ZA200302190B - Spiro-pyrimidine-2, 4, 6-trione metalloproteinase inhibitors. - Google Patents

Description

Background of the fnvention

The present invention relates to S5-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors and to pharmaceutical compositions and methods of treatment of inflammation, cancer and other disorders.

The compounds of the present invention are inhibitors of zinc metalloendopeptidases, especially those belonging to the class of matrix metalloproteinases (also called MMP or matrixin),

The MMP subfamily of enzymes, currently contains seventeen members (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-8, 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 known for their role in regulating the turn-over of extracellular matrix proteins and as such play important roles in normal physiological processes such as reproduction, development and differentiation. In addition, the MMP's are expressed in many pathological situations in which abnormal connective tissue turnover is occurring. For example, MMP-13 an enzyme with potent activity at degrading type il collagen (the principal collagen in cartilage), has been demonstrated to be overexpressed in osteoarthritic cartilage (Mitchell, et al., J. Clin. invest. 97, 761 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are aiso overexpressed in osteoarthritic cartilage and inhibition of some or all of these MMP's is expected to slow or block the accelerated loss of cartilage typical of joint diseases such as osteoarthritis or rheumatoid arthritis.

It is recognized that different combinations of MMP's are expressed in different pathological situations. As such, inhibitors with specific selectivities for individual MMP's may be preferred for individual diseases.

Matrix metalloproteinase inhibitors are well known in the literature. Hydroxamic acid

MMP inhibitors are exemplified in European Patent Publication 606,046, published July 13, 1994. Several pyrimidine-2,4,6-trione MMP inhibitors are referred to in PCT publication WO 98/58925, published December 30, 1998. PCT publication WO 00/475865, published August 17, 2000 refers to certain aryl substituted pyrimidine-2,4,6-trione MMP inhibitors. United

States Non-provisional application 09/635156, filed August 8, 2000 (which claims priority to

United States Provisional application 60/148547 filed August 12, 1999) refers to heteroaryl ) substituted pyrimidine-2,4,6-trione MMP inhibitors. United States Provisional Application " entitled “Pyrimidine-2,4,6-trione Metalloproteinase Inhibitors”, filed October 26, 2000, refers to . certain pyrimidine-2,4,6-triones. Barbituric acids and methods for their preparation are well known in the art, see for example Goodman and Gilman's, “The Phamacological Basis of

Therapeutics,” 345-382 (Eighth Edition, McGraw Hill, 1990). Each of the above referenced publications and applications is hereby incorporated by reference in its entirety.

, Summary of the Invention

The present invention relates to compounds of the formula: . H 0 Tyee

N o=(

N A

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

X-Y-Z-G

X-Y-Z-G b) X-Y-Z-G 0 | o a) | o | 0 Rs

N Re & N rR! NE R® . ’ 3 2 7 3 RE TR ZR 2 . ’ 6 6 rR R ' R'Z2 R® R RRR’ R™

Y-2- X-Y-Z-G d) X-Y-Z-G e) X26 f) 9

Lp | 2 2

N— nA _R° N"N R" $ N—R® : N Rr ox R" 11 . . - 6 rR" R ; R' I Ro : R' Rr? RS R :

X-Y-Z-G

X-Y-Z-G X-Y-Z-G i 9) | h) | ) | rR? 3

N—S0, N-SO, _R N SOR . é L” R J rR3 p R

Sy R® k= T~R® LR . : 1 R® N

R' RZ R' R2 R® R R? RS

X-Y-Z-G

No XYZ6 X-Y-2-G ) R o10 j)] R 10 R 13 rR! R R 8 12

R' N R N R

N 6 ) 7 \ 8

R Z, ' R IY) R - 5 a [3 / R’

R 1 R 1 R®

YR 5 R 5 ; R ;

RR rR* R R® RS

, m) ree n) Te 0) X-Y-Z-G 0 rs < NA 5 NK N R®

DN NR NT and Lon

SO, RZ 0 o wherein each of R', R% R®, RY, R°, R®, R’, R®, R%, R"™, R", R™ and Ris independently selected from the group consisting of hydrogen, (C4-C,)alkyl, (C4-C,)alkenyl, (C4-Cylalkynyl, (Ce-Cyo)aryl, (Ci-Cio)heteroaryl, (Cs-Cg)cycloalkyl and (C,-Cyp)heterocyclyl; wherein each of said (C-Cy)alkyl, (Cs-Cio)aryl, (Ci-Cio)heteroaryl, (Cs-Cs)cycioalkyl and (Cs-

Cio)heterocyclyl may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond with 1-3 substituents per ring independently selected from halo, (C1-Cy)alkyl, (C4-Cy)alkoxy, -CN, -OH and —NH,;

X is (Ce-C1p)aryl or (Cy-Cio)heteroaryl;

Y is selected from the group consisting of a bond, oxygen, sulfur, >C=0, >S0,, >S=0, -CHy-, -CH,0-, -O(CHjy),-, -CH,S-, -S{CH,),-, -CH2S0-, -CH,S0,-, -SO(CH;),-, -S0,(CHy)e-, -NR™, -NR™(CH,)p-, -CHa[N(R')]-, -CHp(CHy)y-, -CH=CH-, -C=C-, -[N(R"'*)]-SO,- and -SON(R™)}-; n is an integer from one to four;

R™ is hydrogen or (C,-C,)alkyl;

Z is selected from the group consisting of (Ce-Cyplaryl, (Cs-Cs)cycloalkyl, (Cs-

Cqo)heterocyclyl and (C4-Cig)heteroaryl; wherein one or two carbon-carbon single bonds of said (C3-Cg)cycioalkyl or (C4-Cip)heterocyclyl may optionally be replaced by carbon-carbon double bonds; wherein each of said X or Z may be independently optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents per ring independently selected from F, Cl, Br, CN, OH, (C4-Cs)alkyl, (C4-Cs)perfluoroalkyl, (C,-

C.)perfluoroalkoxy, (C4-C4)alkoxy and (Cs-Ca)cycloalkyloxy;

G is R"-(CR™R""),-; wherein G is a substituent on any ring carbon atom of Z capable of forming an additional bond and is oriented at a position other than alpha to the point of attachment of the Z ring to Y; - p is an integer from O to 4,

R' is independently selected from the group consisting of halo, -CN, -NO,, OH, (C,- . Cs)alkenyl, (C;-C4)alkynyl, (Ci-C4)perfluoroalkyl, perfluoro(Cy-C,)alkoxy, R'®-, R"-0-, R"®-(C,-

Cyakyl-0-, R™(C=0)-, R"-(C=0)-0-, R®-0-(C=0)- R™-8-, R?(S=0)-, R"-(S0,)-, RZ (SO.)-(NR¥)-, R™-(C=0)-(NR*')-, R®-0-(C=0)-(NR®)-, (R“R®NN-, (R"R®)N-(SO,)-, (RUR®)N-(C=0)-; (R"*R®)N-(C=0)-(NR?")- and (R"*R**)N-(C=0)-O-; each of R" and R" is independently selected from hydrogen and (C4-C,)alkyl;

, or R' and R" may optionally be taken together with the carbon to which they are attached to form a 5 to 10-membered carbocyclic ring; ] R", R", R® and R®' are independently selected from the group consisting of hydrogen, (C-Cy)alkyl, (Ce-Cio)aryl, (Cs-Cs)cycloalkyl, (Ci-Cio)heteroaryl and (Ci- Cio)heterocyclyl; wherein said (Cg-Cyo)aryl, (Cs-Cg)cycloalkyl, (C-Cio)heteroaryl and (Ci-

Cio)heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C4-Cs)alkyl, (C4-C,)perfluoroalkyl, (C,-Cs)perfiuoroalkoxy, (C+-Cy)alkoxy, amino, (C,-Cslalkyl-NH-, [(C-C,)alkyl]-N- and (Cj-Cs)cycloalkyloxy, wherein said (C3-Cs)cycloalkyl and (C4-Cio)heterocyclyl moieties may also optionally be substituted by oxo; wherein said (C:-Cio)heteroaryl and (Ci-C,o)heterocyclyl moieties may optionally be substituted on any ring nitrogen atom able to support an additional substituent by one to two substituents per ring independently selected from the group consisting of (C,-C,)alkyl and (C;-

C,)alkyl-(C=0)-; or R'® and R® may optionally be taken together with the nitrogen to which they are attached to form a 3 to 8-membered heterocyclic ring; or R* and R* may optionally be taken together with the nitrogen, the carbon or the oxygen to which they are attached to form a 3 to 8-membered heterocyclic ring;

R# is selected from the group consisting of (Cy-Cyalkyl, (Ce-Cyo)aryl, (Cs- Cg)cycloalkyl, (Cs-Cioheteroaryl and (Cq-Cio)heterocyclyl; wherein said (Ce-Cyplaryl, (Cs-

Cs)cycloalkyl, (C4-Cio)heteroaryl and (C4-Cio)heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C,-C,)alkyl, (Cs-

C,)perfluoroalkyl, (C;-C4)perfluoroalkoxy, (C,-C,)alkoxy, amino, (C;-Cs)alkyl-NH-, [(Cy- C,)alkyll;-N- and (Cs-Cg)cycloalkyloxy, wherein said (Cs-Cs)cycloalkyl and (C4-Cip)heterocyclyl moieties may also optionally be substituted by oxo; wherein said (C4-Cio)heteroaryl and (C,-

Cio)heterocyclyl moieties may optionally be substituted on any ring nitrogen atom able to support an additional substituent by one to two substituents per ring independently selected from the group consisting of (C,-C,)alkyl and (C4-C4)alkyl-(C=0)-; or R*' and R¥ may optionally be taken together with the nitrogen, the oxygen or the sulfur to which they are attached to form a 3 to 8-membered heterocyclic ring; ’ or the pharmaceutically acceptable salts thereof.

The present invention also relates to the pharmaceutically acceptable acid addition : salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, ie., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,

» tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, para-toluenesulfonate and pamoate . [i.e., 1,1-methylene-bis-(2-hydroxy-3- naphthoate)}salts.

The invention also relates to base addition salts of formula §. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula | that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water- soluble amine addition salts such as N-methylglucamine (meglumine) and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

The term “a bond", as used herein in the group Y, means that the groups X and Z are directly connected through a carbon-carbon bond so as to form pendent aryl rings such as diphenyl. ~

The dashed lines as used in each of the heterocyclic ring “A” of formulae a), b), c), 9), h), i), k) and I) refer to optional double bonds. The exact positions of the optional double bonds for each of the heterocyclic ring “A” of formulae a), b), ¢), g), h), i}, k) and I) are as defined in the specification. Whenever the dashed line extends over two carbon atoms, one skilled in the art will understand that two carbons are tetravalent and that the extra substituent(s) (i.e., any of R', R%, R* R* R%, R®, R, R%, R", R"", R", or R"®) may be absent.

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

Alkyl groups, wherever they occur, may be optionally substituted by a suitable substituent. } The term "alkenyl", as used herein, unless otherwise indicated, includes hydrocarbon radicals containing at least one olefin linkage and having straight, branched moieties, or combinations thereof.

The term "alkynyl", as used herein, unless otherwise indicated, includes hydrocarbon radicals containing at least one carbon-carbon triple bond linkage and having straight, branched moieties or combinations thereof.

The term "cycloalkyl", as used herein, unless otherwise indicated, includes a mono or bicyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1}heptanyl, bicyclo[3.2.1]octany! and bicyclo[5.2.0Jnonanyl, etc.); optionally containing 1or 2 double bonds ) and optionally substituted by 1 to 3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C;-Cs)alkoxy, (Ce-Cio)aryloxy, trifluoromethoxy, difluoromethoxy or (C+-Cs)alkyl, more preferably fiuoro, chloro, methyl, ethyl and methoxy.

: The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is as defined above. ‘ The term "halo", as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one aor more hydrogens, such as phenyl or naphthyl, optionally substituted by 1 to 3 suitable substituents such as fluoro, chloro, cyano, nitro, trifluoromethyl, (C4-Cg)alkoxy, (Ce-Cio)aryloxy, (Cs-Cg)cycloalkyloxy, trifluoromethoxy,- difluoromethoxy, or (C4-Cg)alkyl. :

The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one or more hydrogens, such as benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyi, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl,” furazanyl, furopyridinyl, fury), imidazolyl, indazoly!, indolinyl, indolizinyl, indotyl, 3H- indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazotyl, oxazofyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyi, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, guinazolinyl, quinolinyl, quinoxalinyi, tetrazolyl, thiazoly!, thiadiazoiyl, thienyl, triazinyl and trizzolyl, wherein said (C;-Cio)neteroany is optionally substituted on any of the ring carbon atoms capable of forming an additional band by one or two substituents independently selected from F, Ci, Br, CN, OH, (C,-Cslalkyl, (C4-C,)perfluoroalkyl, (C4-C,)perfiuoroalkoxy, (C4-Cslatkoxy and (Cs-Cp)cycloalkyloxy. The foregoing groups, can be C-attached or N- attached where such is possible. For instance, pyrrolyl can be pyrrol-1-yt (N-attached) or pyrrol-3-yl (C-attached).

The term "heterocyclyl", as used herein, unless otherwise indicated, includes an organic radical derived from a non-aromatic heterocyclic compound by removal of one or more hydrogens, such as 3-azabicyclo[3.1.0lhexanyl, 3-azabicyclo[4.1.0]-heptanyl, azetidinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydroazepinyl, hexahydropyrimidine, imidazolidinyl, imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, ~~ 2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothienyl, tetrahydrothiapyranyl, thiomorpholinyl, thioxanyl and trithianyl, The foregoing groups, can be C-attached or N-attached where such is possible. For example, piperidiny! can be piperidin-1-yl (N-attached) or piperidin-4- ) yi (C-attached). The foregoing groups, as derived from the compounds listed above, can be optionally substituted where such is possible by a suitable substituent, such as oxo, F, Cl, Br,

CN, OH, (Cy-Cui)alkyl, (C-Cy)perfluoroalkyl, (C4-C,)perfluoroalkoxy, (Cq-Cy)alkoxy, or (Ca-

Cg)cycloalkyloxy. :

. The phrase “a suitable substituent’ is intended to mean a chemically and pharmaceutically acceptable functional group i.e., a moiety that does not negate the inhibitory . activity of the inventive compounds. Such suitable substituents may be routinely selected by those skilled in the art. lllustrative examples of suitable substituents include, but are not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, hydroxy groups, 0X0 groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyf groups, aralkoxy or heteroaralkoxy groups, carboxy groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups dialkylamino carbonyl groups, aryicarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, an aryisuifonyl groups and the iike.

The phrase "at a position other than alpha to the point of attachment of the Z ring to

Y", as used herein, unless otherwise indicated, is intended to mean a chemically and pharmaceutically 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 be meta, wherein the Z-G bond is in the 1,3 position relative to the Y-Z bond. Another relative orientation may be para, wherein the Z-G bond is in the 1,4 position relative to the Y-Z bond.

Some compounds of formula | contain chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers, enantiomers, diastereomers and stereoisomers of the compounds of formula | and mixtures thereof. The compounds of the invention also exist in different tautomeric forms. This invention relates to all tautomers of formula I. Those skilled in the art are well aware that the pyrimidine-2,4,6-frione nucleus exists as a mixture of tautomers in solution. The various ratios of the tautomers in solid and liquid form is dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound. in one embodiment of the invention, the heterocyclic ring “A” of the compounds of the formula 1 is selected from the formulae a) or b):

X-Y-2-G X-Y-Z-G a) | o b) | o

N R her R? RZ RS rR; wherein X is (Cg-Cyg)aryl, preferably phenyl. Within this embodiment, Y is selected from the . group consisting of a bond, oxygen, >C=0, -CH,-, -CH,0-, -O(CHy),-, -CH,CH,-, -CH=CH- and -C=C-; wherein n is 1or 2; preferably Y is selected from the group consisting of oxygen, -OCH_- and -CH,0-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has the formulae a) or b), wherein X is (Cg-Cqo)aryl, preferably phenyl. Within this embodiment, Y is selected from

. the group consisting of sulfur, >SO,, >S$=0, -CH,S-, -S(CHa)n-, -CH2S0-, -CH,S0,-, -SOCH;- and -SO,(CHy,)-; wherein n is 1 or 2; preferably Y is sulfur or >SO.. . In another embodiment of the invention, the heterocyclic ring “A” has the formulae a) or b), wherein X is (C¢-C1g)aryl, preferably phenyl. Within this embodiment, Y is selected from the group consisting of CHz[N(R')}-, >NR™, -NR"(CH,)n-, -SO,[N(R™)]- and -[N(R")}-SOz-, wherein R' is hydrogen or methyl; and nis 1 or 2.

In another embodiment of the invention, the heterocyclic ring “A” has the formulae a) or b), wherein X is (C4-Cio)heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (Cs-

C.o)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (C;-

Cyalkyl, (C4-Cy)perfluoroalkyl, (C4-Cy)perfluoroalkoxy, (C4-C4)atkoxy and (Cs-Cs)cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyi, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within this embodiment, Y is a bond, oxygen, sulfur, -CH,-, >80O,, -OCH,- or -CH,0-; preferably Y is oxygen, -OCH,- or -CH,0-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has the formulae a) or b), wherein X is (C4-Cso)heteroaryl selected from the group consisting of benzimidazoiyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl,” furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (C4-

Cio)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (C,-

C,)alkyl, (C4-C,)perfiuoroalkyl, (C4-Cy)perfluoroalkoxy, (C4-Cs)alkoxy and (Ca-Ca)cycloalkyloxy; ’ preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl, more preferably

X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within this embodiment, Y is selected from the group consisting of sulfur, >SO,, >8=0, -CH,S-, -S(CH,),-

. , “CH2S80-, -CH,S0;-, -SOCH,- and -SO,(CHj),-; wherein n is 1 or 2; preferably Y is sulfur or >80,. . In another embodiment of the invention, the heterocyclic ring “A” has the formulae a) or b), wherein X is (C,-Cqo)heteroaryi selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (C:-

Cio)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (C,-

Ca)alkyl, (C4-Cq)perfiuoroalkyl, (C4-C,)perfluoroalkoxy, (C4-C,)alkoxy and (C3-Cs)cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferably

X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within this embodiment Y is selected from the group consisting of CH,[N(R*)}-, >NR"™, -NR(CHy)-, -

SOIN(R™)]- and -[N(R'*)]-SO-, wherein Ris hydrogen or methyl; and n is 1 or 2.

In another embodiment of the invention, the heterocyclic ring “A” has the formula a), wherein X is (Cs-Cio)heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridiny!, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridiny, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (C,-

Cio)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, CI, Br, CN, OH, (Cy-

Ca)alkyl, (C4-Cy)perfiuoroalkyl, (C,-C,)perfluoroalkoxy, (C4-C4)alkoxy and (C3-Cs)cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferably ’ X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH,-, >S0,, ) -OCH_;- and -CH,O-; preferably Y-is oxygen, -OCH,- or -CH,O-; more preferably Y is oxygen.

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 a double bond.

. In another embodiment of the invention, the heterocyclic ring “A” has the formula b), wherein X is (C4-Cyo)heteroaryl selected from the group consisting of benzimidazolyl, . benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiaziny}, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridiny!, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (Cs-

Cio)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, CI, Br, CN, OH, (C;-

C.)alkyl, (C4-Cy)perfluoroalkyl, (C4-Cy)perfluoroalkoxy, (Cs-C,)alkoxy and (Ca-Cg)cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferably

X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CHa-, >SO,, -OCH,- and -CH,0-; preferably Y is oxygen, ~-OCH,- or -CH,0-; 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 a double bond.

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

X-Y-Z-G c) | 0 R* 3

RVR RR wherein X is (C1-Cyg)heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is selected from the group consisting of 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, -CH,-, >S0,, -OCH,- and -CH,0-; preferably Y is : oxygen, -OCH,- or -CH,0O-; more preferably Y is oxygen.

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

Claims (14)

. We Claim:

1. A compound of the formula: . H 0) Yee N o=( N A 0) ! wherein said “A” is a 5-7 membered heterocyclic ring selected from the group consisting of: X-Y-Z-G X-Y-Z-G Xree a) b) ©) | Or o 0 R® NX R? N R* N WR? A LOR JR R

2 . 1 6 6 R' R ' R R? RS R : R' R? Rr® R : X-Y-2- X-Y-Z-G d) . X-Y-Z-G e) v6 f) 0 R° o | P af Nn NA re NTN R" § N—R® N R" IX Rr 6 10’ Rr" ; 1 0 R"2R° R : R R rR? R R X-Y-Z-G X-Y-Z-G X-Y-2-G i g) | h) | ) R* 80, _R SOR? $ EN ES | IF" 7 3 . ’ 7 “uy R 1 i ; R' < R' R® R Rr R® R? RS X-Y-Z-G X-Y-Z- ) Xvze K) EG ) R' 10 R' p10 13 Rr" R R R® R"2 N Rs N 7 N \ 8 R A JJ TR } R A 5 : / 7 R 1 R® 1 A 1 2 : R 5 ; R 1p Yo m) er n) Ta 0 X-YZG o 0 | 1 ENA oo N4 N So DN N° NYT Jo SO, : and R" . 0) 'e) : wherein each of R, R%, R’, R%, R®, R®, R, R, R°, R", R", R” and R" is independently selected from the group consisting of hydrogen, (C;-Cs)alkyl, (C1-C,)alkenyl, (C4-Cu)alkynyl, (Ce-Cro)aryl, (Ci-Cio)heteroaryl, (Cs-Cs)cycloalkyl and (C:-Cig)heterocyciyl; wherein each of said (C-Cs)alkyl, (Ce-Cig)aryl, (C4-Cio)heteroaryl, (Cs-Cg)cycloalkyl and (Cq- Cio)heterocyclyl may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond with 1-3 substituents per ring independently selected from halo, (C4-Cy)alkyl, (C4-Cs)alkoxy, -CN, -OH and —NH,; xX is (Ce-Cyp)aryl or (C4-Cyg)heteroaryl; Y is selected from the group consisting of a bond, oxygen, sulfur, >C=0, >S0,, >8=0, -CHg-, ~CH;0-, -O(CHy)p~, -CH,S-, -S(CH,),-, -CH2S0-, -CH,S0,-, -SO(CH,)r, -80(CHa)n-, -NR™, -NR'(CHy)p-, ~-CHoIN(R")}-, -CHa(CHy)ym, -CH=CH-, ~C=C-, -[N(R")}-SO, and -SO,IN(R™)}-; n is an integer from one to four; - R' is hydrogen or (C,-C,)alkyl; Z is selected from the group consisting of (Cs-Cyg)aryl, (Cs-Cs)cycloalkyl, (Cs- Ciolheterocyclyl and (C,-Cyglheteroaryl; wherein one or two carbon-carbon single bonds of said (Cs-Cg)cycloalkyl or (C-Cqp)heterocyclyl may optionally be replaced by carbon-carbon double bonds; wherein each of said X or Z may be independently optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents per ring independently selected from F, Cl, Br, CN, OH, (C;-Cyalkyl, (C,-Cg)perfiuoroalkyi, (C;-

C.)perfluoroalkoxy, (C-C,)alkoxy and (C3-Cg)cycioalkyloxy; G is R™-(CR"™R"),-; wherein G is a substituent on any ring carbon atom of Z capable of forming an additional bond and is oriented at a position other than alpha to the point of attachment of the Z ring to Y; } p is an integer from 0 to 4; R' is independently selected from the group consisting of halo, -CN, -NO,, OH, (C,- Cu)alkenyl, (Cs-Cs)alkynyl, (C4-Cq)perfluoroalkyl, perfluoro(Ci-Cq)alkoxy, R™-, R™-0-, R™(C,- C,akyl-0-, R*(C=0)., R"™(C=0)-0-, R®-0-(C=0)- R™-8-, R*(S=0)-, R®-(S0,)-, RZ (SO-(NR¥")-, R™-(C=0)-(NR”')., RZ-O-(C=O-NR*')., (RUR®IN-, (RYR®N-(SO,)-, (R™R®)N-(C=0)-; (R"*R®)N-(C=0)-(NR*")- and (R"*R®)N-(C=0)-O-; each of R*® and R" are independently selected from hydrogen and (C;-C,)alkyl;

or R'® and RY may optionally be taken together with the carbon to which they are v attached to form a 5 to 10-membered carbocyclic ring; R*, R™ R® and R* are independently selected from the group consisting of ‘ hydrogen, (Ci-C,)alkyl, (Ce-Ciolaryl, (Cs-Ce)cycloalkyl, (Cs-Cio)heteroaryl and (C+- Caiplheterocyclyl; wherein said (Cg-Cip)aryl, (Cs-Cg)cycloalkyl, (Cs-Cip)heteroaryl and {Cy Cio)heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C:-Cs)alkyl, (C;-Cy)perfluoroalkyl, (C4-C4)perfluoroatkoxy, (Cy-Cs)atkoxy, amino, (C-Cylatkyl-NH-, [(C(-Cs)alkyl]-N- and (C;-Cs)cycioalkyloxy; wherein said (Cs-Cg)cycloalkyl and (C4-Cyg)heteracyclyl moieties may also optionally be substituted by oxo; wherein said {C{-Cio)heteroaryl and (C,-Cig)heterocyclyl moieties may optionally be substituted on any ring nitrogen atom able to support an additional substituent hy one to two substituents per ring independently selected from the group consisting of (C,-C,)alkyl and (Cy- Ca4)alkyl-(C=0)-; or R'® and R® may optionally be taken together with the nitrogen to which they are attached to form a 3 to 8-membered heterocyclic ring; or R" and R*' may optionally be taken together with the nitrogen, the carbon or the oxygen to which they are attached to form a 3 to 8-membered heterocyclic ring; R# is selected from the group consisting of (C,-Cilalkyl, (Ce-Cio)aryl, (Ca- Cg)cycloalkyl, (Cy-Cqo)heteroaryl and (Cy-Cioheterocyclyl; wherein said (Ce-Cip)aryl, (Ca- Cg)oycloalkyl, (Cs-Ciglheteroaryt and (C4-Cio)heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C;-C,)alky}, (C;- Cas)perfluoroalkyl, (C-Cy)perfluoroalkoxy, (C4-Cslalkoxy, amino, (Ci-Cslalkyl-NH-, [(Cy- C,)alkyl]-N- and (Cs-Cg)cycloalkyloxy, wherein said (C;-Cs)cycloalkyl and (C4-Cio)heterocyclyl moieties may also optionally be substituted by oxo; wherein said (C-Cyp)heteroaryl and (C,- Cqo)heterocyclyl moieties may optionally be substituted on any ring nitrogen atom able to support an additional substituent by one to two substituents per ring independently selected from the group consisting of (C-Cy)alkyl and (C4-C)alkyl-(C=0)-; or R*' and R® may optionally be taken together with the nitrogen, the oxygen or the sulfur to which they are attached to form a 3 to 8-membered heterocyclic ring; or a pharmaceutically acceptable salt thereof. 2, The compound according to claim 1 wherein said “A” is selected from the . group consisting of

X-Y-Z:G 0 X-Y-Z-G k) Xy-za . I) R Ro ; | rR" | R eS RY N Rr® y RE , N R® ! rR / rR’ RY R® R' a2 R® cand RR :

3. The compound according to claim 1 wherein said X is (Cg-Cyg)aryl.

4. The compound according to claim 1 wherein said X is (C4-Cyo)heteroaryl.

5. The compound according to claim 1 wherein said Y is oxygen.

5. The compound according to claim 1 wherein said G is R™-(CR™R"),; wherein p is 0.

7. The compound according fo claim 1 wherein said G is R"(CR"R"), wherein p is an integer from 1 fo 4.

8. A compound according to claim 1, wherein said compound is selected from the group consisting of: 1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl}-1,7,9-triaza-spiro[4.5]decane-2,6,8, 10-tetraone; 1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl}-1,8,10-trizza-spiro[5.5]undecane-2,7,9,11- tetraone; 4~{5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro{4.5)dec-1-yl)-pyridin-2-yloxy}-benzonitrile; 1-[6-(4-[1,3,4Joxadiazol-2-yl-phenoxy)-pyridin-3-yi]-1.7 9-triaza-spiro[4.5]decane- 2,6,8,10-tetraone; 1-[6~(4-Ethyl-phenoxy)-pyridin-3-yi]-1.7,9-taza-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-yl}-pyridin-2-yloxy}-benzyl)- acetamide; N-{4-[5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl}-pyridin-2-yloxy}-benzyl}- propionarnide; N-{4-[5~(2,6,8,10-Tetraoxo-1,7,9-triaza-spiraf4,5]dec-1-yl)-pyridin-2-yloxy}-benzyl)- butyramide; Pentanoic acid 4-[S-(2,6,8,10-tetraoxo-1,7,8-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy}- benzylamide; Cyclobutanecarboxylic acid 4-[5-(2.6,8,10-tefraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)- . 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-yimethyl-phenoxy)-pyridin-3-yi]-1,7,9-triaza-spiro[4.5]decane- 2,6,8,10-tetraone; . and a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition for the treatment of a condition selected from the group consisting of connective tissue disorders, inflammatory disorders, immunology/allergy disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system disorders, liver/kidney diseases, reproductive health disorders, gastric disorders, skin disorders and cancers in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier.

10. Use of a compound of claim 1, in the manufacture of a medicament for treating a condition selected from the group consisting of connective tissue disorders, inflammatory disorders, immunology/allergy disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system disorders, liver/kidney diseases, reproductive health disorders, gastric disorders, skin disorders and cancers in a mammal, including a human.

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 a pharmaceutically acceptable carrier.

12. The compound according to claim 1, substantially as herein described and exemplified.

13. A pharmaceutical composition according to claim 9 or 11, substantially as herein described and exemplified.

14. Use according to claim 10, substantially as herein described and exemplified. AMENDED SHEET