3-(3,5-dioxo-4,5-dihydro-3h-(1,2,4)triazin-2-yl)-benzamide derivative as p2x7-inhibitor for the treatment of inflammatory diseases

SIGNATURE OF THE APPLICANT

SIGNATURE OF ATTORNEY

CASE PC25161A

TECHNICAL MEMORY

3-(3,5 -DIOXO-4, 5-DIHYDRO-3H-{1,2,4}TRIAZIN-2-IL) DERIVATIVES OF BENZAMIDES AS P2X RECEPTOR INHIBITORS₇ FOR INFLAMMATORY DISEASES

The present invention relates to new benzamide inhibitors of the P2X receptor.₇, to processes for their preparation, to the intermediates useful in their preparation, to the pharmaceutical compositions that contain them, and to their use in therapy. The active compounds of the present invention are useful in the treatment of inflammatory diseases such as osteoarthritis and rheumatoid arthritis; allergies, asthma, COPD (chronic obstructive pulmonary disease), cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders. Active compounds are also P2X receptor antagonists.₇.

The P2X Receiver₇ (formerly known as the P2Z receptor), which is a ligand-gated ion channel, is present in a variety of cell types, primarily those known to be involved in inflammatory/immune processes, and specifically, macrophages , mast cells and lymphocytes (T and B). Activation of the P2X receptor₇ by extracellular nucleotides, in particular adenosine triphosphate, leads to interleukin-1β (IL-Ιβ) release and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and proliferation (T cells), apoptosis and shedding of L-selectin (lymphocytes). P2X receivers₇ they are also located on antigen-presenting cells (APCs), keratinocytes, salivary atrial cells (parotid cells), hepatocytes, and mesangial cells.

P2X antagonists are known in the art.₇such as those described in International Patent Publications WO 01/46200, WO 01/42104, WO 01/44123, WO 99/29660, WO 00/61569, WO 99/29661, WO 99/29686, WO 00/71529 and WO 01/44170, as well as USSN 60/336,781 (Agent's Docket Number PC23106A, filed November 12, 2002).

Benzamides, heteroarylamides, and reverse amides for uses other than P2X receptor inhibition₇, are described in various publications, such as International Patent Publications WO 97/22600, EP 138,527, WO 00/71509, WO 98/28269, WO 99/17777 and WO 01/58883.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula (I) in which R¹ is alkyl (CrCg), optionally substituted with cycloalkyl (C₃-C₁₀), aryl (C₆-C₁₀), heterocyclyl (C1-C10) or heteroaryl (C1-C10), wherein each of said alkyl (Ci-C₆), cycloalkyl (C₃C.₁₀), aryl (C₆-C₁₀), heterocyclyl (CrC₁₀) or heteroaryl (CrC₁₀) is optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Ο_ΓΟ₆), HO-alkyl (Ο_ΓΟ₆), alkyl (Ο_ΓΟ₆)-ΝΗ(Ο=Ο)-, NH₂(C=O)-, alkoxy (C_rC.₆) or cycloalkyl (C₃C.₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more moieties selected from halogen or alkyl(CpCe)-;

R.² is hydrogen, halogen, -CN and alkyl (Ci-C₆), wherein said alkyl (Ci-C₆) is optionally substituted with one to three suitable moieties, independently selected from the group consisting of halo, hydroxy, amino, -CN, alkyl (Ci-C₆), alkoxy (Ci-C₆), -CF₃, CF₃O-alkyl (Ci-C₆)-NH-, [alkyl (CrCgjk-N-, alkyl (C_rC._yes)-S-, alkyl(C₁-C₆)-(S=O)-, alkyl (C₁-C₆)-(SW₂)-, alkyl (C₁-C₆)-O-(C=O)-, formyl, alkyl (C₁-C₆)-(C=O)- and cycloalkyl (C₃-C₆); and

R.³ is a suitably substituted nitrogen-linked (C1-C10) heterocyclyl of the formula:

<img file="ECSP055884A_D0001.tif" />

(ll) or their pharmaceutically acceptable salts or solvates or prodrugs.

The present invention also relates to a compound of the formula

<img file="ECSP055884A_D0002.tif" />

in which R¹ is alkyl (Ci-C₆), optionally substituted with cycloalkyl (C3-C10), aryl (C₆-ci₀), heterocyclyl (C1-C10) or heteroaryl (C1-C10), wherein each of said alkyl (Ci-C₆), cycloalkyl (C₃C10), aryl (C₆-Cio), heterocyclyl (C1-C10) or heteroaryl (C1-C10) is optionally substituted with one to three suitable moieties independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Ci-C₆), HO-alkyl (CpCe), alkyl (CrCsJ-NH^O)-, NH₂(C=O)-, alkoxy (C^Cs) or cycloalkyl (C₃C.₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more residues selected from halogen or alkyl (Ci-C₆)-;

R.² is hydrogen, halogen, -CN, and alkyl (C^Cg), wherein said alkyl (C^Cg) is optionally substituted with one to three suitable moieties, independently selected from the group consisting of halo, hydroxy, amino, -CN, alkyl (C)_rC.₆), alkoxy (C_rC.₆), -CF₃, CF₃O-, alkyl (CpCej-NH-, [alkyl (Ci-C₆)]₂-N-,alkyl(Ci-C₆)-S-, alkyl (CrC₆)-(S=O)-, alkyl (Ci-C₆)-(SW₂)-, alkyl (Ci-C₆)-O-(C=O)-, formyl, alkyl (^-^)-(0=0)- and cycloalkyl (C₃-C₆);

R.³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula:

(III) where R⁴ is selected from the group of suitable substituents, such as hydrogen, halo, hydroxy, CN, HO-alkyl (CrC6), alkyl (CpCg) optionally substituted with one to three fluorines, alkoxy (CrC6) optionally substituted with one to three fluorines, HO2C -, alkyl (CrC^-O-^O)-, R⁵R.⁶N(O2S)-, alkyl (CrCg)(O₂S)-NH-, alkyl (CrCgjA-S-Kalkyl (CrC^-N]-, R⁵R.⁶N(C=O)-, R⁵R.⁵N(CH)₂)_m-, aryl (C₆-C₁₀), cycloalkyl (C₃-C₈), heteroaryl (CrGo), heterocyclyl (Ci-C₁₀), aryl (C₆-ci₀)-O-, cycloalkyl (C₃-C₈)-O-, heteroaryl(C_rC.₁₀)-O- and heterocyclyl (CrC^-O-; and

R.⁷ is selected from the group of suitable substituents such as hydrogen and alkyl (CrC₆) optionally substituted with one to three halogens, hydroxy, -CN, alkoxy (Ο_ΓΟ₆)-, alkenoxy (C₂-C₆), alkyl (CrCsj-SO,-, NH₂-, (alkyl (CpC^nN-, (alkenyl C₂-C₆))_no-N-,(alkynyl(C₂-C₆))_no-N-, NH₂(C=O)-, alkyl (C_rC._and)-(C=O)-N-, (alkyl (C₁-C₆))_r-N-(C=O)-, alkenyl (C₂-C₈)-(C=O)N-, (alkenyl (C₂-C₆))_no-N-(C=O)-, alkynyl (C₂-C₆)-(C=O)-N-, (alkynyl (C₂-C₆))_no-N-(C=O)-, alkyl (^-^)-(0=0)-, alkenyl (C₂-C₆)-(C=O)-, alkynyl (C₂C.₆)-(C=O)-, cycloalkyl (C₃-C₁₀)-(C=O)-, heterocyclyl (CrCwJ-^O)-, aryl (C₆-C₁₀)-(C=O)-, heteroaryl(CrCw)(C=O)-, alkyl(C₁-C₆)-(C=O)O-, alkenyl (C₂-C₆)-(C=O)O-, alkynyl (C₂-C₆)-(C=O)O-, alkyl (C₁-C₆)-O(C=O)-, alkenyl (C₂-C₆)-O-(C=O)-, alkynyl (C₂-C₆)-O-(C=O)-, cycloalkyl (C3-C10), aryl (C₆-ci₀), heterocyclyl (Cr C10) and heteroaryl (C1-C10);

where each of R⁴ and R⁷ may be optionally substituted on any aliphatic or aromatic carbon atom by one to three suitable moieties, independently selected from the group consisting of halo, hydroxy, amino, -CN, alkyl(Ci-C₅), alkoxy (Ci-C₆), -CF₃, CF₃O-alkyl (Ci-C₆)-NH-,

[alkyl(Ci-C₅)]₂-N-,alkyl(Ci-C₆)-S-, alkyl (Ci-C₆)-(S=O)-, alkyl (Ci-C₅)-(SW₂)-, alkyl (Ci-C₆)-O-(C=O)-, formyl, alkyl (Ci-C₆)-(C=O) and cycloalkyl (C₃-C₆);

each of R⁵ and R^B. is independently selected from the group consisting of hydrogen, alkyl (CpCe), HO-alkyl (C₂-C₆) and cycloalkyl (C₃-C₈), or R⁶ and R⁶ they can optionally be taken together with the nitrogen atom to which they are attached to form a 3 to 8 membered heterocyclyl;

n is an integer from zero to two; ym is an integer from one to two;

or their pharmaceutically acceptable salts or solvates or prodrugs.

The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned compounds in base form of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such such as chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate, and pamoate [ie, 1,1'-methylene-bis-(2-hydroxy¡-3-naphthoate)].

The invention also relates to base addition salts of formula I. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of compounds of formula I which are acidic in nature are those that form base salts non-toxic with such compounds. Such non-toxic base salts include, but are not limited to, those derived from pharmacologically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), ammonium or water soluble amine addition salts such as N-methylglucamine (meglumine), and the lower alkanol ammonium and other pharmaceutically acceptable organic amine base salts.

This invention also encompasses pharmaceutically acceptable compositions containing prodrugs of compounds of formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted to prodrugs. Prodrugs include compounds in which one amino acid residue, or a polypeptide chain of two or more (eg, two, three, or four) amino acid residues are covalently linked through peptide bonds to amino, hydroxy, or acid groups. carboxylic acid free of the compounds of formula I. Amino acid residues include the 20 naturally occurring amino acids commonly designated by three-letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine , ornithine and methionine-sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides, and alkyl esters are covalently attached to the above substituents of formula I through the carbonyl carbon-containing side chain of the prodrug.

This invention also encompasses compounds of formula I that contain protecting groups. Those skilled in the art will also appreciate that the compounds of the invention may also be prepared with certain protecting groups which are useful for purification or storage and which may be removed prior to administration to the patient. Protection and deprotection using functional groups is described in Protection Groups in Organic Chemistry, edited by JWF McOrnie, Plenum Press (1973) and Protective Groups in Organic Synthesis, 3rd Edition, TW Greene and PGM Wuts, WileyInterscience (1999).

The compounds of this invention include all stereoisomers (eg, cis and trans isomers) and all optical isomers of the compounds of Formula I (eg, R and S enantiomers), as well as racemic, diastereomeric, and other mixtures of such isomers.

The compounds, salts and prodrugs of the present invention can exist in various tautomeric forms, including enol form and imine form, and keto and enamine form and geometric isomers and mixtures thereof. All tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, one tautomer usually predominates. Even though a tautomer can be described, the present invention includes all tautomers of the present compounds. An example of a tautomeric structure is one in which R³ is a group of formula

NH

Those skilled in the art will appreciate that this group can also be drawn as its tautomer

ooh

The present invention also includes atropisomers of the present invention. "Atropisomers" refers to compounds of formula I that can be separated into rotationally restricted isomers.

The compounds of this invention may contain olefinic double bonds. When such linkages are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.

A suitable substituent is intended to mean a chemically and pharmaceutically acceptable functional group, ie a moiety which does not negate the biological activity of the compounds of the invention. Such suitable substituents can be routinely selected by those skilled in the art. Illustrative examples of suitable substituents include, but are not limited to, halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups. , aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or heteroaralkoxy groups, HO-(C=O)- groups, amino groups, alkyl- and dialkyl-amino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups, dialkylaminocarbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups, and the like. Those skilled in the art will appreciate that many substituents may be substituted with additional substituents. Additional examples of suitable substituents include those recited in the definition of compounds of Formula I, including R¹ to R⁷, as defined here above.

As used herein, the term spiro refers to a connection between two groups, substituents, etc., where the connection can be effected according to the following formula

As used herein, the term alkyl, as well as alkyl moieties of other groups referred to herein (eg, alkoxy), can be linear or branched (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl); optionally substituted with 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, alkoxy (CpCe), aryl (C₆-C₁₀)-oxy, trifluoromethoxy, difluoromethoxy or alkyl (CrC₆). The phrase each of said alkyl as used herein refers to any of the foregoing alkyl moieties within a group such as alkoxy, alkenyl, or alkylamino. Preferred alkyls include alkyl (Ci-C₆), more preferred are (C1-C4)alkyl and most preferred are methyl and ethyl.

As used herein, the term "cycloalkyl" refers to a carbocyclic mono, bicyclic, or tricyclic ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1jheptanyl, bicyclo[3.2.1 joctanyl and bicyclo[5.2.0]nonanyl, etc.); optionally containing 1 or 2 double bonds and optionally substituted with 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, alkoxy (Ci-C₅), aryl (C₆Cio)-oxy, trifluoromethoxy, difluoromethoxy or alkyl (Ci-C₆).

As used herein, the term halogen includes fluoro, chloro, bromo, or iodo or fluoride, chloride, bromide, or iodide.

As used herein, the term "alkenyl" means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl -1-propenyl, 1-butenyl, 2-butenyl, and the like; optionally substituted with 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, alkoxy (CpCe), aryl (C₆-C₁₀)-oxy, trifluoromethoxy, difluoromethoxy or alkyl (CrCe).

As used herein, the term "alkynyl" is used herein to represent straight or branched chain hydrocarbon radicals having a triple bond including, but not limited to, ethynyl, propynyl, butynyl, and the like; optionally substituted with 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, alkoxy (CpCe), aryl (C₆-C₁₀)-oxy, trifluoromethoxy, difluoromethoxy or alkyl (Ci-C₆).

As used herein, the term carbonite or (C=O) (as used in phrases such as alkylcarbonyl, alkyl-(C=O)-, or alkoxycarbonyl) refers to the attachment of the >C=O moiety to a second moiety such as an alkyl or amino group (ie, an amido group). Alkoxycarbonylamino (ie, (C=0)alkoxy-NH) refers to an alkylcarbamate group. The carbonyl group is also herein equivalently defined as (C=O). Alkylcarbonylamino refers to groups such as acetamide.

As used herein, the term "oxo" is used herein to represent a double bonded oxygen radical (=0) where the bonding partner is a carbon atom. Said radical can also be considered as a carbonyl group.

As used herein, the term alkyl (Ci-C₄)-EITHER₂S-[alkyl(Ci-C₄)-N]- is used here to mean a radical of the formula alkyl

<img file="ECSP055884A_D0003.tif" />

N--alkyl

As used herein, the term "aryl" means aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and the like; optionally substituted with 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, alkoxy (CrC₆), aryl (C₆-ci₀)-oxy, trifluoromethoxy, difluoromethoxy or alkyl (CpCe).

As used herein, the term "heteroaryl" refers to an aromatic heterocyclic group usually with one heteroatom selected from O, S, and N in the ring. In addition to said heteroatom, the aromatic group may optionally have up to four N ring atoms. For example, a heteroaryl group includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (eg, 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (eg, 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (eg, 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (eg, 1, 2,3-oxadiazolyl), thiadiazolyl (eg, 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionally substituted with 1 to 3 suitable substituents as defined above such as fluorine, chlorine, trifluoromethyl, alkoxy (Ci-C₆), aryl (C₆-ci₀)-oxy, trifluoromethoxy, difluoromethoxy or alkyl (Ci-C₆). Particularly preferred heteroaryl groups include oxazolyl, imidazolyl, pyridyl, thienyl, furyl, thiazolyl, and pyrazolyl.

The term heterocyclic, as used herein, refers to a cyclic group containing 1-9 carbon atoms and 1 to 4 heteroatoms selected from N, O, S(O)_no or NR. Ejemplos of tales anillos incluyen azetidinilo, tetrahidrofuranilo, imidazolidinilo, pirrolidinilo, piperidinilo, piperazinilo, oxazolidinilo, tiazolidinilo, pirazolidinilo, tiomorfolinilo, tetrahidrotiazinilo, tetrahidrotiadiazinilo, morfolinilo, oxetanilo, tetrahidrodiazinilo, oxazinilo, oxatiazinilo, indolinilo, isoindolinilo, quinuclidinilo, cromanilo, isocromanilo, benzoxazinilo , and the like. Examples of such saturated or partially saturated monocyclic ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-

4-¡lo, pyrrolidin-1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1 -yl, piperidin-2-yl, piperidin-3-yl, piperazin-1 ¡lo, piperazin-2 -yl, piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl , 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, 1,2,5-oxathiazin-4-yl and the like; optionally containing 1 or 2 double bonds and optionally substituted with 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, alkoxy (CpCg), aryl (C₆-C₁₀)-oxy, trifluoromethoxy, difluoromethoxy or alkyl (CrC₅). Preferred heterocyclic groups include tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.

Nitrogen heteroatoms, as used herein, refer to N=, >N, and -NH; where -N= refers to a nitrogen double bond; >N refers to a nitrogen containing two bond connections and -N refers to a nitrogen containing one bond.

Embodiment, as used herein, refers to a specific grouping of compounds or uses into discrete subgenera. Such subgenera may be recognizable based on a particular substituent such as an R group.¹ or R³ specific. Other subgenera are recognizable according to combinations of various substituents, such as all compounds in which R² is chlorine and R¹ is (CrC4)alkyl, optionally substituted with (C3-C10)cycloalkyl. The phrase in combination with each of the aforementioned embodiments refers to combinations of the identified embodiment with each previously identified embodiment in the specification. Thus, an embodiment of compounds in which R¹ is alkyl (CrC₄), optionally substituted with cycloalkyl (C₃-C₁₀) in combination with each of the aforementioned embodiments refers to additional embodiments comprising combinations with each embodiment previously identified in the specification.

Thus, the invention provides compounds in which R¹ is alkyl (CrC₄), optionally substituted with (C3-C10)cycloalkyl; wherein said alkyl (C1-C4) or cycloalkyl (C₃-ci₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Ci-C₆), HO-alkyl(Ci-C₆), alkyl (Ci-C₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (CpCg) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more residues selected from halogen or alkyl (Ci-C₆)-.

The invention further provides compounds wherein R¹ is alkyl (C_rC.₄), optionally substituted with aryl (C₆-ci₀); wherein said alkyl (C1-C4) or aryl (C₆-ci₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Ci-C₆), HO-alkyl(Ci-C₆), alkyl (CpCgj-NH^O)-, NH₂(C=O)-, alkoxy (Cp

C.₆) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more moieties selected from halogen or alkyl(CrCe)-.

Furthermore, the invention contemplates compounds in which R² is halogen and alkyl (C^Cg), and preferably compounds in which R² is chlorine and methyl or ethyl.

In one embodiment of the invention, R³ is a nitrogen-linked (CrC10) heterocyclyl of formula III, where R⁴ is hydrogen and R⁷ is independently selected from the group of suitable substituents such as hydrogen and alkyl (CrC₆), wherein said alkyl (CrC₆) is optionally substituted with one to three substituents independently selected from halo, hydroxy, -CN, alkoxy (CpCe)-, alkenoxy (C₂-C₆), alkyl (CpCej-SOr, NH₂-, (alkyl (CrCg^-N-, ((alkenyl (C₂-C₆))_r-N-, ((alkynyl C₂-C₆))_no-N-, NH₂(C=O)-, alkyl (Ci-C₆)-(C=O)N-, (alkyl (Ci-C₈))_no-N-(C=O)-, alkenyl (C₂-C₆)-(C=O)-N, (alkenyl (C₂-C₃))_no-N-(C=O)-, alkynyl (C₂-C₆)-(C=O)-N-, ((alkynyl (C₂-C₆))_no-N-(C=O)-, alkyl (Ci-C₆)-(C=O)-, alkenyl C₂-C₆)-(C=O)-, alkynyl (C₂-C₆)-(C=O)-, cycloalkyl (C₃-ci₀)-(C=O)-, heterocyclyl (Ci-Ci₀)-(C=O)-, aryl(C₆-C₁₀)-(C=O), heteroaryl (C_rCio)-(C=0), alkyl (^&lt;₆)-(ΰ=Ο)Ο-, alkenyl (C₂-C₆)-(C=O)O-, alkynyl (C₂C.₆)-(C=O)O-, alkyl (CpCeJ-O^O)-, alkenyl (C₂-C₆)-O-(C=O)-, alkynyl (C₂-C₆)-O-(C=O)-, cycloalkyl (C₃C10), aryl (C₆-Cio), (C1-C10)heterocyclyl and (C1-C10)heteroaryl; where R⁷ may be optionally substituted on any aromatic or aliphatic ring carbon atom by one to three suitable moieties, independently selected from the group consisting of halo, hydroxy, amino, -CN, (C1-C4)alkyl, (CpC^, -CF)alkoxy₃, CF₃O-, alkyl (CpC^-NH-, [alkyl (CpC^-N-, alkyl (C_rC.₄)-S-, alkyl(C_rC.₄)-(S=O)-, alkyl (CrC^-ÍSOs)-, alkyl (CrC^-O-^O)-, formyl, alkyl (^-^)-(0=0)- and cycloalkyl (C₃-C₆).

Another embodiment of the invention are compounds in which R⁷ it's hydrogen.

A further embodiment of the invention are compounds in which R³ is a nitrogen-linked (Ci-C10) heterocyclyl of formula (III), where R⁴ is hydrogen and R⁷ is alkyl (CpC^ optionally substituted with one to three substituents independently selected from halo-, hydroxy, -CN, alkoxy (ΟΓΟ₄)-, alkenoxy (C₂-C₄) and alkyl (CrC₄)-SW₂-, preferably, R³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula (II), wherein R⁴ is hydrogen and R⁷ is (C1-C4)alkyl optionally substituted with one to three substituents independently selected from halo-, hydroxy, -CN, or alkoxy (CpC^-.

Still further, the invention provides compounds in which R³ is a nitrogen-linked (C^C^) heterocyclyl of formula (III), where R⁴ is hydrogen and R⁷ is (CrC4)alkyl optionally substituted with one to three substituents independently selected from NH2-, (alkyl(CpC^nN-, (C2C4alkenyl)nN-, (C2-C4alkynyl)nN-, NH2(C= O)-, (Ci-C4)alkyl-(C=O)N-, ((Ci-C4)alkyl)nN-(C=O)-, (C2C4)alkenyl-(C=O)N-, ( (C2-C4)alkenyl)nN-(C=O)-, (C2-C4)alkynyl-(C=O)N- and ((C2-C4)alkynyl)nN-(C=O)-. Preferably, R.³ is a nitrogen-linked (C1-C10) heterocyclyl of formula (II), where R⁴ is hydrogen and R⁷ is alkyl (CrC₄) optionally substituted with one to three substituents independently selected from NH₂-, (alkyl (Ci-C₄))_no-N-, NH₂(C=O)-, alkyl (Ci-C₄)-(C=O)N- and (alkyl (Ci-C₄))_noN-(C=O)-.

The invention also provides compounds in which R³ is a nitrogen-linked (C1-C10) heterocyclyl of formula (III), where R⁴ is hydrogen and R⁷ is alkyl (C₁-C₄) optionally substituted with one to three substituents independently selected from alkyl (Ci-C₄)-(C=O)-, alkenyl (C₂-C₄) (0=0)-, alkynyl (C₂-C₄)-(C=O)-, cycloalkyl (C₃-C₁₀)-(C=O)-, heterocyclyl (0:-0^)-(0=0)-, aryl (C₆-C₁₀)-(C=O)y heteroaryl (Ci-C₁₀)-(C=O), and preferably, R³ is a nitrogen-linked (ΟΓΟ10) heterocyclyl of formula (II), where R⁴ is hydrogen and R⁷ is alkyl (0Γ0₄) optionally substituted with one to three substituents independently selected from alkyl (Ci-C₄)-(C=O)-, cycloalkyl (C₃-ci₀)-(C=O)-, heterocyclyl (0:-0:0)-(0=0)-, aryl (C₆-C₁₀)-(C=O) and heteroaryl (Ο:-Ο₁₀)-(Ο=Ο).

Another embodiment of the invention are compounds in which R³ is a nitrogen-linked (Ο:-Ο10) heterocyclyl of formula (III), where R⁴ is hydrogen and R⁷ is alkyl (0Γ0₄) optionally substituted with one to three substituents independently selected from alkyl(CrC₄)-(C=O)O-, alkenyl (C₂C.₄)-(C=O)O-, alkynyl (C₂-C₄)-(C=O)O-, alkyl (C:-C₄)-O(C=O)-, alkenyl (C₂-C₄)-O-(C=O)- and alkynyl (C₂-C₄)0-(0=0)-. Preferably, R.³ is a nitrogen-linked (Ci-C10) heterocyclyl of formula (II), where R⁴is hydrogen and R⁷ is (C1-C4)alkyl optionally substituted with one to three substituents independently selected from (Ci-C4)alkyl.-(C=O)O- and (Ci-C4)alkyl₄)-O(C=O)-.

Furthermore, the invention provides compounds in which R³ is a nitrogen-linked (C1-C10) heterocyclyl of formula (III), where R⁴ is hydrogen and R⁷ is alkyl (C_rC.₄) optionally substituted with one to three substituents independently selected from cycloalkyl(C3-C10)-, aryl(C₆-C:o)-, heterocyclyl(C1-C10)- and heteroaryl(C1-C10)-.

The present invention also provides compounds of formula (I) wherein R³ is a heterocyclyl (C:-0_Ί0) linked by nitrogen, of formula (IV):

(iv) and R.⁷ selected from the group consisting of:

HO

HO'

HO'

ooh

HO'

OH > HO'

ooh

ooh

Also provided are compounds of formula (I) wherein R³ is a heterocyclyl (C_r

C.₁₀) linked by nitrogen, of formula (IV), and R⁷ is

<img file="ECSP055884A_D0004.tif" />

The present invention also contemplates compounds of formula (I) wherein R³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula (IV), and R⁷ selected from the group consisting of:

<img file="ECSP055884A_D0005.tif" />

<img file="ECSP055884A_D0006.tif" />

<img file="ECSP055884A_D0007.tif" />

<img file="ECSP055884A_D0008.tif" />

OH • and

Also provided are compounds of formula (I) wherein R³ is heterocyclyl(CrC₁₀) linked by nitrogen, of formula (IV), and R⁷ is

<img file="ECSP055884A_D0009.tif" />

Also provided are compounds of formula (I) wherein R³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula (IV), and R⁷ is selected between:

<img file="ECSP055884A_D0010.tif" />

Finally, the present invention further provides compounds of formula (I) wherein R³ is a nitrogen-linked heterocyclyl (CpC^) of formula (IV), and R⁷ is selected between:

<img file="ECSP055884A_D0011.tif" />

The present invention also provides compounds of formula (I) wherein R³ is a heterocyclyl (Ci-Ci₀) linked by nitrogen, of formula (IV),

R.⁷ selected from the group consisting of:

<img file="ECSP055884A_D0012.tif" />

<img file="ECSP055884A_D0013.tif" />

<img file="ECSP055884A_D0014.tif" />

and R¹ is selected from the group consisting of alkyl (C1-C4), optionally substituted with cycloalkyl (C₃C10), wherein said alkyl (CrC₄) or cycloalkyl (C₃-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Ci-C₆), HO-alkyl(Ci-C₆), alkyl (Ci-C₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (Ci-C₆) or cycloalkyl (C₃Cw), wherein said cycloalkyl (C₃-ci₀) is optionally substituted with one or more residues selected from halogen or alkyl (Ci-C₆)-.

The present invention also provides compounds of formula (I) wherein R³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula (IV),

R.⁷ selected from the group consisting of:

<img file="ECSP055884A_D0015.tif" />

and R¹ is selected from the group consisting of alkyl (C1-C4), optionally substituted with aryl (C₆-ci₀), wherein said alkyl (C1-C4) or aryl (C₆-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Cr C₆), HO-alkyl (C^Cb), alkyl (CtCbJ-NH^O)-, NH₂(C=O)-, alkoxy (CpCe) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more moieties selected from halogen or alkyl(CrCe)-.

Also provided are compounds of formula (I) wherein R³ is a heterocyclyl (Ci-C₁₀) linked by nitrogen, of formula (IV),

R.⁷ is

<img file="ECSP055884A_D0016.tif" />

and R¹ is selected from the group consisting of alkyl (C_rC.₄), optionally substituted with cycloalkyl (C₃C.₁₀), wherein said alkyl (CrC₄) or cycloalkyl (C₃-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Ci-C₆), HO-alkyl(Ci-C₆), alkyl (Ci-C_yes)-NH(C=O)-, NH₂(C=O)-, alkoxy (Ci-C₆) or cycloalkyl (C₃C10), wherein said cycloalkyl (C₃-Cio) is optionally substituted with one or more moieties selected from halogen or alkyl (CpCs)-.

Also provided are compounds of formula (I) wherein R³ is a nitrogen-linked (C3-C10) heterocyclyl of formula (IV),

R.⁷ is

<img file="ECSP055884A_D0017.tif" />

and R¹ is selected from the group consisting of alkyl (CpC^, optionally substituted with aryl (C₆-C₁₀), wherein said alkyl (C1-C4) or aryl (C₆-ci₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl(C_rC.₆), HO-alkyl(CrC_B.), alkyl (CrC₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (CrC_B.) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more residues selected from halogen or alkyl (Ci-C_B.)-.

The present invention also contemplates compounds of formula (I) wherein R³ is a heterocyclyl (Ci-Ci₀) linked by nitrogen, of formula (IV ),

R.⁷ selected from the group consisting of:

<img file="ECSP055884A_D0018.tif" />

ooh

<img file="ECSP055884A_D0019.tif" />

<img file="ECSP055884A_D0020.tif" />

<img file="ECSP055884A_D0021.tif" />

' and and R¹ is selected from the group consisting of (CrC4)alkyl, optionally substituted with (C3C10)cycloalkyl, wherein said (CrC4)alkyl or (Cg-C10)cycloalkyl are optionally substituted with one to three suitable moieties independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (CpCe), HO-alkyl (CpCe), alkyl (CrC^-NH^O)-, NH2(C=O)-, alkoxy (C^Cb) or cycloalkyl (C3Cw), wherein said (C3-C10)cycloalkyl is optionally substituted with one or more moieties selected from halogen or (Ci-C6)alkyl-The present invention also contemplates compounds of formula (I) wherein R³ is a nitrogen-linked (CrC10) heterocyclyl of formula (IV),

R.⁷ selected from the group consisting of:

<img file="ECSP055884A_D0022.tif" />

ooh

<img file="ECSP055884A_D0023.tif" />

ooh

<img file="ECSP055884A_D0024.tif" />

<img file="ECSP055884A_D0025.tif" />

<img file="ECSP055884A_D0026.tif" />

and R¹ is selected from the group consisting of alkyl (CrC₄), optionally substituted with aryl (C₆-C₁₀), wherein said alkyl (CrC₄) or aryl (C₆-ci₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Cr C₆), HO-alkyl(Ci-C₆), alkyl (Ci-C₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (Ci-C₆) or cycloalkyl (C3-C10), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more moieties selected from halogen or alkyl(CpCe)-.

Also provided are compounds of formula (I) wherein R³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula (IV),

R.⁷ is and R¹ is selected from the group consisting of alkyl (C^), optionally substituted with cycloalkyl (C₃C.₁₀), wherein said alkyl (C_rC.₄) or cycloalkyl (C₃-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Ci-C₆), HO-alkyl(Ci-C₆), alkyl (Ci-C_and)-NH(C=O)-, NH₂(C=O)-, alkoxy (Ci-C₆) or cycloalkyl (C₃C10), wherein said cycloalkyl (C₃-ci₀) is optionally substituted with one or more residues selected from halogen or alkyl (Ci-C₆)-.

Also provided are compounds of formula (I) wherein R³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula (IV),

R.⁷ is and R¹ is selected from the group consisting of alkyl (CpC^, optionally substituted with aryl (C₆-C₁₀), where said alkyl (Ο_ΓΟ₄) or aryl (C₆-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Cr C₆), HO-alkyl (CpCs), alkyl (C₁-C₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (CrC₆) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more moieties selected from halogen or alkyl(CpCe)-.

Also provided are compounds of formula (I) wherein R³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula (IV),

R.⁷ is selected between:

<img file="ECSP055884A_D0027.tif" />

<img file="ECSP055884A_D0028.tif" />

OH and R¹ is selected from the group consisting of alkyl (C_rC.₄), optionally substituted with cycloalkyl (C₃C.₁₀), wherein said alkyl (CpC^ or cycloalkyl (C₃-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Ci-C₆), HO-alkyl(CrC₆), alkyl (Ci-C_yes)-NH(C=O)-, NH₂(C=O)-, alkoxy (Ci-C_and) or cycloalkyl (C₃C.₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more residues selected from halogen or alkyl (CrC₆)-.

Also provided are compounds of formula (I) wherein R³ is a nitrogen-linked heterocyclyl (C^Cw) of formula (IV),

R.⁷ is selected between:

<img file="ECSP055884A_D0029.tif" />

<img file="ECSP055884A_D0030.tif" />

OH and R¹ is selected from the group consisting of alkyl (Ci-C₄), optionally substituted with aryl (C₆-ci₀), wherein said alkyl (CrC₄) or aryl (C₆-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Cr

C.₆), HO-alkyl (CpCs), alkyl (C₁-C₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (CrC₆) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more moieties selected from halogen or alkyl(CpCe)-.

The invention further provides compounds of formula (I) wherein R³ is a heterocyclyl (C_r

C.₁₀) linked by nitrogen, of formula (IV),

R.⁷ is selected between:

<img file="ECSP055884A_D0031.tif" />

<img file="ECSP055884A_D0032.tif" />

<img file="ECSP055884A_D0033.tif" />

and R¹ is selected from the group consisting of alkyl (C1-C4), optionally substituted with cycloalkyl (C₃C.₁₀), wherein said alkyl (C_rC.₄) or cycloalkyl (C₃-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (CpCg), HO-alkyl (CpCg), alkyl (CrCgj-NH^O)-, NH₂(C=O)-, alkoxy (C^Cg) or cycloalkyl (C₃C10), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more moieties selected from halogen or alkyl(CpCg)-.

Finally, the invention further provides compounds of formula (I) in which R³ is a heterocyclyl (C^C^) linked by nitrogen, of formula (IV),

R.⁷ is selected between:

<img file="ECSP055884A_D0034.tif" />

ooh

<img file="ECSP055884A_D0035.tif" />

<img file="ECSP055884A_D0036.tif" />

and R¹ is selected from the group consisting of alkyl (CrC₄), optionally substituted with aryl (C₆-C₁₀), wherein said alkyl (CrC₄) or aryl (C₆-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl(C_rC.₆), HO-alkyl (C^Cg), alkyl (C₁-C₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (C^Cg) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C₃-ci₀) is optionally substituted with one or more moieties selected from halogen or alkyl(CrCg)-.

The present invention also provides compounds of formula (I) wherein R³ is a nitrogen-linked (Cj-C^) heterocyclyl of formula (IV),

R.⁷ selected from the group consisting of:

<img file="ECSP055884A_D0037.tif" />

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (CpC^, optionally substituted with cycloalkyl (C₃-C₁₀), wherein said alkyl (C_rC.₄) or cycloalkyl (C₃-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Ci-C₆), HO-alkyl(CrC₆), alkyl (Ci-C₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (Ci-C₆) or cycloalkyl (C₃C.₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more moieties selected from halogen or alkyl(CpCg)-.

The present invention also provides compounds of formula (I) wherein R³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula (IV),

R.⁷ selected from the group consisting of:

<img file="ECSP055884A_D0038.tif" />

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (C1-C4), optionally substituted with aryl (C₆C10), wherein said alkyl (CrC₄) or aryl (C₆-ci₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Cr C₆), HO-alkyl (C^Cb), alkyl (CtCbJ-NH^O)-, NH₂(C=O)-, alkoxy (CpCe) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more moieties selected from halogen or alkyl(CrCe)-.

Also provided are compounds of formula (I) wherein R³ is a heterocyclyl (Ci-C₁₀) linked by nitrogen, of formula (IV),

R.⁷ is

<img file="ECSP055884A_D0039.tif" />

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (CrC₄), optionally substituted with cycloalkyl (C3-C10), wherein said alkyl (CrC₄) or cyclo(C3-C10)alkyl are optionally substituted with one to three suitable moieties independently selected from the group consisting of hydroxy, halogen, CN-, alkyl(Ci-C₆), HO-alkyl(Ci-C₆), alkyl (Ci-C₅)-NH(C=O)-, NH₂(C=O)-, alkoxy (Cr C₆) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more residues selected from halogen or alkyl (Ci-C₆)-.

Also provided are compounds of formula (I) wherein R³ is a nitrogen-linked (C1-C10) heterocyclyl of formula (IV),

R.⁷ is

<img file="ECSP055884A_D0040.tif" />

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (C_rC.₄), optionally substituted with aryl (C₆C.₁₀), wherein said alkyl (CrC₄) or aryl (C₆-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Cp C₆), HO-alkyl(CpC₆), alkyl (CpC₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (CpC₆) or cycloalkyl (C3-C10), wherein said cycloalkyl (C3-C10) is optionally substituted with one or more residues selected from halogen or alkyl (CpC₆)-.

The present invention also contemplates compounds of formula (I) wherein R³ is a heterocyclyl (CpC₁₀) linked by nitrogen, of formula (IV),

R.⁷ selected from the group consisting of:

<img file="ECSP055884A_D0041.tif" />

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (CpC₄), optionally substituted with cycloalkyl (C3-C10), wherein said alkyl (CpC₄) or cyclo(C3-C10)alkyl are optionally substituted with one to three suitable moieties independently selected from the group consisting of hydroxy, halogen, CN-, alkyl(CpC₆), HO-alkyl(CpC₆), alkyl (CpC₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (CpC₆) or cycloalkyl (C₃C.₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more moieties selected from halogen or alkyl (CpC₆)-.

The present invention also contemplates compounds of formula (I) wherein R³ is a nitrogen-linked (C1-C10) heterocyclyl of formula (IV),

R.⁷ selected from the group consisting of:

<img file="ECSP055884A_D0042.tif" />

<img file="ECSP055884A_D0043.tif" />

<img file="ECSP055884A_D0044.tif" />

<img file="ECSP055884A_D0045.tif" />

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (C_rC.₄), optionally substituted with aryl (C₆C.₁₀), wherein said alkyl (CrC₄) or aryl (C₆-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Cr C₆), HO-alkyl(Ci-C₆), alkyl (Ci-C₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (Ci-C₆) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C3-C10) is optionally substituted with one or more residues selected from halogen or alkyl (CpCg)-.

Also provided are compounds of formula (I) wherein R³ is a nitrogen-linked heterocyclyl (CrC™) of formula (IV),

R.⁷ is

<img file="ECSP055884A_D0046.tif" />

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (CpC^, optionally substituted with cycloalkyl (C₃-C₁₀), where said alkyl (Ο_ΓΟ₄) or cycloalkyl (C₃-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Ci-C₆), HO-alkyl(Ci-C₆), alkyl (Ci-C_and)-NH(C=O)-, NH₂(C=O)-, alkoxy (Ci-C₆) or cycloalkyl (C₃C10), wherein said cycloalkyl (C₃-ci₀) is optionally substituted with one or more residues selected from halogen or alkyl (Ci-C₆)-.

Also provided are compounds of formula (I) wherein R³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula (IV),

R.⁷ is

<img file="ECSP055884A_D0047.tif" />

either

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (C₁-C₄), optionally substituted with aryl (C₆C10), wherein said alkyl (C1-C4) or aryl (C₆-ci₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Cr C₆), HO-alkyl(CrC₆), alkyl (Ci-C₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (CrC₆) or cycloalkyl (C₃-ci₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more residues selected from halogen or alkyl (CrC₆)-.

Also provided are compounds of formula (I) wherein R³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula (IV),

R.⁷ is selected between:

HjN'

HjN

<img file="ECSP055884A_D0048.tif" />

' and

ooh

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (CAC4), optionally substituted with cycloalkyl (C3-C10), wherein said alkyl (C1-C4) or cycloalkyl (C₃-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (CrC₆), HO-alkyl(CrC₆), alkyl (CrC_yes)-NH(C=O)-, NH₂(C=O)-, alkoxy (CrC₆) or cycloalkyl (C₃C.₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more residues selected from halogen or alkyl (CrC₆)-.

Also provided are compounds of formula (I) wherein R³ is a heterocyclyl (CrC₁₀) linked by nitrogen, of formula (IV),

R.⁷ is selected between:

> HjN'

HjN

<img file="ECSP055884A_D0049.tif" />

' and

ooh

HjN.

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (C^C^, optionally substituted with aryl (C₆C.₁₀), wherein said alkyl (C1-C4) or aryl (C₆-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl(C_rC.₆), HO-alkyl(CpCg), alkyl(C₁-C₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (Ci-C₆) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more residues selected from halogen or alkyl (Ci-C₆)-.

The invention further provides compounds of formula (I) wherein R³ is a nitrogen-linked (Cr C10) heterocyclyl of formula (IV),

R.⁷ is selected between:

<img file="ECSP055884A_D0050.tif" />

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (C1-C4), optionally substituted with cycloalkyl (C₃-C₁₀), wherein said alkyl (CpC^ or cycloalkyl (C₃-C₁₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl (Ο_ΓΟ₆), HO-alkyl (C^Cg), alkyl (CrC_and)-NH(C=O)-, NH₂(C=O)-, alkoxy (CrC₆) or cycloalkyl (C₃C10), wherein said cycloalkyl (C₃-ci₀) is optionally substituted with one or more moieties selected from halogen or alkyl(CpCg)-.

Finally, the invention further provides compounds of formula (I) in which R³ is a heterocyclyl (C_rC.₁₀) linked by nitrogen, of formula (IV),

R.⁷ is selected between:

<img file="ECSP055884A_D0051.tif" />

R.² is chlorine, methyl or ethyl;

and R¹ is selected from the group consisting of alkyl (Ci-C₄), optionally substituted with aryl (C₆Cw), wherein said alkyl (C1-C4) or aryl (C₆-ci₀) are optionally substituted with one to three suitable residues independently selected from the group consisting of hydroxy, halogen, CN-, alkyl(C_rC.₆), HO-alkyl(CpCg), alkyl(C₁-C₆)-NH(C=O)-, NH₂(C=O)-, alkoxy (CpCg) or cycloalkyl (C₃-C₁₀), wherein said cycloalkyl (C₃-C₁₀) is optionally substituted with one or more residues selected from halogen or alkyl (CrC₆)-.

Examples of other compounds of formula I are as follows:

2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-[4-(2-methanesulfonylamino-ethyl)-3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2- yl]benzamide;

2-Chloro-5-[4-(2-formylaminoethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl]-N-(1-hydroxycycloheptylmethyljbenzamide;

5-(4-(1-Am inocyclopropylmethyl)-3,5-dioxo-4,5-dihídro-3H-[1,2,4]-triazin-2-yl]-2-chloro-N -(1-hydroxycycloheptylmethyljbenzamide;

2-Chloro-N-(1 -hydroxyc¡clohept¡lmethyl)-5-[4-(1 -h¡drox¡-c¡cloprop¡lmethyl)-3,5-d¡oxo-4, 5-d¡h¡dro-3H-

[1,2,4]triazin-2-yl]benzam ida;

5-[4-(2-Am¡no-2-methyl-propyl)-3,5-d¡oxo-4,5-d¡h¡dro-3H-[1,2,4] -triaz¡n-2-¡l]-2-chloro-N-(1-hydroxycycloheptylmethyljbenzamide;

2-Chloro-5-[4-(3-difluoromethox¡-2-h¡drox¡prop¡l)-3,5-d¡oxo-4,5-d¡hydro-3H-[1,2,4 ]triazin-2-yl]-N-(1-hydroxycycloheptylmethyljbenzamide;

N-(1 -H¡drox¡c¡cloheptilmet¡l)-5-[4-(2-h¡drox¡-3-methox¡prop¡l)-3,5-d¡oxo-4,5- d¡d¡dro-3H-[1,2,4]triazin-2yl]-2-methylbenzamide;

5-[4-(2-H¡drox¡-3-methoxypropyl)-3,5-d¡oxo-4,5-d¡h¡dro-3H-[1,2,4]-tr¡ az¡n-2-¡l]-N-(1hydroxymethylcycloheptylmethyl)-2-methylbenzam¡de;

N-(1-H¡drox¡c¡clohex¡lmethyl)-5-[4-(2-hidrox¡-3-methox¡prop¡l)-3,5-d¡oxo-4,5-dihydro- 3 Η-

[1.2.4] triaz¡n-2-il]-2-met¡lbenzam¡de;

Acid amide 1 -({2-chloro-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4]triazin-2-yl]benzoylamino}methyl)cycloheptane-carboxylic;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(2,3-dihydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2 ,4]triazin-2yljbenzamide;

2-Chloro-5-[4-(2,3-dih¡droxypropi I)-3,5-dioxo-4,5-d¡ hydro-3H-[1,2,4]-triazin-2-yl ]-N-(1-hydroxymethylcycloheptylmethyljbenzamide;

1 -({2-chloro-5-[4-(2,3-dihydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazine acid amide -2yl]benzoylamino}methyl)cycloheptanecarboxylic;

2-Chloro-5-[4-(2,3-dihydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl]-N-phenethylbenzamide;

2-Chloro-5-[4-(2,3-dihydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl]-N- (1-hydroxycyclohexylmethyl)benzamide;

2-Chloro-5-[4-(2,3-dihydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl]-N-(1 hydroxycyclopentylmethyl)benzamide;

2-Chloro-5-[4-(2,3-dihydroxypropyl)-3,5-dioxo-4,5-d¡h¡dro-3H-[1,2,4]-triazin-2-¡ l]-N-(1-hydroxycyclobutylmethyl)benzamide;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-3-trifluoro-methoxypropyl)-3,5-dioxo-4,5dihydro-3H-[1,2, 4]triazin-2-yl]benzamide;

2-Chloro-N-(1 -hydroxycyclohept¡lmethyl)-5-[4-(2-hydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-yl]benzam ida;

2-Chloro-5-[4-(2-hydroxybutyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-l]-N-(1-hydroxycycloheptylmethyl) benzamide;

5-[4-(2-Aminopropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1-hydroxycycloheptylmethyl)benzam gives;

2-Chloro-5-[3,5-dioxo-4-(2-oxopropyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl )benzamide;

2-Chloro-5-[3,5-dioxo-4-(2-oxo-ethyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl )benzamida;

2-Chloro-5-[3,5-dioxo-4-(2-trifluoromethoxyethyl)-4,5-dihydro-3H-[1,2,4]-triazin-2-yl]-N-(1hydrox icycloheptylmethyl)benzamide;

2-Chloro-5-[4-(1-hydroxycyclobutylmethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triaz¡n-2-¡l]- N-(1 hydroxycycloheptylmethyl)benzamide;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-2-pyridin-4-ethyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-¡l]benzam ida;

2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-2-pyridin-3-ylethyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-yl]benzam ida;

2-Chloro-N-(1 -h¡drox¡c¡cloheptilmet¡l)-5-[4-(2-h¡drox¡-2-p¡r¡d¡n-2-¡letil)-3 ,5-d¡oxo-4,5-dihydro-3H-

[1.2.4] triazin-2-¡l]benzam ida;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(4-hydroxytetrahydropyran-4-ylmethyl}-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin- 2-¡l]benzamida;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-2-thiophen-2-ylethyl)-3,5-dioxo-4,5-dihydro-3H -

[1.2.4] triazin-2-yl]benzam ida:

2-Chloro-5-[4-(2-furan-2-yl-2-hydroxyethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl ]-N-(1-hydroxycycloheptylmethyljbenzamide;

5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-[2-(2chlorophenyl)ethyl]benzamide ;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(2-methoxyethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4 ]triazin-2yljbenzamide;

5-[4-(2-Carbamoylethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triaz¡n-2-¡l]-2-chloro-N- [2-(2chlorophenyl)ethyl]benzamide;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(2-hydroxyethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazine -2IJbenzamide;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(3-hydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4 ]triaz¡n-2¡IJbenzamide;

5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-¡l)-2-chloro-N-(1-hydroxycycloheptylmethyl)benzamide;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-hydroxyethyl)-3,5-dioxo-4,5-dihydro-3H-

[1,2,4]triazin-2-yl]benzam ida;

2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-[4-(2-methoxyethyl)-3,5-dioxo-4,5-dihydro-3H-

[1,2,4]triazin-2-yl]benzam ida;

2-Chloro-5-[4-(2-dimethylaminoethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl]-N-(1-hydroxycycloheptylmethyljbenzamide;

2-Chloro-5-(4-cyanomethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxycycloheptylmethyl)benzamide;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(3-hydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-

[1,2,4]triazin-2-yl]benzam ida;

5-[4-(2-Aminoethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1-hydroxycycloheptylmethyl )benzamide;

2-Chloro-N-(1 -hydroxycyclohept¡lmethyl)-5-(4-ox¡ranylmethyl-3,5-dioxo-4,5-d¡h¡dro-3H-[1,2,4] triazin2-1)benzamide;

5-[4-(2-Acetylaminoethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1-hydroxycycloheptylmethyljbenzamide;

2-Chloro-5-[4-(2,3-dihydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triaz¡n-2-¡l]-N -(1-hydroxycycloheptylmethyl)benzamide;

2-Chloro-5-(3,5-dioxo-4-phenethyl-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxycycloheptylmeth ¡l)benzamida;

5-(4-Benzyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1-hydroxy¡c¡clohept¡lmet ¡l)benzamide;

2-Chloro-5-[4-(2-cyanoethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-¡l]-N-(1-hydroxycycloheptylmethyl)benzam gives;

2-Chloro-5-(3,5-dioxo-4-pyridin-2-ylmethyl-4,5-dihydro-3H-[1,2,4]triaz¡n-2-yl)-N-( 1-hydroxycycloheptylmethyljbenzamide;

2-Chloro-5-(3,5-dioxo-4-pyridin-3-ylmethyl-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxycycloheptylmethyl )benzamide;

2-Chloro-5-(3,5-dioxo-4-pyridin-4-ylmethyl-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxycyclohept ¡lmet¡l)benzam¡de;

5-[4-(2-Carbamoylethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1-hydroxycycloheptylmethyl)benzam gives;

N-(1-Hydroxycycloheptylmethyl)-5-[4-(2-hydroxyethyl)-3,5-d¡oxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl] -2methylbenzamide;

5-[4-(2,3-D¡hidrox¡prop¡l)-3,5-d¡oxo-4,5-d¡h¡dro-3H-[1,2,4]triaz¡n- 2-¡l]-N-(1 hidrox¡c¡cloheptilmethyl)-2-methylbenzamide;

5-[4-(2-Carbamoylethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl)-2-methylbenzamide;

5-[4-(3-Aminopropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1 hidrox icycloheptylmethyl)benzamide;

2-Chloro-5-[4-(2,3-dihydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-¡l]-N -(1-hydroxycycloheptylmethyl)benzamide;

(2-{4-Chloro-3-[2-(2-chlorophenyl)ethyl-carbamoyl]phenyl}-3,5-dioxo-2,5dihydro-3H-[1,2,4] acid tert-butyl ester triazin-4-yl)acetic;

2-Chloro-5-[4-(2_;3-dih¡drox¡prop¡l)-3,5-d¡oxo-4_;5-dihydro-3H-[1,2,4]-triazin-2-yl]-N-(1-hydroxycycloheptylmethyl)benzamide;

5-(4-Carbamo¡lmet¡l-3,5-d¡oxo-4,5-d¡h¡dro-3H-[1_J2,4]triaz¡n-2-¡l)-2-chloro-N-(1-cyanocycloheptylmethyl)benzamide;

N-Adamantan-1 -¡lmet¡l-5-(4-carbamoylmethyl-3,5-d¡oxo-4,5-d¡h¡dro-3H-[1₅2,4]triazin-2-yl)-2-chlorobenzamide;

5-(4-Carbamoylmethyl-3,5-d¡oxo-4,5-d¡hdro-3H-[1,2,4]triaz¡n-2-¡l)-2-chloro- N-(4,4-difluoro-1phenylcyclohexylmethyl)benzamide;

5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1-ptolylcyclohexylmethyl)benzamide;

5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1-hydroxycyclohexylmethyl)benzamide;

2-Chloro-N-(1-hidrox¡c¡clohex¡lmethyl)-5-[4-(2-hidrox¡et¡l)-3,5-d¡oxo-4,5-d¡hydro -3H-[1,2,4]triazin2-¡l]benzamide;

2-Chloro-N-(1 -hydroxy-3,3-dimethylcyclohexylmethyl)-5-[4-(2-hydroxyethyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-¡l]benzam ida;

2-Chloro-N-(1 -hydroxycyclooct¡lmethyl)-5-[4-(2-hydroxyethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin2- ¡l]benzamide;

2-Chloro-5-[4-(2,3-dih¡droxypropi I)-3,5-dioxo-4,5-d¡ hydro-3H-[1,2,4]-triazin-2 -yl]-N-(1-hydroxycyclohexylmethyl)benzamide;

5-[4-(2,3-Dihydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl)-2- methylbenzamide;

5-[4-(2,3-Dihydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxycyclohept ¡lmethyl)-2-methylbenzamide;

5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1_:2,4]triazin-2-yl)-2-chloro-N-(1-hydroxycyclooctylmethyl)benzamide;

2-Chloro-N-(2-hydroxycycloheptylmethyl)-5-[4-(2-hydroxyethyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4]triazin-2-yl]-benzamide;

5-[4-(3-Amino-2-hydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triaz¡n-2-yl]-2- chloro-N-(1 hydroxycyclohept¡lmethyl)benzamide;

2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-(4-methylcarbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-yl)benzam ida;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-(4-dimethylcarbamoylmethyl-3,5-dioxo-4,5-dihydro-3H[1_:2,4]triazin-2-yl)-benzamida;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(2-morpholin-4-yl-2-oxoethyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-yl]benzamide;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[3,5-dioxo-4-(2-oxo-2-pyrrolidin-1-ylethyl)-4,5-dihydro-3H-

[1,2,4]triazin-2-yl]benzam ida;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(2-methylcarbamoylethyl)-3_J5-dioxo-4,5-dihydro-3H[1,2,4]triazin-2-yl]benzamide;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(2-d¡methylcarbamo¡let¡l)-3,5-dioxo-4,5-dih¡dro-3H-

[1,2,4]triazin-2-yl]benzam ida;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[3,5-dioxo-4-(2-oxo-2-piperazin-1-ylethyl)-4,5-dihydro-3H-

[1,2,4]triazin-2-yl]benzamide;

2-Chloro-5-(4-dimethylcarbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxycycloheptylmethyl)benzamide;

2-Chloro-5-(4-ethylcarbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl)-N-(1-hydroxycycloheptylmethyl)benzamide;

2-Chloro-5-[3,5-dioxo-4-(2-oxo-2-piperdin-1-ylethyl)-4,5-dihydro-3H-[1,2,4]triazin- 2-il]-N-(1 hidroxic¡clohept¡lmet¡l)benzamida;

2-Chloro-N-(1 -h¡drox¡c¡cloheptilmethyl)-5-[4-(2-morphol¡n-4-¡l-2-oxoethyl)-3,5-dioxo-4, 5-d¡h¡dro-3H-

[1,2,4]triazin-2-¡l]benzam ida;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(¡sopropylcarbamoylmethyl)-3,5-dioxo-4,5-d¡hydro-3H-

[1.2.4] triazin-2-¡l]benzam ida;

2-Chloro-5-[3,5-dioxo-4-(2-oxo-2-pyrrolidin-1 -yl-ethyl)-4,5-dihydro-3H-[1,2,4]triazin- 2-yl]-N-(1 hydroxycycloheptylmethyl)benzamide;

2-Chloro-5-{4-[(cyclopropylmethylcarbamol)methyl]-3,5-dioxo-4₃5-dihydro-3H-[1,2,4]triazin-2-yl}-N(1-hydroxycycloheptylmethyl)benzamide;

5-(4-Dimethylcarbamoylmethyl-3_:5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxycloheptylmethyl)-2-methylbenzamide;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4]triazin-2-yl]benzamide;

2-Chloro-5-[4-(2,3-dihydroxy-2-methylpropyl)-3,5-dioxo-4_J5-dihydro-3H-[1_:2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl)benzamide;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-2-methylpropyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triaz¡n-2-¡l]benzam ida;

2-Chloro-N-(1 -hidrox¡c¡clohex¡lmethyl)-5-[4-(2-hidrox¡-2-methylpropyl)-3,5-dioxo-4,5- dihydro-3H-

[1.2.4] triazin-2-yl]benzam ida;

2-Chloro-N-(1-hydroxycyclooctylmethyl)-5-[4-(2-hydroxy-2-methylpropyl)-3,5-dioxo-4,5-dihydro-3H-

[1,2,4]triazin-2-yl]benzam ida;

2-Chloro-N-(1-hydroxycyclooctylmethyl)-5-[4-(2-hydroxy-3-methyloxypropyl)-3,5-dioxo-4,5-dihydro-3H[1_: 2,4]triazin-2-yl]-benzamide;

2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin- 2-yl]benzamide;

2-Chloro-N-(1-hydroxycyclohexylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-

[1,2,4]triazin-2-yl]benzam ida;

2-Chloro-N-(1-hydroxycyclooctylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H[1_; 2,4]triazin-2-yl]benzam ida;

2-Chloro-N-(1-hydroxycyclopentylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-

[1,2,4]triazin-2-yl]benzam ida;

2-Chloro-N-(1-hydroxycyclopentylmethyl)-5-[4-(2-hydroxy-2-methylpropyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-yl]benzamide;

2-Chloro-N-(1-hydroxycyclopentylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4]triazin-2-yl]benzamide;

2-Chloro-N-(1-hydroxycyclobutylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H[1,2,4 Jtriazi n-2 -il]benzamide ida;

2-Chloro-N-(1 -hydroxycyclobutylmethyl)-5-[4-(2-hydroxy-2-methylpropyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-yl]benzam ida;

2-Chloro-N-(1 -h¡drox¡c¡clopentylmethyl)-5-[4-(2-h¡drox¡-3-methox¡prop¡l)-3,5-dioxo-4, 5-dihydro-3H-

[1.2.4] triazin-2-¡l]benzam ida;

2-Chloro-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1_J2,4]triazin-2-yl]-N-(1-hydroxymethylcycloheptylmethyljbenzamide;

2-Chloro-N-(1-hydroxymethylcycloheptylmethyl)-5-[4-(2-hydroxy-2-methyl-propyl)-3,5-dioxo-4,5-dihydro3H-[1,2,4] triazin-2-yl]benzamide;

2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-2-phenylethyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-yl]benzam ida;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-2-phenylethyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-¡l]benzamide;

2-Chloro-5-[4-(3-ethoxy-2-hydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl] -N-(1 hydroxycyclohept¡lmethyl)benzamide;

2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-3-isopropoxy-propyl)-3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin- 2-yl]benzamide;

5-[4-(3-tert-Butoxy-2-hydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2 -chloro-N-(1-hydroxycycloheptylmethyl)benzamide;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-yl]benzam ida;

2-Chloro-5-[3,5-dioxo-4-(3_!3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl)benzamide;

2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-3,3-dimethyl-butyl)-3,5-dioxo-4,5-dihydro3H-[1,2,4] triazin-2-yl]benzamide;

3-(2-{4-Chloro-3-[(1-Hydroxycycloheptylmethyl)-carbamoyl]phenyl}-3,5-dioxo2,5-dihydro-3H-[1,2,4]triazin-4 acid methyl ester -yl)-2-hydroxy-2-methyl-propionic;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-3-morphol¡n-4-ylpropyl)-3,5-dioxo-4,5dihydro-3H-[1,2, 4]triazin-2-yl]benzamide;

5-[4-(3-Benzyloxy-2-hydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl]- 2-chloro-N-(1 hydroxycycloheptylmethyl)benzamide;

2-Chloro-N-[2-(2-chlorofen¡IJet¡l)-5-[4-(2-hidrox¡-2-methylprop¡l)-3,5-dioxo-4,5-dihydro-3H -

[1.2.4] triazin-2-yl]benzamide;

2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(2-hydroxy¡-2-phenylethyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4]triazin-2-yl]benzamide;

2-Chloro-N-(2-hydroxycyclohept¡lmethyl)-5-[4-(2-hydroxy-2-methylprop¡l)-3,5-dioxo-4,5-d¡h¡dro -3H-

[1.2.4] triazin-2-yl]benzam ida;

2-Chloro-N-(2-hydroxycyclohept¡lmethyl)-5-[4-(2-hydroxy-2-phenylethyl)-3,5-d¡oxo-4,5-d¡hydro-3H-

[1,2,4]triazin-2-yl]benzamide;

2-Chloro-N-(2-hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin- 2-yl]benzamide;

2-Chloro-5-[4-(2-h¡drox¡-3-methoxypropyl)-3,5-d¡oxo-4,5-dih¡dro-3H-[1,2,4]triazin-2 -yl]-N-(2-hydroxy¡-2-phenylethyl)benzamide;

2-Chloro-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-( 2-hydroxy-2-phen¡let¡l)benzam¡de;

2-Chloro-5-[4-(2-hydroxy-2-methylpropyl)-3,5-d¡oxo-4,5-d¡hydro-3H-[1,2,4]triazin-2- yl]-N-(2-hydroxy2-phenylethyl)benzamide;

2-Chloro-5-[4-(2-hydroxy¡-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triaz¡n-2 -¡l]-N-phenethylbenzamide; and

2-Chloro-5-[4-(2-hydroxy¡-2-methylpropyl)-3,5-d¡oxo-4,5-d¡hydro-3H-[1,2,4]triazin-2 -¡]-N-(2-hydroxy2-phenylethyl)benzamide.

The present invention also provides the following preferred compounds of the present invention.

2-Chloro-N-(1 -hydroxycyclohexylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triaz¡n-2-¡l]benzam ida;

2-Chloro-5-[4-(2,3-dihydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl]-N-(1 hydroxycyclohexylmethyl)benzamide;

2-Chloro-N-(1 -h¡drox¡ciclohept¡lmet¡l)-5-[4-(2-h¡drox¡et¡l)-3,5-d¡oxo-4,5-d ¡h¡dro-3H-

[1.2.4] triazin-2-yl]benzam ida;

2-Chloro-5-[4-(2,3-dihydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-¡l]-N -(1-hydroxycycloheptylmethyl)benzamide;

2-Chloro-5-(4-cyanomethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxycycloheptylmethyl)benzamide;

2-Chloro-5-[4-(2-hydroxy¡-3-methoxypropyl)-3,5-dioxo-4,5-d¡hydro-3H-[1,2,4]triazin-2-¡ 1]-N-(1-hydroxymethylcycloheptylmethyljbenzamide;

2-Chloro-5-[4-(2-cyanoeth¡l)-3,5-dioxo-4,5-d¡h¡dro-3H-[1,2,4]triazin-2-yl]-N -(1-hydroxycycloheptylmethyl)benzamide;

N-(1-H¡drox¡ciclohept¡lmethyl)-5-[4-(2-hydroxyeth¡l)-3,5-d¡oxo-4,5-d¡hydro-3H-[ 1,2,4]triazin-2-11]-2-methylbenzamide;

2-Chloro-5-[4-(2,3-dihydroxypropyl)-3,5-dioxo-4,5-d¡h¡dro-3H-[1,2,4]-triaz¡n -2-¡l]-N-(1-hydroxycyclohexylmethyl)benzamide;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-2-methylpropyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-¡l]benzam ida;

2-Chloro-N-(1 -h¡drox¡c¡clooct¡lmethyl)-5-[4-(2-hidrox¡-3-methox¡prop¡l)-3,5-d¡oxo- 4,5-d¡h¡dro-3H-

[1.2.4] triazin-2-yl]benzam ida;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-2-phenylethyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazin-2-¡l]benzam ida;

2-Chloro-5-[3,5-dioxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-3H-[1,2,4]triazin- 2-yl]-N-(1-hydroxycycloheptylmethyl)benzamide;

2-Chloro-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N -(2hidroxy¡-2-phenylethyl)benzamide;

5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1-hydroxy¡c¡clohept¡lmet ¡l)benzamide;

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-methoxyethyl)-3,5-d¡oxo-4,5-dihydro-3H-

[1.2.4] triazin-2-yl]benzam ida;

5-[4-(2,3-Dih¡drox¡propyl)-3,5-d¡oxo-4,5-d¡hydro-3H-[1,2,4]triazin-2-yl] -N-(1 hydroxy¡cycloheptylmethyl)-2-methylbenzamide;

5-[4-(3-Amino-2-hydroxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triaz¡n-2-yl]-2-chloro- N-(1 hydroxycycloheptylmethyl)benzamide; and

2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-

[1.2.4]triazin-2-yl]benzamide.

The present invention also includes isotopically labeled compounds, which are identical to those defined in Formula I, but differ in that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as²h,³h,¹³c,¹⁴c,¹⁵No,¹⁸EITHER,¹⁷EITHER,³¹Q,³²Q,³⁵Yes,¹⁸f and³⁵CI, respectively. The compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of said compounds or of said prodrugs containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example, those into which radioactive isotopes are incorporated such as³h and¹⁴C, are useful in drug and/or substrate distribution assays in tissues. The tritium isotopes, that is,³H, and carbon-14, that is,¹⁴C, are particularly preferred for their ease of preparation and detectability. Also, substitution with heavier isotopes such as deuterium, i.e.,²H, may provide certain therapeutic advantages as a result of its increased metabolic stability, eg, increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. The isotopically-labeled compounds of Formula I of this invention and their prodrugs can generally be prepared by carrying out the procedures described in the Schemes and/or in the Examples and Preparations below, using a readily available isotopically-labeled reagent in place of a non-binding reagent. isotopically labeled.

The compounds of Formula I or a pharmaceutically acceptable salt thereof may be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive production. or unregulated of cytokines by cells of said mammal, such as, but not limited to, monocytes and/or macrophages.

The present invention relates to a method of treating a disease mediated by IL-1 in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula I.

The present invention also relates to a method for treating a disorder mediated by IL-1. As defined herein, an IL-1-mediated disorder includes, but is not limited to, a disease or disorder selected from the group consisting of arthritis (including psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, arthritis of rubella, rheumatoid spondylitis, osteoarthritis, gouty arthritis and acute synovitis), inflammatory bowel disease, Crohn's disease, emphysema, acute breathlessness syndrome, adult breathlessness syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, allergic reactions, allergic contact hypersensitivity, eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis coalosa, osteoporosis, bone resorption disease, weakening of artificial joint implants, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, cerebrovascular accident, cerebral ischemia, head injury, neurotrauma, spinal cord injury, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, angiopathy brain amyloid, nootropic or cognitive enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, corneal scarring, sclenitis, abnormal wound healing, burns, autoimmune disorders, Huntington's disease, diabetes, AIDS, cachexia, sepsis, septic shock, endotoxic shock, conjunctivitis shock, gram-negative sepsis, toxic shock syndrome, cerebral malaria, cardiac and renal reperfusion injury, thrombosis, glomerulonephritis, reverse transplant rejection, allograft rejection, organ transplant toxicity, ulcerative colitis or muscle degeneration, in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I effective in treating said disorder.

The present invention relates to a pharmaceutical composition for the treatment of a disease mediated by IL-1 in a mammal, comprising an effective amount of a compound according to formula I and a pharmaceutically acceptable carrier.

The present invention relates to a pharmaceutical composition for the treatment of a disorder mediated by IL-1 in a mammal, including a human being, comprising an amount of a compound of formula I, effective to treat said disorder, and a pharmaceutically acceptable.

Preferably, the compounds of the invention are useful for the treatment of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), airway hyperresponsiveness, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastasis of malignant cells, myoblastic leukemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischemic heart disease, stroke, and varicose veins.

The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein above, for use in therapy.

In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein above, in the manufacture of a medicament for use in therapy.

The invention further provides a method of treating osteoarthritis, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein above.

The invention further provides a method of producing immunosuppression (eg, in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) comprising administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein above.

The invention also provides a method of treating an obstructive airway disease (eg asthma or COPD) which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a salt or pharmaceutically acceptable solvates, as defined herein above.

The term "treat" as used herein refers to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term treatment, as used here, refers to the act of treating, understanding by treating what is defined just above.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein above, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention, which comprises mixing a compound of formula (I), or one of its pharmaceutically acceptable salts or solvates, as defined herein above, with an adjuvant, diluent or pharmaceutically acceptable vehicle.

For the aforementioned therapeutic uses, the dosage administered will, of course, vary depending on the compound employed, the mode of administration, the treatment desired, and the disorder indicated. The daily dosage of the compound of formula (l)/salt/solvate (active ingredient) may be in the range of 1 mg to 1 g, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg.

The present invention also encompasses sustained release compositions.

The present invention also relates to processes for preparing the compounds of formula I and to intermediates used in such processes.

One embodiment of the processes of the invention relates to the preparation of the compounds of formula I, which may be carried out by one or more of the synthetic methods outlined in Schemes I-IV, detailed below. The present invention also provides methods and intermediates useful in the synthesis of compounds of formula (I), and identified in Schemes I-IV below.

Those skilled in the art will appreciate that the compounds of the invention are useful for treating various classes of diseases. Those skilled in the art will also appreciate that when using the compounds of the invention in the treatment of a specific disease, the compounds of the invention can be combined with various existing therapeutic agents used for that 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 Remicade, CDP-870 and D₂AND₇) and TNF-receptor immunoglobulin molecules (such as Enbrel®), COX-2 inhibitors (such as meloxican, celecoxib, rofecoxib, valdecoxib, paracoxib, and etoricoxib), low-dose methotrexate, lefunomide; ciclesonide; hydroxychloroquine; d-penicillamine, auranofin or gold parenterally or orally.

The present invention further relates to the combination of a compound of the invention together with a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist. selected from the group consisting of zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-ditert-butylphenolhydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline compounds such as L-746,750; indole and quinoline compounds such as MK-591, MK-886 and BAY x 1005.

The present invention further relates to the combination of a compound of the invention together with an LTB leukotriene receptor antagonist.₄, LTC₄, LTD₄ and LTE₄ selected from the group consisting of phenothiazin-3-ones such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolalast; benzenecarboximidamides such as BUL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP-45715A), and BAY x 7195.

The present invention further relates to the combination of a compound of the invention together with a PDE4 inhibitor, including inhibitors of the PDE4D isoform.

The present invention further relates to the combination of a compound of the invention together with a Η receptor antagonist._Ί antihistamine, including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.

The present invention further relates to the combination of a compound of the invention together with an H receptor antagonist.₂ gastroprotective.

The present invention further relates to the combination of a compound of the invention together with an adrenergic receptor agonist vasoconstrictor sympathomimetic agent whose₂, including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compound of the invention together with anticholinergic agents, including ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine and telenzepine.

The present invention further relates to the combination of a compound of the invention together with a βτ to β adrenergic receptor agonist₄, including metaprotenerol, isoprotenerol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; or methylxanthanines including thiophylline and aminophylline; sodium cromoglycate; or muscarinic receptor antagonist (Μ1, M2 and M3).

The present invention further relates to the combination of a compound of the invention together with an insulin-like growth factor type I (IGF-1) mimetic.

The present invention further relates to the combination of a compound of the invention together with an inhaled glucocorticoid with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate and mometasone furoate. .

The present invention further relates to the combination of a compound of the invention together with (a) tryptase inhibitors; (b) platelet activating factor (PAF) antagonists; (c) Interleukin converting enzyme (ICE) inhibitors; (d) IMPDH inhibitors; (e) adhesion molecule inhibitors, including VLA-4 antagonists; (f) cathepsins; (g) MAPkinase inhibitors; (h) glucose-6-phosphate dehydrogenase inhibitors; (i) receptor antagonists and B₂ of quinine; (j) anti-gouty agents; eg, colchicine; (k) xanthine oxidase inhibitors, eg, allopurinol; (I) uricosuric agents, eg, probenecid, sulfinpyrazone, and benzobromarone; (m) growth hormone secretagogues; (n) transforming growth factor (TGF6); (o) platelet derived growth factor (PDGF); (p) fibroblast growth factor, eg, basic fibroblast growth factor (bFGF); (q) granulocyte macrophage colony-stimulating factor (GM-CSF); (r) capsaicin cream; (s) ΝΚ receptor antagonists_ή and NK₂ tachykines selected from the group consisting of NKP-608C; SB-233412 (talnetant) and D-4418; and (t) elastase inhibitors selected from the group consisting of UT-77 and ZD-0892.

The present invention further relates to the combination of a compound of the invention together with an inhibitor of matrix metalloproteases (MMPs), that is to say, the stromelysins, collagenases and gelatinases, as well as aggrecanase, especially collagenase-1 (MMP -1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11).

The compounds of the invention may also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Agents suitable for use in combination include classical non-steroidal anti-inflammatory agents (hereinafter referred to as ΑΙΝΕ) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, Sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib, valdecoxib, rofecoxib and etoricoxib, analgesics and intra-articular therapies such as corticosteroids and hyaluronic acids such as hialgan and sinvisc.

The compounds of the present invention may also be used in combination with anti-cancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platin, etoposide, taxol, taxotero and farnesyl transferase inhibitors, VegF inhibitors, of COX-2 and antimetabolites such as methotrexate-based antineoplastic agents, especially antimitotic drugs including Catharantus rosae alkaloids such as vinblastine and vincristine.

The compounds of the invention may also be used in combination with antiviral agents such as Viracept, AZT, aciclovir and famciclovir, and antiseptic compounds such as Valant.

The compounds of the present invention may also be used in combination with cardiovascular agents such as calcium channel blockers, lipid-lowering agents such as statins, fibrates, beta-blockers, Ace inhibitors, angiotensin 2 receptor antagonists, and angiotensin 2 inhibitors. platelet aggregation.

The compounds of the present invention can also be used in combination with agents with action on the Central Nervous System (CNS) such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex , MAOB inhibitors such as selegin and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonist, nicotine agonists, dopamine agonists and neuronal nitric oxide synthase inhibitors) and anti-Alzheimer drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metrifonate.

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

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula I can be prepared according to the following reaction Schemes and their discussion. Unless otherwise indicated, R¹ to R⁷ in the reaction Schemes and in the discussion that follow are as defined above.

Scheme 1

<img file="ECSP055884A_D0052.tif" />

Scheme 2

<img file="ECSP055884A_D0053.tif" />

x

Scheme 3

<img file="ECSP055884A_D0054.tif" />

eleventh

Scheme 1 relates to the preparation of compounds of formula V. Compounds of formula VI may be prepared from compounds of formula I by reaction with a compound of formula VI in the presence of base, wherein L is a suitable leaving group. , such as chlorine, bromine, iodine, tosylate or mesylate. Suitable bases include, but are not limited to, triethylamine, polymer-supported BEMP, cesium carbonate, potassium carbonate, and sodium hydride, with cesium carbonate being preferred. The aforementioned reaction can be carried out at temperatures in the range of 0°C to 100°C in the presence of a polar solvent, including, but not limited to, dimethyl sulfoxide, dimethylformamide, equal amounts of dimethyl sulfoxide and acetone, or amounts ¡ dimethylformamide and acetone, generally over a period of 2 hours to 72 hours, with dimethyl sulfoxide being preferred conditions at room temperature for 18 hours.

Compounds of formula V may also be prepared from compounds of formula I by reaction of an appropriately substituted epoxide of formula VIII either neat or in the presence of a polar solvent, including, but not limited to, dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran. . The aforementioned reaction can be carried out at temperatures in the range of 0°C to 100°C for a period of 2 to 72 hours, with dimethylformamide being preferred conditions at 60°C for 24 hours.

Scheme 2 relates to the preparation of compounds of formula V. Compounds of formula V may be prepared from compounds of formula IX by reaction with a compound of formula XIV, H₂NR¹, in the presence of a coupling reagent such as 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI) and a base such as dimethylaminopyridine (DMAP) or triethylamine in an aprotic solvent, such as methylene chloride, dimethylformamide or dimethylsulfoxide, preferably 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide and dimethylaminopyridine in dimethylformamide. The aforementioned reaction can be carried out at a temperature of from 22°C to 60°C, for a period of 1 hour to 20 hours, preferably 22°C for 18 hours.

Compounds of formula V can also be prepared from compounds of formula X by reaction with a compound of formula XIV in the presence of a base, including, but not limited to, dimethylaminopyridine (DMAP), triethylamine, aqueous sodium hydroxide, or aqueous potassium hydroxide in an aprotic solvent, such as methylene chloride, ethyl acetate, dichloroethane, dimethylformamide or dimethylsulfoxide, preferably aqueous sodium hydroxide and dichloroethane. The aforementioned reaction can be carried out at a temperature of 22°C to 60°C, for a period of 1 hour to 24 hours, preferably at room temperature for 3 hours. Compound X can be prepared from compound IX by reaction with a reagent capable of generating an acid chloride such as thionyl chloride or oxalyl chloride in the presence of a polar aprotic solvent such as ethyl acetate, methylene chloride or dichloroethane. at a temperature of 22Ό to 60°C, for a period of 1 hour to 24 hours, preferably oxalyl chloride in methylene chloride at room temperature for 16 hours.

Scheme 3 relates to the preparation of compounds of formula IX, which can be converted to compounds of formula V by the methods described in Scheme 2. Compounds of formula IX can be prepared from compounds of formula XI using decarboxylation conditions, preferably mercaptoacetic acid in water containing a base such as sodium hydroxide at a temperature of 22°C to 160°C for a period of 1 hour to 24 hours, preferably 100°C for 18 hours.

Scheme 4 refers to the preparation of compounds of formula XIII and XI. Compounds of formula XI can be converted to compounds of formula IX by the methods described in Scheme 3.

A compound of formula XI can be prepared from a compound of formula XIII, wherein R⁸ is an alkyl (CrC₂) suitable, by reaction with an acid such as 50% sulfuric acid at a temperature between 60°C and 120°C, generally for a period between 30 minutes and 6 hours, preferably 2 hours at 120°C.

A compound of formula XIII, wherein R⁸ is a suitable (CrC2)alkyl, it can be prepared from the diazonium intermediate derived from a compound of formula XII. The diazonium intermediate is prepared by reaction of a compound of formula XII with an acid such as hydrochloric acid and/or glacial acetic acid, followed by treatment with sodium nitrite in a solvent such as water at a temperature of 0°C to 25°C. C, and the reaction is generally carried out for a period of 30 minutes to about 2 hours, preferably 10Ό for 30 minutes. A compound of formula XII is prepared by reaction of the above diazonium intermediate with a compound of formula XVII: R⁸O(C=O)N(C=O)CH2(C=O)N(C=O)OR⁸, in basic conditions. Typically, the reaction is carried out with sodium acetate as the base at a temperature of 0°C to 120°C, preferably 10°C, followed by heating to 120°C, and the reaction is generally carried out for a period of 1 hour to 24 hours, preferably 4 hours (Carrool, RD; et al.; J. Med. Chem., 1983, 26, 96-100).

The activity of the compounds of the invention for the various disorders described above can be determined according to one or more of the following assays. All compounds of the invention that were tested had an IC₆₀ less than 10 μΜ in the in vitro assay described below.

Preferably, the compounds of the invention have a Cl₅or in the in vitro assays described below less than 100 nM, more preferably less than 50 nM, and most preferably less than 10 nM. Furthermore, the compounds of the invention preferably have an IC₅₀ in the range of 0.01nM-100nM, more preferably between 0.05nM-50nM, and most preferably between 0.10nM-10nM.

PHARMACOLOGICAL ANALYSIS

Certain compounds such as benzoyl-benzoyl-adenosine triphosphate (bbATP) are known agonists of the P2X receptor.₇, which effect pore formation in the plasma membrane (Drug Development Research (1996), 37(3), p. 126). Consequently, when the receptor is activated using bbATP in the presence of ethidium bromide (a fluorescent DNA probe), an increase in the fluorescence of intracellular DNA-bound ethidium bromide is observed. Alternatively, ethidium bromide can be substituted for the propidium dye YOPRO-1 in order to detect uptake of the dye. The increase in fluorescence can be used as a measure of P2X receptor activation.₇ and therefore to quantify the effect of a compound on the P2X receptor₇.

In this way, the compounds of the invention can be tested for their antagonistic activity at the P2X receptor.₇. 96-well flat-bottomed microtiter plates are filled with 250 μΙ of test solution comprising 250 μΙ of a suspension of THP-1 cells (2.5 x 10⁶ cells/ml, most preferably pre-stimulated as described in the literature with a combination of LPS and TNF to promote receptor expression) containing 10' ethidium bromide⁴ M, 25 μΙ of a high potassium, low sodium buffer solution (10 mM Hepes, 150 mM KCI, 5 mM D-glucose, and 1.0% FBS pH 7.5) containing bbATP 10'⁵ M, and 25 μΙ of the high potassium buffer solution containing test compound 3 x 10'⁵ M (most preferably 5 x 10'⁴ M, more preferably 1 x 10⁴ M, and more preferably 1 x 10³ M). The plate is covered with a plastic sheet and incubated at 37°C for one hour. The plate is then read in a Perkin-Elmer fluorescent plate reader, excitation 520 nm, emission 595 nm, slit widths: Ex 15 nm, Em 20 nm. For comparison purposes, they can be used in the assay separately as controls bbATP (a P2X receptor agonist₇) and pyridoxal 5-phosphate (a P2X receptor antagonist₇). From the readings obtained, a pCI plot can be calculated₅₀ for each test compound, this plot being the reversed logarithm of the concentration of test compound required to reduce the activity of the bbATP agonist by 50%.

Similarly, compounds of the invention can be assayed for antagonistic activity at the P2X receptor.₇ using the cytokine 11-1β as a reporter. Blood collected from healthy volunteers is fractionated in the presence of heparin using lymphocyte separation medium obtained from Organon Technica (Westchester, PA). The resulting region of the gradient containing banded mononuclear cells is collected, diluted with 10 mL of maintenance medium (RPMI1640, 5% FBS, 25 mM Hepes, pH 7.2, 1% penicillin/streptomycin) and cells are collected by centrifugation. The resulting cell pellet was suspended in 10 ml of maintenance medium and cell counts were performed. In an average experiment, 2 x 10⁵ mononuclear cells in each well of 96-well plates in a total volume of 0.1 ml. Monocytes are allowed to adhere for 2 hours, after which the supernatants are discarded and the attached cells are washed twice and then incubated in maintenance medium overnight at 37°C in CO medium.₂ at 5%.

Cultured monocytes can be activated with 10 ng/ml LPS (E. coli serotype 055:B5; Sigma Chemicals, St. Louis, MO). After a 2 hour incubation, the activation medium is removed, cells are washed twice with 0.1 ml Chase medium (RPMI 1640.1% FBS, 20 mM Hepes, NaHCO₃5 mM, pH 6.9), then 0.1 ml of Chase medium containing a test agent is added and the plate is incubated for 30 minutes; each concentration of test agent can be evaluated in triplicate wells. ATP (from 100 mM stock, pH 7) is then introduced to a final concentration of 2 mM and the plate is incubated at 37°C for a further 3 hours. Media is collected and clarified by centrifugation and its IL-1 β content is determined by ELISA (R&amp;D Systems; Minneapolis, MN).

The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (eg, intravenous, intramuscular, or subcutaneous), topical, or rectal administration, or in a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (eg, lactose, microcrystalline cellulose, or calcium phosphate); lubricants (eg, magnesium stearate, talc, or silica); disintegrants (eg, potato starch or sodium starch glycolate), or wetting agents (eg, sodium laurel sulfate). Tablets can be coated by methods well known in the art. Liquid preparations for oral administration may be in the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (eg, sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifying agents (eg, lecithin or acacia); non-aqueous vehicles (eg, almond oil, oily esters, or ethyl alcohol); and preservatives (eg, methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may be in the form of conventionally formulated tablets or lozenges.

Compounds of formula I may also be formulated for controlled administration according to methods well known to those skilled in the art. Examples of such formulations can be found in US Patents 3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397, which are incorporated herein by reference in their entirety.

The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization or infusion techniques. Formulations for injection may be presented in unit dosage form, eg, in ampoules or multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg, sterile, pyrogen-free water, prior to use.

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

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently administered as a solution, dry powder formulation or suspension contained in a pump spray container that is squeezed or pumped by the patient or as a spray presentation. by aerosol in a pressurized container or a nebuliser, using a suitable propellant, eg dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to discharge a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (prepared, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to an adult human of average weight for the treatment of the above-referred disorders (inflammation) is 0.1 to 200 mg of the active ingredient per unit dose which it could be administered, for example, 1 to 4 times daily.

The compound of formula (I) and its pharmaceutically acceptable salts and solvates may be used as such, but will generally be administered in the form of a pharmaceutical composition in which the compound/salt/solvate of formula (I) (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight (weight percentage), more preferably from 0.10 to 70% by weight, of active ingredient, and from 1 to 99.95% by weight, more preferably from 30 to 99.90% by weight, of a pharmaceutically acceptable adjuvant, diluent or carrier, all weight percentages being based on the total composition.

Aerosol formulations for the treatment of the above-referenced disorders in the average-weight adult human are preferably arranged so that each metered dose or aerosol puff contains 20 pg to 1,000 pg of the compound of the invention. The total daily dose with an aerosol will be within the range of 100 pg to 10 mg. The administration can be carried out several times a day, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time.

Combination aerosol formulations for the treatment of the above-referenced conditions (eg, adult respiratory distress syndrome) in the average-weight adult human are preferably arranged so that each metered dose or aerosol pulsation contains about 1 pg to 1,000 pg of the compound of the invention. The total daily dose with an aerosol will be within the range of 100 pg to 10 mg. The administration can be carried out several times a day, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time.

Aerosol formulations for the treatment of the conditions referred to above (eg, adult respiratory distress syndrome) in the average-weight adult human are preferably arranged so that each metered dose or aerosol pulsation contains from about 20 pg to 1,000 pg of the compound of the invention. The total daily dose with an aerosol will be within the range of 100 pg to 10 mg of the P2X receptor inhibitor.₇. The administration can be carried out several times a day, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time.

This invention also encompasses pharmaceutical compositions containing and methods of treatment or prevention comprising administering prodrugs of the compounds of formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted to prodrugs. Prodrugs include compounds in which one amino acid residue, or a polypeptide chain of two or more (eg, two, three, or four) amino acid residues are covalently linked through peptide bonds to amino, hydroxy, or acid groups. carboxylic acid free of the compounds of formula I. Amino acid residues include the 20 naturally occurring amino acids commonly designated by three-letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine. and methionine-sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides, and alkyl esters are covalently attached to the above substituents of formula I through the carbonyl carbon-containing side chain of the prodrug.

The following Examples illustrate the preparation of the compounds of the present invention. Melting points are uncorrected. NMR data are expressed in parts per million (d) and are referenced to the deuterium key signal of the sample solvent (deuteriochloroform, unless otherwise specifically indicated). Mass spectral (MS) data were obtained using a Micromass ZMD APCI mass spectrometer equipped with a Gilson gradient high performance liquid chromatograph. The following solvents and gradients were used for analysis. Solvent A; 98% water/2% acetonitrile/0.01% formic acid and solvent B; acetonitrile containing 0.005% formic acid. Typically, a gradient was eluted over a period of about 4 minutes starting at 95% solvent A and ending at 100% solvent B. The mass spectrum of the principally eluting component was then obtained by scanning in positive or negative ion mode from a molecular weight range of 165 AMU to 1,100 AMU. Specific rotations were measured at room temperature using the sodium D line (589 nm). Commercial reagents were used without further purification. THF stands for tetrahydrofuran. DMF stands for Ν,Ν-dimethylformamide. Chromatography means column chromatography performed using 32-63 mm silica gel and carried out under nitrogen pressure (flash chromatography). Room or laboratory temperature refers to 20-25°C. All non-aqueous reactions were performed under a nitrogen atmosphere for convenience and to maximize yields. Concentration under reduced pressure means that a rotary evaporator was used.

One skilled in the art will appreciate that in some cases protecting groups may be necessary during preparation. Once the desired molecule is synthesized, the protecting group can be removed by methods well known to those skilled in the art, as described in Greene and Wuts, Protective Groups in Organic Synthesis (3rd edition, John Wiley &amp; Sons, 1999). ).

EXAMPLE 1

5-(4-Carbamo¡lmethyl-3,5-dioxo-4.5-d¡h¡dro-3H-[1,2,4ltr¡azin-2-¡l)-N-(1-h¡drox ¡C¡cloheDt¡lmethyl)-2methylbenzamide (A) 5-amlno-2-methylbenzo¡co acid hydrochloride salt

A suspension of 5-nitro-2-methylbenzoic acid (17.1 g, 94.4 mmol) and 10% Pd/C (500 mg) in EtOH (500 mL) was shaken at 2.8 kg/cm² (40 psi) of H₂ at room temperature for 4 hours. HCl was added and the solution was filtered through a pad of celite. The filtrate was concentrated in vacuo to give the title compound (17.2g).

(B) 2-(3-carbox¡-4-methylphenyl)-3,5-d¡oxo-2,3,4,5-tetrahydro-[1,2,4]tr¡az¡ acid n-6-carboxyHco

To a solution of 5-amino-2-methyl-benzoic acid hydrochloride salt (15.2 g, 81.2 mmol) in acetic acid (300 mL) was added concentrated HCl (21.0 mL). The resulting suspension was stirred at room temperature for 30 minutes. The reaction was then cooled to 10°C and a solution of sodium nitrite (6.17g, 89.4mmol) in water (5ml) was added dropwise. The reaction was stirred at 10°C for 30 minutes, then sodium acetate (14.7 g, 179.0 mmol) and acid ethyl ester (3-ethoxycarbon-lam-no-3-oxo-propion-1) were added. carbamide (J. Chem. Soc. Perkins Trans. I, 1991, 2317) (22.0 g, 89.4 mmol). The reaction was allowed to stir at 10°C for 20 minutes, then warmed to room temperature and stirred for 1 hour. Sodium acetate (6.7 g, 81.2 mmol) was then added and the reaction was refluxed for 14 hours. A 50% aqueous solution of H was added₂EITHER₄ (88.0 mL) and the reaction refluxed for 2 hours. The reaction was cooled and then water (50 ml) was added. The resulting tan precipitate was filtered, washed with water and dried to give the title compound (17.8g).

(C) 5-(3,5-d¡ oxo-4,5-d¡ hid ro-3H-[1,2,4]triazi n-2-yl)-2-methyl I benzoic acid

2-(3-Carboxy-4-methylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (110 g) was added to 8 volumes of water with 2.4 equivalents of sodium hydroxide and 1.1 equivalents of mercaptoacetic acid. The reaction mixture was heated at reflux (100-105Ό) for approximately 18 hours at which time the reaction was completed by HPLC. 30% Sodium hydroxide and toluene were added and the resulting mixture was stirred. Upon sedimentation, a large interface was observed. More water, toluene and some ethyl acetate were added. The interface was reduced in size. The aqueous layer was separated and treated with 2N HCI. ApH 2 solids precipitated and the suspension was cooled below 10°C. The solids were slowly filtered off and dried in a vacuum oven to give 69 g of the title compound.

(D) 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]tri azi n-2-i I)-N-(1-hydroxycycl or hepti I methyl) -2methylbenzamide

A suspension of 5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl)-2-methylbenzoic acid (5.0 g, 20.2 mmol), 1-aminomethylcycloheptanol.HCl (5.4 g, 30.3 mmol), EDCI (5.8 g) and DMAP (7.4 g, 60.6 mmol) in DMF (67.3 mL) was stirred at room temperature for 14 hours. The reaction was then poured into 1N HCI (50 mL) and diluted with water (15-fold). The aqueous phase was extracted with CH₂IC₂ (3 times). The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a tan solid. The crude product was recrystallized from CH₂IC₂ to give the title compound as an off-white solid (3.1 g).

(E) 5-(4-Carbamoylmethyl-3,5-d¡oxo-4,5-dihydro-3H-[1,2,4]-triazin-2-yl)-N-(1 hidroxic¡clohept ¡lmet¡l)-2-methylbenzam¡da

A suspension of 5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxycycloheptylmethyl)-2-methylbenzamide (200.0 mg, 0.537 mmol) and Cs₂CO₃ (290.3 mg, 0.891 mmol) was stirred in DMSO (1.79 mL, 0.3 M) at room temperature for 15 minutes. 2-Bromoacetamide (74.1 mg, 0.537 mmol) was added and the reaction stirred at room temperature for 14 hours. The reaction was diluted with water (15 times) and the aqueous phase was extracted with CH₂IC₂ (3 times). The organic phases are dried over sodium sulfate and concentrated, obtaining a tan oil. The crude product was triturated with IPE/Et₂O/CH₂IC₂to give the title compound as a tan solid (105 mg). LCMS (m/z) 430.5 M+1.

The compounds of Examples 2-43, identified in Table 1 below, can be prepared according to the method of Example 1.

TABLE 1

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 2</td><td>ύ Λ °oV Cl 0</td><td>5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]tnazin-2-¡l)- 2-chloro-N-[2-(2-chlorophenyl)ethyl]benzamide</td><td> 462,1</td>

<td> 3</td><td>0 —A °v ψΙγΥΐ Cl 0</td><td>2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(2methoxyethyl)-3,5-d¡oxo4,5-dihydro-3H- [1,2,4]triazin-2-yl]- benzamide</td><td> 463,2</td>

<td> 4</td><td>°A γΛχΑ Cl 0</td><td>5-[4-(2-Carbamoil- ethyl)-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N- [2-(2-chlorophenyl)ethyl]benzamide</td><td> 476,3</td>

<td> 5</td><td>°x W-¿</td><td>2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(2hydroxyethyl)-3,5-dioxo4,5-dihydro-3H- [1,2,4]triazin-2-yl]- benzamide</td><td> 449,4</td>

<td> 6</td><td>TO⁰ TO Wy?</td><td>2-Chloro-N-[2-(2-chloro- phenyl)ethyl]-5-[4-(3- hydroxypropyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]benzamide</td><td> 463,6</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 7</td><td>άΑ^{0 0} 1^No.ΦνΟ Cl 0</td><td>5-(4-Carbamoilmethyl- 3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-¡l)2-chloro-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 450,9</td>

<td> 8</td><td>—Λ Ύ+ο Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-[4(2-hydroxyethyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]benzamide</td><td> 437,9</td>

<td> 9</td><td>0 hA-A⁰ 1 wG Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-(4(2-methoxyethyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]benzamide</td><td> 451,7</td>

<td> 10</td><td>CH, 0 TO wX) Cl 0</td><td>2-Chloro-5-[4-(2- dimethylaminoethyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N(1-hydroxycycloheptylmethyl)benzamide</td><td> 464,5</td>

<td> 11</td><td>«G 1 °Ύ wX) Cl 0</td><td>2-Chloro-5-(4-cyanomethyl-3,5-dioxo4,5-dihydro-3H- [1,2,4]-triazin-2-yl)-N(1-hydroxycycloheptylmethyl)benzamide</td><td> 432,3</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 12</td><td>ho'-^'A °v I Cl 0</td><td>2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4(3-hydroxypropyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]benzamide</td><td> 451,4</td>

<td> 13</td><td>ηΧ'^Λ ICl 0</td><td>5-[4-(2-Aminoethyl)- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl]2-chloro-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 436,5</td>

<td> 14</td><td>either Cl 0</td><td>2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-(4oxiranylmethyl-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)benzamide</td><td> 449,5</td>

<td> 15</td><td>^ηύΟΛ^{0 0} 1 9X) Cl 0</td><td>5-[4-(2-Acetylaminoethyl)-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N(1-hydroxycycloheptylmethyl)benzamide</td><td> 478,4</td>

<td> 16</td><td>0 «ΜΓΎι OH ¿^..N Ό Cl 0</td><td>2-Chloro-5-[4-(2,3- dihydroxypropyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N(1-hydroxycycloheptylmethyl)benzamide</td><td> 467,4</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 17</td><td>W.M. Cl 0</td><td>2-Chloro-5-(3,5-dioxo- 4-phenethyl-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)- N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 497,5</td>

<td> 18</td><td>0 σώ Echo Cl 0</td><td>5-(4-Benzyl,3-5-dioxo- 4,5-dihydro-3H- [1,2,4]triazin-2-yl)-2chloro-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 483,5</td>

<td> 19</td><td>⁰ 1 Cl 0</td><td>2-Chloro-5-[4-(2-cyano- ethyl)-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 446,5</td>

<td> 20</td><td>0 íYn wM Cl 0</td><td>2-Chloro-5-(3,5-dioxo- 4-pyridin-2-ylmethyl-4,5dihydro-3H-[1,2,4]- triazin-2-yl)-N-(1 - hydroxycycloheptylmethyl)benzamide</td><td> 484,4</td>

<td> 21</td><td>0 cr¿¡ Qy'O Cl 0</td><td>2-Chloro-5-(3,5-dioxo- 4-pyridin-3-ylmethyl-4,5dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 484,5</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 22</td><td>p OX Χ Χ ¿1 0</td><td>2-Chloro-5-(3,5-dioxo- 4-pyridin-4-ylmethyl-4,5dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 484,5</td>

<td> 23</td><td>Λ-Α⁰ 1 ςφΧ) ao</td><td>5-[4-(2-Carbamoyl-ethyl)- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]-triazin-2-yl]- 2-chloro-N-(1 hydroxycycloheptylmethyl)benzamide</td><td> 474,5</td>

<td> 24</td><td>—Λ TO_m-^No.oy wl CH₃ 0</td><td>N-(1 -Hydroxy- cycloheptylmethyl)-5-[4(2-hydroxyethyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-2methylbenzamide</td><td> 417,5</td>

<td> 25</td><td>0 «ο'-γ-',Λ ooh 'Mx CH₃ 0</td><td>5-[4-(2,3-Dihydroxy- propyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]- triazin-2-yl]-N-(1-hydroxycycloheptylmethyl)2-methylbenzamide</td><td> 447,3</td>

<td> 26</td><td>to gx CH₃ 0</td><td>5-[4-(2-Carbamoylethyl)- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl]- N-(1 -hydroxy- cycloheptylmethyl)-2methylbenzamide</td><td> 444,6</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 27</td><td>AND; Cl 0</td><td>5-[4-(3-Aminopropyl)- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl]- 2-chloro-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 450,4</td>

<td> 28</td><td>0 “Άϊ OH A zN Cl 0</td><td>2-Chloro-5-[4-(2,3- dihidrox¡prop¡l)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-¡l]-N- (1 -hydroxycycloheptyl- methyl)benzamide</td><td> 467,4</td>

<td> 29</td><td>Cl 0</td><td>Acid (2-{4-chloro-3-[2(2-chlorophenyl)ethylcarbamoyl]phenyl}-3,5dioxo-2,5-dihydro-3H[1,2,4]triaz¡n- tert-butyl ester 4-¡l)acetic</td><td> 519,7</td>

<td> 30</td><td>Ring w^ΛAND Cl 0</td><td>2-Chloro-5-[4-(2,3- dihydroxypropyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)-N- (1 -hydroxycycloheptyl- methyl)benzamide</td><td> 467,6</td>

<td> 31</td><td>TO? 0</td><td>5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)- 2-chloro-N-(1-cyanocycloheptylmethyl)benzamide</td><td> 459,3</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 32</td><td>rM® / y «H, G° H</td><td>N-Adamantan-1ylmethyl-5-(4-carbamoylmethyl-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin-2-yl)-2-chlorobenzamide</td><td> 473,0</td>

<td> 33</td><td>A® ΛN'Y 0 y® 0</td><td>5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)- 2-chloro-N-(4,4difluoro-1 -phenylcyclohexylmethyl)benzamide</td><td> 532,3</td>

<td> 34</td><td> 0</td><td>5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)- 2-chloro-N-(1 -p-tolyl- cyclohexylmethyl)benzamide</td><td> 510,4</td>

<td> 35</td><td>goes °y uX 1(1OH Cl 0</td><td>5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl)2-chloro-N-(1-hydroxycyclohexylmethyl)benzamide</td><td> 436,5</td>

<td> 36</td><td>ho X and 11 TO-^noQ&amp;O Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cyclohexylmethyl)-5-[4(2-hydroxyethyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-¡l]benzamide</td><td> 423,5</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 37</td><td> 9¹ h? ooh ζτφ V 0</td><td>2-Chloro-N-(1 -hydroxy- 3,3-dimethylcyclohexyl- methyl)-5-[4-(2-hydroxy- ethyl)-3,5-dioxo-4,5dihydro-3H-[1,2,4]triaz¡n-2-¡l]benzamide</td><td> 451,5</td>

<td> 38</td><td>φγΜΟ α ο</td><td>2-Chloro-N-(1 -hydroxy- cyclooctylmethyl)-5-[4-(2hydroxyethyl)-3,5-dioxo- 4,5-dihydro-3H- [1,2,4]triazin-2-yl]benzamide</td><td> 451,5</td>

<td> 39</td><td>Ηο-γ-Λ “ΆΑ ζλ CI 0</td><td>2-Chloro-5-[4-(2,3- dihydroxypropyl)-3,5dioxo-4,5-dihydro-3H[1,2,4]triazin-2-yl]-N-(1-hydroxycyclohexylmethyl)benzamide</td><td> 453,5</td>

<td> 40</td><td>0 ΡΡ Υ'Γ CH, 0</td><td>5-[4-(2,3-Dihydroxypropyl)-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl)2-methylbenzamide</td><td> 447,6</td>

<td> 41</td><td>“'χΑ °Π Α. /—\ CHj 0</td><td>5-[4-(2,3-Dihydroxy¡propyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl)2-methylbenzamide</td><td> 447,6</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 42</td><td>^Ηϊ&gt;Λ⁰ °^TOF vN 1nOH Cl 0</td><td>5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl)2-chloro-N-(1 -hydroxy- cyclooctylmethyl)benzamide</td><td>462.4 (M-1)</td>

<td> 43</td><td>π°—Λ α or</td><td>2-Chloro-N-(2-hydroxy- cycloheptylmethyl)-5-[4(2-hydroxyethyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-¡l]benzamide</td><td> 437,3</td>

<td> 44</td><td>0 oh^k_No.,N 'ςχο Cl 0</td><td>5-[4-(3-Amino-2- hydroxypropyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-2- chloro-N-(1 -hydroxy- cycloheptylmethyl)benzamide</td><td> 448,5</td>

EXAMPLE 45

2-Chloro-N-r2-(2-chlorofen¡l)et¡ll-5-(4-methylcarbamo¡lmet¡l-3.5-d¡oxo-4.5-d¡h¡dro-3H-[1.2 .4ltraz¡n-2· ¡Dbenzamide

<img file="ECSP055884A_D0055.tif" />

(A) (2-(4-chloro-3-[2-(2-chlorophenyl)ethylcarbamoyl]phenyl)-3,5-dioxo-2,5-dihydro3H-[1,2,4]triazin acid -4-¡ l)acetic

A solution of Example 34 (358 mg, 0.69 mmol) and TFA (1 mL) was stirred at room temperature for 18 hours. The solvent was removed in vacuo and excess TFA azeotroped off using CH₂IC₂ (3 times). The crude light brown solid was triturated in hexane to give the title compound (295mg).

(B) 2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-(4-methylcarbamoyl-methyl-3,5-dioxo-4,5-dihydro-3H-

[1.2.4] triazi η-2-yl)benzamide

A suspension of acid (2-{4-chloro-3-[2-(2-chlorophenyl)ethyl-carbamoyl]phenyl}-3,5-dioxo-2,5-dihydro-3H-

[1₃2.4]triazin-4-yl)acetic acid (71.4 mg, 0.154 mmol), methylamine.HCl (15.6 mg, 0.231 mmol), EDCI (44.4 mg, 0.231 mmol), and DMAP (75.5 mg, 0.616 mmol) in DMF (1.0 mL) was stirred at room temperature for 20 hours. The reaction was diluted with 1N HCI and allowed to stir for 5 hours. The crude product was filtered and triturated in hexane to give the title compound (20mg). LCMS (m/z) 476.1 M+1.

The compounds of Examples 46-60, identified in Table 2 below, can be prepared according to the method of Example 45.

TABLE 2

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 46</td><td>°°V W.M. Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-(4methylcarbamoylmethyl-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)benzamide</td><td> 464,8</td>

<td> 47</td><td>f Ϊ v'Vyi)⁰ TO_no-^no</td><td>2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-(4dimethylcarbamoylmethyl3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-¡l)benzamide</td><td> 490,1</td>

<td> 48</td><td>θνλ⁰ TO_No.'^noφγΧΛ Cl 0</td><td>2-Chloro-N-[2-(2-chloro- phenyl)ethyl]-5-[4-(2- morpholin-4-l-2-oxoethyl)- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl]- benzamide</td><td> 523,3</td>

<td> 49</td><td>°°Λ WxA Cl 0</td><td>2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[3,5-dioxo-4- (2-oxo-2-pyrrolidin-1 -ylethyl)-4,5-dihydro-3H- [1,2,4]triazin-2-yl]- benzamide</td><td> 516,3</td>

<td> 50</td><td>•sA-'-'A 0V WxA Cl 0</td><td>2-Chloro-N-[2-(2-chloro- phenyl)ethyl]-5-[4-(2-methylcarbamoylethyl)-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]- triazin-2-yl]benzamide</td><td> 490,9</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 51</td><td>0 0 oAY i 1' CH, Cl 0 44</td><td>2-Chloro-N-[2-(2-chlorophenyl)ethyl]-5-[4-(2-dimethylcarbamoylethyl)-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]- triazin-2-yl]benzamide</td><td> 504,5</td>

<td> 52</td><td>$ ^YyS⁰φγϋχΧχΛ α or 44</td><td>2-Chloro-N-[2-(2-chloro- phenyl)ethyl]-5-[3,5-dioxo-4- (2-oxo-2-piperazin-1 -ylethyl)-4,5-dihydro-3H- [1,2,4]triazin-2-yl]- benzamide</td><td> 531,5</td>

<td> 53</td><td>4γ4 °'Ί N-oO Cl 0</td><td>2-Chloro-5-(4-dimethyl- carbamoylmethyl-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)-N-(1 - hydroxycycloheptylmethyl)benzamide</td><td> 478,8</td>

<td> 54</td><td>⁰ &lt;Λ^ν¢1/30 Cl 0</td><td>2-Chloro-5-(4-ethyl- carbamoylmethyl-3,5dioxo-4,5-dihydro-3H[1,2,4]triazin-2-yl)-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 478,8</td>

<td> 55</td><td>^{0 0} 1 wN Cl 0</td><td>2-Chloro-5-[3,5-dioxo-4- (2-oxo-2-piperidin-1 -ylethyl)-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 518,8</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 56</td><td>θΆ Cl 0</td><td>2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-(4-(2morpholin-4-yl-2-oxoethyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2 -il]benzamide</td><td> 520,8</td>

<td> 57</td><td>ΫαΛ¹ or A Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-[4- (isopropylcarbamoylmethyl)-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin- 2-yl]benzamide</td><td> 492,8</td>

<td> 58</td><td>FrA^Ο°Ύ wX&gt; Cl 0</td><td>2-Chloro-5-[3,5-dioxo-4- (2-oxo2-pyrrolidin-1-ylethyl)-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1- hydroxycycloheptylmethyl)benzamide</td><td> 504,4</td>

<td> 59</td><td>^“ίτΛ ° ° 1 φγΟΟ Cl 0</td><td>2-Chloro-5-{4- [(cyclopropylmethylcarbamoyl)methyl]-3,5dioxo-4,5-dihydro-3H[1,2,4]triazin-2-yl}-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 504,4</td>

<td> 60</td><td>V^h' Yo ^ΥΫ1^{0 0} 1 0/5O CH, 0</td><td>5-(4-Dimethylcarbamoylmethyl-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin- 2-yl)-N-(1 -hydroxy- cycloheptylmethyl)-2methylbenzamide</td><td> 458,5</td>

EXAMPLE 61

2-Chloro-N-(1-h¡drox¡c¡cloheDt¡lmet¡l)-5-[4-(2-h¡drox¡-3-methox¡DroD¡l)-3,5-d¡ oxo-4,5-dihydro-3H-

[1,2,41triaz¡n-2-¡l]benzamida

<img file="ECSP055884A_D0056.tif" />

(A) 2-Chloro-N-(1-hydroxy¡c¡clohept¡lmethyl)-5-[4-(2-hidrox¡-3-methox¡prop¡l)-3,5-d¡oxo -4,5- dihydro-3H-[1,2,4]triazin-2-¡l]benzamide

5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxycycloheptylm ethyl)-2-methylbenzamide (1.77 g) was heated , 4.5 mmol) and R-(-)glycidyl-methyl-ether (2.5 mL, 27.8 mmol) in DMF (4.5 mL) at 60°C for 18 hours. The reaction was cooled, diluted with 1N HCI, and extracted with CH₂IC₂. The organic phases were combined, washed with saturated sodium bicarbonate solution, dried over sodium sulfate and charcoal, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (elution with EtOAc) and then recrystallized from ethyl acetate/hexane to give the title compound (1.62 g). LCMS (m/z) 479.5 M-1.

The compounds of Examples 62-99, identified in Table 3 below, can be prepared according to the method of Example 61.

TABLE 3

<td>EXAMPLE</td><td colspan="2">STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 62</td><td colspan="2">0 on_eitherTO_No..N 0/50 Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl]benzamide</td><td> 481,5</td>

<td> 63</td><td colspan="2">Q-.₌^either“0^9° X either X</td><td>2-Chloro-5-[4-(2,3dihydroxy-2-methylpropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl]-N- (1 -hydroxycycloheptylmethyl)benzamide</td><td> 481,6</td>

<td> 64</td><td>AND Cl 0</td><td>0 ooh</td><td>2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-[4-(2-hydroxy-2-methylpropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl]benzamide</td><td> 465,5</td>

<td> 65</td><td colspan="2">AND 0N 1 II oh ao</td><td>2-Chloro-N-(1 -hydroxy- cyclohexylmethyl)-5-[4-(2- hydroxy-2-methylpropyl)3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl]- benzamide</td><td> 451,5</td>

<td> 66</td><td>-¾ oV ΦυΜ ao</td><td>□ )H</td><td>2-Chloro-N-(1 -hydroxy- cyclooctylmethyl)-5-[4-(2- hydroxy-2-methylpropyl)3,5-dloxo-4,5-dihydro3H-[1,2,4]triaz¡n-2-¡l]benzamide</td><td> 479,4</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 67</td><td>HC ^OH r· (/v ao</td><td>2-Chloro-N-(1 -hydroxy- cyclooctylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl]benzamide</td><td> 495,6</td>

<td> 68</td><td>íwo Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-[4-(2hydroxy-3-methoxypropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl]benzamide</td><td>479.4 (M-1)</td>

<td> 69</td><td>χΛ ΦτΧ Cl or</td><td>2-Chloro-N-(1 -hydroxy- cyclohexylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triaz¡n-2-yl]benzamide</td><td> 467,5</td>

<td> 70</td><td>WO Cl 0 —'</td><td>2-Chloro-N-(1 -hydroxy- cyclooctylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl]benzamide</td><td> 495,6</td>

<td> 71</td><td>OH A , N - +=í Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cyclopentylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triaz¡n-2-¡l]benzamide</td><td> 453,5</td>

<td>EXAMPLE</td><td colspan="2">STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 72</td><td colspan="2">and 4-0 Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cyclopentylmethyl)-5-[4-(2- hydroxy-2-methylpropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl]benzamide</td><td> 437,4</td>

<td> 73</td><td>%TO'^bW- Cl 0</td><td>P ooh</td><td>2-Chloro-N-(1 -hydroxy- cyclopentylmethyl)-5-[4-(2hydroxy-3-methoxypropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl]benzamide</td><td> 453,5</td>

<td> 74</td><td colspan="2">^-'-χΛ„ yao</td><td>2-Chloro-N-(1 -hydroxy- cyclobutylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl]benzamide</td><td> 439,5</td>

<td> 75</td><td>-Yo_xΦζ Cl 0</td><td></td><td>2-Chloro-N-(1-hydroxycyclobutylmethyl)-5-[4-(2-hydroxy-2-methylpropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl]benzamide</td><td> 423,3</td>

<td> 76</td><td colspan="2">^0h° ϊ^No. Cl φγ“” Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cyclopentylmethyl)-5-[4-(2-hydroxy-3-methoxypropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triaz¡n-2-¡l]benzamide</td><td> 453,5</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 77</td><td>'Χσ'γ'.Α oh χΐχ_X N\ 0 year</td><td>2-Chloro-5-[4-(2-hydroxy-3-methoxypropyl)-3,5-dioxo4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxymethylcycloheptylmethyl) benzamide</td><td> 495,4</td>

<td> 78</td><td>0 HO I Hee / í il orph^No. r.f. Φυ^{n 0}Cl 0</td><td>2-Chloro-N-(1 -hydroxy- methylcycloheptylmethyl)-5[4-(2-hydroxy-2-methylpropyl)-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin2-yl]benzamide</td><td> 479,4</td>

<td> 79</td><td>loo Φμο Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-[4-(2-hydroxy-2-phenylethyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]benzamide</td><td> 513,4</td>

<td> 80</td><td>Orph H = | II^oohorph^No.ÍW Cl 0</td><td>2-Chloro-N-(1-hydroxycycloheptylmethyl)-5-[4-(2hydroxy-2-phenylethyl)-3,5dioxo-3,5-dihydro-3H- [1,2,4]triazin-2-yl]benzamide</td><td> 513,3</td>

<td> 81</td><td>-GOES No. Φ/ΌCl 0</td><td>2-Chloro-5-[4-(3-ethoxy¡-2-hydroxypropyl)-3,5-dioxo4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl )benzamide</td><td> 495,4</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 82</td><td>mmm</td><td>2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-[4-(2- hydroxy-3-isopropoxy- propyl)-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin2-11]benzamide</td><td> 509,4</td>

<td> 83</td><td>oh₀TO_no^ ÍMO</td><td>5-[4-(3-tert-Butox¡-2hydroxypropyl)-3,5-d¡oxo4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro- N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 523,4</td>

<td> 84</td><td>Ai¹?- ^rCl 0</td><td>2- Chloro-N-[2-(2-chloro- phenyl)ethyl]-5-[4-(2-hydroxy- 3- methoxypropyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]- benzamide</td><td> 494,4</td>

<td> 85</td><td>ύΆ^FfSA'^noulO THHO Cl 0</td><td>2-Chloro-5-[3,5-dioxo-4- (3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-3H[1,2,4]triazin-2-yl]-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 505,3</td>

<td> 86</td><td>“oAz Λ)^hCl 0</td><td>2-Chloro-N-(1 -hydroxycycloheptylmethyl)-5-[4-(2hydroxy-3,3-dimethylbutyl)- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl]- benzamide</td><td> 493,4</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 87</td><td>Cl 0</td><td>acid methyl ester 3-(2-{4-chloro-3-[(1-hydroxycycloheptylmethyl)carbamoyl]phenyl}-3,5dioxo-2,5-dihydro-3H- [1,2,4]triazin-4-yl)-2- hydroxy-2-methylpropionic</td><td> 509,4</td>

<td> 88</td><td>___X TO'^No. ¿( ^No. || J OH Y Jn / \ Cl 0</td><td>2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-[4-(2-hydroxy-3-morpholin-4-ylpropyl)-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin- 2-¡l]benzamide</td><td> 536,4</td>

<td> 89</td><td>p fYYryS M^W_EITHERAND^No.</td><td>5-[4-(3-Benzyloxy-2-hydroxypropyl)-3,5-dioxo4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1-hydroxycycloheptylmethyl)benzamide</td><td> 557,4</td>

<td> 90</td><td>°-O xz TO</td><td>2-Chloro-N-[2-(2-chloro- phenyl)ethyl]-5-[4-(2-hydroxy2-methylpropyl)-3,5-dioxo- 4,5-dihydro-3H[1,2,4]- triazin-2-yl]benzamide</td><td> 478,3</td>

<td> 91</td><td>hoh x,.n⁰ Ϊ ws5</td><td>2-Chloro-N-[2-(2-chloro- phenyl)ethyl]-5-[4-(2-hydroxy2-phenylethyl)-3,5-dioxo-4,5dihydro-3H-[1,2,4]triazin2-¡l]benzamide</td><td> 525,5</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 92</td><td>^cW tOl/NHHO ¿I 0</td><td>2-Chloro-N-(2-hydroxy¡- cycloheptylmethyl)-5-[4-(2- hydroxy-2-methylpropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl]benzamide</td><td> 465,4</td>

<td> 93</td><td>⁰ Ϊ Ϋ-0^Cl 0 HO</td><td>2-Chloro-N-(2-hydroxy- cycloheptylmethyl)-5-[4-(2-hydroxy-2-phenylethyl)-3,5dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-¡l]benzamide</td><td> 513,4</td>

<td> 94</td><td>vo-xA “ W /a ά/τ Cl 0</td><td>2-Chloro-N-(2-hydroxy¡cycloheptylmethyl)-5-[4-(2hydroxy-3-methoxypropyl)3,5-dioxo-4,5-dihydro3H-[1,2,4]triazin-2-yl ]benzamide</td><td> 481,4</td>

<td> 95</td><td>μμΛ “ar M] rr^b</td><td>2-Chloro-5-[4-(2-hydroxy-3- methoxypropyl)-3,5-dioxo4,5-dihydro-3H-[1,2,4]- triazin-2-¡l]-N-(2-hydroxy- 2-phenylethyl)benzamide</td><td> 475,3</td>

<td> 96</td><td>'\X¿ CT No. íll Η Π-./* ΥΎ^NXMp) α or AA</td><td>2-Chloro-5-[4-(2-hydroxy¡-3- methoxypropyl)-3,5-d¡oxo- 4,5-dihydro-3H-[1,2,4]- triazin-2-¡l]-N-(2-h¡drox¡- 2-phenylethyl)benzamide</td><td> 475,3</td>

<td>EXAMPLE</td><td>STRUCTURE</td><td>NAME</td><td>DATA LCMS M/Z</td>

<td> 97</td><td>0 HC II eleven «N,1 No. Qxñ ao</td><td>2-Chloro-5-[4-(2-hydroxy-2methylpropyl)-3,5-dioxo4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(2-hydroxy2- phenylethyl)benzamide</td><td> 459,3</td>

<td> 98</td><td>χΜ Wn Cl 0</td><td>2-Chloro-5-[4-(2-hydroxy¡-3- methoxypropyl)-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]- triazin-2-yl]-N-phenethyl- benzamide</td><td> 459,2</td>

<td> 99</td><td>ncA WX year</td><td>2-Chloro-5-[4-(2-hydroxy¡-2methylpropyl)-3,5-dioxo4,5-dihydro-3H-[1,2,4]triazin-2-¡l]-N-(2- hydroxy- 2-phenylethyl)benzamide</td><td> 459,3</td>

The present invention is not limited in its scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the above description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

All patents, applications, publications, test methods, literature citations, and other materials cited herein are incorporated simply by reference in their entirety.