SK4972003A3 - 5-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors - Google Patents

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

The invention relates to 5-spiropyrimidine-2,4,6-trione metalloproteinase inhibitors, pharmaceutical compositions based thereon, and methods of treating inflammation, cancer and other disorders.

BACKGROUND OF THE INVENTION

The compounds of the invention are inhibitors of metalloendopeptidases, in particular metalloendopeptidases, belong to the subclass of matrix metalloproteinases also referred to as MMPs or matrixins).

zinc which (which are

The MMP enzyme subclass currently includes 17 members (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP11, MMP-12, MMP-13, MMP- 14, MMP-15, MMP-16, MMP-17, MMP-18

MMP-19 and MMP-20). MMPs are known for their role in regulating turnover of extracellular matrix proteins and as such play an important role in normal physiological processes such as reproduction, development and differentiation. In addition, MMPs are expressed when a number of pathologies occur for abnormal remodeling

For example, it has been shown that MMP-13, an enzyme with high activity in degrading collagen type II (essential collagen in cartilage), is overexpressed in osteoarthritic cartilage (Mitchell et al., J. Clin. Invest. 97, 761 (1996)). Other MMPs (MMP-2, MMP-3, MMP8, MMP-9, and MMP-12) are also overexpressed in osteoarthritic cartilage and inhibition of some or all of these MMPs is believed to slow or block the accelerated loss of connective tissue conditions. .

cartilage, which is typical of joint diseases such as osteoarthritis and rheumatoid arthritis.

It is believed that in different pathological conditions there are different combinations of MMPs. Thus, inhibitors with selectivity to individual MMPs could be preferred from an individual point of view.

Detected expressed disease would be specific

Matrix metalloproteinase inhibitors are well known in the literature. For example, hydroxamic acid derivatives are disclosed as MMP inhibitors in European Patent Publication 606,046, published June 13, 1994. Several pyrimidine-2,4,6-trione MMP inhibitors are disclosed in PCT publication WO 98/58925, published December 30, 1998. PCT publication WO 00/47565, published August 17, 2000, relates to certain aryl-substituted pyrimidine-2,4,6-trione MMP inhibitors. US application no. 09/635165, filed August 9, 2000 (claiming priority from US Provisional Application 60/148547, filed August 12, 1999), relates to heteroaryl-substituted pyrimidine-2,4,6-trione MMP inhibitors. The US provisional application, called Pyrimidine-2,4,6-trione Metalloproteinase Inhibitors, filed October 26, 2000, relates to certain pyrimidine-2,4,6triones. Barbituric acids and methods for their preparation are well known in the art (see, for example, Goodman and Gilman, The Farmacological Basis of Therapeutics, 345-382 (Eighth Edition, McGraw Hill, 1990). All of these publications and applications are cited as a substitute for transferring its contents. into this text.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I wherein

A

(I) represents a 5- to 7-membered heterocyclic ring selected from the group consisting of groups a) to o)

c)

j)

f)

Already,

X-Y-Z-G

N N R

10

R ¹ R ² R ^{5 R} XYZG

X-Y-Z-G

R Ŕ

where

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R, R, R, R and R ¹³ are each independently selected from the group consisting of hydrogen, (C 1 -C 4) alkyl , (C 1 -C 4) alkenyl, (C 1 -C ₄ ) alkynyl, (C ₆ -C ₁₀ ) aryl, (C 1 -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) cycloalkyl and (C 1 -C 10) heterocyclyl; wherein the (C 1 -C 4) alkyl, (C ₆ -C ₁₀₎ aryl, _(C-C10) heteroaryl, (C ₃ -C ₈₎ cycloalkyl and (C1 -C10) heterocyclyl is optionally substituted on any carbon atoms of the ring carbon atoms which are capable of forming an additional bond with 1 to 3 ring substituents independently selected from the group consisting of halogen, (C ₃ -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, -CN, -OH and

-NH ₂ ;

X is (C ₆ -C ₁₀ ) aryl or (C 1 -C 10) heteroaryl;

Y is selected from the group consisting of a bond, O, S,> C = 0,> S0 _2,> S = 0, _-CH2 -, _-CH2 O-, -O (CH _{2) n} -,

-CH ₂ S-, -S (CH ₂ ) _n -, CH ₂ SO-, -CH ₂ SO ₂ -, -SO (CH ₂ ) _n -, -SO ₂ (CH ₂ ) _n -,

-NR ¹⁴ , -NR ¹⁴ (CH ₂ ) _n -, (CH ₂ ) 2 [N (R ¹⁴ )] -, -CH 2 (CH ₂ ) _n -, -CH = CH-,

-C = C-, - [N (R ¹⁴ )] -SO ₂ - and -SO ₂ [N (R ¹⁴ )] -;

n is an integer from 1 to 4;

is hydrogen or (C1-C4) alkyl;

R ¹⁴

Z is selected from the group consisting of _(C6 Cio) aryl, (C ₃ -C ₈₎ cycloalkyl, (CiCi ₀₎ heterocyclyl, and (C-exo) heteroaryl; wherein in (C ₃ -C ₈ ) cycloalkyl or (C ₃ C ₁₀ ) heterocyclyl one or two single carbon-carbon bonds are optionally replaced by carbon-carbon double bonds;

wherein each of X and Z is independently optionally substituted on any of the ring carbon atoms capable of forming an additional bond by 1 or 2 ring substituents independently selected from the group consisting of fluoro, chloro, bromo, CN, OH, (C1- 4) alkyl, _(Ci-C4) perfluoroalkyl, (C1 -C4) perfluoroalkoxy, (C1 -C4) alkoxy and (C ₃ -C ₈₎ cycloalkyloxy;

G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; wherein G is a substituent on any ring carbon atom of residue Z capable of forming an additional bond and is oriented at a position different from the alpha position with respect to the point of attachment of the ring Z to residue Y;

p is an integer from 0 to 4;

R ¹⁵ is independently selected from the group consisting of halogen, -CN, -N0 _2, -OH, (CľCj alkenyl, (C 1 -C 4) -alkynylskupiny, (C 1 -C 4) luóralkylskupiny perforation, perforation fluoro- (C _x -C 4) alkoxy groups, groups R ¹⁸ -, R ¹⁸ -O-, R ¹⁸ (C 1 -C 4) -alkyl-Ο-, R ¹⁸ - (C = O) -, R ¹⁸ - (C = O) -O-, R ¹⁸ -0- (C = 0) - R ¹⁸ S, R ²² - (S = O) -, R ¹⁸ - (SO 2) -, R ²² - (S02) - (NR ²¹⁾ -, R ¹⁹ - (C = O) 5 (NR ²¹ ) -, R ²² -O- (C = O) - (NR ²¹ ) -, (R ¹⁹ R ²⁰ ) N-, (R ¹⁹ R ²⁰ ) N- (SO ₂ ) -, (R ¹⁹ R ²⁰ ) -N- (C = O) -; (R ¹⁹ R ²⁰ ) N- (C = O) - (NR ²¹ ) - and (R ¹⁹ R ²⁰ ) N- (C = O) O -;

R ¹⁶ and R ¹⁷ are each independently selected from the group consisting of hydrogen and (C 1 -C ₄ ) alkyl; or

R ¹⁶ and R ¹⁷ may optionally be taken together with the carbon atom to which they are attached to form a 5- to 10-membered carbocyclic ring;

R ^18, R ^19, R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, _(C-C4) alkyl, (C _s -C ₁₀₎ aryl, (C ₃ -C ₈₎ cycloalkyl group, (ΟχC ₁₀₎ heteroaryl and (C 1 -C 6) heterocyclyl groups; wherein the (C ₆ -C ₁₀₎ aryl, (C ₃ -C ₈₎ cycloalkyl, (ΟχC ₁₀₎ heteroaryl and _(C-C10) heterocyclyl optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one up to 3 ring substituents independently selected from the group consisting of fluorine, chlorine, bromine, CN, OH, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) perfluoroalkyl, (C ₄ -C ₄ ) perfluoroalkoxy, (C 1 -C ₄₎ alkoxy, amino, (C 1 -C ₄ ) alkyl-NH-, [(C 1 -C ₄ ) alkyl] ₂ -Na (C ₃ -C ₈ ) cycloalkyloxy groups; wherein (C ₃ -C ₈ ) cycloalkyl and (C 1 -C ₁₀ ) heterocyclyl are also optionally substituted with oxo; and wherein (C _x C ₁₀ ) heteroaryl and (C x -C ₁₀ ) heterocyclyl is optionally substituted on any ring nitrogen atom capable of carrying an additional substituent with 1 to 2 ring substituents independently selected from the group consisting of (C x -) C ₄ ) alkyl and (C 1 -C ₄ ) alkyl- (C = O) -; or

20

R and R may optionally be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocyclic ring; or

R ¹⁹ and R ²¹ may optionally be taken together with the nitrogen, carbon or oxygen atom to which they are attached to form a 3- to 8-membered heterocyclic ring;

R ²² is selected from the group consisting of (C 1 -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C 1 -C ₁₀ ) heteroaryl and (C 1 -C 10) heterocyclyl ; wherein the (C ₆ -C ₁₀ ) aryl-, (C ₃ -C ₈ ) cycloalkyl-, (C ₁ -C ₆ ) heteroaryl- and (C ₁ -C ₆ ) heterocyclyl group is optionally substituted at any of the ring carbon atoms capable of forming an additional bond, 1 to 3 ring substituents independently selected from fluorine, chlorine, bromine, CN, OH, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) perfluoroalkyl, (C 1 -C 4) -perfluoroalkoxy, (C 1 -C ₄₎ alkoxy, amino, (C 1 -C 4) alkyl-NH-, [(C 1 -C ₄ ) alkyl] ₂ -Na (C ₃ -C ₈ ) -cycloalkyloxy groups, wherein the (C ₃ -C ₈ ) cycloalkyl group and (C x) -C ₁₀ ) heterocyclyl is optionally also substituted with oxo, wherein the (C 1 -C 10) heteroaryl and (C 1 -C ₁₀ ) heterocyclyl are optionally substituted on any ring nitrogen atom capable of carrying an additional substituent with 1 to 2 ring substituents independently selected from the group consisting of _(Οχ-C4) alkyl groups and the group (C

C ₄ ) alkyl- (C = O) -; or

R ²¹ and R ²² may optionally be taken together with the nitrogen, oxygen or sulfur atom to which they are attached to form a 3-8 membered heterocyclic ring;

and pharmaceutically acceptable salts thereof.

The invention also provides pharmaceutically acceptable acid addition salts of the compounds of formula (I). For the preparation of pharmaceutically acceptable acid addition salts of the abovementioned basic compounds of the invention, acids which form non-toxic addition salts, i.e. salts containing pharmacologically acceptable anions, are used. Examples of such salts include hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, hydrogensulfates, phosphates, hydrogen phosphates, acetates, lactates, citrates, hydrogen citrates, tartrates, hydrogen tartrates, succinates, maleates, fumarates, gluconates, saccharates, methanesulfonates, benzoates, methanesulfonates , benzenesulfonates, p-toluenesulfonates and pamoates (i.e. 1,1'-methylenebis (2-hydroxy-3-naphthoates)).

The invention also relates to base addition salts of the compounds of the formula I. For the preparation of pharmaceutically acceptable salts of the compounds of the formula I which are acidic in nature with bases, bases which form non-toxic salts with these compounds can be used as reagents. Non-limiting examples of such non-toxic base salts include those derived from pharmacologically acceptable cations, such as alkali metal (e.g., potassium and sodium) and alkaline earth metal (e.g., calcium or magnesium), ammonium, or water-soluble amine addition salts, such as N-methylglucamine (meglumine) and lower alkanolammonium salts and other salts with pharmaceutically acceptable organic amines such as bases.

A bond as used in the definition of Y is understood to mean that the groups X and Z are directly linked via a carbon-carbon bond to form pendant aryl rings, such as a diphenyl group.

The dotted line used in the heterocyclic ring A of formula (a), (b), (c), (g), (h), (i), (k) and (1) denotes optional double bonds. The exact positions of the optional double bonds of each heterocyclic ring A of formula (a), (b), (c), (g), (h), (i), (k) and (1) as defined in the specification. In cases where the dashed line extends along two carbon atoms, one of ordinary skill in the art will recognize that the two carbon atoms are tetravalent and that the substituent or substituents are extra (i.e., any of R ¹ , R ² , R ³ , R ^4). , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ ) may be absent.

The term alkyl, as used herein, unless otherwise indicated, means a saturated monovalent hydrocarbon radical having a straight, branched or combined chain. The alkyl groups are optionally substituted with a suitable substituent at each occurrence.

The term alkenyl, as used herein, unless otherwise indicated, means a hydrocarbon radical containing at least one olefinic bond, straight chained, branched or combined.

The term alkynyl, as used herein, unless otherwise indicated, refers to a hydrocarbon radical containing at least one carbon-carbon triple bond, straight, branched or combined.

The term cycloalkyl, as used herein, unless otherwise indicated, means mono- or bicyclic carbocyclic ring systems (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo [2]). 2,1] heptanyl, bicyclo [3,2,1] octanyl and bicyclo [5,2,0] nonanyl, etc.); which optionally contain 1 or 2 double bonds and are optionally substituted with 1 to 3 suitable substituents defined below, such as fluoro, chloro, trifluoromethyl, (C 1 -C 3 alkoxy), (C ₆ -C ₁₀ ) aryloxy, trifluoromethoxy, difluoromethoxy or (C 1 -C 6) C ₄ ) alkyl, more preferably fluoro, chloro, methyl, ethyl and methoxy.

The term alkoxy, as used herein, unless otherwise indicated, refers to a group of the formula O-alkyl, wherein alkyl is as defined above.

The term halogen as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The term aryl as used herein, unless otherwise indicated, means an organic radical derived from an aromatic hydrocarbon by removal of one or more hydrogen atoms such as phenyl or naphthyl, which radical is optionally substituted with substituents such as fluorine, trifluoromethyl-, (C 1 -C ₆ ) -alkoxy-,

C ₈ ) cycloalkyloxy-, trifluoromethoxyC ₆ ) alkyl.

saturated with 1 to 3 suitable chlorine, cyano, nitro, (C ₆ -C 10) aryloxy, (C ₃ , difluoromethoxy) or (C 10-10)

The term heteroaryl, as used herein, unless otherwise indicated, means an organic moiety derived from an aromatic heterocyclic compound by the removal of one or benzimidazolyl-, benzopyranyl-, benzothiazolyl-, isoxazolyl-, phthalazinyl-, multiple hydrogen atoms, for example benzofuryl-, benzofurazanyl-, 2H-1-benzothiadiazinyl-, benzothiazinyl-, benzothiophenyl-, benzoxazolyl-, chromanyl-, cinnolinyl-, furazanyl-, furopyridinyl-, furyl-, imidazolyl-, indazolyl-, indolinyl-, indolizinyl-, indolizinyl-, indolyl-, indolyl- 3H-indolyl-, isoindolyl-, isoquinolinyl-, isothiazolyl-, naphthyridinyl-, oxadiazolyl-, oxazolyl-, pteridinyl-, purinyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl-, pyrazolyl-, pyrrolyl-, quinazolinyl-, quinolinyl-, quinoxalinyl-, tetrazolyl-, thiazolyl-, thiadiazolyl-, thienyl-, triazinyl- and triazolyl, wherein the (C 1 -C ₁₀ ) heteroaryl is optionally substituted on any of the ring carbon atoms that are capable of forming an additional bond; or 2 substituents independently selected from F, Cl, Br, CN, OH, (C -C alkyl group, _(C-C4) luóralkylskupiny perf, (C _x -C ₄₎ perfluoroalkoxy, (C1 -C4) alkoxy, and (C ₃ -C ₈ ) cycloalkyl oxy groups. Where possible, the above groups may be C-linked or N-linked. For example, the pyrrolyl group may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked).

As used herein, unless otherwise noted, heterocyclyl means an organic moiety derived from a non-aromatic heterocyclic compound by removal of one or azabicyclo [3.1.0] hexanyl-, azetidinyl-, dihydrofuryl-, more. hydrogen atoms such as 33-azabicyclo [4.1.0] heptanyl-, dihydropyranyl-, dihydrothienyl-, dioxanyl-, 1,3-dioxolanyl-, 1,4-dithianyl-, hexahydroazepinyl-, hexahydropyrimidinyl-, imidazolidinyl-, imidazolinyl -, isoxazolidinyl-, morpholinyl-, piperidinyl-, 2H-pyranyl-, pyrazolinyl-, quinolizinyloxazolidinyl-, piperazinyl-, 4H-pyranyl-, pyrazolidinyl-, pyrrolidinyl-, 2-pyrrolinyl-, 3-pyrrolinyl-, tetrahydrofuryl-, tetrahydropyranyl 1,2,3,6tetrahydropyridinyl-, tetrahydrophienyl-, tetrahydrothiopyranyl-, thiomorpholinyl-, thioxanyl- and tritianyl. These groups may, if possible, be C-linked or N-linked. For example, the piperidinyl group may be piepridin-1-yl (N-linked) or piperidin-4-yl (C-linked). These groups, as derived from the compounds listed above, are optionally substituted with a suitable substituent such as oxo, fluoro, chloro, bromo, CN, OH, (C1-C4) alkyl, (C1-C4) perfluoroalkyl, (C1- C4) perfluoroalkoxy, (C1 -C4) alkoxy or (C ₃ -C ₈₎ cycloalkyloxy.

Suitable substituent refers to chemically and pharmaceutically acceptable functional groups, i.e., moieties that do not interfere with the inhibitory activity of the compounds of the invention. One skilled in the art is able to select such suitable substituents within the skill of the art. Illustrative, non-limiting examples of suitable substituents include halogen, perfluoroalkyl, perfluoroalkoxy, alkyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, aryl- or heteroaryl, aryloxy- or heteroaryloxy, carboxy, aralkyl, amino, alkyl and dialkylamino, carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, alkylsulfonyl and arylsulfonyl groups.

The term at a position different from the alpha position relative to the attachment point of the Z ring to the Y moiety as used herein unless otherwise indicated is understood to mean the chemically and pharmaceutically acceptable bond orientation linking the Z group to the G group (ZG bonds) with respect to the bond linking the Y group to the Z group (the YZ bond). Such a relative orientation may be meta when the Z-G bond is at the 1,3-position relative to the Y-Z bond; or para, when the Z-G bond is at position 1,4 relative to the YZ bond.

Certain compounds of Formula I contain chiral centers and may therefore exist in different enantiomeric forms. The present invention includes all optical isomers, enantiomers, diastereomers and stereoisomers of the compounds of formula (I) and mixtures thereof. The compounds of the invention also exist in various tautomeric forms. All tautomers of formula I are within the scope of the invention. It will be apparent to those skilled in the art that the pyrimidine-2,4,6-trione core will be present in solution as a mixture of tautomers. The different ratios of tautomers in solid and liquid form depend on the different substituents on the molecule as well as the particular procedure used to isolate the compound.

In one embodiment of the invention, the heterocyclic ring A in the compounds of formula I is selected from the groups of formula a) and b)

X-Y-Z-G

X-Y-Z-G

wherein X is (C ₆ -C ₁₀ ) aryl, preferably phenyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen and a group of the formula> C = O, -CH ₂ -, -CH ₂ O-, -O (CH ₂ ) _n -,

-CH ₂ CH ₂ -, -CH = CH-, and -OC-; wherein n is 1 or 2; Y is preferably selected from the group consisting of oxygen and -OCH ₂ - and -CH ₂ O-; More preferably, Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula a) or b), wherein X represents a (C6-C10) -aryl group, preferably a phenyl group. In this embodiment, Y is selected from the group consisting of sulfur and> SO ₂ ,> S = O, -CH ₂ S-, -S (CH ₂ ) _n -, -CH ₂ SO-, -CH ₂ SO ₂ -, -SOCH ₂ and -SO ₂ (CH ₂ ) n -; wherein n is 1 or 2; Preferably, Y is sulfur or> S0 _second

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula a) or b), wherein X represents (C ₆ -C ₁₀ ) aryl, preferably phenyl. In this embodiment, Y is selected from the group consisting of CH ₂ [N (R ¹⁴ )] -,> NR ¹⁴ , -NR ¹⁴ (CH 2) n -, -SO 2 [N (R ¹⁴ )] - and - [N ( R ¹⁴ )] -SO 2 -, wherein R ¹⁴ is hydrogen or methyl; and n is 1 or 2.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula a) or b), wherein X represents a (C 1 -C 10) heteroaryl group selected from the group consisting of benzimidazolyl-, benzofuryl-, benzopyranyl-, benzothiazolylbenzofurazanyl-, 2H-1benzothiadiazinyl-, benzothiazinyl -, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, indazolyl, indolinyl, indolizinyl, indolyl, imidazolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl -, isoxazolyl-, naphthyridinyl-, oxadiazolyl-, oxazolyl-, phthalazinyl-, pteridinyl-, purinyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl-, pyrazolyl-, pyrrolyl-, quinazolinyl-, quinolinyl-, tetrazolyl-, thiazolyl-, substituents independently of bromine, CN, OH, (C 1 -C ₄ ) perfluoroalkyl, (C 1 -C 4) alkoxy and quinoxalinyl-, thiadiazolyl-, thienyl-, triazinyl-, and triazolyl- (C 1 -C 10) the heteroaryl group is optionally substituted on any of the rings ových carbon atoms capable of forming an additional bond by one or selected from fluoro, chloro, (C _x -C ₄₎ alkyl, (C1 -C4) perfluoroalkoxy, (C ₃ -C ₈₎ cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl-, isothiazolyl-, isoxazolyl-, oxadiazolyl-, oxazolyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl- and pyrazolyl- groups; more preferably X is pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl; most preferably X is pyridinyl. In this embodiment, Y represents a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH 2 - or -CH ₂ O-; preferably Y is oxygen or -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula a) or b), wherein X represents a (C 1 -C 10) heteroaryl group selected from the group consisting of benzimidazolyl, benzofuryl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazinyl, 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 the (C 1 -C 10) heteroaryl group is optionally substituted on any one of the ring carbon atoms capable of forming an additional bond by one or two substituents nez independently selected from the group consisting of fluorine, chlorine, bromine, CN, OH, (C 1 -C ₄ ) alkyl, (C 1 -C 4) perfluoroalkyl, (C 1 -C 4) perfluoroalkoxy, (C 1 -C 4) alkoxy, and (C ₃ -C ₈₎ cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl-, isothiazolyl-, isoxazolyl-, oxadazolyl-, oxazolyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl- and pyrazolyl- groups; more preferably X is pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl; most preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of> SO ₂ ,> S = O, -CH ₂ S-, -S (CH ₂ ) _n -, -CH ₂ SO-, -CH ₂ SO ₂ -, -SOCH ₂ and -SO ₂ (CH ₂ ) _n -; wherein n is 1 or 2; preferably Y represents sulfur or a group> SO ₂ .

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula a) or b), wherein X represents a (C 1 -C 10) heteroaryl group selected from the group consisting of benzimidazolyl, benzofuryl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazinyl, 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 groups, the (C 1 -C ₁₀ ) heteroaryl group being optionally substituted on any one of the ring carbon atoms capable of forming an additional bond by one or two substituent independently selected from the group consisting of fluorine, chlorine, bromine, CN, OH, (C 1 -C ₄ ) alkyl, (C 1 -C 4) perfluoroalkyl, (C 1 -C 4) perfluoroalkoxy, (C 1 -C 4) alkoxy, and ( C ₃ -C ₈₎ cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl, isothiazolyl, oxadiazolyl, pyridazinyl, and pyrazolyl;

zoxazolyl, pyrazinyl, pyrimidinyl are pyridyl, oxazolyl, pyridines, more preferably X pyrazinyl, pyridazinyl, or pyrimidinyl; most preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of CH ₂ [N (R ¹⁴ )] -,> NR ¹⁴ ,

-NR ¹⁴ (CH ₂ ) _n -, -SO ₂ [N (R ¹⁴ )] [N (R ⁴ )] -SO ₂ -, wherein R ¹⁴ is hydrogen or methyl; and n is 1 or 2.

In another embodiment of the present invention, the heterocyclic ring A is of formula (a) wherein it is (C 1 -C 10) heteroaryl selected from the group consisting of benzimidazolyl-, benzopyranyl-, benzothiazolyl-, benzofuryl-, benzofurazanyl-, 2H-1-benzothiadiazinyl-, benzothiazinyl-, benzothiophenyl-, benzoxazolylcinnolinyl-, furazanyl-, furopyridinyl-, furylindazolyl-, indolinyl-, indolizinyl-, indolylisoindolyl-, isoquinolinyl-, isothiazolyl-, naphthyridinyl-, oxadiazolyl-, oxazolyl-, pyrimidinyl-, pinylidinyl-, purinyl-, purinyl-, purinyl- -, pyrazolyl-, pyrrolyl-, quinolinyl-, quinoxalinyl-, tetrazolyl-,, chromanyl-,, imidazolyl-,, 3H-indolyl-, isoxazolyl-, phthalazinyl-, pyridinyl-, quinazolinyl-, thiazolyl-, two substituents consisting of fluoro, OH, (C 1 -C 4) alkyl, (C 1 -C 4) perfluoroalkoxy, thiadiazolyl, thienyl, triazinyl, and triazolyl, the (C 1 -C 10) heteroaryl optionally substituted on any of the ring carbon atoms R 1 is capable of forming an additional bond by one or independently selected from the group of chlorine, bromine, CN, (C 1 -C 4) perfluoroalkyl, (C 1 -C 4) alkoxy and (C ₃ -C ₈ ) cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl-, isothiazolyl-, isoxazolyl-, oxadiazolyl-, oxazolyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl- and pyrazolinyl-; more preferably X is pyrazinyl-, pyridazinyl-, pyridylamino or pyrimidinyl; most preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y is oxygen or -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula a) as defined in the preceding paragraph, wherein the dotted line in the heterocyclic ring A represents a double bond.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula b), wherein X represents a (C1-C10) heteroaryl group selected from the group consisting of benzimidazolyl-, benzopyranyl-, benzothiazolyl-, benzofuryl-, benzofurazanyl-, 2H-1-benzothiadiazinyl-, benzothiazinyl-, benzothiophenyl-, benzoxazolyl-, chromanyl-, cinnolinyl-, furazanyl-, furopyridinyl-, furyl-, imidazolyl-, indazolyl-, indolinyl-, indolizinyl-, indolyl-, 3H-indolyl-, isoquinolinyl-, isothiazolyl-, isoindolyl-, naphthyridinyl-, oxadiazolyloxazolyl-, isoxazolyl-, phthalazinyl-, pteridinyl-, purinyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl-, pyrazolyl-, pyrrolyl-, quinazolinyl-, quinolinyl-, thiadiazolyl-, quinoxinyl , thienyl, triazinyltato (C 1 -C 10) heteroaryl is tetrazolyl-, thiazolyl-, and triazolyl, optionally substituted on any of the ring carbon atoms capable of or by two substituents consisting of fluorine, OH, (C 1 -C 4) alkyl; pins, (C 1 -C ₄ ) perfluoroalkoxy, form an additional bond, one independently selected from chloro, bromo, CN, (C 1 -C 4) perfluoroalkyl, (C 1 -C 4) alkoxy and (C ₃ -C ₈ ) cycloalkyloxy ; preferably X is selected from the group consisting of imidazolyl-, isothiazolyl-, isoxazolyl-, oxadiazolyl-, oxazolyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl- and pyrazolyl- groups; more preferably X is pyrazinyl-, pyridazinyl-, pyridylamino or pyrimidinyl; most preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y is oxygen or -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula b) as defined in the preceding paragraph, wherein the dashed line in the heterocyclic ring A represents a double bond.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula c)

wherein X is (C 1 -C ₁₀ ) 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. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula c), wherein the dashed line in the heterocyclic ring A represents a double bond such that the heterocyclic ring A of formula C is selected from the group consisting of rings c _x and c ₂

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula d)

wherein X is (C 1 -C ₁₀ ) heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; X is preferably pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl; more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula e)

wherein X is (C 1 -C ₁₀ ) heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; X is preferably pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl; more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-, preferably Y is oxygen or -OCH ₂ - or - CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula f)

f)

X-Y-Z-G

OR ® ^λ Λ ”'N

R

R ¹ R ² R ^{5 R} ;

wherein X is (C 1 -C 10) heteroaryl selected from the group consisting of imidazolyl-, isothiazolyl-, isoxazolyl-, oxadiazolyl-, oxazolyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl- and pyrazolyl- groups; X is preferably pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl; more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula g)

wherein X is (C 1 -C ₁₀ ) 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. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferentially

Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula g) as defined in the preceding paragraph, wherein the dashed line in the heterocyclic ring A represents a double bond.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula h)

wherein X is a {C ₁ -C ₁₀ } heteroaryl group 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. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula h) as defined in the previous paragraph, wherein the dotted line in the heterocyclic ring A represents a double bond.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula (i)

wherein X is (C 1 -C 10) heteroaryl selected from the group consisting of imidazolyl-, isothiazolyl-, isoxazolyl-, oxadiazolyl-, oxazolyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl- and pyrazolyl- groups; X is preferably pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl; more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula i), wherein the dotted line in the heterocyclic ring A represents a double bond such that the heterocyclic ring A of formula i) is selected from the group consisting of rings i _x and i ₂

In a preferred embodiment of the invention, the heterocyclic ring A corresponds to the general formula selected from the group consisting of formulas j), k) and 1)

X-Y-Z-G

wherein X is (C 1 -C 10) heteroaryl selected from the group consisting of imidazolyl-, isothiazolyl-, isoxazolyl-, oxadiazolyl-, oxazolyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl- and pyrazolyl- groups; X is preferably pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl; more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another preferred embodiment of the invention, the heterocyclic ring A corresponds to the general formula j)

j)

X-Y-Z-G

wherein X is (C 1 -C ₁₀ ) heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; Preferably X is pyrazinyl-, pyridazinyl-, pyridyl- or pyrimidinyl; more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y is oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another preferred embodiment of the invention, the heterocyclic ring A corresponds to the general formula k)

wherein X is (C 1 -C ₁₀ ) heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; X is preferably pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl; more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the present invention, the heterocyclic ring A of formula k) is as defined in the preceding paragraph, wherein the dotted line in the heterocyclic ring A represents a double bond.

In another preferred embodiment of the invention, the heterocyclic ring A corresponds to the general formula 1)

wherein X is (C 1 -C ₁₀ ) heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; X is preferably pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl; more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO _{2 /} -OCH ₂ - and -CH ₂ O-; preferably Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula (1), wherein the dashed line in the heterocyclic ring A represents a double bond such that the heterocyclic ring A of general formula 1 is selected from the group consisting of rings of formulas 1 ₂ and 1 ₂

In another embodiment of the invention, the general formula (m) corresponds to the heterocyclic ring A

wherein X is (C 1 -C 10) heteroaryl selected from the group consisting of imidazolyl-, isothiazolyl-, isoxazolyl-, oxadiazolyl-, oxazolyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl- and pyrazolyl- groups; X is preferably pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl;

X is pyridinyl. In this, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferentially

Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

more preferred embodiments

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula (n)

wherein X is (C 1 -C ₁₀ ) heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; X is preferably pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl; more preferably X is pyridyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A corresponds to the general formula o)

o) X-Y-Z-G

wherein X is (C 1 -C 10) heteroaryl selected from the group consisting of imidazolyl-, isothiazolyl-, isoxazolyl-, oxadiazolyl-, oxazolyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl- and pyrazolyl- groups; Preferably X is pyrazinyl-, pyridazinyl-, pyridyl- and pyrimidinyl; more preferably X is pyridyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-; preferably Y represents oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, each of R ¹ , R ² , R ³ , R ⁴ ,

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are selected from the group consisting of hydrogen (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkenyl, (C ₁ -C ₄ ) alkynyl, (C ₆ -C ₁₀ ) aryl, (C 1 -C 10) heteroaryl, (C ₃ -C ₈ ) -cycloalkyl and (C 1 -C 10) heterocyclyl; wherein (C ₃ -C ₄ ) alkyl, (C ₆ -C 10) aryl, (C 1 -C 10) heteroaryl, (C ₃ -C ₈ ) cycloalkyl and (C 1 -C ₁₀ ) heterocyclyl are optionally substituted on any of the ring carbon atoms capable of forming an additional bond with 1 to 3 substituents independently selected from halogen of (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy and -CN, -OH and -NH ₂ .

A generic or subgeneric embodiment of each of the above-described embodiments are compounds wherein each of R ¹ is: p 2 p 3 p 4 p 5 p 6 p 7 p 8 f AX f ax / II f AX f AX f AX and AX f consisting of

R ¹⁰ , R ^{X1 of} hydrogen,

R ¹² and R ¹³ _(Ce-C10) aryl, (C ₃ -C ₈₎ cycloalkyl.

(C 1 -C ₁₀ ) heteroaryl selected from (C 1 -C ₄ ) alkyl,

Preferred generic or subgeneric embodiments are those described above, wherein each of R ¹ pj p4 po to p / po ρκ η ¹

ΑΧ / AX y AX y AX y XX y AX y AX y AX y AX of a group consisting of hydrogen and methyl.

R ^2z and R ^XJ is selected from (C 1 -C ₄ ) alkyl, such as

In another embodiment of the present invention, each of R ⁵ , R ⁶ , R ^7, and R ⁸ is each of the following:

R ⁸ is selected from the group (C _x -C ₄₎ alkyl, _(Ci-C4) alkynyl, (C 1 -C 10) heteroaryl, (C1 -C10) heterocyclyl; (C _x -C ₄₎ alkyl, (C ₆ -C ₁₀₎ aryl, consisting of hydrogen, _(Ci-C4) alkenyl, (C ₆ -C ₁₀₎ aryl, (C ₃ -C ₈₎ cycloalkyl, and wherein each of said (C ₁ -C ₁₀₎ heteroaryl, (C ₃ -C ₈₎ cycloalkyl and (C ~ _C10) heterocyclyl optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to 3 substituents independently selected from halogen, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, -CN, -OH and -NH ₂ .

In another embodiment of the invention, one or two of R ⁵ , R ⁶ , R ⁷ and R ⁸ represent a group other than hydrogen.

In another embodiment of the present invention, R ^{9 is} independently selected from the group consisting of hydrogen (C 1 -C ₄ ) alkyl, (C ₆ -C 10) -aryl, (C 1 -C 10) heteroaryl, (C ₃ -C ₈ ) cycloalkyl, and ( C1-C10) heterocyclyl groups.

In another embodiment of the invention, R ^{9 is} independently selected from the group consisting of hydrogen and (C 1 -C 4) alkyl, such as methyl.

In another embodiment of the present invention, Z is (C ₃ -C ₈ ) cycloalkyl or (C 1 -C 10) heterocyclyl selected from the group consisting of cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, tetrahydrofuryl-, tetrahydropyranyl-, N-methyl-3 -azetidinyl-, piperazinyl-, piperidinyl-, 1,3-oxazolidin-4-one-5-yl-, 1,3-oxazolidin-2,4-dione-5-yl-, 4,5-dihydro-1, 2-Oxazolidin-3-one-4-yl-, 1,3-thiazolidin-4-one-5-yl-, 1,3-thiazolidin-2,4-dion-5-yl-, 1,3-imidazolidin-4-one -5-yl-, 1,3-imidazolidin-2,4-dion-5-yl-, 1,2-pyrazolidin-3-one-4-yl-, tetrahydro-1,3-oxazin-4-one-5- yl-, tetrahydro-1,3-oxazine-2,4-dion-5-yl-, morpholinyl-, morpholin-3-yl-2-yl-, morpholine-3,5-dion-2-yl-, 2,3 -dihydro-1,4-oxazin-3-en-2-yl-, tetrahydro-1,3-thiazin-4-one-5-yl-, tetrahydro-1,3-thiazin-2,4-dion-5-yl-, thiomorpholinyl-, thiomorpholin-3-one-2-yl-, thiomorpholine-3,5-dion-2-yl-, 2,3-dihydro-1,4-thiazin-3-one-2-yl-, hexa- Hydro-1,2-diazin-3-one-4-yl-, 4,5-dihydro-2H-pyridazin-3-yl-4-yl-, hexahydro-1,3-diazine-2,4-dione-5- yl, piperazin-2-on31

3-yl-, piperazin-2,6-dion-3-yl-, tetrahydro-1,3,4-thiadiazin-5-one-6-yl-, 5,6-dihydro-1,3,4-thiadiazine -5-on-6-yl-, 1,3,4-oxadiazin-5-one-6-yl-, 5,6-dihydro-1,2,4-oxadiazin-5-one-6-yl-, tetrahydro-1,2,4-oxadiazin-5-one-, 1,2,4-triazin-5-one-6-yl-, tetrahydro-1,2,4-oxadiazin-5-one- 6-yl-, 5,6-dihydro-1,2,4-oxadiazin-5-one-6-yl-, 1,2,4-oxadiazin-3,5-dion-6-yl- and 1,2 , 4-triazin-6-on-5-yl. In this embodiment, Z is preferably selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuryl, tetrahydropyranyl, N-methyl-3-azetidinyl, piperazinyl, piperidinyl, N-methylpiperidinyl and morpholinyl . In this embodiment, Z is more preferably selected from the group consisting of cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, tetrahydrofuryl- and tetrahydropyranyl. In this embodiment, Z is most preferably selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuryl and tetrahydropyranyl.

In another embodiment of the invention, Z is (C 1 -C 6) heteroaryl selected from the group consisting of benzimidazolyl-, benzofuryl-, 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-, oxadiazolyl- -, oxazolyl-, phthalazinyl-, pteridinyl-, purinyl-, pyrazinyl-, pyridazinyl-, pyridinyl-, pyrimidinyl-, pyrazolyl-, pyrrolyl-, quinazolinyl-, quinolinyl-, quinoxalinyl-, tetrazolyl-, thiazolyl-, thiadiazolyl-, thienyl, triazinyl and triazolyl groups, more preferably pyridinyl, pyrazinyl, pyridazinyl and pyrazolyl groups, wherein the (C 1 -C ₁₀ ) heteroaryl group is optionally substituted on any one of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from the group consisting of F, Cl, Br, CN, OH, (C _x -C ₄₎ alkyl groups, _(C-C4) luóralkylskupiny perf, (C1 -C4) perfluoroalkoxy groups, (C _x -C ₄ ) alkoxy and (C ₃ -C ₈ ) cycloalkyloxy.

In another embodiment of the invention, X or Z is substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from the group consisting of fluorine, chlorine, bromine, CN, OH, (C1-C4) alkyl, (C1 -C4) perfluoro-alkyl group, (C1 -C4) perfluoroalkoxy, (C _x -C ₄₎ alkoxy and (C ₃ -C ₈₎ cycloalkyloxy.

In another embodiment of the invention, X and Z are substituted on any of the ring carbon atoms capable of forming an additional bond independently selected from chlorine, bromine, (C ₄ ) perfluoroalkyl, by one or two substituents of the group consisting of fluorine, CN, OH, (C _x -C ₄₎ alkyl, (C _x (C _x -C ₄₎ perfluoroalkoxy, (C _x -C ₄₎ alkoxy and (C ₃ -C ₈₎ cycloalkyloxy.

In another embodiment of the present invention, G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _P -; wherein p is 0; R ¹⁵ is selected from the group consisting of halogen, -CN, and R ¹⁸ ; wherein R ¹⁸ is selected from (C 1 -C 4) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C 1 -C ₁₀ ) heterocyclyl; (C ₃ -C ₈ ) cycloalkyl-, (C 1 -C 10) -heterocyclyl of any of the rings consisting of hydrogen, (C ₆ -C ₁₀ ) aryl, (C 1 -C 10) heteroaryl and wherein the (C ₆ -C ₁₀ ) aryl -, (C1-C10) heteroaryl- and is optionally substituted on carbon atoms capable of forming an additional bond by 1 to 3 ring substituents independently selected from the group consisting of fluorine, chlorine, bromine, CN, OH, (C1- C1) alkyl, (C1-C4) perfluoroalkyl, (C1-C4) perfluoroalkoxy, (C1-C4) alkoxy, amino, (C3-C4) alkyl-NH-, [(C1-C4) alkyl] 2 -N- and (C ₃ -C ₈ ) cycloalkyloxy; wherein (C ₃ -C ₈ ) cycloalkyl and (C 1 -C ₁₀ ) heterocyclyl is also optionally substituted by oxo; wherein (C 1 -C ₁₀ ) heteroaryl and (Οχ-Οχο) heterocyclyl are optionally substituted on any ring nitrogen atom capable of carrying an additional substituent, 1 or 2 ring substituents independently selected from the group consisting of (θ 1 -θ ₄ ) alkyl and _(Cl-C4) alkyl (0 = 0) -.

In another embodiment of the present invention G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; wherein p is 0 to 4, preferably 1 to 2; R ¹⁵ is selected from the group consisting of halogen, -CN, -N0 _2, -OH, _(χ 0 ₄ -0) alkenyl, (C1-C4) alkynyl, (C 1 -C 4) perfluoro luóralkylskupiny, perfluoro (C1 C4) alkoxy, R ¹⁸ -, R ¹⁸ -0-, R ¹⁸ - (C 1 -C 4) alkyl-O-, R ¹⁸ - (0 = 0) -,

R ¹⁸ - (0 = 0) -0-, R ¹⁸ -0- (0 = 0) - R ¹⁸ -S-, R ²² - (S = 0) -, R ¹⁸ - (S02) -, R ²² - (SO 2) - (NR ²¹ ) -, R ¹⁹ - (O = 0) - (NR ²¹ ) -, R ²² -O- (O = 0) - (NR ²¹ ) -, (R ¹⁹ R ²⁰ ) N- , (R ¹⁹ R ²⁰⁾ N (S0 ₂₎ -, (R ¹⁹ R ²⁰⁾ N (0 = 0) -; (R ¹⁹ R ²⁰ ) N- (O = O) - (NR ²¹ ) - and (R ¹⁹ R ²⁰ ) N- (O = O) -O; R ¹⁶ and R ^{17 are} each independently hydrogen or (O ₄ -O ₄ ) alkyl; R ¹⁸ is selected from the group consisting of hydrogen, (C 1 -C 4) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C 1 -C 10) heteroaryl and (Οχ-Οχο) heterocyclyl -groups; wherein the (C ₆ -C 10) aryl-, (C ₃ -C ₈ ) cycloalkyl-, (Οχ-Ο ₁₀ ) heteroaryl - and (C 1 -C 10) heterocyclyl group is optionally substituted on any of the ring carbon atoms capable of forming an additional bond, 1 to 3 ring substituents independently selected from the group consisting of fluorine, chlorine, bromine, CN, OH, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) fluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, ( C 1 -C ₄ ) alkoxy, amino, (C 1 -C ₄ ) alkyl-NH-, [(C 1 -C ₄ ) alkyl] ₂ -N- and (C ₃ -C ₈ ) cycloalkyloxy groups, wherein (C ₃ - C ₈ ) cycloalkyl and (C 1 -C 10) heterocyclyl are also optionally substituted with oxo, wherein (C 1 -C ₁₀ ) heteroaryl and (C 1 -C ₁₀ ) heterocyclyl are optionally substituted on any ring nitrogen atom capable of carrying an additional substituent, 1 or two substituents per ring independently selected from the group consisting of (C _x -C ₄₎ alkyl, and -S (C ₃ -C ₄ ) alkyl- (C = O) -.

In another embodiment, G is a group

R ¹⁵ - (CR ¹⁶ R ¹⁷⁾ _p -; wherein p is 1; R ¹⁵ is (R ¹⁹ R ²⁰ ) N-; each of R ¹⁶ or R ¹⁷ is independently hydrogen; and each R ¹⁹ and R ²⁰ is hydrogen or (C 1 -C 10) heteroaryl, such as 2-oxazolyl, 2-pyrazolyl or 3-pyrazolyl.

In another embodiment, G is a group

R ¹⁵ - (CR ¹⁶ R ¹⁷⁾ _p -; wherein p is 1; R ¹⁵ is (R ¹⁹ R ²⁰ ) N- (C = O) - (NR ²¹ ) -; each of R ¹⁶ or R ¹⁷ is independently hydrogen; each of R ¹⁹ and R ²⁰ represents a (C 1 -C 4) alkyl group and are taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered ring; and R ²³ is selected from the group consisting of hydrogen and (C 1 -C 4) alkyl.

In another embodiment, G is a group

R ¹⁵ - (CR ¹⁶ R ¹⁷⁾ p; wherein p is 1; R ¹⁵ is R ²² -O- (C = O) - (NR ²¹ ) -; each of R ¹⁶ or R ¹⁷ independently represents hydrogen; R ²¹ is selected from the group consisting of hydrogen and (C 1 -C ₄ ) alkyl; and R ²² is selected from the group consisting of (C ₁ -C ₄ ) alkyl and (C ₃ -C ₈ ) cycloalkyl such as methyl, ethyl, propyl, butyl or cyclobutyl.

In another embodiment, G is a group

R ¹⁵ - (CR ¹⁶ R ¹⁷⁾ p; wherein p is 1; R ¹⁵ is s R ¹⁹ - (C = O) - (NR ²¹ ); each of R ¹⁶ and R ¹⁷ is independently hydrogen or (C _x -C ₄₎ alkyl; R ¹⁹ and R ²¹ are taken together with the carbon or nitrogen atom to which they are attached to form a 3- to 8-membered heterocyclic ring.

In another embodiment, G is a group

R ¹⁵ - (CR ¹⁶ R ¹⁷⁾ _p -; wherein p is 1; R ¹⁵ is (R ¹⁹ R ²⁰ ) N- (C = O) - (NR ²¹ ); each of R ¹⁶ and R ¹⁷ is independently hydrogen or (C _x -C ₄₎ alkyl; R ¹⁹ and R ²¹ are taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocyclic ring.

In another embodiment, G is a group

R ¹⁵ - (CR ^{1 S} R ¹⁷⁾ _p -; wherein p is 1, R ¹⁵ is R ²² -O- (C = O) - (NR ²¹ ) -; each of R ¹⁶ and R ¹⁷ is independently hydrogen or (C _x -C ₄₎ alkyl; R ²¹ and R ²² are taken together with the nitrogen or oxygen atom to which they are attached to form a 3- to 8-membered heterocyclic ring.

In another embodiment, G is a group

R ¹⁵ - (CR ¹⁷ R ^s) p; wherein p is 1 to 4, preferably 1; R ¹⁵ is selected from the group consisting of halogen, -CN, and R ¹⁸ ; each of R ¹⁶ and R ¹⁷ is independently hydrogen or (C 1 -C 4) alkyl; R ¹⁸ is selected from the group consisting of hydrogen, _(C-C4) alkyl, (C ₆ -C _X0) -aryl, (C ₃ -C ₈₎ cycloalkyl, (C _x C _{x 0)} heteroaryl, and (Ci-Cio heterocyclyl; wherein the (C ₆ -C _X0) aryl, (C ₃ -C ₈₎ cycloalkyl, (C ₁ -C ₁₀₎ heteroaryl and (C1 -C10) heterocyclyl may optionally be substituted on any of the ring carbon atoms capable of form an additional bond, 1 to 3 ring substituents independently selected from the group consisting of fluorine, chlorine, bromine, CN, OH, (C 1 -C 4) alkyl, (C 1 -C 4) perfluoroalkyl, (C 1 -C 4) perfluoroalkoxy, (0 ₃ -C ₄₎ alkoxy are buying ins, amino, (C 1 -C 4) alkyl-NH-, [(C 1 -C 4) alkyl] ₂ N-, and (C ₃ -C ₀₎ cycloalkyloxy; wherein (C ₃ -C ₈ ) cycloalkyl and (C 1 -C 10) heterocyclyl are also optionally substituted by oxo; wherein the (C 1 -C 10) heteroaryl and (C 1 -C 3) heterocyclyl groups are optionally substituted on any ring nitrogen atom capable of carrying an additional substituent with 1 or 2 ring substituents independently selected from the group consisting of (C 1 -C 4) alkyl and (C1-C4) -alkyl (C = O) -.

In another embodiment of the present invention G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; wherein p is 1 to 4, preferably 1; R ¹⁵ is selected from the group consisting of R ¹⁸ ; R ¹⁶ and R ¹⁷ are each independently hydrogen or (C 1 -C 4) alkyl; wherein R ¹⁸ is selected from the group consisting of hydrogen and (C 1 -C 4) alkyl.

In another embodiment, G is a group

R ¹⁵ - (CR ¹⁶ R ¹⁷⁾ p; wherein p is 1 to 4, preferably 1; R ¹⁵ is selected from the group consisting of (R ¹⁹ R ²⁰ ) N-, (R ¹⁹ R ²⁰ ) N- (C = O), (R ¹⁹ R ²⁰ ) N- (SO 2); (R ¹⁹ R ²⁰ ) N- (C = O) - (NR ²¹ ) - and (R ¹⁹ R ²⁰ ) N- (C = O) -O; each of R ¹⁶ and R ¹⁷ is independently hydrogen or (C _x -C 4) alkyl group; and R ¹⁹ and R ²⁰ are taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocyclic ring.

In another embodiment, G is R ¹⁵ - (CR ^{1 S} R ¹⁷⁾ _p -; wherein p is 1 to 4, preferably 1;

, 19

R ¹⁵ is selected from the group consisting of R ^{i and} - (C = 0) - (NR

21 \ (R ¹⁹ R ²⁰ ) n - (C = O) - (NR ²¹ ),

-NR ¹⁹ R ²⁰

21 '(R ¹⁹ R ²⁰ ) N- (C = O) - (NR ²¹ ) -;

R ²² (S-O) -; R ²² (SO 2) - (NR ²¹ ) R-O- (C-O) - (NR ¹ ) - and (RR) N- (C = O) -O-; R ¹⁶ and R ¹⁷ are each independently hydrogen or (C 1 -C 4) -alkyl; each of R ¹⁹ , R ²⁰ and R ²¹ is independently selected from the group consisting of hydrogen, (C 1 -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₈ ) heteroaryl and (C 1 -C 10) heterocyclyl; wherein the (C ₆ -C ₁₀ ) aryl-, (C ₃ -C ₈ ) cycloalkyl-, (-χ-ϋχ ₀ ) heteroaryl- and (C 1 -C ₁₀ ) heterocyclyl group is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by 1-3 substituents independently selected from F, Cl, Br, CN, OH, _(Ci-C4) alkyl, (C _x -C ₄₎ luóralkylskupiny perf, _(Ci-C4) perfluoroalkoxy, ( Ci-C ₄₎ alkoxy, amino, _(Ci-C4) alkyl-NH-, [(C _{x C4)} alkyl] 2 -N- and (C ₃ -C ₈₎ cycloalkyl-alkyloxy; wherein (C ₃ -C ₈ ) cycloalkyl and (C 1 -C 10) -heterocyclyl are also optionally substituted with oxo; wherein the (Ci-Cio) heteroaryl and (C-exo) heterocyclyl may optionally be substituted on any ring nitrogen atom able to support an additional substituent by one or two substituents per ring independently selected from the group consisting of (C _x -C ₄₎ alkyl; and (C 1 -C ₄ ) alkyl (C = O) -; and R ²² is selected from the group consisting of (C 1 -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C 1 -C 10) heteroaryl and (C 1 -C ₁₀ ) heterocyclyl; wherein (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₆ ) heteroaryl and (C ₆ -C ₁₀ ) heterocyclyl are optionally substituted on any of the ring carbon atoms capable of forming an additional bond, 1 to 3 substituents independently selected from F, Cl, Br, CN, OH, (C _x -C ₄₎ alkyl, (C3.-C4) luóralkylskupiny perf, (C _x -C ₄₎ perfluoroalkoxy, (C1 -C4) alkoxy, amino, (C _{x C4)} alkyl-NH-, [(C 1 -C 4) alkyl] ₂ N-, and (C ₃ -C _B) cycloalkyloxy; wherein (C ₃ -C ₈ ) cycloalkyl and (C 1 -C 10) heterocyclyl are also optionally substituted by oxo; wherein the (C 1 -C 10) heteroaryl and the (C 1 -C 10) heterocyclyl group is optionally substituted on any ring nitrogen atom capable of carrying an additional substituent with 1 or 2 ring substituents independently selected from the group consisting of (C _x -C ₄ ) alkyl and (C _x -C ₄₎ alkyl (C = O) -.

In another embodiment of the present invention, G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) p -; wherein p is 1 to 4, preferably 1; R ¹⁵ is selected from the group consisting of R ¹⁹ - (C = O) - (NR ²¹ ) -, R ¹⁹ -O- (C = O) - (NR ²¹ ) - and (R ¹⁹ R ²⁰ ) N- ( C = O) - (NR ²¹ ); each of R ^s and R ¹⁷ is independently hydrogen or _(C-C4) alkyl; R ¹⁹ and R ²¹ are taken together with the nitrogen, carbon or oxygen atom to which they are attached to form a 3- to 8-membered heterocyclic ring.

In another embodiment of the present invention, G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _P -; wherein p is 0; and G is oriented at a position different from the alpha position with respect to the point of attachment of the Z ring to the remainder of Y.

In another embodiment of the present invention G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; wherein p is 0; and G is oriented at the meta position with respect to the point of attachment of the Z ring to the remainder of Y.

In another embodiment of the present invention G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; wherein p is 1 to 4, preferably 1; and

G is oriented at a position different from the alpha position with respect to the point of attachment of the Z ring to the remainder of Y.

In another embodiment of the present invention, G is R ¹⁵ - (CR ^S R ¹⁷ ) _p -; wherein p is 1 to 4, preferably 1; and G is oriented at the meta position relative to the point of attachment of the Z ring to the remainder of Y.

In another preferred embodiment of the invention, one or two of R ¹ , R ² , R ³ , R ⁴ , R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are} different from hydrogen.

In a more preferred embodiment of the invention each of R ¹ , R ² ,

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ represent hydrogen.

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

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

In another preferred embodiment of the present invention G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; wherein p is 0; R ¹⁵ is selected from the group consisting of halogen, -CN and (C 1 -C ₁₀ ) heteroaryl. More preferably, R ¹⁵ is bromo, fluoro, -CN, or oxadiazolyl, preferably [1,3,4] oxadiazol-2-yl.

In another preferred embodiment of the present invention, G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) p -; wherein p is 0 or 1; R ¹⁵ is R ¹⁸ ; each of R ¹⁶ and R ¹⁷ represents hydrogen; and R ¹⁸ is independently hydrogen or (C 1 -C 4) alkyl; preferably methyl.

Another preferred embodiment of the invention, G is R ^{1 S} - (CR ^s R ¹⁷⁾ _p -; wherein p is 0 or 1; wherein G is oriented in the para position relative to the point of attachment of the ring Z to the remainder Y.

In another preferred embodiment of the present invention, G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; wherein p is 1; R ¹⁵ is R ¹⁹ - (C = O) - (NR ²¹ ) -; each of R ¹⁶ or R ¹⁷ is independently hydrogen; R ¹⁹ is (C 1 -C ₄ ) alkyl, more preferably methyl, ethyl or butyl; or (C ₃ -C ₈ ) cycloalkyl, more preferably cyclobutyl; and R ²¹ represents hydrogen.

Another preferred embodiment of the invention, G is R ¹⁵ - (CR ^{1 S} R ¹⁷⁾ _p -; wherein p is 1; R ¹⁵ is (C 1 -C 10) heteroaryl, such as 2-pyrazolyl; and each of R ¹⁶ and R ¹⁷ is independently hydrogen.

In another preferred embodiment of the invention, the heterocyclic ring A corresponds to the general formula a) or b)

wherein X is (C 1 -C ₁₀ ) heteroaryl selected from the group consisting of pyrazinyl-, pyridazinyl-, pyridyl- and pyrimidinyl; more preferably X is pyridinyl; and Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - and -CH ₂ O-;

more preferably Y is oxygen, -OCH ₂ - -CH ₂ O-; and most preferably Y represents oxygen.

Other preferred compounds of the invention include those compounds of formula I wherein the heterocyclic ring A is of formula (a) or (b) as defined above; X is (C 1 -C ₁₀ ) heteroaryl selected from the group consisting of pyrazinyl-, pyridazinyl-, pyridyl- and pyrimidinyl; more preferably X is pyridinyl; in the most preferred embodiment, the pyridinyl group together with the ring A and the YZG group corresponds

wherein Y represents a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ ,

-OCH ₂ - or -CH ₂ O-; preferably Y represents oxygen, -OCH ₂ or -CH ₂ O-; more preferably Y is oxygen.

Other preferred compounds of the invention include those compounds of formula I wherein the heterocyclic ring A is of formula (a) or (b) as defined above; X is pyridinyl, most preferably pyridinyl together with ring A and YZG corresponds to the general formula above; Y is (C ₆ -C ₁₀ ) aryl, preferably R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; where

(a) or (b) oxygen; Z phenyl; represent defined as represent number 1;

R ¹ is (C 1 -C ₁₀ ) heteroaryl, such as 2-pyrazolyl; each of R ¹⁶ and R ¹⁷ is independently hydrogen or (C 1 -C ₄ ) alkyl, such as methyl, preferably hydrogen; and G is oriented at the para position with respect to the point of attachment of the ring Z to the remainder Y.

Most preferred compounds of the invention are those compounds of formula I wherein the heterocyclic ring A corresponds to formula a) or b) as defined above; X is pyridinyl, most preferably pyridinyl together with ring A and YZG corresponds to the general formula a) or b) as defined above; Y represents oxygen; Z is (C ₆ -C ₁₀ ) aryl, preferably phenyl; G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; wherein p is 0; R ¹⁵ is selected from the group consisting of hydrogen, -CN, halogen, and oxadiazolyl; and G is oriented at the para position with respect to the point of attachment of the ring Z to the remainder Y.

Other most preferred compounds of the invention include those compounds of formula I wherein the heterocyclic ring A is of formula (a) or (b) as defined above; X is pyridinyl, most preferably pyridinyl together with ring A and YZG corresponds to the general formula a) or b) as defined above; Y represents oxygen; Z is (C ₆ -C ₁₀₎ aryl, preferably phenyl; G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) P -; wherein p is 1; R ¹⁵ is R ¹⁹ - (C = O) - (NR ²¹ ) -; R ¹⁶ and R ¹⁷ are each independently hydrogen; R ¹⁹ is selected from the group consisting of (C 1 -C 4) alkyl and (C ₃ -C ₈ ) cycloalkyl such as methyl, ethyl, propyl, butyl or cyclobutyl; R ²¹ is selected from the group consisting of hydrogen and (C 1 -C ₄ ) alkyl; and G is oriented at the para position with respect to the point of attachment of the ring Z to the remainder 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-triazaspiro [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-tetraazaspiro [4.5] decane-2,6,8, 10-tetraone;

1- [6- (4- [1,3,4] Oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,3,8,10-tetraazaspiro [5.5] undecane-2,7,9, 11-tetraone;

- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,1-dioxo-η ⁶ -thia-2,4,7,9-tetraazaspiro [4, 5] decane-3,6,8,10-tetraone;

1- [6- (4- [1,3,4] Oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraazaspiro [4.5] decane-2,4,6, 8,10-pentaónu;

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -2,2-dioxo-2k ^6- thia-1,7,9-triazaspiro [4.5] ] decane-6,8,10-trione;

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] ^{-2,2-dioxo-2H-6-thia} l, 8,10-triazaspiro [5.5 ] undecane-7,9,11-trione;

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-6,8,10-trione;

1- [6- (4-Cyclobutylmethoxymethyl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone;

1- {6- [4- (2-oxo-pyrrolidin-l-ylmethyl) phenoxy] pyridin-3-yl} -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone;

1- [6- (1H-Indazol-5-yloxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone;

1- [6- (4-Fluorophenoxy) pyridin-3-yl] -3-methyl-1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone;

1- [6- (3-Fluorophenoxy) pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone;

4- [5- (2,7,9,11-tetraoxo-l, 8,10-triaza-spiro [5.5] undec-1-yl) -pyridin-2-yloxy] -benzonitrile;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,8,10-triazaspiro [5.5] undecane-2,7,9,11-tetraone;

N- {4- [5- (2,7,9,11-tetraoxo-1,8,10,10-triazaspiro [5.5] undec-1-yl) -pyridin-2-yloxy] -benzyl} -acetamide;

Azetidine-1-carboxylic acid 4- [5- (2,7,9,11-tetraoxo-1,8,10,10-triazaspiro [5,5] undec-1-yl) -pyridin-2-yloxy] -benzylamide;

1- [6- (4-pyrazol-l-ylmethyl-phenoxy) -pyridin-3-yl] -1,8,10-triazaspiro [5.5] undecane-2,7,9,11-tetraone;

1- [6- (4-Fluorophenoxy) pyridin-3-yl] -1,8,10-triazaspiro [5.5] undecane-2,7,9,11-tetraone;

1- [6- (4-fluorophenoxy) pyridin-3-yl] -1,3,7,9-tetraazaspiro [4.5] decane-2,6,8,10-tetraone;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraazaspiro [4.5] decane-2,6,8,10-tetraone;

- [5- (2,6,8,10-Tetraoxo-1,3,7,9-tetraazaspiro [4,5] dec-1-yl) pyridin-2-yloxy] benzonitrile;

N- {4- [5- (2,6,8,10-tetraoxo-1,3,7,9-tetraazaspiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} -acetamide;

Azetidine-1-carboxylic acid [5- (2,6,8,10-tetraoxo-1,3,7,9-tetraazaspiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzylamide;

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraazaspiro [4.5] decane-2,6,8,10-tetraone;

1- [6- (4-fluorophenoxy) pyridin-3-yl] -1,3,8,10-tetraazaspiro [5.5] undecane-2,7,9,11-tetraone;

1- [6- (4-ethylphenoxy) pyridin-3-yl] -1,3,8,10-tetraazaspiro [5.5] undecane-2,7,9,11-tetraone;

4- [5- (2,7,9,11-tetraoxo-1,3,8,10-tetraazaspiro [5.5] undec-1-yl) pyridin-2-yloxy] benzonitrile;

N- {4- [5- (2,7,9,11-tetraoxo-l, 3,8,10-tetraazaspiro [5.5] undec-l-yl) pyridin-2-yloxy] benzyljacetamidu;

Azetidine-1-carboxylic acid 4- [5- (2,7,9,11-tetraoxo-1,3,8,10-tetraazaspiro [5,5] undec-1-yl) -pyridin-2-yloxy] -benzylamide;

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,3,8,10-tetraazaspiro [5.5] undecane-2,7,9,11-tetraone;

4- [6- (4-fluorophenoxy) pyridin-3-yl] -1,1-dioxo-1X ⁶ -thia-2,4,7,9-tetraazaspiro [4,5] decane-3,6,8, 10-tetraone;

4- [6- (4-ethylphenoxy) pyridin-3-yl] -1,1-dioxo-1k ^6- thia-2,4,7,9-tetraazaspiro [4,5] decane-3,6,8, 10-tetraone;

- [5- (1,1,3,6,8,10-hexaoxo-1X ⁶ -thia-2,4,7,9-tetraazaspiro [4,5] dec-4-yl) pyridin-2-yloxy] benzonitrile;

N- {4- [5- (1,1,3,6,8,10-hexaoxo-1k ^6- thia-2,4,7,9-tetraazaspiro [4,5] dec-4-yl) pyridine- 2-yloxy] -benzyl} -acetamide;

- [5- (1,1,3,6,8,10-hexaoxo-1X ^with -thia-2,4,7,9-tetraazaspiro [4,5] dec-4-yl) pyridin-2-yloxy] azetidine-1-carboxylic acid benzylamide;

1,1-dioxo-4- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1X- ^6- thia-2,4,7,9-tetraazaspiro [4,5] decane-3, 6,8,10-tetraone;

1- [6- (4-Fluorophenoxy) pyridin-3-yl] -1,3,7,9-tetraazaspiro [4.5] decane-2,4,6,8,10-pentaone;

- [5- (2,4,6,8,10-Pentaoxo-1,3,7,9-tetraazaspiro [4,5] dec-1)

-yl) pyridin-2-yloxy] benzonitrile, 47

6- {4- [5- (2,4,6,8,10-Pentaoxo-1,3,7,9-tetraazaspiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl Jacetamide;

Azetidine-1-carboxylic acid 4- [5- (2,4,6,8,10-pentaoxo-1,3,7,9-tetrazaspiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzylamide acid;

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraazaspiro [4.5] decane-2,4,6,8,10-pentaone;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraazaspiro [4.5] decane-2,4,6,8,10-pentaone;

1- [6- (4-fluorophenoxy) pyridin-3-yl] -2,2-άίοχο 2λ ^{6-thia-1,7,9-triaza-spiro} [4.5] decane-6,8,10-trione;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -2,2-dioxo-2Z ⁶ -thia-1,7,9-triazaspiro [4.5] decane-6,8,10-trione;

- [5 - ^{(2,2,6,8,10-pentaoxo-2H-6-thia} l, 7,9-triazaspiro [4.5] dec-l-yl) -pyridin-2-yloxy] -benzonitrile;

N- {4 - [5 - ^{(2,2,6,8,10-pentaoxo-2H-6-thia} l, 7,9-triazaspiro [4.5] dec-l-yl) -pyridin-2-yloxy] benzylJacetamidu;

- [5 - (2,2,6,8,10-pentaoxo-2 H ^p-thia-l, 7,9 - triazaspiro [4.5] dec-l-yl) -pyridin-2-yloxy] benzyl azetidine-l-carboxylate acid;

2,2-dioxo-l- [6- (4-pyrazol-l-ylmethyl-phenoxy) -pyridin-3-yl] -2λ ^6-thia-l, 7,9-trizaspiro _[4; 5] decane-6,8,10-trione;

1- [6- (4-Fluorophenoxy) pyridin-3-yl] -2,2-dioxo-2k ^6- thia-1,8,10-triazaspiro [5.5] undecane-7,9,11-trione;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -2,2-dioxo-2X- ^6- thia-1,8,10-triazaspiro [5,5] undecane-7,9,11-trione;

4- [5- (2,2,7,9, ^{ll-pentaoxo-2H-6-thia-1,8,10} triazaspiro [5.5] undec-l-yl) -pyridin-2-yloxy] -benzonitrile;

N- {4- [5- (2,2,7,9,11-Pentaoxo-2k ^with -thia-1,8,10-triazaspiro [5,5] undec-1-yl) pyridin-2-yloxy] benzyl} acetamide;

Azetidine-1-carboxylic acid - [5- (2,2,7,9,11-pentaoxo-2k ^with -thia-1,8,10,10-triazaspiro [5.5] undec-1-yl) -pyridin-2-yloxy] -benzylamide acid;

2,2-dioxo-l- [6- (4-pyrazol-l-ylmethyl-phenoxy) -pyridin-3-yl] 2L ^6-thia-l, 8,10-triazaspiro [5.5] undecane-7,9, 11-trione;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-6,8,10-trione;

1- [6- (4-Fluorophenoxy) pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-6,8,10-trione;

4- [5- (6,8,10-trioxa-l, 7,9-triazaspiro [4.5] dec-l-yl) -pyridin-2-yloxy] -benzonitrile;

N- {4- [5- (6,8,10-trioxo-l, 7,9-triazaspiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} -acetamide;

Azetidine-1-carboxylic acid [5- (6,8,10-trioxo-1,7,9-triazaspiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzylamide;

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-6,8,10-trione;

1- [6- (3-fluoro-4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,8,10-triazaspiro [5.5] undecane-2,7, 9,11-tetraone;

1- [6- (2-Fluoro-4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,8,10-triazaspiro [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-triazaspiro [5.5] undecane-2,7, 9,11-tetraone;

1- [4- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -phenyl] -1,8,10-tri azaspiro [5,5] undecane-2,7,9,11-tetraone;

1- [6- (pyridin-4-yloxy) pyridin-3-yl] -1,8,10-triazaspiro [5.5] undecane-2,7,9,11-tetraone;

1- [5- (pyridin-4-yloxy) pyridin-2-yl] -1,8,10-triazaspiro [5.5] undecane-2,7,9,11-tetraone;

1- [4- (pyridin-4-yloxy) phenyl] -1,8,10-triazaspiro [5.5] undecane-2,7,9,11-tetraone;

1- [4- (pyridin-4-yloxy) phenyl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone;

Azetidine-1-carboxylic acid 4- [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzylamide; and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula I are selected from the group consisting of

1- [6- (4-Fluorophenoxy) pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone;

1- [6- (4-Fluorophenoxy) pyridin-3-yl] -1,8,10-triazaspiro [5.5] undecane-2,7,9,11-tetraone;

4- [5- (2,6,8,10-tetraoxo-l, 7,9-triazaspiro [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-triazaspiro [4.5] decane-2,6,8,10- tetraone;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone;

N- {4- [5- (2,6,8,10-tetraoxo-l, 7,9-triazaspiro [4.5] dec-1-yl) pyridin-2-yloxy] -benzyl} -acetamide;

N- {4- [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzyl} -propionamide;

N- {4- [5- (2,6,8,10-tetraoxo-l, 7,9-triazaspiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} butyramide;

Pentanoic acid 4- [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzylamide;

Cyclobutanecarboxylic acid [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzylamide;

1- [6- (4-bromo-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone;

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone;

and pharmaceutically acceptable salts thereof.

The present invention also provides a pharmaceutical composition for treating conditions selected from the group consisting of connective tissue disorders, inflammatory disorders, immune / allergic disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system (CNS) disorders, diseases liver / kidney, reproductive disorders, stomach disorders, skin disorders and cancer and other diseases characterized by metalloproteinase activity in mammals, including humans, comprising a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective to such treatment, and a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for inhibiting matrix metalloproteinases or other metalloproteinases involved in matrix degradation in a mammal, including a human, comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount effective in such treatment.

The invention further provides a method of treating conditions selected from the group consisting of connective tissue disorders, inflammatory disorders, immune / allergic disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system (CNS) disorders, liver / kidney, reproductive disorders, stomach disorders, skin disorders and cancer, and other diseases characterized by metalloproteinase activity in a mammal, including a human, comprising administering to the mammal a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective at treating such a condition.

The invention also provides a method of inhibiting matrix metalloproteinases or other metalloproteinases involved in matrix degradation in a mammal, including a human, comprising administering to the mammal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The inventors have also found that it is possible to identify inhibitors of the general formula I having different activity on metalloproteinases (preferably with MMP13 inhibitory activity). The inventors have been able to identify one group of preferred inhibitors that selectively inhibit MMP-13 over MMP-1. The compounds of the invention also show selectivity to a related group of enzymes known as reprolysins such as TACE and aggrecanase. The inventors have identified another group of preferred inhibitors of formula I that selectively inhibit MMP-13 preferentially over MMP-1 and MMP-14, and another group of inhibitors of formula I that selectively inhibit MMP-13 preferentially over MMP-1 and 12. As another preferred group identified by the inventors include inhibitors of Formula I that selectively inhibit

MMP-13 preferably over MMP-1, 12 and 14. Another group identified by the inventors is preferred inhibitors of formula I that selectively inhibit MMP-13 over MMP-1, 2, 3, 7, 9 and 14. Most preferred compounds of the invention selectively inhibit MMP-13 preferably over MMP-1, 2, 3, 7, 9, 12 and 14 and mammalian reprolysins.

The term treatment as used herein refers to reverting, ameliorating, arresting the progression or preventing a disorder or condition to which the term treatment refers, or one or more symptoms of such disorder or condition.

Connective tissue disorders as used herein are disorders such as degenerative cartilage loss following traumatic joint damage, osteoarthritis, osteoporosis, Paget's disease, artificial joint implant release, periodontal disease, and gingivitis.

As used herein, articular cartilage destruction refers to connective tissue disorders that result in cartilage destruction, preferably joint damage, reactive arthritis, acute pyrophosphate arthritis (pseudoderma), psoriatic arthritis or juvenile rheumatoid arthritis, more preferably.

Inflammatory disorders as used herein include disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriatic chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease and cachexia.

Immune / allergic disorders as used herein are disorders such as organ transplant toxicity, allergic reactions, allergic contact hypersensitivity, autoimmune disorders such as disorders associated with granulomatous inflammation / tissue remodeling (such as asthma), immunosuppression, and sarcoid.

Infectious diseases are diseases in which viral, bacterial, fungal or mycobacterial infections are involved, such as septic arthritis, AIDS, fever, prion diseases, myasthenia gravis, malaria, sepsis, hemodynamic shock and septic shock.

As used herein, respiratory diseases include disorders such as chronic obstructive pulmonary disease (such as emphysema), acute respiratory distress syndrome, asthma, hyperoxic alveolar damage, and idiopathic pulmonary fibrosis and other fibrotic lung diseases.

As used herein, cardiovascular diseases are disorders such as atherosclerosis, such as atherosclerotic plaque rupture; aortic aneurysm such as abdominal aortic aneurysm and cerebral aortic aneurysm; congestive heart failure; myocardial infarction and cerebral infarction; stroke; cerebral ischemia; coagulation and response in the acute phase; dilatation of the left ventricular; postischemic reperfusion injury; angiofibroma; hemangiomas and restenosis.

Eye diseases as used herein include disorders such as aberrant angiogenesis, ocular angiogenesis, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, eye tumors, corneal graft rejection, corneal damage, neovascular glaucoma, corneal degeneration, corneal degeneration, corneal ulceration, corneal ulceration, corneal ulceration, such as age-related macular degeneration, wet and dry form), proliferative vitreoretinopathy and retinopathy of prematurity.

Metabolic diseases as used herein are disorders such as diabetes (such as non-insulin dependent diabetes mellitus, diabetic retinopathy, insulin resistance, diabetic ulcerations).

Central nervous system disorders as used herein include disorders such as head trauma, spinal cord injury, inflammatory diseases of the central nervous system, neurodegenerative disorders (acute and chronic), Alhzeimer disease, demyelinating disorders of the nervous system, Huntington's disease, Parkinson's disease, peripheral neuropathy pain, cerebral amyloid angiopathy, nootropic and cognitive disorders, amyotrophic lateral sclerosis, multiple sclerosis, migraine, depression and anorexia.

As used herein, liver / kidney diseases are disorders such as nephrotic syndromes such as glomerulonephritis and glomerular kidney disease, proteinuria, liver cirrhosis and interstitial nephritis.

Reproductive disorders as used herein are conditions such as endometriosis; contraceptive conditions (for men / women); dysmenorrhea; uterine dysfunctional bleeding; premature rupture of the amniotic sac and conditions in which the abortion is administered.

As used herein, gastric disorders are disorders such as anastomosis of the colon and gastric ulcers.

Skin disorders as used herein are disorders such as skin aging, bed sores, psoriasis, eczema, dermatitis, radiation damage, tissue ulceration, decubitus ulcers, epidermolysis bullosis, abnormal wound healing (topical and oral formulations), burns and scleritis.

The term cancer as used herein refers to disorders such as solid tumor cancer, colon cancer, breast cancer, lung cancer and prostate cancer, tumor invasion, tumor growth, tumor metastasis, oral cavity and pharynx cancer (feathers, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary tract, pancreas, larynx, lungs, bones, connective tissues, skin, cervix, endometrium, ovaries, male genital organs, bladder, bladder and other tissues of the urinary tract, eye, brain and central nervous system, thyroid and other endocrine glands, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, and hematopoietic malignancies such as leukemia and lymphomas such as lymphocyte, granulocyte and monocyte.

Also included within the scope of the invention are isotope-labeled compounds that are identical to those of Formula I except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found therein. in nature. Examples of isotopes that can be incorporated into the novel intermediates of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, 15n, 180, 17Oz ³¹ P, ³² P, 35p, 18p _and 36qj. Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of such compounds or prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are also within the scope of this invention. Certain isotopically-labeled compounds of the invention, for example, compounds labeled with radioactive isotopes such as ³ H or ¹⁴ C, are useful in drug or substrate tissue distribution assays. Particular preference is given to tritiated isotopes, i.e., 3?, And isotopes, since they can be readily prepared and detected. By replacing it with heavier isotopes than deuterium, it is possible to achieve certain therapeutic advantages resulting from higher metabolic stability, for example, an increase in half-life in vivo or a reduction in the necessary doses, which is preferred in certain circumstances. Isotopically-labeled compounds of Formula I of the present invention and prodrugs thereof can usually be prepared by carrying out the methods illustrated in the schemes and / or described in the Examples or Preparative Procedures, in which a non-isotopically labeled reagent is replaced by a readily available isotope-labeled reagent.

The present invention also provides pharmaceutical compositions comprising prodrugs of the compounds of Formula I. The invention also provides methods of treating or preventing diseases that can be treated or prevented by inhibiting matrix metalloproteinases or by inhibiting mammalian reprolysin, which comprises administering prodrugs of compounds of Formula I. Compounds of formula I which contain free amino, amido, hydroxy or carboxy groups can be converted into prodrugs. Prodrugs include compounds in which a free amino, hydroxy or carboxy group of a compound of Formula I is covalently, via a peptide bond, linked to an amino acid residue or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues. Amino acid residues include 20 natural amino acids, which are commonly referred to by the three-letter code, and 4-hydroxyproline, hydroxylysine, detnosine, isodemosine, 3-methylhistidine, norvaline, betalanine, gamma-amino-butyric acid, citrulline, homocysteine, homoserine, or homoserine. sulfone. Prodrugs also include compounds wherein carbonate, carbamate, amide, and alkyl ester groups are attached via the carbonyl carbon of the prodrug side chain to the above substituents of the compound of Formula I. Prodrugs also include dimers of compounds of Formula I.

Those skilled in the art will recognize that the compounds of the invention are useful in the treatment of a variety of diseases and that in the treatment of particular diseases, the compounds of the invention may be combined with various existing therapeutic agents that are useful in their treatment.

In the treatment of rheumatoid arthritis, the compounds of the invention may be combined with agents such as TNF-α inhibitors such as anti-TNF monoclonal antibodies (such as imfliximab, D2E7 and CDP-870) and TNF receptor immunoglobulin molecules (such as etanercept), inhibitors ICE, MEKK1 inhibitors, COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib and etoricoxib; low dose methotrexate, lefunimide, steroids, glucosamines, chondrosamines / sulphates, gabapentin, A-agonists, IL-1 processing and release inhibitors, IL-1 receptor antagonists such as Kineret®, CCR-1 antagonists, hydroxychloroquine, d-penicillamine auranofin or parenteral or oral gold.

The compounds of the invention may also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents for this combination include standard nonsteroidal anti-inflammatory agents (NSAIDs) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, phenoprofen, ketoprofen and ibuprofen, phenamates such as acid, indomethacin, sulindac, apazone, apazone, apazone, apazone, apazone, apazone, apazone, apazone. salicylates such as aspirin, COX-2, such as celecoxib, valdecoxib, paracoxib, and rofecoxib, analgesics, chondrosamines / sulphates, gabapentin, IL-1 processing and release, CCR-1 antagonists, inhibitors

LTD-4, LTB-4 and 5-LO, p38 kinase inhibitors and intra-articular therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc.

mefenam pyrazolones, etoricoxib steroid inhibitors, glucosamines, A-agonists, inhibitors

Further, the compounds of the invention may be used in combination with anti-cancer agents such as endostatin and angiostatin, or cytotoxic drugs such as adriamycin, daunomycin, cisplatin, etoposide, paclitaxel, docetaxel, and alkaloids such as vincristine, and antimetabolites such as methotrexate.

The compounds of the invention may also be used in combination with cardiovascular agents such as calcium channel blockers (such as amlodipine and nifedipine), lipid lowering agents such as statins (such as lovastatin, atorvastatin, pravastatin and simvastatin), adrenergic agents such as doxazosin and terazos; fibrates, beta-blockers, Ace inhibitors (such as captopril, lisinopril, fosinopril, enalapril and quinapril), angiotensin-2 receptor antagonists (such as losartan and irbesartan), nitrates, CCB, diuretics such as digitalis, and platelet aggregation inhibitors. The compounds of the invention may also be combined with plaque rupture blocking agents such as statins, zithromax, NSAIDs such as aspirin, heparin, urarfarin, abciximab, TPA, and platelet inhibitors. The compounds of the invention may also be used in combination with agents for treating stroke, such as NIF, HNEI and CCRIR antagonists.

The compounds of the invention may also be combined with CNS agents such as antidepressants (such as sertraline), antiparkinsonian drugs (such as deprenyl, carbadopa, L-dopa, dopamine receptor agonists such as ropinirole, pergolide and pramipexole; MAOB inhibitors such as selegine and rasagiline, inhibitors catechol-O-methyltransferases such as tolcapone, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, NK-1 inhibitors, dopamine agonists and neuronal nitric oxide synthesis inhibitors) and anti-Alzheimer drugs such as donepezil, tacrine, -2, propentophyllin or metryphonate.

Combinations of the compounds of the invention with anti-osteoporosis agents such as roloxifene, droloxifene, lasofoxifene or fosomax and immunosuppressants such as FK-506 and rapamycin are also contemplated.

The compounds of the invention may also be used in combination with agents for treating respiratory diseases such as PDE-IV inhibitors, steroids such as fluticasone, triamcinolone, budesonide, budesonide and beclometasone, anticholinergics such as ipratropium, sympathomimetics such as salmeterol xopenex, by decongestants such as fexofenadine, loratadine and cetirizine; leukotriene antagonists such as zafirlukast and motelukast; and mast cell stabilizers such as zileutone.

The compounds of the invention may also be used in combination with agents for treating skin disorders such as tretinoin, isotretinoin, steroids such as cortisone and mometasone, antibiotics such as tetracycline, antifungal agents such as clotrimazole, miconazole and fluconazole and PDE-IV inhibitors.

The compounds of the invention may also be used in combination with agents for the treatment of diabetes, such as insulin, such as human or humanized insulin and inhaled insulin, aldose reductase inhibitors, sorbitol dehydrogenase inhibitors, antidiabetic agents such as biguanides such as metformin; glitazones, glycosidase inhibitors such as acarbose, sulfonylureas such as glimepiride and glipizide; and thiazolidinediones such as pioglitazone, rosiglitazone and troglitazone. Preferred combinations are useful in the treatment of side effects of diabetes such as retinopathy, nephropathy and neuropathy, preferably retinopathy.

The following is a more detailed description of the invention.

Preparation of the following G, R ¹ , R ² , R ³ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R discussions are different.

The compounds of the invention are shown in the reaction schemes. General symbols X, Y, Z,

P ⁴ p p p ⁷ ρθ p9 plO pil pl ^ p ^ -3 p · ' ⁴ p! 5

X / X / X f X f X / X f X f X / X f X f X / X f ^19, R ^20, R ²¹ and R ²² in the Schemes and the abovementioned meaning, unless

scheme

Η ₂ Ν — XYZG

Ο X-Y-Z-G NH

Η

VI

χζ ζχ

scheme

H ₂ N — XYZG

VI

IVo

IZ ΖΙ, 0 X-Y-Z-G

scheme

NO _Z —X — L X

NOj - X - Y - Z - G VII)

H ₂ N - χ - γ - _Z - _G

Scheme 1 relates to the preparation of a compound of formula (I) In the process of Scheme 1, a compound of formula (I) wherein the heterocyclic ring A is of formula Ia, Ibc, Id, Ie, If, Ig, Ih, Ii, or In

X-Y-Z-G

X-Y-Z-G

X-Y-Z-G

can be prepared by the compound of the formula Hla, Illb, Hlc, Illd, Ille, Illf, Illg, Illh, Illi, Illj, Illk, III1, aleboτη or Illn

X-Y-Z-G

IIIc

nif:

X-Y-Z-G

X-Y-Z-G

X-Y-Z-G

wherein L ¹ and L ² are leaving groups such as alkoxy, preferably methoxy, ethoxy or benzyloxy, more preferably methoxy or ethoxy, reacted with urea of formula II (ie, H ₂ -N (CO) -NH ₂ ) in the presence of a suitable base in a polar solvent. Suitable bases include alkoxide bases such as sodium methoxide, sodium ethoxide or sodium tert-butoxide, preferably sodium ethoxide. Suitable solvents include tetrahydrofuran, alcohols (such as ethanol), preferably dimethylformamide. The above reaction is carried out at a temperature of about 20 to about 90 ° C, preferably about 50 to about 80 ° C, for about 5 minutes to about 8 hours.

dimethylformamide or tetrahydrofuran; or

Compounds of formulas IIIa to III1 may be prepared by reacting a compound of formula IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVi, IVj, IVk or IVI

X-Y-Z-G

X-Y-Z-G nl

2 '

^{0 L3} f> S IVb;

R ^{1 R}

IVC L ³ · ° R ¹ IVa;

XYZG O ' _R 1 r

IVg;

M

IVe

X-Y-Z-G

X-Y-Z-G

wherein L ¹ and L ² are leaving groups such as alkoxy, preferably methoxy, ethoxy or benzyloxy, more preferably methoxy or ethoxy, and L ³ represents a suitable leaving group such as halogen, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy, preferably halogen, such as bromine or iodine, is reacted with a suitable base in a polar solvent. Suitable bases include tertiary amines such as triethylamine. Other suitable bases include strong basic macro-reticular resins or gel type resins such as Amberlyst 400 (R) resin (hydroxide form). Suitable solvents include alcoholic solvents, preferably ethanol. The above reaction may be carried out at a temperature of from about -10 to about 50 ° C, preferably at about 20 ° C, for about 6 to about 36 hours.

Compounds of formulas IIIm to IIIn may be prepared by reacting a compound of formula IVm or IVn

X-Y-Z-G

N ^r a

IVn wherein L ³ is a suitable leaving group, is reacted with a suitable base in a polar solvent in a manner similar to that described above for the preparation of compounds of formulas IIIa to 1111. Suitable leaving groups L ³ include halogen, para-tolylsulfonyloxy ( OTs) or methylsulfonyloxy (OMs). L ³ preferably represents a halogen such as chlorine. The reaction may be carried out at a temperature of about 0 to about 50 ° C, preferably about 20 ° C, for about 1 hour to about 4 hours. Suitable solvents include tetrahydrofuran, dimethylformamide and an alcohol.

Compounds of formula IVa-IVi may be prepared by reacting a compound of formula VI with a compound of formula V

L ³ - (A ') - L ⁴ (V) is a compound of formula Va, Vb, Vc, Vg, Vh or Vi

Vd, Ve, Vf,

hydrocarbon tetrahydrofuran wherein each of L ³ and L ⁴ represents a suitable leaving group such as halogen, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs). L ³ preferably represents halogen such as bromine, chlorine or iodine. L ^{4 is} preferably chlorine or fluorine. This reaction can optionally be carried out in the presence of a tertiary amine base such as N, N-dimethylaniline or pyridine, in the presence of a suitable solvent such as a solvent (benzene or toluene) or methylene chloride. The reaction is carried out at a temperature of about 20 to about 90 ° C, preferably about 50 to about 80 ° C, for about 30 minutes to about 6 hours.

as described above, preferably with a hydrocarbon solvent, such as in the absence of said base.

in benzene or

Reaction with aromatic toluene, to

Compounds of formula IVj to IV1 may be prepared by reacting a compound of formula VI with a compound of formula V

L ³ - (A ¹ ) -L ⁴ (V) is a compound of formula Vj, Vk or VI

wherein each of L ³ and L ⁴ represents a suitable leaving group such as halogen, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs) using methods similar to those described above for the preparation of compounds of formulas IVa-IVi. L ³ preferably represents chlorine, bromine or iodine. L ^{4 is} preferably chlorine, bromine or iodine. The reaction is carried out at a temperature of about 0 to about 50 ° C, preferably at about 20 ° C, for about 30 minutes to about 12 hours.

Compounds of formulas IVm-IVn can be prepared by reacting a compound of formula VI with a compound of formula V

L ³ - (A ¹⁾ · ^4-L (V) to the compound of Formula Vm or Vn

IM ⁰ .9

N /

-SO,

-R 1 H .N

-R

In M

Wherein each of L ³ and L ⁴ represents a suitable leaving group such as halogen, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs) using methods similar to those described above for the preparation of compounds of formulas IVa-IVi. L ³ preferably represents a halogen such as chlorine. L ⁴ preferably represents a halogen such as chlorine. The reaction may be carried out at a temperature of about 0 to about 80 ° C, preferably about 0 to about 40 ° C, for about 30 minutes to about 8 hours.

Alternatively, compounds of formula IVd, IVe or IVf may be prepared by reacting a compound of formula VI with a compound of formula V (A ¹ ) -L ³ (V) that is, a compound of formula Vd ', Ve' or Vf

10 'R

N = C = O

VD

N = C = O 11.10

in '

n

R

R

A _s

R ¹ Ŕ ² R ⁵ r ⁵ in which L ³ preferably represents halogen, more preferably chlorine, bromine or iodine. This reaction may optionally be carried out in the presence of a tertiary amine base in a suitable solvent. Suitable bases include N, N-dimethylaniline or pyridine. A suitable solvent may be a hydrocarbon solvent (benzene or toluene), tetrahydrofuran or methylene chloride, preferably an aromatic hydrocarbon solvent such as benzene or toluene. The reaction is carried out at a temperature of about 20 to about 90 ° C, preferably about 50 to about 80 ° C, for about 30 minutes to about 6 hours. Preferably, it is carried out in the absence of the above base.

Alternatively, compounds of formula IVm or IVn may be prepared by reacting a compound of formula VI with a compound of formula V (A ¹ ) -L ³ (V) that is, a compound of formula Vm 'or Vn'

ABOUT

L ³ —SO-N = C = O — N = C = O

V m ' ^L V n' wherein L ³ preferably represents halogen, more preferably chlorine. This reaction may optionally be carried out in the presence of a tertiary amine base in a suitable solvent. Suitable bases include Ν, Ν-dimethylaniline or pyridine. A suitable solvent may be a hydrocarbon solvent (benzene or toluene), tetrahydrofuran or methylene chloride, preferably an aromatic hydrocarbon solvent such as benzene or toluene. The reaction is carried out at a temperature of about -10 to about 50 ° C, preferably about 0 to about 30 ° C, for about 30 minutes to about 12 hours. Preferably, it is carried out in the absence of the above base.

Compounds of formula VI can be prepared by reacting a compound of formula H ₂ NYYZG with a compound of formula VII

(VII).-L ² II O wherein L ¹ and L ² represent leaving groups such as methoxy, ethoxy or benzyl, preferably ethoxy and L ⁵ represents a leaving group such as halogen, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs) ), preferably halogen, most preferably chlorine or bromine. This reaction may be carried out in substance or in the presence of a suitable solvent, preferably in substance, in the presence of a suitable base. Suitable solvents include tetrahydrofuran or dimethylformamide. Suitable bases include weak tertiary amine bases, preferably tertiary aniline bases, most preferably N, N-dimethylaniline. Preferably, the reaction is carried out at a temperature of about 23 to about 100 ° C, preferably about 50 to about 90 ° C, for about 30 minutes to about 24 hours.

In the reactions described above, each of the compounds of formulas IVj to IV1 may be isolated, but the reactions are preferably carried out without such isolation. Thus, in Scheme 1, the compounds of formulas IIIj to III1 are preferably prepared in a single reaction vessel from a compound of formula VI.

Unless the compounds of formulas IVj to IV1 are isolated, the solvents suitable for the preparation in a single reaction vessel are dimethylformamide, tetrahydrofuran or alcohols, preferably alcohols such as ethanol. The one-pot process is preferably carried out in the presence of an alkoxide base, preferably sodium methoxide or sodium ethoxide. The one-pot process is carried out at a temperature of about 40 to about 90 ° C, preferably about 60 to about 80 ° C, for about 15 minutes to about 12 hours.

Compounds of formula H ₂ NXYZG are commercially available or can be prepared by methods well known to those skilled in the art. Alternatively, compounds of formula H ₂ NXYZG can be prepared as shown in Scheme 3.

Compounds of formula VII may be prepared by methods well known to those skilled in the art, such as those described in PCT Patent Publication WO 98/58925 or in The Organic Chemistry of Drug Synthesis, D. Lednicer and L. A. Mitscher, Volume 1, p. 167-277 and the publications cited therein. All publications mentioned above are cited as a substitute for transferring their content to this text.

The compounds of formula (II) are commercially available or can be prepared by methods well known to those skilled in the art.

Scheme 2 relates to the preparation of compounds of formula I wherein the heterocyclic ring corresponds to formula o, i.e., compounds of formula Io. In the procedure of Scheme 2, the compound of formula (Io) is

(Io) possible

IIIO, to prepare wherein L ¹ and such that the compound of general L ² are leaving groups, of the formula is reacted with urea of formula II (i.e., H ₂ N- (CO) -NH ₂ ) in the presence of a suitable base in a polar solvent. Suitable leaving groups include methoxy, ethoxy or benzyloxy, preferably ethoxy. Suitable bases include alkoxide bases such as sodium methoxide, sodium ethoxide and sodium tert-butoxide, preferably sodium ethoxide. Suitable solvents include tetrahydrofuran, dimethylformamide or alcohols (such as ethanol), preferably tetrahydrofuran or dimethylformamide. The reaction is carried out at a temperature of about 20 to about 90 ° C, preferably about 50 to about 80 ° C, for about 5 minutes to about 8 hours.

Compounds of formula IIIc may be prepared by reacting a compound of formula IVo wherein L ³ is a leaving group in a polar solvent with a suitable base. Suitable leaving groups include alkoxy (such as methoxy, ethoxy or benzyloxy) or halogen, preferably methoxy or ethoxy. Suitable solvents include alcohols, preferably ethanol. The reaction may be carried out at a temperature of about 0 to about 90 ° C, preferably about 60 to about 90 ° C, for about 1 hour to about 36 hours.

Compounds of formula IVo may be prepared by reacting a compound of formula VI with a compound of formula Vo

wherein L ⁶ represents a suitable leaving group, in a suitable solvent. Suitable leaving groups L include ⁶ alkoxy and halogen, such as chloro, preferably alkoxy, more preferably methoxy or ethoxy. This reaction may optionally be carried out in the presence of a suitable tertiary amine base such as triethylamine, N, N-dimethylaniline or pyridine. Suitable solvents include hydrocarbon solvents (benzene or toluene), tetrahydrofuran or methylene chloride, preferably tetrahydrofuran. Preferably, the reaction is carried out in tetrahydrofuran or dimethylformamide in the presence of a suitable tertiary amine base. It may be conducted at a temperature of about 20 to about 90 ° C, preferably about 50 to about 80 ° C, for about 30 minutes to about 6 hours.

In the reactions described above, the compound of formula (IVo) can be isolated, but is preferably carried to the next step without isolation. Thus, in Scheme 1, the compound of formula IIIo is preferably prepared in a single reaction vessel from the compound of formula IV.

Unless the compound of formula (IVo) is isolated, solvents suitable for preparation in a single reaction vessel are dimethylformamide, tetrahydrofuran or alcohols, preferably alcohols such as ethanol. The one-pot process is preferably carried out at a temperature of about 0 to about 70 ° C, preferably about 23 to about 60 ° C, for about 30 minutes to about 24 hours.

Compounds of formula VI can be prepared by reacting a compound of formula H ₂ NXYZG with a compound of formula VII by the method of Scheme 1.

Scheme 3 relates to the preparation of compounds of formula H ₂ NXYZG, which are intermediates useful in the preparation of compounds of formula I according to Schemes 1 and 2. In Scheme 3, compounds of formula H ₂ NXYZG can be prepared by preparing compounds of formula VIII reacting with a reducing agent such as stannous chloride in the presence of a suitable acid, such as hydrochloric acid, in a polar protic solvent. Suitable solvents include alcoholic solvents, water and mixtures thereof. The reaction may be conducted at a temperature of about 40 to about 100 ° C for about 1 hour to about 12 hours.

Alternatively, compounds of formula H ₂ NXYZG can be prepared by reacting a compound of formula VIII with hydrogen gas at atmospheric pressure up to 343.5 kPa in the presence of a catalyst and a polar solvent. Suitable catalysts include palladium or platinum containing catalysts, preferably an Adams catalyst (i.e. platinum oxide) or palladium on carbon. Suitable solvents include alcoholic solvents, preferably methanol. The reaction may be carried out at a temperature of about 20 to about 50 ° C, preferably about 23 ° C, for about 30 minutes to about 6 hours.

Compounds of formula VIII wherein Y is oxygen, sulfur or a group of formula -CH ₂ S-, -CH ₂ O-,> NR ¹⁴ ,

CH ₂ [N (R ¹⁴ )] - or -SO ₂ [N (R ¹⁴ )] -, can be prepared by reacting a compound of formula X wherein L ⁷ is fluorine or chlorine with a compound of formula IX

GZYH (IX) wherein Y represents oxygen, sulfur or -CH ₂ S-, -CH ₂ O-,> NR ¹⁴ , -CH 2 [N (R ¹⁴ )] - or -SO 2 [N (R ¹⁴ )] -, in the presence of a base in a polar aprotic solvent. Suitable bases include alkali metal hydrides, preferably sodium hydride. Suitable solvents include dimethylformamide, tetrahydrofuran or 1,2-dimethoxyethane, preferably dimethylformamide. The reaction may be carried out at a temperature of about 40 to about 140 ° C, preferably about 80 to about 120 ° C, for about 1 hour to about 24 hours.

Alternatively, a compound of formula (VIII) wherein Y is oxygen, sulfur, or -CH ₂ S-, -CH ₂ O-,> NR ¹⁴ ,

-CH ₂ [N (R ¹⁴ )] - or -SO ₂ [N (R ¹⁴ )] -, may be prepared in the presence of an alkali metal hydroxide, such as a base, preferably potassium hydroxide, optionally in the presence of a phase transfer catalyst such as quaternary ammonium or a phosphonium salt, preferably tetrabutylammonium bromide, in an aromatic hydrocarbon solvent. Such a solvent is preferably benzene or toluene. The reaction may be carried out at a temperature of about 0 to about 120 ° C, preferably about 23 ° C, for about 1 hour to about 12 hours.

Alternatively, compounds of formula (VIII) wherein Y is oxygen, sulfur or -CH ₂ S-, -CH ₂ O-,> NR ¹⁴ , -CH 2 [N (R ¹⁴ )] - or -SO 2 [N (R ¹⁴⁾ )] -, prepare under conditions of so-called. Ulman's coupling. Under such conditions, compounds of formula VIII may be prepared by reacting a compound of formula X wherein L ⁷ is bromine or chlorine with a compound of formula IX

GZYH (IX) wherein Y represents oxygen, sulfur or -CH ₂ S-, -CH ₂ O-,> NR ¹⁴ , -CH 2 [N (R ¹⁴ )] - or -SO 2 [N (R ¹⁴ )] -, in the presence of a base and a catalyst in a polar aprotic solvent. Suitable bases include alkali metal carbonates or hydroxides, preferably potassium carbonate. Suitable catalysts are those containing copper in an oxidation state of 0, preferably fine powdered bronze. Suitable solvents include dimethylformamide or 1-methyl-2-pyrrolidinone. The reaction may be carried out at a temperature of about 80 to about 140 ° C for about 6 to about 24 hours.

Compounds of formula I wherein Y is an oxidized group, i.e. > SO ₂ , > S = O, -CH ₂ SO-, -CH ₂ SO ₂ -,

SO (CH ₂ ) _n - or -SO ₂ (CH ₂ ) _n - may be prepared by reacting the corresponding compound of formula VIII, wherein Y is a corresponding group having a lower oxidation degree, with a suitable oxidizing agent in a solvent. For compounds of formula I wherein Y is> SO ₂ or> S = O, the compound wherein Y is the corresponding lower oxidation group is a compound of formula VIII where Y is sulfur. For compounds of formula VIII wherein Y is -SO ₂ (CH ₂ ) _n - or -SO (CH ₂ ) _n -, the compound where Y is the corresponding lower oxidation group is a compound of formula VIII where Y is -S- (CH _{2) n} - · suitable oxidants include a peroxy acid, preferably peracetic acid, or organic peroxide, preferably m-chloroperoxybenzoic acid or tert-butyl hydroperoxide. Suitable solvents include methylene chloride and an alcohol such as ethanol. The reaction may be carried out at a temperature of from about -10 to about 30 ° C for about 1 hour to about 8 hours.

Compounds of formula VIII wherein Y is -O (CH ₂ ) _n -, -S (CH ₂ ) _n - or -NR ¹⁴ (CH ₂ ) _n - may be prepared by reacting a compound of formula X wherein: L ⁷ represents a group L ^e - (CH 2) _n -, wherein L ⁸ represents a halogen such as chlorine, bromine, iodine, methylsulfonyloxy (MsO) or tolylsulfonyloxy (TsO), reacted with a compound of formula IX

GZWH (IX) wherein W represents oxygen, sulfur or -NR ¹⁴ , in the presence of a base in a polar aprotic solvent. Suitable bases include alkali metal carbonates, preferably potassium carbonate or cesium carbonate. A suitable solvent may be dimethylformamide or tetrahydrofuran. The reaction may be carried out at a temperature of about 20 to about 50 ° C for about 1 hour to about 24 hours.

Compounds of formula VIII wherein Y is> C = O, -CH = CH- or -OC- may be prepared by the preparation of a compound of formula X wherein L ⁷ is dihydroxyborane; a zinc halide such as zinc chloride or a trialkyltin such as tributyltin is reacted with a compound of formula IX

GZYL ⁹ (IX) wherein Y is> C = O, -CH = CH- or -C = C-; and L ⁹ represents halogen, preferably chlorine, bromine or iodine; in the presence of a catalyst in a solvent. Suitable catalysts include palladium or nickel catalysts, preferably tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ ).

Suitable solvents include toluene, tetrahydrofuran, dimethylformamide or dimethylsulfoxide. The reaction may be carried out at a temperature of about 23 to about 110 ° C for about 1 hour to about 24 hours. The presence of a copper salt such as copper (I) iodide or copper (I) bromide may simplify such reactions.

Alternatively, compounds of formula VIII wherein Y is -C =C- may be prepared by reacting a compound of formula X wherein L ⁷ is halogen or trifluoromethanesulfonate, preferably bromine or iodine, with a compound of formula IX

GZYH (IX) in the presence of a base such as a trialkylamine base, preferably triethylamine, and a palladium-containing catalyst, preferably Pd (PPh ₃ ) ₄ in a solvent. Suitable solvents include tetrahydrofuran or dimethylformamide. The reaction may be carried out at a temperature of about 23 to about 60 ° C for about 1 hour to about 24 hours.

Compounds of formula VIII wherein Y is -CH ₂ (CH ₂ ) _n - may be prepared by leaving the above compound of formula VIII wherein Y is -CH = CH- or -C = C- react with hydrogen gas at ambient pressure up to 343.5 kPa in the presence of a palladium-containing catalyst in a solvent. The palladium-containing catalyst is preferably palladium on carbon. Suitable solvents include methanol or ethyl acetate. The reaction may be carried out at a temperature of about 20 to about 50 ° C for about 1 hour to about 24 hours.

Compounds of formula X and XI (i.e., compounds of formula GZYH, GZWH or GZYL ⁹ ) are commercially available or can be prepared by methods known to those skilled in the art.

The compounds of formula I which are basic in nature are capable of forming a variety of different salts with inorganic and organic acids. While these salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to isolate a compound of Formula I from the reaction mixture first as a pharmaceutically unsuitable salt, then convert the unsuitable salt to the free base by treatment with an alkaline reagent and finally convert the resulting free base into an addition salt with a pharmaceutically acceptable acid. The acid addition salts of the basic compounds of the invention are readily prepared by treating the basic compound with a substantially equivalent amount of a selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. The desired solid salt can then be obtained after careful evaporation of the solvent.

For the preparation of pharmaceutically acceptable acid addition salts of the basic compounds of the invention, acids that form non-toxic addition salts, i.e., salts that contain pharmacologically acceptable anions, are used. Examples of such salts include hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, hydrogensulfates, phosphates, hydrogen phosphates, acetates, lactates, citrates, hydrogen citrates, tartrates, hydrogen tartrates, succinates, maleates, fumarates, gluconates, saccharates, methoates, benzoates, methoates (i.e., 1,1'-methylenebis (2-hydroxy-3-naphthoates)).

The compounds of formula I which are acidic in nature are capable of forming salts with bases containing various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts, especially the sodium and potassium salts. All these salts are prepared by conventional methods. Suitable bases which can be used as reagents for the production of pharmaceutically acceptable salts with the bases of the invention include bases which form non-toxic salts with the above-described acidic compounds of formula I. Non-toxic salts of these compounds with bases include salts derived from pharmacologically acceptable cations such as sodium, potassium, calcium, magnesium, etc. These salts can be readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure.

Alternatively, such salts can be prepared by mixing a solution of an acidic compound in a low alkanol with the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as described above. In both cases, stoichiometric amounts of reagents are preferably used to ensure completeness of reaction and maximum yields of desired end products.

The ability of the compounds of formula I or their pharmaceutically acceptable salts (also collectively referred to herein as the compounds of this invention) to inhibit metalloproteinases or mammalian reprolysin, and thus the efficacy of the compounds of the invention in treating diseases characterized by metalloproteinase applications, can be demonstrated. using the following in vitro test procedures.

Biological tests

MMP tests

Selective MMP-13 inhibitors can be identified by evaluating the inhibitors of the invention using the MMP fluorescence assays described below and selecting agents whose IC 50 inhibition ratio of MMP-13 / MMP-X is 100 or greater and the potency is less than 100nM, wherein MMP-X refers to one or more other MMPs.

The term non-selective collagenase inhibitors as used herein refer to agents which exhibit less than a hundredfold selectivity for the inhibition of MMP-13 enzyme activity over MMP-X and efficacy, expressed as values of _IC50 results from the MMP-13 / MMP-X fluorescence assays described below more than 100nM.

The ability of collagenase inhibitors to inhibit collagenase activity is well known in the art. The degree of inhibition of a particular MMP has been well documented for several compounds, and one of skill in the art will be able to normalize the results of various assays relative to the assays described below. The following assays can be used to identify matrix metalloproteinase inhibitors.

Inhibition of human collagenase (MMP-1)

Human recombinant collagenase is activated with trypsin using a ratio of 10 µg trypsin per 100 µg collagenase. Trypsin and collagenase are incubated at room temperature for 10 minutes and then a five-fold excess (50 µg / 10 µg trypsin) of soybean trypsin inhibitor is added to the incubation mixture.

Stock solutions of 10 mM inhibitors were made using dimethylsulfoxide and then diluted according to the following scheme:

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

25 µl of each concentration is then added (3 replicates) to the appropriate wells of a 96-well microfluor plate. The final inhibitor concentration after enzyme and substrate addition is reduced 1: 4. Positive control samples (enzyme but no inhibitor) are placed in wells D1 to D6 and blanks (no enzyme, no inhibitor) are placed in wells D7 to D12.

Collagenase-1 is diluted to a concentration of 240 ng / ml and 25 µL of the diluted preparation is added to the appropriate wells of the microfluor plate. The final collagenase concentration in this assay is 60 ng / ml.

The substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH ₂ ) was made as a 5 mM stock solution in dimethylsulfoxide and then diluted in assay buffer to 20 µM concentration. The assay is initiated by adding 50 µl of substrate to the well of the microfluor plate, resulting in a final concentration of ΙΟρΜ.

Fluorescence readings (360 nm excitation and 460 nm emission) are read at time 0 and then at 20 minute intervals. The test is carried out at room temperature with a typical duration of 3 hours.

For both the blank and the collagenase samples, the fluorescence versus time is then plotted (data from the three replications are averaged). To determine IC ₅₀ values, a time point that provides a good signal (blank) and which is located in the linear part of the curve (usually about 120 minutes) is selected. The value at time 0 is used for all concentrations of all compounds as a reference value, which is subtracted from the data at 120 minutes. Data are plotted as inhibitor concentration versus control percentage (inhibitor fluorescence ratio and collagenase alone fluorescence multiplied by 100). IC ₅₀ values are determined from the concentration of inhibitor that provides a signal representing 50% of the control.

If IC5Q values are less than 0.03μΜ, then inhibitors are tested at concentrations of 0.3μΜ, 0.03μΜ and 0.003μΜ.

Gelatinase Inhibition (MMP-2)

Human recombinant 72 kD gelatinase (MMP-2, gelatinase A) is activated for 16-18 hours with 1 mM p-aminophenylmercuryacetate (from a freshly prepared 100 mM stock solution in 0.2 M sodium hydroxide) at 4 ° C with gentle rocking.

Stock solutions of inhibitors at 10mM concentration were prepared using dimethylsulfoxide and then serially diluted with assay buffer (50mM Tris, pH 7.5, 200mM sodium chloride, 5mM calcium chloride, 20μΜ zinc chloride and

0.02% (v / v Brij-35) according to the following scheme:

lOmM - »120μΜ - 12μΜ - 1.2μΜ -» 0.12μΜ

If necessary, further dilutions are made according to the same scheme. Each assay is performed with at least four inhibitor concentrations for each compound. 25 μΐ of each concentration is then added (in triplicate) to the appropriate round bottom wells of a 96-well black microfluor plate. The test is performed at a final volume of 100 μΐ and the final inhibitor concentrations are the result of a further dilution at a ratio of 1: 4 (ie 30 0 0Μ - 3μΜ -> 0,3μΜ -> 0,03μΜ, etc.). In triplicate, blank experiments (no enzyme, no inhibitor) and positive controls (enzyme, but no inhibitor) were also prepared.

Dilute the activated enzyme to 100 ng / ml with assay buffer and add 25 μΐ of the diluted preparation to the appropriate wells of the plate. The final enzyme concentration in this assay is 25 ng / ml (0.34 nM).

The substrate (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH 2) ^was made as a 5 mM stock solution in dimethylsulfoxide and then diluted with assay buffer to a 20μΜ concentration. The assay is initiated by the addition of 50 μΐ of the diluted substrate to achieve a 10 μΜ final substrate concentration. Fluorescence readings (excitation 320 nm and emission 390 nm) are read at time 0 and then at 15 minute intervals. The assay is performed at room temperature using a PerSeptive Biosystems CytoFluor Multi-Well Plate Reader with an increment of 90 units.

For both the blank experiments and the experiments involving the enzyme samples, the mean fluorescence versus time is then plotted. The early time point located in the linear part of the curve is selected to determine IC ₅₀ values. The value at time 0 for all concentrations of all compounds is subtracted from the data later. The data obtained is then expressed as a percentage of the enzyme control (the ratio of inhibitor fluorescence to that of the positive enzyme control multiplied by 100). Data are plotted as inhibitor concentration versus percent enzyme control. IC ₅₀ values are defined as the concentration of inhibitor that provides a signal representing 50% of the positive enzyme control.

Inhibition of stromelysin activity (MMP-3)

Human recombinant stromelysin (MMP-3, stromelysin-1) is activated with 2mM ΑΡΜΑ (β-aminophenylmercurylacetate) (from a freshly prepared 100mM stock solution in 0.2M sodium hydroxide) for 20-22 hours at 37 ° C.

Stock solutions of inhibitors at 10mM concentration were prepared using dimethylsulfoxide and then serially diluted with assay buffer (50mM Tris, pH 7.5, 150mM sodium chloride, 10mM calcium chloride, and 0.05% (v / v) Brij35) according to the following scheme:

10mM -, 120μΜ - 12μΜ - 1.2μΜ - 0.12μΜ

If necessary, further dilutions are made according to the same scheme. Each assay is performed with at least four inhibitor concentrations for each compound. 25 μΐ of each concentration is then added (in triplicate) to the appropriate round bottom wells of a 96-well black microfluor plate. The test is performed at a final volume of 100 μΐ and the final inhibitor concentrations are the result of a further dilution at a ratio of 1: 4 (ie 30 0 0 -> 3μΜ - 0,3μΜ - 0,03μΜ, etc.). In triplicate, blank experiments (no enzyme, no inhibitor) and positive controls (enzyme, but no inhibitor) were also prepared.

Dilute the activated enzyme to 200 ng / ml with assay buffer and add 25 μΐ of the diluted preparation to the appropriate wells of the plate. The final enzyme concentration in this assay is 50 ng / ml (0.875nM).

The substrate (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys- (Dnp) -NH 2) was made as a 10 mM stock solution in dimethylsulfoxide and then diluted with assay buffer to 6µΜ concentration. The assay is initiated by the addition of 50 μΐ of the diluted substrate to give a 3μΜ final substrate concentration. Fluorescence readings (excitation 320 nm and emission 390 nm) are read at time 0 and then at 15 minute intervals. The assay is performed at room temperature using a PerSeptive Biosystems CytoFluor Multi-Well Plate Reader with an increment of 90 units.

For both the blank experiments and the experiments involving the enzyme samples, the mean fluorescence versus time is then plotted. The early time point located in the linear part of the curve is selected to determine IC ₅₀ values. The value at time 0 for all concentrations of all compounds is subtracted from the data later. The data obtained is then expressed as the fluorescence of the percentage of fluorescent inhibitor (the ratio of the positive enzyme control multiplied by 100). Data are plotted as inhibitor concentration versus percent enzyme control. IC ₅₀ values are defined as the concentration of inhibitor that provides a signal representing 50% of the positive enzyme control.

Inhibition of Human 92kD Gelatinase (MMP-9)

The 92kD gelatinase inhibition assay (MMP-9) was performed using the Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH ₂ substrate (ΙΟμΜ) under similar conditions to those described for the inhibition of human collagenase (MMP- 1).

Human recombinant 92kD gelatinase (MMP-9, gelatinase B) is activated with 1mM ΑΡΜΑ (p-aminophenylmercurylacetate) (from a freshly prepared 100mM stock solution in 0.2M sodium hydroxide) for 2 hours at 37'C.

Stock solutions of inhibitors at 10 mM concentration were prepared using dimethylsulfoxide and then serially diluted with assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mM calcium chloride, 20 µΜ zinc chloride, and 0.05% v / v). 35) on the following scheme:

10mM - 120μΜ -, 12μΜ - 1.2μΜ - 0.12μΜ

If necessary, further dilutions are made according to the same scheme. Each assay is performed with at least four inhibitor concentrations for each compound. 25 μΐ of each concentration is then added (in triplicate) to the appropriate round bottom wells of a 96-well black microfluor plate. The test is performed at a final volume of 100 μΐ and the final inhibitor concentrations are the result of an additional 1: 4 dilution (ie 30μΜ -> 3μΜ - 0,3μΜ - 0,03μΜ, etc.). In triplicate, blank experiments (no enzyme, no inhibitor) and positive controls (enzyme, but no inhibitor) were also prepared.

Dilute the activated enzyme to 100 ng / ml with assay buffer and add 25 μΐ of the diluted preparation to the appropriate plate wells. The final enzyme concentration in this assay is 25 ng / ml (0.27nM).

The substrate (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH 2) is diluted with assay buffer to a 20μΜ concentration. The assay is initiated by the addition of 50 μΐ of diluted substrate to give a ΙΟμΜ final substrate concentration. Fluorescence readings (excitation 320 nm and emission 390 nm) are read at time 0 and then at 15 minute intervals. The assay is performed at room temperature using a PerSeptive Biosystems CytoFluor Multi-Well Plate Reader with an increment of 90 units.

For both the blank experiments and the experiments involving the enzyme samples, the mean fluorescence versus time is then plotted. The early time point located in the linear part of the curve is selected to determine IC ₅₀ values. The value at time 0 for all concentrations of all compounds is subtracted from the data later. The data obtained are then plotted on the enzymatic control (fraction and fluorescence of the positive data) as the percent fluorescence of the enzyme control inhibitor multiplied by 100) as a concentration of inhibitor versus the percentage of enzyme control. IC ₅₀ values are defined as the concentration of inhibitor that provides a signal representing 50% of the positive enzyme control.

Inhibition of MMP-13

Human recombinant MMP-13 is activated with 2 mM ΑΡΜΑ (β-aminophenylmercuryacetate) for 1.5 hours at 37 ° C and then diluted with assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mM calcium chloride, 20 µΜ zinc chloride, 0.02% surfactant Brij) at a concentration of 400 mg / ml. Add 25 μΐ of diluted enzyme to each well of a 96-well microfluor plate. In the well, the enzyme is further diluted 1: 4 in the assay by the addition of inhibitor and substrate so that its final assay concentration is 100 mg / ml.

Dimethylsulfoxide inhibitor stock solutions of 10 mM were made and then diluted with assay buffer using the inhibitor dilution system indicated in the human collagenase inhibition assay (MMP-1). 25 μΐ of each concentration (3 replications) is added to the wells of the micro-fluorine plate. The final test concentration is 30μΜ, 3μΜ, 0.3μΜ and 0.03μΜ.

The substrate (Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) is treated as in the human collagenase inhibition (MMP-1) assay and 50 ml is added to each well. of the resulting solution to give a final test concentration of 10μΜ. Fluorescence (360 nm excitation, 450 nm emission) is read at time 0 and then every 5 minutes for 1 hour.

Positive control samples contain enzyme and substrate without inhibitor, while blank samples contain substrate alone.

IC ₅₀ values are determined in the same manner as the human collagenase (MMP-1) inhibition assay. If the values are lower than the IC _5Q 0,03μΜ, inhibitors are then assayed at final concentrations 0,3μΜ, 0,03μΜ, 0,003μΜ and 0,0003μΜ.

MMP-13 thin film collagen assay

Rat type I collagen is labeled with ¹⁴ C acetic anhydride (TE Cawston and AJ Barrett, Anal. Biochem. 99, 340-345 (1979)) and used to prepare radiolabelled 96-well thin collagen plates (Barbara Johnson-Wint, Anal. Biochem., 104, 175-181 (1980)). When a solution containing collagenase is added to the well, this enzyme cleaves the insoluble collagen, which expands and is thus solubilized. Collagenase activity is directly proportional to the amount of solubilized collagen given by the ratio of radioactivity released into the supernatant which scintillation counter. Inhibitors are compounds that reduce the number compared to no inhibitor controls. One particular embodiment of this assay is described in detail below.

is measured by standard collagenases are thus radioactive pulses

To determine the selectivity of the compounds on MMP-13 over MMP-1 using collagen as a substrate, the procedure is as follows. Recombinant human for MMP-13 or proMMP-1 is activated as in the above-described assays. Activated MMP-13 or MMP-1 is diluted to a concentration of 0 with buffer (50 mM Tris, pH 7.5, 150 mM sodium chloride, 10 mM calcium chloride, ΙμΜ zinc chloride, 0.05% Brij-35, 0.02% sodium azide). , 6 pg / ml.

Stock solutions of the test compound in dimethylsulfoxide at 10mM were prepared. The concentration of test compounds is adjusted to 0.2, 2.0, 20, 200, 2000 and 20,000 mM in the Tris buffer above.

100 μΐ of the appropriate concentration of drug solution and 100 μΐ of diluted enzyme are pipetted into the wells of a 96-well plate containing a thin layer of collagen labeled with β-collagen. The final enzyme concentration is 0.3 µg / ml and the final drug concentration is 0.1, 1.0, 10, 100 and 100mM. The concentration and control are analyzed in triplicate. The triplicate control is also performed for conditions in which no enzyme is present and for the enzyme in the absence of compound.

Plates are incubated at 37 ° C until about 30-50% of available collagen is dissolved, as determined by counting additional control wells at different times. In most cases, about nine hours of incubation is required. In an adequate assay procedure, the supernatant is removed from each well and the count is counted in a scintillation counter. Background impulses (determined from values for wells without enzyme) are subtracted from each sample and the percent release is calculated relative to wells without enzyme only. The triplicate values for each point are averaged and the data plotted as a percent release versus concentration. IC ₅₀ values are determined from the point at which 50% inhibition of radiolabelled collagen release was achieved.

Identification of active collagenases in cartilage conditioned media is performed using collagen as a substrate, cartilage conditioned media containing collagenase activity, and inhibitors of varying selectivity. The cartilage conditioned medium is collected during the time at which collagen degradation occurs and is thus typical of the collagenases responsible for collagen degradation. The assays are performed as described above except that the source of the enzyme is cartilage conditioned medium instead of using recombinant MMP-13 or recombinant MMP-1.

Cartilage collagen degradation induced by IL-1 on bovine nasal cartilage.

This assay is performed on bovine nasal cartilage explants, which are typically used to test the effectiveness of various compounds in inhibiting IL-1-induced proteoglycan degradation or IL-1-induced collagen degradation. Bovine nasal cartilage is a tissue that is very similar to articular cartilage, that is, chondrocytes are surrounded by a matrix that is predominantly collagen type II and aggrecan. This tissue is used because (1) is very similar to articular cartilage, (2) is readily available, (3) is relatively homogeneous, and (4) the kinetics of degradation upon IL-1 stimulation is predictable.

Compounds were tested using two variants of this assay. Similar data were obtained for both variants described below.

Variant 1

Three rolls of bovine nasal cartilage (about 2 mm in diameter and 1.5 mm thick) are placed in all wells of a 24-well tissue culture plate. 1 ml serum free medium is added to each well. Stock solutions of the compounds in dimethylsulfoxide at 10mM are prepared, which are then diluted with serum-free medium to a suitable concentration, for example 50, 500 and 5000nM. Each concentration is tested in triplicate.

Human recombinant IL-1α (5 ng / ml) is added to the triple wells containing the control and each well containing the drug. Also triplicate control wells are prepared that contain neither drug nor IL-1. The medium is removed and fresh medium containing IL-1 and the compound at the appropriate concentration is added on days 6, 12, 18 and 24 or, if necessary, every 3-4 days. All collected media was stored at -20 ° C for later analysis. When the cartilage is almost resorbed in wells with IL-1 alone (about day 21), the assay is terminated. The medium is collected and stored. Aliquots (100 μΐ) from each well for each time point are pooled, digested with papain and then analyzed for hydroxyproline content. The background hydroxyproline value (mean for IL-1 and drug-free wells) is subtracted from all data and the mean value is calculated for all triplicate embodiments. Data are expressed as a percentage of the mean value obtained with IL-1 alone and plotted. The IC 50 value is determined from this graph.

Variant 2

Until day 12, the assay is performed as described above. On day 12, conditioned medium is removed from each well and frozen. To each well is added 1 ml phosphate buffered saline (PBS) containing 0.5 µg / ml trypsin. Incubation is continued for an additional 48 hours at 37 ° C. After a 48 hour incubation with trypsin, the PBS solution is removed. Aliquots (50 μΐ) of PBS / trypsin and from the previous two donations (days 6 and 12) are pooled and hydrolyzed. The hydroxyproline content is determined. Background hydroxyproline (mean values for wells without IL-1 and drug free) is subtracted from the data at each time point and the mean is calculated for each triplicate. Data are expressed as a percentage of the average value for IL-1 alone and plotted. IC ₅₀ is determined from this graph. The test run time is significantly reduced in this variant. In a 48-hour trypsin incubation after day 12 of stimulation, IL-1 is likely to release any type of collagen II that has been damaged by collagenase but has not yet released from the cartilage matrix. In the absence of IL-1 stimulation when incubated with trypsin, only low levels of background (collagen degradation) are achieved in cartilage explants.

Inhibition of TNF production

The ability or inability of the compounds or their pharmaceutically acceptable salts to inhibit TNF production is demonstrated by the following in vitro assay.

Human monocyte assay

Human mononuclear cells are isolated from anticoagulated human blood using a one-step Ficoll-hypaque separation procedure. (2) The mononuclear cells were washed three times in Hanks balanced salt solution (HBSS) with divalent cations and resuspended to a density of 2 x 10 ⁶ / ml in HBSS containing 1% BSA. Differential counts determined using the Abbott Cell Dyn 3500 analyzer show that in these preparations monocytes make up 17 to 24% of the total cell count.

Flat-bottomed 96-well plates (Costar) are each plated with 180 μ vždy of cell suspension. Add the test compound and LPS (final concentration 100 ng / ml) to adjust the volume in each well to 200 μΐ. The assays under all conditions are performed with three replicates. After a four hour incubation at 37 ° C in a humidified incubator containing carbon dioxide, the plates are removed and centrifuged (10 minutes at about 250 x g). Supernatants were collected and analyzed for TNF using an R&D ELISA kit.

Agrekanasová skúška

Primary porcine chondrocytes are isolated from joint cartilage by sequential digestion with trypsin and collagenase and further cleaved by collagenase overnight. 2 x 10 ⁵ cells are plated in each well of a 48-well plate with 5 pCi / ml ³⁵ S (1000 Ci / mmol) of S-type I coated plates. The cells are maintained at 37 ° C under a 5% carbon dioxide atmosphere for about 1 week. the label was incorporated into the proteoglycan matrix.

The night before the start of the assay, chondrocyte monolayers are washed twice in DMEM / 1% PSF / G and incubated overnight in fresh DMEM / 1% FBS.

The following morning, chondrocytes are washed once with DMEM / 1% PSF / G, the last wash bath is incubated in the incubator and in the meantime diluted dilutions of the test drug are prepared.

Media and diluted solutions are prepared as shown in the following table:

Control medium DMEM alone (control medium) IL-1 medium DMEM + IL-1 (5 ng / ml) Dilute solutions drug A stock solution of each is prepared compounds in DMSO with a concentration of 10mM.

Prepare a ΙΟΟμΜ stock solution of each compound in DMEM in a 96-well plate. The solutions were stored in the freezer overnight.

The next day, serial dilutions are made in DMEM with IL-1 at concentrations of 5μΜ, 500nM, and 50nM.

The last bath is aspirated from the wells and 50 µL of the diluted compound solution prepared as described above is added to 450 µL of IL-1 medium in the appropriate wells of a 48-well plate.

Final compound concentrations are 500nM, 50nM, and 5nM.

All samples are prepared in triplicate with a single control and IL-1 sample on each plate.

Plates are labeled and only 24 inner wells are used. On one plate, several columns are prepared as IL-1 (no drug) and control (no IL-1, no drug). These control columns are periodically monitored for pulse counts to monitor 35S-proteoglycan release. Control well and IL-1 medium (450 μΐ) are added to the wells followed by compound (50 μΐ) to start the assay. The plates are incubated at 37 ° C in an atmosphere of 5% carbon dioxide.

At about 40 to 50% release (when the IL-1 pulses per minute of the medium is 4-5 times the control medium), according to the liquid scintillation (LSC) of the media samples, the assay is terminated (9-12 hours). The medium is removed from all wells

100 and placed in scintillation tubes. Radioactive counts (LSC) values are obtained after the scintillate is added. Add 500 μΐ of papain cleavage buffer (0.2 M Tris, pH 7.0, 5 mM EDTA, 5 mM DDT and 1 mg / ml papain) to each well to solubilize the cell layers. The cleavage plates are incubated overnight at 60 ° C. The next day, the cell layer is removed from the plates and the cells are placed in scintillation tubes. Scintillate is added and the sample counts (LSC) are determined.

The percentage of isotope released from the total amount present in each well is determined. Mean values for triplicate samples are calculated and control background is subtracted. The percentage of inhibition for the compound is determined, based on IL-1 samples as 0% inhibition (100% of the total value).

The compounds of the invention that were tested showed an IC _{50 of} less than 100µΜ, preferably less than 100nM, in at least one of the above-described assays. Some preferred classes of compounds show different selectivity to different MMPs or ADAMs. One group of preferred compounds exhibits selective activity against MMP-13 over MMP-1. Another group of preferred compounds exhibits selective activity against MMP-13 over MMP-1, MMP-3, and MMP-7. Another preferred group of compounds exhibits selective activity against MMP-13 over MMP-1, MMP-3, MMP-7 and MMP-17. Another preferred group of compounds exhibits selective activity against MMP-13 over MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and MMP-14. Another group of preferred compounds exhibits selective activity against MMP-13 over MMP-12 and MMP-14.

101

Various conventional routes, such as oral, parenteral (e.g., intravenous, intramuscular or subcutaneous), buccal, rectal, and topical administration, can be used for administration to mammals, such as humans, to inhibit matrix metalloproteinases. Typically, the compound of the invention (hereinafter also referred to as the active compound) will be administered orally or parenterally at a dose ranging from about 0.1 to about 25 mg / kg body weight of the subject to be treated per day, with a preferred daily dose being approximately 0.3 to 5 mg / kg. Oral and parenteral administration is preferred. Depending on the condition of the subject being treated, there will necessarily be some variation in dosage. The appropriate dose for the individual patient will in any case be determined by the attending physician.

The compounds of the invention may be administered in a wide variety of dosage forms in which the therapeutically active compounds of the invention will be present in a concentration ranging from about 5.0 to about 70% by weight.

Tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be used for oral administration together with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, as well as granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and resin. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc are also often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers for gelatin capsules; lactose and high molecular weight polyethylene glycols are also preferred. When to be used for oral administration

102 aqueous suspensions and / or elixirs, the active ingredient is mixed with various sweetening or flavoring agents, coloring agents or coloring agents and, if necessary, emulsifying and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerol and mixtures thereof. In the case of animals, administration in feed or drinking water at a concentration of 5 to 5000 ppm, preferably 25 to 500 ppm, is preferred.

For parenteral administration, for example, intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile injectable solutions of the active ingredients are usually employed. In this connection, solutions of the therapeutically active compound according to the invention can be used either in sesame or peanut oil or in aqueous propylene glycol. The pH of the aqueous solutions should be suitably adjusted and buffered, if necessary, preferably above 8, and the liquid diluent first rendered isotonic. Such aqueous solutions for administration in the form of injection solutions.

oil intravenous solutions are suitable for intraarticular,

All of these in accordance with which intramuscular and subcutaneous injection solutions are made under sterile conditions by standard pharmaceutical technologies well known to those skilled in the art. In the case of animals, the compounds may be administered intramuscularly or subcutaneously at a daily dose in the range of about 0.1 to 50 mg / kg, preferably in the range of about 0.2 to 10 mg / kg, which can be administered in a single dose or in the form of up to 3 sub-benefits.

The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas. Suppositories contain conventional bases such as cocoa butter or other glycerides.

103

For intranasal or inhalation administration, the active compounds of the invention are conveniently delivered in the form of a solution or suspension that is released from the container by a patient-controlled spray pump or an aerosol that is released from a pressurized or nebulizer using suitable propellants such as dichlorodifluoromethane , trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. With a pressurized aerosol, the dosage unit can be determined first using a valve that releases a metered amount. The pressures or nebulizers may contain a solution or suspension of the active compound. It is also possible to prepare capsules or cartridges (made, for example, of gelatin) for inhalers and insufflators, which contain a powder mix of a compound of the invention and suitable powder bases such as lactose or starch.

For topical ocular administration, direct application to the affected eye, formulations such as eye drops, aerosols, gels or ointments may be used. The active compounds may also be incorporated into a collagen matrix (such as poly-2-hydroxyethyl methacrylate or copolymers thereof) or hydrophilic polymer matrices. These agents can also be administered as contact lenses or via a local reservoir or as formulations intended to be administered under the conjunctiva.

For intra-orbital administration, sterile injectable solutions of the active ingredient are usually prepared. Solutions of the therapeutically active compound of the invention in aqueous solution or suspension (with particle size less than 10 µm) can be used. The aqueous solutions should preferably be adjusted and buffered, preferably to a pH of 5-8, and the liquid diluent first rendered isotonic. In order to increase the viscosity or achieve a long-term release it is possible to add it

104 small amounts of polymers (such as cellulose polymers, dextran, polyethylene glycol or alginic acid). These solutions are suitable for intraorhital injection. All of these solutions are readily prepared under sterile conditions using standard pharmaceutical procedures well known to those skilled in the art. In the case of animals, daily dosages in the range of about 0.1 to 50 mg / kg, preferably in the range of about 0.2 to 10 mg / kg, can be administered intraorbitally, which can be administered as a single dose or as one to three divided doses. .

As with the other routes of administration described and the corresponding dosage forms, the oral dosage forms are preferably formulated so as to provide controlled, sustained and / or delayed release of the active ingredient. Typical examples are delayed-release oral tablets, capsules and microparticles, as well as enteric-coated tablets and capsules that prevent the release and absorption of the active ingredient in the patient's stomach and facilitate enteric drug delivery to the distal regions of the gastrointestinal tract. Typical oral dosage forms include sustained release oral tablets, capsules, and multiparticulates that allow controlled systemic delivery of the active ingredient over an extended period of time, such as 24 hours. If rapid delivery of the active ingredient is desired or necessary, controlled release oral dosage forms can be used, such as rapid dissolution tablets, preferably containing highly soluble salt forms of the active ingredient.

The invention is illustrated by the following examples. These examples are illustrative only and do not limit the scope of the invention in any way.

105

The melting points given in these examples are uncorrected. NMR data are given in parts per million (δ) and are based on the deuterium keyed signal from the solvent sample (unless otherwise specified, deuterium chloroform is used). The reagents available on the market are used without further purification. Chromatography refers to column chromatography on silica gel (32 to 63 mm) carried out under nitrogen pressure (flash chromatography). Ambient temperature refers to a temperature of 20 to 25 ° C. All non-aqueous reactions are conducted under nitrogen for reasons of convenience and to maximize yields. Concentration under reduced pressure refers to the use of a rotary evaporator.

DETAILED DESCRIPTION OF THE INVENTION

General procedures

General example

Compounds of formula I may be prepared by reacting a suitable compound of formula III with urea of formula II (i.e., H ₂ N (CO) -NH ₂ ) in the presence of a suitable base, such as an alkoxide base, preferably sodium ethoxide, in polar a solvent such as an alcoholic solvent, preferably ethanol, at a temperature of from 20 ° C to the boiling point of the solvent used, preferably 80 ° C, for 15 minutes to 3 hours.

106

General preparatory procedure

The compound of formula III may be prepared by reacting the corresponding compound of formula IV with a suitable base, such as a tertiary amine or resin-bound base, such as Amberlyst 400® (hydroxide form), in a polar solvent such as an alcoholic solvent, preferably ethanol, at a temperature of about 0 to about 50 ° C, preferably at about 20 ° C, for about 6 to about 36 hours.

Compounds of formula IV may be prepared by treating the corresponding compounds of formula VI with a compound of formula V, i.e. L ³ - (A ¹⁾ and L ⁴ -L ³ - (A ') in an aprotic solvent, preferably an aromatic hydrocarbon such as benzene or toluene, at a temperature of about 40 DEG C. to the boiling point of the solvent, preferably 80 ^and C, for about 1 hour to about 6 hours.

Compounds of formula VI may be prepared by treating the corresponding compounds of the formula NH ₂ -XYZG with a compound of formula VII, which is 2-halogénmalonátový ester, preferably a 2-brómdietylmalonát, the presence of a suitable base such as a tertiary amine base, preferably a N, N-dimethylaniline, at a temperature of about 20 to about 100 ° C, preferably at about 80 ° C, for about 4 to about 48 hours.

Example 1

1- [6- (4-Bromo-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone

107

Example number structure MS, MS (APCI, m / z) [M + H] < ⁺ > ^. 1 η-s, [l U 445.238 445

Sodium metal (29 mg, 1.26 mmol) was added to 1.3 mL of ethanol. The resulting mixture was stirred until homogenized and then 1- [6- (4-bromo-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g, 0.42 mmol) was added and then urea (75 mg, 1.26 mmol). The resulting mixture was stirred at 80 ° C for 5 minutes, cooled to ambient temperature, acidified with 1M hydrochloric acid, and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexane / ethyl acetate (3: 1). 28 mg of 1- [6- (4-bromophenoxy) pyridin-3-yl] -1,7,9-triazaspiro [4,5] decane-2,6,8,10-tetraone are obtained as a colorless solid. HPLC Ret. time: 2.201 min; MS (APCI, m / z): 436 [MH] +; 438 [M + H] < ^{+ &gt};.

Preparatory procedure

2- (4-Bromophenoxy) -5-nitropyridine

4-Bromophenol (5.5 g, 32 mmol) was added to 42 mL of 50% sodium hydroxide. The mixture was stirred for 30 minutes, then 44 mL of toluene was added followed by 2-chloro-5108 nitropyridine (5.0 g, 32 mmol) and tetrabutylammonium bromide (10 g, 32 mmol). The reaction mixture was stirred at 23 ° C for 1.5 h, then diluted with 200 mL of water, neutralized with 12M aqueous hydrochloric acid, and extracted 3 times with ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. 6 g of 2- (4-bromophenoxy) -5-nitro-pyridine are obtained. 1 H NMR (CDCl ₃ , 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 + H] < ^{+ &gt};.

- (4-Bromo-phenoxy) -pyridin-3-ylamine

A mixture of 2- (4-bromophenoxy) -5-nitropyridine (6.0 g, 22.7 mmol), 200 mL of methanol and 50 mg of platinum oxide was shaken for 1 hour at 23 ° C under 50 psi of hydrogen, then filtered through a pad of celite and the filtrate was concentrated under reduced pressure. 6 g of 6- (4-bromophenoxy) pyridin-3-ylamine are obtained. 1 H NMR (CD ₃ OD, 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 + H] < ^{+ &gt};.

Preparatory procedure

1- [6- (4-Bromo-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester

A mixture of 6- (4-bromophenoxy) pyridin-3-ylamine (4.5 g, 16.9 mmol), 2-bromodimethylmalonate (4.1 g, 17 mmol) and N, N-dimethylaniline (2.1 g, 17 mmol) was stirred at 80 ° C for 24 h. The resulting mixture was cooled to 23 ° C and diluted with 50 mL of benzene. 7 ml of 2-bromopropionyl chloride are added to the diluted mixture. The reaction mixture was heated to reflux for 3 hours, then cooled to 23 ° C and concentrated under reduced pressure. The residue was diluted with 750 mL

Amberlyst-400 (hydroxide form) resin (75 g) was added to the ethanol mixture. The resulting mixture was stirred at 23 ° C for 24 h, then filtered and the resin was washed with 50 mL of methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with hexane / ethyl acetate (2: 1).

6 g of 1- [6- (4-bromophenoxy) pyridin-3-yl] pyrrolidine-2,2-dicarboxylic acid diethyl ester is obtained. 1 H NMR (CDCl ₃ , 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 (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 = 7.5 Hz) ppm. MS (APCI, m / z): 479 [M + H] < ^{+ &gt};.

The following compounds were prepared in a similar manner to that described in Example 1 using the appropriate pyridine and diethyl ester.

Table 1

Example number structure MS, MS (APCI, m / z) [M + H] < ⁺ > ^. 2 '9 at 384.327 385.1 3 HN H W ° F 398.354 399.1

110

Example 4

- [5- (2,6,8,10-tetraoxa-l, 7,9-triazaspiro [4.5] dec-l-yl) -pyridin-2-yloxy] -benzonitrile

Example number structure MS, MS (APCI, m / z) [M + H] < ⁺ > ^. 4 X HI't'-NH 0 391.346 392.1

Using the procedure described for the preparation of the pyrimidinetrione in Example 1, reaction of 1- [6- (4-cyanophenoxy) pyridin-3-yl] pyrrolidine-2,2-dicarboxylic 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 ethanol gives 14.3 mg of 4- [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [4,5] dec- 1-yl) pyridin-2-yloxy] benzonitrile as a colorless solid. 1 H NMR (CD ₃ OD, 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 (APCI, m / z): 390 [MH] +; 392 [M + H] < ^{+ &gt};.

111

Preparatory procedure

1- [6- (4-Cyanophenoxy) pyridin-3-yl] pyrrolidine-2,2-dicarboxylic acid diethyl ester

A mixture of 1- [6- (4-bromophenoxy) pyridin-3-yl] pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.28 g, 0.53 mmol), zinc cyanide (0.037 g, 0.32 mmol), tetrakis (triphenylphosphine) palladium (0) (0.024 g, 0.021 mmol) and 0.66 mL of dimethylformamide were heated at 80 ° C for 24 h. An additional 37 mg of zinc cyanide and 24 mg of tetrakis (three phenylphosphine) palladium (0) were added to the reaction mixture. The reaction mixture was stirred at 80 ° C for an additional 48 hours, then cooled to room temperature and diluted with toluene. The toluene mixture was washed with 2M ammonium hydroxide (2x) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by radial chromatography using a mixture of ethyl acetate and hexanes and then methanol as eluent. 58 mg of 1- [6- (4-cyanophenoxy) pyridin-3-yl] pyrrolidine-2,2-dicarboxylic acid diethyl ester is obtained in the form of a colorless syrup. 1 H NMR (CDCl ₃ , 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 + H] < ^{+ &gt};.

Example 5

1- [6- (4- [1,3,4] Oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4,5] decane-2,6,8,10-tetraone

112

Example number structure MS, MS (APCI, m / z) [M + H] < ⁺ > ^. 5 434.371 435.1

By the method described for the preparation of the pyrimidinetrione in Example 1, by reacting 1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2- diethyl ester. of dicarboxylic acid (200 mg, 0.44 mmol) with urea (0.080 g, 1.3 mmol) in 1.3 mL IM sodium ethoxide in ethanol yields 25 mg of 1- (6- (4- [1,3,4]) oxadiazol-2-ylphenoxy) pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone as a colorless solid 1 H NMR (CD ₃ OD, 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), 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] < ^{+ &gt};.

Preparatory procedure

1- [6- (4-Carboxyphenoxy) pyridin-3-yl] -5-oxopyrrolidine-2,2-dicarboxylic acid diethyl ester

113

A mixture of 1- [6- (4-formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.70 g, 1.64 mmol), sodium carbonate (0.26 g, 1.64 mmol) ) and 16.4 ml of a 1: 1 mixture of tert-butanol and water were treated with potassium permanganate (0.26 g, 1.64 mmol). The resulting mixture was stirred at room temperature for 2 hours, then quenched with sodium sulfite, hydrochloric acid, and extracted with 1M ethyl acetate.

The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. 1- [6- (4-Carboxyphenoxy) pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester was obtained as a colorless syrup (0.5 g). 1 H NMR (CDCl 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, 1H, 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 + H] < ^{+ &gt};.

Preparatory procedure

1- [6- (4-Hydrazinocarbonylphenoxy) pyridin-3-yl] -5-oxopyrrolidine-2,2-dicarboxylic acid diethyl ester

A mixture of 1- [6- (4-carboxy-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.4 g, 0.97 mmol), 1-hydroxybenzotriazole hydrate (0.176 g, 1). , 3 mmol), 1,2-dichloroethane (0.25 g, 1.3 mmol) and 6 mL of methylene chloride were stirred at room temperature for 20 min and then treated with bochydrazide (0.17 g, 1.3 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with ethyl acetate and washed with 1M hydrochloric acid, sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 5 ml of the mixture

114 methylene chloride / trifluoroacetic acid 1: 1 (v / v). The solution was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1M sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated. There was thus obtained 1- [6- (4-hydrazinocarbonylphenoxy) pyridin-3-yl] -5-oxopyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g) as a colorless syrup. HPLC: 2.770 min.

Preparatory procedure

1- [6- (4- [1,3,4] Oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester

A mixture of 1- [6- (4-hydrazinocarbonylphenoxy) pyridin-3-yl] -5-oxopyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g, 0.44 mmol), trimethyl orthoformate (0.1 mL, 0) (91 mmol) and 1 ml of xylenes are heated at reflux for 24 hours and then concentrated under reduced pressure. 1- [6- (4- [1,3,4] Oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g) was obtained as a colorless solid. syrup. MS (APCI, m / z): 467.2 [M + H] < ^{+ &gt};.

115

Example 6

1- [6- (4-Ethyl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4,5] decane-2,6,8,10-tetraone

Example number structure MS, MS (APCI, m / z) [M + H] < ⁺ > ^. 6 Xa CH, 394.39 395.3

Following the procedure described for the preparation of the pyrimidine trione in Example 1, by reaction of 1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (200 mg, 0.41 mmol) with urea (0.088 g, 1.4 mmol) in 1.4 mL of 1M sodium ethoxide in ethanol yields 25 mg of 1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone as a colorless solid. 1 H NMR (CDCl ₃ , 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 (t, 3H, J = 8.0 Hz) ppm.

116

Preparatory procedure

1- [6- (4-Ethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester

A mixture of 1- [6- (4-vinyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g), 50 mg of 10% palladium on carbon and 20 ml of ethyl acetate was shaken under an atmosphere for 2 hours. of hydrogen (343.5 kPa), then filtered and the filtrate was concentrated under reduced pressure. 0.20 of 1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester is obtained as a colorless syrup. 1 H NMR (CDCl ₃ , 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 = 7.5Hz) 7.05 (d, 2H, J = 8.0 Hz), 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 = 8.0Hz), 1.20 (t, 6H, J = 7.5Hz) ppm. P r d 1 and d 7

N- {4- [5- (2,6,8,10-tetraoxa-l, 7,9-triazaspiro [4.5] dec-l-yl) -pyridin-2-yloxy] -benzyl} -acetamide

Example number structure MS, MS (APCI, m / z) [M + H] < ⁺ > ^. 7 about 437.415 438.2

117

A mixture of 1- {6- [4- (tert-butoxycarbonylamino-methyl) -phenoxy] -pyridin-3-yl} -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.52 mmol) and a 2 mL solution of trifluoroacetic acid in methylene chloride (1: 1, The mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The residue was dissolved in 2.6 ml of methylene chloride. The resulting solution was mixed with MMP-resin (polymer-bound N-methylmorpholine base, 0.86 g, 1.75 mmol) and acetyl chloride (0.055 g, 0.7 mmol). The resulting mixture was shaken for 24 hours, then filtered and the resin was washed with methylene chloride. The combined filtrates were concentrated in vacuo. The residue is dissolved in 1.5 ml of 1M sodium ethoxide in ethanol and mixed with 94 mg of urea. The reaction mixture was stirred at 80 ° C for 10 minutes and treated with the polystyrene resin bound with sulfonic acid. The resulting mixture was filtered and the resin was washed with 10 mL of 2M ammonia in methanol. The combined filtrates were concentrated under reduced pressure, and the residue was purified by reverse phase chromatography eluting with acetonitrile: water: trifluoroacetic acid followed by radial chromatography using 10% methanol in methylene chloride as eluent. N- {4- [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [4,5] dec-1-yl) pyridin-2-yloxy] benzyl} acetamide is obtained in the form of: colorless solid. HPLC Ret. time: 2.201 min; MS (APCI, m / z): 436 [MH] +; 438 [M + H] < ^{+ &gt};.

Preparatory procedure

1- [6- (4-Vinyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester

A mixture of 1- [6- (4-bromo-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (5.8 g, 12.2 mmol),

118 vinyltributyltin (3.9 mL, 12.3 mmol), tetrakis (triphenylphosphine) palladium (0) (0.60 g, 0.52 mmol) and 24 mL of toluene were heated at reflux for 1 hour then cooled to room temperature. and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Flash 40) eluting with 20% to 50% ethyl acetate in hexanes. 4.8 g of 1- [6- (4-vinylphenoxy) pyridin-3-yl] pyrrolidine-2,2-dicarboxylic acid diethyl ester are obtained in the form of a colorless syrup.

Preparatory procedure

1- [6- (4-Formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester

A mixture of 1- [6- (4-vinylphenoxy) pyridin-3-yl] pyrrolidine-2,2-dicarboxylic acid diethyl ester (4.8 g, 11.3 mmol), sodium periodate (4.8 g, 22 mmol), osmium tetroxide (10 mg) and dioxane / water (189 mL) 2: 1 were stirred at ambient temperature for 6 hours. The reaction was quenched with sodium sulfite, diluted with water, and extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 1- [6- (4-Formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester was obtained as a colorless syrup (4.6 g).

Preparatory procedure

1- {6- [4- (tert-Butoxycarbonylaminomethyl) phenoxy] pyridin-3-yl} pyrrolidine-2,2-dicarboxylic acid diethyl ester

A mixture of 1- [6- (4-formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.1 g, 0.24 mmol),

119 tert-butoxycarbonylamide (0.083 g, 0.71 mmol), triethylsilane (0.11 mL, 0.083 g, 0.71 mmol) and acetonitrile (1 mL) were mixed with trifluoroacetic acid (0.035 mL, 0.46 mmol). The resulting mixture was stirred at ambient temperature for 48 hours, then diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. 1- {6- [4- (tert-Butoxycarbonylaminomethyl) phenoxy] -pyridin-3-yl} -pyrrolidine-2,2-dicarboxylic acid diethyl ester is obtained as a colorless syrup.

The following compounds were prepared in a similar manner to that described in Example 7 using the corresponding pyridine and diester.

Table 2

Example number structure MS, MS (APCI, m / z) [M + H] < ⁺ > ^. 8 0 451.443 452.2 9 ABOUT 465.47 466.2

120

10 Ya "Φ 0 479.497 480.2 11 U ⁰ n 477.481 478.4

Example 12

1- [6- (4-Pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4,5] decane-2,6,8,10-tetraone

Example number structure MS, MS (APCI, m / z) [M + H] < ⁺ > ^. 12 o3Uo CP b ^ 0 446.43 447.2 x about

121

By the method described for the preparation of the pyrimidinetrione in Example 1, by reaction of 5-oxo-1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g, 0.4 mmol) with urea (0.074 g, 1.2 mmol) in 1.2 mL IM sodium ethoxide in ethanol gives 6 mg of 1 [6- (4-pyrazol-1-ylmethylphenoxy) pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone as a colorless solid. ¹ H NMR (CD ₃ OD, 500 MHz): 7.99 (d, 1H, J = 2.5 Hz), 7.72

(M, 2H), 7 53 (D, IH , J = 2.5 Hz) , 7.29 (d, 2H, J = 8.5 Hz 7.10 (D, 2H, d = 8 5 Hz), 6. 97 (d, 1 H, J-8.5 Hz), 6.35 (t, 1H, J = 2.0) Hz), 5.38 ( with, 2H), 2 76 (m, 2H) 2.65 (m, 2H) ppm. MS (APCI, m / z) : 447, 2 [H + H] ⁺ . P r í p r and in n ý P o s t u p 1

1- [6- (4-Hydroxymethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester

To a solution of 1- [6- (4-formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (1.0 g, 2.3 mmol) in 30 mL of ethanol at 0 ° C was added sodium borohydride (0.090 g, 2.3 mmol). The resulting mixture was stirred for 3 hours and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and water. The aqueous layer was carefully acidified with 1M hydrochloric acid and then neutralized with saturated aqueous sodium bicarbonate. The resulting mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. 0.80 g (80%) of 1- [6- (4-hydroxymethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester is obtained as a colorless syrup. ¹ H NMR (CDCl ₃ , 400 MHz): 8.04 (d, 1H, J = 2.4 Hz), 7.72 (dd, 1H, J = 2.4, 8.8 Hz), 7.40 (d, 2H, J = 8.8 Hz), 7.12 (d, 2H, J = 8.4 Hz), 6.91

122 (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 + H] < ^{+ &gt};.

Preparatory procedure

1- [6- (4-Bromomethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester

To a solution of 1- [6- (4-hydroxymethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.80 g, 1.9 mmol) in 9.4 mL of methylene chloride was added triethylamine (0.46 mL, 0.33 g, 3.3 mL). The resulting mixture was cooled to -40 ° C and treated with methanesulfonyl chloride (0.20 mL, 0.30 g, 2.61 mmol). The reaction mixture was stirred for 1 hour, additional methanesulfonyl chloride (0.10 mL) and triethylamine (0.4 mL) were added and stirring was continued for another hour. A solution of anhydrous lithium bromide (1.6 g, 19 mmol, flame dried under reduced pressure) in tetrahydrofuran (20 mL) was added via cannula. The reaction mixture was warmed to room temperature, stirred for 2 hours and diluted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered and the filtrate is concentrated under reduced pressure. The residue was passed through a pad of silica gel using 1: 1 ethyl acetate / hexanes as eluent. 0.65 g of 1- [6- (4-bromomethyl-phenoxy) -pyridin-3-yl] -5- isopropyl ester is obtained.

oxo-pyrrolidine-2,2-dicarboxylate ej of VO a colorless syrup. ¹ H NMR (CDC ₁₃₀₀ , 500 MHz): 8.07 (d, 1 H, J = 3.0 Hz), 7.76 (dd, 1H, J = 2) 5. 8.5 Hz), 7.44 (D, 2H, J = 8.5 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 = 7.0Hz), 2.75 (m, 2H), 1.20 (T, 6H, J = 7.0 Hz) ppm.

123

Preparatory procedure

5-Oxo-1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester

To a solution of 1- [6- (4-bromomethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g, 0.4 mmol) in 0.8 mL of dimethylformamide is added pyrazole. (0.056 g, 0.82 mmol) and potassium carbonate (0.11 g, 0.82 mmol). The resulting mixture was stirred at 50 ° C for 24 h and then diluted with water. The aqueous mixture was extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product is obtained in the form of a colorless oil which is used directly in the next step.

While the invention has been described and illustrated with reference to some particular embodiments, it will be apparent to those skilled in the art that the methods and processes described herein may be adapted, varied, modified and replaced, deleted, and added individual steps or components in a manner avoiding this. to move away from the spirit of the invention and escape from its scope. For example, based on the sensitivity of the mammal being treated for any indication with a compound of the invention, effective dosages that differ from the particular dosages listed above can be used. Similarly, pharmacological responses may vary depending upon the particular active compound selected, the choice of choice. pharmaceutical carriers and type of formulation and route of administration. Such variations or differences in results are consistent with the objectives and methods of practicing the invention. The scope of the invention is given by the appended claims, which are interpreted in acceptable width.

Claims (11)

PATENT CLAIMS Compounds of general formula I (I) wherein A represents a 5- to 7-membered heterocyclic ring selected from the group consisting of groups a) to o) X-Y-Z-G 125 where R ¹² and R ¹³ are each R · ¹ D ³ D ° D 'D ° D-' X f X \. f X \. / X * - / X \ f Xv / XX. f XX. f XX. f XX independently selected from the group consisting of hydrogen, (C 1 -C 4) alkyl, (C _x -C ₄₎ alkenyl, (C _x -C ₄₎ alkynyl, (C ₆ -C ₀₎ aryl, (C _x0) heteroaryl, (C ₃ -C ₈₎ cycloalkyl and (C _x -C _{* o)} heterocyclyl; wherein the (C _x -C ₄₎ alkyl, (C ₆ -C ₁₀₎ aryl, _(C-C10) heteroaryl, (C ₃ -C ₈₎ cycloalkyl and (C _{* o)} heterocyclyl moieties may be optionally substituted on any carbon of the the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from the group consisting of halogen, (C _x -C ₄₎ alkyl, (C _x -C ₄₎ alkoxy, -CN, -OH, and -NH ₂ ; X is (C ₆ -C ₁₀₎ aryl radical or _(Ο χ -Ο ₁₀₎ heteroaryl; Y is selected from the group consisting of a bond, oxygen, sulfur, > C = O, > SO ₂ , > S = O, -CH ₂ -, -CH ₂ O-, -O (CH ₂ ) _n -, 126 -SO ₂ (CH ₂ ) _n -, -CH ₂ S-, -S (CH ₂ ) _n -, CH ₂ SO-, -CH ₂ SO ₂ -, -SO (CH ₂ ) _n -, -NR ¹⁴ , -NR ¹⁴ (CH ₂ ) _n -, (CH ₂ ) 2 [N (R ¹⁴ )] -, -CH 2 (CH ₂ ) _n -, -CH = CH-, -C = C-, - [N (R ¹⁴ )] -SO ₂ - and -SO ₂ [N (R ¹⁴ )] -; n is an integer from 1 to 4; R ¹⁴ is hydrogen or (C 1 -C 4) alkyl; Z is selected from the group consisting of (C ₆ -C 10) aryl, (C ₃ -C ₈₎ cycloalkyl, (C _x -C 10) heterocyclyl or (C-C, o) heteroaryl; wherein in (C ₃ -C ₈ ) cycloalkyl or (C _x C 10) heterocyclyl one or two single carbon-carbon bonds are optionally replaced by carbon-carbon double bonds; wherein each of X and Z is independently optionally substituted on any of the ring carbon atoms capable of forming an additional bond by 1 or 2 ring substituents independently selected from the group consisting of fluoro, chloro, bromo, CN, OH, (C1- 4) alkyl, (C 1 -C 4) perfluoro alkyl group, (C1 -C4) perfluoroalkoxy, (C1 -C4) alkoxy and (C ₃ -C ₈₎ cycloalkyloxy; G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; wherein G is a substituent on any ring carbon atom of residue Z capable of forming an additional bond and is oriented at a position different from the alpha position with respect to the point of attachment of the ring Z to residue Y; p is an integer from 0 to 4; 127 R ¹⁵ is independently selected from the group consisting of halogen, -CN, -NO ₂ , OH, (C 1 -C 4) alkenyl, (C 1 -C 4) -alkynyl, (C 1 -C 4) perfluoroalkyl, perfluoro- (C 1 -C 4) -alkynyl; C4) alkoxy, R ¹⁸ -, R ¹⁸ -0-, R ¹⁸ (C 1 -C 4) -alkyl-O-, R ¹⁸ - (C = O) -, R ¹⁸ - (C = 0) -0-, R ¹⁸ -0- (C = O) - R ¹⁸ S-, R ²² - (S = O) -, R ¹⁸ - (SO 2) -, R ²² - (SO 2) - (NR ²¹ ) -, R ¹⁹ - (C = O) (NR ²¹ ) -, R ²² -O- (C = O) - (NR ²¹ ) -, (R ¹⁹ R ²⁰ ) N -, (R ¹⁹ R ²⁰ ) N- (SO ₂ ) - , (R ¹⁹ R ²⁰⁾ N (C = 0) -; (R ¹⁹ R ²⁰⁾ N- (C = 0) - (NR ²¹⁾ -, and (R ¹⁹ R ²⁰⁾ N- (C = O) 0-; R ¹⁶ and R ¹⁷ are each independently selected from the group consisting of hydrogen and (C 1 -C 4) alkyl; or R ¹⁶ and R ¹⁷ may optionally be taken together with the carbon atom to which they are attached to form a 5- to 10-membered carbocyclic ring; R ^18, R ^19, R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, (C 1 -C 4) alkyl, (C ₆ -C 10) aryl, (C ₃ -C ₈₎ cycloalkyl, (C ₃ -C 10) heteroaryl and (C 1 -C 10) heterocyclyl; wherein the (C ₆ -C ₁₀₎ aryl, (C ₃ -C ₈₎ cycloalkyl group, a (C ₃ -C 10) heteroaryl and (C1 -C10) heterocyclyl optionally substituted on any of the ring carbon atoms capable of forming an additional bond, 1 to 3 substituents per ring independently selected from the group consisting of F, Cl, Br, CN, OH, (C 1 -C 4) alkyl, _(Ci-C4) luóralkylskupiny perf, (C ₃ -C ₄₎ perfluoroalkoxy, (C1 4) alkoxy, amino, (C 1 -C 4) alkyl-NH-, [(C 1 -C 4) alkyl] ₂ -Na (C ₃ -C _B) cycloalkyloxy; wherein (C ₃ -C ₈ ) cycloalkyl and (C 1 -C ₁₀ ) heterocyclyl are also optionally substituted with oxo; and where (C ₃ 128 C ₁₀ ) heteroaryl and the (C 1 -C ₁₀ ) heterocyclyl group is optionally substituted on any ring nitrogen atom capable of carrying an additional substituent with 1 to 2 ring substituents independently selected from the group consisting of (C 1 -C ₄ ) alkyl, and (C 1 -C ₄ ) alkyl- (C = O) -; or R ¹⁹ and R ²⁰ may optionally be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocyclic ring; or R ¹⁹ and R ²¹ may optionally be taken together with the nitrogen, carbon or oxygen atom to which they are attached to form a 3- to 8-membered heterocyclic ring; R ²² is selected from the group consisting of (C _x -C ₄₎ alkyl, (C ₆ -C ₁₀₎ aryl, (C ₃ -C ₈₎ cycloalkyl, (C-oxo) hetero roarylskupiny a (Ci-Cio) heterocyclyl ; wherein (C ₆ -C ₁₀ ) aryl-, (C ₃ -C ₈ ) cycloalkyl-, (C ₁ -C ₁₀ ) heteroaryl- and (C 1 -C 10) heterocyclyl is optionally substituted at any of the ring carbon atoms that are capable of forming an additional bond, from 1 to 3 substituents per ring independently selected from F, Cl, Br, CN, OH, _(Ci-C4) alkyl, (C 1 -C 4) perfluoro luóralkylskupiny, (C 1 -C 4) -perf luóralkoxyskupiny, (C1- 4) alkoxy, amino, (C 1 -C 4) alkyl-NH-, [(C 1 -C 4) alkyl] ₂ -Na (C ₃ -C ₈₎ -cykloalkyloxyskupiny; wherein (C ₃ -C ₈ ) cycloalkyl and (C 1 -C ₁₀ ) heterocyclyl is optionally also substituted with oxo; wherein the (C 1 -C ₁₀ ) heteroaryl and (C 1 -C ₁₀ ) heterocyclyl groups are optionally substituted on any ring nitrogen atom capable of carrying an additional substituent, 1 to 2 129 Two substituents per ring independently selected from the group consisting of _(Ci-C4) alkyl groups and a group (C _x -C ₄₎ alkyl- (C = 0) -; or R ²¹ and R ²² may optionally be taken together with the nitrogen, oxygen or sulfur atom to which they are attached to form a 3-8 membered heterocyclic ring; and pharmaceutically acceptable salts thereof. Compounds according to claim 1, wherein A is selected from the group consisting of radicals of formulas j), k) and 1) Compounds according to claim 1, wherein X is (C ₆ -C ₁₀ ) aryl. Compounds according to claim 1, wherein X is (C 1 -C ₁₀ ) heteroaryl. Compounds according to claim 1, wherein Y represents oxygen. Compounds R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p - wherein according to claim p represents 1, where G is 0. represents a group Compounds R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p - wherein according to claim p represents 1 wherein G is an integer from 1 to 4. group 130 8. Compounds according to claim 1 selected from the group consisting of 1- [6- (4-fluorophenoxy) pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone; 1- [6- (4-fluorophenoxy) pyridin-3-yl] -1,8,10-triazaspiro [5.5] undecane-2,7,9,11-tetraone; 4- [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [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-triazaspiro [4.5] decane-2,6,8,10- tetraone; 1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone; N- (4- [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} -acetamide; N- {4- [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} propionamide; N- {4- [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} butyramide; Pentanoic acid 4- [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzylamide; Cyclobutanecarboxylic acid 4- [5- (2,6,8,10-tetraoxo-1,7,9-triazaspiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzylamide; 1- [6- (4-bromo-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone; 131 1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone; and pharmaceutically acceptable salts thereof. A pharmaceutical composition for the treatment of conditions selected from the group consisting of connective tissue disorders, inflammatory disorders, immune / allergic disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system (CNS) disorders, liver / kidney, reproductive disorders, stomach disorders, skin disorders and cancers of mammals, including humans, comprising the compound of claim 1 in an amount effective in such treatment, and a pharmaceutically acceptable carrier. A method of treating conditions selected from the group consisting of connective tissue disorders, inflammatory disorders, immune / allergic disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system (CNS) disorders, liver / kidney disorders, reproductive disorders, stomach disorders, skin disorders, and cancer of a mammal, including a human, comprising administering to the mammal the compound of claim 1 in an amount effective to treat such a condition. A pharmaceutical composition for treating a condition that can be treated by inhibiting matrix metalloproteinases in a mammal, including a human, comprising the compound of claim 1 in an amount effective in such treatment and a pharmaceutically acceptable carrier.