BG107653A - 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 other disorders. 11 claims

Description

Technical field

The present invention relates to 5-spiro-pyrimidine-

2,4,6-trion inhibitors of metalloproteinase and to pharmaceutical compositions and methods for the treatment of inflammation, cancer and other disorders.

The compounds of the present invention are inhibitors of zinc metalloendopeptidases, and in particular those that belong to the class of matrix metalloproteinases (also referred to as MMP or matrixin).

BACKGROUND OF THE INVENTION

The subfamily of matrix metalloproteinase enzymes currently has seventeen members (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13 , MMP-14, MMP-15, MMP-16, MMP-17, MMP-18, MMP-19, MMP-20). Matrix metalloproteinases are best known for their involvement in regulating the conversion of extracellular matrix proteins, and thus play an important role in normal physiological processes such as reproduction, development and differentiation. In addition, matrix metalloproteinases are expressed in a number of pathological situations in which atypical alteration of connective tissue occurs. For example, MMP-13 has been shown to be an enzyme that

possesses strong degradation activity of type II collagen (the major collagen in cartilage), is overexpressed in osteoarthritic cartilage (Mitchell, et al., J. Clin. Invest. 97, 761 (1996)). Other matrix metalloproteinases (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are also overexpressed in osteoarthritic cartilage and inhibition of some or all of the matrix metalloproteinases is expected to decrease or stop accelerated, accelerated characteristic of joint diseases such as osteoarthritis or rheumatoid arthritis.

It can be appreciated that different combinations of matrix metalloproteinases are expressed in different pathological conditions. Therefore, inhibitors with specific selectivity for individual MMPs may be preferred for individual diseases.

Matrix metalloproteinase inhibitors are known from the literature. European Patent Publication 606,046, issued July 13, 1994, describes certain hydroxamic acids, inhibitors of matrix metalloproteinases. PCT Publication WO 98/58925, published December 30, 1998, refers to some pyrimidine-2,4,6-trione inhibitors of matrix metalloproteinases. PCT Publication WO 00/47565, published August 17, 2000, relates to certain aryl-substituted pyrimidine-

2,4,6-trionic MMP inhibitors. US Non-provisional Application 09/635156, filed Aug. 9, 2000 (taking precedence of U.S. Preliminary Application 60/148547, filed Aug. 12, 1999), relates to heteroaryl-substituted pyrimidine-2,4,6-trionic MMP inhibitors. An American provisional application entitled Pyrimidine-2,4,6-trione metalloproteinase inhibitors, filed October 26, 2000, relates to certain pyrimidine-2,4,6-trione. Barbituric acids and methods for their preparation are known in the art, see for example Goodman and Gilman's, The Phamacological Basis of Therapeutics. 345-382 (Eighth Edition, McGraw Hill, 1990). Each of the publications and applications cited above is incorporated by reference in its entirety.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula:

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

X-Y-Z-G

X-Y-Z-G

wherein each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ ,

12 13

R, R and R are independently selected from the group consisting of hydrogen, (C 1 -C 4 alkyl, (C 1 -C 4 alkenyl, (C 1 -C 4 alkynyl, (C 1 -C 10) aryl, (C 1 -C 10) -heteroaryl, (C 3 -C 8) ) cycloalkyl and (C 1 -C 4 heterocyclyl; wherein each of said (C 1 -C 6 alkyl, (C 6 -C 10) aryl, (C 1 -C 10) heteroaryl, (C 3 -C 8) cycloalkyl and (C 1 -C 10) heterocyclyl may be optionally substituted at each of the ring carbon atoms capable of forming an additional bond, with 1-3 ring substituents independently selected from halo, (Cf.

C4) alkyl, (C1-C4) alkoxy, -CN, -OH and -NH2;

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

Y is selected from the group consisting of bond, oxygen, sulfur,> C = O,> SO ₂ ,> S = O, -CH ₂ -, -CH ₂ 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 [N (R ¹⁴ )] -, -CH ₂ (CH ₂ ) _n -, -CH = CH-, -OC-, - [N (R ¹⁴ )] SO ₂ - in -SO ₂ [ N (R ¹⁴ )] -;

n is an integer from one to four;

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 1 -C 10) heterocyclyl and (C 1 -C 10) heteroaryl; wherein one or two carbon-carbon single bonds of said (C 3 -C 8) cycloalkyl or (C 1 -C 6 heterocyclyl may optionally be replaced by carbon-carbon double bonds;

wherein each of said X or Z may be optionally independently substituted at each of the ring carbon atoms capable of forming an additional bond with one or two ring substituents independently selected from F, Cl, Br, CN, OH, (C1 -C 4) alkyl, (C 1 -C 4) perfluoroalkyl, (C 1 -C 4) perfluoroalkoxy, (C 1 -C 4) alkoxy and (C 3 -C 8) cycloalkyloxy;

16 17

G is R - (CR R) p-; wherein G is a substituent on each ring carbon of Z capable of forming an additional bond and is oriented in a position other than alpha relative to the attachment point of the ring Z to Y;

p is an integer from 0 to 4;

R ¹⁵ is independently selected from the group consisting of halo, -CN, -NO 2, OH, (C 1 -C 4 alkenyl, (C 1 -C 4 alkynyl, (C 1 -C 4) 18 18 18 perfluoroalkyl, perfluoro (C 1 -C 4) alkoxy, R -, R -O-, R - (C 4 -C 4) alkyl-O-, R ¹⁸ - (C = O) -, R ¹⁸ - (C = O) -O-, R ¹⁸ -O- (C = O) - , R ¹⁸ -S-, R ²² (s = o) -; r ¹⁸ - (so2) -, r ²² - (so2) - (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 = O) - (NR ²¹ ) - (R ¹⁹ R ²⁰ ) N- (C = O) -O-;

^W each of R ¹⁶ and R ¹⁷ is independently selected from hydrogen and (C 1 -C 4) alkyl;

17 or R and R may optionally be taken together with the carbon to which they are attached, forming a 5 to 10 membered carbocyclic ring;

19 20 21

R, R, R and R 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 1 -C 6)) heteroaryl, and (C 1 -C 4). C10) heterocyclyl; wherein said (C 1 -C 10) aryl, (C 3 -C 8) cycloalkyl, (C 1 -C 10) heteroaryl and (C 1 -C 8)

C10) heterocyclyl structures may optionally be substituted at each of the ring carbon atoms, capable of forming an additional bond, with one to three ring substituents independently selected from F, Cl, Br, CN, OH, (C1-C4) alkyl, (C 1 -C 4) perfluoroalkyl, (C 1 -C 4) perfluoroalkoxy, (C 1 -C 4) alkoxy, amino, (C 1 -C 4) aAkuA-NH-, [(C 1 -C 4) alkyl] ₂ -H- and (C 3 -C 8) cycloalkyloxy ;

wherein said (C 3 -C 8) cycloalkyl and (C 1 -C 6) heterocyclyl structures may also be optionally substituted by oxo; where mentioned (Cf.

C1-10) heteroaryl and (C1-C10) heterocyclyl structures may optionally be substituted at each ring nitrogen atom capable of supporting an additional substituent with one to two ring substituents independently selected from the group consisting of (C1-C4) alkyl and (C 1 -C 4) alkyl- (C = O) -;

20 or R and R may optionally be taken together with the nitrogen to which they are attached, forming a 3 to 8 membered heterocycle;

21 or R and R may optionally be taken together with the nitrogen, carbon or oxygen to which they are attached, forming a 3 to 8 membered heterocycle;

R is selected from the group consisting of (C 1 -C 4) alkyl, (C 1 -C 10) aryl, (C 3 -C 8) cycloalkyl, (C 1 -C 10) heteroaryl, and (C 1 -C 3) heterocyclyl; wherein said (C 6 -C 10) aryl, (C 3 -C 5) cycloalkyl, (C 1 -C 10) heteroaryl and (C 1 -C 6 heterocyclyl structures may be optionally substituted at each of the ring carbon atoms capable of forming an additional bond up to three ring substituents independently selected from F, Cl, Br, CN, OH, (C1-C4) alkyl, (C1-C4) perfluoroalkyl, (C4-C4) perfluoroalkoxy, (C1-C4) alkoxy, amino, ( C 1 -C 4 alkyl-MH-, [(C 1 -C 4) alkyl] 2-N- and (C 3 -C 8) cycloalkyloxy; wherein said (C 3 -C 8) cycloalkyl and (C 1 -C 10) heterocyclyl structures may also optionally be substituted oxo; wherein said (C 1 -C 10) heteroaryl and (C 1 -C 4 heterocyclyl) structures may optionally be substituted at each ring nitrogen atom capable of supporting an additional substituent with one to two ring substituents independently selected from the group consisting of from (C 1 -C 4 alkyl) and (C 1 -C 4) alkyl- (C = O) -;

22 or R and R may optionally be taken together with the nitrogen, oxygen or sulfur to which they are attached, forming a 3 to 8 membered heterocycle;

or pharmaceutically acceptable salts thereof.

The present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids that can be used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of the invention are those which form non-toxic acid addition salts, i. e. salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, nitrate, tartrate, tartrate, tartrate, tartrate methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e. 1,1-methylene-bis- (2-hydroxy-3-naphthoate)] salts.

The invention also relates to base addition salts of formula I. The chemical bases that can be used as reagents for the preparation of pharmaceutically acceptable base salts of compounds of formula I, which are acidic in nature, are those which form non-toxic base salts with the compounds in question. These non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations as alkali metal cations (e.g. potassium and sodium) and

cations of alkaline earth metals (eg calcium and magnesium), ammonium or water-soluble amino-addition salts such as N-methylglucamine (meglumine) and lower alkanolammonium and other basic salts of pharmaceutically acceptable organic amines.

The term bond, as used herein in group Y, means that the groups X and Z are directly bonded through a carbon carbon bond to form suspended aryl rings such as diphenyl.

The dotted lines as used in each of the heterocyclic rings A in formulas a), b), c), g), h),

(i), (k) and (1) relate to possible double bonds. The exact positions of the possible double bonds for each heterocyclic ring A of formulas a), b), c), g), h), i), k) and 1) are as defined in the specification. When the dashed line ends at two carbon atoms, it will be appreciated by one skilled in the art that the two carbons are tetravalent and that additional substituent (s) may be missing {i.e., each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ , R ¹² or R ¹³ ).

The term alkyl, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched structures or combinations thereof. The alkyl groups, wherever occurring, may optionally be substituted with a suitable substituent.

The term alkenyl, as used herein, unless otherwise indicated, includes hydrocarbon radicals containing at least one olefin bond and having straight or branched structures or combinations thereof.

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

The term cycloalkyl, as used herein, unless otherwise indicated, includes a mono- and bicyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, 1cyclopentyl, cyclohexenyl, bicyclopentyl, cyclohexenyl, bicyclohexycyclohexyl, cyclohexenyl, bicyclohexyl, cyclohexenyl, bicyclohexycyclohexyl, cyclohexenyl, cyclohexenyl, bicyclohexyl) [3.2.1] octanyl, bicyclo [5.2.0] nonanil, etc.); optionally containing 1 or 2 double bonds and optionally substituted with 1 to 3 suitable substituents as defined below, such as fluoro, chloro, trifluoromethyl, (C 1 -C 4 alkoxy, (C 6 -C 10) aryloxy, trifluoromethoxy, difluoromethoxy, difluoromethoxy, C 1 -C 4 alkyl, more preferably fluoro, chloro, methyl, ethyl and methoxy.

The term alkoxy as used herein includes Oalkyl groups, the alkyl being as defined above.

The term halo, as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The term aryl, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one or more hydrogen atoms, such as phenyl or naphthyl, optionally substituted with 1 to 3 suitable substituents such as fluoro, chloro, cyano , nitro, trifluoromethyl, (C 1 -C 6) alkoxy, (C 6 -C 6) aryloxy, (C 3 -C 8) cycloalkyloxy, trifluoromethoxy, difluoromethoxy or (C 1 -C 6) alkyl.

The term heteroaryl, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one or more hydrogen atoms, such as benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranzine, benzothyranine, benzothyranin

benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 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, C-substituted and of ring carbon atoms capable of forming an additional bond with one or two substituents independently selected from F, Cl, Br, CN, OH, (C 1 -C 4 alkyl, (C 1 -C 4) perfluoroalkyl, (C 1 -C 4) perfluoroalkoxy, ( C1-C4) alkoxy and (C3-C8) cycloalkyloxy The above groups can be attached to C or attached to N where possible For example pyrrolyl may be pyrrol-1-yl (N attached) or pyrrol-3-yl (C-attached).

The term heterocyclyl, as used herein, unless otherwise indicated, includes an organic radical derived from a non-aromatic heterocyclic compound by removal of one or more hydrogen atoms, such as 3azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, azetyl, pyrrolidone, pentoxide , n razolinil, pyrrolidinyl, 2pirolinil, 3-pyrrolinyl, quinolizinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl and trithianyl. Wherever possible, the above groups may be C-attached or N-attached. For example, piperidinyl may be piperidin-1-yl (N-attached) or piperidin-4-yl (C-attached). The above groups obtained from the above compounds may optionally be substituted, where possible, with a suitable substituent such as oxo, F, Cl, Br, CN, OH, (C 1 -C 4 alkyl, (C 1 -C 4) perfluoroalkyl, ( C 1 -C 4 perfluoroalkoxy, (C 4 -C 4) alkoxy, or (C 3 -C 8) cycloalkyloxy.

A suitable substituent is understood to mean a chemical and pharmaceutically acceptable functional group, i. a group that does not interfere with the inhibitory activity of the compounds disclosed. Such suitable substituents can be routinely selected by one of ordinary skill in the art. Examples of suitable substituents include, but are not limited to, halogen groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryl groups , aralkyl or heteroaralkyl groups, aralkoxy or heteroaralkoxy groups, carboxy groups, amino groups, alkyl and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups, dialks aminocarbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups and the like.

The expression in a position other than alpha relative to the place of attachment of the ring Z to Y, as used herein, unless otherwise indicated, means a chemically and pharmaceutically acceptable orientation of the bond linking Z with G (ZG bond) with respect to the bond, connecting Y with Ζ (YZ bond). Such relative orientation may be meta when the Ζ-G bond is at position 1.3 relative to the Y-Ζ bond. Another relative orientation may be steam when the ZG link is at position 1.4 relative to the Y-Z link.

Some compounds of formula I contain chiral centers and therefore occur in different enantiomeric forms. The invention relates to all optical isomers, enantiomers, diastereoisomers and stereoisomers of the compounds of formula I and mixtures thereof. The compounds of the invention also exist in the form of various tautomeric forms. The invention relates to all tautomers of the compounds of formula I. The person skilled in the art has a clear idea that in solution pyrimidine-2,4,6-trionic nuclei are in the form of a mixture of tautomers. The different ratio of tautomers in solid and liquid form depends on the different substituents in the molecule, as well as on the specific crystallization technique used to isolate the compound.

In one embodiment of the invention, the heterocyclic ring A of the compounds of formula I is selected from the formulas

a) or b):

wherein X is (C 6 -C 10) aryl, preferably phenyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, > C = O, -CH2-, -CH2O-, -O (CH2) _n- , -CH2CH2-, CH = CH-, and -C = C-; where n is 1 or 2; preferably Y is selected from the group consisting of oxygen, -OCH 2 - and -CH 2 O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A has the formula a) or b) wherein X is (C 6 -C 10) aryl, preferably phenyl. In this embodiment, Y is selected from the group consisting of sulfur,>SO2,> S = O, -CH2S-, -S (CH2) _n , -CH2SO-, -CH2SO2-, -SOCH2-, and -SO2 (CH ₂ ) _n -; where n is 1 or 2; preferably Υ is sulfur or> SO2V In another embodiment of the invention the heterocyclic ring A has the formula a) or b) wherein X is (C 6 -C 10) aryl, preferably phenyl. In this embodiment, Y is selected from the group consisting of CH2 [N (R ¹⁴ )] -,> NR ¹⁴ , -NR ¹⁴ (CH2) _n -, -SO2 [N (R ¹⁴ )] - u - [N (O) 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 has the formula a) or b) wherein X is (Cp

Heteroaryl selected from benzymidazolium, benzofuran, indole, isoindolyl, isoquinoline, isoxinyl, indole, isopropylamine benzthiazolyl, quinazolinyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (Cj15

Hc)) heteroaryl is optionally substituted on each of the ring carbon atoms, capable of forming an additional bond, with one or two substituents independently selected from F, Cl, Br, 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, oxadiazolyl, oxazolyl, pyrazinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl ; more preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably, V is hex piperidinyl. In this embodiment Y is a bond, oxygen, sulfur, -CH 2,> SO _2, -OCH 2 or -SN2O-; preferably Y is oxygen or OSN2- -SN2O-; more preferably Y is oxygen.

In another embodiment of the invention, heterocyclic ring A has the formula a) or b), wherein X is (C 1 -C 3)) heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofuranazinyl, 2H-1benzopyranyl, benzothiadiazine, benzothiazolidine benzoxazol, quinolin, furozanil, furon, indolent, indolent nyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (Cc-C10-substituted) is substituted bond, with one or two substituents independently selected from F, Cl, Br, CN,

OH, (C1-C4) alkyl, (C1-C4) perfluoroalkyl, (C1-C4) perfluoroalkoxy, (C1-C4) alkoxy and (C3-C8) cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of sulfur,>SO2,> S = O, -CH2S-, -S (CH2) _n- , -CH2SO-, -CH2SO2-, -SOCH2- and -SO2 (CH ₂ ) _n -; where n is 1 or 2; preferably Υ is sulfur or> SO2 In another embodiment of the invention the heterocyclic ring A has the formula a) or b), wherein X is (QC10) heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofuranazil, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazines , pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, and triazenatetinolate; carbon atoms capable of forming an additional bond with one or two substituents independently selected from F, Cl, Br, CN, OH, (C1-C4) alkyl, (C1-C4) perfluoroalkyl, (C1-C4) perfluoroalkoxy, ( C1-C4) alkoxy and (C3-C8) cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. 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 )] - u - [N (R ¹⁴ )] - SO 2 -, wherein R ¹⁴ is hydrogen or methyl; and n is 1 or 2.

In another embodiment of the invention, heterocyclic ring A has the formula a) wherein X is (C 1 -C 10) heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazolyl, benzothiazolyl, benzothiazolyl, chrominol, quinolin, furosanil, furopyrinidyl, furyl, imidazolyl, indazolyl, indolinyl, indolinyl, indolyl, nindolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridyl iridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (C1-C10) heteroaryl heteroaryl, heteroaryl, heteroaryl bond, with one or two substituents independently selected from F, Cl, Br, CN, OH, (C 1 -C 4 alkyl, (C 1 -C 4) perfluoroalkyl, (C 1 -C 4) perfluoroalkoxy, (C 3 -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; more preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH2-, > SO2, -OCH2-, and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A has the formula a) as defined in the above paragraph, wherein in the heterocyclic ring A the dashed line is a double bond.

In another embodiment of the invention, the heterocyclic ring A has the formula (b), wherein X is (C 1 -C 10) heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiazinyl, benzothiazolyl, benzothiazolyl, benzothiazolyl , cinolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinol, oxadiazolidin iridazinyl,

pyridinyl, quinolinyl, pyrimidinyl, quinoxalinyl, pyrazolyl, tetrazolyl, pyrrolyl, thiazolyl, quinazolinyl, thiadiazolyl, thienyl, triazinyl and triazolyl, where said (Cf.

Cl 10) heteroaryl is optionally substituted on each of the ring carbon atoms, capable of forming an additional bond, with one or two substituents independently selected from F, Cl, Br, 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, oxadiazolyl, oxazolyl, pyrazinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl; more preferably X is

pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH-, > SO2, -OCH2-, and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A has the formula b) as defined in the above paragraph, wherein in the heterocyclic ring A the dashed line is a double bond.

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

wherein X is (C1-C10) 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 bond, oxygen, sulfur, -CH2-, > SO2, OCH2-, and -CH2O-; preferably Y is oxygen, -OCH2- or CH2O-; more preferably Y is oxygen.

In another embodiment of the invention heterocyclic ring A has the formula c), wherein in the heterocyclic ring A the dashed line is a double bond so that the heterocyclic ring

A of formula (c) is selected from the group consisting of:

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

wherein X is (C1-C10) 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; r is more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of 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 embodiment of the invention heterocyclic ring A has the formula f):

wherein X is (C1-C10) 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 bond, oxygen, sulfur, -CH2-, > SO2, -OCH2-, and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferably Y is oxygen.

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

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 and pyrimidinyl; more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH2-, > SO2, -OCH2-, and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferably Y is oxygen.

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

wherein X is (C 1 -C 4 heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyridinyl, pyridinyl, pyrazinyl, pyrazinyl; is pyridinyl In this embodiment Y is selected from the group consisting of bond, oxygen, sulfur, -CH 2 -,> SC 2, -OCH 2 - and -CH 2 O-, preferably Y is oxygen, -OCH 2 - or -CH 2 O - more preferably Y is oxygen.

In another embodiment of the invention the heterocyclic ring A has the formula g) as defined in the above paragraph, wherein in the heterocyclic ring A the dashed line is a double bond.

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

wherein X is (C1-C10) 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 bond, oxygen, sulfur, -CH2-, > 802,

-OCH2- and -CH2O-; preferably Y is oxygen, -OCH 2 - or -CO 6 -; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A has the formula h) as defined in the above paragraph, wherein in the heterocyclic ring A the dashed line is a double bond.

In another embodiment of the invention, the heterocyclic ring A has the formula (i):

wherein X is (C 1 -C 4 heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is pyridinyl, pyridinyl, pyrazinyl, pyrazinyl; is pyridinyl In this embodiment Y is selected from the group consisting of bond, oxygen, sulfur, -CH 2 -,> SC 2, -OCH 2 - and -CH 2 O-, preferably Y is oxygen, -OCH 2 - or -CH 2 O - more preferably Y is oxygen.

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

In a preferred heterocyclic ring A, the group consisting of an embodiment of the invention has a formula selected from

wherein X is (C 1 -C 10) heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, w 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 bond, oxygen, sulfur, -CH2-, > SC > 2, -OCH2-, and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferably Y is oxygen.

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

j)

X-Y-Z-G

Where X is (C 1 -C 10) xemepoapuA 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 bond, oxygen, sulfur, -CH2-, > SO2, -OCH2-, and -CH2O-; preferably Y is oxygen, -OCH2- or -CH2O-; more preferably Y is oxygen.

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

X-Y-Z-G

Where 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 bond, oxygen, sulfur, -CH2-, > SO2, -OCH2-, and -CH2O-; preferably Y is oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring A has the formula k) as defined in the above paragraph, wherein in the heterocyclic ring A the dashed line is a double bond.

In another embodiment of the invention, the heterocyclic ring A has the formula (1):

wherein X is (C 1 -C 6) 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 W · embodiment Y is selected from the group consisting of 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 embodiment of the invention, the heterocyclic ring A has formula 1), wherein in the heterocyclic ring A the dotted line is a double bond, such that the heterocyclic ring A of formula 1 is selected from the group consisting of:

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

wherein X is (C1-C10) 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 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 embodiment of the invention heterocyclic ring A has the formula n):

wherein X is (C1-C10) 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 bond, oxygen, sulfur, -CH2-, > SC > 2, -OCH2-, and -CH2O-; preferably Y is oxygen, -OClb- or -CH2O-; more preferably Y is oxygen.

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

Chin * 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 bond, oxygen, sulfur, -CH2-, > SC > 2, -OCH2-, and -CH2O-; preferably Y is oxygen, -OCO- or -CH2O-; more preferably Y is oxygen.

2

In another embodiment of the invention, each of R, R,

4 10 11 12 13

R, R, R, R, R and R is 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 5) aryl, (C 1 -C 6). C 10) heteroaryl, (C 3 -C 8) cycloalkyl and (C 1 -C 10) heterocyclyl; and wherein each of said (C 1 -C ₄ ) alkyl, (C 6 -C 10) aryl, (C 1 -C 10) xemepoapuA, (C 3 - C 8) cycloalkyl and (C 1 -C 10) heterocyclyl may be optionally substituted on each of the ring carbon atoms, capable of forming an additional bond, with 1-3 substituents independently selected from halo, (C 1 -C 4 alkyl, (C 1 -C ₄ ) alkoxy , -CN, -OH and -NH ₂ .

An implementation of the type or subspecies of each of the above

7 h embodiments include compounds wherein each of R, R, R, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is selected from the group consisting of hydrogen, (C 1 -C 6 alkyl, (C 6 -C 10) aryl, (C 1 -C 10) heteroaryl and (C 3 -C 8) cycloalkyl.

The preferred embodiment of the type or subspecies of each of the foregoing embodiments is directed to those given in the foregoing embodiments, wherein each of R, R, R, R, R, R, R, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are selected from hydrogen and (C 1 -C 6) alkyl, for example as methyl.

In another embodiment of the invention, each of R ⁵ , R ⁶ , R and R is 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 8) aryl, (C 1 -C 10) heteroaryl, (C 3 -C 8) cycloalkyl and (C 1 -C 10) heterocyclyl; and wherein each of said (C 1 -C 6 alkyl, (C 6 -C 10) aryl, (C 1 -C 10) heteroaryl, (C 3 -C 8) cycloalkyl and (C 1 -C 10) heterocyclyl may be optionally substituted on any of the ring carbon atoms suitable for form an additional bond with 1-3 substituents independently selected from halo, (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 ,

7 8

R, R and R is / are a group other than hydrogen.

Fr.

In another embodiment of the invention, R is independently selected from hydrogen, (C 1 -C 6 alkyl, (C 6 -C 10) aryl, (C 1 -C 6 heteroaryl, (C 3 -C 8) -cycloalkyl, and (C 1 -C 4 heterocyclyl.

Fr.

In another embodiment of the invention R is independently selected from hydrogen and (C 1 -C 6 alkyl, e.g. as methyl.

In another embodiment of the invention, Z is (C 3 C 8) cycloalkyl or (C 1 -C 4 heterocyclyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, N-methyl-azetidinyl, piperazinyl, piperidinyl, piperidinyl, piperidinyl, piperazinyl). 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-dione-5-yl, 1,3-imidazolidin-4-one-5-yl, 1,3-imidazolidin-2, 4-dione-5-yl, 1,2-pyrazolidin-3-one-4-yl, tetrahydro-1,3-oxazin-4-one-5-yl, tetrahydro-1,3-oxazine-2,4-dione- 5-yl, morpholinyl, morpholin-3-one2-yl, morpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-oxazin-3-one-2-yl, tetrahydro-1, 3-thiazin-4-one-5-yl, tetrahydro-1,3-thiazine-2,4-dione-

5-yl, thiomorpholinyl, thiomorpholin-3-one-2-yl, thiomorpholin-3,5-dione-2-yl, 2,3-dihydro-1,4-thiazin-3-one-2-yl, hexahydro-1, 2-diazin-3on-4-yl, 4,5-dihydro-2H-pyridazin-3-one-4-yl, hexahydro-1,3-diazine-

2.4-dion-5-yl, piperazin-2-one-3-yl, piperazin-2,6-dion-3-yl, tetrahydro-1,3,4-thiadiazin-5-one-6-yl, 5, 6-dihydro-1,3,4-thiadiazin-5on-6-yl, 1,3,4-oxadiazin-5-one-6-yl, 5,6-dihydro-1,2,4-oxadiazin-5- he-

6-yl, tetrahydro-1,2,4-oxadiazin-5-one-6-yl, 1,2,4-triazin-5-one-6yl, 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-dione-6-yl and 1,2,4-triazine31 b -on-5-yl. In this embodiment, Z is preferably selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, N-methyl-3-azetidinyl, piperazinyl, piperidinyl, N-methylpiperidinyl and morpholinyl. In this embodiment, more preferably Z is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl. In this embodiment, most preferably Z is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.

In another embodiment of the invention, Z is (C 1 -C 10) heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzinoxazolyl, benzonoxazolyl furidol, indazol, indolent, indolent, indolent quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, more preferably pyridinyl, pyrazinyl, pyridazinyl and pyrazolyl, wherein said (C 1 -C 10) heteroaryl substituted heteroaryl substituted heteroaryl bond, with one or two substituents independently selected from F, Cl, Br, 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 - C8) cycloalkyloxy.

In another embodiment of the invention X or Z is substituted at each of the ring carbon atoms, capable of forming an additional bond, with one or two substituents independently selected from F, Cl, Br, 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.

In another embodiment of the invention, X and Z are simultaneously substituted at each of the ring carbon atoms, capable of forming an additional bond, with one or two substituents independently selected from F, Cl, Br, CN, OH, (C 1 -C 4) alkyl, ( C1-C4) perfluoroalkyl, (C1-C4) perfluoroalkoxy, (Cp-C4) alkoxy and (C3-C8) cycloalkyloxy.

In another embodiment of the invention G is R - (CR R) _p -; where p is 0; R ¹⁵ is selected from the group consisting of halo, -CN, and R; wherein said R 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 (C 1 -C 6 -heterocyclyl; wherein said (C 1 -C 10) aryl, (C 3 -C 8) cycloalkyl, (C 1 -C 6 heteroaryl and (C 1 -C 10) heterocyclyl structures may be optionally substituted on any of the ring carbon atoms suitable to form an additional bond with one to three ring substituents independently selected from F, Cl , Br, 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-MH-, [(C 1 -C 4) alky ] 2-b [- and (S3S8) cycloalkyloxy; wherein said (C-C8) cycloalkyl and (C1-S1o) heterocyclyl structures may also be optionally substituted; wherein said (Cj

Cio) xemepoapuAo6u u (C 1 -C 10) heterocyclyl structures may optionally be substituted at each ring nitrogen atom capable of supporting an additional substituent with one to two ring substituents independently selected from the group consisting of (C 1 -C 6) alkyl and (C 1 -C 4) alkyl- (C = O) -.

16 17

In another embodiment of the invention G is R - (CR R) _p -; wherein p is O to 4, preferably 1 to 2; R ¹⁵ is selected from the group consisting of halo, -CN, -NO2, -OH, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) perfluoroalkyl, perfluoro (C1-C4) alkoxy, R ¹⁸ -, R ¹⁸ -O-, K ¹⁸ - (C 1 -C 4) alkyl-O-, R ¹⁸ - (C = O) -, R ¹⁸ - (C = O) -O-, R ¹⁸ -O (C = O) -, R ¹⁸ -S-, R ²² - (S = O) -, R ¹⁸ - (SO2) -, R ²² - (SO2) - (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 = O) -; (R ¹⁹ R ²⁰ ) N- (C = O) - (NR ²¹ ) - (R ¹⁹ R ²⁰ ) N- (C = O) -O; each of R 1 and R 4 is independently hydrogen or (C 1 -C 4) alkyl; R 2 is selected from the group consisting of hydrogen, (C 1 -C 4) alkyl, (C 6 -C 10) aryl, (C 3 -C 8) and, cycloalkyl, (C 1 -C 4 heteroaryl and (C 1 -C 4 heterocyclyl;

* wherein said (C6-C10) aryl, (C3-C8) cycloalkyl, (Cf.

C 10) heteroaryl and (C 1 -C 10) heterocyclic structures may be optionally substituted on each of the ring carbon atoms, capable of forming an additional bond, with one to three ring substituents independently selected from F, Cl, Br, 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-MH-, [(C 1 -C 4) alkyl] 2 -N- and (C3-C8) cycloalkyloxy; wherein said (C 3 -C 8) cycloalkyl and (C 1 -C 6 heterocyclyl structures may also be optionally substituted by oxo;

said (C1-C10) heteroaryl and (C1-C10) heterocyclyl structures may optionally be substituted at each ring nitrogen atom capable of supporting an additional substituent with one to two ring substituents independently selected from the group consisting of (CpC alkyl and (C 1 -C 4) alkyl (OO) -.

In another embodiment of the invention G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; where he sang; R ¹⁵ is (R ¹⁹ R ²⁰ ) N-; each of R ¹⁶ or R ¹⁷ is independently hydrogen; and each of R and R is hydrogen or (C 1 -C 10) heteroaryl, such as 2-oxazolyl, 2-pyrazolyl or 3-pyrazolyl.

In another embodiment of the invention G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; where he sang; R ¹⁵ is (R ¹⁹ R ²⁰ ) N - (C = O) - (NR ²¹ ) -; each of R ¹⁶ or

19 20

R is independently hydrogen; each of R and R is (C 1 -C 4) alkyl and taken together with the nitrogen to which they are attached, forming a 3 to 8 membered ring; and wherein R is selected from the group consisting of hydrogen and (C 1 -C 4) alkyl.

16 17

In another embodiment of the invention G is R - (CR R) _p -;

where he sang; R ¹⁵ is R ²² -O- (C = O) - (NR ²¹ ) -; each of R ¹⁶ or R ¹⁷ is independently hydrogen; R is selected from the group consisting of hydrogen and (C1 and where R 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.

16 17

In another embodiment of the invention G is R - (CR R) _p -;

where he sang; R ¹⁵ is R ¹⁹ - (C = O) - (NR ²¹ ); each of R ¹⁶ and R ¹⁷ is

21 independently hydrogen or (C 1 -C 4) alkyl; R and R are taken together with the carbon or nitrogen to which they are attached, forming a 3 to 8 membered heterocycle.

In another embodiment of the invention G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; where p is 1; R ¹⁵ is (R ¹⁹ R ²⁰ ) N - (C = O) - (NR ²¹ ); each of R ¹⁶ and 17 19 21

R is independently hydrogen or (Ci ^ alkyl; R ^{iy and} R ^Z1 taken together with the nitrogen to which they are attached to form a 3 to 8chlenen heterocyclic ring.

In another embodiment of the invention G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; where he sang; R ¹⁵ is R ²² -O- (C = O) - (NR ²¹ ) -; each of R ¹⁶ and R ¹⁷ is 21 22 independently hydrogen or (C 1 -C 4 alkyl); R and R are taken together with the nitrogen or oxygen to which they are attached, forming a 3 to 8 membered heterocyclic ring.

D 1 n

In another embodiment of the invention G is R - (CR R) _p -; wherein p is 1 to 4, preferably 1; R ¹⁵ is selected from the group 18 16 17 consisting of halo, -CN and R; each of R and R is independently hydrogen or (C 1 -C 8 alkyl) said R is selected from the group consisting of hydrogen, (C 1 -C 6 alkyl) (C 6 -C 8) aryl, (C 3 -C 8) cycloalkyl, (C 1 -C 10) heteroaryl and (C 1 -C 10) heterocyclyl; wherein said (C 1 -C 10) aryl, (C 3 -C 8) cycloalkyl, (C 1 -C 10) heteroaryl and (C 1 -C 10) heterocyclyl structures may be optionally substituted at any of the ring carbon atoms suitable for form an additional bond with one to three ring substituents independently selected from F, Cl, Br, CN, OH, (C 1 -C 4 alkyl, (C 1 -C 4) perfluoroalkyl, (C 1 -C 4) perfluoroalkoxy, (C 1 -C 4) alkoxy, amino, (CpC 4) alkaline-NH-, [(C 1 -C 4) alkyl] 2-N- and (C 3 -C 8) cycloalkyloxy; wherein said (C 3 -C 8) cycloalkyl and (C 1 -C 4) heterocyclyl structures may also optionally substituted by oxo; wherein said (C 1 -C 3) heteroaryl and (C 1 -C 6 heterocyclyl structures may optionally be substituted at each ring nitrogen atom capable of supporting an additional substituent with one to two ring substituents independently selected from the group consisting of (C 1 -C 4 alkyl) and (C 1 -C 10) alkyl (C = O) -.

In another embodiment of the 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; each of R and R is independently hydrogen or (C 1 -C 4 alkyl); wherein said R is selected from the group consisting of hydrogen and (C 1 -C 4 alkyl).

With £ 1 * 7

In another embodiment of the invention G is R - (CR R) _p -; wherein p is 1 to 4, preferably 1; R 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 ) - (R ¹⁹ R ²⁰ ) N- (C = O) -O; each of R ¹⁶ and R is independently hydrogen or (C 1 -C 4 alkyl; and wherein R and R are taken together with the nitrogen to which they are attached, forming a 3 to 8 membered heterocyclic ring.

In another embodiment of the 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 R ²⁰ ) N- (C = O) - (NR ²¹ ), NR ¹⁹ R ²⁰ , ( R ¹⁹ R ²⁰ ) N - (C = O) - (NR ²¹ ) -; R ²² (S = O) -; R ²² (SO 2) - (NR ²¹ ) -; R ²² -O (C = O) - (NR ²¹ ) - in (R ¹⁹ R ²⁰ ) N- (C = O) -O-; each of R ¹⁶ and R ¹⁷ is independently hydrogen or (C 1 -C 4 alkyl; wherein each of R ¹⁹ ,

21

R u R is independently selected from the group consisting of hydrogen, (C 1 -C 6 alkyl, (C 6 -C 8) aryl, (C 3 -C 8) cycloalkyl, (C 1 -C 3) heteroaryl, and (C 1 -C 3 -heterocyclyl; where (C 6 -C 10) aryl, (C 3 -C 8) cycloalkyl, (C 1 -C 6 heteroaryl and (C 1 -C 10) heterocyclyl structures may be optionally substituted at each of the ring carbon atoms, capable of forming an additional bond, with 1-3 substituents independently selected from F, Cl, Br, 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-MH-, [(C 1 -C 4) alkyl] _2- N- and ( C3C8) cycloalkyloxy; wherein said (C 3 -C 8) cycloalkyl and (C 1 -C 10) heterocyclyl structures may also be optionally substituted by oxo; maintains an additional substituent with one to two ring substituents independently selected from the group consisting of (C 1 -C 4) alkyl and (C 1 -C 4) alkyl- (C = O) -; and wherein R is selected from the group consisting of (C 1 -C 4) alkyl, (C 1 -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 1 -C 10) heteroaryl and (C 1 -C 10) heterocyclyl structures may be optionally substituted at each of the ring carbon atoms capable of forming an additional bond with 1-3 substituents, independently selected from F, Cl, Br, CN, OH, (C 1 -C 4) alkyl, (C 1 -C 3) perfluoroalkyl, (C 1 -C 4)

C4) perfluoroalkoxy, (C4-C4) alkoxy, amino, (C1-C4) alkyl-MH-, [(C1-C4) alkyl] 2-N- and (C3-C8) cycloalkyloxy; wherein said (C 3 -C 8) cycloalkyl and (C 1 -C 10) heterocyclyl structures may also be optionally substituted by oxo; wherein said (C 1 -C 10 C heteroaryl and (C 1 -C 10) heterocyclyl structures may optionally be-substituted at each ring nitrogen atom capable of supporting an additional substituent with one to two ring substituents independently selected from the group (C 1 -C 4) ) alkyl and (C 1 -C 4) alkyl- (C = O) -.

In another embodiment of the 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 ¹⁶ and R ¹⁷ is independently hydrogen or (C 1 -C 4) alkyl; where R and R are taken together with the nitrogen, carbon or oxygen to which they are attached, forming a 3 to 8 membered heterocyclic ring.

16 17

In another embodiment of the invention G is R - (CR R) _p -; where p is 0; and G is oriented in a position other than alpha relative to the location of the ring Z to Y.

16 17

In another embodiment of the invention G is R - (CR R) _p -; where p is 0; and G is oriented in the meta position relative to the location of the ring Z to Y.

16 17

In another embodiment of the invention G is R - (CR R) _p -;

wherein p is 1 to 4, preferably 1; and G is oriented in a position other than alpha relative to the location of the ring Z to Y.

16 17

In another embodiment of the invention G is R - (CR R) _p -; wherein p is 1 to 4, preferably 1; and G is oriented in the meta position relative to the location of the ring Z to 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 a group other than hydrogen.

In a more preferred embodiment of the invention d ι r> 1 η ² _n 3 _o 4 _o 5 _n 6 _n 7 _o 8 _d 9 _o 10 _ώ 11 _ώ 12 _n 13 each omR, R, R, R, R, R, R, R, R, R, R, R and R is hydrogen.

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

In another preferred embodiment of the invention, both X and Z are not substituted by any additional substituents.

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

In another preferred embodiment of the 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 18 is hydrogen; and R is independently hydrogen or (C 1 -C 4 alkyl; preferably methyl.

In another preferred embodiment of the invention G is R ¹⁵ 1 Ζ 1 * 7 (CR R) p-; wherein p is 0 or 1; where G is oriented in the position of steam relative to the place of attachment of the ring Z to Y.

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

In another preferred embodiment of the invention G is R ¹⁵ (CR ¹⁶ R ¹⁷ ) _p -; where he sang; R ¹⁵ is (C 1 -C 3)) heteroaryl such as 2 pyrazolyl; and wherein each of R and R is independently hydrogen.

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

wherein X is (C1-C10) 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, -CH2-, > SO2, -OCH2-, and -CH2O-; more preferably Y is oxygen, -OCH2- or -CH2O-; most preferably Y is oxygen.

Other preferred compounds of the invention include compounds of formula I wherein the heterocyclic ring A has formulas a) or b) as defined above; X is (C1-C10) heteroaryl selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl; Most preferably, the pyridinyl together with the ring "A" and the group Y-Z-G has the formula:

wherein Y is a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ - or CH ₂ O-; preferably Y is oxygen, -OCH ₂ - or -CH ₂ O-; more preferably Y is oxygen.

Other preferred compounds of the invention include compounds of formula I wherein the heterocyclic ring A has formulas a) or b) as defined above; X is pyridinyl, most preferably when the pyridinyl together with the ring "A" and the group YZG have the formulas a ") or b") as defined above; Y is oxygen; Z is (C6-C10) aryl, preferably phenyl; G is R - (CR R) _p -; where he sang; R ¹⁵ is (C1-Cio) heteroaryl, such as 2-pyrazolyl; each of R ¹⁶ and R ^{17 is} independently hydrogen or (C 1 -C 10) alkyl, for example as methyl, preferably hydrogen; and where G is oriented in the vapor position relative to the location of the ring Z to Y.

Most preferred compounds of the invention include compounds of formula I, wherein the heterocyclic ring A has formulas a) or b) as defined above; X is pyridinyl, most preferably when the pyridinyl together with the ring "A" and the group YZG have the formulas a ") or b") as defined above; Y is oxygen; Z is (C6-C3) aryl, preferably phenyl; G is R - (CR R) _p -; where p is 0; R is selected from the group consisting of hydrogen, -CN, halo and oxadiazolyl; and where G is oriented in the vapor position relative to the location of the ring Z to Y.

Other most preferred compounds of the invention include compounds of formula I, wherein the heterocyclic ring A has formulas a) or b) as defined above; X is pyridinyl, most preferably when the pyridinyl together with the ring "A" and the group YZG have the formulas a ") or b") as defined above; Y is oxygen; Z is (C6-C10) aryl, preferably phenyl; G is R ¹⁵ (CR ¹⁶ R ¹⁷ ) _p -; where he sang; R ¹⁵ is R ¹⁹ - (C = O) - (NR ²¹ ) -; each of R and R is independently hydrogen; R is selected from the group consisting of (C 1 -C 6 alkyl and (C 3 -C 8) cycloalkyl, for example as methyl, ethyl, propyl, butyl, or cyclobutyl; R is selected from the group consisting of hydrogen or (C 1 -C 6 alkyl; and wherein G is oriented in the vapor position relative to the location of the ring Z to Y.

Other compounds of the invention are selected from the group consisting of:

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

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

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

4- [6- (4- [1,3,4] Oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,1-dioxoyl-thia-2,4,7,9-tetraaza-spiro [4.5] decane-3,6,8,10-tetraone;

- [6- (4- [1D4] Oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,3,7,9tetraaza-spiro [4.5] decane-2,4,6,8,10- pentaone;

1- [6- (4- [1,3,4] Oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -2,2-dioxo2H ^6- thia-1,7,9-triaza-spiro [ 4.5] decane-6,8,10-trion;

1- [6- (4- [1,3,4] Oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -2,2-dioxo2H ⁶ -thia-1,8,10-triaza-spiro [ 5.5] undecane-7,9,11-trion;

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

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

1- {6- [4- (2-Oxo-pyrrolidin-1-ylmethyl) -phenoxy] -pyridin-3-yl} -

1,7,9-triaza-spiro [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-Fluoro-phenoxy) -pyridin-3-yl] -3-methyl-1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone;

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

4- [5- (2,7,9,11-Tetraoxo-1,8,10-triaza-spiro [5.5] unde, -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-triaza-spiro [5.5] undec-1-yl) pyridin-2-yloxy] -benzyl} -acetamide;

Azetidine-1-carboxylic acid 4- [5- (2,7,9,11-tetraoxo 1,8,8-triaza-spiro [5.5] unde, 4-yl) -pyridin-2-yloxy] -benzylamide;

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

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

1- [6- (4-Fluoro-phenoxy) -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;

4- (5- (2,6,8,10-Tetraoxo-1,3,7,9-tetraaza-spiro [4.5] dec-1-yl) pyridin-2-yloxy] -benzonitrile;

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

Azetidine-1-carboxylic acid 4- (5- (2,6,8,10-tetraoxo-1,3,7,9tetraaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzylamide;

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

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

* 1- [6- (4-Ethyl-phenoxy) -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-tetraaza-spiro [5.5] undec-1-yl) pyridin-2-yloxy] -benzonitrile;

N- {4- [5- (2,7,9,11-Tempooxo-1,3,8,10-methyl-3a-benzo [5.5] ylhexyl) -pyridin-2-yloxy] -benzyl} -acetamide;

Azetidine-1-carboxylic acid 4- (5- (2,7,9,11-tetraoxo-

1,3,8,10-tetraaza-spiro [5.5] undec-1-yl) -pyridin-2-yloxy] -benzylamide;

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

4- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -1,1-dioxo-1? ^{B-thia-2,4,7,9-tetraaza-spiro} [4.5] decane-3,6, 8,10-tetraone;

4- [6- (4-Ethyl-phenoxy) -pyridin-3-yl] -1,1-dioxo-1? ^{6-thia-2,4,7,9tetraaza-spiro} [4.5] decane-3,6,8 , 10-tetraone;

4- [5- (1,1,3,6,8,10-Heksaokso-1X ^{6-thia-2,4,7,9-tetraaza-spiro} [4.5] dets4-yl) -pyridin-2-yloxy] -benzonitrile;

N44-t5- (1,1, 3,6,8,10-Xecoacco-lX ^6- mua-2,4,7,9-mempa3aspiro [4.5] dec-4-yl) -pyridin-2-yloxy] - benzyl} -acetamide;

Azetidine-1-carboxylic acid 4- [5- (1,1,3,6,8,10-hexooxo-1X ⁶ thia-2,4,7,9-tetraaza-spiro [4.5] dec-4-yl) -pyridin-2-yloxy] -benzylamide;

1,1-Dioxo-4- [6- (4-pyrazol-ylmethyl-phenoxy) -pyridin-3-yl] -1H ⁶ thia-2,4,7,9-tetraaza-spiro [4.5] decan-3 6,8,10-tetraone;

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

4- [5- (2,4,6,8,10-Pentaoxo-1,3,7,9-tetraaza-spiro [4.5] dec-1-yl) pyridin-2-yloxy] -benzonitrile;

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

Azetidine-1-carboxylic acid 4- [5- (2,4,6,8,10-pentaoxo-

1,3,7,9-tetraaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzylamide;

1- [6- (4-Pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraaza-spiro [4.5] decane-2,4,6,8,10-pentane;

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-Fluoro-phenoxy) -pyridin-3-yl] -2,2-dioxo-2X ^6- thia-1,7,9-triaza-spiro [4.5] decane-6,8,10-trion ;

1- [6- (4-Ethyl-phenoxy) -pyridin-3-yl] -2,2-dioxo-2 * ^{6-thia-1,7,9triaza-spiro} [4.5] decane-6,8,10-trione ;

4- [5- (2,2,6,8,10-Pentaokso-2X ^6-thia-1, Ί, 9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzonitrile;

N- {4- [5- (2,2,6,8,10-Pentaokso-2X ^{6-thia-1,7,9-triaza-spiro} (4.5] dets1-yl) -pyridin-2-yloxy] - benzyl} -acetamide;

Azetidine-1-carboxylic acid 4- (5- (2,2,6,8,10-pentaokso-2X ⁶ thia-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2 -yloxy] -benzylamide;

2,2-Dioxo-1- [S- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -2H ⁶ thia-1,7,9-triaza-spiro [4.5] decane-6,8, 10-saw;

w 1- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -2,2-dioxo-2X-thia-1,8,10triaza-spiro [5.5] undecane-7,9,11-trione ;

1- [6- (4-Ethyl-phenoxy) -pyridin-3-yl] -2,2-dioxo-2 * ^{6-thia-1,8,10triaza-spiro} (5.5] undecane-7,9,11-trione ;

4- (5- (2,2,7,9,11 -Pentaokso-2X ^{6-thia-1,8,10-triaza-spiro} [5.5] unde, -1il) -pyridin-2-yloxy] -benzonitrile;

N- {4- [5- (2,2,7,9,11-Pentaoxo-2X ^6- thia-1,8,10-triazaspiro [5.5] undec-1-yl) -pyridin-2-yloxy] - benzyl} -acetamide;

Azetidine-1-carboxylic acid 4- (5- (2,2,7,9,11-pentaoxo-2X ⁶ thia-1,8,10-triaza-spiro [5.5] undec-1-yl) -pyridine-2 -yloxy] -benzylamide;

2,2-Dioxo-1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -2H ⁶ thia-1,8,10-triaza-spiro [5.5] undecane-7,9, 11-saw;

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

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

4- (5- (6,8,10-Trioxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2yloxy] -benzonitrile;

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

Azetidine-1-carboxylic acid 4- [5- (6,8,10-trioxo-1,7,9triaza-spiro [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-triaza-spiro [5.5] undecan-2,7, 9,11-tetraone;

1- [6- (2-Fluoro-4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -

1,8,10-triaza-spiro [5.5] undecane-2,7,9,11-tetraone;

V 1- [6- (3-Methyl-4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -

1.8.10- triaza-spiro [5.5] undecane-2,7,9,11-tetraone;

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

1- [6- (Pyridin-4-yloxy) -pyridin-3-yl] -1,8,10-triazaspiro [5.5] undecan-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-triaza-spiro [5.5] undecane2,7,9,11-tetraone;

1- [4- (Pyridin-4-yloxy) -phenyl] -1,7,9-triaza-spiro [4.5] decane-

2.6.8.10- tetraone;

Azetidine-1-carboxylic acid 4- [5- (2,6,8,10-tetraoxo-1,7,9triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzylamide;

and their pharmaceutically acceptable salts.

Specific preferred compounds of formula I are selected from the group consisting of:

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

1- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -1,8,10-triaza48 spiro [5.5] undecane-2,7,9,11-tetraone;

4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) pyridin-2-yloxy] -benzonitrile;

1- [6- (4- [1,3,4] 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-triaza-spiro [4.5] dec-1-yl) pyridin-2-yloxy] -benzyl} -acetamide;

N * N- {4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) pyridin-2-yloxy] -benzyl} -propionamide ;

N- {4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [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,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzylamide;

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

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

and their pharmaceutically acceptable salts.

The present invention also relates to a pharmaceutical composition for the treatment of a condition selected from the group consisting of connective tissue disorders, inflammatory diseases, immunological / allergic disorders, infectious diseases, respiratory diseases, cardiovascular diseases, ocular diseases, metabolic diseases , central nervous system (CNS) disorders, liver / kidney diseases, reproductive disorders, gastric disorders, skin disorders, carcinomas and other diseases characterized by metalloproteinase activity in a mammal, including a human comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective for such treatment and a pharmaceutically acceptable carrier.

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

The present invention also relates to a method of treating a condition selected from the group consisting of connective tissue disorders, inflammatory diseases, immunological / allergic disorders, infectious diseases, respiratory diseases, cardiovascular diseases, ocular diseases, metabolic diseases, central nervous system (CNS) disorders, liver / kidney diseases, reproductive disorders, stomach disorders, skin disorders, carcinomas and other diseases characterized by matrix metalloproteinase activity in b a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective for treating such a condition.

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

The inventors have also found that it is possible to identify inhibitors of formula I with different metalloproteinase activity (preferably MMP-13 inhibitory activity). One group of preferred inhibitors of Formula I inventors have identified as including those that selectively inhibit MMP-13 over MMP-1. The compounds of the invention also have selectivity over the corresponding group of enzymes known as reprolysins, such as TACE and aggrecanase. Another group of preferred inhibitors of Formula I inventors define as those that selectively inhibit MMP-13 with preference over MMP-1 and MMP-14. Another group of preferred inhibitors of Formula I inventors define as including those that selectively inhibit MMP-13 over MMP-1 and 12. Another group of preferred inhibitors of Formula I inventors define as include those that selectively inhibit MMP-13 over MMP-1,12 and 14. Another group of preferred inhibitors of Formula I inventors define as including those that selectively inhibit MMP-13 with priority over MMP-1, 2, 3, 7, 9 and 14. The most preferred compounds of the invention selectively inhibit MMP-13 with an advantage over MMP-1, 2, 3, 7, 9, 12 and 14 and mammalian reprolysins.

The term treatment as used herein refers to the reverse development, alleviation, inhibition of development or prevention of such disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term treatment, as used herein, refers to the act of healing itself, the term treatment being defined immediately above.

Connective tissue disorders, as used herein, refer to disorders such as degenerative cartilage loss after traumatic damage to the joint, osteoarthritis, osteoporosis, Paget's disease, loosening of artificial joint implants, periodontal disease and gingivitis.

Articular cartilage destruction, as used herein, refers to disorders in connective tissue leading to destruction of articular cartilage, in particular joint damage, reactive C arthritis, acute pyrophosphate arthritis (pseudogout), psoriatic arthritis, or juvenile arthritis, more preferably osteoarthritis.

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

Immunological / allergic disorders, as used herein, refer to disorders such as V intoxication, allergic reactions, allergic contact hypersensitivity, autoimmune disorders such as granulomatous inflammation / tissue remodeling disorders (such as anastomosis, and sarcoma).

Infectious diseases, including those caused by viruses, bacteria, fungi or myobacterial infection, as used herein, relate to disorders such as septic arthritis, AIDS, fever; Prion disease, myasthenia gravis, malaria, sepsis, hemodynamic shock and septic shock.

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

Cardiovascular diseases as used herein refer to disorders such as atherosclerosis, including rupture of atherosclerotic plaques; aortic aneurysm, including abdominal aortic aneurysm and cerebral aortic aneurysms; congestive heart failure; myocardial and cerebral infarction; blow; cerebral ischemia; _d coagulation and acute phase response; left ventricular dilatation; disturbed postischemical reperfusion; angiofibromas; hemangiomas; and restenosis.

Ocular diseases as used herein refer to disorders such as aberrant angiogenesis, ocular angiogenesis, ocular inflammation, keratoconus, Sjogren syndrome, myopia, ocular tumors, corneal implant rejection, corneal injury, neovasculus, neovasculus, neovasculus corneal macular degeneration (including age-related macular degeneration including both wet and dry form), proliferative vitreoretinopathy and prematurity.

Metabolic diseases as used herein refer to disorders such as diabetes (including insulin-dependent diabetes mellitus, diabetic retinopathy, insulin resistance, ulcer formation).

Central nervous system disorders as used herein refer to disorders such as head trauma, spinal damage, inflammatory diseases of the central nervous system, neurodegenerative disorders (acute and chronic), Alzheimer's disease, demyelinating diseases of the nervous system, disease Huntington's disease, Parkinson's disease, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognitive activation, amyotropic lateral sclerosis, multiple sclerosis, migraine, depression and anorexia.

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

Reproductive disorders, as used herein, refer to disorders such as endometriosis, contraception (male / female), dysmenorrhea, dysfunctional uterine bleeding, premature rupture of fetal membranes, and abortion agent.

Gastric disorders, as used herein, refers to disorders such as colon anastomosis and gastric ulcers.

Skin disorders, as used herein, refer to disorders such as skin aging, pressure wounds, C * psoriasis, eczema, dermatitis, sun damage, skin ulcers, decubital ulcers, epidermolysis bullosa, atypical skin healing (topical and skin healing) ), burns and scleritis.

Carcinomas as used herein refer to disorders such as solid tumor, including colon cancer, breast cancer, lung cancer and prostate cancer, tumor invasion, tumor growth, tumor metastases, oral cancer and pharynx ( lips, tongue, mouth, pharynges), esophagus, stomach, small intestines, long intestines, rectum, liver and biliary tract, pancreas, larynx, lung, bone, connective tissues, on the skin, on the uterine canal, on the endo etrium, ovaries, testes, bladder, kidneys and other urinary tract, eyes, brain and central nervous system, thyroid and other endocrine glands, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma and hematopoiesis diseases, including leukemias and lymphomas, including lymphocytes, granulocytes and monocytes.

The present invention also includes isotopically-labeled compounds identical to those cited in Formula I, provided that one or more atoms are substituted by an atom having an atomic mass or mass other than the atomic mass or mass number commonly found in nature. Examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, respectively, as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O , ¹⁷ O, ³¹ R. ³² P, ³⁵ S, ¹⁸ F and ³⁶ C1. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs containing the isotopes and / or other isotopes of other atoms mentioned above are within the scope of the invention. Certain isotope-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in the analysis of drug and / or substrate distribution in tissue. The third, ie. H and carbon-14, i. C is especially preferred isotopes because of their easy preparation and detectability. Furthermore, the substitution with heavier isotopes such as deuterium, i. H, may confer some therapeutic benefits as a result of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in certain circumstances. The isotopically labeled compounds of formula I of the invention and their prodrugs can generally be prepared by the methods described below in the Schemes and / or Examples and Preparations by substituting an isotopically unlabeled reagent with an easily accessible isotopically labeled reagent.

The invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula I. The invention also encompasses methods of treating or preventing diseases that can be treated or prevented by inhibiting matrix metalloproteinases or inhibiting mammalian reprolysin comprising administering prodrugs of compounds of Formula I. Compounds of formula I having free amino, amido, hydroxy, sulfonamide or carboxyl groups can be converted to prodrugs. Prodrugs include compounds wherein an amino acid residue or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently linked by a peptide bond to free amido, amino, hydroxy or carboxylic groups of compounds of formula I. Amino acids include the twenty natural amino acids, usually indicated by three letters and also include 4-hydroxyproline, hydroxylisin, demosin, isodemosin, 3-methylhistidine, norvaline, beta-alanine, selina, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein the carbonates, carbamates, amides and alkyl esters are covalently linked to the above substituents of Formula I via the carbonyl carbon by the side chain of the prodrug.

One of ordinary skill in the art may appreciate that the compounds of the invention are useful in the treatment of a number of different diseases. Such a specialist may also appreciate that when the compounds of the invention are used to treat a particular disease, those compounds of the invention may be combined with various existing therapeutic agents used for the disease.

For 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 infliximab, D2E7 and CDP-870) and TNF receptor immunoglobulin molecules (such as etanercept) inhibitors, MEKK1 inhibitors, COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib and etoricoxib; low dose methotrexate, lefunimide, steroids, glucosamines, chondrosamines / sulfates, gabapentrin, A-agonists, IL-1 processing and release inhibitors, IL-1 receptor antagonists such as Kineret®, CCR-1 antagonists, hydroxychloroxylamines, hydroxylamines , auranofine or parenteral or orally applicable gold.

The compounds of the invention may also be administered in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents for use in combination include standard non-steroidal anti-inflammatory agents (referred to as NSAIDs) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, phenoprofen, ketoprofen and ibuprofen, phenamates such as mefenacetin, indomethacin, indomethenicin, indomethenicin, indomethacin, indomethacin aspirin, COX-2 inhibitors such as celecoxib, valdecoxib, paracoxib and rofecoxib, analgesic LTD-4, LTB-4 and 5-LO inhibitors, p38 kinase inhibitors and intra-articular therapists such as corticosteroids and chi luronovi acids such as hyalgan and synvisc.

The compounds of the present invention may also be administered in combination with anticancer agents such as endostatin and angiostatin or cytotoxic agents such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids such as vincristine and antimetabolites such as methotrexate.

The compounds of the present invention may also be administered in combination with cardiovascular agents such as calcium channel blockers (such as amlodipine and nifedipine), lipid-lowering agents (such as lovastatin, atorvastatin, pravastatin and simvastatin), adrenergics such as doxazosin and terazosin fibrates, beta-blockers, angiotensin-converting enzyme inhibitors (ACEs such as captopril, lisinopril, fosinopril, enalapril and quinapril) angiotensin-2 receptor antagonists (such as losartan and ib nitrates, CCS, diuretics such as digitalis and inhibitors of blood cell aggregation.

The compounds of the present invention can be used in combination with plaque-preventing agents such as statins, zithromax, non-steroidal anti-inflammatory drugs, including aspirin, heparin, urafarin, abciximab, TPA and clotting inhibitors. The compounds of the present invention can be used in combination with stroke treatment agents such as NIF, NHEI and CCRIR antagonists.

The compounds of the present invention may also be administered in combination with central nervous system agents such as antidepressants (such as sertraline), antiparkinsonian drugs (such as deprenil, carbadopa, L-dopa, dopamine receptor agonists such as ropinirole, pergolide and pramipexole, inhibitor monoamino oxidase type B (MAB) such as selegiline and rasagiline, catechol-methyltransferase inhibitors such as tolcapone, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotinic agonists, NK-1 inhibitors, opaminovi agonists and inhibitors of neuronal nitric oxide synthase) and antialtshaymerovi drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.

The compounds of the present invention may also be used in combination with osteoporosis agents such as roloxifene, droloxifene, lasofoxifene or fosomax and immunosuppressants such as FK-506 and rapamycin.

The compounds of the present invention can be used in combination with agents for the treatment of respiratory diseases such as PDE-IV inhibitors, steroids <** · such as fluticasone, triamcinolone, budesonide, budesonide and beclomethasone, anticholinergics such as ipratropium, sympathomythromyethylmethylmethimethymethyl , decongestants such as fexofenadine, loratadine and cetirizine; leukotriene antagonists such as zafirlukast and motelukast; and fat cell stabilizers such as cileutone.

The compounds of the present invention can be used in combination with agents for the treatment of skin disorders such as threonine, isotretionine, steroids such as cortisone and mometasone, antibiotics such as tetracycline, antifungals such as clotrimazole, miconazole and fluconazole and

PDE-IV inhibitors.

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

Detailed description of the invention

The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless otherwise stated, each of X, Y, Z, G, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , p7 p $ plO pH p! 2 · ρ13 p14 p15 p16 p17 p18 p19 p20 p21 p22 in the reaction schemes and subsequent discussions is defined as above.

SCHEME 1

H ₂ NXYZ-G ▼

Η

I

SCHEME 2 h ₂ nxyzg

Ο

SCHEME 3

N0 ₂ —XL ⁷

Goat — X-Y-Z-G

VIII

H ₂ NXYZG

Scheme 1 relates to the preparation of compounds of formula I. Referring to Scheme 1, compounds of formula I in which the heterocyclic ring A is of formulas a-n (i.e., a compound of formula Ia-1n):

W> * '

can be obtained by the formula Sha-IIn respectively:

interaction of

Compound with

X-Y-Z-G

X-Y-Z-G

X-Y-Z-G

X-Y-Z-G

and

wherein L leaving alkoxy, preferably preferably methoxy, ethoxy methoxy or ethoxy, are groups such as or benzyloxy, more with urea of formula II (i.e.

H2N- (CO) -NH2) in the presence of a suitable base in a polar solvent. Suitable bases include alkoxide bases such as sodium methoxide, sodium ethoxide, or potassium tert-butoxide, preferably sodium ethoxide. Suitable solvents include tetrahydrofuran, dimethylformamide or alcohols (such as ethanol), preferably tetrahydrofuran or dimethylformamide. The aforementioned reaction is carried out at a temperature of from about 20 ° C to about 90 ° C, preferably from about 50 ° C to about 80 ° C, for a time from about 5 minutes to about 8 hours.

A compound of formula IIIa-III can accordingly be prepared by reacting a compound of formula IVa-IVI, respectively:

x-Y-z-G

x-Y-z-G o

x-y-z-g

X-Y-Z-G

2 where L and L are leaving groups such as alkoxy, preferably methoxy, ethoxy or benzyloxy, preferably methoxy or ethoxy, and where L is a suitable leaving group such as halo, n-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs). preferably halo, such as bromo or iodo, with a suitable base in a polar solvent. Suitable bases include tertiary amines such as triethylamine. Other suitable bases include a highly basic macro-networked resin or a gel type resin such as the Amberlyst 400 resin (hydroxide form). Suitable solvents include alcohol solvents, preferably ethanol. The aforementioned reaction can be carried out at a temperature of about -10 ° C to about 50 ° C, preferably about 20 ° C, for a time of about 6 to about 36 hours.

A compound of formula IIIm-IIIn can be prepared by reacting a compound of formula IVm-IVn, respectively:

X-Y-Z-G

X-Y-Z-G

h wherein L is a suitable leaving group, with a suitable base in a polar solvent according to methods analogous to those for the preparation of the compounds of formulas Illa-IIIi in the above paragraph. Suitable leaving groups of formula L include halo, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs).

with

Preferably L is halo, for example as chloro. The reaction mentioned above67 can be carried out at a temperature of about

0 ° C to about 50 ° C, preferably about 20 ° C, for about an hour to about 4 hours. Suitable solvents include tetrahydrofuran, dimethylformamide and alcohol.

A compound of formula IVa-IVi can accordingly be prepared by reacting a compound of formula VI with a compound of general formula

N - (A ') -L ⁴ (V) (ie compound of formula Va-Vi respectively):

where each one of

a leaving group such as halo, peratolylsulfonyloxy (OTs) or methylsulfonyloxy

(OMs). Preferably L is halo, such as bromo, chloro or iodo. Preferably L ⁴ is chloro or fluoro. Optionally, the above reaction may be carried out in the presence of a tertiary amine base such as α, α-dimethylaniline or pyridine in the presence of a suitable solvent such as a hydrocarbon solvent (benzene or toluene), tetrahydrofuran or methylene chloride. The aforementioned reaction is carried out at a temperature of from about 20 ° C to about 90 ° C, preferably from about 50 ° C to about 80 ° C, for a time from about 30 minutes to about 6 hours.

Preferably the above reaction is carried out in an aromatic hydrocarbon solvent such as benzene or toluene in the absence of the aforementioned base.

A compound of formula IVj-IVl can be prepared by reacting a compound of formula VI with a compound of formula:

L ³ - (A ') - L ⁴ (V) (ie compound of formula Vj-Vl, respectively):

where each one of I? and L ⁴ is a suitable leaving group such as halo, pert-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs) according to methods analogous to those described for the preparation of the compounds of formulas IVa-IVi in the above paragraph. Preferably I? is chloro, bromo or iodo. Preferably L ⁴ is chloro, bromo or iodo. The aforementioned reaction can be carried out at a temperature from about 0 ° C to about 50 ° C, preferably about 20 ° C, for a time from about 30 minutes to about 12 hours.

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

L ³ - (A ') -L ⁴ (V) (ie, compound of formulas Vm-Vn, respectively):

# where each of L ³ and L ⁴ is a suitable leaving group such as halo, ηαρα-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs) according to methods analogous to those described for the preparation of the compounds of formulas IVa-IVi in the above paragraph. Preferably L ³ is halo, for example as chloro. Preferably L ⁴ is halo, for example as chloro. The aforementioned reaction can be carried out at a temperature from about 0 ° C to about 80 ° C, preferably about 0 ° C to about 40 ° C, for a time from about 30 minutes to about 8 hours.

Alternatively, compounds of formulas IVd, IVe and IVf may be prepared by reacting a compound of formula VI with a compound of formula (A ') - L ³ (V) (i.e., a compound of formula respectively Vd', Ve * and Vf):

N = C = O

N = C = O

and wherein L is preferably halo, most preferably chloro, bromo, or iodo. Optionally, the above reaction can be carried out in the presence of a tertiary amine base in a suitable solvent. Suitable bases include N, N-dimethylaniline or pyridine. Suitable solvents include a hydrocarbon solvent (benzene or toluene), tetrahydrofuran or methylene chloride, preferably an aromatic hydrocarbon solvent such as benzene or toluene. Mentioned above oh

the reaction is carried out at a temperature of from about 20 ° C to about 90 ° C, preferably from about 50 ° C to about 80 ° C, for a time from about 30 minutes to about 6 hours. Preferably the above reaction is carried out in the absence of any of the aforementioned bases.

Alternatively, compounds of formulas IVm and IVn may be prepared by reacting a compound of formula VI with a compound of formula (A ') - L ³ (V) (i.e., a compound of formula Vm' and Vn ', respectively):

Oh

L ³ —SO ₂ —N = C = O and ^ ₃ ^ JL _{n = c == 0}

Vm 'Vri where L is preferably halo, most preferably chloro. The above reaction may optionally be carried out in the presence of a tertiary amine base in a suitable solvent. Suitable bases include A, A-dimethylaniline or pyridine. Suitable solvents include a hydrocarbon solvent (benzene or toluene), tetrahydrofuran or methylene chloride, preferably an aromatic hydrocarbon solvent such as benzene or toluene. The aforementioned reaction may be carried out at a temperature of from about -10 ° C to about 50 ° C, preferably about 0 ° C to about 30 ° C, for a time from about 30 minutes to about 12 hours. Preferably, said reaction is carried out in the absence of any of the aforementioned bases.

A compound of formula VI can be prepared by reacting a compound of formula H2N-X-Y-Z-G with a compound of formula VII:

VII,

2 wherein L and L are leaving groups such as methoxy, ethoxy or benzyloxy; preferably ethoxy; and L ⁵ is a leaving group such as halo, naphthalenesulfonyloxy (OTs) or methylsulfonyloxy (OMs); preferably halo; most preferably chloro or bromo. The aforementioned reaction can be carried out either in pure form or in the presence of a suitable solvent, preferably in pure form in the presence of a suitable base. Suitable solvents include tetrahydrofuran or dimethylformamide. Suitable bases include a weak tertiary amine base, preferably tertiary aniline bases, most preferably A, A-dimethylaniline. Preferably the above reaction is carried out at a temperature of from about 23 ° C to about 100 ° C, preferably from about 50 ° C to about 90 ° C, for a further 30 minutes to about 24 hours.

In the aforementioned reactions, any of the compounds of formulas IVj-rVl can be isolated, but is preferably used in the next step without isolation. Thus, in Scheme 1, the compound of formula IHj-IIIl is preferably prepared by reaction in one vessel of a compound of formula VI. '

If the compounds of formulas IVj-IVl - are not isolated, the suitable solvent for the preparation in one vessel is dimethylformamide, tetrahydrofuran or alcohols, preferably alcohols such as ethanol. Preferably the preparation in one container is carried out in the presence of an alkoxide base, preferably sodium methoxide or sodium ethoxide. The above-mentioned preparation in one vessel is carried out at a temperature of from about 40 ° C to about 90 ° C, preferably about 60 ° C to about 80 ° C, for a time from about 15 minutes to about 12 hours.

The compounds of formula H2N-X-Y-Z-G are commercially available or can be prepared by methods known to one skilled in the art. Alternatively, the compounds of formula H2N-X-Y-ZG can be prepared as described in Scheme 3.

Compounds of formula VII can be prepared by methods known to one skilled in the art, such as those described in PCT patent publication WO 98/58925 or discussed in The Organic Chemistry of Drug Synthesis. D. Lednicer and L. A. Mitscher, Volume 1, p.p. 167 - 277 and the sources cited therein. Each of the publications and requests cited above is incorporated herein by reference in its entirety.

Compounds of formula II are commercially available or can be prepared by methods known to one skilled in the art.

Scheme 2 relates to the preparation of a compound of formula I, wherein the heterocyclic ring A has the formula o, i.e., a compound of formula IO. Referring to Scheme 2, a compound of formula Ia:

Chev * can be obtained by reacting a compound of formula IIIa, wherein L and L are leaving groups, with urea of formula II (i.e., H2N- (CO) -NH2) in the presence of a suitable base in polar solvent. Suitable leaving groups include methoxy, ethoxy or benzyloxy, preferably ethoxy. Suitable bases include alkoxide bases such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, preferably sodium ethoxide. Suitable solvents include tetrahydrofuran, dimethylformamide or alcohols (such as ethanol), preferably tetrahydrofuran or dimethylformamide. The aforementioned reaction is carried out at a temperature of from about 20 ° C to about 90 ° C, preferably from about 50 ° C to about 80 ° C, for a time from about 5 minutes to about 8 hours.

A compound of Formula III can be prepared by reacting a compound of Formula IVo, wherein L is a leaving group, with a suitable base in a polar solvent. Suitable leaving groups include alkoxy (such as methoxy, ethoxy or benzyloxy) or halo, preferably methoxy or ethoxy. Suitable bases include an alkoxide base, preferably sodium methoxide or sodium ethoxide. Suitable solvents include alcohols, preferably ethanol. The aforementioned reaction may be carried out at a temperature of from about 0 ° C to about 90 ° C, preferably from about 60 ° C to about 90 ° C, for a time from about 1 hour to about 36 hours.

A compound of formula IVo can be prepared by reacting a compound of formula VI with a compound of formula Vo:

R ¹⁰

wherein L ⁶ is a suitable leaving group, in a suitable solvent. Suitable L ⁶ includes alkoxy or halo such as chloro; preferably alkoxy, more preferably methoxy or ethoxy. The above 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 above reaction is carried out in tetrahydrofuran or dimethylformamide in the presence of the appropriate tertiary amine base mentioned above. The above reaction can be carried out at a temperature of from about 20 ° C to about 90 ° C, preferably from about 50 ° C to about 80 ° C, for a time from about 30 minutes to about 6 hours.

In the reactions mentioned above, the compound of formula

IVo can be isolated, but is preferably used in the next step without isolation. Thus, in Scheme 1, a compound of formula III is preferably prepared by reaction in a vessel of a compound of formula VI.

If the compounds of formulas IVo are not isolated, the suitable solvent for the preparation in one vessel is dimethylformamide, tetrahydrofuran or alcohols, preferably an alcohol such as ethanol. The above-mentioned preparation is conveniently carried out at a temperature from about 0 ° C to about 70 ° C, preferably from about 23 ° C to about 60 ° C, for a time from about 30 minutes to about 24 hours.

A compound of formula VI can be prepared by reacting a compound of formula H2N-X-Y-Z-G with a compound of formula VII, as shown in Scheme 1.

Scheme 3 relates to the preparation of compounds of formula H2N-XYZG, which are intermediates useful in the preparation of compounds of formula I in Schemes 1 and 2. Referring to Scheme 3, compounds of formula H2N-XYZG can be prepared by reacting a compound of formula VIII with a reducing agent such as tin II chloride in the presence of a suitable acid such as hydrochloric acid in a polar protic solvent. Suitable solvents include an alcoholic solvent, water or a mixture thereof, preferably a mixture of ethanol and water. The above reaction may be carried out at a temperature of from about 40 ° C to about 100 ° C for a time from about 1 to about 12 hours.

Alternatively, compounds of formula H2N-X-Y-Z-G can be prepared by reacting a compound of formula VIII with hydrogen gas at a pressure between atmospheric pressure and 50 psi in the presence of a catalyst and a polar solvent.

Suitable catalysts include palladium or platinum catalysts, preferably Adams catalyst (i.e., platinum oxide) or palladium adsorbed on carbon. Suitable solvents include an alcoholic solvent, preferably methanol. The aforementioned reaction can be carried out at a temperature from about 20 ° C to about 50 ° C, preferably about 23 ° C, for a time from about 30 minutes to about 6 hours.

A compound of formula VIII wherein Y is oxygen, sulfur, -CH2S-,

-CH ₂ O-,> NR ¹⁴ , -CH 2 [N (R ¹⁴ )] - or -SO 2 [N (R ¹⁴ )] -, can be obtained by reacting a compound of formula X, wherein the group or chloro, with compound of formula:

G-Z-Y-H (IX)

wherein Y is oxygen, sulfur, -CH2S-, -SN2O-,> NR ^14, -CH2 [N (R ^14)] - or -SO2 [N (R ^14)] -, in the presence of a base in a polar aprotic solvent. Suitable bases include an alkali metal hydride base; preferably sodium hydride. Suitable solvents include dimethylformamide, tetrahydrofuran or 1,2-dimethoxyethane; preferably dimethylformamide. The above reaction can be carried out at a temperature of from about 40 ° C to about 140 ° C, preferably from about 80 ° C to about 120 ° C for about 1 hour to about 24 hours.

Alternatively, the above-mentioned compound of formula VIII, wherein Y is oxygen, sulfur, -CH2S-, -SN2O-,> NR ^14, -CH2 [N (R ^14)] - or -SO2 [N (R ¹⁴⁾ ] -, may be obtained in the presence of an alkali metal hydroxide base, preferably potassium hydroxide, optionally in the presence of a phase-converting catalyst, such as a quaternary ammonium or phosphonium salt, preferably tetrabutylammonium bromide, in an aromatic hydrocarbon solvent. Preferably the solvent is benzene or toluene. The above reaction may be carried out at a temperature of from about 0 ° C to about 120 ° C, preferably at about 23 ° C, for about 1 hour to about 12 hours.

Alternatively, the above-mentioned compound of formula VIII, wherein Υ is oxygen, sulfur, -CH2S-, -SN2O-,> NR ^14,

-CH2 [N (R ^14)] - or -SO2 [N (R ^14)] -, can be prepared in a so-called coupling conditions Ulman. Under these conditions, the aforementioned compound of formula VIII can be prepared by reacting a compound of formula X, wherein the group L is bromo or chloro, with a compound of formula:

GZYH (IX), wherein Y is oxygen, sulfur, -CH2S-, -SN2O-,> NR ^14, -CH2 [N (R ^14)] - or -SO2 [N (R ^14)] -, in the presence of base and a catalyst in a polar aprotic solvent. Suitable bases include carbonate or an alkali metal hydroxide base, preferably potassium carbonate. Suitable catalysts include copper (O) catalysts, preferably finely divided copper bronze. Suitable solvents include dimethylformamide or 1methyl-2-pyrrolidinone. The above reaction may be carried out at a temperature of from about 80 ° C to about 140 ° C for about 6 hours to about 24 hours.

A compound of formula VIII, wherein the group Y is in an oxidized state, i.e.,>SO2,> S = O , -CH2SO-, -CH2SO2-, SO (CH2) n - or -SO2 (CH _{2) n} -, can be obtained by reacting the corresponding compound of formula VIII, wherein the group Y is in the corresponding lower oxidized state, with a suitable oxidizing agent in a solvent. The corresponding lower oxidation state for any compound of formula VIII, wherein the group Y is>SC> 2 and> S = O, is the compound of formula VIII, where the group Y is S. The corresponding lower oxidized state for each compound of formula VIII, where the group Y is -CH2SO2- and -CH2SO-, is a compound of formula VIII, wherein the group Y is -CH2S-. The corresponding lower oxidized state for any compound of formula VIII, wherein the group Y is -SO2 (CH2) _n - and -SO (CH2) _n -> is a compound of formula VIII, where the group Y is -S- (CH2) _n Suitable oxidants include peroxyacid, preferably peracetic acid, or organic peroxide, preferably m-chloroperoxybenzoic acid or tert-butyl hydroperoxide. Suitable solvents include methylene chloride or alcohol such as ethanol. The above reaction can be carried out at a temperature of about -10 ° C to about 30 ° C for about 1 hour to about 8 hours.

A compound of formula VHI wherein Y is -O (CH 2) _n -> -S (CH 2) _n - or -NR ¹⁴ (CH 2) _n - respectively, can be obtained by reacting a compound of formula X, wherein the group L is L - (CH ₂ ) _n - and wherein the L group is halo, such as chloro, bromo, iodo, mesyloxy (MsO) or tosyloxy (TsO), with a compound of the formula:

GZWH (IX) wherein the group W is oxygen, sulfur or -NR ^14, respectively, in the presence of a base in a polar aprotic solvent. Suitable bases include an alkali metal carbonate base, preferably potassium carbonate or cesium carbonate. Suitable solvents include dimethylformamide or tetrahydrofuran. The above reaction may be carried out at a temperature of from about 23 ° C to about 80 ° C, preferably from about 20 ° C to about 50 ° C, for about 1 to about an hour.

A compound of formula VIII wherein Y is> C = O, -CH = CH or -C = C-, can be prepared by reacting a compound of formula X, wherein the group L is dihydroxyborane; zinc halide such as zinc chloride; or trialkyl tin as tributyl tin, with a compound of the formula:

GZYL ⁹ (IX) o where Y is> C = O, -CH = CH- or - C = C-; and wherein the group L is halo; preferably chloro, bromo or iodo; in the presence of a catalyst in a solvent. Suitable catalysts include palladium or nickel catalysts, preferably tetrakistriphenylphosphine palladium (O) (Pd (PPh3) 4). Suitable solvents include toluene, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide. The above reaction can be carried out at a temperature of from about 23 ° C to about 110 ° C for a time from about 1 hour to about 24 hours. Such reactions can be facilitated by the presence of a copper salt such as copper iodide or copper bromide.

Alternatively, a compound of formula VIII, wherein Y is -C = C-, can be prepared by reacting a compound of γ of formula X, wherein L is halo or triflate, preferably bromo or iodo, with a compound of formula:

G-Z-Y-H (IX) in the presence of a base such as a trialkylamine base, preferably triethylamine, and a palladium catalyst, preferably Pb (PPb3) 4, in a solvent. Suitable solvents include tetrahydrofuran or dimethylformamide. The above reaction can be carried out at a temperature of from about 23 ° C to about 60 ° C for a time from about 1 to about 24 hours.

A compound of formula VIII, wherein Y is -CH 2 (CH ₂ ) n-, can be prepared by reacting the above-mentioned compound of formula VIII, wherein Y is -CH = CH- or -C = C ~, with hydrogen gas at atmospheric pressure to about 50 psi in the presence of palladium catalyst in solvent. Preferably the palladium catalyst is palladium adsorbed on carbon. Suitable solvents include methanol or ethyl acetate. The above reaction may be carried out at a temperature of from about 20 ° C to about 50 ° C for about 1 hour to about 24 hours.

The compounds of formulas X and IX (i.e., compounds of formulas G-Z-Y-H, G-Z-W-H, or G-Z-Y-L) are either commercially available or are known and can be prepared by methods known in the art.

The compounds of formula I, which are basic in nature, can form a wide variety of different salts with a variety of inorganic and organic acids. Although such salts for their administration to animals must be pharmaceutically acceptable, in practice it is often desirable first to isolate the compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt and then convert the latter elementally back to the free base compound by treating it with an alkaline reagent and subsequently converting the free base into a pharmaceutically acceptable acid addition salt. 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 the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Careful evaporation of the solvent yields the desired solid salt.

The acids used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of the invention are those which form non-toxic acid addition salts, i. salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitarticatone, succinate, succinate, succinate, succinate, succinate, succinate, succinate methanesulfonate and pamoate [i.e. 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)] salts.

These compounds of formula I, which are also acidic in nature, can form base salts with a number of pharmacologically acceptable cations. Examples of such salts include the alkali and alkaline earth metal salts, in particular the sodium and potassium salts. All these salts are prepared by conventional methods. The chemical bases used as reagents to prepare the pharmaceutically acceptable base salts of the invention are those which, with the acid compounds of formula I described herein, form non-toxic base salts. Such non-toxic base salts include those obtained with pharmacologically acceptable cations such as sodium, potassium, calcium, magnesium and the like. These salts can be readily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution dry, preferably under reduced pressure.

Alternatively, they may also be prepared by mixing lower alkanol solutions of the acidic compounds and the desired alkali metal alkoxides and subsequently evaporating the resulting solution to dryness in the same manner as above. In each case, it is preferable to use stoichiometric amounts of the reagents to ensure complete reaction and to obtain the maximum yield of the desired final product.

Biological analyzes

The ability of the compounds of formula I or their pharmaceutically acceptable salts (hereinafter referred to as the compounds of the present invention) to inhibit metalloproteinases or mammalian reprolysins and, therefore, to demonstrate their efficacy in treating diseases characterized by metalloproteinase activity, has been shown in in vitro analitics. in vitro and in vitro.

MMP analyzes

Selective MMP-13 inhibitors can be C identified by screening inhibitors of the present invention by the fluorescence analysis of MMPs described below and selection of agents with IC50 MMP-13 / MMP-X 100 inhibition ratios and strength less than 100 nM, where MMP-X refers to one or more matrix metalloproteinases

Non-selective collagenase inhibitors as used herein refer to agents that exhibit less than 100-fold selectivity for inhibiting collagenase-3 enzymatic activity against collagenase-1 enzyme activity and a potency greater than 100 nM, as determined by the IC50 results from the fluorescence analysis of MMP-13 / MMP-X described below.

The ability of collagenase inhibitors to inhibit collagenase activity is known in the art. The degree of inhibition of individual MMPs for different compounds has been documented and one skilled in the art knows how to normalize the different test results compared to those reported here. The following assays can be used to identify matrix metalloproteinase inhibitors.

Inhibition of human collagenase (MMP-1)

Human recombinant collagenase is activated by trypsin. The amount of trypsin is optimized for each sample of collagenase-1, but the typical reaction uses the following ratio: 5 pg trypsin per 100 μg collagenase. Trypsin and collagenase were incubated at room temperature for 10 minutes, after which a five-fold excess (50 mg / 10 mg trypsin) inhibitor of soybean trypsin was added.

Stock solutions (10 mM) of dimethyl sulfoxide inhibitors were prepared and then diluted using the following scheme:

tM 120 μΜ -> 12 μΜ -> 1.2 μΜ -> 0.12 μΜ

Twenty-five microliters of each concentration were then added to three corresponding wells on a 96-well microfluoric plate. The final inhibitor concentration is a 1: 4 dilution after the enzyme and substrate are added. Positive controls (enzyme without inhibitor) were placed in wells D7-D12, and negative controls (without enzyme and inhibitor) were placed in wells D1-D6.

Collagenase-1 was diluted to 240 ng / ml and then 25 μΐ was added to the corresponding wells of the microfluoric plate.

The final collagenase concentration in this assay is 60 ng / ml.

A substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-AlaLys (NMA) -NH2) was prepared in the form of a 5 mM stock solution in dimethyl sulfoxide and then diluted to 20 μфер in assay buffer. The assay was started by adding 50 μΐ of substrate per well of the microfluoric plate to give a final concentration of 10 μΜ.

Fluorescence readings (360 nM excitation, 460 pt emission) were made at 0 and then at 20-minute intervals. The assay is performed at room temperature for a typical test time of 3 hours.

Then, the fluorescence curve versus time is plotted for blank samples and for collagenase-containing samples (data from triplicate experiments are averaged). A time point giving a good signal (at least five times higher than the blank sample) and lying on the linear part of the curve (usually about 120 minutes) is selected to determine the IC50 values. Zero time is used as a blank for each compound at each concentration, and these values are subtracted from the data for 120 minutes. Data are plotted as the inhibitor concentration relative to the% control (fluorescence of an inhibitor divided by the fluorescence of collagenase x 100 only). IC50 values are determined by the concentration of inhibitor giving a signal that is 50% of the control.

If values for IC50 lower than 0.03 μΜ were reported, then inhibitors were analyzed at concentrations of 0.3 μΜ, 0.03 μΜ and 0.003 μΜ.

Gelatinase Inhibition (MMP-2)

Human recombinant gelatinase 72 kD (MMP-2, gelatinase A) was activated for 16-18 hours at 4 ° C and shaken gently with 1 mM p-aminophenyl acetate (from freshly prepared 100 mM stock solution in 0.2 N NaOH).

mM dimethyl sulfoxide stock inhibitors were serially diluted in assay buffer (50 mM TRIS, pH 7.5, 200 mM NaCl, 5 mM CaCl 2, 20 μΜ ZnCh and 0.02% Brij-35 (v / v)) using the following scheme :

tM - + 120 μΜ - + 12 μΜ - + 1.2 μΜ - + 0.12 μΜ

Further dilutions should be made using the same scheme, if necessary. In each assay, a minimum of four concentrations were obtained for each compound. Then, 25 µL of each inhibitor concentration was added to three wells of a black 96-well U-shaped microfluoric plate. Since the final test volume is 100 µL, the final concentrations of the inhibitor result from an additional dilution of 1: 4 (ie 30 μ + - + 3 μΜ - + 0.3 μΜ - + 0.03 μΜ, etc.). Blank (no enzyme and inhibitor) and positive enzyme control were also prepared three times.

The activated enzyme was diluted to 100 ng / mL in assay buffer and 25 µL per well was added to the corresponding wells of the microplate. The final enzyme concentration of the assay was 25 ng / mL (0.34 nM).

The 5mM dimethyl sulfoxide substrate stock solution (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2) was diluted in assay buffer to 20 μΜ. The assay was started by adding 50 µL of the diluted substrate to give a final concentration of 10 µΜ of the substrate. At zero time, fluorescence readings (320 excitations; 390 emissions) were read immediately, and subsequent readings were made every 15 minutes at room temperature with a PerSeptive Biosystems CytoFluor Multi-Well Plate Reader Multifunction C max at 90 units.

The average fluorescence value of the enzyme and the blank were plotted against time. To determine the IC50, select a point from the linear part of the curve at a small time value. The zero time point for each compound at each dilution was subtracted from the late time point and the data expressed as a percentage of the enzyme control (fluorescence of an inhibitor divided by the fluorescence of the positive enzyme control x 100).

Data are plotted as an inhibitor concentration relative to a percentage of the enzyme control. IC50 values are defined as the concentration of inhibitor that produces a signal that is 50% of the positive enzyme control.

Inhibition of stromelysin activity (MMP-3)

Human recombinant stromelysin (MMP-3, stromelysin-

1) is activated for 20-22 hours with 2 mM p-aminophenylmercuric acetate (from freshly prepared 100 mM stock solution in 0.2 N NaOH) at 37 ° C.

mM dimethyl sulfoxide stock inhibitors were serially diluted in assay buffer (50 mM TRIS, pH 7.5, 150 mM NaCl, 10 mM CaCl 3 and 0.05% Brij-35 (v / v)) using the following scheme:

tM -> 120 μΜ -> 12 μΜ - »1.2 μΜ - + 0.12 μΜ

Further dilutions should be made using the same scheme, if necessary. In each assay, a minimum of four concentrations were obtained for each compound. Then 25 µL of each inhibitor concentration was added in three wells to a black 96-well U-shaped microfluoric plate. Since the final test volume is 100 µL, the final inhibitor concentrations result from an additional dilution of 1: 4 (i.e., 30 μΜ -> 3 μΜ -> 0.3 μΜ 0.03 μΜ, etc.). Blank (without enzyme and inhibitor) and positive enzyme control (with enzyme without inhibitor) are also prepared three times.

The activated enzyme was diluted to 200 ng / mL in assay buffer and 25 μΕ per well was added to the corresponding wells of the microplate. The final enzyme concentration of the assay is 50 ng / mL (0.875 nM).

The mM dimethyl sulfoxide stock solution w (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys (Dnp) -NH2) was diluted in assay buffer to 6 μΜ. The assay was started by adding 50 µL of the diluted substrate, yielding a final concentration of 3 µΜ of substrate. Fluorescence reading (320 excitation; 390 emission) at zero time is made immediately, and subsequent readings are made every 15 minutes at room temperature with a PerSeptive Biosystems CytoFluor Multi-Well Plate Reader Multifunction C max at 90 units.

Cr The average fluorescence value of the enzyme and the blank are plotted against time. A point from the linear portion of the curve at a small time value is selected to determine IC50. The zero time point for each compound at each dilution was subtracted from the point at a later time and the data expressed as a percentage of the enzyme control (fluorescence of an inhibitor divided by the fluorescence of the positive enzyme control x 100). Data are plotted as an inhibitor concentration relative to a percentage of the enzyme control. IC50 values are defined as the concentration of inhibitor that produces a signal that is 50% of the positive enzyme control.

92 kD human gelatinase inhibition (MMP-9)

Inhibition of 92 kD gelatinase activity (MMP9) was assayed using a Mca-Pro-Leu-Gly-Leu-DpaAla-Arg-NH2 substrate (10 μΜ) under similar conditions for inhibition of human collagenase (MMP) described above. -1).

Human recombinant 92 kD gelatinase (MMP-9, gelatinase B) was activated for 2 hours with 1mM raminophenyl mercury acetate (from freshly prepared 100 mM stock solution in 0.2 N NaOH) at 37 ° C.

mM dimethyl sulfoxide stock inhibitors were serially diluted in assay buffer (50 mM TRIS, pH 7.5, 200 mM NaCl, 5 mM CaCl 2, 20 μΜ ZnCl.2, 0.02% Brij-35 (v / v)) using the following scheme:

tM -> 120 μΜ -> 12 μΜ -> 1.2 μΜ 0.12 μΜ

Further dilutions should be made using the same scheme, if necessary. In each assay, a minimum of four concentrations were obtained for each compound. Then 25 µL of each inhibitor concentration was added in three wells of a black 96-well U-shaped microfluoric plate. Since the final test volume is 100 µL, the final concentrations of the inhibitor result from a further dilution of 1: 4 (ie 30 μΜ -> 3 μΜ -γ 0.3 μΜ -> 0.03 μΜ, etc.). Blank (without enzyme and inhibitor) and positive enzyme control (with enzyme without inhibitor) were also prepared three times.

The activated enzyme is diluted to 25 ng / mL in assay buffer and 25 pL per well is added to the corresponding wells of the microplate. The final enzyme concentration of the assay was 25 ng / mL (0.27 nM).

The 5mM dimethyl sulfoxide substrate stock solution (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2) was diluted in assay buffer to 20 μΜ. The assay was started by adding 50 µL of the diluted substrate to give a final concentration of 10 µΜ of the substrate. At zero time, fluorescence readings (320 excitations; 390 emissions) were made immediately, and subsequent readings were made every 15 minutes at room temperature with a PerSeptive Biosystems CytoFluor 'Multi-Well Plate Reader multi-wave reader with a maximum of 90 units.

The average fluorescence value of the enzyme and the blank were plotted against time. A point from the linear portion of the curve at a small time value is selected to determine IC50. The zero-time point for each compound at each dilution is subtracted from the point at a later time and the data is expressed as a percentage of the enzyme control (fluorescence of an inhibitor divided by the fluorescence of the positive enzyme control x 100). Data are plotted as an inhibitor concentration relative to a percentage of the enzyme control. IC50 values are defined as the concentration of inhibitor that produces a signal that is 50% of the positive enzyme control.

Inhibition of MMP-13

Human recombinant MMP-13 was activated with 2 mM Aβ (p-aminophenyl mercury acetate) for 1.5 hours at 37 ° C and diluted to 400 mg / ml in assay buffer (50 mM TRIS, pH 7.5, 200 mM sodium chloride, 5 mM calcium chloride, 20 μΜ zinc chloride, 0.02% Brij). Then, 25 μΐ of the diluted enzyme is added per well of a 96-well microfluoric plate. The enzyme is then diluted to a ratio of 1: 4 by the addition of inhibitor and substrate to a final concentration for analysis of 100 mg / ml.

Prepare 10 mM stock solutions of dimethyl sulfoxide inhibitors and then dilute them in buffer for dilution of the human collagenase inhibitor scheme (MMP-1): 25 μΐ of each concentration in three wells of microfluoric plate is added. . The final concentration for analysis is 30 μΜ, 3 μΜ, 0.3 μΜ and 0.03 μΜ.

A substrate (Dnp-Pro-Cha-Gly-Cys (Me) -His-AlaLys (NMA) -NH2) was prepared as in human collagenase inhibition (MMP-1) and 50 µL was added to each well to obtain a final concentration 10 μΜ. Fluorescence counting (360 nM excitation; 450 emission) was done at zero time and every 5 minutes for 1 hour.

Positive controls consist of enzyme and substrate without inhibitor, and blank samples consist of substrate only.

IC50 values were determined as in human collagenase inhibition (MMP-1). If IC50 values are reported to be less than 0.03 μΜ, the inhibitors are subsequently analyzed at a final concentration of 0.3 μΜ, 0.03 μΜ, 0.003 μΜ and 0.0003 μΜ.

Collagen film assay from MMP-13

Rat collagen type I isotope isotopically labeled with ¹⁴ C acetic anhydride (TE Cawston and A. J. Barrett, Anal. Biochem., 99, 340-345 (1979)) and used to produce 96-well radiolabeled plates. collagen films (Barbara Johnson-Wint, Anal. Biochem. 104, 175-181 (1980)). When a solution containing collagenase is added to the well, the enzyme breaks down the insoluble collagen, which develops and thus dissolves. Collagenase activity is directly proportional to the amount of soluble collagen determined by the fraction of radiated radioactivity in the supernatant measured in a standard scintillation counter. Collagenase inhibitors are therefore compounds that reduce the number of radioactive impulses relative to controls in which no inhibitor is involved. A specific embodiment of the assay is described in detail below.

The following method is used to determine the selectivity of compounds to MMP-13 over MMP-1 using collagen as a substrate. Recombinant human prMMP-13 or prMMP-1 is activated as described above. Activated MMP-13 or MMP-1 was diluted to 0.6 pg / ml with buffer (50 mM TRIS pH 7.5, 150 mM NaCl, 10 mM CaCl ₂ , 1 μΜ ZnC12, 0.05% Brij-35, 0.02% sodium azide).

Stock solutions of test compound (10mM) in dimethyl sulfoxide are prepared. Dilute the test compounds in the above TRIS buffer to 0.2, 2.0, 20, 200, 2000 and 20000 nM.

100 μΐ of the respective drug dilution and 100 μΐ diluted enzyme were added to the wells of a 96-well plate containing collagen films labeled with ¹⁴ C-collagen. The final enzyme concentration is 0.3 pg / ml, while the final drug concentration is 0.1, 1.0, 10, 100, 1000 nM. Each drug concentration and control was analyzed three times. Control analyzes were also performed three times for cases where no enzyme was involved and for the enzyme in the absence of any compound.

The plates are incubated at 37 ° C for such a period of time for which about 30-50% of the collagen present is dissolved, which is determined by counting additional control wells at different times. In most cases, 9 hours of incubation is required. When the analysis was satisfactory, the layer above the precipitate from each well was removed and counted in a scintillation counter. From each sample, baseline counts (determined by enzyme-free counting) are subtracted and% emission calculated for the enzyme-free and inhibitor-free wells is calculated. The values for the three samples are averaged for each point and the data are plotted as a percentage of the drug concentration. IC50 values are determined from the point at which 50% inhibition of radiolabelled collagen emission is obtained.

Assays for determining the identity of active collagenases in conditioned cartilage are performed using collagen as a substrate, cartilage conditioned medium having collagenase activity and inhibitors with different selectivity. The cartilage conditioned medium collects over the time during which collagen degradation takes place and is thus representative of the involvement of collagenase in the destruction of collagen. Assays were performed as described above with the exception that conditioned cartilage medium was used as the source of the enzyme instead of recombinant MMP-13 or recombinant MMP-1.

IL-1 Induced degradation of cartilage collagen from bovine nasal cartilage

In this analysis, bovine nasal cartilage grafts are used which typically serve to test the efficacy of various compounds to inhibit either IL-1-induced proteoglycan degradation or IL-1-induced collagen degradation. Bovine nasal cartilage is tissue that is very similar to articular cartilage, ie.

chondrocytes surrounded by a matrix that is mainly collagen type II and aggrecan. The tissue is used because it is: (1) very similar to articular cartilage, (2) readily accessible, (3) relatively homogeneous, and (4) degraded by predictable kinetics after stimulation with IL-1.

Two variants of this assay were used to test the compounds. The two options produce similar results. The options are described below:

Version 1

Three pins of bovine nasal cartilage (approximately 2 mm in diameter and 1.5 mm in length) were placed in each well on a 24-well tissue culture plate. To each well was added 1 ml of serum-free medium. Compounds are prepared as 10 mM stock solutions in dimethyl sulfoxide and then diluted respectively in serum-free medium to final concentrations, for example 50, 500 and 5000 nM. Each concentration is tested three times.

Human recombinant IL-Ια (5ng / ml) (IL-1) was added to the three control wells and to each drug well. Three control wells were also prepared, to which neither drug nor IL-1 was added. The medium was removed and fresh medium containing IL-1 and the drug was added at appropriate concentrations at 6, 12, 18 and 24 days or every 3-4 days if necessary. The separated medium is stored at -20 ° C at a later time for later analysis. When the cartilage in the wells with IL-1 alone was absorbed almost completely (about 21 days), the experiment was considered complete. The medium is separated and stored. Aliquots (100 μϊ) were poured from each well and at all times, papain digested and then analyzed for hydroxyproline content. Basic hydroxyproline (mean of IL-1 and IL-free wells) was subtracted from all data and the mean was calculated for each three samples. The data are then expressed as a percentage of the average for IL-1 alone and plotted. This chart determines the IC50.

Option 2

The experimental conditions are the same as those described above for Option 1 until day 12. On day 12, condition the well and freeze from each well. To each well was added 1 ml of phosphate buffered saline (PBS) containing 0.5 µg / ml trypsin and the incubation was continued for 48 hours at 37 ° C. After 48 hours incubation in trypsin, phosphate buffered saline was removed. Aliquots (50 μΐ) of the PBS / trypsin solution and the previous two time points (6 and 12 days) were poured, hydrolyzed and the hydroxyproline content determined. Baseline hydroxyproline (mean of wells without IL-1 and drug free) was subtracted from all data and the mean value for each three samples calculated. The data are then expressed as a percentage of the average for IL-1 alone and plotted. This chart determines the IC50. In this embodiment, the experiment time is significantly shortened. The addition of trypsin for 48 hours after 12 days of IL-1 stimulation probably secretes any type II collagen that is damaged by collagenase activity but is not yet separated from cartilage matrixes. In the absence of IL-1 stimulation, trypsin treatment produces only low baseline degradation rates of collagen cartilage grafts.

Inhibition of tumor necrosis factor (TNF) production

The ability of the compounds or their pharmaceutically acceptable salts to inhibit TNF production and therefore to show efficacy in the treatment of diseases involving TNF production is demonstrated in the following in vitro assay:

Analysis of human monocytes

Human mononuclear cells were isolated from uncoagulated human blood using the one-step Ficoll-hypaque method. (2) The mononuclear cells are 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 performed on an Abbott Cell Dyn 3500 analyzer indicate that monocytes are in the range of 17 to 24% of the total number of cells in these preparations.

180 μΐ of the cell suspension was distributed into flat-bottomed 96-well plates (Costar). Addition of compounds and LPS (100 ng / ml final concentration) gave a final volume of 200 μΐ.

The analyzes were performed three times. After incubation at 37 ° C for 4 hours in a humidified CO2 incubator, the plates were removed and centrifuged (10 minutes at about 250 x g) and the supernatant liquids were separated and analyzed for TNFα using the R&D ELISA Kit.

Agreganase analysis

Primary porcine chondrocytes from articular cartilage were isolated by sequential feeding with trypsin and collagenase, followed by overnight collagenase feeding and placed in 2 x 10 ⁵ cells per well in 48-well plates with 5 gCi / ml. S (1000 Ci / mmol) sulfur in collagen type I coated plates. Cells were allowed to include a marker in their proteoglycan matrix (approximately 1 week) at 37 ° C under an atmosphere of 5% CO2.

The night before starting the experiment, the chondrocyte monolayers were washed twice in DMEM / 1% PSF / G and then left overnight for incubation in fresh DMEM / 1% FBS.

In the morning, chondrocytes were washed once in DMEM / 1% PSF / G. The final wash solution is left on the plates in the incubator until dilutions are made.

The media and dilutions can be made as described in the table below.

Control environment DMEM only (control medium) IL-1 medium DMEM + IL-1 (5 ng / ml) Dilution of the drug Preparation of stock solutions from all compounds at 10 mM in DMSO. Preparation of 100 μΜ stock solution of each compound in DMEM in a 96-well plate. Storage overnight in the freezer. Next day serial dilutions in DMEM with IL-1 to 5 μΜ, 500 nM and 50 nM. Suction extraction from the final wash from the wells and add 50 μΐ of the compound from the above dilutions to 450 μΐ IL-1 medium in the respective wells of the 48 well plates. Final compound concentrations equal to 500 nM, 50 nM and 5 nM. All samples were run three times with control samples and only with IL-1 on each plate.

The plates are labeled and only the inner 24 wells of the plate are used. On one of the plates, several columns are designated as IL-1 (without drug) and as control (without IL-1 and without drug). These control columns were periodically counted to monitor the release of S-proteoglycan. Control and IL-1 medium (450 μΐ) were added to the well to start the wells, followed by compound (50 μΐ). The plates were incubated at 37 ° C in an atmosphere of 5% CO2.

The assay is considered complete at 40-50% release (when the CPM of IL-1 medium is 4-5 times the control medium), evaluated by liquid scintillation counting (LSC) of medium samples (9-12 hours). The medium from all wells was removed and placed in scintillation tubes. Scintillate was added and radioactive counting (LSC) was performed. To the dissolved cell layers from each well were added 500 μΐ papain feed buffer (0.2 M TRIS, pH 7.0, 5 mM EDTA, 5 mM DTT, and 1 mg / ml papain). The plates with nutrient solution were incubated overnight at 60 ° C. The next day, the cell layer was removed from the plates and placed in scintillation tubes. Scintillate is added and sample counting (LSC) is performed.

Determine the percentage of released number relative to the total percentage in each well. The three samples were averaged and the reference value subtracted from each well. The percent inhibition of compound was based on 0% inhibition in IL-1 samples (100% of total).

The compounds of the present invention, as all compounds tested, have IC 50 values in at least one of the above assays of less than 100 µΜ, preferably less than 100 nM. Some preferred groups of compounds have differing selectivity for individual MMPs or ADAMs. One group of preferred compounds has activity that is selectively targeted to MMP13 more than to MMP-1, MMP-3 and MMP-7. Another preferred group of compounds has aggrecanase activity in addition to the greater selectivity for MMP-13 compared to MMP-1, MMP-3, MMP-7 and MMP-17. Another preferred group of compounds has aggrecanase activity in addition to the greater selectivity for MMP-13 compared to MMP-1, MMP-2, MMP-3, MMP-7, MMP-9 and MMP-14. Another preferred group of compounds has aggrecanase activity in addition to the higher selectivity for MMP-13 compared to MMP-12 and MMP-14.

In the administration of mammals, including humans, to inhibit matrix metalloproteinases or mammalian reprolysin, various conventional routes of administration may be used, including oral, parenteral (eg, intravenous, intramuscular or subcutaneous), buccal, anal and topical. Generally, the compounds of the invention (hereinafter referred to as the active compounds) will be administered at dosages between about 0.1 and 25 mg / kg body weight of the treated patient per day, preferably from about 0.3 to 5 mg / kg. The active compound is preferably administered orally or parenterally. However, it may be necessary to adjust the dosage depending on the condition of the patient being treated. In each case, the person responsible for administering the drug will also determine the appropriate dose for the designated patient.

The compounds of the present invention can be administered in a wide variety of different dosage forms, with the generally therapeutically effective compounds of the invention being present in the dosage forms in concentrations ranging from about 5.0% to about 70% by weight.

Tablets for oral administration contain a number of excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, which can be used together with various disintegrants such as starch (preferably corn, potato or tapioca), alginic acid and alginic acid and alginic acid , together with granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be particularly useful in the tableting process. Solid compositions of a similar type can also be used to fill gelatin capsules, the preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are preferred for oral administration, the active ingredient may be combined with a number of sweetening or flavoring agents, coloring agents or dyes and, if necessary, emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. In the case of animals, it is recommended that they be added to animal feed or drinking water at a concentration of 5-5000 ppm, preferably 25 to 500 ppm.

For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous), sterile injectable solutions of the active ingredient are usually prepared. Solutions of the therapeutic compound of the present invention may be used, either in sesame or in peanut oil, or in aqueous propylene glycol. Water

The 100 solutions should be suitably balanced and buffered, preferably at a pH greater than 8, and if necessary the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection. The oily solutions are suitable for intramuscular, intramuscular and subcutaneous injection. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical methods known to one skilled in the art. In the case of animals, the compounds may be administered intramuscularly or subcutaneously at a dosage of about 0.1 to 50 mg / kg per day, preferably 0.2 to 10 mg / kg per day, given as a single dose or divided into 3 doses.

The active compounds of the invention may also be formulated in the form of rectal compositions such as suppositories or enemas containing, for example, traditional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, it is appropriate to deliver the active compounds of the invention in the form of a solution or suspension from a container of injection pump being compressed or pumped by the patient, or in the form of an aerosol spray from a pressurized container or nebulizer at use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol dispenser, the dosage unit can be determined by providing a valve supplying metered quantities. The pressure container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made of, for example, gelatin) may be formulated for use in an inhaler or insufflator containing a powder mixture of

101 compound of the invention and a suitable powder base such as lactose or starch.

For topical ocular administration, direct application to the affected eye of formulations such as eye drops, aerosol, gels or ointments may be used or may be incorporated into collagen (such as poly-2-hydroxyethyl methacrylate and its copolymers) or hydrophilic polymeric protection. Substances can be administered in the form of contact lenses, either through local reservoirs or as a sub-conjunctive formulation.

For intra-orbital administration, a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention in aqueous solution or suspension (particle size less than 10 microns) may be used. The aqueous solutions, if necessary, should be suitably adjusted and buffered, preferably at a pH between 5 and 8, and the liquid diluent first rendered isotonic. Small amounts of viscosity or sustained release polymers (such as cellulosic polymers, Dextran, polyethylene glycol or alginic acid) may be added. These solutions are suitable for the purpose of intra-orbital injection. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical methods known to one skilled in the art. In the case of animals, the compounds can be administered intra-orbital at doses of about 0.1 to 50 mg / kg per day, preferably 0.2 to 10 mg / kg per day, given as a single dose or up to three separate doses.

As with the other routes of introduction and the corresponding

The 102 dosage forms described herein, dosage forms for oral administration are also suitably formulated to provide controlled, sustained and / or delayed release of the active ingredient. Typically, these include oral sustained-release tablets, capsules and multiparticulates, as well as enteric coated tablets and capsules that prevent the release and adsorption of the active ingredient in the patient's stomach and facilitate delivery to the stomach, e.g. in the gut. Other typical oral dosage forms include oral sustained release tablets, capsules, and multiparticulates that provide a systematic delivery of the active ingredient in a controlled manner over an extended period of time, for example, for 24 hours. When rapid release of the active ingredient is required or desired, a controlled release oral dosage form in the form of a fast-dissolving tablet, which also preferably includes highly soluble salts of the active ingredient, may be prepared.

The following examples show the preparation of the compounds of the present invention. Melting point is not adjusted. NMR data are given in parts per million (δ) and are relative to the deuterium signal from the sample solvent (deuterochloroform, unless otherwise indicated). Commercial reagent products were used without further purification. Chromatography refers to column chromatography performed using silica gel 32-63 mmol and under nitrogen pressure (flash chromatography). Room or ambient temperature refers to 2025 ° C. All the reactions in a non-aqueous environment for convenience and increase in yield were carried out in a nitrogen atmosphere. Concentration under reduced pressure or in vacuum means that

103 a rotary evaporator was used.

A general experiment

General example:

Compounds of formula I can be prepared by reacting the appropriate compound of formula III with urea of formula II (i.e. H2N (CO) -NH2) 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 20 ° C to the boiling point of the solvent, preferably 80 ° C, for 15 minutes to 3 hours.

General preparation:

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

The compound of formula IV can be prepared by reacting the appropriate compound of formula VI with a compound of formula V, which is of general formula L ³ - (A ') - L ⁴ or L - (A'), in a non-protic solvent, for preferably an aromatic hydrocarbon solvent such as benzene or toluene, at a temperature of about 40 ° C and a reflux temperature of the solvent, preferably about 80 ° C, for a time from about 1 to about 6 hours.

The compound of formula VI can be prepared by

104 reacting the appropriate compound of formula NH2-XY-ZG with a compound of formula VII which is a 2-halomalonate ester, preferably 2-bromodiethylmalonate, in the presence of a suitable base as a tertiary amine base, preferably Ν, мети dimethylaniline, at a temperature of about 20 ° C to about 100 ° C, preferably about 80 ° C, for a time of about 4 to about 48 hours.

Example 1:

1- [6- (4-Bromo-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-

2,6,8,10-tetraone:

An example No Structure Molecular weight MS (APCI, m / z): [M + H] ⁺ 1 f ”O. 445.238 445

Metallic sodium (29 mg, 1.26 mmol) was added to 1.3 mL of ethanol and stirred until homogenized. 1- [6- (4-Bromo-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g, 0.42 mmol) was added followed by urea (75 mg, 1.26 mmol) and the mixture stirred for 5 minutes at 80 ° C. The mixture was cooled to ambient temperature, acidified with 1M hydrochloric acid and extracted 3x with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gel chromatography (3: 1 hexane-ethyl acetate) to give 28 mg of 1- [6- (4-bromo-phenoxy) pyridin-3-yl] -1,7,9-triaza-spiro [4.5 ] decane-2,6,8,10-tetraone as a colorless solid. HPLC Time of

105 detention: 2.201 minutes; MS (APCI, m / z): 436 [MH] '; 438 [M + H] ⁺ .

Preparation 1:

2- (4-Bromo-phenoxy) -5-nitro-pyridine:

4-Bromophenol (5.5 g, 32 mmol) was added to 42 mL of a 50% w / w aqueous sodium hydroxide solution. After stirring for 30 minutes, 44 mL of toluene was added, followed by 2-chloro-5-nitropyridine (5.0 g, 32 mmol) and tetrabutylammonium bromide (10 g, 32 mmol). After stirring for 1.5 hours at 23 ° C, the mixture was diluted with 200 mL of water, neutralized with 12M aqueous hydrochloric acid, and the mixture was extracted 3x with ether. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give 6 g of 2- (4-bromo-phenoxy) -5-nitro-pyridine. 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] ⁺ .

6- (4-Bromo-phenoxy) -pyridin-3-ylamine:

A mixture of 2- (4-bromo-phenoxy) -5-nitro-pyridine (6.0 g, 22.7 mmol), 200 mL of methanol and 50 mg of PO 2 was shaken under H2 pressure at 50 psi for 1 hour at 23 ° C. The mixture was filtered through a pad of Celite (R) and the filtrate was concentrated in vacuo to give 6 g of 6- (4-bromo-phenoxy) -pyridin-3-ylamine. ^X 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] ⁺

Preparation 2:

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

106

A mixture of 6- (4-bromo-phenoxy) -pyridin-3-ylamine (4.5 g, 16.9 mmol), 2-bromodimethylmalonate (4.1 g, 17 mmol) and Ν, dimethylaniline (2.1 g, 17 mmol) was stirred at 80 ° C for 24 hours. The mixture was cooled to 23 ° C, diluted with 50 mL of benzene and treated with 7 mL of 2-bromopropionyl chloride. After stirring at reflux for 3 hours, the mixture was cooled to -23 ° C, concentrated in vacuo and diluted with 750 mL of ethanol. Amberlyst-400 resin (hydroxide form) (75 g) was added and the mixture was stirred in for 24 hours at 23 ° C. The mixture was filtered and the resin was washed with 50 mL of methanol. The filtrate was concentrated in vacuo and the residue was purified by gel chromatography on silica gel (2: 1 hexane-ethyl acetate) to give 6 g of 1- [6- (4-bromophenoxy) -pyridin-3-yl] -pyrrolidin-2 diethyl ester. 2-Dicarboxylic acid. 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] ⁺ .

The following compounds were prepared according to methods analogous to those of Example 1, introducing, when appropriate, the exact pyridine and diester:

107

Table 1

An example No Structure Molecular weight MS (APCI, m / z): [M + H] ⁺ 2 and 384.327 385.1 3 K ° t; F 398.354 399.1

Example 4

4- [5- (2,6,8,10-Tetraoxo-1,7,9-shriaza-spiro [4.5] dec-1-yl) -pyridin2-yloxy] -benzonitrile:

An example No Structure Molecular weight MS (APCI, m / z): [M + H] ⁺ 4 I HN NH 391.346 392.1

Following the procedure for the preparation of the pyrimidinetrion described in Example 1, the reaction of 1- [6- (4-cyano-phenoxy) -pyridin-3-yl] -pyrrolidine2,2-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 gave 14.3 mg of 4- [5108 (2,6,8,10-tetraoxo-1,7,9-triaza-spiro [4.5] dec. 1-yl) -pyridin-2yloxy] -benzonitrile as a colorless solid. 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] ⁺ .

Preparation 1:

1- [6- (4-Cyano-phenoxy) -pyria-3-yl] pyrrolidine-2,2-dicarboxylic acid diethyl ester:

1- [6- (4-Bromo-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.28 g, 0.53 mmol), zinc cyanide (0.037 g, 0.32 mmol), tetrakistriphenylphosphine palladium (0) (0.024 g, 0.021 mmol) and 0.66 mL of dimethylformamide were heated to 80 ° C for 24 hours. An additional 37 mg of zinc cyanide and 24 mg of tetrakistriphenylphosphine palladium (0) were added and the mixture was stirred at 80 ° C for a further 48 hours. After cooling to room temperature, the mixture was diluted with toluene and washed with 2M ammonium hydroxide (twice) and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by radial chromatography (ethyl acetate-hexanes, then methanol) afforded 58 mg of 1- [6- (4-cyano-phenoxy) -pyridin-3-yl] -pyrrolidine dimethyl ester-

2,2-dicarboxylic acid as a colorless syrup.

NMR (CDCl3, 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] ⁺ .

Example 5

1- [6- (4- [1,3,4] Oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triaza109

cnupo [4.5] decane-2,6,8,10-tetraone:

An example No Structure Molecular weight MS (APCI, m / z): [M + H] ⁺ 5 ύΚ Ah ^ν -ν 434.371 435.1

Following the procedure for the preparation of the pyrimidinetrion described in Example 1, the reaction of the diethyl ester of 1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] 5- oxo-pyrrolidine-2,2-dicarboxylic acid (200 mg, 0.44 mmol) with urea (0.080 g, 1.3 mmol) in 1.3 mL of 1M sodium ethoxide in ethanol gave 25 mg 1- [6- (4- [1,3, 4] Oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone as a colorless solid. NMR (CD3OD, 500 MHz): 9.02 (s, 1H), 8.14 (d, 2H, J = 8.0 Hz), 8.06 (d, 1H, J = 2.0 Hz), 7.78 (dd, 1H, J = 2.5, 9.0 Hz), 7.35 (d, 2H, J = 9.0 Hz), 7.12 (d, 1 H, J = 9.0 Hz), 2.74 (m, 2H), 2.66 (m, 2H) ppm. MS (APCI, m / z): 435 [M + H] ⁺ .

Preparation 1:

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

1- [6- (4-Formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.70 g, 1.64 mmol),

110

sodium carbonate (0.26 g, 1.64 mmol) and 16.4 mL of 1: 1 tert-butyl alcohol-water were treated with potassium permanganate (0.26 g, 1.64 mmol). After stirring for 2 hours at room temperature, the mixture was quenched with sodium sulfite, acidified with 1M hydrochloric acid and extracted 3x with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1- (6- (4carboxy-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester) as a colorless syrup (0.5 g). A 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] ⁺ .

Preparation 2:

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

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 for 20 minutes at room temperature. The mixture was treated with Losshydrazide (0.17 g, 1.3 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 5 mL of 1: 1 v / v methylene chloride-trifluoroacetic acid, stirred for 1 hour at ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M sodium hydroxide and brine, dried over

Ill

sodium sulfate, filtered and concentrated to give 1- [6- (4-Hydrazinocarbonyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g) as a colorless syrup. HPLC: 2.770 minutes.

Preparation 3:

1- [6- (4- [1.3.4] Oxadiazol-2-yl-phenoxy) -pyridine- diethyl ester

3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid:

1- [6- (4-Hydrazinocarbonylphenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g, 0.44 mmol), trimethylorthoformate (0.1 mL, 0.91 mmol) ) and 1 mL of xylene was refluxed for 24 hours. The mixture was concentrated in vacuo to give diethyl ester of 1 [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-

2,2-dicarboxylic acid (0.2 g) as a colorless syrup. MS (APCI, m / z): 467.2 [M + H] ⁺ .

Example 6

1- [6- (4-Ethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane 2,6,6,8,10-tetraone:

Example No. Structure Molecular weight MS (APCI, m / z): [M + H] ⁺ 6 ° L SN ₃ 394.39 395.3

112

Following the procedure for the preparation of the pyrimidinetrion described in Example 1, the reaction of the diethyl ester of 1- [6- (4-ethyl) -phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-

2,2-Dicarboxylic acid (200 mg, 0.41 mmol) with urea (0.088 g, 1.4 mmol) in 1.4 mL of 1M sodium ethoxide in ethanol gave 25 mg of 1- (6- (4- [1,3,4] oxadiazole- 2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone as a colorless solid ^X 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.

Preparation 1:

1- [6- (4-Ethyl-phenoxy) -pyridin-3-yl] -5-oxopyrrolidine-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 at hydrogen gas pressure of 50 psi for 2 hours. The mixture was filtered and concentrated in vacuo to give 0.20 g of 1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -5-oxopyrrolidine-2,2-dicarboxylic acid diethyl ester 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 = 7.5 Hz), 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 = 8.0 Hz), 1.20 (t, 6H, J = 7.5 Hz) ppm.

Example 7

N- {4- [5- (2,6,8,10-Tempo-oxo-1,7,9-methyl-3-benzo [4.5] geo-1-UA) pyridin-2-yloxy] -benzyl} -acetamide:

113

An example No Structure Molecular weight MS (APCI, m / z): [M + H] ⁺ 7 6 ⁿ Ο 437.415 438.2

1- {6- [4- (Tert-Butoxycarbonylamino-methyl) -phenoxy] -pyridin-3-yl} -pyrrolidine-2,2-dicarboxylic acid dimethylacetate mixture (0.52 mmol) and 2 mL of trifluoroacetic acid solution in methylene chloride 1: 1 volume / volume was stirred for 1 hour at ambient temperature and then concentrated in vacuo. The residue was dissolved in 2.6 mL of methylene chloride and treated with MMP resin (polymer-bound N-methylmorpholine-type base, 0.86 g, 1.75 mmol) and treated with acetyl chloride (0.055 g, 0.7 mmol). After shaking for 24 hours, the mixture was filtered and the resin was washed with methylene chloride. The combined filtrates were concentrated in vacuo, dissolved in 1.5 mL of 1M sodium ethoxide in ethanol and treated with 94 mg of urea. After stirring for 10 minutes at 80 ° C, the mixtures were treated with 2 g of polystyrene bound sulfonic acid, filtered and the resin was washed with 10 mL of 2M ammonia in methanol. The combined filtrates were concentrated in vacuo and purified by reverse phase chromatography (eluent acetonitrile-hydrofluoroacetic acid) followed by radial chromatography (10% methanol-methylene chloride) to give: N- {4- [5 (2,6,8,10- tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2114 yloxy] -benzyl} -acetamide as a colorless solid. HPLC retention time: 2.201 minutes; MS (APCI, m / z): 436 [M-H] '; 438 [M + H] ⁺

Preparation 1:

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

2.2-Dicarboxylic acid:

1- [6- (4-Bromo-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (5.8 g, 12.2 mmol), vinyl tributyltin (3.9 mL, 12.3 mmol), tetrakistriphenylphosphine palladium (0 ) (0.60 g, 0.52 mmol) and 24 mL of toluene was refluxed for 1 hour. After cooling to room temperature, the mixture was concentrated in vacuo and purified by gel chromatography on silica gel (Flash 40, 20% -50% ethyl acetate-hexanes) to give 4.8 g of 1- [6- (4-vinylphenoxy) -pyridine diethyl ester. -3-yl] -pyrrolidine-2,2-dicarboxylic acid as a colorless syrup.

Preparation 2:

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

1- [6- (4-Vinyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (4.8 g, 11.3 mmol), sodium metaperiodate (4.8 g, 22 mmol), osmium tetroxide (10 mg) and 2: 1 dioxane-water (189 mL) were stirred for 6 hours at ambient temperature. The mixture was quenched with sodium sulfite, diluted with water and extracted 3x with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 1- [6- (4-formyl-phenoxy) -pyridin-3-yl] pyrrolidine-2,2-dicarboxylic acid diethyl ester. colorless syrup (4.6 g).

115

Preparation 3:

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

1- [6- (4-Formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.1 g, 0.24 mmol), tert-butoxycarbonylamide (0.083 g, 0.71 mmol), triethylsilane (0.11 mL, 0.083 g, 0.71 mmol) and acetonitrile (1 mL ·) were treated with trifluoroacetic acid (0.035 mL, 0.46 mmol) and stirred for 48 hours at ambient temperature. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 1- {6- [4- (tert-butoxycarbonylaminomethyl) -phenoxy dimethyl ester ] -pyridin-3-yl} -pyrrolidine-2,2-dicarboxylic acid as a colorless syrup.

The following compounds were prepared according to methods analogous to those of Example 7, introducing, where appropriate, the exact pyridine and diester:

Table 2

Example No. Structure Molecular weight MS (APCI, m / z): [M + H] ⁺ 8 n • L. 451.443 452.2 0

116

9 ⁰ 1 Τ-ν 0 465.47 466.2 10 n ° f You 0 479.497 480.2 11 ° γ ^Ν y ° “A Chu XX“ at 0 477.481 478.4

Example 12

1- [6- (4-Pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone:

An example No Structure Molecular weight MS (APCI, m / z): [M + H] ⁺ 12 HH, 0 446.43 447.2

117

Following the procedure for the preparation of the pyrimidinetrion described in Example 1, the reaction of dimethyl ester of 5-oxo-1- [6- (4-pyrazol-1-ylmethyl-phenoxy) pyridin-3-yl] -pyrrolidin-2,2 -Dicarboxylic acid (0.2 g, 0.4 mmol) with urea (0.074 g, 1.2 mmol) in 1.2 mL of 1M sodium ethoxide in ethanol gave 6 mg of 1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3 -yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone as a colorless solid. ^X H NMR (CD 3 OD, 500 MHz): 7.99 (d, 1H, J = 2.5 Hz), 7.72 (m, 2H), 7.53 (d, 1H, J = 2.5 Hz), 7.29 (d, 2H, J = 8.5) Hz), 7.10 (d, 2H, J = 8.5 Hz), 6.97 (d, 1H, J = 8.5 Hz), 6.35 (t, 1H, J = 2.0 Hz), 5.38 (s, 2H), 2.75 (m. 2H), 2.65 (m, 2H) ppm. MS (APCI, m / z): 447.2 [M + H] ⁺ .

Preparation 1:

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

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) diethyl ester ) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid (1.0 g, 2.3 mmol) in 30 mL ethanol at 0 ° C was added sodium borohydride (0.090 g, 2.3 mmol). After stirring for 3 hours, the mixture was concentrated in vacuo, diluted with ethyl acetate and water and the aqueous layer was carefully acidified with 1M hydrochloric acid and then neutralized with saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 0.80 g (80%) diethyl ester of 1 [6- (4-hydroxymethyl-phenoxy) -pyridin-3-yl ] -5-Oxo-pyrrolidine-2,2-dicarboxylic acid as a colorless syrup. In NMR (CDCl3, 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 (d, 1H, J)

118 = 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] ⁺ .

Preparation 2:

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

To a solution of 1- [6- (4-hydroxymethylphenoxy) -pyridin-3; yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.80 g, 1.9 mmol) in 9.4 mL methylene chloride was added triethylamine ( 0.46 mL, 0.33 g, 3.3 mL). After cooling to -40 ° C, the mixture was treated with methanesulfonyl chloride (0.20 mL, 0.30 g, 2.61 mmol). After stirring for 1 hour, 0.10 mL of methanesulfonyl chloride and 0.4 mL of triethylamine were added and stirring continued for 1 hour. A solution of anhydrous lithium bromide (1.6 g, 19 mmol, dried before use of the flame in vacuo) in tetrahydrofuran (20 mL) was added through a tube, the mixture warmed to room temperature and stirred for 2 hours. It was diluted with ethyl acetate and the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was filtered through a pad of silica gel eluting with 1: 1 ethyl acetate-hexanes to give 0.65 g of 1- [6- (4-bromomethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidin-2 dimethyl ester. 2dicarboxylic acid as a colorless syrup. ⁴ H NMR (CDCl ₃ , 500 MHz): 8.07 (d, 1H, J = 3.0 Hz), 7.76 (dd, 1H, J = 2.5, 8.5 Hz), 7.44 (d, 2H, J = 8.5 Hz), 7.12 (d, 2H, J = 8.0 Hz), 6.95 (d, 1H, J = 9.0 Hz), 4.53 (s, 2H), 4.22 (q, 4H, J = 7.0 Hz), 2.75 (m, 2H), 2.65 (m, 2H), 1.20 (t, 6H, J = 7.0 Hz) ppm.

Preparation 3:

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

To a solution of 1- [6- (4-bromomethyl-phenoxy) diethyl ester

119 Pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid (0.2 g, 0.4 mmol) in 0.8 mL of dimethylformamide was added pyrazole (0.056 g, 0.82 mmol) and potassium carbonate (0.11 g, 0.82 mmol). ). After stirring for 24 hours at 50 ° C, the mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product as a colorless syrup, which is used directly in the next step. MS (APCI, m / z): 479.2 [M + H] ⁺ .

Although the invention has been described and explained with respect to certain individual embodiments thereof, one skilled in the art may appreciate that various adaptations, changes, modifications, substitutions, deletions or additions of procedures and protocols may be made without led to a departure from the spirit and scope of the invention. For example, effective dosages other than the individual dosages set forth herein may be administered as a result of differences in the mammalian response treated for each of the indications with the above compounds of the invention. Also, the observed specific pharmacological responses may vary according to and depending on the individual active compounds selected or whether pharmaceutical carriers are present, as well as the type of formulation and the route of administration used, and such expected variations or differences in results are discussed in in accordance with the tasks and accomplishments of the present invention. Therefore, it is contemplated that the invention will be determined by the scope of the claims that follow, and that these claims will be interpreted as broadly as might be accepted.

Claims (11)

Patent Claims 1. A compound of formula: I wherein said A is a 5-7 membered heterocyclic ring selected from the group consisting of: X-Y-Z-G 121 where each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , 11 12 13 R, R and R are independently selected from the group consisting of hydrogen, (C 1 -C 6 alkyl, (C 1 -C 6 alkenyl, (C 1 -C 10 alkynyl, (C 1 -C 10) aryl, (C 1 -C 10) -heteroaryl, (C 3 -C 8) cycloalkyl and ( C 1 -C 10 heterocyclyl; wherein each of said (C 1 -C 10 alkyl, (C 6 -C 10) aryl, (C 1 -C 10) xemepoapuA, (C 3 -C 8) cycloalkyl and (C 1 -C 10) heterocyclyl may be optionally substituted at each of ring carbon atoms capable of forming an additional bond with 1-3 ring substituents independently selected from halo, (C 1 -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 bond, oxygen, sulfur,>C-O,> SO ₂ ,> S = O, -CH 2 -, -CH 2 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) '-, -CH 2 [N (R ¹⁴ )] -, -CH ₂ (CH ₂ )' -, -CH = CH-, -GC-, - [N (R ¹⁴ )] 122 are ₂ - U -so ₂ [N (r ¹⁴ )] -; n is an integer om one go four; R ¹⁴ is hydrogen or (C 1 -C 6 alkyl; Z is selected from the group consisting of (C 6 -C 8) aryl, (C 3 C 8) cycloalkyl, (C 1 -C 6 heterocyclyl and (C 1 -C 6 heteroaryl; wherein one or two carbon-carbon single bonds of said (C 3 -C 8) cycloalkyl or (C 1 -C 6 alkyl) be replaced by carbon-carbon double bonds; wherein each of said X or Ζ may be optionally independently substituted on each of the ring carbon atoms, capable of forming an additional bond, with one or two ring substituents independently selected from F, Cl, Br, CN, OH, (C 1 -C 6 alkyl) , (C 1 -C ₆ perfluoroalkyl, (C ₁ C ₄ ) perfluoroalkoxy, (C ₃ -C ₆ alkoxy and (C ₃ C ₈ ) cycloalkyloxy; G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -; wherein G is a substituent on each ring carbon of Z capable of forming an additional bond and is oriented in a position other than alpha relative to the attachment point of the ring Z to Y; p is an integer from 0 to 4; R is independently selected from the group consisting of halo, -CN, -NO2, OH, (C 1 -C 4 alkenyl, (C 1 -C 4 alkynyl, (C 1 -C 4) 18 18 18 perfluoroalkyl, perfluoro (C 1 -C 4) alkoxy, R -, R-0 -, R - (Wed Cdalkyl-O-, R ¹⁸ - (C = O) -, R ¹⁸ - (C = O) -O-, R ¹⁸ -O- (C = O) -, R ¹⁸ -S- , R ²² (S = O) -, R ¹⁸ - (SO2) -, R ²² - (SO2) - (NR ²¹ ) -, R ¹⁹ - (C = O) - (NR ²¹ ) -, r ²² -o123 (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 ) - (R ¹⁹ R ²⁰ ) N- (C = O) -O-; 1617 each om R u R is independently selected om hydrogen and (C 1 -C 4 alkyl); 1617 or R and R may optionally be taken together with the carbon to which they are attached, forming a 5 to 10 membered carbocyclic ring; 18 19 2021 R, R, R and R are independently selected from the group consisting of hydrogen, (C 1 -C 6 alkyl, (C 6 -C 10) aryl, (C 3 -C 8) cycloalkyl, (QC 10) heteroaryl and (C 1 -C 10) heterocyclyl; said (C 6 -C 8) aryl, (C 3 -C 8) cycloalkyl, (C 1 -C 10) heteroaryl and (C 1 -C 10) heterocyclyl structures may optionally be substituted at each of the ring carbon atoms capable of forming an additional bond with one to three substituents of ring independently selected from F, Cl, Br, 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-MH- , [(C 1 -C 4) alkyl] 2- H- and (C3-C8) cycloalkyloxy; wherein said (C3-C8) cycloalkyl and (C3-C8) heterocyclyl structures may also be optionally substituted by oxo; where said (C 1 -C 10) heteroaryl and (C 1 -C 10) heterocyclyl structures may optionally be substituted at each ring nitrogen atom capable of supporting an additional substituent with one to two ring substituents independently selected from the group consisting of (C1-C4) alkyl and (C1-C4) alkyl- (C) = O) -; or R ¹⁹ and R ²⁰ may optionally be taken together with 124 to which they are attached, forming a 3 to 8 membered heterocyclic ring; 19 21 or R and R may optionally be taken together with the nitrogen, carbon or oxygen to which they are attached, forming a 3 to 8 membered heterocycle; R is selected from the group consisting of (C 1 -C 4 alkyl, (C 1 -C 6)) aryl, (C 3 -C 8) cycloalkyl, (C 1 -C 10) heteroaryl, and (C 1 -C 10) heterocyclyl; wherein said (C 6 -C 10) aryl, (C 3 -C 8) cycloalkyl, (C 1 -C 6)) heteroaryl and (C 1 -C 6) heterocyclyl structures may be optionally substituted at each of the ring carbon atoms capable of forming an additional bond with one to three ring substituents independently selected from F, Cl, Br, CN, OH, (C 1 -C 4 alkyl, (C 1 -C 4 perfluoroalkyl, (C 1 -C 4) perfluoroalkoxy, (C 1 -C 6 alkoxy, amino, (C 1 -C 4 alkyl-MH-, [(C 1 -C 4 alkyl) N-X- and (C 3 -C 8) cycloalkyloxy; wherein said (C 3 C 8) cycloalkyl and (C 1 -C 8) heterocyclyl structures may also be optionally substituted wherein said (C 1 -C 10) heteroaryl and (C 1 -C 10) heterocyclyl structures may be optionally substituted at each ring nitrogen atom capable of supporting an additional substituent with one to two ring substituents independently selected from the group, consisting of (C1-C4) alkyl and (C1-C4) alkyl- (C = O) -; 21 22 or R and R may optionally be taken together with the nitrogen, oxygen or sulfur to which they are attached, forming a 3 to 8 membered heterocycle; or pharmaceutically acceptable salts thereof. The compound of claim 1, wherein 125 said A is selected from the group consisting of The compound of claim 1, wherein said X is (C 6 -C 10) aryl. The compound of claim 1, wherein said X is (C 1 -C 10) heteroaryl. The compound of claim 1, wherein said Y is oxygen. The compound of claim 1, wherein said G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) _p -, wherein p is 0. The compound of claim 1, wherein said G is R ¹⁵ - (CR ¹⁶ R ¹⁷ ) p-, wherein p is an integer from 1 to 4. The compound of claim 1, wherein said compound is selected from the group consisting of: 1- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane- 2,6,8,10-tetraone; 1- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -1,8,10-triazaspiro [5.5] undecane-2,7,9,11-tetraone; 4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin2-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-triaza-spiro [4.5] 126 decane-2,6,8,10-tetraone; N- {4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) pyridin-2-yloxy] -benzyl} -acetamide; N- {4- [5- {2,6,8,10-Tempoaco-1,7,7,9-pyrazole-4,5-yl] -1,5-pyridin-2-yloxy] -benzyl} -propionamide; N- {4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [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; With Cyclobutanecarboxylic acid, 4- (5- (2,6,8,10-tetraoxo-1,7,9triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzylamide; 1- (6- (4-Bromo-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro (4.5] decane-2,6,8,10-tetraone; 1- (6- (4-Pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,7,9-triazaspiro [4.5] decane-2,6,8,10-tetraone; and a pharmaceutically acceptable salt thereof. Use of the compounds of claim 1 for the preparation of a pharmaceutical composition for the treatment of a condition selected from the group consisting of connective tissue disorders, inflammatory diseases, immunological / allergic disorders, infectious diseases, respiratory diseases, cardiovascular diseases , ocular diseases, metabolic diseases, CNS disorders, liver / kidney diseases, reproductive disorders, stomach disorders, skin disorders and carcinomas in a mammal, including humans containing callus amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier. Use of the compounds according to claim 1 for 127 receiving a medicament for the treatment of a condition selected from the group consisting of connective tissue disorders, inflammatory diseases, immunological / allergic disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, disorders of the central nervous system system, liver / kidney diseases, reproductive disorders, gastric disorders, skin disorders and cancers in a mammal, including a human comprising administering to said mammal an amount of a compound according to the invention. dance with claim 1 effective in treating such a condition. Use of the compounds of claim 1 for the preparation of a pharmaceutical composition for treatment by inhibiting matrix metalloproteinases in a mammal, including a human comprising an amount of a compound of claim 1 effective for such treatment and a pharmaceutically acceptable carrier.