OA12978A - 3-(3,5-dioxo-4,5-dihydro-3H-(1,2,4)triazin-2-yl)-benzamide derivatives as P2X7-inhibitors for the treatment of inflammatory disesses. - Google Patents

3-(3,5-dioxo-4,5-dihydro-3H-(1,2,4)triazin-2-yl)-benzamide derivatives as P2X7-inhibitors for the treatment of inflammatory disesses. Download PDF

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OA12978A
OA12978A OA1200500193A OA1200500193A OA12978A OA 12978 A OA12978 A OA 12978A OA 1200500193 A OA1200500193 A OA 1200500193A OA 1200500193 A OA1200500193 A OA 1200500193A OA 12978 A OA12978 A OA 12978A
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alkyl
hydroxy
dioxo
dihydro
chloro
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OA1200500193A
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Dombroski Mark Anthony
Duplantier Allen Jacob
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Pfizer Prod Inc
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Publication of OA12978A publication Critical patent/OA12978A/fr

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Description

1 Ο 1 297 8
3-(3,5-DIOXO-4,5-DIHYDRO-3H- (1,2,4)TRIAZIN-2-YL)-BENZAMIDE DERIVATIVES AS Ρ2Χ7-INHIBITORS FOR THE TRATMENT OF INFLAMMMATORY DISEASES ισ 15 20 25
The présent invention relates to novel benzamide inhibitors of the P2X7 receptor,processes for their préparation, intermediates useful in their préparation, pharmaceuticalcompositions containing them, and their use in therapy. The active compounds of the présentinvention are useful in the treatment of inflammatory diseases such as osteoarthritis andrheumatoid arthritis; allergies, asthma, COPD,. cancer, reperfusion or ischemia in stroke orheart attack, autoimmune diseases and other disorders. The active compounds are alsoantagoniste of the P2X7 receptor.
The P2X7 receptor (previously known as P2Z receptor), which is a ligand-gated ionchannel, is présent on a variety of cell types, largely those known to be involved ininflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T andB). Activation of the P2X7 receptor by extracellular nucléotides, in particular adenosinetriphosphate, leads to the release of interleukin-ΐβ (IL-Ιβ) and giant cell formation(macrophages/microglial cells), degranulation (mast cells) and prolifération (T cells),apoptosis, and L-selectin shedding (lymphocytes). P2X7 receptors are also located onantigen-presenting cells (APC), kératinocytes, salivary acinar cells (parotid cells), hépatocytesand mesangial cells. P2X7 antagoniste are known in the art, such as those described in InternationalPatent Publications WO 01/46200, WO 01/42194, WO 01/44213, WO99/29660, WO00/61569, WO 99/29661, WO 99/29686, WO 00/71529·, and WO 01/44170, as well as inUSSN 60/336,781 (attorney docket number PC23106A, filed November 12, 2002).
Benzamides, heteroarylamides and reverse amides for uses other than inhibition ofthe P2X7 receptor are described in various publications, such as International PatentPublications WO 97/22600, EP 138,527, WO 00/71509, WO 98/28269, WO 99/17777 andWO 01/58883.
SUMMARY OF THE INVENTION
The présent invention relates to a compound of the formula 30
wherein R1 is (CrCeJalkyl, optionally substituted by (C3-C10)cycloalkyl, (C6-C10)aryl, (Ci- C10)heterocyclyl, or (Ci-Cio)heteroaryl, wherein each of said (CrC6)alkyI, (C3-C10)cycloalkyl, (C6-Cio)aryl, (CrCioJheterocyclyl, or (Ci-C10)heteroaryl are optionally substituted by one to three suitable moieties independently selected from the group consisting of hydroxy, halogen,
Ü1297 8 -2- CN-, (CrCe)alkyl, HO(CrC6)alkyl, (C1-C6)alkyl-NH(C=O)-1 NH2(C=O)-, (CrC6)alkoxy, or (C3-Cio)cycloaikyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (CrCiOalkyl-; R2 is hydrogen, halogen, -CN, and (Ci-C6)alkyl, wherein said (C^CeJalkyl is optionally5 substituted by one to three suitable moieties, independently selected from the groupconsisting of halo, hydroxy, amino, -CN, (CrCeJalkyl, (Ci-C6)alkoxy, -CF3, CF3O-,(CrCgJalkyl-NH-, [(CrCejalkylk-N-, (CrC6)alkyl-S-, (CrCeJalkyl-iSO)-, (CrCûalkyl-fSOz)-, (CrCeJalkyl-O-ÎC^)-, formyl, (C-i-CgJalkyl-fC^)-, and (C3-C6)cycloalkyl; and
R3 is a suitably substituted nitrogen linked (CrC-ioJheterocyclyl of the formula:O 10 (||) or the pharmaceutically acceptable salts or solvatés or prodrugs thereof.The présent invention also relates to a compound of the formula R2 o
H wherein R1 is (CrC6)alkyl, optionally substituted by (C3-C,0)cycloalkyl, (C6-C10)aryl, (C-j-15 Cio)heterocyclyl, or (C^C-ioJheteroaryl, wherein each of said (Cï-CeQalkyl, (C3-C10)cycloalkyl, (C6-C10)aryl, (Ci-C10)heterocyclyl, or (CrC10)heteroaryl are optionally substituted by one tothree suitable moieties independently selected from the group consisting of hydroxy, halogen,CN-, (CrC6)alkyl, HO(C.,-C6)alkyl, (C1-Ce)alkyl-NH(C=O)-, NH2(C=O)-, (CrC^alkoxy, or (C3-Cio)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or more 20 moieties selected from halogen, or (CrC^alkyl-; R2 is hydrogen, halogen, -CN, and (C-rC^alkyl, wherein said (CrCejalkyl is optionally substituted by one to three suitable moieties, independently selected from the groupconsisting of halo, hydroxy, amino, -CN, (CrCeJalkyl, (CrC6)alkoxy, -CF3, CF3O-,(CrCeJalkyl-NH-, [(C1-C6)alkyl]2-N-, (C,-C6)alkyl-S-, (CrCeJalkyl-^O)-, (C1-C6)alkyl-(SO2)-, 25 (C1-C6)alkyl-O-(C=O)-, formyl, (Ci-C6)alkyl-(C=O)-, and (C3-C6)cycloalkyl; R3 is a nitrogen linked (Ci-C10)heterocyclyl of the formula: 012978 -3- ο r7\ JL /R4
N
I 'Zv^- (III) wherein R4 is selected from the group of suitable substitueras, such as hydrogen, halo,hydroxy, -CN, HO-iCrCfOalkyl, (C^CeJalkyl optionally substituted with one to three fluoro, (C,-C6)alkoxy optionally substituted with one to three fluoro, HO2C-, (C1-C6)alkyl-O-(C=O)-,R5R6N(O2S)-, (CrC6)alkyl-(O2S)-NH-, (CrCeJalkyl-OzS-KC^CsJalkyl-NJ-, RSR6N(C=O)-,R5R6N(CH2)m-, (C6-C10)aryl, (C3-C8)cycloalkyl, (CrC^Jheteroaryl, (Ci-C10)heterocyclyl, (C6-C10)aryl-O-, (C3-C8)cycloalkyl-O-, (Ci-C10)heteroaryl-O- and (C1-Ci0)heterocyclyl-O-; and R7 is selected from the group of suitable substituents such as hydrogen and (CrC6)alkyl optionally substituted with one to three halogens, hydroxy, -CN, (C1-C6)alkoxy-, (C2-C6)alkenoxy, (CrCeJalkyl-SOz-, NH2-, ((CrC^alkylVN-, ((C2-C6)alkenyl)n-N-, ((C2-C6)alkynyl)n-N-, NH2(C=O)-, (CrC6)alkyl-(C=O)N-, ((C1-C6)alkyl)n-N-(C=O)-, (C2-C6)alkenyl-(C=O)N-, ((C2-C6)alkenyl)n-N-(C=O)-, (C2-C6)alkynyl-(C=O)N-, ((C2-C6)alkynyl)n-N-(C=O)-,(CrCeJalkyl-iCO)-, (C2-C6)alkenyl-(C=O)-, (C2-C6)alkynyl-(C=O)-, (C3-C10)cycloalkyl-(C=O)-,((C1-C10)heterocyclyl-(C=O)-, (C6-C10)aryl-(C=O), (CrC10)heteroaryl-(C=O), (CvCeJalkyl-(C=O)O-, (C2-C6)alkenyl-(C=O)O-, (C2-C6)alkynyf-(C=O)O-, (C1-C6)alkyl-O(C=O)-, (C2- C6)alkenyl-O-(C=O)-, (C2-C6)alkynyl-O-(C=O)-, (C3-C10)cycloalkyl, (C6-C10)aryl,(Ci-Cio)heterocyclyl, and (C1-C10)heteroaryl; wherein R4 and R7 may each be optionally substituted on any aliphatic or aromaticcarbon atom by one to three suitable moieties, independently selected from the groupconsisting of halo, hydroxy, amino, -CN, (CrC6)alkyI, (C.,-C6)alkoxy, -CF3, CF3O-,(C1-C6)alkyl-NH-, [(CrCeJalkylfe-N-, (C.,-C6)alkyl-S-, (CrCeJalkyHSO)-, (CrC^alkyl-iSOz)-,(CvC^alkyl-O-^O)-, formyl, (CrCeJalkyl-iCsO)-, and (C3-C6)cycloalkyl; R5 and R6 are each independently selected from the group consisting of hydrogen,(CrC6)alkyl, HO-(C2-C6)alkyl and (C3-C8)cycloalkyl, or R5 and R6 may optionally be takentogether with the nitrogen atom to which they are attached to form a 3 to 8 memberedheterocycle; n is an integer from zéro to two; andm is an integer from one to two; or the pharmaceutically acceptable salts or solvatés or prodrugs thereof.
The présent invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to préparé the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are 012978 -4- those which form non-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the 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, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The invention also relates to base addition salts of formula I. The Chemical bases thatmay be used as reagents to préparé pharmaceutically acceptable base salts of thosecompounds of formula I that are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limited to those derived fromsuch pharmacologically acceptable cations such as alkali métal cations (e.g., potassium andsodium) and alkaline earth métal cations (e.g., calcium and magnésium), ammonium or water-soluble amine addition salts such as N-methyiglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptable organic amines.
This invention also encompasses pharmaceutical compositions containing prodrugs ofcompounds of the formula I. Compounds of formula I having free amino, amido, hydroxy Orcarboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein anamino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acidresidues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylicacid groups of compounds of formula I. The amino acid residues include the 20 naturallyoccurring amino acids commonly designated by three letter symbole and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocystéine, homoserine, omithine andméthionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates,amides and alkyl esters which are covalently bonded to the above substituents of formula Ithrough the carbonyl carbon prodrug sidechain.
This invention also encompasses compounds of formula I containing protectivegroups. One skilied in the art will also appreciate that compounds of the invention can alsobe prepared with certain protecting groups that are useful for purification or storage and canbe removed before administration to a patient. The protection and deprotection of functionalgroups is described in “Protective Groups in Organic Chemistry”, edited by J.W.F. McOmie,Plénum Press (1973) and “Protective Groups in Organic Synthesis", 3rd édition, T.W. Greeneand P.G.M. Wuts, Wiley-lnterscience (1999).
The compounds of this invention include ali stereoisomers (e.g., cis and trans isomers) and ail optical isomers of compounds of the formula I (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers. -5-
012978
The compounds, salts and prodrugs of the présent invention can exist in severaltautomeric forms, including the enoi and imine form, and the keto and enamine form andgéométrie isomers and mixtures thereof. Ail such tautomeric forms are included within thescope of the présent invention. Tautomers exist as mixtures of a tautomeric set in solution.In solid form, usually one tautomer prédominâtes. Even though one tautomer may bedescribed, the présent invention includes ail tautomers of the présent compounds. Oneexample of a tautomeric structure is when R3 is a group of the formula
NH N'
One skilled in the art will appreciate that this group can also be drawn as its tautomer
OH
The présent invention also includes atropisomers of the présent invention.Atropisomers refer to compounds of formula I that can be separated into rotationally restrictedisomers.
The compounds of this invention may contain olefm-like double bonds. When suchbonds are présent, the compounds of the invention exist as cis and trans configurations and asmixtures thereof. A “suitable substituent" is intended to mean a chemically and pharmaceuticallyacceptable functional group i.e., a moiety that does not negate the biological activity of theinventive compounds. Such suitable substituents may be routinely selected by those skilled inthe 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, aikoxy groups, aryl orheteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy orheteroaralkoxy groups, HO-(C=O)- groups, amino groups, alkyl- and dialkylamino groups,carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groupsdialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkyisulfonyigroups, arylsulfonyl groups and the like. Those skilled in the art will appreciate that manysubstituents can be substituted by additional substituents. Further examples of suitable 0 1297 a -6- substituents include those recited in the définition of compounds of Formula I, including R1through R7, as defined hereinabove.
As used herein, the term “spiro" refers to a connection between two groupe,substituents etc., wherein the connection can be depicted according to the following formula
As used herein, the term "alkyl,” as well as the alkyl moieties of other groups referredto herein (e.g., alkoxy), may be linear or branched (such as methyl, ethyl, n-propyl, /sopropyl,n-butyl, /so-butyl, seconda/y-butyl, terf/a/y-butyl); optionally substituted by 1 to 3 suitablesubstituents as defined above such as fluoro, chloro, trifluoromethyl, (C^CeJalkoxy,(C6-Cio)aryloxy, trifluoromethoxy, difluoromethoxy or (CrC6)alkyl. The phrase “each of saidalkyl” as used herein refers to any of the preceding alkyl moieties within a group such alkoxy,alkenyl or alkylamino. Preferred alkyls include (CrC6)alkyl, more preferred are (C1-C4)alkyl, andmost preferred are methyl and ethyl.
As used herein, the term "cycloalkyl" refers to a mono, bicyclic or tricyclic carbocyclicring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl - andbicyclo[5.2.0]nonanyl, etc.); optionally containing 1 or 2 double bonds and optionally substitutedby 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl,(CrCeJalkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C^-Cejalkyl.
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
•i, : . >·'· ·!·. " i ,| 4·:,;.* J ; j i (allyl), Zso-propenyl, 2-methyl-1-propenyl, l-Hinènyi, tq&amp; ^}<e; optionally substituted by 1 to 3 suitable substituents as defined aboV^, such as fluoro, chloro, trifluoromethyl, (CrCB)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1-C6)alkyl.
As used herein, the term "alkynyl” is used herein to mean straight or branched hydrocarbon chain radicals having one triple bond including, but not limited to, ethynyl, propynyl, butynyt, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (CrC^alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (CrCeJalkyl. -7-
As used herein, the term “carbonyl" or “(0=0)" (as used in phrases such asalkylcarbonyl, alkyl-(C=O)- or alkoxycarbonyl) refers to the joinder of the >C=0 moiety to asecond moiety such as an alkyl or amino group (i.e. an amido group). Alkoxycarbonylamino(i.e. alkoxy(C=O)-NH-) refers to an alkyl carbamate group. The carbonyl group is also 5 equivalently defined herein as (C=O). Alkylcarbonylamino refers to groups such asacetamide.
As used herein, the term “oxo” is used herein to mean a double bonded oxygen (=O)radical wherein the bond partner is a carbon atom. Such a radical can also be thought as acarbonyl group. 10 As used herein, the term “(C1-C4)alkyl-O2S-[(C1-C4)alkyl-N]-“ is used herein to mean a radical of the formula alkyl O2S^ alkyl
As used herein, the term “aryl” means aromatic radicale such as phenyl, naphthyl,tetrahydronaphthyl, indanyl and the like; optionally substituted by 1 to 3 suitable substituents as 15 defined above such as fluoro, chloro, trifluoromethyl, (Ci-C6)alkoxy, (C6-C10)aryloxy,trifluoromethoxy, difluoromethoxy or (CrCe)alkyl.
As used herein, the term “heteroaryl” refers to an aromatic heterocyclic group usuallywith one heteroatom selected from O, S and N in the ring. In addition to said heteroatom, thearomatic group may optionally hâve up to four N atoms in the ring. For example, heteroaryl 20 group includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl,oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl,tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazoiyl (e.g., 1,2,3-oxadiazolyl),thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl,and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as 25 fluoro, chloro, trifluoromethyl, (Ci-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxyor (CrCe)alkyl. 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 carbonatoms and 1 to 4 hetero atoms selected from N, O, S(O)n or NR. Examples of such rings 30 include azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro- thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyi, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, and the like. Examples of -8- said monocyclic saturated or partially saturated ring Systems are tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl,piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidine, 1,3-thiazoIidin-3-yl, 1.2- pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl, 1.3- tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl, 1,2-tetrahydrodiazin-2-yl, 1.3- tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, 1,2,5-oxathiazin-4-yi and the like; optionallycontaining 1 or 2 double bonds and optionally substituted by 1 to 3 suitable substituents asdefined above such as fluoro, chloro, trifluoromethyl, (Ci-C6)alkoxy, (C6-Ci0)aryloxy,trifluoromethoxy, difluoromethoxy or (C1-C6)alkyl. Preferred heterocyclics includetetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
Nitrogen heteroatoms as used herein refers to N=, >N and -NH; wherein -N= refers toa nitrogen double bond; >N refers to a nitrogen containing two bond connections and -N refersto a nitrogen containing one bond. “Embodiment" as used herein refers to spécifie groupings of compounds or uses intodiscrète subgenera. Such subgenera may be cognizable according to one particularsubstituent such as a spécifie R1 or R3 group. Other subgenera are cognizable according tocombinations of various substituents, such as ail compounds wherein R2 is chloro and R1 is(CrC^alkyl, optionally substituted by (C3-C10)cycloalkyl. The phrase “in combination witheach of the aforementioned embodiments” refers to combinations of the identifiedembodiment with each embodiment previously identified in the spécification. Thus anembodiment of compounds wherein R1 is (Ci-C4)alkyl, optionally substituted by (C3-Cio)cycloalkyl “in combination with each of the aforementioned embodiments” refers toadditional embodiments comprising combinations with each embodiment previously identifiedin the spécification.
Thus, the invention provides compounds in which R1 is (CrCOalkyl, optionallysubstituted by (C3-C10)cycloalkyl; wherein said (C1-C4)alkyl or (C3-C10)cycloalkyl are optionallysubstituted by one to three suitable moieties independently selected from the group consistingof hydroxy, halogen, CN-, (CrC6)alkyl, HO(Ci-C6)alkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-,(Ci-C6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C1o)cycloalkyl is optionally substitutedby one or more moieties selected from halogen, or (C5-C6)alkyl-.
The invention further provides compounds in which R1 is (CrC4)alkyl, optionallysubstituted by (C6-C10)aryl; wherein said (CrC4)alkyl or (C6-C10)aryI are optionally substitutedby one to three suitable moieties independently selected from the group consisting ofhydroxy, halogen, CN-, (CrC6)alkyl, HO(CrCe)alkyl, (C5-C6)alkyl-NH(C=O)-, NH2(C=O)-, (C5-C6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (Ci-C6)alkyl-, 0 1 297 8 -9-
Moreover, the invention contemplâtes compounds in which R2 is halogen and (Ci-C6)alkyl, and preferably compounds in which R2 is chloro and methyl or ethyl.
In one embodiment of the invention, R3 is a nitrogen linked (Ci-C10)heterocyclyl offormula (III), wherein R4 is hydrogen and R7 is independently selected from the group ofsuitable substituents such as hydrogen and (Ci-C6)alkyl, wherein said (Ci-Cgjalkyl isoptionally substituted with one to three substituents independently selected from halo,hydroxy, -CN, (C^CeJalkoxy-, (C2-C6)alkenoxy, (Ci-C6)alkyl-SO2-, NH2-, (C1-C6)alkyl)n-N-,((C2-C6)alkenyl)n-N-, ((C2-C6)alkynyl)n-N-, NH2(C=O)-, (C1-C6)alkyl-(C=O)N-, ((CrC6)alkyl)n-N-(C=O)-, (C2-C6)alkenyl-(C=O)N-, ((C2-C6)alkenyl)n-N-(C=O)-, (C2-C6)alkynyl-(C=O)N-, ((C2-C6)alkynyl)n-N-(C=O)-, (C1-C6)alkyl-(C=O)-, (C2-C6)alkenyl-(C=O)-, (C2-C6)alkynyl-(C=O)-, (C3-C10)cycloalkyl-(C=O)-, ((Ci-C10)heterocyclyl-(C=O)-, (C6-C10)aryl-(C=O), (CrC^Jheteroaryl-(C=O), (Ci-C6)alkyl-(C=O)O-, (C2-C6)alkenyl-(C=O)O-, (C2-C6)alkynyl-(C=O)O-, (C,-C6)alkyl-O(C=O)-, (C2-C6)alkenyl-O-(C=O)-, (C2-C6)alkynyl-O-(C=O)-, (C3-Ci0)cycloalkyl, (C6-C10)aryl,(CrC 10)heterocyclyl, and (C-i-CwJheteroaryl; wherein R7 may optionally be substituted on anyring aliphatic or aromatic carbon atom by one to three suitable moieties, independentlyselected from the group consisting of halo, hydroxy, amino, -CN, (Ci-C4)alkyl, (C1-C4)alkoxy, -CF3, CF3O-, (CrC4)alkyl-NH-, [(C1-C4)aikyl]2-N-, (CrC4)alkyl-S-, (CrC4)alkyl-(S=O)-, (CrC4)alkyl-(SO2)-, (C1-C4)alkyl-O-(C=O)-, formyl, (C1-C4)alkyl-(C=O)-, and (C3-C6)cycloalkyl.
Another embodiment of the invention are compounds in which R7 is hydrogen. A further embodiment of the invention are compounds in which R3 is a nitrogen linked(Ci-C10)heterocyclyl of formula (lll), wherein R4 is hydrogen and R7 is (CrC4)alkyl optionallysubstituted with one to three substituents independently selected from halo-, hydroxy, -CN,(C1-C4)alkoxy-, (C2-C4)alkenoxy, and (Ci-C4)alkyl-SO2-. Preferably, R3 is a nitrogen linked(Ci-C10)heterocyclyl of formula (II), wherein R4 is hydrogen and R7 is (CrC4)alkyl optionallysubstituted with one to three substituents independently selected from halo-, hydroxy, -CN, or(CrC^alkoxy-,
Still further, the invention provides compounds in which R3 is a nitrogen linked (CrC10)heterocyclyl of formula (lll), wherein R4 is hydrogen and R7 is (CrC4)alkyl optionallysubstituted with one to three substituents independently selected from NH2-, (C1-C4)alkyl)n-N-,((C2-C4)alkenÿl)n-N-, ((C2-C4)alkynyl)n-N-, NH2(C=O)-, (CrC4)aikyl-(C=O)N-, .((C,-C4)alkyl)n-N-(C=O)-, (C2-C4)alkenyl-(C=O)N-, ((C2-C4)alkenyl)n-N-(C=O)-, (C2-C4)alkynyl-(C=O)N-, and((C2-C4)alkynyl)n-N-(C=O)-. Preferably, R3 is a nitrogen linked (C1-Ci0)heterocyclyl of formula(II), wherein R4 is hydrogen and R7 is (CfC^alkyl optionally substituted with one to threesubstituents independently selected from NH2-, (C1-C4)alkyl)n-N-, NH2(C=O)-, (C-,-C4)alkyl-(C=O)N-, and ((C1-C4)alkyl)n-N-(C=O)-.
The invention also provides compounds in which R3 is a nitrogen linked(C-,-Cio)heterocyclyl of formula (III), wherein R4 is hydrogen and R7 is (Ci-C4)alkyl optionally
012918 -10- substituted with one to three substitueras independently selected from (Ci-C4)alkyl-(C=O)-, (C2-C4)alkenyl-(C=0)-, (C2-C4)alkynyl-(C=O)-, (C3-C10)cycloalkyl-(C=O)-, ((C1-C10)heterocyclyl-(C=O)-, (C6-C10)aryl-(C=O), and (CrC10)heteroaryl-(C=O), andpreferably, R3 is a nitrogen linked (C1-C,0)heterocyclyl of formula (II), wherein R4 is bydrogen 5 and R7 is (Ci-C4)alkyl optionally substituted with one to three substituents independentlyselected from (C1-C4)alkyl-(C=O)-, (C3-C10)cycloalky|-(C=O)-, ((C1-C10)heterocyclyl-(C=O)-,(C6-C10)aryl-(C=O), and (C1-Ci0)héteroaryl-(C=O).
Another embodiment of the invention are compounds in which R3 is a nitrogen linked(C-,-Cio)heterocyclyl of formula (III), wherein R4 is hydrogen and R7 is (C1-C4)alkyl optionally 10 substituted with one to three substituents independently selected from (CrC4)alkyl-(C=O)O-,(C2-C4)alkenyl-(C=O)O-, (C2-C4)alkynyl-(C=O)O-, (CrC4)alkyl-O(C=O)-, (C2-C4)alkenyl-O-(0=0)-, and (C2-C4)alkynyl-O-(C=O)-. Preferably, R3 is a nitrogen linked (C^CioJheterocyclylof formula (II), wherein R4 is hydrogen and R7 is (C-,-C4)alkyl optionally substituted with one tothree substituents independently selected from (C1-C4)alkyl-(C=O)O- and (Ci-C4)alkyl- 15 0(0=0)-'
Furthermore, the invention provides compounds in which R3 is a nitrogen linked (Ci-Cio)heterocyclyl of formula (III), wherein R4 is hydrogen and R7 is (C1-C4)alkyl optionallysubstituted with one to three substituents independently selected from (C3-Ci0)cycloalkyl-,(C6-CiQ)aryl-, (C-i-C^Jheterocyclyl-, and (O1-C10)heteroaryl-. 20 The présent invention also provides compounds of formula (I) wherein R3 is a nitrogen linked (C^CicJheterocyclyl of formula (IV): and R7 is selected from the group consisting of: (IV)
Ο 1297 8
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (C-i-Cio)heterocyclyl of formula (IV), and R7 is
The présent invention also contemplâtes compounds of formula (I) wherein R3 is anitrogen linked (Ci-C10)heterocyclyl of formula (IV), and R7 is selected from the groupconsisting of: h3co'
h3co'
, and
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (C5- 10 C10)heterocyclyl of formula (IV), and R7 is
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (C·,-C10)heterocyclyl of formula (IV), and R7 is selected from: 0 1 297 8 -12- h2n
OH
Finally, the invention further provides compounds of formula (I) wherein R3 is a nitrogenlinked (Ci-C10)heterocyclyl of formula (IV), and RT * 7 is selected from:
The présent invention also provides compounds of formula (I) wherein R3 is a nitrogen linked (Ci-Cio)heterocyclyl of formula (IV), R7 is selected from the group consisting of:
OH
and R1 is selected from the group consisting of (Ci-C4)alkyl, optionally substituted by (C3- 10 Cio)cycloalkyl, wherein said (Ct-C4)alkyl or (C3-Cio)cycioalkyl are optionally substituted by one to three suitable moieties independentiy selected from the group Consisting of hydroxy, halogen, CN-, (C1-C6)alkyl, HO(CrC6jalkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-, (C,- 01297 8 -13- C6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted byone or more moieties setected from halogen, or (C1-C6)alkyl-.
The présent invention also provides compounds of formula (I) wherein R3 is anitrogen linked (Ci-C10)heterocyclyl of formula (IV), R7 is selected from the group consisting of:
and R1 is selected from the group consistirig of (CrC4)alkyl, optionally substituted by (C6-Cio)aryl, wherein said (Ci-C4)alkyl or (C6-C10)aryl are optionally substituted by one to threesuitable moieties independently selected from the group consisting of hydroxy, halogen, CN-,(CrCeJalkyl, HO(CrCe)alkyl, (CrCsJalkyl-NHiCO)-, NHZ(C=O)-, (CTCfOalkoxy, or (C3-Cio)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (CrC6)alkyl-.
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (C-i-C10)heterocyclyl of formula (IV), R7is
and R1 is selected from the group consisting of (Ci-C4)alkyl, optionally substituted by (C3-Cio)cycloalkyl, wherein said (C-i-C4)alkyl or (C3-Ci0)cycloalkyl are optionally substituted by oneto three suitable moieties independently selected from the group consisting of hydroxy,halogen, CN-, (CrC6)alkyl, HOiCrCeJalkyl, (C1-Ce)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C1o)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (CrCeJalkyl-.
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (C-i- C10)heterocyclyl of formula (IV), R7 is 0 1 297 8 -14-
and R1 is selected from the group consisting of (CrC^alkyl, optionally substituted by (C6-C10)aryl, wherein said (C-,-C4)alkyI or (C6-C10)aryl are optionally substituted by one to threesuitable moieties independently selected from the group consisting of hydroxy, halogen, CN-, 5 (CrCelalkyl, HO(C..,-C6)alkyl, (CrCeJalkyl-NhKCO)-, NH2(C=O)-, (CrC6)alkoxy, or (C3-Cio)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (C^-Cejalkyl-.
The présent invention also contemplâtes compounds of formula (I) wherein R3 is anitrogen linked (C1-C10)heterocyclyl of formula (IV), 10 R7 is selected from the group consisting of:
h3co t
OH
, and 15 and R1 is selected from the group consisting of (Ci-C4)alkyl, optionally substituted by (C3-C10)cycloalkyl, wherein said (C1-C4)alkyl or (C3-C10)cycloalkyl are optionally substituted by oneto three suitable moieties independently selected from the group consisting of hydroxy,halogen, CN-, (CrCeJalkyl, HO^-CfOalkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (Ci-C6)alkyl-.
The présent invention also contemplâtes compounds of formula (I) wherein R3 is anitrogen linked (C-i-CioJheterocyclyl of formula (IV), R7 is selected from the group consisting of: 20 Ο 1297 8 -15- h3co
OH
OH
OH
OH
,and
OH
OH and R1 is selected from the group consisting of (C^C^alkyl, optionally substituted by (C6-C10)aryl, wherein said (Ci-C4)alkyl or (C6-C10)aryl are optionally substituted by one to threesuitable moieties independently selected from the group consisting of hydroxy, halogen, CN-, 5 (CrCeJalkyl, HOtCrCeJalkyl, (C^C^alkyl-NHfC^)-, NH2(C=O)-, (C.,-C6)alkoxy, or (C3-Cio)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (Ci-C6)alkyl-.
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (CrC10)heterocyclyl of formula (IV), 10 R7 is and R1 is selected from the group consisting of (Ci-C4)alkyl, optionally substituted by (C3-Cio)cycloalkyl, wherein said (C^C^alkyl or (C3-C10)cycloalkyl are optionally substituted by oneto three suitable moieties independently selected from the group consisting of hydroxy, 15 halogen, CN-, (C1-C6)alkyl, HO(C1-C6)alkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (CrCeJalkyl-.
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (Ci-Cio)heterocyclyl of formula (IV), 20 R7 is and R1 is selected from the group consisting of (C1-C4)alkyl, optionally substituted by (C6-
Cio)aryl, wherein said (C.,-C4)alkyl or (C6-C10)aryl are optionally substituted by one to three suitable moieties independently selected from the group consisting of hydroxy, halogen, CN-, 0 1297 8 -16- (CrCeJalkyl, HO(C1-C6)alkyl, (CrC^alkyl-NHiCO)-, NH2(C=0)-, (CrCeJalkoxy, or (C3-C10)cycloalkyl, wherein said (C3-Ci0)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (Ci-C6)alkyl-.
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (CrC10)heterocyclyl of formula (IV), R7 is selected from: , and
OH and R1 is selected from the group consisting of (CrC^alkyl, optionally substituted by (C3-Cio)cycloalkyl, wherein said (CrC^alkyl or (C3-C10)cycloalkyl are optionally substituted by oneto three suitable moieties independently selected from the group consisting of hydroxy,halogen, CN-, (C1-C6)alkyl, HO^-C^alkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-, (C,-C6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (Ci-C6)alkyl-,
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (C-rC10)heterocyclyl of formula (IV), R7 is selected from:
OH and and R1 is selected from the group consisting of (CrC^alkyl, optionally substituted by (C6-Cio)aryl, wherein said (Ci-C4)alkyl or (C6-C10)aryl are optionally substituted by one to threesuitable moieties independently selected from the group consisting of hydroxy, halogen, CN-,(CrC6)alkyl, HOiC^CeJalkyl, (C.,-C5)alkyl-NH(C=O)-, NHZ(C=O)-, (CrCsJalkoxy, or (C3-Ci0)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (CrCeJalkyl-,
The invention further provides compounds of formula (I) wherein R3 is a nitrogen linked (CrC 10)heterocyclyl of formula (IV), R7 is selected from: 0 1 297 8 -17- 10
and R1 is selected from the group consisting of (Ci-C4)alkyl, optionally substituted by (C3-C10)cycloalkyl, wherein said (C-i-C4)alkyl or (C3-C10)cycloalkyl are optionally substituted by oneto three suitable moieties independently selected from the group consisting of hydroxy,halogen, CN-, (CrC8)alkyl, HO(C,-CB)alkyl, (CrC6)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)aîkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (CrC6)alkyl-.
Finally, the invention further provides compounds of formula (I) wherein R3 is a nitrogenlinked (CpCwJheterocyclyl of formula (IV), R7 is selected from:
o 15 and R1 is selected from the group consisting of (Cv^Jalkyl, optionally substituted by (C6-
Cio)aryl, wherein said (C1-C4)alkyl or (C6-C10)aryl are optionally substituted by one to three suitable moieties independently selected from the group consisting of hydroxy, halogen, CN-, (CrC6)alkyl, HOiCrCeJalkyl, (C1-Cs)alkyl-NH(C=O)-, NH2(C=O)-, (CrC^alkoxy, or (C3- -18- Ο 1297 8 C10)cycloalkyl, wherein said (C3-Cio)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (Ci-C6)alkyl-.
The présent invention also provides compounds of formula (I) wherein R3 is anitrogen linked (CrC10)heterocyclyl of formula (IV), R7 is selected from the group consisting of:
10 15 R2 is chloro, methyl or ethyl; and R1 is selected from the group consisting of (Ci-C4)alkyl, optionally substituted by(C3-Cio)cycloalkyl, wherein said (C^-C^alkyl or (C3-Ci0)cycloalkyl are optionally substituted byone to three suitable moieties independently selected from the group consisting of hydroxy,halogen, CN-, (C1-C6)alkyl, HO(CrC6)alkyl, (C^alkyl-NH^O)-, NH2(C=O)-, (C·,-C6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (C^-C^alkyk
The présent invention also provides compounds of formula (i) wherein R3 is anitrogen linked (C5-Ci0)heterocyclyl of formula (IV), R7 is selected from the group consisting of:
R2 is chloro, methyl or ethyl;
-19- 0 1297 8 and R1 is selected from the group consisting of (Ci-C4)alkyl, optionally substituted by(C6-C10)aryI, wherein said (CrC^alkyl or (C6-C1Q)aryl are optionally substituted by one tothree suitable moieties independently selected from the group consisting of hydroxy, halogen,CN-, (CrC6)alkyl, HO(CrC6)alkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)alkoxy, or (C3-Cio)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (CrCeJalkyl-.
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (CrC10)heterocyclyl of formula (IV), O-
R2 is chloro, methyl or ethyl; and R1 is selected from the group consisting of (CrC^alkyl, optionally substituted by(C3-C10)cycloalkyl, wherein said (Ci-C4)alkyl or (C3-C10)cycloalkyl are optionally substituted byone to three suitable moieties independently selected from the group consisting of hydroxy,halogen, CN-, (CrCB)alkyl, HO(C1-C6)alkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (Ci-C6)alkyk
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (C-i-C10)heterocyclyl of formula (IV), R2 is chloro, methyl or ethyl; and R1 is selected from the group consisting of (C1-C4)alkyl, optionally substituted by(C6-C10)aryl, wherein said (CrC4)alkyl or (C6-C10)aryl are optionally substituted by one tothree suitable moieties independently selected from the group consisting of hydroxy, halogen,CN-, (CrC6)alkyl, HO(C1-C6)aIkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (Ci-C6)alkyl-,
The présent invention also contemplâtes compounds of formula (I) wherein R3 is a nitrogen linked (C-i-C^heterocyclyl of formula (IV), R7 is selected from the group consisting of; 0 1 297 8 -20-
10
,and R2 is chloro, methyl or ethyl; and R1 is selected from the group consisting of (Ci-C4)alkyl, optionally substituted by(C3-C10)cycloalkyl, wherein said (C-rC^alkyl or (C3-C10)cycloalkyl are optionally substituted byone to three suitable moieties independently selected from the group consisting of hydroxy,halogen, CN-, (CrC6)alkyl, HOiCrC^aikyl, (C.,-C6)alkyl-NH(C=O)-, NH2(C=O)-, (CrCe)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (CrCeJalkyl-.
The présent invention also contemplâtes compounds of formula (I) wherein R3 is anitrogen linked (CrCuOheterocyclyl of formula (IV), R7 is selected from the group consisting of:
15
R2 is chloro, methyl or ethyl; and R1 is selected from the group consisting of (Ci-C4)alkyl, optionally substituted by (C6-Cio)aryl, wherein said (C1-C4)alkyl or (C6-Ci0)aryl are optionally substituted by one to three suitable moieties independently selected from the group consisting of hydroxy, halogen, CN-, (CrCeJalkyl, HOiCrCeJalkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)alkoxy, or (C3- 0 1297 8 -21-
Cio)cycloalkyl, wherein said (C3-C-io)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (CrC6)alkyl-.
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (CrC10)heterocyclyl of formula (IV), R7 is
R2 is chloro, methyl or ethyl; and R1 is selected from the group consisting of (Ci-C4)alkyl, optionally substituted by(C3-C10)cycloalkyl, wherein said (Ci-C4)alkyl or (C3-C10)cycloalkyl are optionally substituted byone to three suitable moieties independently selected from the group consisting of hydroxy,halogen, CN-, (CrC6)alkyl, HO^-CeJalkyl, (C^C^alkyl-NH^O)-, NH2(C=O)-, (C!-C6)alkoxy, or (C3-Ci0)cycloalkyl, wherein said (C3-C1o)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (Ci-C6)alkyl-,
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (CrCio)heterocyclyl of formula (IV), R7 is
R2 is chloro, methyl or ethyl; and R1 is selected from the group consisting of (C1-C4)alkyl, optionally substituted by(C6-C10)aryl, wherein said (Ci-C4)alkyl or (C6-C10)aryl are optionally substituted by one tothree suitable moieties independently selected from the group consisting of hydroxy, halogen,CN-, (CrCsJalkyl, HO^-Cfûalkyl, (C,-C6)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)alkoxy, or (C3-Cio)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (Ci-C6)alkyl-.
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (CrCio)heterocyclyl of formula (IV), R7 is selected from:
OH R2 is chloro, methyl or ethyl; -22- 0 1 297 8 and R1 is selected from the group consisting of (C^-C^alkyl, optionally substituted by(C3-C10)cycloalkyl, wherein said (C.,-C4)alkyl or (C3-C10)cycloalkyl are optionally substituted byone to three suitable moieties independently selected from the group consisting of hydroxy,halogen, CN-, (C.,-C6)alkyl, HO(C1-C6)alkyl, (CrC6)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)alkoxy, or (C3-Ci0)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (CrCelalkyl-.
Also provided are compounds of formula (I) wherein R3 is a nitrogen linked (C5-Cio)heterocyclyl of formula (IV), R7 is selected from:
R2 is chloro, methyl or ethyl; and R1 is selected from the group consisting of (CrC4)alkyl, optionally substituted by(C6-Cio)aryl, wherein said (C1-C4)alkyl or (C6-C10)aryl are optionally substituted by one tothree suitable moieties independently selected from the group consisting of hydroxy, halogen, 15 CN-, (C-|-C6)alkyl, HOfC^C^alkyl, (CrCgJalkyl-NH^O)-, NH2(C=O)-, (C1-C6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (CvCgJalkyl-.
The invention further provides compounds of formula (I) wherein R3 is a nitrogen linked(CrCwJheterocyclyl of formula (IV), 20 R7 is selected from:
R2 is chloro, methyl or ethyl; 01297 8 -23- and R1 is selected from the group consisting of (CrC-tJalkyl, optionally substituted by(C3-C10)cycloalkyl, wherein said (CrC4)aIkyi or (C3-C10)cycloalkyl are optionally substituted byone to three suitable moieties independently selected from the group consisting of hydroxy,halogen, CN-, (CrC6)alkyl, HO(C1-C6)alkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)alkoxy, or (C3-C10)cycloalkyl, wherein said (C3-Ci0)cycloalkyl is optionally substituted byone or more moieties selected from halogen, or (C1-C6)alkyl-,
Finally, the invention further provides compounds of formula (I) wherein R3 is a nitrogenlinked (C1-C10)heterocyclyl of formula (IV), R7 is selected from:
R2 is chloro, methyl or ethyl; and R1 is selected from the group consisting of (C^-C^alkyl, optionally substituted by(C6-C10)aryl, wherein said (CrC4)alkyl or (C6-C10)aryl are optionally substituted by one tothree suitable moieties independently selected from the group consisting of hydroxy, halogen,CN-, (CrCeJalkyl, HOCCrC^alkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-, (CrC6)alkoxy, or (C3-Cio)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (Ci-C6)alkyl-.
Examples of other compounds of formula I are the following: 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methanesulfonylamino-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-5-[4-(2-formylamino-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1 -hydroxy-cycloheptylmethyl)-benzamide; 5-[4-(1-Amino-cyclopropylmethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2- chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(1-hydroxy-cyclopropylmethyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 0 1297 8 -24- 5-[4-(2-Amino-2-methyl-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1 -hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-[4-(3-difluoromethoxy-2-hydroxy-propyl)-3,5-dioxo-4,5-dibydro-3H- [1.2.4] triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzaniide; N-(1-Hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-methyl-benzamide; 5-[4-(2-Hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2>4]triazin-2-yl]-N-(1- hydroxymethyl-cycloheptylmethyl)-2-methyl-benzamide; N-(1-Hydroxy-cyclohexylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yI]-2-methyl-benzamide; 1- ({2-Chloro-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H- [1.2.4] triazin-2-yl]-benzoylamino}-methyl)-ycloheptanecarboxyIicacid amide; 2- Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N- (l-hydroxymethyl-cycloheptylmethyl)-benzamide; 1- ({2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzoylamino}-methyl)-cycloheptanecarboxylic acid amide; 2- Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2l4]triazin-2-yl]-N-phenethyl-benzamide; 2-Chloro-5-[4-(2,3-dihydroxy-propyi)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(l-hydroxy-cÿclohexylmethyl)-benzamide; 2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N- (l-hydroxy-cyclopentylmethyl)-benzamide; 2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yI]-N-(1 -hydroxy-cyclobutylmethyl)-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-trifluoromethoxy-propyl)- 3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yI]-benzamide; 2-Chioro-5-[4-(2-hydroxy-butyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 5-[4-(2-Amino-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1- hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-[3,5-dioxo-4-(2-oxo-propyl)-4,5-dihydro-3H-[1,2,4]triazin-2-ylJ-N-(1- hydroxy-cycloheptylmethyl)-benzamide; 0 1297 8 -25- 2-Chioro-5-[3,5-dioxo-4-(2-oxo-ethyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-( 1 -hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-[3,5-dioxo-4-(2-trifluoromethoxy-ethyl)-4l5-dihydro-3H-[1,2l4]triazin-2-yl]- N~(1-hydroxy-cycloheptylrnethyl)-benzamide; 2-Chloro-5-[4-(1-hydroxy-cyciobutylmethyl)-3,5-dioxo-4,5-dihydro-3H-[1)2,4]tnazin-2- yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-N-(1-hydroxy-cycIoheptylmethyl)-5-[4-(2-hydroxy-2-pyridin-4-yl-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-çycloheptyimethyl)-5-[4-(2-hydroxy-2-pyridin-3-yl-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-pyridin-2-yl-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(4-hydroxy-tetrahydro-pyran-4- ylmethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]trïazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-thiophen-2-yl-ethyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzannide; 2-Chiorb-5-[4-(2-furan-2-yl-2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yI)-2-chloro-N-[2-(2- chloro-phenyl)-ethyl]-benzamide; 2-Cbloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[4-(2-methoxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 5-[4-(2-Carbamoyl-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-[2-(2-chloro-phenyl)-ethyl]-benzamide; 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[4-(3-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1- hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyI)-3,5-dioxo-4,5-dihydro-3H-[1,2,4jtriazin-2-yI]-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-5-[4-(2-dimethylamino-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N- (l-hydroxy-cycloheptylmethyl)-benzamide; 012978 -26- 2-Chloro-5-(4-cyanomethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy- cycloheptylmethyl)-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(3-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3 H-[1,2,4]triazin-2-yl]-benzam ide; 5-[4-(2-Amino-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(4-oxiranylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide; 5-[4-(2-Acetylamino-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1- hydrôxy-cyclobeptylmethyl)-benzamide; 2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-( 1 -hydroxy-cycloheptylm ethyl )-benzam ide; 2-Chloro-5-(3,5-dioxo-4-phenethyl-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy- cycloheptylmethyl)-benzamide; 5-(4-Benzyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-[4-(2-cyano-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1- hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-(3,5-dioxo-4-pyridin-2-ylmethyl-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-(3,5-dioxo-4-pyridin-3-ylmethyl-4,5-dihydro-3H-[1,2,4]tnazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-(3,5-dioxo-4-pyridin-4-yimethyl-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hyd roxy-cycloheptylmeth yl)-benzam ide; 5-[4-(2-Carbamoyl-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide; N-(1-Hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-2-methyl-benzamide; 5-[4-(2,3-DÎhydroxy-propyl)-3,5-dÎoxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy- cycloheptylmethyl)-2-methyl-benzamide; 5-[4-(2-Carbamoyl-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycioheptylmethyl)-2-methyl-benzamide; 5-[4-(3-Amino-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1- hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N- ( 1 -hydroxy-cycloheptyl m ethyl )-benzam ide; 01297 8 -27- (2-{4-Chloro-3-(2-(2-chloro-phenyl)-ethylcarbamoyl]-phenyl}-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yI)-acetic acid tert-butyl ester; 2-Chloro-5-[4-(2,3-dihydroxy-propyI)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1 -hydroxy-cycloheptylmethyl)-benzamide; 5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1- cyano-cycloheptylmethyl)-benzamide; N-Adamantan-1-ylmethyl-5-(4-carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)-2-chloro-benzamide; 5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(4,4- difluoro-1-phenyl-cyclohexylmethyl)-benzamide; 5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1-p- tolyl-cyclohexylmethyl)-benzamide; 5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1-hydroxy-cyclohexylmethyl)-benzamide; 2-Chloro-N-(1-hydroxy-cyclohexylmethyl)-5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-3,3-dimethyl-cyclohexylmethyl)-5-(4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]- benzamide; 2-Chloro-N-(1-hydroxy-cyclooctylmethyl)-5-[4-(2-hydroxy-ethyl)-3,5-dîoxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H- (1,2,4]triazin-2-yl]-N-(1 -hydroxy-cyclohexylmethyl)- benzamide; 5-(4-(2,3-Dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide; 5-(4-(2,3-Dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycioheptylmethyl)-2-methyi-benzamide; 5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1-hydroxy-cyclooctyimethyl)-benzamide; 2-Chloro-N-(2-hydroxy-cycloheptylmethyl)-5-(4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 5-[4-(3-Amino-2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1-hydroxy-cycloheptylrnethyl)-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(4-methyicarbamoylmethyl-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide; 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-(4-dimethylcarbamoylmethyl-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl)-benzamide; 012978 -28- 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-3,5-dioxo- 4.5- dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[3,5-dioxo-4-(2-oxo-2-pyrrolidin-1-yl-ethyl)- 4.5- dihydro-3H-[1,2,4]triazin-2-yl]-benzannide; 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[4-(2-methylcarbamoyl-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[4-(2-dimethylcarbamoyl-ethyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[3,5-dioxo-4-(2-oxo-2-piperazin-1-yl-ethyl)- 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-yi)- N-(1-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-(4-ethylcarbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(l-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-[3,5-dioxo-4-(2-oxo-2-piperidin-1-yl-ethyl)-4,5-dihydro-3H-[1,2,4]triazin-2- yIj-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yI]-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(isopropylcarbamoyl-methyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 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-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-{4-[(cyclopropylmethyl-carbamoyl)-methyl]-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl}-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 5-(4-Dimethylcarbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-5-[4-(2,3-dihydroxy-2-methyl-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-methyl-propyI)-3,5-dioxo-4,5*dihydro-3H-[1,2,4]triazin-2-yl]- benzamide; 2-Chloro-N-(1-hydroxy-cyclohexylmethyl)-5-[4-(2-hydroxy-2-methyl-propyl)-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cyclooctylmethyI)-5-[4-(2-hydroxy-2-methyl-propyl)-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; -29- 0 1297 8 2-Chloro-N-(1-hydroxy-cyciooctylmethy[)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cyclohexylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cyclooctylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cyclopentylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4Jtriazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cyclopentylmethyl)-5-[4-(2-hydroxy-2-methyl-pcopyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cyclopentylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-ChloiO-N-(1-hydroxy-cyclobutylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl )-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cyclobutylmethyl)-5-[4-(2-hydroxy-2-methyl-propyl)-3,5-dioxo- 4.5- dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cyclopentylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5- dioxo^.S-dihydro-SH-fl^^ltriazin^-yll-benzamide; 2-Chloro-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2- yl]-N-(1-hydroxymethyl-cycloheptylmethyl)-benzamide; 2-Ghloro-N-(1-hydroxymethyl-cycloheptylmethyl)-5-[4-(2-hydroxy-2-methyl-propyl)- 3.5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-phenyl-ethyl)-3,5-dioxo- 4.5- dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-phenyl-ethyl)-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-5-[4-(3-ethoxy-2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 2-ChJoro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-isopropoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 5-[4-(3-tert-Butoxy-2-hydroxy-propyI)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2- ch!oro-N-(1 -hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; -30- 0 ι2978 2-Chloro-5-[3,5-dioxo-4-(3,3,3-triftuoro-2-hydroxy-propyl)-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1 -hydroxy-cycloheptylmethyl)-benzamide; 2- Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3,3-dimethyl-butyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 3- (2-{4-Chloro-3-[(1-hydroxy-cycloheptylmethyl)-carbamoyl]-phenyl}-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-2-hydroxy-2-methyl-propionic acid methyl ester; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-morpholin-4-yl-propyl)- 3.5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 5-[4-(3-Benzyloxy-2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2- chloro-N-(1-hydroxy-cycloheptylmethyî)-benzamide; 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[4-(2-hydroxy-2-methyl-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[4-(2-hydroxy-:2-phenyl-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(2-hydroxy-cycloheptylmethyI)-5-[4-(2-hydroxy-2-methyl-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chioro-N-(2-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-phenyi-ethyl)-3,5-dioxo- 4.5- dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(2-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(2-hydroxy-2-phenyl-ethyl)-benzamide; 2-Chloro-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2- yl]-N-(2-hydroxy-2-phenyl-ethyl)-benzamide; 2-Chloro-5-[4-(2-hydroxy-2-methyl-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2- yl]-N-(2-hydroxy-2-phenyl-ethyl)-benzamide; 2-Chloro-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-phenethyl-benzamide; and 2-Chloro-5-[4-(2-hydroxy-2-methyl-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(2-hydroxy-2-phenyl-ethyl)-benzamide.
The présent invention also provides the following preferred compounds of the présentinvention: 2-Chloro-N-(1-hydroxy-cyclohexylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyI)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]tnazin-2-yl]-benzamide; 2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yi]-N- (l-hydroxy-cyclohexylmethyl)-benzamide; 0 1297 8 -31- 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N- (l-hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-5-(4-cyanomethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy- cycloheptylmethyl)-benzamide; 2-Chloro-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1-hydroxymethyl-cycloheptylmethyl)-benzamide; 2-Chloro-5-[4-(2-cyano-ethyl)-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1 -hydroxy-cycloheptylmethyl)-benzamide; N-(1-Hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethy!)-3,5-dioxo-4,5-dihydro-3H- [1.2.4] triazin-2-yl]-2-methyl-benzamide; 2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(l-hydroxy-cyclohexylmethyl)-benzamide; 2-Chloro-W-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-methyl-propyl )-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cyclooctylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-phenyl-ethyl)-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 2-Chloro-5-[3,5-dioxo-4-(3,3,3-trifluoro-2-hydroxy-propyl)-4,5-dihydro-3H- [1.2.4] triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide; 2-Chioro-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(2-hydroxy-2-phenyl-ethyl)-benzamide; 5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-(1,2,4]triazin-2-yl)-2-chloro-N-(1 -hydroxy-cycloheptylmethyl)-benzamide; 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 5-(4-(2,3-Dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide; 5-[4-(3-Amino-2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide; and 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide.
The présent invention also includes isotopically-labeled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass 0 1 297 8 -32- number usually found in nature. Examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 170,31P, 32P, 35S, 18F,and 36CI, respectively. Compounds of the présent invention, prodrugs thereof, andpharmaceuticafly acceptable salts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are within the scope of thisinvention. Certain isotopically-labelled compounds of the présent invention, for examplethose into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drugand/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C,isotopes are particularly preferred for their ease of préparation and detectability. Further,substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeuticadvantages resulting from greater metabolic stability, for example increased in vivo half-life orreduced dosage requirements and, hence, may be preferred in some circumstances.Isotopically-labelled compounds of Formula I of this invention and prodrugs thereof cangenerally be prepared by carrying out the procedures disclosed in the Schemes and/or in theExamples and Préparations below, by substituting a readily available isotopically-labelledreagent for a non-isotopically-labelled reagent.
The compounds of Formula I or a pharmaceutically acceptable sait thereof can beused in the manufacture of a médicament for the prophylactic or therapeutic treatment of anydisease state in a human, or other mammal, which is exacerbated or caused by excessive orunregulated cytokine production by such mammal's cells, such as but not limited tomonocytes and/or macrophages.
The présent invention relates to a method for treating a IL-1 mediated disease in amammal in need thereof, which comprises administering to said mammal an effective amountof a compound of formula I.
The présent invention also relates to a method for treating an IL-1 mediated condition.As defined herein, a “IL-1 mediated condition” includes but is not limited to a disease or disorderselected from the group consisting of arthritis (including psoriatic arthritis, Reiter's syndrome,rheumatoid arthritis, goût, traumatic arthritis, rubella arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and acute synovitis), inflammatory bowel disease, Crohn’sdisease, emphysema, acute respiratory distress syndrome, adult respiratory distresssyndrome, asthma, bronchitis chronic obstructive pulmonary disease, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoidosis, allergie reactions, allergie contacthypersensitivity, eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulcération,restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, bone résorption disease,loosening of artificial joint implants, atherosclerosis, aortic aneurysm, congestive heart failure,myocardial infarction, stroke, cérébral ischemia, head trauma, neurotrauma, spinal cord injury, -33- 0 1297 8 neuro-degenerative disorders, Alzheimer’s disease, Parkinson’s disease, migraine, dépréssion,peripheral neuropathy, pain, cérébral amyloid angiopathy, nootropic or cognition enhancement,amyotrophie latéral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, maculardegeneration, corneal scarring, scleritis, abnormal wound healing, burns, autoimmunedisorders, Huntington’s disease, diabètes, AIDS, cachexia, sepsis, septic shock, endotoxicshock, conjunctivitis shock, gram négative sepsis, toxic shock syndrome, cérébral malaria,cardiac and rénal reperfusion injury, thrombosis, glomerularonephritis, graft vs. host reaction,allograft rejection, organ transplant toxicity, ulcerative colitis, or muscle degeneration, in amammal, including a human, comprising administering to said mammal an amount of acompound to formula I, effective in treating such a condition.
The présent invention relates to a pharmaceutical composition for the treatment of aIL-1 mediated disease in a mammal which comprises an effective amount of a compoundaccording to formula I and a pharmaceutically acceptable carrier.
The présent invention relates to a pharmaceutical composition for the treatment of aIL-1 mediated condition in a mammal, including a human, comprising an amount of a compoundto formula I, effective in treating such a condition and a pharmaceutically acceptable carrier.
Preferably, the compounds of the invention are useful for the treatment of rheumatoidarthritis, osteoarthritis, psoriasis, allergie dermatitis, asthma, chronic obstructive pulmonarydisease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis,irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth andmétastasés of malignant cells, myoblastic leukemia, diabètes, Alzheimer’s disease,meningitis, osteoporosis, burn injury, ischémie heart disease, stroke and varicose veins.
The présent invention also provides a compound of formula (I), or a pharmaceuticallyacceptable sait or solvaté thereof, as hereinbefore defined for use in therapy.
In another aspect, the invention provides the use of a compound of formula (I), or apharmaceutically acceptable sait or solvaté thereof, as hereinbefore defined in themanufacture of a médicament for use in therapy.
The invention further provides a method of treating osteoarthritis which comprisesadministering a therapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable sait or solvaté thereof, as hereinbefore defined to a patient.
The invention further provides a method of effecting immunosuppression (e.g. in thetreatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) whichcomprises administering a therapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable sait or solvaté thereof, as hereinbefore defined to a patient.
The invention also provides a method of treating an obstructive airways disease (e.g.asthma or COPD) which comprises administering to a patient a therapeutically effective 01297 8 -34- amount of a compound of formula (I), or a pharmaceutically acceptable sait or solvaté thereof,as bereinbefore defined to a patient.
The term "treating", as used herein, refers to reversing, alleviating, inhibiting theprogress of, or preventing the disorder or condition to which such term appiies, or one or moresymptoms of such disorder or condition. The term “treatment”, as used herein, refers to the actof treating, as “treating" is defined immediately above.
The présent invention also provides a pharmaceutical composition comprising acompound of formula (I), or a pharmaceutically acceptable sait or solvaté thereof, ashereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent orcarrier.
The invention further provides a process for the préparation of a pharmaceuticalcomposition of the invention which comprises mixing a compound of formula (I), or apharmaceutically acceptable sait or solvaté thereof, as hereinbefore defined with apharmaceutically acceptable adjuvant, diluent or carrier.
For the above-mentioned therapeutic uses the dosage administered will, of course,vary with the compound employed, the mode of administration, the treatment desired and thedisorder indicated. The daily dosage of the compound of formula (l)/salt/solvate (activeingrédient) may be in the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, morepreferably 10 mg to 100 mg.
The présent invention also encompasses sustained release compositions.
The présent invention also relates to processes of preparing the compounds offormula I and intermediates used in such processes.
One embodiment of the processes of the invention relates to the préparation ofcompounds of formula I, which may be carried out by one or more of the synthetic methodsoutlined in Schemes l-IV, detailed below. The présent invention also provides methods andintermediates useful in the synthesis of compounds of formula (I), and identified in Schemes I-IV below.
One of ordinary skill in the art will appreciate that the compounds of the invention areuseful in treating a diverse array of diseases. One of ordinary skill in the art will alsoappreciate that when using the compounds of the invention in the treatment of a spécifiedisease that the compounds of the invention may be combined with various existingtherapeutic agents used for that disease.
For the treatment of rheumatoid arthritis, the compounds of the invention may be combined with agents such as TNF-α inhibitors such as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 and D2E7) and TNF recéptor immunoglobulin molécules (such as Enbrel®), COX-2 inhibitors (such as meloxicam, celecoxib , rofecoxib, valdecoxib, 0 1297 8 -35- paracoxib, and etoricoxib) low dose methotrexate, lefunomide; ciclesonide;hydroxychloroquine, d-penicillamine, auranofin or parentéral or oral gold.
The présent invention still further relates to the combination of a compound of theinvention together with a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or5-lipoxygenase activating protein (FLAP) antagonist selected from the group consisting ofzileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761 ; A/-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-ferf-butylphenol hydrazones; methoxytetrahydropyranssuch as Zeneca ZD-2138; the compound SB-210661; pyridinyl-substituted2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline compounds such asL-746,530; indole and quinoline compounds such as MK-591, MK-886, and BAY x 1005.
The présent invention still further relates to the combination of a compound of theinvention together with a receptor antagonists for leukotrienes LTB4, LTC4, LTD4, and LTE4selected from the group consisting of the phenothiazin-3-ones such as L-651,392; amidinocompounds such as CGS-25019c; benzoxalamines such as ontazolast;benzenecarboximidamides such as BIIL 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 présent invention still further relates to the combination of a compound of theinvention together with a PDE4 inhibitor including inhibitors of the isoform PDE4D.
The présent invention still further relates to the combination of a compound of theinvention together with a antihistaminic Hi receptor antagonists including cetirizine,loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.
The présent invention still further relates to the combination of a compound of theinvention together with a gastroprotective H2 receptor antagonist.
The présent invention still further relates to the combination of a compound of theinvention together with an a!- and a2-adrenoceptor agonist vasoconstrictor sympathomimeticagent, including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine,naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride,xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride.
The présent invention still further relates to the combination of a compound of theinvention together with anticholinergic agents including ipratropium bromide; tiotropiumbromide; oxitropium bromide; pirenzepine; and teienzepine.
The présent invention still further relates to the combination of a compound of the invention together with a βι~ to p4-adrenoceptor agonists including metaproterenoi, isoproterenol, isoprénaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; or methylxanthanines including theophylline -36- 012978 and aminophylline; sodium cromoglycate; or muscarinic receptor (M1, M2, and M3)antagonist.
The présent invention stiii further relates to the combination of a compound of theinvention together with an insulin-like growth factor type I (IGF-1 ) mimetic.
The présent invention still further relates to the combination of a compound of theinvention together with an inhaled glucocorticoid with reduced systemic side effects, includingprednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate,budesonide, fluticasone propionate, and mometasone furoate.
The présent invention still further relates to the combination of a compound of theinvention together with (a) tryptase inhibitors; (b) platelet activating factor (PAF) antagonists;(c) interleukin converting enzyme (ICE) inhibitors; (d) IMPDH inhibitors; (e) adhesion moléculeinhibitors including VLA-4 antagonists; (f) cathepsins; (g) MAP kinase inhibitors; (h) glucose-6phosphate dehydrogenase inhibitors; (i) kinin-B, - and B2 -receptor antagonists; (j) anti-goutagents, e.g., colchicine; (k) xanthine oxidase inhibitors, e.g., allopurinol; (I) uricosuric agents,e.g., probenecid, sulfinpyrazone, and benzbromarone; (m) growth hormone secretagogues;(n) transforming growth factor (TGFp); (o) platelet-derived growth factor (PDGF); (p) fibroblastgrowth factor, e.g., basic fibroblast growth factor (bFGF); (q) granulocyte macrophage colonystimulating factor (GM-CSF); (r) capsaicin cream; (s) Tachykinin NK·, and NK3 receptorantagonists selected from the group consisting of NKP-608C; SB-233412 (talnetant); andD-4418; and (t) elastase inhibitors selected from the group consisting of UT-77 and ZD-0892.
The présent invention still further relates to the combination of a compound of theinvention together with an inhibitor of matrix métalloprotéases (MMPs), /.e., the stromelysins,the collagénases, and the 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 can also be used in combination with existingtherapeutic agents for the treatment of osteoarthritis. Suitable agents to be used incombination include standard non-steroidal anti-inflammatory agents (hereinafter NSAID's)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 inhibitorssuch as celecoxib, valdecoxib, rofecoxib and etoricoxib, analgésies and intraarticularthérapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc.
The compounds of the présent invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin,
daunomycin, cis-platinum, etoposide, taxol, taxotere and farnesyl transferase inhibitors, VegF 012978 -37- inhibitors, COX-2 inhibitors and antimetabolites such as methotrexate antineoplastic agents,especially antimitotic drugs including the vinca alkaloids such as Vinblastine and vincristine;.
The compounds of the invention may also be used in combination with antiviralagents such as Viracept, AZT, aciclovir and famciclovir, and antisepsie compounds such as 5 Valant.
The compounds of the présent invention may also be used in combination withcardiovascular agents such as calcium channel blockers, lipid lowering agents such asstatins, fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptor antagoniste and plateletaggregation inhibitors.
10 The compounds of the présent invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such asdeprenyl, L-dopâ, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comPinhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagoniste,Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase), and 15 anti-Alzheimer’s drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline ormetryfonate.
The compounds of the présent invention may also be used in combination withosteoporosis agents such as roloxifene, droloxifene, lasofoxifene or fosomax andimmunosuppressant agents such as FK-506, rapamycin, cyclosporine, azathioprine, and 20 methotrexate.
DETAILED DESCRIPTION OFTHE INVENTION
Compounds of the formula I may be prepared according to the following reactionschemes and discussion. Unless otherwise indicated R1 through R7 in the reaction schemesand discussion that follows are as defined above. 0 1 297 8
Scheme 1
Cl 01297 8 -39-
Scheme 3
xi ιχ
Scheme 4
ΧΠ ΧΠΙ
XI -40-
Scheme 1 refers to the préparation of compounds of the formula V. Compounds ofthe formula VI can be prepared from compounds of formula I by reaction with a compound ofthe formula VII in the presence of base, wherein L is a suitable leaving group, such as chloro,bromo, iodo tosylate or mesylate. Suitable bases include, but are not limited to, triethylamine,polymer supported BEMP, césium carbonate, potassium carbonate, and sodium hydride,where césium carbonatè is preferred. The aforesaid reaction can be performed attempératures ranging from 0 °C to 100 °C in the presence of a polar solvent including but notlimited to dimethylsulfoxide, dimethylformamide, equal amounts of dimethylsulfoxide andacetone, or equal amounts of dimethylformamide and acetone, generally for a period of 2hours to 72 hours, where the preferred conditions are dimethylsulfoxide at ambienttempérature for 18 hours.
Compounds of the formula V may also be prepared from compounds of the formula Iby reaction of an appropriately substituted epoxide of the formula VIII either neat or in thepresence of a polar solvent including but not limited to dimethylformamide, dimethylsulfoxide,and tetrahydrofuran. The aforesaid reaction can be performed at températures ranging from0 °C to 100 °C for a period of 2 to 72 hours, where the preferred conditions aredimethylforamide at 60 °C for 24 hours.
Scheme 2 refers to the préparation of compounds of the formula V. Compounds ofthe formula V can be prepared from compounds of formula IX by reacting with a compound offormula XIV, H2N-R1, in the presence of a coupling reagent such as 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 1,1’-carbonyldiimidazole (CDl) and a base such as dimethylaminopyridine (DMAP) ortriethylamine in an aprotic solvent, such as methylene chloride, dimethylformamide, ordimethylsulfoxide, preferably 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide anddimethylaminopyridine in dimethyl formamide. The aforesaid reaction may be run at atempérature from 22 °C to 60 °C, for a period of 1 hour to 20 hours, preferably 22 °C for 18hours.
Compounds of the formula V may also be prepared from compounds of the formula Xby reaction by reacting with a compound of formula XIV in the presence of a base includingbut not limited to dimethylaminopyridine (DMAP), triethylamine, aqueous sodium hydroxide oraqueous potassium hydroxide in an aprotic solvent, such as methylene chloride, ethylacetate, dichloroethane, dimethylformamide, or dimethylsulfoxide, preferably aqueous sodiumhydroxide and dichloroethane. The aforesaid reaction may be run at a température from 22°C to 60 °C, for a period of 1 hour to 24 hours, preferably at ambient température for 3 hours.Compound X can be prepared from compound IX by reaction with a reagent capable ofgenerating an acid chloride such as thionyl chloride or oxalyl chloride in the presence of apolar aprotic solvent such as ethyl acetate, methylene chloride, or dichloroethane at a 0 1 297 8 -41- température of 22 °C to 60 °C, for a period of 1 hour to 24 hours, preferably oxalyl chloride inmethylene chloride at ambient température for 16 hours.
Scheme 3 refers to the préparation of compounds of the formula IX, which can beconverted into compounds of formula V by the methods described in Scheme 2. Compoundsof formula IX can be prepared from compounds of formula XI using décarboxylationconditions, preferably mercaptoacetic acid in water containing a base such as sodiumhydroxide at a température from 22 °C to 160 °C for a period of 1 hour to 24 hours, preferably100 °C for 18 hours.
Scheme 4 refers to the préparation of compounds of the formula XIII and XI,Compounds of the formula XI can be converted into compounds of the formula IX by themethods described in Scheme 3. A compound of formula XI can be prepared from a compound of formula XIII, whereinR8 is a suitable alkyl (CrC2), by reaction with an acid such as 50% sulfuric acid at atempérature between 60°C and 120°C, generally for a period between 30 minutes and 6hours, preferably 2 hours at 120°C. A compound of the formula XIII, wherein R8 is a suitable alkyl (C^-C2), can beprepared from the diazonium intermediate derived from a compound of formula XII. Thediazonium intermediate is prepared by reaction of a compound of the formula XII with an acidsuch as hydrochloric acid and/or glacial acetic acid, followed by treatment with sodium nitritein a solvent such as water at a température from 0°C to 25 °C, and the reaction is generallyrun from a period of 30 minutes to about 2 hours, preferably 10 °C for 30 minutes. Acompound of the formula XII is prepared by the reaction of the above diazonium intermediatewith a compound of the formula XVII: R8O(C=O)N(C=O)CH2(C=O)N(C=O)OR8, under basicconditions. The reaction is typically carried out with sodium acetate. as the base at atempérature from 0°C to 120°C, preferably 10°C, then warmed to 120 °C, and the reaction isgenerally run for a period of 1 hour to 24 hours, preferably 4 hours (Carrool, R.D.; et.al.; J.Med. Chem., 1983, 26, 96-100).
The activity of the compounds of the invention for the various disorders describedabove can be determined according to one or more of the following assays. Ali of thecompounds of the invention that were tested had an IC50 of less than 10 μΜ in the in vitroassay described below.
Preferably, the compounds of the invention hâve an IC50 in the in vitro assays described below of less than 100 nM, more preferably less than 50 nM, and most preferably less than 10 nM. Still further, the compounds of the invention preferably hâve an IC50 in the range of 0.01 nM -100 nM, more preferably between 0.05 nM - 50 nM, and most preferably between 0.10 nM-10 nM. -42- 0 1 297 §
PHARMACOLOGICAL ANALYSIS
Certain compounds such as benzoylbenzoyl adenosine triphosphate (bbATP) areknown to be agonists of the P2X7 receptor, effecting the formation of pores in the plasmamembrane (Drug Development Research (1996), 37(3), p. 126), Consequently, when thereceptor is activated using bbATP in the presence of ethidium bromide (a fluorescent DNAprobe), an increase in the fluorescence of intracellular DNA-bound ethidium bromide isobserved. Alternatively, the propidium dye YOPRO-1 can be substituted for ethidium bromideso as to detect uptake of the dye. The increase in fluorescence can be used as a measure ofP2X7 receptor activation and therefore to quantify the effect of a compound on the P2X7receptor.
In this manner, the compounds of the invention can be tested for antagonist activity atthe P2X7 receptor. 96-Well fiat bottomed microtitre plates are filled with 250 pl of test solutioncomprising 200 pl of a suspension of THP-1 cells (2.5 x 106 cells/ml, more preferablyprestimulated as described in the literature with a combination of LPS and TNF to promotereceptor expression) containing lO^M ethidium bromide, 25 pl of a high potassium, lowsodium buffer solution (10mM Hepes, 150 mM KCI, 5 mM D-glucose and 1.0% FBS at pH7.5) containing 10'5M bbATP, and 25 pl of the high potassium’buffer solution containing 3 x10'5M test compound (more preferably 5 x lO^M, more preferably 1 x lO^M.more preferably 1x 10’3M). The plate is covered with a plastic sheet and incubated at 37°C for one hour. Theplate is then read in a Perkin-Elmer fluorescent plate reader, excitation 520 nm, émission 595nm, slit widths: Ex 15 nm, Em 20 nm. For the purposes of comparison, bbATP (a P2X7receptor agonist) and pyridoxal 5-phosphate (a P2X7 receptor antagonist) can be usedseparately in the test as Controls. From the readings obtained, a plC50 figure can becalculated for each test compound, this figure being the négative logarithm of theconcentration of test compound necessary to reduce the bbATP agonist activity by 50%.
In like manner, the compounds of the invention can be tested for antagonist activity atthe P2X7 receptor using the cytokine IL-1 β as the readout. Blood collected from normalvolunteers in the presence of heparin is fractionated using lymphocyte séparation mediumobtained from Organon Technica (Westchester, PA). The région of the resulting gradientcontaining banded mononuclear cells is harvested, diluted with 10 ml of Maintenance Medium(RPMI 1640, 5% FBS, 25 mM Hepes, pH 7.2, 1% penicillin/streptomycin), and cells arecollected by centrifugation. The resulting cell pellet was suspended in 10 ml of MaintenanceMedium and a cell count was performed. In an average experiment, 2 x 10s mononuclearcells are seeded into each well of 96-well plates in a total volume of 0.1 ml. Monocytes areallowed to adhéré for 2 hours, after which the supernatants are discarded and the attachedcells are rinsed twice and then incubated in Maintenance Medium overnight at 37°C in a 5%CO2 environment. -43- 0 1 297 8
The cultured monocytes can be activated with 10 ng/ml LPS (E. coli serotype 055:B5;Sigma Chemicals, St. Louis, MO). Following a 2-hour incubation, the activation medium isremoved, the cells are rinsed twice with 0.1 ml of Chase Medium (RPMI 1640, 1% FBS, 20mM Hepes, 5 mM NaHCO3, pH 6.9), and then 0.1 ml of Chase Medium containing a testagent is added and the plate is incubated for 30 minutes; each test agent concentration canbe evaluated in triplicate wells. ATP then is introduced (from a 100 mM stock solution, pH 7)to achieve a final concentration of 2 mM and the plate is incubated at 37°C for an additional 3hours. Media were harvested and clarified by centrifugation, and their IL-1 β content wasdetermined by ELISA (R&amp;D Systems; Minneapolis, MN).
The compositions of the présent invention may be formulated in a conventionalmanner using one or more pharmaceutically acceptable carriers. Thus, the activecompounds of the invention may be formulated for oral, buccal, intrànasal, parentéral (e.g.,intravenous, intramuscular or subcutaneous), topicàl or rectal administration or in a formsuitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, forexample, tablets or capsules prepared by conventional means with pharmaceuticallyacceptable excipients such as binding agents (e.g., pregelatinized maize starch,polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnésium stéarate, talc or silica);disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulphate). The tablets may be coated by methods well known in the art. Liquidpréparations for oral administration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitution with water or othersuitable vehicle before use. Such liquid préparations may be prepared by conventionalmeans with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitolsyrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); andpreservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration, the composition may take the form of tablets or lozengesformulated in conventional manner.
The compounds of formula I can also be formulated for sustained delivery accordingto methods well known to those of ordinary skill in the art. Examples of such formulations canbe found in United States Patents 3,538,214, 4,060,598, 4,173,626, 3,119,742, and3,492,397, which are herein incorporated by reference in their entirety.
The active compounds of the invention may be formulated for parentéral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in amputes or -44- 01297 8 'in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or émulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingrédient may be in powder form for reconstitution with a suitable vehicle, e.g., stérile pyrogen-free water, before use.
The active compounds of the invention may also be formulated in rectal compositionssuch as suppositories or rétention enemas, e.g., containing conventional suppository basessuch as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds ofthe invention are conveniently delivered in the form of a solution, dry powder formulation orsuspension from a pump spray container that is squeezed or pumped by the patient or as anaérosol spray présentation from a pressurized container or a nebulizer, with the use of asuitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or other suitable gas. In thecase of a pressurized aérosol, the dosage unit may be determined by providing a valve todeliver a metered amount. The pressurized container or nebulizer may contain a solution orsuspension of the active compound. Capsules and cartridges (made, for example, fromgelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of acompound 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, parentéral orbuccal administration to the average adult human for the treatment of the conditions referredto above (inflammation) is 0.1 to 200 mg of the active ingrédient per unit dose which could beadministered, for example, 1 to 4 times per day.
The compound of formula (I) and pharmaceutically acceptable salts and solvatésthereof may be used on their own but will generally be administered in the form of apharmaceutical composition in which the formula (I) compound/salt/solvate (active ingrédient)is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Dependingon the mode of administration, the pharmaceutical composition will preferably comprise from0.05 to 99% w (percent by weight), more preferably from 0.10 to 70% w, of active ingrédient,and, from 1 to 99.95% w, more preferably from 30 to 99.90% w, of a pharmaceuticallyacceptable adjuvant, diluent or carrier, al) percentages by weight being based on totalcomposition. Aérosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or “puff" of aérosol contains 20pg to 1000pg of the compound of the invention. The overall daily dose with an aérosol will be within the range 100pg to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time. -45- 012978 Aérosol combination formulations for treatment of the conditions referred to above(e.g., adult respiratory distress syndrome) in the average adult human are preferablyarranged so that each metered dose or “puff” of aérosol contains from about 1 pg to 1000 pgof the compound of the invention. The overall daily dose with an aérosol will be within therange 100 pg to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8times, giving for example, 1,2 or 3 doses each time. Aérosol formulations for treatment of the conditions referred to above (e.g., adultrespiratory distress syndrome) in the average adult human are preferably arranged so thateach metered dose or “puff’ of aérosol contains from about 20 pg to 1000 pg of thecompound of the invention. The overall daily dose with an aérosol will be within the range100 pg to 10 mg of the P2X7 receptor inhibitor. Administration may be several times daily, forexample 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
This invention also encompasses pharmaceutical compositions containing andmethods of treating or preventing comprising administering prodrugs of compounds of theformula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups canbe converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide Chain of two or more (e.g., two, three or four) amino acid residues which arecovalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups ofcompounds of formula I. The amino acid residues include the 20 naturally occurring aminoacids commonly designated by three letter symbols and also include, 4-hydroxyproline,hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citruiline homocystéine, homoserine, ornithine and méthionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esterswhich are covalently bonded to the above substituents of formula I through the carbonyl carbonprodrug sidechain.
The following Examples illustrate the préparation of the compounds of the présentinvention. Melting points are uncorrected. NMR data are reported in parts per million (d) andare referenced to the deuterium lock signal from the sample solvent (deuteriochloroformunless otherwise specified). Mass Spectral data were obtained using a Micromass ZMDAPCI Mass Spectrometer equipped with a Gilson gradient' high performance liquidchromatograph. The following solvents and gradients were used for the analysis. Solvent A;98% water/2% acetonirile/0.01% formic acid and solvent B; acetonitrile containing 0.005%formic acid. Typically, a gradient was run over a period of about 4 minutes starting at 95%solvent A and ending with 100% solvent B. The mass spectrum of the major elutingcomponent was then obtained in positive or négative ion mode scanning a molecular weightrange from 165 AMU to 1100 AMU. Spécifie rotations were measured at room températureusing the sodium D line (589 nm). Commercial reagents were utilized without further -46- 012978 purification. THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide.Chromatography refers to column chromatography performed using 32-63 mm silica gel andexecuted under nitrogen pressure (flash chromatography) conditions. Room or ambienttempérature refers to 20-25°C. Ail non-aqueous reactions were run under a nitrogenatmosphère for convenience and to maximize yields. Concentration at reduced pressuremeans that a rotary evaporator was used.
One of ordinary skill in the art will appreciate that in some cases protecting groupsmay be required during préparation. After the target molécule is made, the protecting groupcan be removed by methods well known to those of ordinary skill in the art, such as describedin Greene and Wuts, “Protective Groups in Organic Synthesis” (3rd Ed, John Wiley &amp; Sons1999). EXAMPLE 1 5-(4-Carbamovlmethvl-3,5-dioxo-4,5-dihvdro-3H-ri,2.4ltriazin-2-v0-N-(1-hvdroxv- cvcloheptvlmethvl)-2-methyl-benzamide
(A) 5-Amino-2-methyl-benzoic acid hydrochloride sait
Aslurry of 5-nitro-2-methyl-benzoic acid (17.1 g, 94.4 mmol) and 10% Pd/C (500 mg)in EtOH (500 mL) was shaken under 40 psi H2 at ambient température for 4 hours. HCl wasadded and the solution filtered through a pad of celite. The filtrate was concentrated in vacuoto give the title compound (17.2 g). (B) 2-(3-Carboxy-4-methyl-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid
To a solution of 5-Amino-2-methyl-benzoic acid hydrochloride sait (15.2 g, 81.2mmol) in acetic acid (300 mL) was added concentrated HCl (21.0 mL). The resulting slurrywas stirred at ambient température for 30 minutes. The reaction was then cooled to 10 °C,and a solution of sodium nitrite (6.17 g, 89.4 mmol) in water (15 mL) was added dropwise.The reaction was stirred at 10 °C for 30 minutes, when sodium acetate (14.7 g, 179.0 mmoi)and (3-ethoxycarbonylamino-3-oxo-propionyl)-carbamic acid ethyl ester (J. Chem. Soc.Perkins Trans. 1,1991, 2317) (22.0 g, 89.4 mmol) were added. The réaction was let stir at 10 01297 8 -47- °C for 20 minutes, then warmed to room température and stirred for 1 hour. Sodium acetate(6.7 g, 81.2 mmol) was then added and the reaction refluxed for 14 hours. A 50% aqueoussolution of H2SO4 (88.0 mL) was added and the reaction refluxed for 2 hours. The reactionwas cooled, then water (50 mL) added. The resulting tan precipitate was filtered, washedwith water, and dried to give the title compound (17.8 g). (C) 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-benzoic acid 2-(3-Carboxy-4-methyl-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6- carboxylic acid (110 gm) was added to 8 volumes of water with 2.4 équivalents of sodiumhydroxide and 1.1 équivalents of mercaptoacetic acid. The reaction mixture was heated toreflux (100-105 °C) for approximately 18 hours at which point the reaction was complété byHPLC. 30% Sodium hydroxide and toluene were added and the resulting mixture was stirred.Upon settling a large interface was noted. More water, toluene and some ethyl acetatè wereadded. The interface was minimized. The water layer was separated and treated with 2NHCl. At pH 2 solids precipitated out and the slurry was cooled to <10 °C. The solids werefiltered off in a slow filtration and dried in a vacuum ovén to give 69 gm of the title compound. (D) 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1 -hydroxy-cycloheptylmethyl)-2-methyI-benzamide A slurry of 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-benzoic acid (5.0g, 20.2 mmol), 1-aminomethyl-cycloheptanol 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 ambient température for 14 hours. Thereaction was then poured into 1N HCl (50 mL) and diluted with water (15 fold). The aqueouswas extracted with CH2CI2 (3x). The organics were combined, washed with brine, dried oversodium sulfate, and concentrated in vacuo to give a tan solid. The crude was recrystallizedfrom CH2CI2 to give the title compound as an off-white solid (3.1 g). (E) 5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yI)-N-(1 -hydroxy-cycloheptylmethyl)-2-methyl-benzamide A slurry of 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide (200.0 mg, 0.537 mmol) and Cs2CO3 (290.3 mg,0.891 mmol) were stirred in DMSO (1.79 mL, 0.3 M) at ambient température for 15 minutes.2-Bromoacetamide (74.1 mg, 0.537 mmol) was added and the reaction stirred at ambienttempérature for 14 hours. The reaction was diluted with water (15-fold) and the aqueousextracted with CH2CI2 (3x). The organics were dried over sodium sulfate, and concentrated invacuo to a tan oil. The crude was triterated from IPE/Et2O/CH2CI2 to give the title compoundas 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. -48- Ο 1297 8 TABLE 1 EXAMPLE STRUCTURE NAME DATA LCMS IW2 A 0 cÂf N M h 5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro- 2 Cl I 3H-[1,2,4]triazin-2-yl)-2- chloro-N-[2-(2-chloro- 462.1 Λ phenyl)-ethyl]- Cl O benzamide —A <A'n Γ1 h 2-Chloro-N-[2-(2-chloro- phenyl)-ethyl]-5-[4-(2- 3 Cl I methoxy-ethyl)-3,5- dioxo-4,5-dihydro-3H- 463.2 A [1,2,4]triazin-2-yl]- Cl O benzamide O O <Af li H 5-[4-(2-Carbamoyl- ethyl)-3,5-dioxo-4,5- 4 Cl I dihydro-3H-[1,2,4]triazin- 2-yl]-2-chloro-N-[2-(2- 476.3 YiY Ά chloro-phenyl)-ethyl]- Cl 0 benzamide h°oA <Af Q h 2-Chloro-N-[2-(2-chloro- phenyl)-ethyl]-5-[4-(2- 5 Cl I hydroxy-ethyl)-3,5-dioxo- 4,5-dihydro-3H- 449.4 A [1,2,4]triazin-2-yl]- Cl O benzamide O ho^^A <A-“ il h 2-Chloro-N-[2-(2-chloro- phenyl)-ethyl]-5-[4-(3- 6 Cl I hydroxy-propyl)-3,5- dioxo-4,5-dihydro-3H- 463.6 A [1,2,4]triazin-2-yl]- Cl O benzamide 012978 -49- EXAMPLE STRUCTURE NAME DATA LCMS M/Z 7 Η·^χ 0 ° ± Ao Cl O 5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1 -hydroxy-cycloheptylmethyl)- benzamide 450.9 8 h°^A A/ Άο Cl O 2-Chloro-N-( 1-hydroxy-cycloheptylmethyl)-5-[4- (2-hydroxy-ethyl )-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 437.9 9 h.c'°^Â A--x> Cl O 2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-[4- (2-methoxy-ethyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yI]- benzamide 451.7 10 CH, O 0 1 ÇMXD Cl 0 2-Chloro-5-[4-(2- dimethylamino-ethyl)- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl]-N- (1-hydroxy- cycloheptylmethyl)- benzamide .464.5 11 O Ai Ά Cl 0 2-Chloro-5-(4- cyanomethyl-3,5-dioxo- 4,5-dihydro-3H- [1,2,4]triazin-2-yl)-N-(1 - hydroxy- cycloheptylmethyl)- benzamide 432.3 -50- 01 297 8 "example STRUCTURE NAME DATA LCMS M/Z 12 0 Λ ,V w^o Cl 0 2-Chloro-N-( 1 -hydroxy- cycloheptylmethyl)-5-[4- (3-hydroxy-propyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 451.4 13 O ° 1 wX) Cl 0 5-[4-(2-Amino-ethyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-2- chloro-N-(1 -hydroxy-cycloheptylmethyl)- benzamide 436.5 14 O "θύ <1/50 Cl 0 2-Chloro-N-(1-hydroxy- cycloheptylmethyl)-5-(4- oxiranylmethyl-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)- benzamide 449.5 15 0 H II H,C. .N. >0 ï /X ï <0=10 Cl O 5-[4-(2-Acetylamino- ethyl)-3,5-dioxo-4,5- dihydro03H-[1,2,4]triazin- 2-yl]-2-chloro-N-(1- hydroxy- cycloheptylmethyl)- benzamide 478.4 16 O „o^A 0H An^n "</.50 Cl 0 2-Chloro-5-[4-(2,3- dihydroxy-propyl )-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1 - hydroxy- cycloheptylmethyl)- benzamide 467.4 012978 -51- EXAMPLE STRUCTURE NAME DATA LCMS M/Z 17 ,ίγ- Cl ο 2-Ch loro-5-(3,5-d ioxo-4- phenethyl-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N- (1-hydroxy- cycloheptylmethyl)- benzamide 497.5 18 ο 07f ν/Ο Cl ο 5-(4-Benzyl-3,5-dioxo- 4,5-dihydro-3H- [1,2,4]triazin-2-yl)-2- chloro-N-(1-hydroxy- cycloheptylmethyl)- benzamide 483.5 19 NC^Â °v χοΟ Ci 0 2-Chloro-5-[4-(2-cyano- ethyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]-N-(1- hydroxy- cycloheptylmethyl)- benzamide 446.5 20 O 07?- ψγΟΟ Cl 0 2-Chloro-5-(3,5-dioxo-4- pyridin-2-ylmethyl-4,5- dihydro-3H-[1,2,4]triazin- 2-yl)-N-(1 -hydroxy- cycloheptylmethyl)- benzamide 484.4 21 O cçô. V7O Cl 0 2-Chloro-5-(3,5-dioxo-4- pyridin-3-ylmethyl-4,5- dihydro-3H-[1,2,4]triazin- 2-yl)-N-(1 -hydroxy- cycloheptylmethyl)- benzamide 484.5
-52- 012978 EXAMPLE STRUCTURE NAME DATALCMSM/Z 22 0 ιΐ Ά Cl O 2-Chloro-5-(3,5-dioxo-4- pyridin-4-yImethyl-4,5-dihydro-3H-[1,2,4]triazîn- 2-yl)-N-(1-hydroxy-cycloheptylmethyl)- benzamide 484.5 23 O 0 °ύν ÇV3O Cl O 5-[4-(2-Carbamoyl- ethyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin- 2-yl]-2-chloro-N-(1 - hydroxy- cycloheptylmethyl)- benzamide 474.5 24 h°AÔ 0 1 ch3 O N-(1 -Hydroxy- cycloheptylmethyl)-5-[4- (2-hydroxy-ethyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-2- methyl-benzamide 417.5 25 0 OH An-n Ά çh3 O 5-[4-(2,3-Dihydroxy- propyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin- 2-yl]-N-( 1 -hydroxy-cycloheptylmethyl)-2- methyl-benzamide 447.3 26 O o 0 1 l^OiO ch3 O 5-[4-(2-Carbamoyl- ethyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl]-N-(1 -hydroxy-cycloheptylmethyl)-2-methyl-benzamide 444.6 -53- 012978 EXAMPLE STRUCTURE ΝΑΜΕ DATA LCMS M/Z ' 27 0 Λμ-Ν ο ψγΟΟ CI ο 5-[4-(3-Amino-propyl)- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl]-2- chl oro-N-( 1 -hyd roxy- cycloheptylmethyl)- benzamide 450.4 28 0 ÔH -Λν-ν “άγΰΟ CI ο 2-Chloro-5-[4-(2,3- dihydroxy-propyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1- hydroxy- cycloheptylmethyl)- benzamide 467.4 29 ΥυίΑ °<Α'ν ÇÇti^X Cl 0 (2-{4-Chloro-3-[2-(2- chloro-phenyl)- ethylcarbamoylj-phenyl}- 3,5-dioxo-2,5-dihydro- 3H-[1,2,4]triazin-4-yl)- acetic acid tert-butyl ester 519.7 30 “ΎιΧιι “Α" -'Λ X CI 0 2-Chloro-5-[4-(2,3- dihydroxy-propyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1- hydroxy- cycloheptylmethyl)- benzamide 467.6 31 y « φφ ί?ΟγΝ'ίί ηΛυ 0 5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2- chloro-N-(1-cyano- cycloheptylmethyl)- benzamide 459.3 -54- 0 1 297 8 EXAMPLE STRUCTURE NAME DATA LCMS M/Z 32 N-Adamantan-1- ylmethyl-5-(4- carbamoylmethyl-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)-2- chloro-benzamide 473.0 33 A N-V° 0 O 5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)-2- chloro-N-(4,4-difluoro-1 - phenyl- cyclohexylmethyl)- benzamide 532.3 34 0 a K-yo O 5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)-2- chloro-N-(1-p-tolyI- cyclohexylmethyl)- benzamide 510.4 35 vA°\N OyO Cl O 5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)-2- chloro-N-( 1 -hydroxÿ- cyclohexylmethyl)- benzamide 436.5 36 h°^A ° ï cxuo T II HO Cl 0 2-Chloro-N-(1 -hydroxy- cyclohexylmethyl)-5-[4- (2-hydroxy-ethyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 423.5 01297 a -55- EXAMPLE STRUCTURE NAME DATA LCMS M/Z .. f ü ÛH ψΑΑ O 2-Chloro-N-(1 -hydroxy- 3,3-dimethyl-cyclohexylmethyl)-5-[4-(2-hydroxy- ethyl)- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yi]- benzamide 451.5 38 “—A φγΟΟ T il HO Cl O 2-Chioro-N-( 1 -hydroxy- cyclooctylmethyl )-5-(4- (2-hydroxy-ethyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]- benzamide 451.5 39 H0"Y^A °νν Çy φγί/5’ Cl O 2-Chloro-5-(4-(2,3- dihydroxy-propyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1- hydroxy- cyclohexylmethyl )- benzamide 453.5 40 O AA CHj 0 5-(4-(2,3-Dihydroxy- propyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl]-N-(1 -hydroxy- cycloheptylmethyl)-2- methyl-benzamide 447.6 41 0 AA ch3 O 5-(4-(2,3-Dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin- 2-yl]-N-(1 -hydroxy-cycloheptylmethyI)-2-methyl-benzamide 447.6 012978 -56- EXAMPLE STRUCTURE NAME DATA LCMS M/Z 42 Hiv A ° «a J*ΨνΑΑ IL °H Cl 0 5-(4-Carbamoylmethyl- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)-2- chloro-N-(1 -hydroxy- cyclooctylmethyl)- benzamide 462.4 (M-1) 43 A zQ Cl 0 2-Chloro-N-(2-hydroxy- cycloheptylmethyl)-5-[4- (2-hydroxy-ethyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-ylJ- benzamide 437.3 44 O h2n^Y^n-^|) OH An-N ÇvX) Cl O 5-[4-(3-Amino-2- hydroxy-propyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-2- chloro-N-(1 -hydroxy- cycloheptylmethyl)- benzamide 448.5 EXAMPLE 45 2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-(4-methylcarbamoylmethyl- 3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide
(A) (2-{4-Chloro-3-[2-(2-chloro-phenyl)-ethylcarbamoyl]-phenyl}-3,5-dioxo- 2,5-dihydro-3H-[1,2,4]triazin-4-yl)-acetic acid A solution of Example 34 (358 mg, 0.69 mmol) and TFA (1 mL) was stirred at ambient température for 18 hours. The solvent was removed in vacuo, and excess TFA azeotroped -57- 0 1 297 8 using CH2CI2 (3x). The crude pale brown solid was triterated in hexane to give the titlecompound (295 mg). (B) 2-Chloro-N-(2-(2-chloro-phenyl)-ethyl)-5-(4-methylcarbamoylmethyl- 3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide 5 A slurry of (2-{4-Chloro-3-[2-(2-chloro-phenyl)-ethylcarbam'oyl]-phenyl}-3,5-dioxo-2,5- dihydro-3H-[1,2,4]triazin-4-yl)-acetic acid (71.4 mg, 0.154 mmol), methylamine HCl (15.6mg,0.231 mmol), EDCI (44.4 mg, 0.231 mmol), and DMAP (75.5 mg, 0.616 mmol) in DMF (1.0mL) were stirred at ambient température for 20 hours. The reaction was diluted with 1N HCl,and let stir for 5 hours. The crude was filtered and triterated from hexane to give the title 10 compound (20 mg). 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 Exampie 45. TABLE 2 EXAMPLE STRUCTURE NAME DATA LCMS M/Z 46 0 v'SrA ° Çy'X) Cl 0 2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-(4- methylcarbamoylmethyl- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)- benzamide 464.8 47 CH, 0 v'vVS ° 2-Chloro-N-[2-(2-chloro- phenyl)-ethyl]-5-(4- dimethylcarbamoyimethy l-3,5-d ioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)- benzamide 490.1 48 O'''''''] 0 ° W—'Λ Cl 0 2-Chloro-N-[2-(2-chloro- phenyl)-ethyl]-5-[4-(2- morpho!in-4-yl-2-oxo- ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide 523.3 012978 -58- EXAMPLE STRUCTURE NAME DATA LCMS M/Z 49 ° cAf ci o 2-Chloro-N-[2-(2-chloro- phenyl)-ethyl]-5-[3,5- dioxo-4-(2-oxo-2- pyrrolid in-1 -yl-ethyl)-4,5-dihydro-3H-[1,2,4]triazin- 2-yl]-benzamide 516.3 50 0 0 •vsA^A, H I II A„'N O An ci W-Λ ci o AA 2-Chloro-N-[2-(2-chloro- phenyl)-ethyl]-5-[4-(2- methylcarbamoyl-ethyl)- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl]- benzamide 490.9 51 CH, X 3 </γ 2-Chloro-N-[2-(2-chloro- phenyl)-ethyl]-5-[4-(2- dimethylcarbamoyl- ethyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin- 2-yl]- benzamide 504.5 52 MO s^νύ^Λ ° <An VAatS Cl o AA 2-Chloro-N-[2-(2-chloro- phenyl)-ethyl]-5-[3,5- dioxo-4-(2-oxo-2- piperazin-1 -yl-ethyl)-4,5- dihydro-3H-[1,2,4]triazin- 2-yl]-benzamide 531.5 53 ^άΑ 0 ° iN A Cl o 2-Chloro-5-(4- dimethylcarbamoylmethy l-3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)-N- (1-hydroxy- cycloheptylmethyl)- benzamide 478.8 -59- 012978 [ EXAMPLE STRUCTURE NAME DATA LCMS M/Z 54 H-C-VÂ ° o^VN Cl 0 2-Chloro-5-(4- ethylcarbamoylmethyl- 3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)-N- (1-hydroxy- cycloheptylmethyl)- benzamide 478.8 55 ° <Ân"n φγθΟ Cl O 2-Chloro-5-[3,5-dioxo-4- (2-oxo-2-piperidin-1 -yl-ethyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1 -hydroxy- cycloheptylmethyl)- benzamide 518.8 56 ° Λν"ν wO Cl O 2-Chloro-N-(1 -hydroxy-cycloheptylmethyl)-5-[4- (2-morpholin-4-yl-2-oxo- ethyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin- 2-yl]-benzamide 520.8 57 yVA ' 0 ZyN QyCO Cl 0 2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-[4- (isopropylcarbamoyl- methyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin- 2-yl]-benzamide t- 492.8 58 °n5° ° ± Qy’X) Cl O 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 - hydroxy- cycloheptylmethyl)- benzamide 504.4 01297 8 -60- EXAMPLE STRUCTURE NAME DATA LCMS M/Z 59 °0 iN Cl 0 2-Chloro-5-{4- [(cyclopropylmethyl-carbamoyl)-methyl]-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl}-N-(1- hydroxy- cycloheptylmethyl)- benzamide 504.4 60 CH, O ° ¢1,.=50 CK3 O 5-(4- Dimethylcarbamoylmeth yl-3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)-N- (1-hydroxy- cycloheptylmethyl)-2- methyl-benzamide 458.5 EXAMPLE 61 2-Chloro-N-(1-hvdroxv-cvcloheptvlmethvl)-5-f4-(2-hvdroxv-3-methoxv-propyl)-3,5- dioxo-4.5-dihvdro-3H-H.2,41triazin-2-vll-benzamide
A) 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yI)-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide (1.77 g, 4.5 mmol) and R-(-)-glycidyl methyl ether (2.5 mL, 27.8 mmol) in 10 DMF (4.5 mL) were heated at 60 °C for 18 hours. The reaction was cooled, diluted with 1NHCI, and extracted with CH2CI2. The organics were combined, washed with sat'd sodiumbicarbonate, dried over sodium sulfate and charcoal, filtered, and concentrated in vacuo. Thecrude was purified by silica gel flash chromatography (elution with EtOAc), then recrystallizedfrom ethyl acetate/hexane to give the title compound (1.62 g). LCMS (m/z) 479.5 M-1. 15 The compounds of Examples 62-99, identified in Table 3 below, can be prepared according to the method of Example 61. 01297 8 -61- TABLE 3 EXAMPLE STRUCTURE NAME DATA LCMS M/Z 62 0 Λ OH Cl 0 2-Chloro-N-(1-hydroxy- cycloheptylmethyl)-5-[4- (2-hydroxy-3-methoxy- propyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl]- benzamide 481.5 63 ,OH 0 "Τ'? Il A3 Cl O 2-Chloro-5-[4-(2,3- dihydroxy-2-methyl- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]-N-(1- hydroxy- cycloheptylmethyl)- benzamide 481.6 64 ° ÏN Ôv-43 Cl 0 2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-[4- (2-hydroxy-2-methyl-propy I )-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 465:5 65 oA"n Cl O 2-Cbloro-N-(1 -hydroxy- cyclohexylmethyl)-5-[4- (2-hydroxy-2-methyl- propyl )-3,5-d ioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 451.5 66 Φυν'-ΧΖ) Cl 0 2-Chloro-N-( 1 -hydroxy-cyclooctyl methyl )-5-[4-(2-hydroxy-2-methyl-propyl)-3,5-dioxo-4,5-dihydro-3H- 479.4 0 1 297 8 -62- EXAMPLE STRUCTURE NAME DATA LCMS M/2 [1,2,4]triazin-2-yl]- benzamide 67 H,C^ /v. ,oh 3 ο o Ύ>. O^N ÇL-bYD I II oh Cl O 2-Chloro-N-(1-hydroxy- cyclooctylmethyl)-5-[4- (2-hydroxy-3-methoxy- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamïde 495.6 68 0 Cl 0 2-Chloro-N-(1 -hydroxy- cycloheptylmethyl)-5-[4- (2-hydroxy-3-methoxy- propyI)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 479.4 (M-1) 69 0HcÂxN Cl ο 2-Chloro-N-(1-hydroxy- cyclohexylmethyl)-5-[4- (2-hydroxy-3-methoxy- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 467.5 70 ο ΨύΑο Cl 0 — 2-Chloro-N-(1 -hydroxy-cyclooctylmethyI)-5-[4- (2-hydroxy-3-methoxy- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 495.6 -63- 01 297 8 EXAMPLE STRUCTURE N AME DATA LCMS M/Z 71 r'-'X W" “ Cl O 2-Chloro-N-(1 -hydroxy- cyclopentylmethyl)-5-[4- (2-hydroxy-3-methoxy- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 453.5 72 0 H,C 0 Cl 0 2-Chloro-N-(1 -hydroxy- cyclopentylmethyl)-5-[4- (2-hydroxy-2-methyf- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl)- benzàmide 437.4 73 Λ Cl O 2-Chloro-N-(1 -hydroxy- cyclopentyimethyl)-5-[4- (2-hydroxy-3-methoxy- propyl )-3,5-d ioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yI]- benzamide 453.5 74 u1 i P o 2-Chloro-N-( 1 -hydroxy- cyclobutylmethyl)-5-[4- (2-hydroxy-3-methoxy-propy I )-3,5-d ioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 439.5 75 ch, ff An HO A XN 4/ Cl 0 2-Chloro-N-( 1 -hydroxy-cyclobutylmethyl)-5-[4-(2-hydroxy-2-methyl- propyl)-3,5-d ioxo-4,5- dïhydro-3H- [1,2,4]triazin-2-yl]- benzamide 423.3 -64- 0 1 297 8 EXAMPLE STRUCTURE NAME DATA LCMS MZ2 76 -o^A OHcArA Q ΨΑ Cl 0 2-Chloro-N-(1 -hydroxy- cyclopentylmethyl)-5-[4- (2-hydroxy-3-methoxy- propy!)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 453.5 77 ^Ο^νΛ οη<Αν'" ΑΑγ-ΝΗ OH Cl 0 2-Chloro-5-[4-(2- hydroxy-3-methoxy- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]-N-(1- hydroxymethyl- cycloheptylmethyl)- benzamide 495.4 78 τ/, cArZ Α~Λ Φύ" ° Cl O 2-Chloro-N-(1- hydroxymethyl- cycloheptylmethyl)-5-[4- (2-hydroxy-2- methyl- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-ylj- benzamide 479.4 79 Ά=ό Cl 0 2-Chloro-N-(1 -hydroxy-cycloheptylmethyl)-5-[4- (2-hydroxy-2-phenyl- ethyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 513.4 80 Cl 0 2-Ch loro-N-( 1 -hydroxy- cycloheptylmethyl)-5-[4- (2-hydroxy-2-phenyl- ethyl)-3,5-dioxo-4,5- dihydro-3H- 513,3 012978 -65- EXAMPLE STRUCTURE NAME DATA LCMS M/Z [1,2,4]triazin-2-yl]- benzamide Λ · 81 AA οηοΛν.μ aao Cl O 2-Chloro-5-[4-(3- ethoxy-2-hydroxy- propyl )-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1- hydroxy- cycloheptylmethyl)- benzamide 495.4 82 H3C^O O Va Cl O 2-Chloro-N-( 1 -hydroxy- cyclohepty!methyl)-5-[4- (2-hydroxy-3- isopropoxy-propyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 509.4 83 H.C.. ~ ^VA OH<ArTN Ά CI ο 5-[4-(3-tert-Butoxy-2- hydroxy-propyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-2-chloro-N-(1 -hydroxy-cycloheptylmethyl)- benzamide 523.4 84 ohoVn^ A-a Cl 0 2-Chloro-N-[2-(2-chloro-phenyl)-etbyl]-5-[4-(2- .hydroxy-3-methoxy- propyl )-3,5-d ioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 494.4 0 1297 8 -66- EXAMPLE STRUCTURE NAME DATA LCMS M/Z 85 HY- iXUD I II HO Cl 0 2-Chloro-5-[3,5-dioxo-4- (3,3,3-trifluoro-2- hydroxy-propyl )-4,5- dihydro-3H- [1,2,4]triazin-2-yl]-N -(1-hydroxy- cycloheptylmethyl)- benzamide 505.3 86 Cl 0 2-Chloro-N-( 1 -hydroxy- cycloheptylmethyl)-5-[4- (2-hydroxy-3,3- dimethyl-butyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]- benzamide 493.4 87 OH \ : - 3-(2-{4-Chloro-3-[(1- hydroxy- cycloheptylmethyl)- carbamoyl]-phenyl}-3,5- dioxo-2,5-dihydro-3H- [1,2,4]triazin-4-yl)-2-hydroxy-2-methyl- propionic acid methyl ester 509.4 88 O “oAr" Γ\ W“" Cl 0 2-Chloro-N-(1 -hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-morpholin-4-yl-propyl)-3,5-dioxo- 4,5-dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 536.4 -67- 012978 EXAMPLE STRUCTURE NAME DATA LCMS M/Z 89 0 V %A'N Cl 0 5-[4-(3-Benzyloxy-2- hydroxy-propyl)-3,5- dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-2- chloro-N-( 1 -hydroxy- cycloheptylmethyi)- benzamide 557.4 90 0 CH, II H-CWS HO Jn Φύε'^Λ Cl 0 2-Chloro-N-[2-(2-chloro- phenyl)-ethyl]-5-[4-(2- hydroxy-2-methÿl- propyl)-3,5-dioxo-4,5- dihydro-3H -[1,2,4]triazin-2-yl]- benzamide 478.3 91 θχ?Α HOH X rN O N π h ç‘ 2-Chloro-N-[2-(2-chloro- phenyl)-ethyl]-5-[4-(2- hydroxy-2-phenyl- ethyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 525.4 92 Η^°ηοΛ> Çy l^szKxNHHO Cl 0 2-Chloro-N-(2-hydroxy- cycl oheptylmethyl )-5-[4- (2-hydroxy-2-m ethyl-propyl)-3,5-d ioxo-4,5- dihydro-3 H-[1,2,4]triazin-2-yl]- benzamide 465.4 93 y-* o CVa HO'H X N O N iyjp C! 0 HO 2-Chloro-N-(2-hydroxy- cycloheptylmethyl)-5-(4- (2-hydroxy-2-phenyl- eth yl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 513.4 -68- 01297 8 EXAMPLE STRUCTURE NAWIE DATA LCMS M/Z 94 ” Λ rQ L-JL/NHHO Cl 0 2-Chloro-N-(2-hydroxy- cycloheptylmethyl)-5-[4- (2-hydroxy-3-methoxy- propyI)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]- benzamide 481.4 95 0 H.C^ JL O N H° 'H A Jn CT N Cl 0 2-Chloro-5-[4-(2- hydroxy-3-methoxy- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]-N-(2- hydroxy-2-phenyl- ethyl)-benzamide 475.3 96 O H,CV ^χ/χ. Λ H° 'ηΛ 1 CT N λ H H OH τπ N'^ifîJ ci 0 2-Chloro-5-[4-(2- hydroxy-3-metboxy- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]-N-(2- hydroxy-2-phenyl- ethyl)-benzamide 475.3 97 9/¾ α o 2-Ch)oro-5-[4-(2- hydroxy-2-methyl- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]-N-(2- hydroxy-2-phenyl- ethy!)-benzamide 459.3 98 o "‘co^.<x,A, H 0HA Jn cr n Vy^tQ 2-Chloro-5-[4-(2- hydroxy-3-methoxy- propyl)-3,5-dioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]-N- phenethyl-benzamide 459.2 -69-
EXAMPLE STRUCTURE NAME DATA LCMS M/Z 99 ".<= ο„ΛΝ.!1 Ml h \..°H inci o 2-Chloro-5-[4-(2- hydroxy-2-methyl- propyl)-3,5-d ioxo-4,5- dihydro-3H- [1,2,4]triazin-2-yl]-N-(2- hydroxy-2-phenyl- ethyl)-benzamide 459.3 ★ * *
The présent invention is not to be limited in scope by the spécifie embodimentsdescribed herein. Indeed, various modifications of the invention in addition to those describedherein will become apparent to those skilled in the art from the foregoing description and the 5 accompanying figures. Such modifications are intended to fall within the scope of theappended daims.
Ail patents, applications, publications, test methods, literature, and other materialscited herein are hereby incorporated herein by reference in their entireties.

Claims (2)

  1. 01 297 8 -70- CLAIMS 1. A compound of the formula
    (l) wherein R1 is (Ci-C6)alkyl, optionally substituted by (C3-Ci0)cycloalkyl, (C6-C10)aryl, (CrCio)heterocyclyl, or (Ci-C10)heteroaryl, wherein each of said (CrC6)alkyl, (C3-C10)cycloalkyl,(C6-Cio)aryl, (C1-C10)heterocyclyl, or (CrCu^heteroaryl are optionally substituted by one tothree suitable moieties independently selected from the group consisting of hydroxy, halogen,CN-, (Ci-C6)alkyl, HO(CrCe)alkyl, (C1-C6)alkyl-NH(C=O)-, NH2(C=O)-, (CrCeJalkoxy, or (C3-Cio)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionally substituted by one or moremoieties selected from halogen, or (Ci-C6)alkyl-; R2 is hydrogen, halogen, -CN, and (CrC6)alkyl, wherein said (Ci-C6)alkyl is optionallysubstituted by one to three suitable moieties, independently selected from the groupconsisting of halo, hydroxy, amino, -CN, (CrCelalkyl, (C-|-C6)alkoxy, -CF3, CF3O-,(C-|-C6)alkyl-NH-, [(C^CeJalkylh-N-, (CrC^alkyl-S-, (C1-C6)alkyl-(S=O)-, (CrCeJalkyl-fSOz)-,(C^CeJalkyl-O-^O)-, formyi, (Ci-C6)alkyl-(C=O)-, and (C3-C6)cycloalkyl; R3 is a nitrogen linked (C-i-C^Jheterocyclyl of the formula:
    (IN) wherein R4 is independently selected from the group of suitable substituents, such ashydrogen, halo, hydroxy, -CN, HO-(CrC6)alkyl, (CrCeJalkyl optionally substituted with one tothree fluoro, (Ci-C6)alkoxy optionally substituted with one to three fluoro, HO2C-,(C1-C6)alkyl-O-(C=O)-, R5R6N(O2S)-, (CrC6)alkyl-(O2S)-NH-, (CrCeJalkyl-OzS-KCrCeJalkyl-N]-, R5R6N(C=O)-, R5R6N(CH2)m-, (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl, (C1-C1o)heterocyclyl, (C6-C10)aryl-O-, (C3-C8)cycloalkyl-O-, (C-j-CioJheteroaryl-O- and (C-i-C^Jheterocyclyl-O-; and R7 is independently selected from the group of suitable substituents such as hydrogen and (C^Ceîalkyl optionally substituted with one to three halogens, hydroxy, -CN, 01297 8 -71- (CrCeJalkoxy-, (C2-C6)alkenoxy, (C1-C6)alkyl-SO2-, NH2-, ((CrCeJalkylVN-, ((C2-C6)aikenyl)n-N-, ((C2-C6)alkynyl)n-N-, NH2(C=O)-, (C5-C6)alkyl-(C=O)N-, ((C5-Ce)alkyl)n-N-(C=O)-, (C2-C6)alkenyl-(C=O)N-, ((C2-C6)alkenyl)n-N-(C=O)-, (C2-C6)alkynyl-(C=O)N-, ((C2-C6)alkynyl)n-N-(C=O)-, (Ci-C6)alkyl-(C=O)-, (C2-C6)alkenyl-(C=O)-, (C2-C6)alkynyl-(C=O)-, (C3-C10)cycloalkyl-(C=O)-, ((C1-C10)heterocyciyl-(C=O)-, (C6-C10)aryl-(C=O), (CrC10)heteroaryl-(C=O), (C,-C6)alkyl-(C=O)O-, (C2-C6)alkenyl-(C=O)O-, (C2-C6)alkynyl-(C=O)O-, (CrC6)alkyl-O(C=O)-,(C2-C6)alkenyl-O-(C=O)-, (C2-C6)alkynyl-O-(C=O)-, (C3-C10)cycloalkyl, (C6-C10)aryl,(CrCwJheterocydyl, and (C1-C10)heteroaryl; wherein R4 and R7 may each be optionally substituted on any aliphatic or aromaticcarbon atom by one to three suitable moieties, independently selected from the groupconsisting of halo, hydroxy, amino, -CN, (CrC6)alkyl, (C^CgJalkoxy, -CF3, CF3O-,(Ci-C6)alkyl-NH-, [(C1-C6)alkyl]2-N-, (C.,-C6)alkyl-S-, (C1-C6)alkyl-(S=O)-, (CrCeJalkyl-fSOz)-,(C1-C6)alkyl-O-(C=O)-, formyl, (C^CeJalkyl-^O)-, and (C3-C6)cycloalkyl; R5 and R6 are each independently selected from the group consisting of hydrogen,(CrCeJalkyl, HO-(C2-Ce)alkyl and (C3-C8)cycloalkyl, or Rs and R6 may optionally be takentogether with the nitrogen atom to which they are attached to form a 3 to 8 memberedheterocycle; n is an integer from zéro to two; andm is an integer from one to two; or the pharmaceutically acceptable salts or solvatés or prodrugs thereof.
    2. A compound of any of the preceding daims wherein R1 is (Ci-C4)alkyi,optionally substituted by (C3-Cto)cycloalkyl; wherein said (CrC4)alkyl or (C3-C10)cycloalkyl areoptionally substituted by one to three suitable moieties independently selected from the groupconsisting of hydroxy, halogen, CN-, (CrCeJaikyl, HO(C1-C6)alkyl, (Ci-C6)alkyl-NH(C=O)-,NH2(C=O)-, (Ci-C6)alkoxy, or {C3-C10)cycloalkyl, wherein said (C3-C10)cycloalkyl is optionallysubstituted by one or more moieties selected from halogen, or (CrCeJalkyl-..
    3. A compound of any of the preceding daims wherein R1 is (Ci-C4)alkyl,optionally substituted by (C6-C10)aryl; wherein said (CrC4)alkyl or (C6-C10)aryl are optionallysubstituted by one to three suitable moieties independently selected from the group consistingof hydroxy, halogen, CN-, (CrCgJalkyl, HO(CrC6)alkyl, (CrC6)alkyl-NH(C=O)-, NH2(C=O)-,(Ci-C6)alkoxy, or (C3-C10)cycioalkyl, wherein said (C3-C10)cycloalkyl is optionally substitutedby one or more moieties selected from halogen, or (Ci-C6)alkyi-.
    4. A compound of any of the preceding daims wherein R2 is chloro, methyl or ethyl.
    5. A compound of any of the preceding daims wherein R3 is a nitrogen linked(CrCioJheterocyclyl of formula (III), wherein R4 is hydrogen and R7 is independently selectedfrom the group of suitable substituents such as hydrogen and (CrC6)alkyl, wherein said (C-i- 04297 8 -72- 10 15 C6)alkyl is optionally substituted with one to three substituants independently selected fromhalo, hydroxy, -CN, (C^C^alkoxy-, (C2-C6)alkenoxy, (C1-C5)alkyl-SO2-, NH2-, (CrC6)alkyl)n-N-, ((C2-C6)alkenyl)n-N-, {(Cz-C6)alkynyl)n-N-, NH2(C=O)-, (C1-C6)alkyl-(C=O)N-, ((C5- C6)aikyl)n-N-(C=O)-, (C2-C6)alkenyl-(C=O)N-, ((C2-C6)alkenyl)n-N-(C=O)-, (C2-C6)alkynyl-(C=O)N-, ((C2-C6)alkynyl)n-N-(C=O)-, (C1-C6)alkyl-(C=O)-, (C2-C6)alkenyl-(C=O)-, (C2-C6)alkynyl-(C=O)-, (C3-C10)cycloalkyl-(C=O)-, ((Ci-C10)heterocyclyl-(C=O)-, (Ce-C10)aryl-(C=O), (C,-Cio)heteroaryi-(C=0), (CrC6)alkyl-(C=O)O-, (C2-C6)alkenyl-(C=O)O-, (C2-C6)alkynyl-(C=O)O-, (C^CeJalkyl-OCC^O)-, (C2-C6)alkenyl-O-(C=O)-, (C2-C6)alkynyl-O-(C=O)-,(C3-C10)cycloalkyl, (C6-C10)aryl, (C-i-Cmjheterocyclyl, and (Ci-Cio)heteroaryl; wherein R7 mayoptionally be substituted on any ring aliphatic or aromatic carbon atom by one to threesuitable moieties, independently selected from the group consisting of halo, hydroxy, amino,-CN, (CrC^alkyl, (C^alkoxy, -CF3, CF3O-, (C1-C4)alkyl-NH-, [(C1-C4)alkyl]2-N-, (CrC4)alkyl-S-, (CrC4)alkyl-(S=O)-, (C1-C4)alkyl-(SO2)-, (CrC4)alkyl-O-(C=O)-, formyl,(CrC4)alkyl-(C=O)-, and (C3-C6)cycloalkyl.
    6. A compound of any of the preceding daims wherein R7 is hydrogen.
    7. A compound of any of the preceding daims wherein R3 is a nitrogen linked(C-i-C^heterocyclyl of formula (IV):
    (IV) and R7 is selected from the group consisting of: ΗΟ-
    ’ HO HO„ OH , and 20
    8. A compound of any of the preceding daims wherein R3 is a nitrogen linked(Ci-C10)heterocyclyl of formula (IV), and R7 is -73- 012978
    9. A compound of any of the preceding daims wherein R3 is a nitrogen linked(Ci-C10)heterocyclyl of formula (IV), and R7 is selected from the group consisting of: K3CO'
    h3co‘
    ,and
    10. A compound of any of the preceding daims wherein R is a nitrogen linked(Ci-C10)heterocyclyl of formula (IV), and R7 is
    11. A compound of any of the preceding daims wherein R3 is a nitrogen linked(Ci-C10)heterocyclyl of formula (IV), and R7 is selected from: H2N h2nx
    12. A compound of any of the preceding daims wherein R3 is a nitrogen linked (C1-C1o)heterocyclyl of formula (IV), and R7 is selected from:
    10 -74- 01297 8
    13. A compound selected from the group consisting of:2-Chloro-N-(1-hydroxy-cyclohexylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide;
    2-Chloro-5-[4-(2,3-dihydroxy-propyI)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N- ( 1 -hydroxy-cyclohexylm ethyl )-benzam ide;
    2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yi]-benzamide;
    2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(l-hydroxy-cycloheptylmethyl)-benzamide;
    2-Chloro-5-(4-cyanomethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy- cycloheptylmethyl)-benzamide;
    2-Chloro-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1-hydroxymethyl-cycloheptyimethyl)-benzamide;
    2-Chloro-5-[4-(2-cyano-ethyl)-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide; N-(1-Hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-methyl-benzamide;
    2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl]-N-(l-hydroxy-cyclohexylmethyl)-benzamide;
    2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-methyl-propyl)-3>5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide;
    2-Chloro-N-(1-hydroxy-cyclooctylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide;
    2-Chloro-N-(1-hydroxy-cycloheptyImethyl)-5-[4-(2-hydroxy-2-phenyl-ethyl)-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; -75- 012978
    2-Chloro-5-[3,5-dioxo-4-(3,3,3-trifluoro-2-hydroxy-propyl)-4,5-dihydro-3H- [1,2,4]triazin-2-yI]-N-(1-hydroxy-cycloheptylmethyl)-benzamide;
    2-Chloro-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4}trlazin-2- yl]-N-(2-hydroxy-2-phenyl-ethyl)-benzamide; 5 5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triâzin-2-yl)-2-chloro-N-(1 - hydroxy-cycloheptylmethyl)-benzamide;
    2-Chloro-N-(1-hydroxy-cycloheptylmethyi)-5-[4-(2-methoxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide; 5-[4-(2,3-Dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy- 10 cycloheptylmethyl)-2-methyl-benzamide; 5-[4-(3-Amino-2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro- N-(1-hydroxy-cycloheptylmethyl)-benzamide; and
  2. 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide. 15 14. A pharmaceutical composition for treating a IL-1 mediated disease in a mammal in need thereof, comprising a tberapeutically effective amount of a compoundaccording to claim 1 or a sait or prodrug thereof, and a pharmaceutically acceptable carrier ordiluent. 15 Use of a compound according to claim 1 or a sait or prodrug thereof in the 20 manufacture of a médicament for treating an IL-1 mediated disease in a mammal in need thereof.
OA1200500193A 2002-12-31 2003-12-19 3-(3,5-dioxo-4,5-dihydro-3H-(1,2,4)triazin-2-yl)-benzamide derivatives as P2X7-inhibitors for the treatment of inflammatory disesses. OA12978A (en)

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US7176202B2 (en) 2007-02-13
US7407956B2 (en) 2008-08-05
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BR0317803A (pt) 2005-11-29
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ZA200503912B (en) 2006-07-26
AU2003285716A1 (en) 2004-07-22
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AP1997A (en) 2009-04-22
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