo, or iodo. The aforesaiti reaction can beconducted at a température of about 0°C to about 50°C, preferably about 20°C, for a timeperiod of about 30 minutes to about 12 hours.

Compounds of formulae IVm-IVn, respectively, can be prepared by reacting acompound of formula VI with a compound of formula L3-(A')-L4 (i.e., a compound of formulas Vm-Vn, respectively):

O (V)

.0

O Vn wherein each of L3 and L4 is a suitable leaving group, such as halo, para-tolylsulfonyloxy (OTs)or methylsulfonyloxy (OMs), according to the methods analogous to those described in the préparation of the compounds of formulae IVa-IVi in the foregoing paragraph. Preferably L3 is 012529 -41- halo, such as chloro. Preferably L* is halo, such as chloro. The aforesaid reaction can beconducted at a température of about 0°C to about 80°C, preferably about 0°C to about 40°C,for a time period of about 30 minutes to about 8 hours.

Altematively, compounds of formulae IVd, IVe and IVf, respectively, can be prepared byreacting a compound of formula Vi with a compound of formula (A’)-l3 (V) (i.e., a compound of formulae Vd’, Ve' and Vf, respectively):

N=C=O

R r2 R5 R 10 15 20 wherein L3 is preferably halo, most preferably chloro, bromo, or iodo. Optionally, theaforementioned reaction can be conducted In the presence of a tertiary amine base in asuitable solvent. Suitable bases include W,/V-dimethylaniiine or pyridine. Suitable solventsinclude hydrocarbon solvent (benzene or toluene), tetrahydrofuran, or methyiene chloride,preferably aromatic hydrocarbon solvent, such as benzene or toluene. The aforementionedreaction is conducted at a température of about 20°C to about 90°C, preferably about 50°C to about 80°C, for a time period of about 30 minutes to about 6 hours. Preferably, the / aforementioned reaction is conducted in the absence of any aforementioned base.

Altematively, compounds of formulae IVm and IVn, respectively, can be prepared by reacting a compound of formula VI with a compound of formula(A’)-L3 (V) (i.e., a compound of formulae Vm’ and Vn’, respectively):

L3—SO2-N=C=O

Vm' and

N=C—O

Vn' 25 30 wherein L3 is preferably halo, most preferably chloro. The aforementioned reaction can beconducted optionally in the presence of a tertiary amine base in a suitable solvent. Suitablebases include W,A/-dimethylaniline or pyridine. Suitable solvents include a hydrocarbon solvent(benzene or toluene), tetrahydrofuran or methyiene chloride, preferably aromatic hydrocarbonsolvent, such as benzene or toluene. The aforesaid réaction can be conducted at atempérature of about -10°C to about 50°C, preferably about 0°C to about 30°C, for a timeperiod of about 30 minutes to about 12 hours. Preferably, the aforementioned reaction isconducted in the absence of any aforementioned base. A compound of formula VI can be prepared by reacting a compound of formula HZN-X-Y-Z-G with a compound of the formula Vil: 012529 -42- 10 15 20 25 30

wherein L1 and L2 are leaving groups, such as methoxy, ethoxy, or benzyloxy; preferablyethoxy; and Ls is a leaving group, such as halo, para-toiylsulfonyioxy (OTs) ormethylsulfonyioxy (OMs); preferably halo; most preferably chloro or bromo. The aforesaidreaction can be performed either neat or in the presence of a suitable solvent, preferably neat,in the presence of a suitable base. Suitable solvents include tetrahydrofuran ordimethyiformamide. Suitable bases include a weak tertiary amine base, preferably tertiaryaniline bases, most preferably Ν,Ν-dimethylaniIine. Preferably, the aforementioned reaction isconducted at a température of about 23°C to about 100°C, preferably about 50°C to about90°C, for a time period of about 30 minutes to about 24 hours.

In the aforesaid réactions, each of the compounds of formulae IVj-IVI may be isolated,but are preferably carried on to the next step without isolation. Thus, in Scheme 1, thecompound of formulae IIIj-HII is preferably prepared in a one pot préparation from a compoundof the formula VI.

If the compounds of the formulae IVj-IVI are not isolated, the suitable solvent for theone-pot préparation is dimethyiformamide, tetrahydrofuran, or alcohols, preferably alcohols,such as éthanol. Preferably, the one-pot préparation is conducted in the presence of analkoxide base, preferably sodium methoxide or sodium ethoxide. The aforesaid one potpréparation is conducted at a température of about 40°C to about 90°C, preferably about 60°Cto about 80°C, for a time period of about'15 minutes to about 12 hours.

The compounds of formula H2N-X-Y-Z-G are commercially availabie or can be madeby methods well known to those skilled in the art. Alternatively, the compounds of formulaH2N-X-Y-Z-G can be prepared as described ίη Scheme 3. A compound of the formula VII can be made by methods well known in the art such asthose described in PCT Patent Publication WO 98/58925 or reviewed in The OrganicChemistry of Druq Svnthesis. D. Lednicer and L. A. Mitscher, Volume 1, pages 167 to 277 andréférencés therein. Each of the above referenced publications and applications is herebyincorporated by référencé in its entirety.

Compounds of the formula II are commercially availabie or can be made by methodswell known to those skilled in the art.

Scheme 2 refers to the préparation of a compound of the formula I, wherein theheterocyclic ring “A" has the formula o, i.e., a compound of formula lo. Referring to Scheme 2,a compound of formula lo: 012529 -43-

can be prepared by reacting a compound of the formula lllo, wherein t? and Lz are leavinggroupe, with a urea of formula II (i.e., H2N-(CO)-NH2) in the presence of a suitable base in apolar solvent. Suitable leaving groups include methoxy, ethoxy, or benzyloxy, preferablyethoxy. Suitable bases include alkoxide bases, such as sodium methoxide, sodium ethoxide Iand potassium terf-butoxide, preferably sodium ethoxide. Suitable soivents includetetrahydrofuran, dimethyiformamide, or alcohols (such as éthanol), preferably tetrahydrofuranor dimethyiformamide. The aforesaid reaction is conducted at a température of about 20°C toabout 90°C, preferably about 50°C to about 80°C, for a time period of about 5 minutes toabout 8 hours. A compound of formula lllo can be prepared by reacting a compound of formula IVo,wherein L3 is a leaving group, with a suitable base in a polar solvent. Suitable leaving groupsinclude alkoxy (such as methoxy, ethoxy, or benzyloxy) or halo; preferably methoxy or ethoxy.Suitable bases include alkoxide bases, preferably sodium methoxide or sodium ethoxide.Suitable solvents include alcohols, preferably éthanol. The aforesaid reaction can beconducted at a température of about 0 °C to about 90 °C, preferably of about 60 °C to about90 °C, for a period of about 1 hour to about 36 hours. A compound of formula IVo can be prepared by reacting a compound of formula VIwith the compound of formula Vo:

wherein L6 is a suitable leaving group, in a suitable solvent. Suitable L6 indudes alkoxy orhalo, such as chloro; preferably alkoxy; more preferably methoxy or ethoxy. Optionally, theaforesaid reaction may be conducted in the presence of a suitable tertiary amine base, suchas triethylamine, N,N-dimethyiani!ine, or pyridine. Suitabte solvents, include hydrocarbonsolvents (benzene or toluene), tetrahydrofuran, or methylene chloride, preferablytetrahydrofuran. Preferably, the aforementioned reaction is conducted in tetrahydrofuran ordimethyiformamide, in the presence of the aforementioned suitable tertiary amine base. Theaforesaid réaction may be conducted at a température of about 20°C to about 90°C,preferably about 50°C to about 80°C, for a time period of about 30 minutes to about 6 hours. 012529 -4.4- ln the aforesaid reactions, a compound of formula IVo may be isolated, but ispreferably carried on to the next step without isolation. Thus, in Scheme 1, a compound offormula Illo is preferably prepared in a one-pot préparation from a compound of the formulaVI.

If the compounds of the formulae IVo are not isolated, the suitable solvent for the one-pot préparation is dimethylformamide, tetrahydrofuran, or alcohols, preferably alcohoi, such aséthanol. The aforesaid one pot préparation is suitably conducted at a température of aboutO°C to about 70°C, preferably about 23°C to about 60°C, for a time period of about 30 minutesto about 24 hours. A compound of formula VI can prepared by reacting a compound of formula H2N-X-Y-Z-G with a compound of the formula VII as described Scheme 1.

Scheme 3 refers to the préparation of compounds of the formula H2N-X-Y-Z-G, whichare intermediates useful in the préparation of compounds of formula I in Schemes 1 and 2.Referring to Scheme 3, compounds of formula H2N-X-Y-Z-G can be prepared by reacting acompound of formula VIH with a reducing agent, such as tin II chloride, in the presence of asuitable acid, such as hydrochloric acid, in a polar protic solvent. Suitable solvents include analcoholic solvent, water, or mixtures thereof, preferably a mixture of éthanol and water. Theaforesaid réaction can be conducted at a température of about 40°C to about 100°C for aperiod of about 1 to about 12 hours.

Alternatively, the compounds of formula H2N-X-Y-Z-G can be prepared by reacting acompound of formula VIII with hydrogen gas, at a pressure between atmospheric pressureand 50 psi, in the presence of a catalyst and a polar solvent. Suitable catalysts include apalladium or platinum catalyst, preferably Adams catalyst (i.e., platinum oxide), or palladiumadsorbed on charcoal. Suitable solvents include an alcoholic solvent, preferably methanol.The aforesaid réaction can be conducted at a température of about 20°C to about 50°C,preferably about 23°C, for a period of about 30 minutes to about 6 hours. A compound of the formula VIII, wherein Y is oxygen, sulfur, -CH2S-, -CH2O-, >NR14,-CH2[N(R14)]- or -SO2[N(R14))-, can be prepared by reacting a compound of formula X, whereinthe group L7 is fluoro or chloro, with a compound of the formula: G-Z-Y-H (IX) wherein Y is oxygen, sulfur, -CH2S-, -CH2O-, >NR14, -CH2[N(R14)]- or -SO2{N(R’4)]-, in thepresence of a base in a polar aprotic solvent. Suitable bases include an alkali métal hydridebase; preferably sodium hydride. Suitable solvents include dimethylformamide,tetrahydrofuran or 1,2-dimethoxyethane; preferably dimethylformamide. The aforesaidreaction can be conducted at a température of about 40°C to about 140°C, preferably about80°C to about 120°C, for about 1 hour to about 24 hours.

Alternatively, the aforesaid compound of formula VIII, wherein Y is oxygen, sulfur, 012529 -45- -CH2S-, -CH2O-, >NR14, -CH2[N(R14)]- or -SO2[N(R14)]-, can be prepared in presence of analkali métal bydroxide base, preferably potassium hydroxide, optionally in the presence of aphase transfer catalyst, such as a quaternary ammonium or phosphonium sait, preferablytetrabutylammonium bromide, in an aromatic hydrocarbon solvent. Preferably the solvent isbenzene or toluene. The aforesaid reaction can be conducted at a température of about 0°Cto about 120°C, preferably at about 23°C, for about 1 hour to about 12 hours.

Alternativeiy, the aforesaid compound of formula VIII, wherein Y is oxygen, sulfur,-CH2S-, -CH2O-, >NR14, -CH2[N(R’4}]- or -SO2[N(R14)]-, can be prepared under so called"Ulman coupling” conditions. Under such conditions, the aforesaid compound of formula VIIIcan be prepared by reacting a compound of formula X, wherein the group L7 is bromo orchlore, with a compound of the formula: • G-Z-Y-H (IX) , wherein Y is oxygen, sulfur, -CH2S-, -CH2O-, >NR14, -CH2[N(R14)]- or -SO2(N(R14)]-, in thepresence of a base and a catalyst in a polar aprotic solvent. Suitable bases include an alkalimeta! carbonate or hydroxide base, preferably potassium carbonate. Suitable catalysts includea copper (0) catalyst, preferably finely powdered copper bronze. Suitable solvents includedimethylformamide or l-methyl-2-pyrrolidinone. The aforesaid reaction can be conducted at atempérature of about 80 °C to about 140 °C, for about 6 hours to about 24 hours. . A compound of formula VIH, wherein the group Y is in an oxidized state, i.e., >SO2l>S=O, -CH2SO-, -CH2SO2-, SO(CH2)n- or -SO2(CH2)n-, can be prepared by reacting acorresponding compound of formula VIII, wherein the group Y is in a corresponding loweroxidation State, with a suitable oxidizing agent in a solvent. The corresponding lower oxidationstate for each compound of formula VIH, wherein the group Y is >SO2 and >S=O is acompound of formula VIH, wherein the group Y is S. The corresponding lower oxidation statefor each compound of formula VIH, wherein the group Y is -CH2SO2- and -CH2SO- is acompound of formula VIII, wherein the group Y is -CH2S-. The corresponding lower oxidationstate for each compound of formula Vllt, wherein the group Y is -SO2(CH2)n- and -SO(CH2)n-is a compound of formula VIII, wherein the group Y is -S-(CH2)n-, Suitable oxidizing agentsinclude a peroxy acid, preferably peracetic acid, or an organic peroxide, preferably m-chloroperoxybenzoic acid or terf-butyl hydroperoxide. Suitabie solvents include methyienechloride or alcohoî, such as éthanol. The aforesaid reaction can be conducted at atempérature of about -10°C to about 30°C, for about 1 hour to about 8 hours. A compound of the formula VIH, wherein Y is -O(CH2)n-, -S(CH2)n- or -NR14(CH2)O-,respectively, can be prepared by reacting a compound of the formula X, wherein the group L7is LB-(CH2)„- and wherein the group L6 is halo, such as chloro, bromo, iodo, mesyloxy (MsO),or tosyloxy (TsO), with a compound of formula: G-Z-W-H (IX) 012529 -46- whereîn the group W is oxygen, sulfur, or -NR14, respectively, in the presence of a base in apolar aprotic solvent. Suitable bases include an alkali métal carbonate base, preferablypotassium carbonate or césium carbonate. Suitable solvents include dimethylformamide ortetrahydrofuran. The aforesaid reaction can be conducted at a température of about 23°C toabout 80°C, preferably about 20°C to about 50°C, for about 1 to about 24 hours. A compound of the formula Viii, wherein Y is >C=O, -CH=CH- or - C&C-, can beprepared by reacting a compound of formula X, wherein the group L7 is dihydroxyborane; zinchalide, such as zinc chloride; or trialkyl tin, such as tributyl tin, wïth a compound of the formula: G-Z-Y-L9 (IX) wherein Y is >C=O, -CH=CH- or - CsC-; and wherein the group Ls is halo; preferably chloro,bromo or iodo; in the presence of a catalyst in a solvent. Suitable catalysts include apalladium or nickel catalyst, preferably tetrakis triphenyl phosphine palludium (0) (Pd(PPh3)4).Suitable solvents include toluene, tetrahydrofuran, dimethylformamide, or dimethylsulfoxide.The aforesaid réaction can be conducted at a température of about 23°C to about 110°C, for aperiod of about 1 hour to about 24 hours. Such reactions can be faciiitated by the presence ofa copper sait, such as cuprous iodide or cuprous bromide.

Altematively, a compound of the formula VIII, wherein Y is -CsC-, can be prepared byreacting a compound of formula X, wherein L7 is halo or triflate, preferably bromo or iodo, witha compound of the formula: G-Z-Y-H (IX) in the presence of a base, such as a trialkylamine base, preferably triethylamine and apalladium catalyst, preferably Pd(PPha)4 in a solvent. Suitable solvents includetetrahydrofuran or dimethylformamide. The aforesaid reaction can be. conducted at atempérature of about 23°C to about 60°C for a period of about 1 to about 24 hours. A compound of the formula VIII, wherein Y is -CH2(CH2)n-, can be prepared byreacting the aforementîoned compound of the formula VIII, wherein Y is -CH=CH- or -CsC-,with hydrogen gas, at ambient pressure to about 50 psi, in the presence of a palladiumcatalyst in a solvent. Preferably the palladium catalyst is palladium adsorbea on charcoal.Suitable solvents include methanol or ethyl acetate. The aforesaid reaction can be conductedat a température of about 20°C to about 50°C, for about 1 hour to about 24 hours.

Compounds of the formulae X and IX (Le., compounds of the formulas G-Z-Y-H, G-Z-W-H, or G-Z-Y-L8) are either commercially available or are well known and can be preparedby methods known to those skilled in the art.

The compounds of the formula I, which are basic in nature, are capable of forming awide variety of different salts with various inorganic and organic acids. Although such saltsmusl be pharmaceutically acceptable for administration to animais, it is often désirable inpractice to initially isolate a compound of the formula I from the reaction mixture as a 012529 -47- pharmaceuticaily unacceptable sait and then simply convert the latter back to the free basecompound by treatment with an alkaline reagent and subsequently convert the free base to a.pharmaceutically acceptable acid addition sait. The acid addition salts of the basecompounds of this invention are readily prepared by treating the base compound with asubstantially équivalent amount of the chosen minerai or organic acid in an aqueous solventmedium or in a suitable organic solvent such as methanol or éthanol. Upon carefuiévaporation of the solvent, the desired solid sait is obtained.

The acids which are used to préparé the pharmaceutically acceptable acid additionsalts of the base compounds of this invention are those which form non-toxic acid additionsaits, i.e., salts containing pharmacoiogically acceptable anions, such as hydrochioride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate,iactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate and pamoate [/.e., 1,T-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula i which are aiso acidic in nature, are capable offorming base salts with various pharmacoiogically acceptable cations. Examples of such saltsinclude the alkali métal or alkaline-earth métal salts and particularly, the sodium andpotassium salts. These salts are ail prepared by conventional techniques. The Chemicalbases which are used as reagents to préparé the pharmaceutically acceptable base salts ofthis invention are those which form non-toxic base salts with the herein described acidiccompounds of formula I. These non-toxic base salts include those derived from suchpharmacoiogically acceptable cations as sodium, potassium, calcium and magnésium, etc.These saits can easily be prepared by treating the corresponding acidic compounds with anaqueous solution containing the desired pharmacoiogically acceptable cations and thenevaporating the resulting solution to dryness, preferably under reduced pressure.

Alternativeiy, these salts may also be prepared by mixing lower alkanolic solutions ofthe acidic compounds and the desired alkali métal alkoxide together and then evaporating theresulting solution to dryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensure completeness of reactionand maximum product yieids.

B1OLOGICAL ASSAYS

The abiüty of the compounds of formula I or iheir pharmaceutically acceptable salts(hereinafter also referred to as the compounds of the présent invention) to inhibitmetalloproteinases or mammalian reprolysins and, consequently, demonstrate theireffectiveness for treating diseases characterized by metalloproteinase activity is shown by thefoliowing in vitro and in vivo assay tests. 012529 -48- ΜΜΡ Assavs ΜΜΡ-13 sélective inhibitors can be identified by screening the inhibitors of the présentinvention through the MMP fluorescence assays described below and selecting those agentswith MMP-13/MMP-X inhibition ICæ ratios of 100 or greater and potency of iess than 100 nM, 5 where MMP-X refers to one or more other MMP's.

Non-selective collagénase inhibitors as used herein, unless otherwise mentioned, referto agents which exhibit Iess than a 100 fold sélectivity for the inhibition of MMP-13 enzymeactivity over MMP-X enzyme activity or a potency of more than 100nM as defined by the ICæresults from the MMP-13/MMP-X fluorescence assays described below. 10 The ability of coiiagenase inhibitors to inhibit collagénase activity is well known in the art.

The degree of inhibition of a particular MMP for severai compounds has been well documentedin the art and those skilled in the art will know how to normalize different assay results to thoseassays reported herein. The following assays may be used to identifÿ matrix metalloproteinaseinhibitors.’ 15 Inhibition of Human Coiiagenase (MMP-1)

Human recombinant coiiagenase is activated with trypsin. The amount of trypsîn is optimized for each lot of coilagenase-1 but a typical reaction uses the following ratio: 5 pg trypsinper 100 pg of coiiagenase. The'trypsin and coiiagenase are incubated at room température for10 minutes then a five fold excess (50 mg/10 mg trypsin) of soybean trypsin inhibitor is added. 20 Stock solutions (10 mM) of inhibitors are made up in dimethylsulfoxide and then diluted using the following scheme:

10 mM-> 120 pM-> 12 pM-> 1.2 pM-> 0.12 pM

Twenty-five microiiters of each concentration is then added in triplicate to appropriate wells ofa 96 well microfluor plate. The final concentration of inhibitor will be a 1:4 dilution after 25 addition of enzyme and substrate. Positive Controls (enzyme, no inhibitor) are set up in welisD7-D12 and négative Controls (no enzyme, no inhibitors) are set in wells D1-D6.

Collagenase-1 is diluted to 240 ng/ml and 25 pl is then added to appropriate welis of themicrofluor plate. Final concentration of coiiagenase in the assay is 60 ng/ml.

Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is made as a 5 mM30 stock in dimethyisulfoxide and then diluted to 20 pM in assay buffer. The assay is initiated by the addition of 50 pl substrate per well of the microfiuor plate to give a final concentration of 10 pM.

Fluorescence readings (360 nM excitation, 460 nm émission) are taken at time 0 andthen ai 20 minute intervals. The assay is conducted at room température with a typicat assaytime of 3 hours 35 Fluorescence versus time is then plotted for both the blank and coiiagenase containing samples (data from triplicate déterminations is averaged). A time point that provides a goodsignal (at least five fold over the blank) and that is on a linear part of the curve (usually around 01252g -49- 120 minutes) is chosen to détermine ICæ values. The zéro time is used as a blank for eachcompound at each concentration and these values are subtracted from the 120 minute data.Data is plotled as inhibitor concentration versus % control (inhibitor fluorescence divided byfluorescence of collagénase alone x 100). ICso's are determined from the concentration of 5 inhibitor that gives a signal that is 50% of the control.

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

Inhibition of Gélatinase (ΜΜΡ«2)

Human recombinant 72 kD gelatînase (MMP-2, gélatinase A) is activated for 16-1810 hours with 1mM p-aminophenyl-mercuric acetate (from a freshiy prepared 100 mM stock in 0.2 N NaOH) at 4°C, rocking gentîy. 10 mM dimethylsutfoxide stock solutions of inhibitors are diluted serially in assaybuffer (50 mM TRIS, pH 7.5, 200 mM NaCI, 5 mM CaCI2, 20 μΜ ZnCI2 and 0.02% BRIJ-35(vol./vol.» using the following scheme: 15 10 mM—>120μΜ—>12μΜ—>1.2μΜ--> 0.12 μΜ

Further dilutions are made as necessary following this same scheme. A minimum of fourinhibitor concentrations for each compound are performed in each assay. 25 pL of eachconcentration is then added to tripiicate welis of a black 96 well tJ-bottomed microfluor plate.As the final assay volume is 100 pL, final concentrations of inhibitor are the resuit of a further 20 1:4 dilution (i.e. 30 μΜ —» 3 μΜ —> 0.3 μΜ —» 0.03 μΜ, etc.). A blank (no enzyme, no inhibitor) and a positive enzyme control (with enzyme, no inhibitor) are aiso prepared intripiicate.

Activated enzyme is diluted to 100 ng/mL in assay buffer, 25 pL per well is added toappropriais welis of the microplate. Final enzyme concentration in the assay is 25 ng/mL 25 (0.34 nM). A five mM dimethyisuifoxide stock solution of substrate (Mca-Pro-Leu-Gly-Leu-Dpa-Aia-Arg-NH2) is diluted in assay buffer to 20 μΜ. The assay is initiated by addition of 50 pL ofdiluted substrate yielding a final assay concentration of 10 μΜ substrate. At time zéro,fluorescence reading (320 excitation; 390 émission) is immediately taken and subséquent 30 readings are taken every fifteen minutes at room température with a PerSeptive BiosystemsCytoFluor Multi-Well Plate Reader with the gain at 90 units.

The average value of fluorescence of the enzyme and blank are plotted versus time.An early time point on the linear part of this curve is chosen for IC50 déterminations. The zérotime point for each compound at each dilution is subtracted from the latter time point and the 35 data then expressed as percent of enzyme control (inhibitor fluorescence divided byfluorescence of positive enzyme control x 100). Data is plotted as inhibitor concentration 012529 -50- versus percent of enzyme contrat. IC5o’s are defined as the concentration of ïnhibitor thatgives a signal that is 50% of the positive enzyme control.

Inhibition of Stromelysin Activity (MMP-3)

Human recombinant stromelysin (MMP-3, stromeiysin-1) is activated for 20-22 hourswith 2 mM p-aminophenyl-mercuric acetate (from a freshiy prepared 100 mM stock in 0.2 NNaOH) at37°C. 10 mM dtmethyisuifoxide stock solutions of inhibitors are diluted serially in assaybuffer (50 mM TRIS, pH 7.5, 150 mM NaCI, 10 mM CaCI2 and 0.05% BRIJ-35 (volJvol.))using the following scheme: 10 mM—» 120 μΜ—» 12 μΜ--» 1.2 μΜ-> 0.12 μΜ

Further dilutions are made as necessary following this same scheme. A minimum of fourïnhibitor concentrations for each compound are performed in each assay. 25 pL of eachconcentration is then added to triplicate wells of a black 96 well U-bottomed microfluor plate.As the final assay volume is 100 pL, final concentrations of ïnhibitor are the resuit of a further1;4 dilution (i.e. 30 μΜ —» 3 μΜ —> 0.3 μΜ —» 0.03 μΜ, etc.). A blank (no enzyme, noïnhibitor) and a positive enzyme control (with enzyme, no ïnhibitor) are also prepared intriplicate.

Activated enzyme is diluted to 200 ng/mL in assay buffer, 25 μ!_ per well is added toappropriate wells of the microplate. Final enzyme concentration in the assay is 50 ng/mL(0.875 nM). A ten mM dimethylsulfoxide stock solution of substrate (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NHa) is diluted in assay buffer to 6 μΜ. The assay is initiated byaddition of 50 pL of diluted substrate yielding a final assay concentration of 3 μΜ substrate. Attime zéro, fluorescence reading (320 excitation; 390 émission) is immediately taken andsubséquent readings are taken every fifteen minutes at room température with a PerSeptiveBiosystems CytoFluor Multi-Well Plate Reader with the gain at 90 units.

The average value of fluorescence of the enzyme and blank are plotted versus time.An early time point on the iinear part of this curve is chosen for IC50 déterminations. The zérotime point for each compound at each dilution is subtracted from the latter time point and thedata then expressed as percent of enzyme control (ïnhibitor fluorescence divided byfluorescence of positive enzyme control x 100). Data is plotted as ïnhibitor concentrationversus percent of enzyme control. ICSo's are defined as the concentration of ïnhibitor thatgives a signal that is 50% of the positive enzyme control.

Inhibition of Human 92 kD Geiatinase (MMP-9)

Inhibition of 92 kD geiatinase (MMP-9) activity is assayed using the Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NHî substrate (10 μΜ) under similar conditions as described above for theinhibition of human collagénase (MMP-1 ). 012529 -51-

Human recombinant 92 kD gélatinase (MMP-9, gélatinase B) is activated for 2 hourswith 1mM p-aminophenyi-mercuric acetate (from a freshly prepared 100 mM stock in 0.2 N.NaOH) at 37 C. 10 mM dimetbylsulfoxide stock solutions of inhibitors are diiuted serially in assaybuffer (50 mM TRIS, pH 7.5, 200 mM NaCI, 5 mM CaCi2l 20 μΜ ZnCI2, 0.02% BRIJ-35(vot./vo!.)) using frie following scheme: 10 mM—> 120 μΜ—» 12 μΜ—» 1.2 μΜ—» 0.12 μΜ

Further dilutions are made as necessary following friis same scheme. A minimum offour inhibitor concentrations for each compound are performed in each assay. 25 pL of eachconcentration is frien added to triplicate wells of a black 95 well U-bottomed microfluor plate.As the final assay volume is 100 μ!_, final concentrations of inhibitor are the resuit of a further1:4 dilution (i.e. 30 μΜ —> 3 μΜ —>· 0.3 μΜ —> 0.03 μΜ, etc.). A blank (no enzyme, noinhibitor) and a positive enzyme control (with enzyme, no inhibitor) are also prepared intriplicate.

Activated enzyme is diiuted to 100 ng/mL in assay buffer, 25 pL per well is added toappropriate wells of the microplate. Final enzyme concentration in the assay is 25 ng/mL(0.27 nM). A five mM dimethylsulfoxide stock solution of substrate (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2) is diiuted in assay buffer to 20 μΜ. The assay is initiated by addition of 50 pL ofdiiuted substrate yielding a final assay concentration of 10 μΜ substrate. A 0 limefluorescence reading (320 excitation: 390 émission) is immediately taken and subséquentreadings are taken every fifteen minutes at room température with a PerSeptive BtosystemsCytoFluor Multi-Well Plate Reader with the gain at 90 units.

The average value of fluorescence of the enzyme and blank are plotted versus time.An early time point on the iinear part of this curve is chosen for IG5d déterminations. The 0time point for each compound at each dilution is subtracted from the latter time point and thedata then expressed as percent of enzyme control (inhibitor fluorescence divided byfluorescence of positive enzyme control x 100). Data is plotted as inhibitor concentrationversus percent of enzyme control. ICso’s are defined as the concentration of inhibitor thatgives a signal that is 50% of the positive enzyme control.

Inhibition of MMP-13

Human recombinant MMP-13 is activated with 2 mM ΑΡΜΑ (p-aminophenyl mercuricacetate) for 1.5 hours, at 37°C and is diiuted to 400 mg/ml in assay buffer (50 mM Tris, pH 7.5,200 mM sodium chloride, 5 mM calcium chioride, 20 μΜ zinc chloride, 0.02% brij). Twenty-fivemicroliters of diiuted enzyme is added per well of a 96 well microfluor plate. The enzyme is thendiiuted in a 1:4 ratio in the assay by the addition of inhibitor and substrate to give a finalconcentration in the assay of 100 mg/ml. 012529 -52- 10 mM stock solutions of inhibitors are made up in dimethyl suifoxide and then diluted inassay buffer as per the inhibitor dilution scheme for inhibition of human collagénase (MMP-1):Twenty-five microliters of each concentration is added in triplicate to the microfluor plate. Thefinal concentrations in the assay are 30 μΜ, 3 μΜ, 0.3 μΜ and 0.03 μΜ.

Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is prepared as forinhibition of human collagénase (MMP-1 ) and 50 μΙ is added to each well to give a final assayconcentration of 10 μΜ. Fluorescence readings (360 nM excitation; 450 émission) are tak'en attime 0 and every 5 minutes for 1 hour.

Positive contrais consist of enzyme and substrate with no inhibitor and blanks consist ofsubstrate only. ICso's are determined as per inhibition of human collagénase (MMP-1). tf ICso's arereported to be less than 0.03 μΜ, inhibitors are then assayed at final concentrations of 0.3 μΜ, - 0.03 μΜ, 0.003 μΜ and 0.0003 μΜ.

Coilagen fiim MMP-13 Assay

Rat type I coilagen is radiolabeled with 14C acetic anhydride (T.E. Cawston and A.J.Barrett, Anal. Siochem.. 99, 340-345 (1979)) and used to préparé 96 well plates containingradiolabeled coilagen films (Barbara Johnson-Wint, Anal. Biochem.. 104, 175-181 (1980)).When a solution containing collagénase is added to the well, the enzyme cleaves the insolublecoilagen which unwinds and is thus solubiiized. Collagénase activity is directly proportional tothe amount of coilagen solubiiized, determined by the proportion of radioactivity reieased intothe supernatant as measured in a standard scintillation counter. Collagénase inhibitors are,therefore, compounds which reduce the radioactive counts reieased with respect to thecontrais with no inhibitor présent. One spécifie embodiment of this assay is described in detailbelow.

For determining the selectivity of compounds for MMP-13 versus MMP-1 usingcoilagen as a substrate, the following procedure is used. Recombinant human proMMP-13 orproMMP-1 is activated according to the procedures outlined above. The activated MMP-13 orMMP-1 is diluted to 0.6 ug/ml with buffer ( 50 mM Tris pH 7.5,150 mM NaCI, 10 mM CaCI2,1uM ZnCI2,0.05% Brij-35,0.02% sodium azide).

Stock solutions of test compound (10mM) in dimelhylsulfoxide are prepared. Dilutionsof the test compounds in the Tris buffer, above, are made to 0.2, 2.0, 20, 200, 2000 and20000 nM. 100 μΙ of appropriate drug dilution and 100 μΙ of diluted enzyme are pipetted into wellsof a 96 well plate containing coilagen films labeled with 14C-coîlagen. The final enzymeconcentration is 0.3 pg/ml while the final drug concentration is 0.1, 1.0, 10, 100, 1000 nM.Each drug concentration and contrai is analyzed in triplicate. Triplicate Controls are also run 012529 -53- for the conditions in which no enzyme is présent and for enzyme in the absence of anycompound.

The piates are incubated at 37°C for a time period such that around 30 - 50% of theavailabie collagen is solubilized - determined by counting additional controi weils at varioustime points. In most cases around 9 hours of incubation are required. When the assay hasprogressed sufficientiy, the supernatant from each well is removed and counted in ascintillation counter. The background counts (determined by the counts in the weils with noenzyme) are subtracted from each sample and the % release calculated in relation to the weilswith enzyme only and no inhibitor. The triplicate values for each point are averaged and thedata graphed as percent release versus drug concentration. IC5o's are determined from thepoint at which 50% inhibition of release of radiolabeled collagen is obtained.

To détermine the identity of the active collagénases in cartilage conditioned medium,assays were conducted using collagen as a substrate, cartilage conditioned mediumcontaining collagénase activity and inhibitors of varying selectivity. The cartilage conditionedmedium was collected during the time at which collagen dégradation was occurring and thusis représentative of the collagénases responsible for the collagen breakdown. Assays wereconducted as outlined above except that instead of using recombinant MMP-13 orrecombinant MMP-1, cartilage conditioned medium was the enzyme source. 1L-1 Induced Cartilage Collagen Dégradation From Bovine Nasal Cartilage

This assay uses bovine nasal cartilage expiants which are commonly used to test theefficacy of various compounds to inhibit either IL-1 induced proteoglycan dégradation or IL-1induced collagen dégradation. Bovine nasal cartilage is a tissue that is very simiîar to articuîarcartilage, i.e. chondrocytes surrounded by a matrix that is primarily type II collagen andaggrecan. The tissue is used because It: (1) is very similar to articuîar cartilage, (2) is readilyavaiiabte, (3) is relatively homogeneous and (4) dégradés with predictable kinetics after IL-1stimulation.

Two variations of this assay hâve been used to assay compounds. Both variationsgive similar data. The two variations are described befow:

Variation 1

Three piugs of bovine nasal cartilage (approximately 2 mm diameter x 1.5 mm long)are placed into each well of a 24 well tissue culture plate. One ml of serumless medium isthen added to each well. Compounds are prepared as 10 mM stock solutions in DMSO andthen diluted appropriately in serumless medium to final concentrations, e.o.. 50, 500 and 5000nM. Each concentration is assayed in triplicate.

Human recombînant IL-1 a (5ng/mL) (fL-1 ) is added to triplicate contro! weils and toeach well containing drug. Triplicate controi weils are aiso set up in which neither drug nor IL-1 are added. The medium is removed and fresh medium containing IL-1 and the appropriate 012529 -54- drug concentrations is added on days 6,12,18 and 24 or every 3-4 days if necessary. Themedia removed at each lime point is stored at -20°C for later analysis. When the cartilage.inthe IL-1 alone wells bas almost completely resorbed (about day 21), the experiment isterminated. The medium, is removed and stored. Aliquots (100 μΐ) from each well at eachtime point are pooled, digested with papain and then anaiyzed for hydroxyproline content.Background hydroxyproline (average of welis with no IL-1 and no drug) is subtracted fromeach data point and the average calculated for each tripiicate. The data is then expressed asa percent of the IL-1 alone average value and piotted. The IC50 is determined from this plot.

Variation 2

The experimental set-up is the same as outlined above in Variation 1, until day 12.On day 12, the çonditioned medium from each well is removed and frozen. Then one ml ofphosphate buffered saline (PBS) containing 0.5 pg/ml trypsin is added to each well andincubation continued for a further 48 hours at 37°C. After 48 hours incubation in trypsin, thePBS solution is removed. Aliquots (50 μΙ) of the PBS/trypsin solution and the previous twotime points (days 6 and 12) are pooled, hydrolyzed and hydroxyproline content determined.Background hydroxyproline (average of wells with no IL-1 and no drug) is subtracted fromeach data point and the average calculated for each tripiicate. The data is then expressed asa percent of the IL-1 alone average value and piotted. The ICso is determined from this plot.In this variation, the time course of the experiment is shortened considerably. The addition oftrypsin for 48 hours after 12 days of IL-1 stimulation likely releases any type II collagen thathas been damaged by collagénase activity but not yet released from the cartilage matrix. Inthe absence of IL-1 stimulation, trypsin treatment produces only low background levels ofcollagen dégradation in the cartilage expiants.

Inhibition of TNF Production

The ability or inability of the compounds or the pharmaceutically acceptable saits thereofto inhibit the production of TNF is shown by the foliowing in vitro assay:

Human Monocyte Assay

Human mononuclear cells were isolated from anti-coagulated human blood using a one-step Ficoll-hypaque séparation technique. (2) The mononuclear cells were washed three timesin Hanks balanced sait solution (HBSS) with divalent cations and resuspended to a denslty of 2 x106 /ml in HBSS containing 1% BSA. Differential counts determined using the Abbott Cell Dyn3500 analyzer indicated that monocytes ranged from'17 to 24% of the total cells in thesepréparations. 180 μΙ of the cell suspension was aliquoled into fiat bottom 95 well plates (Costar).Additions of compounds and LPS (100 ng/ml final concentration) gave a final volume of 200 μΐ.Ail conditions were performed in tripiicate. After a four hour incubation at 37°C in an humidified 012529 -55- CO2 incubator, piates were removed and centrifuged (10 minutes at approximately 250 x g) andthe supernatants removed and assayed for TNF a using the R&D ELiSA Kit.

Aggrecanase Assay

Primary porcine chondrocytes from articular joint cartilage are isolated by sequential5 trypsin and coilagenase digestion followed by collagénase digestion overnight and are platedat 2 X 105 cells per well into 48 well plates with 5 pCi / ml 35S (1000 Ci/mmol) sulphur in type 1collagen coated plates. Cells are allowed to incorporate label into their proteoglycan matrix (approximately 1 week) at 37eC, under an atmosphère of 5% CO2.

The night before initiating the assay, chondrocyte monolayers are washed two limes10 in DMEM/1% PSFZG and then allowed to incubate in fresh DMEM /1% FBS overnight.

The following morning chondrocytes are washed once in DMEM/1%PSF/G. The finalwash is allowed to sit on the plates in the incubator while making dilutions.

Media and dilutions can be made as described in the Table below.

Control Media DMEM alone (control media) IL-1 Media DMEM + IL-1 (5 ng/ml) Drug Dilutions Make ail compounds stocks at 10 mM in DMSO. Make a 100 μΜ stock of each compound in DMEM in 96 well plate. Store in freezer overnight The next day perform serial dilutions in DMEM with IL-1 to 5 μΜ, 500 nM and 50 nM. Aspirate final wash from weils and add 50 μΙ of compound from above dilutions to 450 μΙ of IL-1 media in appropriate welis of the 48 weli plates. Final compound concentrations equal 500 nM, 50 nM and 5 nM. Ali samples completed in triplicate with Control and IL-1 alone samples on each plate, 15 Plates are labeled and only the interior 24 weils of the plate are used. On one of the plates, several coiumns are designated as IL-1 (no drug) and Control (no IL-1, no drug).These control coiumns are periodically counted to monitor 35S-proteoglycan release. Controland IL-1 media are added to welis (450 μΙ) followed by compound (50 μ!) so as to initiale theassay. Plates are incubated at 37°C, with a 5% CO2 atmosphère. 20 At 40-50 % release (when CPM from IL-1 media is 4-5 times control media) as assessed by Iiquid scintillation counting (LSC) of media samples, the assay is terminated (9-12 hours). Media is removed from ail wells and pîaced in scintillation tubes. Scintillate isadded and radioactive counts are acquired (LSC). To solubiiize cell iayers, 500 μΙ of papain 012529 -56· ”ΤΡ·: digestion buffer (0,2 M Tris, pH 7.0, 5 mM EDTA, 5 mM DTT and 1 mg/m! papain) is added toeach well. Plates with digestion solution are incubated at 60°C overnight The cell layer isremoved from the plates the next day and placed in scintillation tubes. Scintillate is thenadded and samples counted (LSC).

The percent of released counis from the total présent in each well is determined.Averages of the triplicates are made with control background subtracted from each well. Thepercent of compound inhibition is based on 1L-1 samples as 0% inhibition (100% of totalcounts).

The compounds of the présent invention that were tested ali hâve ICso’s in at leastone of the above assays of less than 100 μΜ preferably less than 100nM. Certain preferredgroups of compounds possess differential selectivity toward the various MMP's or ADAMs.One group of preferred compounds possesses sélective activity towards MMP-13 over MMP-1. Another preferred group of compounds possesses sélective activity towards MMP-13 overMMP-1, MMP-3 and MMP-7. Another preferred group of compounds possesses sélectiveactivity towards MMP-13 over MMP-1, MMP-3, MMP-7 and MMP-17. Another preferred groupof compounds possesses sélective activity towards MMP-13 over MMP-1, MMP-2, MMP-3,MMP-7, MMP-9 and MMP-14 Another preferred group of compounds possesses sélectiveactivity towards MMP-13 over MMP-12 and MMP-14.

For administration to mammals, including humans, for the inhibition of matrixmetalloproteinases, a variety of conventional routes may be used including oral, parentéral (e.g.,intravenous, intramuscular or subcutaneous),· buccal, anal and topical. In general, thecompounds of the invention (hereinafter also known as the active compounds) wi!l beadministered at dosages of about 0.1 and 25 mg/kg body weight of the subject to be treated perday, preferably from about 0.3 to 5 mg/kg. Preferably the active compound will be administeredorally or parenterally. However, some variation in dosage will necessarily occur depending on thecondition of the subject being treated. The person responsible for administration will, in anyevent, détermine the appropriate dose for the individuai subject.

The compounds of the présent invention can be administered in a wide variety ofdifferent dosage forms, in general, the therapeutically effective compounds of this invention areprésent in such dosage forms at concentration levels ranging from about 5.0% to about 70% byweight

For oral administration, tablets containing various excipients such as microcrystaliinecellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be ernployedalong with various disintegrants such as starch (and preferably corn, potato or tapioca starch),alginic acid and certain complex silicates, together with granulation binders likepolyvinyipyrrolidone, sucrose, gélation and acacia. Additianally, lubricating agents such asmagnésium stéarate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. 012529 -57-

Solid compositions of a simitartype may also be empioyed as fillers in gelatin capsules; preferredmaterials in this connection also include lactose or milk sugar as well as hîgh molecuiar weightpolyethylene glycols. When aqueous suspensions and/or élixirs are desired for oraladministration, the active ingrédient may be combined with various sweetening or flavoring 5 agents, coioring matter or dyes and, if so desired, emulsifying and/or suspending agents as weil,together with such diluents as water, éthanol, propylene glycol, glycerin and various iikecombinations thereof. In the case of animais, they are advantageously contained in an animalfeed or drinking water in a concentration of 5-5000 ppm, preferabiy 25 to 500 ppm.

For parenterai administration (intramuscular, intraperitoneal, subcutaneous and10 intravenous use) a stérile injectable solution of the active ingrédient is usually prepared.Solutions of a therapeutic compound of the présent invention in either sesame or peanut oil or inaqueous propylene glycoi may be empioyed. The aqueous solutions shouid be suitabiy adjustedand buffered, preferabiy at a pH of greater than 8, if necessary and the Iiquid diluent ftrstrendered isotonie, These aqueous solutions are suitabie intravenous injection purposes. The 15 oily solutions are suitabie for intraarticuiar, intramuscular and subcutaneous injection purposes.The préparation of ali these solutions under stérile conditions is readily accompiished bystandard pharrnaceutical techniques weil known to those skilled in the art. In the case ofanimais, compounds can be admjnistered intramuscularly or subcutaneously at dosage ievels ofabout 0.1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to 3 20 divided doses.

The active compounds of the invention may also be formulated in rectal compositionssuch as suppositories or rétention enemas, e.g., containing conventional suppository basessuch as cocoa butter or other glycerides.

For intranasai administration or administration by inhalation, the active compounds of25 the invention are conveniently delivered in the form of a solution or suspension from a pumpspray container that is squeezed or pumped by the patient or as an aérosol spray présentationfrom a pressurized container or a nebuiizer, with the use of a suitabie propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitabie gas. In the case of a pressurized aérosol, the dosage unit may be determined 30 by providing a valve to deliver a metered amount. The pressurized container or nebuiizer maycontain a solution or suspension of the active compound. Capsules and cartridges (made, forexampie, from gelatin) for use in an inhaler or insufflator may be formulated containing apowder mix of a compound of the invention and a suitabie powder base such as lactose orstarch. 35 For topica! ocular administration, direct application to the affected eye may be empioyed in the form of a formulation as eyedrops, aérosol, gels or ointments, or can be incorporated intocollagen (such as poly-2-hydroxyethylmethacrylate and co-polymers thereof), or a hydrophilic 012529 -58- polymer shield. The materials can also be applied as a contact iens or via a local réservoir or asa subconjunctival formulation.

For intraorbita! administration a stérile injectable solution of the active ingrédient isusually prepared. Solutions of a therapeutic compound of the présent invention in an aqueous 5 solution or suspension (particle size less than 10 micron) may be employed. The aqueoussolutions should be suitably adjusted and buffered, preferably at a pH between 5 and 8, ifnecessary and the iiquid diluent First rendered isotonie. Small amounts of polymère can beadded to increase viscosity or for sustained release (such as cellulosic polymère, Dextran,polyethylene giycol, or alginic acid). These solutions are suitabie for intraorbital injection 10 . purposes. The préparation of ail these solutions under stérile conditions is readily accomplishedby standard pharmaceutical techniques weil known to those skilled in the art. In the case ofanimais, compounds can be administered intraorbitaiiy at dosage ievels of about 0.1 to 50mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to 3 divided doses.

As with the other routes of administration and corresponding dosage forms described 15 herein, dosage forms intended for oral administration are atso suitably formulated to providecontrolied-, sustained- and/or delayed reiease of the active ingrédient. Typically, these wouldinclude delayed-release oral tablets, capsules and multiparticulates, as weil as enteric-coatedtablets and capsules which prevent release and adsorption of the active ingrédient in thestomach of the patient and facilitate enteric delivery distal to the stomach, i.e., in the intestine. 20 Other typicai oral dosage forms would include sustained-release oral tablets, capsules andmultiparticulates which provide systemic deiivery of the active ingrédient in a controliedmanner over a prolonged period of time, e.g., a 24-hour period. Where rapid delivery of theactive ingrédient is required or désirable, a controlled-release oral dosage form may beprepared in the form of a fast-dissolving tabiet, which would also preferably include highly 25 soluble sait forms of the active ingrédient.

The following Examples illustrate the préparation of the compounds of the présent invention. Melting points are uncorrected. NMR data are reported in parts per million (5) andare referenced to the deuterium iock signal from the sample solvent (deuteriochloroformunless otherwise specified). Commercial reagents were utiiized without further purification. 30 Chromatography refers to column chromatography performed using 32-63 mm silica gel andexecuted under nitrogen pressure (flash chromatography) conditions. Room or ambienttempérature refers to 20-25"C. Ail non-aqueous reactions were run under a nitrogenatmosphère for convenience and to maximize yields. Concentration at reduced pressure or invacuo means that a rotary evaporator was used. 012529

I ’ -59-

General Expérimentais

General Example:

Compounds of the formula I can be prepared by reacting the appropriate compoundof formula III with a urea of the formula H (/'.e., H2N(CO)-NH2) in the presence of a suitable 5 base, such as an alkoxide base, preferably sodium ethoxide, in a polar solvent, such as analcoholic solvent, preferably ethanot, at a température of 20°C to the boiling point of thesolvent, preferably 80°C for 15 minutes to 3 hours.

General Préparation: A compound of formula III can be prepared by reacting an appropriate compound of10 formula IV with a suitable base, such as a tertiary amine base or a polymer bound base,preferably Amberiyst-400® resin (hydroxide form), in .a polar solvent, such as an alcoholicsolvent, preferably éthanol, at a température of about 0°C to about 50°C, preferably about 20°C, for a period of about 6 to about 36 hours.

The compound of formula IV can be prepared by reacting the appropriate compound15 of the formula VI with a compound of the formula V, which has a general formula of LS-(A')-L4or L3-(A’), in an aprotic solvent, preferably and aromatic hydrocarbon solvent such as benzeneor toluene, at a température of about 40°C and the boiling point of the solvent, preferably about 80°C, for a period of about 1 to about 6 hours.

The compound of formula VI can be prepared by reacting the appropriate compound20 of the formula NH2-X-Y-Z-G with a compound of the formula Vil, which is a 2-haio malonateester, preferably 2-bromodiethyi malonate, in the presence of a suitable base, such as atertiary amine base, preferably N,N-dimethyianiline, at a température of about 20°C to about 100°C, preferably about 80°C, for a period of about 4 fo about 48 hours. EXAMPLE 1: 25 1-r6-(4-BROMO-PHENOXYVPYRIDIN-3-YL1-1,7.9-TRIAZA-SPIRQf4.51PECANE- 2,6,8,10-TETRAONE:

Example Number Structure Moiecuiar Weight MS (APCI, m/z):{M+Hf 1 vUo 445.238 445 Φ» U

Sodium métal (29 mg, 1.26 mmol) was added to 1.3 mL of éthanol and stirred untilhomogeneous. of 1-[6-(4-Bromo-phenoxy)-pyridin-3-yl3-pyrrolidine-2,2-dÎcarboxy!ic acid diethy! 30 ester (0.20 g, 0.42 mmol) was added, foilowed by urea (75 mg, 1.26 mmol) and the mixture 012529 4,0- was stirred for 5 minutes at 80 °C. The mixture was cooled to ambient température, acidifiedwith 1M hydrochloric acid and extracted 3x with ethyl acetate. The combined organic phaseswere dried over sodium suiphate, filtered and concentrated in vacuo. The residue was purifiedby siîica gel chromatography (3:1 hexane-ethyi acetate), affordtng 28 mg of 1-[6-(4-Bromo-phenoxy)-pyridin-3-yI]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraone as a colorless solid.HPLC Ret. time: 2.201 min; MS (APCi, m/z): 435 [M-Hp, 438 [M+Hf.

Préparation 1: 2-(4-Bromo-phenoxv)-5-nitro-pyridine: 4-Bromophenol (5.5 g, 32 mmol) was added to 42 mL of 50% w/w aqueous sodiumhydroxide. After stirring for 30 min, 44 mL of toluene was added, foliowed by 2-chloro-5-nitropyridine (5.0 g, 32 mmol) and tetrabutylammonium bromide (10 g, 32 mmol). Afterstirring for 1.5 hours at 23°C, the mixture was diluted with 200 mL of water, neutraiized with12M aqueous hydrochloric acid and the mixture was extracted 3x with ether. The combinedorganic la’yers were dried over MgSO4l filtered and concentrated in vacuo, affording 6 g of 2-(4-bromo-phenoxy)-5-nitro-pyridine. 1H NMR (CDCI3, 500 MHz): 9.05 (d, 1H, J = 3.5 Hz), 8.51(dd, 1H, J ~ 3.5, 9.5 Hz), 7.58 (d, 2H. J ~ 9.0 Hz), 7.08 (m, 3H) ppm. MS (APCI, m/z): 295[M+Hf. 6-(4-Bromo-phenoxv)-pyridin-3-vi3mine: A mixture of 2-(4-bromo-phenoxy)-5-nitro-pyridine (6.0 g, 22.7 mmoi), 200 mL ofmethanol and 50 mg of PtO2 was shaken under 50 psi of H2 for 1 hour at 23 °C. The mixturewas filtered through a pad of ceiite® and the filtrate was concentrated in vacuo, affording 6 g of 6-(4-bromo-phenoxy)-pyridin-3-ylamine. 1H NMR (CD3OD, 500 MHz): 7.65 (d, 1H, J = 3.5 Hz),7.48 (d, 2H, J = 8.5 Hz), 7.25 (dd, 1H, J = 3.5, 9.0 Hz), 6.91 (d, 2H, J = 9.0 Hz), 6.80 (d, 1H, J= 9.0 Hz) ppm. MS (APCi, m/z): 265 [M+Hf.

Préparation 2: 1-f6-(4-Bromo-phenoxv)-pvridin-3-vll-pyrrolidine-2.2-dicarboxvlic acid diethyl ester: A mixture of of 6-(4-bromo-phenoxy)-pyridin-3-ylamine (4.5 g, 16.9 mmol), 2-bromodimethylmalonate (4.1 g, 17 mmol) and Λ/,/V-dimethylaniline (2.1 g, 17 mmol) wasstirred at 80 °C for 24 hours. The mixture was cooied to 23 °C, diluted with 50 mL of benzeneand was treated with 7 mL of 2-bromopropionyl chloride. After stirring at refiux for 3 h, themixture was cooied to 23 °C, concentrated in vacuo and was diluted with 750 mL of ethanoi.Amberiyst-400 (hydroxide form) resin (75 g) was added and the mixture was stirred for 24hours at 23 °C. The mixture was filtered and the resin was washed with 50 mL of methanol.The filtrate was concentrated in vacuo and the residue was purified by siîica gelchromatography (2:1 hexane-ethyi acetate), affording 6 g of 1-[6-(4-bromo-phenoxy)-pyridin-3-y|]-pyrrolidine-2,2-dicarbûxylic acid diethyl ester. 1H NMR (CDCI3, 500 MHz): 8.06 (d, 1H, J =2.5 Hz), 7.75 (dd, 1H, J = 2.5, 8.0 Hz), 7.52 (d, 2H, J = 9.0 Hz), 7.04 (d, 2H, J = 8.5 Hz), 6.95 012529 -61- (d, 1H, J = 9.0 Hz), 4.22 (q, 4H, J = 7.0 Hz), 2.75 (m, 2H), 2.66 (m, 2H), 1.12 (t, 6H, J = 7.5Hz) ppm. MS (APCI, m/z): 479 (M+Hf.

The foJlowing compounds were prepared according to methods analogous to that ofExample 1, substituting where appropriate the correct pyridine and diester: 5 TABLE 1

Example Number Structure Molecular Weight MS (APCI, m/z):[M+Hf 2 Y “XX, 384.327 385.1 3 rW //-Λ HN )=o X_N \- 0H Q F 398.354 399.1

Example 4 4-(5-(2,6,8,10-TETRAOXO-1,7,9-TRIAZA-SPIROF4.5lDEC-1-YL)-PYRiDIN-2-YLOXY}- BENZONITRILE:

Example Number Structure Moiecular Weight MS (APCI, m/z):[M+Hf 4 z î A O 391.346 392.1

Following the procedure for pyrimidinetrione formation outlined in Example 1, reactionof 1-[6-(4-Cyana-phenoxy)-pyridin-3-yl)-pyrroIidine-2,2-dicarboxyiic acid diethyl ester (58 mg,0.14 mmol) with urea (0.030 g, 0.5 mmol) in 0.5 mL of 1M sodium ethoxide in éthanol afforded14.3 mg of 4-(5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yI)-pyridin-2-yioxy]-benzonitrile 15 as a colorless solid. 1H NMR (CDaOD, 500 MHz): 8.06 (d, 1H, J = 3.5 Hz), 7.78 (m, 3H), 7.31(d, 2H, J = 8.5 Hz), 7.13 (d, 1H, J = 9.0 Hz), 2.75 (m, 2H), 2.68 (m, 2H) ppm. MS (APGI, m/z):390 [M-Hjf; 392 [M+Hf. 012529 -62-

Preparation 1: 1-f6-(4-Cvano-phenoxv)-pvridin-3-vli-pvrrolidine-2.2-dicarboxviic acid diethyl ester: A mixture of 1-[6-(4-brorno-phenoxy)'pyridin-3-yl]-pyrroiidÎne-2,2-dicarboxy!ic aciddiethyl ester (0.28 g, 0.53 mmoi), zinc cyanide (0.037 g, 0.32 mmoi),tetrakistriphenyiphosphine patiadium (0) (0.024 g, 0.021 mmoi) and 0.66 ml ofdimethyiformamide was heated to 80 °C for 24 bours. An additionai 37mg of zinc cyanide and24 mg of tetrakistriphenyiphosphine palladium (0) was added and the mixture was stirred at 80°C for an additionai 48 hours. After cooling to room température, the mixture was diluted withtoluene and was washed with 2M ammonium hydroxide (twice), brine, dried over sodiumsuiphate, filtered and concentrated in vacuo. Purification by radial chromatography (ethylacetate-hexanes, then methanol) afforded 58 mg of 1-[6-(4-Cyano-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup. 1K NMR (CDCI3, 500 MHz):8.07 (d, 1H, J = 3.5 Hz), 7.80 (dd, 1H, J = 2.5, 9.0 Hz), 7.69 (d, 2H, J = 9.0 Hz), 7.25 (d, 2H, J= 9.0 Hz),'7.02 (d, 1H, J = 9.0 Hz), 4.21 (q, 4H, J = 7.5 Hz), 2.74 (m, 2H), 2.66 (m, 2H), 1.19(t, 6H, J = 7.0 Hz) ppm. MS (APCI, m/z): 424 [M+Hf.

Example 5 146-(441,3,4iOXADlAZOL-2-YL-PHENOXY)-PYRiPlN-3-YU-1,7,9-TRIAZA-

Following the procedure for pyrimidinetrione formation outlined in Example 1, reactionof 1-(6-(4-(1,3,4]oxadiazot-2-yl-phenoxy)-pyridin-3-yÎ]-5-oxo-pyrrolidine-2,2-dicarboxyfic aciddiethyl ester (200 mg, 0.44 mmoi) with urea (0.080 g, 1.3 mmoi) in 1.3 ml of 1M sodiumethoxide in éthanol afforded 25 mg of 1 -(6-(4-(1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5ldecane-2,6,8,10-tetraone as a colorless solid. 1H NMR (CD3OD, 500 MHz):9.02 (s, 1H), 8.14 (d, 2H, J = 8.0 Hz), 8.06 (d, 1H, J = 2.0 Hz), 7.78 (dd, 1H, J = 2.5, 9.0 Hz), 012529 -63- 7.35 (d, 2H, J = 9.0 Hz), 7.12 (d, 1H, J = 9.0 Hz), 2.74 (m, 2H), 2.66 (m, 2H) ppm. MS (APCi,m/z): 435 [M+H]+.

Préparation 1: 1 -i6-<4-Carboxv-phenoxv)-PvridÎn-3-vn-5-oxo-ovrrolidine-2.2-dicarboxvlic acid diethvl ester: A mixture of 1-[6-(4-Formyi-phenoxy)-pyridïn-3-yIJ-pyrroiidine-2,2-dicarboxylic aciddiethyl ester (0.70 g, 1.64 mmoi), sodium carbonate (0.26 g, 1.64 mmol) and 16.4 mL of 1:1ferf-butyi aicohol-water was treated with potassium permanganate (0.26 g, 1.64 mmol). Afterstirring for 2 hours at room température, the mixture was quenched with sodium sulfite,acidified with 1M hydrochloric acid and extracted 3x with ethyl acetate. The combined organiclayers were dried over sodium sulphate, filtered and concentrated in vacuo, affording 1-(6-(4-Carboxy-phenoxy)-pyridin-3-yl]-5-oxo-pyrroiÎdine-2,2-dicarboxylic acid diethyl ester as acolorless syrup (0.5 g). 1H NMR (CDC!3, 500 MHz): 8.14 (d, 2H, J = 8.5 Hz), 8.10 (d, 1H, J =3.0 Hz), 7.80 (dd, 1H, J = 2.5, 8.5 Hz), 7.24 (d, 2H, J = 8.0 Hz), 7.02 (d.'lH, J = 9.0 Hz), 4.21(q, 4H, J = 7.0 Hz), 2.74 (m, 2H), 2.66 (m, 2H), 1.21 (t, 6H, J = 7.5 Hz) ppm. MS (APCI, m/z):443 (M+Hf.

Préparation 2: 1-f6-(4-Hydrazinocarbonvl-phenoxy)-pvridin-3-vi1-5-oxo-pyrrolidine-2.2-dicarboxvlic acid diethvl ester: A mixture of affording 1-[6-(4-Carboxy-phenoxy)-pyridin-3-yi]-5-oxo-pyrroIidine-2,2-dicarboxyiic acid diethyl ester (0.4 g, 0.97 mmol), 1-hydroxybenzotriazole hydrate (0.176 g, 1.3mmoi), 1,2-dichloroethane (0.25 g, 1.3 mmol) and 6 mL of methyiene chloride was stirred atroom température for 20 minutes. The mixture was treated with boc-hydrazide (0.17 g, 1.3mmol) and stirred at room température overnight. The mixture was diluted with ethyî acetate,washed with 1M hydrochloric acid, sodium bicarbonate solution, brine, dried over sodiumsulphate, filtered and concentrated in vacuo. The residue was dissolved in 5 mL of 1:1 v/vmethyiene chloride-trifluoroacetic acid, stirred fer 1 hours at ambient température and wasconcentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M sodiumhydroxide, brine, dried over sodium sulphate, filtered and concentrated, affording 1-(6-(4-Hydrazinocarbonyl-pKenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarbaxy!ic acid diethyl ester(0.20 g) as a colorless syrup. HPLC: 2.770 min.

Préparation 3: 1-i6-(4-f1.3.41oxadiazol-2-vl-phenoxv)-Pvridin-3-vn-5-oxo-pvrrolidine-2,2-dicarboxvlic acid diethvl ester: A mixture of affording 1-[6-(4-Hydrazinocarbonyl-phenoxy)-pyridin-3-ylJ-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g, 0.44 mmol), trimethyiorthoformate (0.1mL, 0.91 mmol) and 1 mL of xylenes was refluxed for 24 hours. The mixture was 01252g -64- concentrated in vacuo, affording 1-[6-(4-[1,3,4)oxadiazol-2-yJ-phenoxy)-pyndin-3-yl3-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g) as a colorless syrup. -MS (APCI, m/z):467.2 [M+Hf.

Example 6 5 1-r6-(4-ETHYL-PHENOXY)-PYRIDIN-3-YLM,7,9-TRIA2A-SPiROf4.51DECANE- 2,6,8,10-TETRAONE:

Example Number Structure Molecular Weight MS (APCI, m/z):[M+Hf 6 -yU. CH, 394.39 395.3

Following the procedure for pyrimidinetrione formation outiined in Example 1, reactionof 1-[6-(4-ethyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (200 10 mg, 0.41 mmol) with urea (0.088 g, 1.4 mmol) in 1.4 mL of 1M sodium ethoxide in éthanolafforded 25 mg of 1-[6-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl3-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraone as a colorless solid. 1H NMR (CDCI3, 500 MHz): 8.73 (bs,2H), 7.97 (d, 1H. J = 2.0 Hz), 7.78 (d, 1H, J = 8.5 Hz), 7.22 (d, 2H, J = 8.5 Hz), 7.05 (d, 2H, J= 9.0 Hz), 6.91 (d, 1H, J = 9.0 Hz), 2.81 (q, 2H, J = 7.5 Hz), 2.74 (m, 2H), 2.64 (m, 2H), 1.26 15 (t, 3H, J = 8.0 Hz) ppm.

Préparation 1 : 1 -f6-(4-Ethyl-ohenoxv)-pvridin-3-vll-5-oxo-PvrrolidÎne-2.2-dicarboxylic acid diethyl ester: A mixture of 1-[6-(4-vinyl-phenoxy)-pyridin-3-ylJ-pyrroiidine-2,2-dicarboxylic acid 20 diethyl ester (0.20 g), 50 mg of 10% palladium on charcoal and 20 mL of eihyl acetate wasshaken under 50 psi of hydrogen gas for 2 hours. The mixture was filtered and concentratedin vacuo, affording 0.20 g of 1-[6-(4-ethyl-phenoxy)-pyridin-3-yi]-5-oxo-pyrrûlidine-2,2-dicarboxyiic acid diethyl ester as a colorless syrup. 1H NMR (CDCI3, 500 MHz): 8.08 (d, 1H, J= 2.5 Hz), 7.73 (dd, 1H, J = 2.5, 8.5 Hz), 7.24 (d, 2H, J = 7.5 Hz), 7.05 (d, 2H, J = 8.0 Hz), 25 6.89 (d, 1H, J = 9.0 Hz), 4.21 (q, 4H, J = 7.0 Hz), 2.74 (m, 2H), 2.65 (m, 4H), 1.27 (t, 3H, J = 8.0 Hz), 1.20 (t, 6H, J = 7.5 Hz) ppm. 012529 -65-

Exampie 7 N-f4-f5-(2.6.8,10-TETRAOXO-1,7,9-TRIAZA-SPIRQf4.5(D£C-1-YL)-PYRIDIN-2- YLOXY1-BENZYLVACETAMIDE;

Example Number Structure Molecular Weight MS (APCI, m/z):[M+Hf 7 9 O 437.415 438.2 A mixture of 1-{6-[4-(tert-butoxycarbonylarnino-methyl)-phenoxy}-pyridin-3-yl}-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.52 mmoi) and 2 mL of a 1:1 v/v solution oftrifiuoroacetic acid in methylene chloride was stirred for 1 hours at ambient température andwas then concentrated in vacuo. The residue was dissoived in 2.6 mL of methyiene chlorideand was treated with MMP-resin (polymer bound N-methyl morpholine-type base, 0.86 g, 1.75mmol) and was treated with acétyi chloride (0.055 g, 0.7 mmoi). After shaking for 24 h, themixture was filtered and the resin was washed with methylene chloride. The combinedfiltrâtes were concentrated in vacuo, dissoived in 1.5 mL of 1M sodium ethoxide in éthanol andtreated with 94 mg of urea. After stirring for 10 minutes at 80 °C, the mixtures were treated

V with 2 g of a polystyrene-bound sulfonic acid resin. fiitered and the resin was washed with 10mL of 2M ammonia in methanol. The combined filtrâtes were concentrated in vacuo andpurified by reverse-phase chromatography (acetonitrïle-water-trifluoroacetic acid eluent)foîlowed by radial chromatography (10% methanol-methyiene chloride), affording; N-{4-(5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yioxy]-benzyl}-acetamide as acoiorless soiid. HPLC Ret. time: 2.201 min; MS (APCI, m/z): 436 [M-H]'; 438 [M+Hf.

Préparation 1: 1-f6-(4-vinvl-phenoxv)-pvridin-3-vfl-pvrroiidine-2,2-dicarboxvlic acid diethyl ester: A mixture of 1-[6~(4-bromo-phenoxy)-pyridin-3-yl}-pyrrolidine-2,2-dicarboxyltc aciddiethyl ester (5.8 g, 12.2 mmoi), vinyltributyltin (3.9 mL, 12.3 mmoi), tetrakistriphenylphosphinepalladium (0) (0.60 g, 0.52 mmoi) and 24 mL of toluene was heated to reflux for 1 hour. Aftercooling to room température, the mixture was concentrated in vacuo and purified by silica gelchromatography (Flash 40,20% - 50% ethyl acetate-hexanes), affording 4.8 g of 1 -[6-(4-Vinyl-phenoxy)-pyridin-3-yi]-pyrroiidine-2,2-dicarboxylÎc acid diethyl ester as a coiorless syrup. 01252$ -66-

Preparation 2: 1-fe-(4-Formvl-phenoxv)-pvridin-3-vll-pyrrolidine-2.2-dicarboxvlic acid diethyl ester: A mixture of 1-[6-(4-Vinyl-phenoxy)-pyridin-3-ylJ-pyrroIidine-2,2-dicarboxylic aciddiethyl ester (4.8 g, 11.3 mmoi), sodium metaperiodate (4.8 g, 22 mmol), osmium tetroxide 5 (10 mg) and 2:1 dioxane-water (189 mL) was stirred for 6 hours at ambient température. The mixture was quenched with sodium sulfite, diluted with water and extracted 3x with ethylacetate. The combined organic phases were dried over sodium sulphate, fîitered andconcentrated in vaiw,affording 1-[6-(4-Formyl-phenoxy)-pyridin-3-yl3-pyrrolidine-2,2- ... dicarboxyiic acid diethyl ester as a colorless syrup (4.6 g). 10 Préparation 3: 1-{6-f4-(tert-Butoxvcarbonvlamino-methvi)-phenoxy)-pvridin-3-vl)-pvrrolidine-2,2- dicarboxyiic acid diethyl ester: A mixture of 1-[6-(4-Formyl-phenoxy)-pyridin-3-yIJ-pyrrolidine-2,2-dicarboxyiic aciddiethyl ester (0.1 g, 0.24 mmol), iert-butoxycarbonylamide (0.083 g, 0.71 mmol), triethylsilane 15 (0.11 mL, 0.083 g, 0.71 mmol) and acetonltrile (1 mL) was treated with trifluoroacetic acid (0.035 mL, 0.46 mmol) and stirred for 48 at ambient température. The mixture was dilutedwith ethyl acetate, washed with saturated sodium bicarbonate solution, brine, dried oversodium sulphate, fîitered 'and concentrated in vacuo, affording 1-{6-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-pyridin-3-yl}-pyrroiidine-2,2-dicarboxylic acid diethyl 20 ester as a colorless syrup.

The following compounds were prepared according to methods analogous to that ofExample 7, submitting where appropriate the correct pyridine and diester: TABLE 2

Example Number Structure Molecular Weight MS (APCI, m/z):[M+H)+ 8 b O 451.443 452.2 012529 -67-

Example Number Structure Molecular Weight MS (APCI, m/z):[M+H]+ 9 “Φ 0 465.47 466.2 10 φ h 0 479.497 480.2 11 "VP., Φ 477.481 478.4

Exampie 12 1.f6-(4-PYRAZOL-1-YLMETHYL-PHENOXY)-PYRtDlN-3-YL'I-1,7,9-TRIAZA- SPIROf4.5|PECANE-2,6,8,1Q-TETRAONE:

Example Number Structure Molecular Weight MS (APCI, m/z):[M+Hf 12 H rr^° 446.43 447.2 Xœ 012529 <7, :? -68-

Following the procedure for pyrimidinetrione formation outlined in Exàmpie 1, reactionof 5-oxo-1 -[6-(4-pyrazol-1 -ylmethyl-phenoxy)-pyridin-3-yl]-pyrroIidine-2,2-dicarboxyIic aciddiethyi ester (0.2 g, 0.4 mmol) with urea (0.074 g, 1.2 mmol) in 1.2 mL of 1M sodium ethoxidein éthanol afforded 6 mg of 1-[6-(4-Pyrazol-1-yimethyi-phenoxy)-pyridin-3-yi]-1,7,9-triaza- 5 spiro(4.5)decane-2,6,8,10-tetraone as a coloriess soiid. ’H NMR (CD3OD, 500 MHz): 7.99 (d,1H, J = 2.5 Hz), 7.72 (m, 2H), 7.53 (d, 1H, J = 2.5 Hz), 7.29 (d, 2H, J = 8.5 Hz). 7.10 (d, 2H, J= 8.5 Hz), 6.97 (d, 1H, J = 8.5 Hz), 6.35 (t, 1H, J = 2.0 Hz), 5.38 (s, 2H), 2.75 (m, 2H), 2.65(m, 2H) ppm. MS (APCI, m/z): 447.2 [M+H]+.

Préparation 1: 10 1 -f6-(4-Hvdroxyrnethyl-phenoxv)-pyridin-3-vil-5-PXO-pyrroiidine-2,2-dicarboxvliG acid diethyi ester: 1-[6-(4-Hydroxymethyl-phenoxy)-pyridin-3-yl3-5-oxo-pyrrolidine-2,2-dicarboxylic aciddiethyi ester: To a solution of 1-[6-(4-formyl-phenoxy)-pyridin-3-ylJ-pyrolidine-2,2-dicarboxyiic.acid diethyi ester (1.0 g, 2.3 mmol) in 30 mL of éthanol was added sodium borohydride (0.090 15 g, 2.3 mmol) at 0 °C. After stirring for 3 hours, the mixture was concentrated in vacuo, dilutedwith ethyl acetate and water, and the aqueous l.ayer was cautiously acidified with 1Mhydrochioric acid, then neutralized with saturated aqueous sodium bicarbonate. The mixturewas extracted three times with ethyl acetate, and the combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo, affording 0.80 g (80%) of 1-(6-(4- 20 hydroxymetby!-phenoxy)-pyridin-3-yi]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyi ester as acoloriess syrup. 1H NMR (CDCI3,400 MHz): 8.04 (d, 1H, J = 2.4 Hz), 7.72 (dd, 1H, J = 2.4, 8.8Hz), 7.40 (d, 2H, J = 8.8 Hz), 7.12 (d, 2H, J = 8.4 Hz), 6.91 (d, 1H, J = 8.8 Hz), 4.70 (s, 2H).4.19 (q. 4H, J = 7.6 Hz), 2.75 {m, 2H), 2.65 (m, 2H), 1.18 (t, 6H, J = 7.2 Hz) ppm. MS (APCI,m/z): 429.1 (M+Hf. 25 Préparation 2: 1-[6-(4-Brompmethyl-phenoxv)-pyr'idin-3-vn-5-oxo-pvrrolidine-2,2-dicarboxy!ic acid diethyi ester:

To a solution of 1-[6-(4-hydroxymethyl-phenoxy)-pyridin-3-yfJ-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyi ester (0.80 g, 1.9 mmol) in 9.4 mL of methylene chloride was added 30 triethylamine (0.46 mL, 0.33 g, 3.3 mL). After cooling to -40 °C, the mixture was treated withmethanesulfonyl chloride (0.20 mL, 0.30 g, 2.61 mmol). After stirring for 1 hour, an additional0.10 mL of methanesulfonyl chloride and 0.4 mL of triethylamine were added, and stirring wascontinued for 1 hour. A solution of anhydrous lithium bromide (1.6 g, 19 mmol, flame driedunder vacuum beFore use) in tetrahyd.rofuran (20 mL) was added via cannula, and the mixture 35 was warmed to room température and stirred for 2 hours. The mixture was diluted with ethylacetate, and the organic phase was washed with water, dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was filtered through a pad of silica gei eiuting with 1:1 012529 -69- ethyl acetate-hexanes, affording 0.65 g of 1-[6-(4-bromomethyl-phenoxy)-pyridin-3-y!J-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup. ’H NMR (CDCt3,500 MHz):8.07 (d, 1H, J = 3.0 Hz), 7.76 (dd, 1H, J = 2.5, 8.5 Hz), 7.44 (d, 2H, J = 8.5 Hz), 7.12 (d, 2H. J= 8.0 Hz), 6.95 (d, 1H, J = 9.0 Hz), 4.53 (s, 2H), 4.22 (q, 4H, J = 7.0 Hz), 2.75 (m, 2H), 2.65 5 (m, 2H), 1.20 (t. 6H, J = 7.0 Hz) ppm.

Préparation 3: 5-Oxo-146-(4-pvrazoi-1-vlrriethyÎ-phenoxv)-pvridin-3-vff-pvrrol(dine-2,2-dicarboxviic acid diethvi ester:

To a solution of 1-[6-(4-bromomethyl-phenoxy)-pyridin-3-y!]-5-oxo-pyrrolidine-2,2- 10 dicarboxyiic acid diethyt ester (0.2 g, 0.4 mmol) in 0.8 mL of dimethylformamide was addedpyrazoie (0.056 g, 0.82 mmo!) and potassium carbonate (0.11 g, 0.82 mmof). After stirring for24 hours at 50 °C, the mixture was diluted with water, extracted three times with ethyl acetate,and the combined organic phases were driéd over sodium sulfate, filtered and concenirated invacuo, affording the crude product as a colorless syrup that was used directly in the next step. 15 MS (APC1, m/z): 479.2 [M+H]+.

Whiie the invention has been described and ittustrated with reference to certainparticuiar embodiments thereof, those skiiied in the art wiii appreciate that variousadaptations, changes, modifications, substitutions, délétions, or additions of procedures andprotocois may be made without departing from the spirit and scope of the invention. For 20 example, effective dosages other than the particuiar dosages as set forth herein above maybe applicable as a conséquence of variations in the responsiveness of the mamma! beingtreated for any of the indications with the compounds of frie invention indicated above.Likewise, the spécifie pharmacoiogical responses observed may vary according ta anddepending upon the particuiar active compounds seiected or whether there are présent 25 pharmaceutical carriers, as weii as the type of formulation and mode of administrationempioyed and such expected variations or différences in the results are contemplated inaccordance with the objects and practices of the présent invention. It rs intended, therefore,that the invention be defined by the scope of the daims which follow and that such daims beinterpreted as broadly as is reasonable.

Claims

0Î2529 -70- We Claim:

1. A compound of the formula:

wherein said “A” is a 5-7 membered heterocyclic ring selected from the group consisting of: j)

012529 -71-

O X-Y-Z-G

Ο wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R’3 is independently selected from the group consisting of hydrogen, (CrC4)alkyl, (CrC^alkenyl,(C,-C4)alkynyl, (C6-C10)aryi, (C,-C,0)heteroaryl, (C3-Cfl)cycloalkyl and (Ci-Cia)heterocyciyl;wherein each of said (Ci-C4)alkyl, (CrCw)aryl, (C,-C,0)heteroaryl, (C3-C8)cycloalkyî and (Ci-C10)heterocyclyl may be optionally substituted on any of the ring carbon atoms capable offorming an additional bond with 1-3 substituent per ring independently selected from halo,(CrC4)aikyi, (CrC4)alkoxy, -CN, -OH and -NH2; X is (C6-C,0)aryl or (CrC50)heteroaryf; Y is selected from the group consisting of a bond, oxygen, sulfur, >C=O, >SO2, >S=O,-CH2-, -CHzO-, -O(CH2)„-, -CH2S-, -S(CH2)„-, -CH2SO-, -CH2SOr, -SO(CH2)n-, -SO2(CH2)n-, -NR14, -NR14(CH2)n-, -CH2[N(R14)]-, -CH2(CH2)n-, -CH=CH-, -CsC-, -[N{R14)]-SOrand -SO2[N(R14)]-; n is an integer from one to four; · R14 is hydrogen or (C,-C4)alkyl; Z is selected from the group consisting of (C8-C10)aryl, {C3-Cs)cycioalkyi, (CrCw)heterocyclyl and (C1-C10)heteroaryl; wherein one or two carbon-carbon single bonds ofsaid (C3-CB)cycioalkyi or (Ci-C10)heterocyclyl may optionally be replaced by carbon-carbondouble bonds; wherein each of said X or Z may be independently optionally substituted on any of thering carbon atoms capable of forming an additional bond by one or two substituents per ringindependently selected from F, Cl, Br, CN, OH, (CrC4)alkyl, (C1-C4)perfluoroalkyl, (C<-C4)perfluoroalkoxy, (C,-C4)alkoxy and (C3-C8)cycloalkyioxy; G is R15-(CR16R17)P-; wherein G is a substituent on any ring carbon atom of Z capableof forming an additional bond and is oriented at a position other than alpha to the point ofattachment of the Z ring to Y; p is an integer from 0 to 4; R15 is independently selected from the group consisting of halo, -CN, -NO2, OH, (CrC4)alkenyl, (C1-C4)alkynyi, (CrC4)perfluoroalkyl, perfluoro(C1-C4)alkoxy, R18-, R18-O-, R18-(Cî-C4)alkyl-O-, R1S-{C=O>-, R,e-(C=O)-O-, R,8-O-(C=O)- R18-S-, R22-(S=O}-, R18-(SO2}-, R22-(SO2)-(NR21)-, R1S-(C=O)-(NR21)-, R22-O-(C=O>-(NR2’)-, (R18R20)N-, (R13R20)N-(SO2)-, (r«r20)N-(C=O)-; (RieRZ0)N-(C=O)-(NR21)- and (R18R20)N-(C=O)-O-; each of R16 and R17 are independentiy seiected from hydrogen and (Ct-C4)alkyl; 012529 -72- or R16 and R17 may opiionaliy be taken together with the carbon to which they areattached to form a 5 to 10-membered carbocyclic ring; R1S, R19, R20 and R21 are independentiy selected from the group consisting ofhydrogen, (Ci-C4)alkyl, (C6-C10)aryl, (C3-CB)cycloalkyi, (Ch-C^heteroaryl and (CrCw)heterocyciyl; wherein said (C6-Ci0)aryi, (C3-CB)cycloalkyl, (Ci-C10)heteroaryl and (C,-Cio)heterocyclyi moieties may be optionally substituted on any of the ring carbon atomscapable of forming an additional bond by one to three substituents per ring independentiyselected from F, Cl, Br, CN, OH, (Ci-C4)aikyl, (CrC4)perfluoroaîkyi, (CrC4)perfluoroalkoxy,(CrC4)alkoxy, amino, (CrC4)aikyl-NH-, [(C,-C4)alkyl]2-N- and (C3-CB)cycloaikyloxy; whereinsaid (C3-Ce)cycloalkyl and (Ci-Cio)heterocyclyl moieties may afso optionally be substituted byoxo; wherein said (CrCio)heteroaryl and {CrC10)heterocyclyl moieties may optionally besubstituted on any ring nitrogen atom able to support an additional substituent t*y one to twosubstituents per ring independentiy selected from the group consisting of {C,-C4)alkyl and (CrC4)alkyl-(C=O)-; or R19 and R20 may optionally be taken together with the nitrogen to which they areattached to form a 3 to 8-membered heterocyclic ring; or R19 and R21 may optionally be taken together with the nitrogen, the carbon or theoxygen to which they are attached to form a 3 to 8-membered heterocyclic ring; R22 is selected from the group consisting of (Ct-C4)alkyl, (C6-Cio)aryi, (C3-C8)cycloalkyl, <Cj-C,0)heteroaryl and (Ci-C,0}heterocyclyl; wherein said (C6-C10)aryl, (C3-CB)cycloalkyl, (CrC10)heteroaryl and , (CrCio)heterocyciyl moieties may be optionallysubstituted on any of the ring carbon atoms capable of forming an additional bond by one tothree substituents per ring independentiy selected from F, Cl, Br, CN, OH, (C1-C4)alkyi, (CrC4)perfluoroaikyl, (Ct-C4)perfluoroalkoxy, (C,-C4)aikoxy, amino, (CrC4)alkyl-NH-, [(CrC4)alkyl]2-N- and (C3-CB)cycloalkyloxy; wherein said (C3-Cs)cycioalkyi and (C<-Cio)heterocyclylmoieties may also optionally be substituted by oxo; wherein said (CrC40)heteroaryI and (CrC,Q)heterûcyclyf moieties may optionall^ be substituted on any ring nitrogen atom able tosupport an additional substituent by one' to two substituents per ring independentiy selectedfrom the group consisting of (C,-C4)alkyl and (Ci-C4)alkyl-(C=O)-; or R21 and R22 may optionaiiy be taken together with the nitrogen, the oxygen or thesulfur to which they are attached to form a 3 to 8-membered heterocyclic ring; or a pharmaceutically acceptable sait thereof.
2. The compound according to claim 1 wherein said “A" is selected from thegroup consisting of 012529 -73-
4. The compound according ta claim 1 wherein said X is {Cf-C(0)hetefoaryL
5. The compound according to daim 1 wherein said Y is oxygen.
6. The compound accûrding to claim 1 wherein said G is R15-(CRieR’7)p-;wherein p is 0.
7. The compound according to daim 1 wherein said G is R1s-{CRMft%-;wherein p is an integer from 1 to 4. S. A compound according to ciaim 1, wherein said compound is seiected fromfrie graup consisting of: 1-[6-(4-Fluaro-phenoxy)-pyridin-3-y!]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraane;1-[6-(4-Fluoro-phenoxy)-pyridin-3-yi]-1,8,10-triaza-spiro[5.5ïundecane-2,7,9.11- tetraone; 4-(5-(2,6,8,10-T etraoxo-1,7,94riaza-spiro(4.53dec-1 -yi)-pyridin-2-yioxy]-benzonîtrile;1-[6-(4-I1,3.4]oxadiazo!-2-yI-phenoxy}-pyridin-3-yl]-1>7l9-triaza-spiro[4.5]decane- 2,6,8,1 Q-tetraone; 1-[6-(4-Efriyi-phenoxy)-pyridin-3-y!}-1.7,9-triaza-spiro(4.5]decane-2,6,8,10-tetraone;N-{4-[5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro(4.5Jdec-1 -y|)-pyrïdin-2-ylaxy]-benzyI}- aoetamide; N-{4-[5-(2,6)8,10-Tetraoxo-1l7,Ô-triaza-spiro[4.5idec-1-yl)-pyridin-2-yloxyî-benzyi}- propionamide; N-{4-[5-{2,6,8,10-Tetraoxo-1,7 ,9-triaza-spiro[4.5]dec-1 -yi)-pyridin-2-yioxy3-benzyi}-butyramîde; Pentanoic acid 4-(5-(2,6,8,10-tetraoxo-1,7r9-tria2a-spiro(4.5]dec-1 -yI)-pyridin-2-yioxyï-benzylamide; Cyctobütanecarboxyiic acid 4-(5-(2,6,8,10-tetraoxo-1,7,9-triaza-spiro(4.53dec-1-yIJ-pyridin-2-yloxy]-benzylamide; 1 -[6-(4-Bromo-phenoxy)-pyridin-3-yi]-1,7,9-triaza-spiro[4.5ldecane-2,6,8,10-tetraone;1-[6-(4-pyrazol-1«ylmethyl-phenoxy)-pyridin-3-yI3-1,7,9-triaza-spïro[4.5}deçane- 2,6,8,10-tetraone; and a pharmaceutically acceptable sait thereof. * -74- ο î 25.2 9
9. A pharmaceutical composition for the treatment of a condition seiected fromthe group consisting of connective tissue disorders, inflammatory disorders,immunology/allergy disorders, infectious diseases, respiratory diseases, cardiovasculardiseases, eye diseases, metabolic diseases, central nervous System disorders, iiver/kidney 5 diseases, reproductive health disorders, gastric disorders, skin disorders and cancers in amammal, including a human, comprising an amount of a compound of claim 1 effective insuch treatment and a pharmaceutically acceptable carrier.
10. Use of a compound of claim 1, in the manufacture of a médicament fortreating a condition seiected from the group consisting of connective tissue disorders,inflammatory disorders, immunology/allergy disorders, infectious diseases, respiratorydiseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous Systemdisorders, liver/kidney diseases, reproductive health disorders, gastric disorders, skindisorders and cancers in a mammal, including a human. 15 11. A pharmaceutical composition for the treatment of a condition which can be treated by the inhibition of matrix metalloproteinases in a mammal, including a human,comprising an amount of a compound of claim 1 effective in such treatment and apharmaceuticaily acceptable carrier.