Title of Invention	"A DIKETOPIPERAZINE COMPOUND OF FORMULA (I) AND A PHARMACEUTICAL COMPOSITION THEREOF"
Abstract	The present invention relates to a diketopiperazine compound of formula (I): wherein R1, R2, R3 and R4 are as described in the specification. The present invention also relates to a pharmaceutical composition thereof.

Full Text

The present invention relates to a diketopiperazine compound of formula (I) and a pharmaceutical composition thereof. This invention relates to the use of a class of diketopiperazine derivatives as potent and selective antagonists of oxytocin, to novel compounds within that class and to processes for their preparation. USP5817751 describes combinatorial and solid phase methods for the synthesis of diverse diketopiperazine derivatives and the use of these methods to create libraries of diverse diketopiperazine derivatives. W099/47549 describes diketopiperazine derivatives including 3-benzyl-2,5 diketopiperazine derivatives as inhibitors of fructose 1,6-bisphospate (FBPase). W099/38844 describes a method for preparing N-[aliphatic or aromatic) carbonyl]-2-aminoacetarnide compounds and their cyclisation to give inter alia diketopiperazine derivatives. WO99/37304 describes oxaheterocyclyl compounds including oxapiperazinyl compounds that are inhibitors of Factor Xa. The hormone oxytocin is potent contractor of the uterus and is used for the induction or augmentation of labour. Also the density of uterine oxytocin receptors increases significantly by >100 fold during pregnancy and peaks in labour (pre-term and term). Pre-term births/labour (between 24 and 37 weeks) causes about 60% of infant mortality/morbidity and thus a compound which inhibits the uterine actions of oxytocin e.g. oxytocin antagonists, should be useful for the prevention or control of pre-term labour. We have found a class of diketopiperazine derivatives which exhibit a particularly useful level of activity as selective antagonists at the oxytocin receptor. The present invention thus a method of treating or preventing diseases or conditions mediated through the action of oxytocin which comprises administering to a mammal in need thereof of an effective amount of a compound of the formula (I) (Formula Removed) and/or a physiologically acceptable derivative thereof, wherein: RJ represents aryl I CM) allcyl or a 5-7 membered cycloalkyl group optionally substituted with one or more hydioxyl groups which is fused to an optionally substituted benzene ring; R-,. represents C^alkyl (optionally substituted by a Ci.2alkoxy, Ci^alldthio, di(Ci.2alkyl) ammo or a CW) cycloalkyl group) or Cs.ecycloalkyi, or 5-6 membered heterocyclic group containing a single lietero atom selected from O, S or N, which nitrogen atom carries a hydrogen atom or a methyl or ethyl group; R.3 represents optionally substituted phenyl, a 5 or 6 membered hetero aryl group or a fused bicyclic ring system containing 9-10 ring members which may be a carbocyclic group or il may contain up to 3 heteroatoms selected from O, S or N and one of the fused rings is benzene; R,( represents OH or OC 1.4 alky I (optionally substituted with Ci^alkylcarbonyloxy) or NR5R6; Rs represents hydrogen, Chalky! (optionally substituted with Cmalkoxy) or C3. -/cycloalkyi; Re represents hydrogen, CMalkoxy, Ca^cycloalkyl, Cj^alkyl [optionally substituted with one or more groups selected from., carboxyl, Ci^alkylsulphonyl, or Ci^alkoxycarbonyl], Chalky! [optionally substituted with one or more groups selected from halogen, hydroxy, C| .^ilkoxy or NRvRs wherein R? and RS independently represent hydrogen or Chalky! or together with the nitrogen atom to which they are attached to form a 3-7 membered saturated heterocyclic ring which may contain an additional heteroatom selected from O, S or N (and which heterocyclic group may be substituted by 1 to 3 groups selected from fV;talkyl, hydroxy, C-i-a alkoxy (optionally substituted by C 3.6cycloalkyl or optionally suhlituted phenyl), C j^cycloalkyl or NRcRj wherein Re and Rj each independently represent a group selected from C ualkyl (optionally substituted by C 3.5 cycloalkyl or optionally substituted phenyl) or C 3.6 cycloalkyl)] or R& represents a phenyl or benzyl group (optionally substituted by one or more methoxy or benzyloxy groups) or an optionally substituted heteroarylmethyl group or aheteroaryl group or €3.7 cycloalkyl or the group O'MaCONRqRio wherein Rg represents hydrogen or Chalky!, RIO represents hydrogen, Ci^alkyl optionally substituted by a 5 or 6 membered heteroaryl group or Rg, RIO and the nitrogen atom to which they are attached together form a 5 or 6 membered salurated heterocyciic ring and wherein the 6 membered heterocyclic group may contain an additional heteroatom selected from oxygen, sulphur or nitrogen and the additional nitrogen atom either carries a hydrogen atom or a Chalky! or Ci-4alkanoyl group; or RS and R(, together with the nitrogen atom to which they are attached form a 3 to 7 membered saturated heterocyclic ring which heterocycle may contain an additional heteroatom selected from oxygen, sulphur and nitrogen and wherein the sulphur atom may be in an oxidised form e.g. SO2 and the additional nitrogen atom either carries a hydrogen atom or a C| 4alkyl or a Ci.4alkanoyl group or a Ci^alkylsulphonyl group or a C'.'i-j alkoxyC2..| alkyl [and which heterocyclic groups may be substituted by one or more halogen atoms or a group selected from C^alkyl, hydroxy, oxo, C 3_6cycloalkyl or NReRf wherein Rc and Rf each independently represent a group selected from C u (optionally substituted by C 3.6 cycloalkyl or optionally substituted phenyl) or C 3.6 cycloalkyl]. The invention also provides novel compounds of formula (I). A particularly useful class of novel compounds of formula (I) are those wherein RI is 2-indanyl optionally substituted by hydroxyl and more particularly a 2-indanyl group and R2, R3 and R4 have the meanings defined above and/or physiologically acceptable derivatives thereof. A further useful class of novel compounds of formula (I) are those wherein RI is a 2-phenethyl and R2, R3 and R4 have the meanings defined above and/or physiologically acceptable derivatives thereof. The compounds of formula (I) contain at least three centers of asymmetry, namely the carbon atoms carrying the substituents RI , R2 and R3 respectively and it is to be understood that formula (1) includes all possible stereoisomers and mixtures thereof. The substituent Ra may exist in more than one tautomeric form and it is to be all understood that formula (1) includes all possible tautomeric forms and mixtures thereof. The compounds of formula (I) wherein at least one of the groups RI, R2,R3 or R4 contains a basic or acidic grouping may form salts with physiologically acceptable acids or bases and reference to compounds of formula (I) herein includes such salts. As used herein, the terms "physiologically acceptable derivative" or " pharmaceutically acceptable derivative", mean any pharmaceutically acceptable salt, solvate, or prodrag e.g. ester or carbamate, or salt or solvate of such a prodnig, of a compound of formula (I), which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I), or an active metabolite or residue thereof. Preferred pharmaceutically acceptable derivatives are salts and solvates. As used herein, the term "prodrug" means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form mat has medical effects. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. Esters may be active in their own right and /or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt. Examples of such esters include alkyl and 1 -(acetyloxy)ethyl esters. The term alkyl as a group or part of a group refers to a straight or branched alkyl group e.g. methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, t-butyl, pentyl or hexyl. The term C 3. The term halogen refers to fluorine, chlorine, bromine or iodine. Unless otherwise specified the term optionally substituted phenyl refers to a phenyl group which may be substituted by 1 to 3 substituents which may be the same or different and selected from halogen, hydroxy, Chalky! (optionally substituted by 1-3 halogen atomsor NRgRi, | wherein Rg is hydrogen or CM alkyl, RI, is hydrogen, CM alkyl, or Rg and RH together with the nitrogen atom to which they are attached to form a 5 to 7 membered ring, which ring is saturated and may contain an additional heteroatom selected from nitrogen, oxygen or sulphur]), CM alkylsulphonyl, carboxyl, CM alkoxycarbonyl, di(Ci. ,ialkyl)aminocarboiiyloxy, Ci^alkoxy (optionally substituted by 1-3 halogen atoms, amino, CM alkylamino or di-(C|_4alkyl) amino), phenyl (optionally substituted by halogen or alkylaminosulphonyl), Ci.,ialkoxy, NRaRb [wherein Ra is hydrogen or CM filkyl, RI, is hydrogen, CM alkyl, CM alkaiioyl or CM alkylsulphonyl orRa and Rb together with the nitrogen atom to which they are attached to form a 5 to 7 membered ring, which ring is saturated and may be substituted by hydroxyl or 1 or 2 CMalkyl groups or may be spiro-rused to a dioxalane ring or may contain an additional heteroatom selected from nitrogen, oxygen or sulphur and may be substituted by 1 or 2 CMalkyl groups, or which ring is unsaturated and contains 1-3 additional nitrogen atoms], a 5 or 6 membered heteroaryl group, an optionally N-substituted aminocarbonyl or aminosulphouyl group (wherein the substituents may be 1 or 2 CM alkyl groups) or a clihyclroxyboryl group). The term 5 membered heteroaryl refers to a 5 membered ring which contains a heteroatom selected from oxygen, sulphur or nitrogen and which may also contain from 1 to 3 additional nitrogen atoms and which groups may be substituted by 1 or more groups selected from halogen, trifluoromethyl, CM alkyl, cycloalkyl, heteroaryl, saturated heterocyclic, or phenyi groups. Examples of such 5 membered heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadia/olyl, thiadiazolyl, triazolyl or tetrazolyl and these heterocycles may be substituted as described above. The term 6-membered heteroaryl group refers to a 6-membered unsaturated ring which contains from 1 to 3 nitrogen atoms and which may be substituted by 1 to 3 CM alkyl groups, or irilluoromelhyl, or alkoxy groups. Examples of such groups include pyridyl, methylpyridyl, tritluoromethylpyridyl, pyrimidinyl and triazinyl. When ]?.-) is a 5 or 6 membered heteroaryl group tliis is linked to the rest of the molecule via a carbon atom m the ring. When ]13 is a fused bicyclic carbocyclic dug system this may be for example a naphthyl, lelrahydronaphthyl, indanyl orindenyl group. When Ra is a fused bicylic system containing up to 3 heteroatoms which may be the same or different, this is conveniently a 6,5 or 6,6 ring system wherein the heterocycle may be partially saturated or together with the benzene ring to which it is fused to form a heteroaryl group and the heterocycle may be substituted by 1 or 2 groups selected from CM alkyl or halogen or haloalkyl and or may contain a carbonyl group. The said RS group may be linked to the rest of the molecule via a carbon atom in the benzene ring or a carbon atom in the heterocyclic group. When HI is a fused 6,6 heteroaryl group the hetero ring contains from 1 to 3 nitrogen atoms and examples of such heteroaryl groups include quinolinyl, isoquinolinyl, phthalazinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,2,3 benzotriazinyl or 1,2,4 benzotriazinyl. When Rj is a 6,5 bicyclic heteroaryl group the 5 membered heterocycle contains a hetero atom selected from O, S or N and may in addition also contain a further 1 or 2 nitrogen atoms and the heterocyclic ring may also be substituted by 1 or 2 CM alkyl or halogen or haloalkyl and or may contain a carbonyl group. Examples of such 6, 5 bicyclic heteroaryl groups include ben/oruranyl, benzothienyl, indolyl, benzo-oxadiazolyl, benzothiadiazolyl, benzo-oxazolyl, benzotlu'azolyl, benzoisothiazolyl, benzoisoxazolyl, bcnximidazolyl, indazolyl or benzotriazolyl and these groups may be substituted as described above. When I When R;i is a fused bicyclic heteroaryl linked via the benzene ring therein men suitable examples of such a group include 6-quinolinyl, 4-isoindolinyl, 4-(N-methyl-isoindolinyl, benzinudazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzirnidazolyl bcnzoxazolyl, 2 methyl-benzo-oxazolyl, benzothiadiazolyl, benzotriazolyl and 1-methylbenzotriazolyl. When RJ is a fused bieyclic heteroaryl group linked via the heteroaryl ring this may be for example a 2-benzofufanyl, 2-benzothienyl or 2-N-methylindolyl group . When R j is a 6,6 or 6,5 heterocyclic group wherein the heterocycle is partially saturated iliis is conveniently linked via the benzene ring therein and suitable examples include dihydrobenzofuraii, dihydrobenzopyrrole, 1,3-benzodioxolyl, 2)2-difluoro-l,3-benzodioxolyl, and 1,4-benzodioxanyl. When R) is a substituted phenyl group the said group conveniently carries from 1 to 3 substituents which may be the same or different selected from fluorine, chlorine, bromine Ci-3a]kyl(methyl), Gijhaloalkyl (trilluoromethyl), Ci^alkoxy (methoxy, ethoxy), baloalkoxy (irifluoromethoxy), aminoethoxy e.g. dimethylaminoethoxy, Ci. .jalkoxycarbonyl, carboxy, hydroxy, phenyl or phenyl (substituted by halogen or alkylaminosulphonyl), NRJlb [wherein Ra is hydrogen or Ci-aalkyl and Rb is C].2alkyl, (.'i./ialkanoyl, Ci^alkylsulphonyl, C^alkylaminocarbonyl] or NRaRb represents a pyrrolidino or piperidino ring, which ring may be substituted by a Ci^alkyl, hydroxyl or a 2,2- 1,3-diox.olane group or NRaRb represents a morpholino or a piperazino group which groups may be substituted by ] or 2 C^alkyl groups or NRaRb represents a 5 or 6 mcrnbcred heteroaryl group containing from 1 to 4 nitrogen atoms (such as a 1-imida/.olyl, 1,2-pyray.olyl, 1,2,3-triazolyl or 1,2,4-triazolyl substitittent), C\. ;ialkylsulphonyl, C| salkylaminocarbonyl, Ci-salkylaminosulphonyl, dihydroxyboryl or a 5 or 6 membered atom heteroaiyl group containing from 1 to 4 nitrogen atoms and which is linked to the phenyl group via a carbon atom in the heteroaryl group (for example pyridyl, pyrazolyl, imidazolyl or tetrazol 5-yl, which heteroaryl groups may be substituted by 1 or more CM alkyl groups. 1 examples of suitable Rj, groups wherein Ra is optionally substituted phenyl include phenyl, halophenyl such as 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 2,3-difluorophenyl, 3,4-tiilluoiophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 2-chloro-4-lluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2 fluoro-4-bromophenyl, 4-chloro-3-fluorophenyl 2,3,4-trifluorophenyl 2,4,5-trifluorophenyl or 2,4,6-trifluorophenyl, 2-fluoro~4,5-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 2-fluoro-4 inethoxyphenyl, 2- fluoro-4 hydroxyphenyl, 2-fluoro-4-diinelhylaminomethylphenyl, 2-fluoro-4-hydroxymethylphenyl, 3-fluoro-4-(4-morpholino)phenyl, 3 •fluoro-4-carboxymethyloxyphenyl, 3-fluoro-4-t-bulyloxycarbonylmethyloxyphenyl, 3-fluoro-4-dimethylaminocarbonyloxyphenyl, 3-chloro-4 trilluorornethoxyphenyl, 2,3-difluoro-4-methyl-phenyl, 4-iriJlnoromethoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl, 4-metlioxyphenyl, 4-melhoxycarbonylphenyl, 3-methoxycarbonyphenyl, 4-methylsulphonylphenyl, 4-methylarninocarbonylphenyl, 4- aminocarbonylphenyl, 4-methylaminosulphonylphenyl, 3-(3-pyrazyolyl)]ihenyl, 4-(3-pyrazolyl)phenyl, 4-(4-pyrazolyl)phenyl, 4-(3-]->yridyl)phenyl, 4-(2-pyridylphenyl), 4-(2-imidazolyl)phenyl5 3-(2-imidazolyl)phenyl, 4- (i -l-butyl-tetrazol-.vyl)phenyl, 4-methylaminophenyl, 4-dimethylaminopheny], 4-diethylaminophenyl, 4-acetylaminophenyl, 3-acetylaminophenyl, 4-hydroxy-3-acetylaminophenyl, 4-inethylstilphonylaminophenyl, 4-N-methylpiperazinophenyl, 4-N-pyjlolidinophenyl, 2-lluoro-4-(4-morpholino)phenyl, 4-(4-morpholino)phenyl, 4-(4-hydroxypiperidino)phenyl, 2-fluoro-4-(4-hydroxypiperidino)phenyl, 3-(l-pyrazolyl)phenyl, 4-(l-pyrazolyl)phenyl,, 4-(l-3,5 di-t-butylpyrazolyl)phenyl, 3-(l-imidazolyOphenyl, 4-( 1 -imidazolyl)phenyl, 4-( 1 -1,2,4-triazolyl)phenyl, 4-( 1 -1,2,3-(riazQlyOphenyl, 4-(2-4,-t-butylthiazoIyl)phenyl, 4-(5- 2-t-butyltetrazolyl)phenyl, 4-(4 spiro-1 ,3-dioxolauyl)piperidinophenyl, 4-(4-fluorophenyl)phenyl, 4-(4-ethylaminosulphonylphenyl)phenyl, 4-dimethylaminoethoxyphenyl or 3-( diliydroxyboryl)phenyl. When Ka is a 5 or (> membered heteroaryl group suitable examples of such groups include 2-furanyl, 3-thienyl, 3-fiiraiiyl, 2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chloro-2-lhienyl, 3--lluoro-5-methyl-2-tliienyl, 5-fluoro-2-thienyl, 5-methyl-2-thienyl, 5-methyl-2-ftiraiiyl, 5-bromo-2-furanyl, 4,5-dimethyl-2-furanyl, 2,3-dimethyl-5-thienyl, 5-trifluoromelhyl-2-iiiranyl, 2-furanyl-4-caiboxylic acid methylamide, 2-furanyl-5-carboxylic acid methylamide, 2-pyridyl, 6-methyl-2-pyridyl, 6-methyl-3-pyridyl, 6-hydroxy-3-pyridyl, 6-methoxy-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 3-pyridyl, 4-pyridyl, 3,5-pyrimidinyl, 2-thiazolyl, 4-oxazolyl, 4-thiazolyl, 2-methyl-4-oxazolyl, 2-ethyl-4-oxaxolyl., 2-cyclopropyl-4-oxazolyl, 2-trifluoromethyl-4-oxazolyl, 2,5-dimethyl-4-oxazoJyl, 4-thiazolyl, 2-metliyl-4-thiazolyl, 2-trifluoromethyl-4-thiazolyl, 2-trifluoromethyl-5-tliiazolyJ, 4-isoxazolyl, l-methyl-4-pyrazolyl, l,3-dimethyl-5-pyrazolyl, 5-(2-pyridyl)-2-thienyl, 2-(4-morpholino)-5-thiazolyl or 2-(4-methyl-l-pipera/.ino )-5-thiazolyl. Wiien K.3 is an optionally substituted fused bicyclic ring system examples of suitable groups include 2,3-dihydro-l-benzofuran-5-yl, l,3-benzodioxol-5-yl, 1H-1,2,3-benzotriiizol-5-yl, 2,3-'dihydro-l,4-benzodioxin-6-yl, 2,2-difluoro-l53-benzodioxol-5-yl, l,3-benzothiazol-6-yl, l-methyl-lH-l,2,3-benzotriazol-5-yl, 1-methyl-1H-1,2,3-bcnzolriazol-6-yl, 1,2,3-benzothiadiazol-6-yl, 2-methyl-l,3-benzoxazol-5-yl, 2-methyl-l,3-benz.oxazol-6-yl, l-benzofuran-5-yl, 1 -methyl-lH-lindol-5-yl, 1-benzothien-5-yl, 1-benzofiiran-6-yl, lH-indol-6-yl, 1 -methyl-1 H-benzirnidazol-6-yl, 1-methyl-1H-benamidazol-5-yl, 3-methyl-l,2-benzoisoxa2ol-5-yl, 2-fluoro-l-benzofuran-5-yl, 1H-indol-5-yl, 2-methyl-lH-benzofuran-5-ylJ lH-indazol-5-yl, lH-indazol-6-yl, 1-benzofuran-2-yl or 1 -niethyl-lH-benzimidazol-2-yl. When the group R( is a 5-7 membered cycloalkyl group which is fused to an optionally substituted benzene ring the optional substituents may be from 1 to 3 groups which may be the same or different and selected from halogen, alkyl, alkoxy, hydroxy, trifluoromelhyl, niiro, carboxyl, alkoxycarbonyl or carboxamido. When the group R, is; aralkyl the aryl moiety is phenyl optionally substituted by 1 to 3 groups which may be the same or different and selected from halogen, alkyl, alkoxy, hydroxy, trifluoromethy], nitro, carboxyl, alkoxycarbonyl or carboxamido. Examples of suitable R| groups include phenethyl or indanyl optionally substituted by liydroxyl e.g. 2-indanyl, 1-hydroxy-2-indanyl, 5-hydroxy -2-indanyl. Examples of suitable R2 groups include Cs^alkyl e.g. isopropyl, 1-methylpropyl or 2-inethylpropyl ,C 3.,, cycloalkyl e.g cyclopentyl. Conveniently IM is hydroxy , C 1.4 alkoxy e.g. methoxy, propoxy, t-butoxy , 1-acetyloxycthoxy or NRjRg. A preferred class of compounds of formula (I) are those wherein Rj represents hydroxy or (he group NRsR& A further preferred class of compounds is represented by formula (la) (Figure Removed) wherein the groups Rj, R2( RS and R4 have the meanings defined for formula (I) Conveniently R.i is a group selected from 2-phenethyl or 2-indanyl optionally substituted by liydroxyl and more particularly 2-indanyl. Conveniently Ra is a group selected from isopropyl, 1-methyl propyl, 2-metliylpropyl or cyclopentyl and more preferably Ra is a group selected from 1 -methylpropyl, or 2-methylpropyl. (..'.onveniently R/j is a group selected from phenyl, halophenyl such as 2-fluorophenyl, 3-lluoro]-)henyl, 4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-bromo])henyl, 2,3-ditluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 3,5-tlifluorophenyl, 2,5-difluorophenyl, 2-chloro-4-fluorophenyl3 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2 iluoro-4-bromophenyl, 4-chJoro-3-fluorophenyl 2,3,4-trifluorophenyl 2,4,5-tritluorophenyl or 2,4,6-trifluorophenyl, 2-fluoro-4,5-dimethoxyphenyl, 3-fluoro-4-nielhoxyphenyl, 4-tluoro-3-methoxyphenyl, 2-fluoro-4 methoxyphenyl, 2- fluoro-4 liydroxyphenyl, 2-tluoro-4-dimethylaminometliylphenyl, 2-fluoro-4-hydroxymethylphenyl, 3-fluoro-4-(4-morpholino)phenyl, 3-fluoro-4-carboxymethyloxyphenyl, 3-fluoro-4-t-butyloxycarbonylmethyloxyphenyl, 3-fluoro-4-dimethylaminocarbonyloxyphenyl, 3-chloro-4 trifluoromethoxyphenyl, 2,3-difluoro-4-rnethyl-phcnyl, 4 trifluoromethoxyphenyl, 4-tiifluoromethylphenyl, 4-hydroxyphenyl, 4- methoxyphenyl, 4-inethoxycarbonylphenyl, 3-niethoxycarbonyphenyl, 4-methylsulphonylphenyl, 4-methylaminocarbonylphenyl, 4- aminocarbonylphenyl, 4-methylaminosulphonylphenyl, 3-(3-pyrazyolyl)phenyl, 4-(3-pyrazolyl)phenyl, 4-(4-pyrazolyDphcnyl, 4-(3-pyridyl)phenyl, 4"(2-pyridylphenyl), 4-(2-imidazolyl)phenyl. 3-(2-iinidazolyl)phenyl, 4-( 1 -t-butyl-tetrazol-5-yl)phenyl, 4-methylaminophenyl, 4-dimethylaminopheayl, 4-diethylaminophenyl, 4-acetylaminophenyl, 3-acetylaminophenyl, -I -hydroxy-3-acetylaminophenyl, 4-methylsulphonylaminophenyl, 4-N -metlrylpiperazinophenyl, 4-N-pyrrolidinophenyl, 2-fluoro-4-(4-morpholino)phenyl, 4-(4-!norpholino)phenyl, 4-(4-hydroxypiperidino)phenyl, 2-fluoro-4-(4-hydroxypiperidino)phenyl, 3-(l-pyrazolyl)phenyl, 4-(l-pyrazolyl)phenyl,, 4-(l-3,5 di-t-bulylpyrazolyl)pheiiyl, 3-(l-imidazolyl)phenyl, 4-(l-imidazolyl)phenyl, 4-(l-1,2,4-ti-iazolyl)phenyl, 4-(l -l,2,3-triazolyl)phenyl, 4-(2-4,-t-butylthiazolyl)phenyl, 4-(5- 2-t-bulyltetrazolyl)phenyl, 4-(4 spiro-l,3-dioxolanyl)piperidinophenyl, 4-(4-II uorophenyl)phenyl, 4-(4-ethylaminosulphonylphenyl)phenyl, 4-climcthyIaminoethoxyphenyl,3-(dihydroxyboryl)phenyl, 2-ftiranyl, 3-thienyl, 3-foranyl, 2-tliienyl, 4-bromo-2-lhienyl, 5-bronio-2-thienyl, 5~clJoro-2-thienyl, 3-fluoro-5-methyl-2-thienyI, 5-methyl-2-thienyl, 5--methyl-2-furanyl, 5-bromo-2-furanyl, 4,5-dimethyl-2-luranyl, 5-lrifhiorotnethyl-2-furanyl, 2-fnranyl-4-carboxylic acid methylamide, 2-foranyl-5-carboxyiic acid methylamide, 2-pyridyl, 6-methyl-2-pyridyl, 6-methyl-3-pyridyl, 6-melhoxy-3-pyridyl, 6-hydroxy-3-pyridyl, 6-trifluorometliyl-3-pyridyl, 3-pyridyl, 4-pyridyl, 3,5-pyrimidinyl, 2-thiazolyl,, 2-metliyl-4-oxazolyl, 2-ethyl-4-oxazolyl, 2-cyclopropyl-4-oxazojyl, 2-trifluoromethyl-4-oxazolyl, 2,5-dimethyl-4-oxazolyl, 4-tliiazolyl, 2-methy]-4-thiazolyl, 2-trifluoromethyl-4-thiazolyl, 2-trifluoromethyl-5-(hiazolyl, 1 -methyl-4-pyrazolyl, l,3-dimethyl-5-pyrazolyl, 5-(2-pyridyl)-2-thienyl, 2,3-diliydni-l-benzoturan-5-yl, l,3-benzodioxol-5-yl, lH-l,2,3-benzotriazol-5-yl, 2,3-d iliydro- L ,4-ben/.odioxin-6-yl, 2,2-difluoro-1,3-benzodioxol-5-yl, 1,3-benzothiazol-6-yl, l-inethyl-iri-l,2.,3-beim)triazol-5-yl, l-methyl-lH-l,2,3-benzotriazol-6-yl, 1,2,3-benzothiadiazol-6-yl, 2-methyl-l,3-benzoxazol-5-yl, 2-methyl-l,3-benzoxazol-6-yl, 1-bonzofurari-5-yl, l-methy-lH-lindol-5-yl, l-benzotliien-5-yl, l-benzofuran-6-yl, 1H-indol-()-yl, 1 -methyl-1 H-benzimidazol-6-yl, l-memyl-lH-benzimidazol-5-yl, 3-methyl-l,2-benzoisoxazol--5-yl, 2-fluoro-l-benzomran-5-yl, lH-indol-5-yl, 2-methyl-lH-berizofuran-5-yl, 1 H-indazol-5-yl, lH-indazol-6-yl, 1-benzoiuran-2-yl or 1-methyl-lH-benzirnidazol-2-yl- ('oiivcnientJy the group RS is hydrogen, CMalkyl e.g. methyl or Ci-4alkoxyC2^alkyl e.g. 2-methoxyetliyl and R& is a group selected from hydrogen, Ci^alkoxy e.g. methoxy, C\. ,ialkyl e.g. methyl, n-propyl, isopropyl or t-butyl, C^ alkyl substituted by 1 to 3 halogen atoms e.g. 2,2,2-lrifluoroethyl or 2-fluoroethyl, Ci^alkyl substituted by alkoxycarbonyl or carboxyl e.g. metlioxycarbonylmethyl or carboxymethyl, alkyl substituted by alkoxy e.g methoxyethyJ, 2,2-diinetlioxyethyl, alkyl substituted by hydroxy e.g. hydroxyethyl or alkyl substituted by dialkylamino e.g. dimethylaminoethyl, 2-benzyloxyphenyl, (liniethoxybenzyl, (jptionally substituted heteroarylmethyl e.g. 2-pyridylmethyl, 3- pyridylmethyl, 4-pyridyImethyl, 3-methylimidazolylmethyl, heteroaryl such asthiazolyl e.g. 2 -1,3-thiazolyl, alkyl substituted by NR7R8 [wherein NR7Rg form a 6-membered heterocyclic ring (e.g. piperidinoethyl or rnorpholinoethyl)], cycloalkyl e.g. cyclopropyl or cyclohexyl, or NRjRf, represents, azetidino, 3-hydroxyazetidino, 3-methoxyazetidino, pyrrolidino, piporidino, 4-dimcthylaminopiperidino, 4-methyl 1,4-diazepan-l-yL, morpholino, an optionally substituted piperazino ring e.g. N-methylpiperazino,N-methanesulphonylpiperazino, N-2-methoxyethylpiperazino, miomorpholino or the sulphoxide or sulplione thereof. A preferred class of compounds of the invention are those of formula (la) wherein Rjis 2-indanyl, Ra is a group selected from 1-methylpropyl or 2-methylpropyl and R4 is hydroxy and/or more particularly the group A further preferred class of compounds of the invention are those of formula (la) wherein RS is a group selected from hydrogen, Cj^alkyl e.g. methyl or C]JialkoxyC2-4alkyl e.g. 2-methoxyethyl and R(, is a group selected from hydrogen, C^alkoxy e.g. methoxy, GI_ ,inlkyl e.g. methyl, n-propyl, isopropyl or t-butyl, €(.4 alkyl substituted by 1 to 3 halogen atoms e.g. 2,2,2 -trifluoroethyl or 2-fluoroethyl, Cj^alkyl substituted by alkoxycarbonyl or carboxyl e.g. methoxycarbonyhnethyl or carboxymethyl, alkyl substituted by alkoxy e.g methoxyetliyl, 2,2~dimethoxyethyl, alkyl substituted by hydroxy e.g. hydroxyethyl or alkyl substituted by dialkylamino e.g. dimethylaminoethyl, 2-benzyloxyphenyl, dirnethoxybenzyl, optionally substituted heteroarylmethyl e.g. 2-pyridylmethyl, 3-pyridylmetriyl, 4-pyridylmethyl, 3-methylimidazolyhnethyl, heteroaryl such as thiazolyl e.g. 2- 1,3-thiazolyl, alkyl substituted by NR?Rg [wherein NR?Rg form a 6-membered lielerooyclic ring (e.g. piperidinoethyl or rnorpholinoethyl)], cycloalkyl e.g. cyclopropyl or cyclohexyl, or NRsRg represents, azetidino, 3-hydroxyazetidino, 3-methoxyazetidino, pyrrolidino, piperidino, 4-dimethylaminopiperidino, 4-metliyl 1,4-diazepan-l-yl, morpholino, an optionally substituted piperazino ring e.g. N-methylpiperazino, N-methancsulphonylpiperazino, N-2-methoxyethylpiperazino, thiomorpholino or the sulphoxide or sulphone thereof. A yet further preferred class of compounds of the invention are those of formula (la) wherein RS is a group selected from phenyl, halophenyl such as 2-fluorophenyl, 3-iluorophenyl, 4-lhiorophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-clilorophenyl, 4-bromophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 3,5-dilluorophcnyl, 2,5-difluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2 fluoro-4-bromophenyl, 4-chloro-3-fluorophenyl 2,3,4-trifluorophenyl 2,4,5-trifluoropheny] or 2,4,6-trifluorophenyl, 2-fluoro-4,5-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-fluoro-3-methoxyphenylJ 2-fluoro-4 methoxyphenyl, 2- fluoro-4 hydroxyphenyl, 2-lluoro-4-dimethylaminomethylphenyl, 2-fluoro-4-hydroxymethylphenyl, 3-fluoro-4-(4-morpholino)phenyl, 3-fluoro-4-carboxymethyloxyphenyI,3-fluoro-4-t-butyloxycarbonylmethyloxyphenyI, 3-fluoro-4- dunetliylarninocarbonyloxyphenyl, 3-chloro-4 trifluoromethoxyphenyl, 2,3-difluoro-4-inethyl-phenyl, 4-irilluorom.ethoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl, 4-incthoxyphenyl, 4-methoxycarbonylphenyl, 3-methoxycarbonyphenyl, 4-methyisulphonylphenyl, 4-metliylaminocarbonylphenyl, 4- aminocarbonylphenyl, 4-mcthylaminosulphonylphenyl, 3-(3-pyrazyolyl)phenyl, 4-(3-pyrazolyl)phenyl, 4-(4-pyrazolyl)phenyl, 4-(3-pyridyl)phenyl, 4-(2-pyridylphenyl)3 4-(2-imidazolyl)phenyl, 3-(2-iraidazolyOphenyl, 4-(l-t-butyl-tetrazol-5-yl)phenyl, 4-methylaminophenyl, 4-diinethylaminophenyl, 4-diethylaminophenyl, 4-acetylaminophenyl, 3-ucetylaminophenyl, 4-hydroxy-3-acetylaminophenyl, 4-methylsulphonylaminophenyl, 4-N-methylpiperazinophenyl, 4-N-pyrrolidinophenyl, 2-fluoro-4-(4-morpholino)phenyl, 4-(4-moipholino)phcnyl, 4-(4-hydroxypiperidino)phenyl, 2-fluoro-4-(4-liydroxypiperidino)plienyl, 3-(l-pyrazolyl)phenyl, 4-(l-pyrazolyl)phenyl,, 4-(l-3,5 di-t-bnlylpyrazolyljphenyl, 3-(l-imiclazolyl)phenyl, 4-(l-imidazolyl)phenyl, 4-(l-1,2,4-triazolyi)phenyi, 4-(l -1 ^..S-triazolyOphenyl, 4-(2-4,-t-butylthiazolyl)phenyl, 4-(5- 2-t-butyltelrazolyl)plienyl, 4-(4 spiro-l,3-dioxolanyl)piperidinophenyl, 4-(4-nuorophenyl)phenyl, 4-(4-ethylaminosulphonylphenyl)phenyl, 4-diinethylaminoeth()xyphenyl,3-fdihydroxyboryl)phenyl, 2-furanyl, 3-thienyl, 3-fbranyl, 2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chloro-2-thienyl, 3-fluoro-5-methyl-2-tIiienyl, 5-methyl-2-thienyl, 5-methyl-2-furanyl, 5-bromo-2-furanyl, 4,5-dimethyl-2-iiiranyl, 5 trilluoromelhyl-2-fiiranyl, 2-ftiranyl-4-carboxylic acid methylamide, 2-furanyl-5-e.arboxylic acid methylamide, 2-pyridyl, 6-niethyl-2-pyridyl, 6-metliyl-3-pyridyl, 6-incthoxy-j-pyridyl, 6-liydroxy-3-pyridyl, 6-trifluororaethyl-3-pyridyl, 3-pyridyl, 4-|iyiidyl, 3,5-pyrimidinyl, 2-thiazolyl,, 2-methyl-4-oxazolyl, 2-ethyl-4-oxazolyl, 2-c;yctopropyl-4-oxazolyl, 2-trifluoroinethyl-4-oxazolyl, 2,5-dimethyl-4-oxazolyl, 4-Ihiazolyl, 2-methyl-4-thiazolyl, 2-trifluoromethyl-4-thiazolyl, 2-trifluoromethyl-5-Iliiazolyl, 1 -methyl-4-pyrazolyl, l,3-dimethyl-5-pyrazolyl, 5-(2-pyridyl)-2-thienyl, 2,3-dihydro-1 -benzofuran-5-yl, 1,3-benzodioxol-S-yl, lH-l,2,3-benzotriazol-5-yl, 2,3-diliydro-l,4-benzodioxin-6-yl, 2,2-difluoro-l,3-benzodioxol-5-yl, l,3-benzothiazol-6-y], I -methyl-1 H-l ,2,3-bcnzotriazol-5-yl, 1-methyl-lH-l,2,3-benzotriazol-6-yl, 1,2,3-benzolhiadia/.ol-6-yl, 2-inethyl-l ,3-benzoxazol-5-yl, 2-methyl-l,3-benzoxazol-6-yl, 1-benzoiiiran-S-yl, l-methy-lH-lindol-5-yl, l-benzothien-5-yl, l-benzofliran-6-yl, 1H-indol-6-yl, 1 -methyl-1 H-benziniidazol-6-yl, l-methyl-lH-benzimidazol-5-yl, 3-methyl-1,2--b(ii)Zoisoxazol-5-yl, 2-fluoro-l-benzofuran-5-yl, lH-indol-5-yl, 2-methyl-lH-benzotviran-5-y], 111 indazol-5-yl, lH-indazol-6-yl, l-benzofuran-2-yl or 1-methyl-1H-benzimidazol-2-yl. Particular preferred compounds of the invention include: (2K)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- clinxopiperazin-]-yr|'-N,N-dimethylethanamide (2jg-2-(4-fliioro]ihenyl)-2-[(3R,6R)-3-(2)3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1 yl| N.N-dimethylethanamide (2RV2-(4-lluorophenyl)-2-f(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2>5- dioxopiperaziu-l-yl |- jnorpholinamide (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2J3-dihydro-lH-inden-2-yl)-6-isobutyl-2J5- diox.opiperazin-1-ylJ-N-isopropylethanamide. (2R)-N-(tert-butyl)-2-|;(3R,6R)-3-(2,3-diliydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-2-[4-(4-hydroxypiperidin-l-yl)phenyl]ethanamide. (2R)-2-{(3R,6R)-3-(2J3-dihydro-lH-inden-2-yl)-6-[(lR)-l-methylpropyl]-2,5- dioxopiperazin-1 -yl }-2-(2-fluoro-4-morpholin-4-ylphenyl)-N-isopropylethanamide. (2R)-2-[(3R)6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-2- (4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide. (2R)-2-(2,4-ditluorophenyl)-2-|'(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- (lioxopiperazia-1-ylj-N-isopropylethanamide. (2R)-N-cyclopropyl-2-r(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-l-yl]ethanamide. (2R)-2-(2,4-difluorophenyl)-2-f(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2J5- dioxopiperazin-1 -yl)-N-methylethanarnide (2R)-2-(2,4-ciifluoiophenyl)-2-[(3R,6R)-3-(2)3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]ethanamide (3R,6R)-1 -f(l R)-1 -(2,4-difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro- 1 n-inden-2-yl)-6-isolnUylpiperazine-2,5-dione (!5 K,610-1 -|'(I R)-1 • (2,4-difluorophenyl)-2-(3-hydroxyazetidin-l-yl)-2-oxoethyl]-3-(2,3- clibydro-l 11-iiideii-2-yl)-6-isobutylpiperazine-2,5-dione (3 R,6R)-1 -1 (1 R.)-2-azeti din-1 -yl -1 -(2,4-difluorophenyl)-2-oxoethyl]-3-(2,3 -dihydro-1H- inden-2-yl)-6-isob\itylpiperazine-2,5-dione (2R)-2-(2)4-dit1uorophenyl)-2-[(3R,6R)-3-(2,3-dilaydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopipera^in-l-yl]-N-(2-hydroxyethyl)-N-methylethanamide (2R)-2-(2,4-difluoroplienyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyI-2,5- di oxopiperazi n-1 -y 1] -N-methyl-N-[2-(methylsulfonyl)ethyl]ethanamide (2R)-2-(2,4-diiluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yll-N-metliyl-N-(2,2,2-trifluoroethyl)ethanainide (2R)-2-(2,4-di-iluorophenyl)-2-[(3R,6R)-3-(233-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- (lioxopiperazin-l-yl]-N-inetliyl-N-(pyridiii-2-y]methyl)ethanamide (3R,6R)-1 - {(1 R)-1 -(2.,4-difluorophenyl)-2-[4-(metliylsulfonyl)piperazin-l -yl]-2- i)XoethyI}-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutylpiperazme-2,S-diene (2R)-2 (2,4-difluorophenyl)-2-f(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- cl i oxopiperazin-1 -yl]-N-methoxy-N-methyletlianamide (2R)-(2,4-difluorophenyl)[(3R16R)-3-(213-dihydro-l.H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1 -yl]ethanoic acid inethyJ(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2J3-dihydro-lH-inden-2-yl)-6-isobutyl-2>5 cl ioxopiperaziii-1 -y IJethanoate propyl(2R)-{'2,4-diniioroplienyl)[(3RJ6R)-3-(2J3-dihydro-lH-inden-2-yl)-6-isobutyl-2J5- tlioxojiiperazin-1 -yl |t:tlianoate 1 -(acetyloxy)ethyl (2R)-(2s4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-l H-inden-2-yl)-6-isobutyl-2,5~dioxopiperazin-l-yl]ethanoate (2R)-N-(tert-butyn-2-(2,4-difluorophenyl)-2-{(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6- [(J R.)-i -incUiylpropyl|-2,5-dioxopiperazin-l-yl}ethauamide (2R)-N-(tert-butyl)-2-(2>4-difluorophenyl)-2-{(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6- [(1 S)-l -methylpro])yl]-2,5-dioxopiperazin-l-yl}ethanamide (3R,6R)-1 -['(1R)-1 -(2,4-difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(253-dihydro- 11 I~inden-2-yl)-6-| (1S)-1 -methylpropyl]piperazine-2,5-dione. (3 R, 6R >1 -1 (1 R)-1 -(2,4-difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3 -(2,3 -dihydro- j 11 -inden-2-yl)-6-| (1R)-1 -metliylpropyl]piperazine-2,5-dione. (31^,6R)-l-[(lR)-l-(2,4-difluorophenyl)-2-(3-fluoroazetidin-l-yl)-2-oxoethyl]-3-(2,3- dihydro-lH-inden-2-yl)-6-isobutylpiperazine-2,5-dione. (2R)-2-[(3R,6R)-3-(2)3-dihydro-.lH-inden-2-yl)-6-isobutyl-2J5-dioxopiperazin-l-yl]-N- isopropyl-2-| 5-(trilluororaethyl)-2-furyrjethanamide, (2S)-2-|X3R,6R)-3-(2)3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N- i,sopropyl-2-(5-raelhylthien-2-yl)ethanamide. (2R)-2-|'(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]- N, N-dimethyl-2-| 5-(lrilluoromediyl)-2-fuiyl]ethanamide. (2R)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]- 'N,N-dirnethyl-2-(2-methyl-l,3-oxazol-4-yl)etlianamide. (3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-l-[(lR)-l-(2-methyl-l,3-oxazol-4-yl)- 2-morpholin-4-yl-2-oxoethyl]pipera2;ine-2,5-dione. (2S)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N>N- dimethyI-2-(5-raethylthien-2-yl)ethanamide (2S)-2-[(3R)6R.)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopipera2in-l-yl]-2-(3- ilui)ro-5-methylthien-2-yl)-N,N-dimetliylethaiiamide (2R)-2-(l-l->enzofuran-5-yl)-2-[(3RJ6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-isopropylethanamide. (2R)-2-(l,2,3-benzothiadiazol-6-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden- 2 y!)-6-isobutyl-2,5-dioxopiperazin-l-yl]ethaiiamide. (2R)-2-(2,3-tliiiydro-l-benzofuran-5-yl)-2-[(3R16R)-3-(2,3-dihydro-lH-inden-2-yl)-6- isobuty]-2,5-dioxopiperazin-l-yl]-N-isopropyletlianamide. (2R)-2-(l)3-benzodioxoi-5-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)- 6-i,sobulyl-2J5-dioxopiperazin-l-yl]ethanamide. (2R)-2-(benzofi.iran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1 -yl ]-N,N-dimethylethanamide. (2R)-2-|(3R,6R)-3-(2J3-dihydro-lH-inden-2-yl)-6-isobutyl-2)5-dioxopiperazin-l-yl]- N,N-dimethyl-2--(2-niethyl-]~benzofuian-5-yl)et:lianamide. (2R)-2-|(3R!6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N- isopropyl-2-(2-methyl-l-benzofuran-5-yl)ethanamide. (3R;,6R)-3-(2,:i-di]iydro-lH-inden-2-yl)-6-isobutyl-l-f(lR)-l-(2-methyl-l-benzoftiran-5-yl)-2-inorphoJin-4-yl-2-oxoethyl]piperazin-2,5-dione. (2R)-2-f(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-2- (2-fluoro-i-benzoJiiran-5-yl)-NJN-dimethylethananiide. (2R)-2 -1 (3 R,6R)-3 -(2,3 -dihydro- lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1 -yl]-2- (2-rtuoro-l-benzoi'uran-5-yl)-N~isopropylethanainide. (:!R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-l-[(lR)-l-(2-fluoro-l-benzofuran-5-yl)-2- morpholin-4-yl-2-oxoethyl]-6-isobutylpiperazine-2s5-dione. (2R )-2 -| (3 R,6R)-3 -(2,3-dilvydro-l H-inden-2-yl)-6-isobutyl-235-dioxopiperazin-l -yl]-2- OH-indol~6-yl)-N.N-dimethylethanamide. (2R)-2-(l-benzothien-5-yl)-2-[(3R,6R)-3-(2)3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1 -yl |-N,N-dimethylethanamide. The ability of the compounds of formula (I) to inhibit the actions of oxytocin may be determined using a variety of conventional procedures. Thus, compounds of formula (1) have a high affinity for the oxytocin receptors on the uterus of rats and humans and this may be determined using conventional procedure. For example the affinity for the oxytocin receptors on the rat uterus may be determined by the procedure olTetlibone et al, Drug Development Research 30. 129-142 (1993). The compounds of the invention also exhibit high affinity at the human recombinant oxytocin roceplor in C11O cells and this may be conveniently demonstrated using the procedure described by Wyatt et al. Bioorganic & Medicinal Chemistry Letters, 2001 (11) p!301-1305. The compounds of the invention are therefore useful in the treatment or prevention of diseases and/or conditions mediated through the action of oxytocin. Examples of such diseases and/or conditions include pre-term labour, dysmenorrhea and endometriosis. The compounds may also be useful to delay labour prior to elective caesarean section or transfer of the patient to a tertiary care centre. The compounds of the invention may also be useful for improving fertility rates in animals, e.g. farm animals. The invention therefore provides for the use of a compound of formula (I) and/or physiologically acceptable salts for use in therapy and in particular use as medicine for antagonising the effects of oxytocin upon the oxytocin receptor. The invention also provides for the use of a compound of formula (I) and/or a physiologically acceptable salt thereof for the manufacture of a medicament for antagonising the effects of oxytocin on the oxytocin receptor. According to a timber aspect, the invention also provides for a method for antagonising the effects of oxytocin upon the oxytocin receptor, comprising administering to a patient in need thereof an antagonistic amount of a compound of formula (I) and/or a physiologically acceptable salt thereof. It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylactics as well as the treatment of established diseases or symptoms. It will further be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated, the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 2 to SOOmg per day, dependent upon the route of administration. Thus for parentera! administration a daily dose will typically be in the range 2 to 50mg, preferably 5 to 25mg per day. For oral administration a daily dose will typically be within the range 10 to SOOmg, e.g. 20 to 150 mgper day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or non-toxic metabolically labile esters thereof together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, inhalation or insufflation, implant or rectal administration. Tablets and capsules for oral administration may contain conventional excipients such binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium slearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, foras example, potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions eirtulsioiii), syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl or propyl p-hydroxybenzoates or ascorbic acid. The compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. 'I ;or buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner. The composition according to the invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain fonmilatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form tor constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. The compositions according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations. Compounds of formula (I) wherein R4 is the group NRsRe may be prepared by cyclisation of the compound of formula (11) (Figure Removed) wherein Rj, RT and R3 have the meanings defined in formula (I) RU is hydrogen and R]2 is a Ci-3alkyl group( e.g. methyl) in a suitable solvent such as an alkanol e.g. methanol and/or 2,2,2-trifluoroethanol, dioxan or a mixture thereof or a halohydrocarbon e.g. dichloromethane. The, compound of formula (II) wherein RU is hydrogen is conveniently prepared in-situ by treating a compound of formula (II) wherein RH is an acid labile nitrogen protecting group and R|2 is hydrogen or Cualkyl, with an acid in a suitable solvent followed by treatment with a hydrohalic acid and methanol if Ri2 in the starting material is hydrogen, and then addition of a suitable base e.g. triethylamine or by treating a compound of formula (II) wherein RH is an hydrogenolysable nitrogen protecting group and R)2 is C\. 3iilkyl in a suitable solvent such as metlianol or 2,2,2-trifluoroethanol with hydrogen in the presence of a suitable catalyst e.g. palladium on carbon. Examples of suitable nitrogen protecting groups Ra include alkoxycarbonyl e.g. t-buiyloxycarbonyl or an optionally substituted benzyloxycarbonyl group. When RK> is Cj^alkyl this is conveniently ethyl or more particularly methyl. Examples of a suitable acids include mineral acids such as hydrohalic acids e.g. hydrochloric acid or organic acids such as trifluoroacetic acid. The reaction is conveniently carried out in a solvent such as 1,4-dioxan or an alkanol e.g. methanol or a mixture thereof, or halohydrocarbon e.g. dichloromethane. 'The compounds ol formula (II) may be prepared by reaction of the mixed anhydride (III) (Figure Removed) wherein RI and li.\\ have the meanings defined above and wherein RB is a Ci_6 straight or branched chain alkyl, optionally substituted phenyl or benzyl group, with the amine (TV) (Figure Removed) wherein R;, ivi, R:, and R^ have the meanings defined above, and Rj2 is hydrogen. The reaction is preferably earned out in an aprotic solvent such as an ether e.g. tetrahydrofuran or a tertiary amide such as N, N-dimethylformamide or a mixture thereof. The compounds of formula (III) may be prepared by treating the N-protected amino acid (V) (Figure Removed) wherein Rj and R] i have the meanings defined above with the corresponding haloformate (VI; R i^COaX wherein RB has the meaning defined in formula (III) and X is halogen e.g. chlorine, or bromine) in the presence of a suitable tertiary organic amine e.g. N-methyhnorpholine and in an aprotic solvent e.g. an ether such as tetrahydrofuran or a hydrocarbon e.g. toluene. '1 he arnine (1V) wherein R? is hydrogen may be prepared treating the amino acid (VII) R1202CCH(R2)NH2 (VII) wherein R^ has the meanings defined above and Rn is hydrogen with the aldehyde (VIII; R3CIK) wherein Rj has the meaning defined in formula (I)) in a suitable solvent such as an alkanol e.g. methanol followed by reaction with the isonitrile (IX; ReN=C wherein Rt has the meanings defined in formula I other than hydrogen). Alternatively, the compounds of formula (II) wherein R], I Compounds of formula (II) wherein RU is a Ci-salkyl group may also be prepared by reacting the carboxylic acid (X) or an activated derivative thereof (Figure Removed) wherein Rj, R.2, Rj and Rn have the meanings defined above and RJ2 is a Cj^alkyl group, with the aniine NHRjRf, wherein RS and R^ have the meanings defined in formula (I). Examples of a suitable activated derivative of the carboxylic acid (X) include those commonly used in peptide synthesis e.g. that derived from reaction of benzotriazol-1-yloxylri-pyrrolidinophosphonium hexafluorophosphate in the presence of a suitable aniine such as disopropylethylamine. The carboxylic acid (X) may be prepared from the corresponding compound of formula (11) wherein RS represents hydrogen and Rg represents the 2-hydroxyphenyl by reaction with carbon yldiimidazole or thiocarbonyldimidazole in a suitable solvent such as dichloromclhane and subsequent reaction of the product thus formed with aqueous acetone. Compounds of formula (II) wherein Rg represents 2-hydroxyphenyl are conveniently prepared by catalytic hydrogenolysis (e.g. Pd/H^) of the corresponding compound wherein Re is a 2 benyioxyphenyl group. In a further aspect of the invention compounds of formula (I) as defined above may be converted into other compounds of formula (I). Thus compounds of formula (I) wherein RI is hydroxyl maybe prepared from a compound of formula (I) wherein R4is the group NRsRo and RS is hydrogen Re is 2-hydroxyphenyl by reaction with carbonyldiimidazole or thiocarbonyldiimidazole in a suitable solvent such as dichloromethane and subsequent reaction of the product thus formed with aqueous acetone. ("(impounds of formula (I) wherein RS is hydrogen and R^ is 2-hydroxphenyl may be from the corresponding compound of formula (I) wherein Rg is a 2-benyloxyphenyl group by hydrogenolysis using hydrogen and a palladium catalyst. Compounds of formula (I) wherein R4 is the group NRsR^ may be prepared by reaction of (.he compound of formula (I) wherein R4 is hydroxyl or an activated derivative thereof with the ainino N I IRjRr, wherein RS and Rg have the meaning defined in formula (I) under the standard condition for preparing amides from a carboxylic acid and an amine such as NHR5R(i. Thus (he amides may be prepared by treating the compound of formula (I) wherein R4 is hydroxyl with an activating agent such as BOP (benzotriazol-1-yloxy-tns(dimethylamino)phosphonium hexafluorophosphate),TBTU (2-(lH-benzotriazol-l-y! )-J , ! AJ-tetramethyiuronium tetrafluoroborate), BOP-C1 (bis(2-oxo-3-(ixazolidinyl)phosphinic chloride) or oxalyl chloride in an aprotic solvent such as dichloromethane optionally in the presence of a tertiary amine such as triethylamine and subsequent reaction of the product thus formed with the Alternatively compounds of formula (1) wherein IL\ is the group NRsR^ may be prepared by reacting a compound of formula (I) wherein RS is hydrogen and Re is 2-hydroxyphenyl with carbonyldiimidazole or thiocarbonyldiimidazole in a suitable solvent such as dichloromethane and subsequent reaction of the product thus formed with the amine Compounds of formula (I) wherein Rjjis OC|_4alkyl (optionally substituted with GI_ .lalkylcarbonyloxy ) may be prepared by reacting the corresponding carboxylic acid (R4 is OH) or an activated derivative thereof with the appropriate alcohol (R4OH) or alkyl lialide (R^halide) under standard conditions for preparing such esters. Suitable activated derivatives include the acid halides, mixed anhydrides, those formed with coupling reagents commonly used in peptide synthesis e.g. carbonyldiimidazole and base salts of [he acid e.g. alkali mental salts. Compounds of formula (IV) may be converted into other compounds of formula (IV) using standard procedures. Thus compound of formula (IV) wherein RS is hydrogen and Rh is ?.-benzyloxyphenyl may be converted into other compounds of formula (IV) wherein RS and R« have other meanings as defined in formula (I) using the same procedures as described above for carrying out analogous reactions on compounds of formula (1). Compounds of formula (I) wherein the stereochemistry of any of the substituents Rj, R? and R) is as shown in formula (la) may be prepared starting from the corresponding single isomers of the intermediates (III), (IV) and (VII) and/or the various isomeric mixtures may be separated by conventional procedures. The intermediates (V), (VI), (VII), (VIII) and (IX) are either known compounds may be prepared by analogous methods to those known for preparing structurally related compounds. Compounds of formula group (I) wherein R4 is OH may be prepared by cyclisation of a corresponding compound of formula (II) under the conditions described above for preparing compounds of formula (I). PlO'siologically acceptable salts of a compound of formula (I) wherein 1^ is OH or one of (he groups RI, Rx, R:i or NR,|R5 has a basic or acidic centre may be prepared by treating [lie said base or acid with the required physiologically acceptable acid or base and this reaction is conveniently carried out in a solvent for the said compound of formula (I). Physiologically acceptable derivatives of a compound of formula (I) may be prepared from the appropriate intermediate corresponding to formula (II) using the process described above for preparing compounds of formula (I) or directly from the compounds of formula (1) by conventional procedures for preparing such derivatives. Thus nietabolically labile esters may be prepared by esterification of the free carboxyl or hydroxyl group using standard esterification techniques. The following examples are illustrative, but not limiting of the embodiments of the present invention. (,em-nil purification and analytical methods Analytical 1IPLC was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID), eluting with 0.1% HCOiH and 0.01 M ammonium acetate in water (solvent A), and 0.05% HCOjM 5% water in acetonitrile (solvent B), using the following elution gradient 0-0.7 minutes 0%B, 0.7-4.2 minutes 0%-100%B, 4.2-5.3 minutes 100%B, 5.3-5.5 minutes 0%B at a flow rate of 3 ml/minute. The mass spectra (MS) were recorded on a Fisons V( i Platform spectrometer using electrospray positive [(ES+ve to give Mtf and M('N1 LI) ' molecular ions] or electrospray negative [(ES-ve to give (M-H)"molecular ion] modes on a Micrornass series 2 or a Waters ZQ mass spectrometer. *H NMR spectra were recorded using a Bruker DPX 400MHz spectrometer using tetramethylsilane as the external standard. BiotageIM clvromatography refers to purification carried out using equipment sold by Dyax Corporation (either the Flash 40i or Flash 150i) and cartridges pre-packed with KPSil. Mass directed autoprep refers to methods where the material was purified by high performance liquid chromatography on aHPLCABZ+ 5um column (5cmxlOmm i.d.) with 0.1% HCO2H in water and 95% MeCN, 5% water (0.5% HCO2H) utilising gradient elution at a flow rate of 8ml minutes"1. The Gilson 202-fraction collector was triggered by a VG Platform Mass Spectrometer on detecting the mass of interest. Hydrophobic frits refer to filtration tubes sold by Whatman. SPE (solid phase extraction) refers to the use of cartridges sold by International Sorbent Technology Ltd. TLC (thin layer chromatography) refers to the use of TLC plates sold by Merck coated with silica gel 60 I'254. Oasis™ refers to Waters® Oasis™ HLB Extraction Cartridges, sold by Waters Corporation®. Method I Example 1 (2R)-2-(4-fluoroplieuvl)-2-fr3R.6RV3-C2.3-dihvdro-lH-inden-2-vn-6-isobutvl-2.S-dioxopiperazin-1 -yl] -N-isopropvlethanamide To a solution of (D)-leucine methyl ester hydrochloride (300mg) in methanol (4ral) was added triethylamirie (230 ul) arid 4-fluorobenzaldehyde (177u.l). The mixture was stirred for 2.5 hours before (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-lH-inden-2-yl)ethanoic acid (481 nig) and isopropylisocyanide (225ul) were sequentially added. After stirring for 16hr, the solvent was removed in vacua and the residue was dissolved in chloroform. This solution was washed with a saturated aqueous sodium carbonate .solution (x2), aqueous citric acid (0.5M, x2) and brine (xl), dried over magnesium sulphate and evaporated in vacua. The residue was dissolved in dichloromethane (2ml) ami trilluoroacetic acid (5ml) and stirred for 3 hours at ambient temperature. After this time, the solvent was removed in vacua and the residue co-evaporation with toluene (x3) and cyclohexane/ ether (1:1, x2). The residue was treated with a solution of triethylamine in dioxane (2% solution, 10ml) and was left to stir overnight. After this time, the dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with citric acid solution (0.5M, x2), saturated aqueous sodium bicarbonate solution (xl) and brine (xl). The liquors were then dried over magnesium sulphate and in vacuo and were then co-evaporated with cyclohexane: ether (1:1, x2). This crude material was purified by Biotagc1M (90g, silica) eluting with toluene: ethyl acetate: cyclohexane (~y. 3: 1) with 5% (liethylamine to give (2R)-2-(4-fluorophenyn-2-[(3R,6R')-3-(2,3-diJQ^:g-lH-inden-2-yl)-6-isQbutvl-2,5-dioxopiperazin-l-vl]-N4sQprQpvlethanainide (I49mg) 11PLC Rt = 3.42 minutes; m/z [M+H]' = 480. 'H NMR (CDC13) 8 7.44 (m, 2H), 7.22 (in, 2H), 7.16 (m, 2H), 7.11 (t, 2H), 6.50 (d, 1H), 5.60 (d, 1H), 5.11 (s, 1 H), 4.10 (m, 1H), 3.96 (m, 2H). 3.16 (dd, 1H), 3.07 (d, III), 2.91 (m, 111), 2.77 (in, 111), 1.84 (m, 1H), 1.73 (m, 1H), 1.42(m, 1H), 1.13 (d, 3H), 1.12 (d, 310, 0.84 (d, 3H), 0.79 (d,3H) Similarly prepared Example 2 (2jll-N-(tert-butyn-2-[(3RJR)-3-(2.3-dihydro-lH-inden-2-vl)-6-isobutvl-2.5- dioxopiperazin-l-vlj-2-[4-(4-hvdroxypiperidin-l-Yl)phenyl]ethanamide, HPLC Rt = 3.27 minutes; m/z [M+H]+ = 575. (CDC13) JS 7.3 (d,2H), 7.2 (m, 2H), 7.15 (m, 2H), 6.9 (d, 2H), 6.1-(d, 1H), 5.5 (s, 1H), 5.15 (s, III), 3.95 (m, 2H), 3.9 (m, 1H), 3.6 (m, 2H), 3.15 (m, 1H), 3.1 (m, 2H), 3.0 (m, 21-1), 2.y (m, 11T), 2.75 (in, IH), 2.0 (m, 2H), 1.75 (m, 1H), 1.65 (m, 3H), 1.45 (m, 1H), 1J (K, 9H)5 0.8 (d, 311), 0.7 (d, 311). Example 3 (2R')-l).-|(3R.6RVJ-(2.3-dihyda-o-lH-inden-2-yn-6-rflRVl-methvlpropvl1-2.5-dioxopiperazin-l-vli-2-('2-iluoro-4-moipholin-4-vlphenvl)-N-isopropvlethanamide. HPLC Rt - 3.34 minutes; m/z [M+H]+ - 565 Mi NMR (CDQO 8 7.52 (t, 1H), 7.22-7.11 (m, 4H), 7.04 (br s, 1H), 6.66 (dd, 1H), 6.56 (dd, 1H), 5.07 (s, IH), 4.19-4.08 (m, 2H), 3.98 (dd, 1H), 3.86-3.81 (4H, m), 3.21-2.91 (m, 811), 2.80-2.73 (m, 1H), 1.96-1.86 (m, 1H), 1.72-1.61 (m, 1H), 1.51-1.40 (m, 1H), 1.19 (d, 311), 1.16 (d, 311), 1.06 (d, 3H), 0.92 (t, 3H). Method 2 LCxample 4 (2 RV2-:K3R,6Rj-3 r(2,3 -dihydrp-1 H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1 -yl] -2-(4-fluorpphenyl)-N-(2,2,2-trifliioroethyl)ethananiide Methyl (2RKHJi t R,S)-2- {[2-(benzyl oxv)phenyl]amino} -1 -(4-fluorophenyl)-2- n>JlM^JI[(2R)-2-[(tert-butoxYcarbonyl)ammo1-2-(2,3-dihydro-lH-inden-2- yl).ethfmoyi].amino}-4-Tnethylpentaiioate A mixture of 4-fluorobenzaldehyde (l-2g), (D)-leucine methyl ester hydrochloride (1.7g), d iethylarnine and melhanol (56ml) was stirred at room temperature for 3 hours. 2-Bea/,yloxyphenylisocynanide (2.0g) and N-/e/-/-butoxycarbonyl-(D)-indanyl glycine (2 77g) were then added sequentially. After 40 hours the reaction mixture was partitioned between 2M hydrochloric acid and ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated in vacua. The resultant crude material was purified by column chromatography (eluting with 0.5% and 0.2% rnethanol/ dichloromethane) to afford methyl (2R)-2-{[( lR,S)-2-{[2-(benzyloxy)phenyl]amino}-l-(4-fluorophenyl)-2-i)Xoelhy]"||.(2R)-2-|'(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-lH-inden-2-yl)etrumoyr|amino} -4-methylpentanoate (4.3g) HPLC Rt - 4.34 minutes, m/z fM+H]4"- 752 M^ffj_N-_jX2J^2-£(t^ j^jjQJj^S}J-(4-tluoix)phenvl)-2-[(2-hvdrQXvphenvnamino1-2-oxoethvU-D-Ieucinate A mixture of methyl .(2R)-2-{[(lR,S)-2-{[2-(benzyloxy)phenyl]amino}-l-(4-tluoropheuyl)-2-oxoethyl]t(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-lH-inden-2-yl)ethanoyl]amino}-4-methylpentanoate (560mg), palladium on carbon (70mg) and clhanol (15ml) was stirred under an atmosphere of hydrogen for 5 hours. The mixture was filtered through Celite and the filtrate was evaporated in vacua. The crude product was purified by column chromatography (silica) eluting with ethyl acetate: cyclohexane (10% to 15%) to give methyl N-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro- H-I-inden-2-yl)et]]anoylJ-N-{(lR,S)-l-(4-fluorophenyl)-2-[(2-hydroxyphenyl)amino]-2- oxoethyl} -D-leucinate. l-Il'LC Rt = 4.06 minutes, ra/z [M+H]+ =-- 662 (2J yl)ethanoyl]f(lR)-l-(inethoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid. Carbonyldiimidazole (558mg) was added to a solution of methyl N-[(2R)-2-[(tert-butoxycarbonyl)arnino]-2-(2,3-dihydro-lH-inden-2-yl)ethanoyl]-N-{(lR,S)-l-(4-nuoropheriyl)-2-f(2-hydroxyphenyl)arnino]-2-oxoethyl}-D-leucinate(2.0g)in (lichloromethane (20ml) and the resultant mixture was stirred at room temperature for 24 hours. The reaction was then concentrated to dryness, dissolved in a mixture of acetone: water (6()ml: 40ml) and stirred for 17 hours at room temperature. The solution was then partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution and brine before being dried over magnesium sulphate and evaporated in vacua. Half of the material was taken to be used crude in further experiments. The second half was purified by BiotagerM (silica, 90g) eluting with methanol: dichloromethane: ammonia (1: 98.5: 0.5 to 2.5: 86.5: I). Evaporation of the appropriate fractions gave (2R)-{[(2R)-2-|(tert-buioxycarbonyl)aniino|-2-(2,3-dihydro-lH-inden-2-yl)ethanoyl][(lR)-l-(inethoxycarbonyll-3-inethylbutyl]amino}(4-fluorophenyl)ethanoicacid. (173mg). I ll'LC Rt - 3.91 minutes, m/z IM-Hif = 571 (2R):2-[(3]l16R)-3-(2J-dihvdro4H-inden-2-vl)-6-isobutvl-2.5-dioxopiperazin-l-yl1-2-(:i-lliig£ODilenyD-"N-(.212.2-trifluoro6thYl)ethanamide A solution of (2R)-{[(2R)-2-[(tert-butoxycarbonyl)ammo]-2-(2,3-dihydro-lH-inden-2-y Dethanoylj [(1 R)-l-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid (73mg) in N,N-dimethylformamide (2ml) was sequentially treated with diisopropylethylamine (51 u.1), phosphorus' (1 -hydroxy-1 H-benzotriazolato-O)tri-1 -pyrrolidinyl-(T-4)-hexafluorophosphate (80mg) and then after 2 minutes, 2,2,2-Irifluoroethylamine (25ul). This reaction mixture was stirred for 2 hours before being partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine before being dried over magnesium sulphate and evaporated in vacua. The residue was dissolved in 4M hydrogen chloride in dioxane and stirred for 7 hours at room temperature. The reagent was removed in vacua and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The separated organic fraction was washed with brine before being dried over magnesium sulphate and evaporated in vacua. The crude material was purified by column chromatography (silica) eluting with methanol: dichloromelhane (1% to 3%) to furnish ((2RV2-[f3R,6R)-3-(2.3-dihvdro-lH: inclen-2-y[)-6-iso|nityl-2,5-dioxopiperazin-l-yl]-2-f4-fluorophenyl')-N-(2.2.2- l!ifl]ffiBie^X)^iajn^mide_( 1 Om g) HPLC Rt = 3 .4 minutes, m/z [M+Hj+ = 520 'M NMR (CDC13) 6 7.42 (m, 2H), 7.34 (d, 1H), 7.20-7.10 (m, 6H), 6.61 (t, 1H), 5.28 (s, 1 1 i), 4.08-3.96 (in, 3H), 3.88 (m, 1H), 3.14 (dd, 1H), 3.02 (m, 2H), 2.95-2.77 (m, 211), 1 .88- 1 .70 (m, 211), 1 .40 (ddd, 1 H), 0.85 (d, 3H), 0.79 (d, 3H). '.I 'he following compounds were prepared in a similar manner Example 5 r2Rl-2-C4-j]uorophenyn-2-rf3R.6RV3-f2.3-dihvdro-lH--iiiden-2-vlV6-isobutyl-2,5- diijjcoi>jp^razm-i-yl]-N,N-dimethvlethanamide HPLC Rt = 3.37minutes, m/z [M+Hf = 466 111 NMR (CDCJ3); 4.15 (dd. 111), 3.98 (dd, 1H), 3.21-3.01 (m, 311), 2.99 (s, 3H), 2.92-2.73 (m, 2H), 2.83 (m, 311), 1 .59-1.49 (m, 1H), 1.42 (dt, 1H), 0.66-0.57 (m, 1H), 0.62 (d, 3H), 0.40 (d, 3H). I C.vample 6 ]- morpholinamide HPLC Rt - 3.32 minutes, m/z |M+H]+ = 508 HI NMR (CDC13); o 7.44-7.39 (m, 2H), 7.26-7.12 (m, 6H), 6.87 (d, 1H), 6.51 (s, 1H), 4. 12 (dd, 1H), 4.00 (dd, 1H), 3.73-3.62 (m, 3H), 3.60-3.54 (m, 2H), 3.37 (m, 1H), 3.23 (m, III), 3.20-3.02 (m, 4H), 2.91-2.75 (m, 2H), 1.60-1.50 (m, 1H), 1.45 (dt, 1H), 0.63 (d, 311), 0.62-0.55 (m, 1H), 0.42 (d, 3H). The 2 lluoro ~4-(morpholin6)-benzaldehyde used in this synthesis was prepared by the Co llowing procedure. A solution ol'2,4-difluorobenzonitrile (6.03g, 43.35mmol) and morpholine (8.3ml, 95 . 1 7mmoi) in tetrahydrofuran (27ml) was stirred at room temperature for 24hr. The mixture was evaporated and the white solid purified by Biotage™ column (90g, silica) elating with cyclohexane: ethyl acetate: (4: 1) to give 2-fluoro-4-(morpholino)- bcnzonilrile as a white solid (5.81g, 65%). HPLC Rt = 2.83 minutes; m/z [M+H]+ - 207. 2- KliLOTOr4-(uioiphcilino)-benzaldehyde To a solution o stirred lor 23.5hr at room temperature. The mixture was cooled to -50 °C and the excess DIBAL-H deastoyed by careful addition of tnethanol (27ml). The mixture was then stirred at room temperature for 10 mins, saturated ammonium chloride (27ml) added and the resulting mixture stirred at room temperature for 40 mins., and then evaporated under reduced pressure to a yellow solid. This solid was partitioned between dichloromethane (1 20ml) and water (120ml) and solid potassium carbonate added until the aqueous phase was pH 1 0. The phases were separate via a hyrophobic frit and the oraganic phase evaporated and the residue purified by a Biotage™ column (40g, silica) eluting with cyolohexane: ethyl acetate: (7:3) to give 2-fluoro-4-(morpholino)-benzaldehyde (1.96g, (>8%) as a white solid. 1-ll'LC Rt - 2.63 minutes; m/z |MTH]H ••= 210. Method 3 Example 7 (2K)-2-(2.4-difluorophenvl)-2-[(3R.6R)-3-(2,3-dihvdro-lH-inden-2-vl)-6-isobutvl-2.5-~yjj -N-isopropylethanamide rK 1 ID: 1 -:(234-difluorophenyl)-2-(isopropvlamino)-2-oxoethvr|-L-leucinate To a stirred suspension of (L)-Leucine (1.3g) in methanol (100ml) under a nitrogen atmosphere was added 2,4-difluorobenzaldehyde (1.42g). After stirring at ambient temperature lor 3 days, the suspension was cooled to — 30°C and a solution of isopropylisocyanide (O.'691g) in methanol (5ml) was added. After 3 hours at-30°C the reaction was allowed to warm to room temperature and was stirred for a further 20 hours. The solvent was removed in vacua, the residue purified using a Biotage™ column (40g; silica) eluting with cyclohexane: ethyl acetate (gradient from 8:1 to 1:1). The required tractions were combined and concentrated in vacua to furnish methyl N-[(lR)-l-(2,4-di fluorophcnyl)-2-(isopropylamino)-2-oxoetiiyl]-L-leucinate (1.326g). ]H NMR (CDC13) d 7.32. (in, 111), 6,88 (m, Hi), 6.82 (m, 1H), 6.78 (m, 1H), 4.42 (s, 1H), 4.07 (m, 1H), 3.o9 (s, 311), 118 ((, 111), 1.66 (m, III), 1.49 (t, 2H), 1.18 (d, 3H), 1.15 (d, 3H), 0.88 (d, 311), 0.77 (d, 311) N -]jJJ^J^£2,4-diiiuorophenvl)-2-(isoprQpylamino)-2-oxoethyl]-L-leucine To a solution of methyl N-[(lR)-l-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucinate (1 .32g) in methanol (15ml) was added a solution of lithium hydroxide (2.94mg) in water (1 5ml). The reaction was rapidly stirred for 1.5 hours and then evaporated in vacua. The residue was dissolved in water and neutralised using 2N hydrochloric acid. 1 he resulting solid was collected by filtration and dried in vacua. The 111 I rate was applied to 4 Oasis cartridges (6g), which were eluted with water (x2) and methanol (x2). The required fractions were combined and concentrated in vacua to afford N-[(1 R)-l-(2,4-(litliinropheiiyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine(1.01g). 1IPLC Rt = 2.51 minutes; m/z [M+Hf = 343. .(2 Lv}::2^{2A-djJllHiroflhejiYll-2 iU oxopiperazin-1 -vl i-N-isopropYlethanamide. To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-lH-inden-2-yl)ethanoic acid (29ling) in dry letrahydrofuran (5ral) under a nitrogen atmosphere at -20°C was added N-methylmorpholine (lOlmg) and a solution of isopropylchloroformate in toluene (1 ,OM, 1ml). After 10 minutes, a solution of N-[(lR)-l-(2,4-difluorophenyl)-2- (i.sopropylamino)-2-oxoethyl]-L-leucine (342rng) in N,N-dimethylformamide/ tetrahydrofuran (5ml/ 10ml) was added and the resultant mixture was stirred at room temperature lor 4 hours. The solvent was then removed in vacua and the residue was treated with 4N hydrochloric acid in dioxane (2ml). After 4 hours, methanol (5ml) was added to the reaction mixture and this was left to stand for 18 hours. The solvent was then removed in vacua and the residue was purified on an SPE cartridge (50g, silica) eluting with cyclohexane/ ethyl acetate (gradient from 4:1 to neat ethyl acetate), which furnished the two diastereomers as white solids (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3- dihydro-]H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N-isopropyletlianamide; (0.137g) IIPLC Rt - 3.47 minutes, m/z |M+H]+ --= 498 11! NMK. (CDCh) 8 7.68 (in, 111), 7.21 (m, 2H), 7.17 (m, 2H), 6.95 (m, 1H), 6.89 (m, 1II), 6.79 (d, 111), 5.91 (d, Hi), 5.33 (s, IH), 4.12 (m, 1H),4.02 (m, IH), 3.92 (dd, 1H), 3.16 (m, Hi), 3.05 (m, 2H), 2.90 (m, IH), 2.78 (m, IH), 1.85 (m, IH), 1.79 (m, IH), 1.49 (m, ! 11), 1.17 (m, 611), 0.88 (d, 3H), 0.82 (d, 3H) Method 4 Example 8 (2R)-2-(2,4-difliu)rQphenyl)-2-|'(3R.6R)-3-(2,3-dihydro-lH-inden-2-vlV6-isQbutyl-2.5-d_K)2cojjip_ejay.in-)._-y|]-N.N-dimethylethanamide Methyl N-£( 1E1-2 -ij2r{bgnzyjnxy)phenyl] amino} -1 -(2.4-difluorophenvl)-2-oxoethyl1 -L- leucinate To a suspension of L-leucine (2.33g) in methanol (200ml) at-30°C under nitrogen was added a solution of 2,4-difluorobenzaldehyde (2.52g) in methanol (10ml) and a suspension of 2-benzyloxyphenylisonitrile (3.7g) in methanol (40ml). The reaction was stirred at 30UC for 2.5 hours and then allowed to warm to room temperature and stirred for a further 6 days. The solvent was removed in vacua and the residue was passed through a Biotage™ column (90g) eluting with cyclohexane: ethyl acetate (8:1 and 7:1) to afford after evaporation of the appropriate fractions methyl N-[(lR)-2-{[2- (ben/i'Joxy)phenyl]amino}-l'(2J4-difluorophenyl)-2-oxoe1h.yl]-L-leucinate(5.06g). 11.1'LC Rl =4.0 minutes, in/z [M-H]" = 495 Methyl N- ((' 1R)-1 -(2,4-difluorpphenyi)-2-[ ('2-hvdroxyphenvl)amino1-2-oxoethvl} -L- lejicinate A mixture of palladium on carbon (10%, 300mg), methyl N-[(lR)-2-{[2-(benzyloxy)phenyl|amino}-l-(2>4-difluorophenyl)-2-oxoethyl]-L-leucinate (2.88g) and ethyl acetate (30ml) was stirred under a hydrogen atmosphere for 3 hours. The reaction was then filtered through Celite and the filter pad was washed with further portions of ethyl acetate. The combined organic fractions were evaporated to give methyl N-{(1R)-1-(2,4-diiluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (2.179g). 1IPLC Rt-3.52 min, m/z [M-H]' = 405 Methyl N-[ 1 -(2,4-difluorophenyl)-2-(dimethvlamino)-2-oxoethYl]-L-leucinate A solution of methyl N-{(lR)-l-(2,4-difluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (203mg) and l,r-thiocarbonyldiimidazole (lOOmg) in dichloromethane (5ml) was left to stand for 18 hours. Water (10D1) was added to the reaction mixture and this was then stirred rapidly for 30 minutes. After this, 1H- I icnzotriazolium, 1 -| bis(dimethylamino)methylene]-, tetrafluoroborate(l-), 3-oxide (TBTU, 321 mg) and'a solution of dimethylamine in tetrahydrofuran (0.5ml of2M solution) were added. The reaction mixture was stirred for a further 18 hours and was then passed down an SPE (5g, silica) elnting with a gradient (8:1 to 1:2 cyclohexane: ethyl acetate). The required fractions were combined and evaporated to furnish methyl N- I1 -(2,4-di tluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (1 OOmg). 1IPLC Rt - 3.16 minutes m/z |M+Hf = 343 II- LLd2^ To a solution of methyl N-[l-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinale (lOOmg) in methanol (3ml) was added a solution of lithium hydroxide (15.4mg) in water (1ml). After stirring vigorously for 4 hours the solvent was removed in vacuo. The residue was diluted with water (10ml) then neutralised with 2N hydrochloric acid. This solution was applied to an Oasis™ cartridge (6g) and eluted with water (x2) and methanol (x2). The required fractions were combined and evaporated to afford N-[l-(2,4-ditluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine(95mg). ITPLC Rt = 2.23 minutes m/z [M+H]+ = 329 (2in-^£2^difluorophenyl)I2rrj[3J^^ d I ojjopJJ2gr§gJIL:.L-ylJ-H^N~dj.|njQivjethanamide To a solution of ('2R)-[(tert-butoxycarbonyl)aiiiino](2,3-dihydro-lH-inden-2-yl)ethanoic acid (84tng) in dry tetrahydrofuran (6ml) at ~20°C under a nitrogen atmosphere was added N-methylmorpholine (32D1) and a solution of isopropylchloroformate in toluene (I .OM5 29001). After 10 minutes, a solution of N-[l-(2,4-difluorophenyl)-2-(dimeLhylamino)-2-oxoethyl]-L-leucine (95mg) in tetrahydrofuran (10ml) was added and the reaction was allowed to warm to room temperature. After 20 hours, the solvent was removed in vacuo and the residue was dissolved in 4N hydrochloric acid in dioxan (4ml). After 4 hours methanol (5ml) was added and the reaction was left to stand for a furtherlS hours. The solvent was then removed in vacuo and the residue was dissolved in dioxan (5ml) and to this was added triethylaminp (0.5ml). After 1 hour, the solvent was removed and the residue was applied to an SPE (lOg, silica). The product was eluted using methanol. A second SPE was used to further purify the material (2g, silica) using an ethyl acetate: methanol gradient (20:1 to 1:1) to afford (2R)-2-(2,4-difluorophenvl)-2-((3R.6RV 3-(2.3-clihYdro-lH-inden-2-yl)-6-isobutyl-2.5-dioxopiperazin-l-yl]-N.N-climethylethanamide (3 8mg) . IIPLC Rt=3.5 minutes, m/z [M+H]+ = 484 'H NMR (CDC13) ft 7.42 (m, HI), 7.22 (m, 2H), 7.17 (m, 2H), 7.02-6.90 (m, 2H), 6.62 (s, 1 H), 6.37 (m, 1 M), 4.09 (m, IH), 3.98 (dd, IH), 3.20-3.02 (m, 3H), 2.99 (s, 3H), 2.87 (m, 1 H), 2.85 (s, 311), 2.74 (m, IH), 1.55 (m, 2H), 0.70 (m, IH), 0.67 (d, 3H), 0.41 (d, 3H) Similarly prepared (2R)-N-cyclopropvl-2-(2.4-difluorophenvlV2-fr3R.6R)-3-r2.3-dihvdrQ-lH-inden-2-vn-6- i.sobiityl-2v5-dioxopiperaan-l-yriethanamide, HTLC Rt=3.41 minutes, m/z [M+H]+ - 496. '11 NMR (CDC13) 8 7,67 (dt, IH), 7.59 (IH, d), 7.21-7.11 (m, 4H), 6.99-6.92 (m, IH), 6.92-6.84 (m, IH), 6.35 (d, IH), 5.43 (s, IH), 3,99 (dd, IH), 3.93 (dd, IH), 3.17-2.71 (m, 6! I), 1 .88-1 .70 (in. 2H), 1 .48-1.38 (m, III), 0.86 (s, 3H), 0.81-0.74 (m, 5H), 0.51-0.45 (m, 211). Example 10 lZll)i2r(ZA-^L^ dlojcoj,]i.nerazin- 1 - vl ] -N .N-dimethvlethanamide : £2Jj^r2d[M^.i'loroP^ dioxopiperazin-1 -vH-N-(2-ben2rs4oxvphenvl)ethanamide A mixture of 2,4-difluorobenzaldehyde (1.421g), (D)-leucine methyl ester hydrochloride (1 .817g), triethylamine (1.391ml) and methanol (20ml) was stirred at room temperature Cor 16 hours. N-/e/7-butoxycarbonyl-(D)-indanylglycine (2.914g) and 2-benzyloxy-phenylisocyanide (2.090g) were then added sequentially. After 24 hours the solvent was removed under reduced pressure and the reaction mixture was taken up in ilichloromethane (ca. 20ml) and purified by Biotage™ flash column chromatography (2x90g silica cartridges on a Biotage Quad 3 system eluted with 1:9 ethyl acetatexyclohexane) to afford methyl (2R)-2-{[(lR,S)-2-{[2-(benzyloxy)phenyl]amino}-l-(2,4-(1ifluorophenyl)-2-oxoethyl][(2R)-2-[(tert-biitoxycarbonyl)amino]-2-(2,3-dihydro-1 1 f-inden-2-yl)ethanoyl]aanino}-4-methylpentanoate (S.lOOg) (HPLC Rt = 4.40 minutes m/z [M+H]1 = 770). This was taken up in 4M hydrogen chloride in 1,4-dioxane (20ml) and the mixture was left at room temperature for 3 hours. The solvent and hydrogen chloride were blown off using a stream of nitrogen overnight. The crude material was taken up in methanol (90ml) containing triethylamine (10ml). After 30 minutes, the mcthanol and excess of triethylamine were removed under reduced pressure. The cnide product was purified by Biotage rM flash column chromatography (2x90g silica cartridges on a Biotage Quad 3 system eluted with 1:2 ethyl acetate:cyclohexane) to yield (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazm- 1 -yl |-N-(2-benzyloxyphenyl)ethanamide (3.381g). 11 PLC Rt = 3 .99 minutes, m/z |M+H] ' = 638 4_-c^ clj oxppiperazin- 1 -yl] -N-(2-hvdrQxyphenyl)ethanamide (2RS)-2-(2,4-dilluorophenyl)-2-[(3R36R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin- 1 -yl |-N-(2-benzyloxyphenyl)ethanarnide (3.381g) was dissolved in ethyl acetate (200ml) and hydrogenated at atmospheric pressure over 10% palladium on carbon catalyst (0.980g of 1 0% Pd/C:water 1 :1 w/w) at room temperaure for five hours. The reaction mixture was filtered through Celite and the sovent was removed under reduced pressure to give the (2RS)-2-(2,4-difluorophenyl)-2-[(3R)6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isol)utyl-2,5-dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)ethanamide as a cream-coloured foam (2.65()g). HPLC Rt = 3.61 minutes, m/z [M-IT1]' = 546 (no [M+H}* visible) -J. ;jlj^thanoic_ ^apidL (2RS)-2-(2,4-difluorophenyl)-2-[(3R>6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2J5-dioxopiperazin-l-yrj-N-(2-hydroxyphenyl)ethanamide (2.650g) was stirred in dichloromelhane (20ml) and carbonyldiimidazole (1.178g) was added, the mixture was left at room temperature for 16 hours then the solvent was removed under reduced pressure. The residue was men taken up in 1 :1 acetone:water (v/v) (80ml) and left at room temperature for 30 minutes. The bulk of the acetone was then removed under reduced pressure and the residue was partitioned between dichloromethane and 0.5M hydrochloric acid. The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure. The crude product was purified (Biotage™ flash chromatography column, 90g silica cartridge eluted with (i) 1:1 ethyl acetate:cyclohexane (ii) ethyl acetate (Hi) ethyl acetateimethanol 9:1) to afford (2RS)-2-(2,4-difluorophenyl)-:;-|"(3R,6R)-J-(2;?-clihydro-lPI~inden-2-yl)-6-isobutyl-2,5-dioxopiperazJn-]-yl]-etha]ioic acid.as a colourless solid 1.524g as a mixture of epimers. I1PLC Rt - 3.44 and 3.58 minutes, bothm/z [M+H*] = 457 (2JR.l-2-(2,4:dij1iiQronh^yl>T2-rf3R,6RV3-(2,3-dihvdro-lH-inden-2-vl)-6-isobutyl-2.5-dioxopipcrazin-1 -vlj-N,N-dimethylethanarnide The acid (2RS)-2-(2,4-dilluorophenyl)-2-[(3R,6R)-3-(2,3-diliydro-lH-inden-2-yl)-6-i,sobutyl-2,5-dioxopiperazin-l-yl]-ethanoic acid (0.747g) prepared as described above was dried over R)O|o in vacuo for five hours to give 0.724g drier material; this was dissolved in anhydrous dichloromethane:acetonitrile (1:1 v/v, 6ml) and treated with triethylamine (0.223ml) and BOP-C1 (bis(2-oxo-3-oxazolidinyl)phosphinic chloride, dissolved in anhydrous dichloromethane:acetonitrile (1:1 v/v, 6ml) and treated with Irietlrylamine (0.223ml) and BOP-C1 (his(2-oxo-3-oxazolidinyl)phosphinic chloride, 0.450g) and the mixture was sonicated for ca. 1 min to give a gelatinous mass. After 10 minutes at room temperature a solution of dimethylamine in tetrahydrofuran (10ml of 2M solution) was added to give a clear solution; this was left for 16 hours at room temperature. The solvents were removed under reduced pressure and the mixture was parlilioned bcween dichloromethane and O.IM hydrochloric acid. The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure. The crude product was purified by flash column chromatography (12g Biotage™ silica cartridge eluted with (i) 1:1 ethyl acetate:cyclohexane (ii) ethyl acetate (iii) ethyl acetate:methanol 9:1) to give I lie (J1D-2- (2-4 -dif)uorophenyl)-2-[(3R.6R)-3-(2,3-dihydro-1 H-inden-2-yl)-6-isobutvl-?,5-jjuixopingrazin~ 1 -yl]-N,N-dimethylethanamide as a colourless solid 0.285g. [IPLC Rt - 3.43 minutes, m/z [M+Hf = 484 'l 1 NIMR (CDC10 o' 7.47 -7.40 (m, 1H), 7.24-7.11 (m, 4H), 7.01-6.91 (m, 3H), 6.62 (s, 11-1), 4.09 (dd, 111), 3.98 (dd, 1H), 3.19-3.01(m, 3H), 2.99 (3, 3H), 2.92-2.75 (m, 5H), 1.64-1.51 (m, 211), 0.76-0.66 (m, 4H), 0.43 (d, 3H). Method 5 Kxamplc 11 (2JiI-Jrl2^4-djf1ii()rophenvl)-2-[(3R,6R)-3-f23-dihvdro-lH (Hojarpjpgrazin-1 -yi |-N ,N-dimethyletlianarnide {2R1J(benzyloxvciirbonvl)aminoJ(2.3-dihvdro-lH-inden-2-vnethanoic acid R-Indanylglycine (1 ,91g) was suspended in dioxane (10ml) and water (10ml). To this was added Iriethykmine (1.7ml) andN-(benzyloxycarbonyloxy)succinimide (2.54g) and the reaction mixture was stirred rapidly at room temperature for 2 days. The reaction mixture was poured into water (50ml) and extracted with chloroform (100ml). The organic phase was washed with IN hydrochloric acid (50ml) and water (50ml). This was dried over magnesium sulphate and the solvent removed in vacua to give (2R)-[(henzy]oxycarbonyl)amino](2,3-dihydro-lH-inden-2-yl)ethanoic acid (3.06g). HPLC Rt = 3.35 minutes; m/z [M+Hf = 326. 'II NMR (CDCI3) 8 7.40-7.29 (m, 5H), 7.21-7.11 (m, 4H), 5.28 (d, III), 5.11 (s, 2H), 4.57 (in, III), 3.14-2.79 (m, 5H). (2RS)-2-(2.4-difliiorophenvl)-2-[T3R,6R)-3-(2.3-dihvdro-lH-mden-2-vl)-6-isobutyl-2.5-dioxopiperazin-l-yiJ-N-(2-hvdroxyphenyl)ethanamide To a solution of (D)-leucine methyl ester hydrochloride (1.45g) inmethanol (10ml) was added triethylamine (1.12ml) and 2,4-difluorobenzaldehyde (0.875ml). The mixture was stirred for 3 days before (2R)-[(benzyloxycarbonyl)amino](2,3-dihydro-lH-inden-2-yl)elhanoic acid (2.6g) and 2-benzyloxyphenylisocyanide (1.76g) were sequentially added. Tlie reaction mixture was left to stand for 24 hours. The solvent was removed in vacua and the residue was separated between ethyl acetate (200ml) and water (200ml). The organic phase was washed with brine. To this solution was added palladium on carbon (2.0g) and acetic acid (10ml) and the reaction mixture was stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered through Celite and washed with water (3xlOOml), saturated sodium bicarbonate solution, brine and dried over magnesium sulphate. The solvent was evaporated in vacua. The crude product was purified by column chromatography (silica) eluting with ethyl acetate: cyclohexane (50% to 66%) to give (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2J3-dihydro-lH-inden-2-yl)-o isobiityl-2,5-dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)ethanamide(2.0g). I-'IPLC Rt = 3.59 minutes; m/z [M+Hf = 548. Carbonyldiirnidazole (4.80g, 1.54 equiv.) was suspended in anhydrous dichloromethane (40m L) and the suspension was left at room temperature for 15 minutes. (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-ylj-N'(2-hydroxyphenyl)ethanamide (10.50g, pre-dried in vacuo over P,iOU) for 24 hours) was then added with stirring and the resultant solution was stirred at room temperature for 6 hours. The resulting yellow solution was then treated with a 2.0M solution of dimethylamine in tetrahydrofuran (54mL, 5.6 equiv .)and the resulting mixture was stirred at room temperature for 16 hours. The solvents plus residual dimethylamine were removed under reduced pressure and the reaction mixture was taken up in dichloromelhane (200mL) and washed with IM hydrochloric acid (200mL). The organic phase was separated using a hydrophobia frit and was evaporated under reduced pressure lo oa. SOrnL, The crude product was applied to 4x90g silica Biotage™ columns on a Quad 3 system; each column being eluled with (i) 2:lv/v ethyl acetatexyclohexane (12x50mL fractions), (ii) ethyl acetate (12x50mL fractions), (iii) 9:lv/v ethyl acetate:methanoi to give (2RV2-(2.4-difluorophenvl)-2-[(3R.6R)-3-C2.3-dihvdro-lH-ind^i>2-vJ)-6-igobutYl-2.5-dioxQpiperazin-l-vl]-N.N-dimethvletfaanainide (5.753g, 62%) as a colourless solid, I1PLC lit = 3.41 minutes, m/z [M+H]+ = 484 1H NMR (CDC13) fi 7.48 -7.38 (m, 2H), 7.24-7.11 (m, 4H), 7.01-6.90 (m, 2H), 6.62 (s, 111), 4.09 (del, 1H), 3.98 (dd, 1H), 3.19-3.01(m, 3H), 2.99 (3, 3H), 2.92-2.75 (m, 5H), 1.64-1.51 (m, 211), 0.76-0.66 (in, 4H), 0.43 (d, 3H). Similarly prepared: Example 12 (2R)-2-f2,4-difluorophenvl)-2-r(3R.6RV3-(2.3-dihvdro-lH-inden-2-vn-6-isobutvl-2.5-djoxppiperaziri-1 -vj]-N-methylethanamide colourless solid, 41% 11PLC Rt = 3.4 minutes, m/z fM+H]+ = 470 Example T3 (2R>2-(2,4-ditluorophenvl)-2-[(3R.6R)-3-(23-dihvdro-lH-inden-2-vn-6-isobutvl-2.5-djoxopiperazin-1 -yljethanamide colourless solid, 36% 11PLC Rt = 3.3 minutes, m/z [M+H]+ = 456 Example 14 IlR^RV.l -[(1 R)-1 -(2.4-difluorophenvl)r.2-motpholin-4-yl-2-oxoethyl]-3-(2.3-dihvdro-_lH-inden-2-vl)-6-isobutylpiperazin.e-2,5-dione colourless solid, 61% ITPT.C Rt - 3.4 minutes, m/z [MH-Hf = 526 Example 15 i lR-()R)-l-|YiRVI-(2.4-difluoTophenvlV2-(3-hvdroxvazetidin-l-vlV2-oxoethvl'l-3-(2,3- cl i hydro-111-inden-2-yl)-6-isobutvlpiperazine-2,5-dione colourless solid, 45% HPLC Rt = 3.2 minutes, m/z [M+H]+ = 512 (azetidin-3-ol prepared by the method of S S Chatterjee and D J Triggle; J Chem. Soc. Chem. Comm. (2) 93 (1968) Example 16 {3_R,6R>1-I (1 R)r2-azetidin-l -Yl-l_:(2J4-JifluQrophenyn-2-oxoethvl1-3-(2.3-dihvdrQ-l H-mdm:2ryn-6-is_obutylpipera2ine-2.5-diQne colourless solid, 46% I1PLC Rt = 3.4 minutes, m/z |M+FI]+ = 496 Example 17 (2R)-2-(2.4-difluorophetivl)-2-rr3R.6R)-3-(2,3-dihvdro-lH-inden-2-vl)-6-isobutvl-2.5-JiQxopipera2inrl-vl]-N-(2-hydrQxye_thy])-jS[-methylethanamide colourless solid, 59% HPLC Rt - 3.3 minutes, m/z [M+Hf = 514 Example 18 r2tO-2-f2.4 22% 11PLC Kt - 3.2 minutes, m/z [M+Hf = 576 Example 19 £2Rl-Jj:(214-difluorophenvlV2-r(3R,6R)-3-(2,3-dihvdro-lH4nden-2-vl)-6~isobuW djoxQpiperazin-l-vlJ-N-methvl-N-(2,2,2-trifluoroethyl)ethananiide colourless solid, 11 % HPLC Rt = 3.5 minutes, m/z [M+H]"1" = 552 ('2,2,2-trirluoroethylmethylamme hydrochloride was prepared by the method of E R Bissell and M Finger; J. Org. Chem. 24 1256-1259 (1959)) Example 20 )-2-[(3R.6RV3-(2,3-dihvdro-lIi-indea-2-vlV6-isobutvl-2.5- d[o^g^p^ra^u-J-yl]-N-methvl-N-(pYi-idin-2-ylmethvl)ethanamide tan foam, 19% 1 1 PLC Rt = 3.5 minutes, m/z [M+H]+ = 561 Example 21 » ( 2 [il-2r(M-difliu)rpphenvl)-2-r(3R.6R')-3-f2.3-dihvdro-lH-inden-2-vlV6-isobutvl-2,S- IIP!./: Rt =3.4 minutes, m/z [M+H]1' = 500 Example 22 ^ Carbonyldiimidazole (1 .42g, 1 .6 equiv.) was suspended in anhydrous dichloromethane (1 OrnDaud the suspension was left at room temperature for 15 minutes. (2RS)-2-(2,4-dilluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl ]-N-(2-hydroxyphenyl)ethanamide (3.00g) was then added and tlae resultant solution was stirred at room temperature for 16 hours. The resulting yellow solution was was then evaporated under reduced pressure and the residue was treated with a 1 : 1 (v/v) mixture of water and acetone (10 mL). The mixture was stirred for 2 hours, then (he acetone was removed under reduced pressure and the residue was partitioned between dichloromethane and O.lM HC1 aq. The organic phase was separated using a hydrophobic frit: then evaporated to low volume and purified by chromatography on a Biotage Quad 3 system (90g silica column) eluted with l:l(v/v) ethyl acetatexyclohexane, then ethyl acetate, then 1:1 (v/v) ethyl acetate :methaaol to give a mixture of diastereoniers (2.61g). These were separated on a chiral reverse-phase column (Chiralcel OD, eluted with 15% propan-2-ol/heptane containing 0.1%TFA) to give: (2RVf2.4-diiluorophenyl)[(3R.6R')-3-r2,3-dihvdro-lH-inden-2-vlV6-isoburvl-2.5-dk)xopiperazin-l-yl]ethanoic acid (1.60g) HPLC Rt = 3.4 minutes, m/z [M+H]+ = 457 Example 23 methyl (2RVr2.4-difluorophenvl')|'('3R.6RV3-(2.3-dihvdro-lH-inden-2-Yn-6-isobutvl-2.5- dioxopiperazin-l-yl]ethanoate Carbonyldiimidazole (0.324g, 1 .6 equiv.) was suspended in anhydrous dicbloromethane (4mL)and the suspension was left at room temperature for 15 minutes. (2RS)-2-(2,4- diiluorophenyl)-2-[(3R,6R)-3-(2>3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)ethanamide (O.SOOg) was then added with stirring and the resultant solution was left at room temperature for 16 hours. The mixture was then treated with methanol (lOmL) and left at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified by preparative plate chromatography on silica (20x20cm plates x4 eluted with 1:3 ethyl acetatexyclohexane x5) to give methyl (2RV(2.4-difluorophenyr)[(3R.6R>3-(2,3- djhjghx>ljH^ridje^^ (0.453g, 66%) 1 1PLC Rt - 3.42 minutes, m/z [M+H]+ = 471 Similarly prepared: Example 24 I li'LC Rt = 3.71 minutes, m/z [M+Hf = 499 Example 25 - 1 -yl |ethanoate (2R>(2,4-difluorophenyl)[(3R,6R)-3-(23-dihydro-lH-inden-2-yl)-6-isobutyl-2)5-dioxopipera?.in-l-yl]etlianoic acid (example 22) (0.1 30g) was stirred in anhydrous DMF (ImL) and anhydrous potassium carbonate (0.020g, 0.5 eq.) was added. The mixture was stirred at room temperature for 1 hour then cooled to -10°C (ice-salt bath). The heterogeneous mixture was treated with 1-bromoethyl acetate (0.120mL, excess) and stirred for 3.5 hours keeping the bath temperature between -10 and -5°C. It was then partitioned between 1-)CM and IM HO aq. (20 mL each). The organic phase was separated (hydrophobia frit) and evaporated under reduced pressure to give a purple gum; this was purified by SPE cartridge (5g, silica eluted with (i) cyclohexane x2, (ii) DCM x2, (iii) cliethl ether x2, (iv) ethyl acetate x2, (v) methanol x2 to give l-(acetyloxv)ethvl f2RV L2^tiflu^oj)hj^j^ dioxopiperazin-1 -yljethanoate (O.OSlg) as a yellow foam. HPLC Ri - 3.5 iiiinutes, m/z [Ml llf = 543 Similarly prepared: In the table below, Examples 26, 54-55, 66-104, 107-117, 124-131 were prepared via method 1. The t-hutyl ester Example 39 was prepared via perchloric acid-catalysed transesterificatiori of the corresponding acid (Example 22) with t-butyl acetate by the procedure of T Kolasa and M J Miller; Journal of Organic Chemistry (1990), 55(6), 1711-21. Other Examples in the table below were prepared via method 5. (Table Removed) Henzofuran-5-carboxaldehyde (215 mg, 1.47 mmol) and D-leucine t-butyl ester hydrochloride (329 ing, 1.47 mmol) were dissolved in methanol (1.5ml) and Irieihylamine (0.205 ml, 1.47 mmol) added. The mixture, a pale yellow solution, was left to stand at room temperature overnight (23.5 hours). Then Boc-D-indanylglycine (429 mg, 1.47 mmol) was added followed by isopropylisonitrile (0.138 ml, 1.51 mmol). The mixture, a yellow solution, was left to stand at room temperature overnight (23.5 hours) before the solvent was evaporated unaer reduced pressure to leave a yellow gum. The gum was dissolved in 4M hydrogen chloride in dioxan (3 ml, 12 mmol) and left to stand at room temperature for 7.5 hours before it was evaporated under reduced pressure to leave an orange / brown gum. The gum was dissolved in methanol (2 ml) and 4M hydrogen chloride in dioxan (1 nil, 4 mmol) added. The mixture was left to stand at room temperature for 5.5 hours before the solvent was removed by evaporation under reduced pressure. The residue was dissolved in dichloroniethane (4ml) and triethylamine (0.5 ml, excess) added. The mixture was stirred at room temperature overnight (18.3 hours) before the solvent was removed by evaporation under reduced pressure. The residue was loaded in dichloroniethane onto a SPE column (lOg silica, Mega Bond Elut cartridge, pre-eluted with cyclohexane). The column was eluted stepwise (40 - 45 ml each step) with 100% chloroform, 3 : 1 cyclohexane : diethyl ether, 1 : 1 cyclohexane : diethyl ether, 1 : 3 cyclohexane : diethyl ether, 100% diethyl ether, 1 : 1 cyclohexane : ethyl acetate, 1 : 2 cyclohexane : ethyl acetate and 100% ethyl acetate. The 1 : 3 cyclohexane : diethyl ether lot: 2 cyclohexane : ethyl acetate fractions inclusive were combined to give a pale yellow solid (336 mg). The solid was loaded in dichloroniethane onto 6 preparative clnomatograpliy plates (silica gel 60 plates, 20 x 20 cm ). The plates were eluted four times with 30 : 1 dichloromethane : isopropanol. The required band was extracted with 9 : 1 ethyl acetate : methanol to give _(2R>2-( 1 -benzofuran-5-yl)-2-f(3R.6RV3-(2.3-dihydro-1 ll-inden-2-vl)-6-isobutvl-2,5-diQxopiperazin-l-yl]-N-isopropylethanamideas a white solid (141mg, 0.28 mmol) 1-LPLC Rt = 3.46 minutes; m/z [M+H]+ = 502. 1FFMMR 8 7.95 (d, 111), 7.73 (d, 1H), 7.68 (d, 1H), 7.53 (d, 1H), 7.37 (dd, 1H), 7.16 (m, 411), 6.79 (d. 111), 5.79 (d, 1H), 5.37 (s, 1H), 4.11 (m, 1H), 4.03 (brdd, 1H), 3.99 (dd, 111), 3.10-2.97 (m, 3H), 2.95-2.78 (in, 2H), 1.79(m, 1H), 1.69 (m, 1H), 1.33 (m, 1H), 1.09 (1.611), 0.78 (d, 311), 0.67 (d, 3H). Similarly prepared Example 137 (2R)^2-(l,2,3-benzothtadiazol-6-yl)-N-(tert-butvn-2-r(3R.6R)-3-(2.3-dihvdro-lH-inden-2-vl)-6-isobutyl-2,5-dioxopipera2in-l-vl1ethanamide. 11PLC Rt '11 NMR 8 8,66 (d, III), 7.82 (d, 1H), 7.67 (dd, 1H), 7.20 (m, 4H), 6.72 (br d, 1H), 6.13 (s, 111), 5.19 (s, 111), 4.06 (br dd, 1H), 4.00 (dd, 1H), 3.18 (m, 1H), 3.07 (m, 2H), 2.92 (in, 1H), 2.81 (m, HI), 1.86(m, 1H), 1.80 (m, 1H), 1.54 (m, 1H), 1.36 (s, 9H), 0.85 (d, :U1), 0.78(d, 3H). Example 138 (2RV2-(2.3-dihvdro-l-beii2ofiu-an-5-vl)-2-('f3R.6RV3-(2,3-dihvdro-lH-inden-2-vlV6- i sobutyl-2,5-diQXQpiperazin- 1 -ylj-N-isopropylethanamide. HPLC Rt = 3.34 minutes; m/z [M+Hf = 504. '11 NMR 5 7.81 (br s, 1H), 7.18 (m, 5H), 6.79 (d, 1H), 6.44 (br d, 1H), 5.50 (d, 1H), 5.06 (s, 111.), 4.61 (t, 2H), 4.08 (m, 1H), 3.96 (m, 211), 3.22 (t, 2H), 3.15 (m, 1H), 3.07 (d, 2H), 2.90 (m, 1H), 2.79 (dd, Hi), 1.82(m, 1H), 1.71 (m, 1H), 1.42 (m, 1H), 1.12 (dd, 6H), 0.83 (d, 311), 0.77 (d, 31-1). Example 139 6 jsobutyj-^S-dioxppiperazin- 1 -vllethanamide. HPLC Rt = 3.48; m/z [M+Hf = 520 'H NMR (CDC13) 8 7.21 (m, 211), 7.16 (m, 2H), 6.97 (d, 1H), 6.88 (dd, 1H), 6.82 (d, 1H), 6.58 (m, 111), 6.06 (m, 2H), 5.64 (s, 1H), 5.02 (m, 1H), 3.95 (m, 2H), 3.16 (m, 1H), 3.07 (in, 211), 2.89 (m, 1H), 2.77 (m, 1H), 1.82 (m, 1H), 1.71 (m, 1H), 1.41 (m, 1H), 1.32 (s, 911), 0.83 (d, 311), 0.79 (d, 3H) Example 140 Ll!i)i2Jjjenzofean:S dHjjiopipera/.in-l-Yll-N^-dtmethvletlianamide Meth^[Jl~lilR)I2jJJ.2H32Mizyio leucinate ']'o a suspension of L-leucine (2.62g) in methanol (250ml) at-30°C under nitrogen was added a solution of benzofuran-5-carbaldehyde (2.92g) in methanol (15ml) and a suspension of 2-benzyloxyphenylisonilrile (4.19g) in methanol (15ml). The reaction was stirred at --30UC Jbr 2 hours and then allowed to warm to room temperature and stirred for a I iirlher 3 days. The solvent was removed in vacua and the residue was passed through a Biotage™ column (3x90g) eluting with cyclohexane: ethyl acetate (5:1) to afford after evaporation of the appropriate fractions methyl N-[(lR)-2-{[2(benzyloxy)phenyl]amino}-I -(benzofuran-5-yl)-2-oxoethyl]-L-leucinate (5.1 Ig). HPLC Rt-3.97 minutes, m/z [M+H]'1 = 499 Methyl JS_.iiilILkHkgJl™iMrail^r¥D-2-r(2-hydrQXYphenynarnino]-2-oxoethvll-L- A mixture of palladium on carbon (10%, SOOmg), methyl N-[(lR)-2-{[2-(benzyloxy)phenyl]tunino}-l-(benzofuran-5-yl)-2-oxoethyl]-L-leucinate(5.1g) and ethyl acetate (60nii) was stirred under a hydrogen atmosphere for 5 hours. The reaction was then filtered through Celite and the filter pad was washed with further portions of ethyl acetate. The combined organic fractions were evaporated to give methyl N-{(1R)-1-(benzofuran-5-yl)-2-j(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (3.429g). HPLC RK3.49 min, ni/z |M+H]+ - 41 1 Methyl N-[l-(benzofi]ran-5-yl)-2-(diniethylamino)-2-oxoethvl1-L-leucinate A solution of methyl N-{(lR)-l-(benzofuran-5-yl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (410mg) and IJ'-thiocarbonyldiimidazole (196mg) in dichloromethane (5ml) was left to stand for 18 hours. Water (20 Dl) was added to the reaction mixture and this was then stirred rapidly for 30 minutes. After this, 1H-Benzotriazolium, l-[bis(dimethylamino)methylene]-, tetrafluoroborate(l-), 3-oxide (TBTU, VIOmg) and a solution of dimethylamine in tetrahydrofuran (3ml of 2M solution) were added. The reaction mixture was stirred for a further 18 hours and was then passed down an SPE (5g, silica) eluting with a gradient (3:1 to 1:2 cyclohexane: ethyl acetate). The required fractions were combined and evaporated to furnish methyl N-[l-(ben7oluran-5-yl)-2-(dimethylaniino)-2-oxoethyl]-L-leucinate(140mg). MPLC Rt = 2.70 minutes rn/z [M+H]+ = 347 N-IL(benzofiiran-5-yl)-2-(dimethvlainino)-2-oxoetIiyl]-L-leucme To a solution of methyl N-[l-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (520mg) in methanol (5ml) was added a solution of lithium hydroxide (91mg) in water (3ml). Alter stirring vigorously for 24 hours the solvent was removed in vacuo. The residue was diluted with water (10ml) then neutralised with 2N hydrochloric acid. This solution was applied to an Oasis 1M cartridge (2x6g) and eluted with water (x2) and methanol (x2). The required fractions were combined and evaporated to afford N-[l-(benzo1iiran-5-yl)-2-(dimethylamino)-2-oxoetlayl]-L-leucine (478mg). HPLC Rt = 2.27 minutes rn/z [M+H]+ = 333 i2Mi2^QTenzot^^ ch^cc^rjgrazmjjjjQ^N-dimethvlethanamide To a solution of (2R)-| (tert-butoxycarbonyl)aminoJ(2,3-dihydro-lH-inden-2-yl)ethanoic acid (4H>mg) in dry tetrahydrofuran (5ml) at -20°C under a nitrogen atmosphere was added N-melhyhnorpholine (158ul) and a solution of isopropylchloroformate in toluene ( 1 .OM, 1 .44ml). A Her 1 0 minutes, a solution of N-[l-(benzofuran-5-yl)-2-(dimethylmnino)-2-oxx>ethyl]-L-leucine (47Smg) in dimethylformamide (5ml) was added and the reaction was allowed to warm to room temperature. After 20 hours., the solvent was removed in vacua and the residue was dissolved in 4N hydrochloric acid in dioxan (4ml). After 4 hours methanol (13ml) was added and the reaction was left to stand for a further 1 8 hours. The solvent was then removed in vacua and the residue was separated between dichloromethane and saturated sodium bicarbonate solution. The organic phase was evaporated in vacua and the residue was applied to an SPE (lOg, silica). The product was eluted using an ethyl acetate: methanol gradient (3:1 to 1:3) to afford (2R)-2-rhenzoiiiran-S-vl)-2-((3R.6R)-3-(2.3-dihvdro-lH-inden-2-vlV6-isobutvl-2,5-djoxopip_grazia-l -yl]-N,N-dimethylethanamide (5 Img). 11PLC Rt=3.36 minutes, m/z [M+Hf = 488 'l 1 NMR (Du-DMSO) 8 8.47 (d, IH), 8.07 (d, IH), 7.71 (m, IH), 7.69 (d, IH), 7.38 (dd, ] 11), 7.21 (m, 21-1), 7.12 (m, 211), 7.03 (m, IH), 6.47 (s, IH), 3.88 (m, IH), 3.69 (dd, IH), 3.07-2.67 (m, 511), 2.87 (s, 3H), 2.77 (s, 3H), 1.40-1.70 (m, 2H), 0.46 (m, IH), 0.42 (d, 311), 0.02 (d, 3H) Example 141 )-H N^N^|jiMthyi-2-(2-niethyl-l-benzofuran-5-vl)ethanamide H -hen2ofuran-S-vl)-2-r(3R,6R)-3-(2,3-dihvdro-lH-inden-2-yl)-6- A mixture of 2-methyl-5-formylbenzofuran (1.26g), (D)-leucine methyl ester hydroehioride (1.57g), triethylamine (1.2ml) and methanol (20ml) was stirred at room temperature for 6 hours and then left to stand for 19 hours. N-benzylcarbonyl-(D)-indanylglycine (2.80g) and 2-benzyloxy-phenylisocyanide (1.89g) were then added sequentially and the mixture stirred for 2 days. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. This was washed with IN hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic phase was dried over MgSO4 and concentrated in vacua. The residue was diluted with ethyl acetate (100ml) and acetic acid (10ml) and hydrogenated at atmospheric pressure over 1 0% palladium on activated carbon (1 .5g). After 4 hours the catalyst was removed by filtration through a pad of celite and washed with dichloromethane/methanol (500ml of 1 : 1 v/v). The filtrate and washings were combined, evaporated under reduced pressure. The residue was separated between ethyl acetate and water. The organic phase was washed with water, saturated sodium bicarbonate solution and brine. The organic phase was dried over K4gSC>4 and evaporated under reduced pressure. The residue was applied to a silica cartridge ( lOOg) and eluted with cyclohexane/ethyl acetate (500ml of 3:1, 2:1, 1 : 1 v/v) and ethyl acetate (500ml). The required fractions were combined and evaporated in VCICHO to give (2RS)-2-(2-jnethylbenzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-lH-indcn-2-yl)-6-isc)butyl-235-dioxopiperazin-l-y]]-N-(2-hydroxyphenyl)ethanamide (1.58g). 1 IP! .C Rt -- 3.60 minutes; m/z [M+H]+ = 566. (2RV2- 1 (3 R.6R)-3 -(Z3 -dihvdro- 1 H-inden-2-vn-6-isobutvl-2.5-dioxopiperazin- 1 -vl] -RN-dimethy! -2-(2-metfayl- 1 -benzofuran-5-vl)ethanamide r.arbonyldiimidazole (92mg, 1.6 equiv.) was suspended in anhydrous dichloromethane (5mL) and the suspension was left at room temperature for 15 minutes. (2RS)-2-(2-uirthylbenzoi\iran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-ylj-N-(2-hydroxyphenyl)ethanamide (200mg) was then added and the mixture was stirred at room temperature for 5 hours. The resulting brown solution was then treated with a 2.0M solution of dimethylamine in tetrahydrofuran (1.06mL, 6 equiv.) and the resulting mixture was stirred for 30 minutes and then left to stand at room temperature for 1 8 hours. The reaction mixture was diluted with dichloromethane (2mL) and washed with I M hydrochloric acid (2mL). The organic phase was separated using a hydrophobia frit and was evaporated under reduced pressure to leave a brown gum. The crude product was applied to a silica cartridge (1 Og). This was eluted with cycloh6xane (100ml), cyclohexane/ethyl acetate (100ml of 2:1, 3:2, 1:1, 2:3 and 1:2 v/v), ethyl acetate (200ml) and ethyl acetate/methanol (100ml of 19:1 v/v). The required fractions were combined and evaporated in vacua to give (2R)-2-fr3R,6R)-3-(2.3-dihydro--lI-I-inden-2-)dli(i:Lsi>lmLvh2.5-dioxopiperazin-]-yri-N,N-dimethvl-2-(2-methYl-l-benzoruran-5-ylkllMiarnide_as an off-white solid (88mg). I 1PLC Rt =- 3.40 minutes; m/z [M+H]"' = 502. 1 1 [ NMR (CDC13) ft 7.52 (d, 1H), 7.43 (d, 1H), 7.27-7.13 (m, 5H), 6.54 (s, IH), 6.38 (m, 1 H), 6.31 (d, 111), 4.24 (m, 1H), 3.99 (dd, IH), 3.22-3.05 (m, 3H), 2.99 (s, 3H), 2.86 (m, 1 1-1), 2.82 (s, 311), 2.75 (m, HI), 2.48 (m, 3H), 1.45 (m, 1H), 1.36 (m, 1H), 0.57 (m, 1H), 0.51 (cl, 31-1), 0.19 (d,3H). Similarly prepared: - Kxample 142 n.Kl-2:t[QIL^B)--3-(2.3-d}hvdro-lH-inden-2-vlV6-isobutvl-2.5-dipxopiperazin-l-vl1--N- _ HPLC Rt =- 3.40 minutes; m/z [M+H]+ = 516. M-I NMR (CDC13) 8 7.57 (m, 1H), 7.41 (d, 1H), 7.28-7.1 1 (m, 5H), 6.61 (m, 1H), 6.37 (m, 1 H), 5.49 (d, IH), 5.23 (s, 1H), 4.1 1 (m, 1H), 4.02-3.93 (m, 2H), 3.19-3.05 (m, 3H), 2.92 (m, III), 2.77 (in, 111), 2.48 (m, 3H), 1.79 (m, IH), 1.70 (m, IH), 1.38 (m, IH), 1.10 (m, 61 f), 0.78 (d, 3H), 0.69 (d, 311). Example 143 (:3I^R>3-{2J-dihvdro-lH-inden-2-yl)-6-isobuM yj)-2-mQi-pholin-4-vl-2-Qxoethvl]piperazin-2,5-dione HPLC1 Rt = 3.38 minutes; rn/z [M+H]+ - 544. 'II NMR (CDClj) 8 7.51 (d, IH), 7.45 (d, IH), 7.26-7.14 (m, 5H), 6.57 (s, IH), 6.39 (m, 111), 6.34 (m, IH), 4.20 (m, IH), 3.99 (m, IH), 3.73-3.33 (6H), 3.22-3.03 (m, 5H), 2.88 (in, IH), 2.75 (m, 111), 2,49 (m, 3H), 1.45 (m, IH), 1.37 (m, IH), 0.54 (m, IH), 0.51 (d, 311), 0.20 (d, 311). Example 144 (2R)-2-r(3R.6R)-3-(2,3-dihvdro-lH-inden-2-vl)-6-isobutvl-2.5-dioxopipera2in-l-vl]-2- (2-fliioro-l.;beiiz_ofiiran-5-yl)-N,N-dirnethYlethanamide HPLC Rl = 3.39 minutes; m/z [M+H]+ - 505. 'i;i NMR (CDC13) 8 7.56 (d, III), 7.45 (d, IH), 7.32 (dd, IH), 7.23 (m, 2H), 7.16 (m, 2H), 6.55 (s, 111), 6.23 (d, IH), 5.89 (d, IH), 4.22 (m, IH), 3.99 (dd, IH), 3.21-3.04 (m, 3H), 3.00 (s, 3H), 2.87 (m, IH), 2.84 (s, 3H), 2.75 (m, IH), 1.47 (m, IH), 1.38 (m, 111), 0.58- 0.49 (m, 4H), 0.22 (d, 3H). 5 -Brpnio-2-flupro-1 -benzoturan 5"Bromobenzofuran-2-carboxylic acid (4.68g) was suspended in carbon tetrachloride (150ml) and water (50ml). To this was added sodium bicarbonate (3.36g), followed by Selectllor (7.1 g) and the reaction mixture was stirred rapidly for 20 hours. The reaction mixture was diluted with dichloromethane and 2N sodium hydroxide solution. The organic phase was separated, washed with brine and dried over anhydrous MgSO^. The solvent was evaporated under reduced pressure at room temperature. The residue was applied to a silica cartridge (20g) and eluted with diethyl ether. This gave 5-bromo-2- fliioro-1 -benzofuran (1.4g). 'l I NMR (CDC13) 8 7.61 (d, HI), 7.36 (dd, IH), 7.26 (d, IH), 5.84 (dd, IH). 2-l'luoro--5-formyl-l-henzofuran A shiny of magnesium powder (219mg) and iodine (cat) in dry tetrahydrofuran (3ml) was heated at 50°C under nitrogen for 20 minutes. 5-Bromo-2-fluoro-l-benzofuran (1.4g) was dissolved in dry tetrahydrofuran (6ml). A 1ml portion of the solution was added to I he slurry at 50°C without stirring. After 30 minutes the rest of the solution was added slowly and the reaction was heated at reflux for 3 hours. The reaction was cooled in an ice/water bath and dimethylforrnamide (1ml) was added dropwise maintaining the temperature below 10°C. After 1 hour a mixture of 2N hydrochloric acid (12.5ml) and brine (12.5ml) was added. The reaction mixture was extracted using ethyl acetate (3x25ml). The combined organics were washed with brine and dried over anhydrous n lagnesium sulphate. The solvent was removed in vacuo and the residue applied to a silica cartridge (50g). This was eluted with cyclohexane, cyclohexane/ethyl acetate (6:1, 5:1 v/v). This gave 2-Huoro-5-fofmyl-l-benzofuran (376mg). 'l-l NMR (CDCI3) 5 10.05 (s, 1H), 8.04 (m, IH), 7.83 (dd, IH), 7.54 (d, 1H), 6.01 (dd, III). Example 145 (2RV2-IY3R,6R)-3-(23-dihvdro-lH-inden-2-yl)-6-isobutvl-2.5-dioxopiperazin-l-vll-2- (2-fluoro-l-benzoi\iran-5-vll-N-isopropvlethatiamide HPLC Rl = 3.42 minutes; m/z [M+H]+ = 520. 'J -J NMR (CDC13.) 8 7.61 (d, III), 7.42 (d, 1H), 7.31 (dd, 1H), 7.21 (m, 2H), 7.16 (m, 2H), 6 70 (d, I H), 5.89 (d, IH), 5.57 (d, 1H), 5.18 (s, 1H), 4.11 (m, 1H), 3.98 (m, 2H), 3.16 (in, 1 11), 3.08 (m, 211), 2.91 (m, IH), 2.78 (m, IH), 1.82 (m, IH), 1.73 (m, IH), 1.41 (m, 1 fl), 1.12 (d, 311), 1.10 (d, 311), 0.81 (d, 3H), 0.72 (d, 3H). Example 146 (3R,6R)-3-(2.3-dihvdro-lH-inden-2-vlVl-raR)-l-(2-fluoro-l-benzofuran-5-yl)-2- m()ipholin-4-yl-2-oxoethvl|-6-isobutvlpiperazine-2,5-dione 11PLC Rt = 3.35 minutes; m/z [M+Hf = 548. 'H NMR (CDCU) 8 7.55 (d, IH), 7.47 (d, IH), 7.31 (dd, IH), 7.27-7.14 (m, 4H), 6.58 (s, 111), 6.38 (d, III), 5.91 (d, IH), 4.19 (m, IH), 4.00 (dd, IH), 3.73-3.50 (m, 511), 3.39 (m, 1 H), 3.23-3.04 (m, 511), 2.87 (m, IH), 2.76 (m, IH), 1.47 (m, IH), 1.40 (m, IH), 0.53 (d, 311), 0.51 (m, III), 0.24 (d, 311). Example 147 (?Ji)-2j(lR^6R)-3-(2.3-dihvdro-lH-inden-2-vl)-6-isobutvl-2.5-dioxopiperazin-l-yl]-2- HPLC Rt = 3.38 minutes; m/z [M+I-I]+ = 487. 'll NMR (CDCI3) 8 9.03 (s, IH), 7.66 (d, IH), 7.49 (d, IH), 7.30 (m, Hi), 7.21 (m, IH), 7.1 8-7. 1 0 (in, 4H ), 7.02 (m, IH), 6.57 (s, IH), 6.55 (m, IH), 4.29 (m, IH), 4.00 (dd, IH), 3.22-3.03 (m; 311), 3.00 (s, 3H), 2.92-2.73 (m, 5H), 1.40 (m, IH), 1.33 (m, IH), 0.57 (m, 111), 0.45 (d, 311), 0.06 (d, 311). Example 148 (2R)-2ilJIIi^lU-3:J.2.3-dihvdro-lH-inden-2-vl)-6-isobulvl-2,S-dioxopip HPLC Rl = 3.20 minutes; m/z [M+Hf = 579. 'H NMR (CDC13) 8 9.62 (s, IH), 7.64 (d, IH), 7.41 (d, IH), 7.30 (m, IH), 7.26-7.10 (m, 611), 6.51 (m, 111), 6.48 (s, IH), 4.18 (m, IH), 4.05-3.90 (m, 2H), 3.68-3.50 (m, 2H), 3.28-3.01 (m, 411), 2.96-2.69 (m, 8H), 1.41 (m, 211), 0.65 (m, IH), 0.47 (d, 3H), -0.10 (d, 311). Example 149 dioxopip_era/in-l-y)']rN1N-dimethylethanamide (2RSV2~(l-ben2othiei>5-yl)-2-[(3R;6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-255-dioxopiperazin- 1 -yl ]~N~(2-benzyloxyphenyl)ethanamide A mixture of 5-formylbenzotliiophene (2,0g), (D)-leucine methyl ester hydrochloride (2.24g), triethylamine (1 .72ml) and methanol (20ml) was stirred at room temperature for 24 hours. N-toY~biitoxycarbonyl-(D)-indanylglyeine (3.59g) and 2-benzyloxy-phenylisocyanide (2.58g) were then added sequentially and the mixture stirred for 4 days. Then the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (20ml) and 4M hydrogen chloride in 1,4-dioxane (20ml) and the mixture was stirred at room temperature for 2 hours. The solvent and hydrogen chloride were evaporated under reduced pressure. The crude material was dissolved in dichloromelhane (30ml) and triethylamine (1 Oml) added. The mixture was stirred for 1 8 hours before the dichloromethane and excess of triethylamine were removed under reduced pressure. The crude product was dissolved in dichloromethane (100ml) and washed with IN hydrochloric acid (ZxlOOml) and brine. The organic phase was dried over MgSCXi and evaporated in vacua to yield (2RS)-2-(l-benzothien-5-yl)-2-[(3R,6R)-3~ (2,3-dihyciro-llI-in(ien-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N-(2-benzyloxyphenyl)ethananude as a brown foam (7.5g). HPLC Rt = 3.88 minutes, m/z [M+Hf = 658. (2RS)-2-(l-benzothien-5-vlV2-[(3R.6RV3-f2,3-dihvdro-lH-inden-2-vlV6-isobutvl-2.5-dioxopiperazjn-l-Yl'|-N-(2-hydrpxyphgnyl)ethanamide (2RS)-2-(l-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2J5-dioxopiperazin-1 -yl]-N-(2-benzyloxyphenyl)ethanamide (l.Og) was dissolved in dichloromethane (5ml) and to this was added dropwise a l.OM solution of BBr3 in dichloromethane (2.0ml). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added IN hydrochloric acid (30ml) and dichloromethane (20ml). The phases were separated and the organic phase was washed with IN hydrochloric acid (30ml) and brine (30ml). The organic phase was dried over MgSO.i and evaporated in vacua. The residue was purified by Biotage1 flash column chromatography, eluting with 3:2 ethyl acetate:cyclohexane. The required fractions were combined and evaporated in vacua to give (2RS)-2-(l-benzothien-5-yl)-2-[(3R,6R)-3~ (2,3 -dihydro- 1 H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)ethanamide (21 Omg). HPLC Rt - 3.55 minutes, m/z [M+Hf = 568. ^^ dioxopiperazin-1-yll-N.N-dimetliyletliananiide Carbonyldiimidazolc: (lOOmg) was suspended in anhydrous dichloromethane (ImL) and the suspension was leit at room temperature for 15 minutes. 2RS)-2-(l-benzothien-5-yl)-2-|(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)ethanamide (200mg) was then added and the mixture was stirred at room temperature for 5 hours 20 minutes. The resulting brown solution was then treated with a 2.0M solution of dimethylamine in tetrahydrofuran (l.OmL, 6 equiv.) and the resulting mixture was stirred for 30 minutes and men left to stand at room temperature for IS hours 15 minutes. The reaction mixture was evaporated under reduced pressure. The crude product was purified by silica column chromatography eluting with l:lv/v ethyl acetateieyelohexane. The required fractions were combined and evaporated in vacno to yive(2R)-2-(benzothJen-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-(Jioxopiperaiin-i -ylj-NjN-dimethylethanamide as a white solid (90mg). HPLC Rt = 3.35 minutes, m/z [M+H]+ = 504. '11NMR (CDC13) 5 7.94 (d, HI), 7.89 (m, IH), 7.70 (d, IH), 7.54 (d, IH), 7.41 (m, IH), 7.35 (d, HI), 7.23 (m, IH), 7.13 (in, 3H), 6.63 (s, IH), 4.25 (m, IH), 4.02 (dd3 IH), 3.23-3.04 (m, 311), 3.0! (s, 311), 2.93-2.77 (m, 5H), 1.50-1.32 (m, 2H), 0.52 (m, IH), 0.49 (d, 311), 0.12 (d,3H). Compounds 150-169 and 174-175 were prepared via method 1. Compound 170 was prepared via method 2. Compounds 171, 172 and 173 were prepared via method 5. (Table Removed) ICxnmple 176 (2RV2-[(3R.6RV3-(2.3 dihydro-lH-inden-2-vl)-6-isobutyl-2,5-dioxopipera2in-l-vri-N-i sojroi2yj-2-[5-(trifluoroniethylV2-iurvl3ethanamide To a solution of 5-tritluoromethyl-furan-2-carbaldehyde (140mg)[prepared as in ref. Cbem. Ilelerocycl. Compd. 13, 7977, 1280-1282 by R.V.Grigorash, V.V.Lyalin, L.A.Alekseeva and L,.M.Yagiipol'skii: 5-Trifluoromethylftiran Derivatives] inmethanol (1.1 ml) was added triethylamine (118 |il) and (D)-leucine t-butyl ester hydrochloride (190mg). The mixture was left to stand for 16.33 hours before (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-lH-inden-2-yl)ethanoic acid (246mg) and isopropylisocyanide (77.4p,l) were sequentially added. The mixture, a yellow solution, was left to stand for 24 hours before the solvent was removed in vacua. The residue was dissolved in 4M hydrogen chloride in dioxane (3ml) and left to stand for 6.75 hours at ambient temperature. After this time, the solvent was removed in vacua. The residue was dissolved in methanol (4ml) and treated with a solution of 4M hydrogen chloride in dioxane (0.2ml) and was left to stand overnight. After this time, the solvent was removed in vacua. The residue was stirred in dioxane (9.5ml) containing triethylamine (0.5ml) and dichlorometliane (5ml) for 4,75 hours. Then the mixture was evaporated in vacua to leave a light brown solid. This crude material was purified by SPE column (lOg, silica Mega Bond Elut1M) eluting stepwise with 100% chloroform, 4:1 cyclohexane : diethyl ether, 3:1 cyclohexane : diethyl ether, 2:1 cyclohexane : diethyl ether, 1:1 cyclohexane : diethyl ether, 1:2 cyclohexane : diethyl ether, 1:3 cyclohexane :>diethyl ether, 100% die/thy] ether, 1:1 ethyl acetate : cyclohexane, 2:1 ethyl acetate : cyclohexane, 3:1 ethyl acetate : cyclohexane, 100% ethyl acetate. The 1:2 cyclohexane : diethyl ether to 2:1 ethyl acetate : cyclohexane fractions inclusive were combined to give an orange gum (215mg). The gum was purified further, to separate the isomers, by preparative plate chromatography, Whatman PKL6F silicagel 60 plates 20 x 20 cm2, eluted in 1:1 ethyl acetate : cyclohexane six times and extracted with 9:1 ethyl acetate : methanol to give (2RV2-[(3R.6R)-3-(2.3-dihvdro-lH-mden-2-vn-6-isobutvl-2.5-dioxopiperazin-l-vl'|-N-isopropyl-2-[5-(trifluoromethvlV2-furyl1ethanamide (64mg), 11PLC Rt = 3.59 minutes; m/z [M+H]+ = 520. 'I I NMR (CDC]3) 8 7.88 (d, 1H), 7.16 (in, 4H), 6.85 (d, 1H), 6.74 (d,lH), 6.30 (d,!H), 5.73 (s, H), 4.19 (dd, Hi), 4.08 (m, 1H), 3.97 (dd, 1H), 3.14 (m, 2H), 3.01 (m, 1H), 2.84 (in, 211), 1.81 (m, 111), 1.68 (m, 1H), 1.15 (d, 6H), 1.11 (m, 1H), 0.82 (dd, 6H). Similarly prepared Example I77 (2S^bHf3R^}r3rI2.3-dilwdro-lH-inden-2-vlV6-isobutvl-2.5-dioxopiperazin-l-yl]-N- lsorjror)yJr2H[5jjTicthylthien-2-yl)ethanainide By the procedure of Example 176 but using 5-methyl-thiophene-2-carbaldehyde 11PLC Rt = 3.46 minutes; m/z [M+H]+ = 482. '11 NMR (CDC1,) 8 7.21 (m, 2H), 7.16 (m, 2H), 6.94 (d, 1H), 6.67 (d, 1H), 6.63 (d, 1H), 5.73 (d, 1H), 4.94 (s, 1H), 4.07 (m, 1H), 3.93 (m, 2H), 3.16 (dd, 1H), 3.05 (m, 2H), 2.93 (m, 11-1), 2.77 (n», 111), 2.47 (s, 3H), 1.96 (m, 1H), 1.86 (m, 1H), 1.72 (m, 1H), 1.17 (d, 311), 1.12 (d, 3H), 0.94 (d, 3H), 0.92 (d, 3H) Example 178 (2R3-2-|'(3R,6RV3-(2J-dihvdro-lH-inden-2-yl)-6-isobutyl-2.S-dio?cppiperazin-lryl]r N.N:(iiirigthyl-2-[5-(trifluoromethyl)-2-furyl]ethanatnide N-[2-(beiizvloxv')phenvn-2-|'(3R.6RV3-(2.3-dihvdro-lH-inden-2-vlV6-isobutvl-2.5-( lioxopiperazin- 1 -yl |-2-[5-(trifluoromethvl)-2-farvl]acetamide A mixture of 5-trilluoromethyl-furan-2-carbaldehyde (351mg), (D)-leucine methyl ester hydrochloridc (389ing), triethylamine (0.298ml) and methanol (2.2ml) was stirred at room temperature for 4 hours and then left to stand for 19 hours. N-ftyf-butoxycarbonyl-(D)-iudanylglycine (623mg) and 2-benzyloxy-phenylisocyanide (448mg) were then added sequentially and the mixture stirred for 7 hours before being left to stand at room temperature for 4 1 hours. Then the solvent was removed under reduced pressure to leave an orange / brown syrup. This was taken up in 4M hydrogen chloride in 1,4-dioxane (2.8ml) and the mixture was stirred at room temperature for 2 hours. The solvent and hydrogen chloride were evaporated under reduced pressure. The crude material was dissolved in methanol (5ml) and triethylamine (0.54ml) added. The mixture was stirred for 1 8 hours before the methanol and excess of triethylamine were removed under reduced pressure. The crude product was purified by Biotage flash column chromatography (40g silica cartridge eluted with 1 :5 ethyl acetate:cyclohexane (600ml), 1 :3 ethyl acetate: cyclohexane (400ml) and 1 :2 ethyl acetate:cyclohexane (450ml)) to yield N~[2-(ben/.yIoxy)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-lH-rnden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-2-15-(trifluoromethyl)-2-furyl]acetamide as an orange solid (/I72rng). I'lPLC Rt - 4.04 minutes, m/z [M+H]* = 660. r3-QJi^ N-r2-(benzyloxy)phenyl]-2-[(3RJ6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopipera/.in-l -yl]-2-[5~(trifliioromemyl)-2-furyl]acetamide (469mg) was dissolved in ethyl acetate (10ml) and hydro genated at atmospheric pressure over 10% palladium on activated carbon (lOOmg). After 4 hours the catalyst was removed by filtration through glass fibre filters and washed with ethyl acetate. The filtrate and washings were combined, evaporated under reduced pressure and dried in vacua at room temperature to leave a yellow / brown solid (400mg). The solid was dried over P2O5 overnight to give 2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N-(2-hydroxypheiiyl)-2-|5-(trifluoromethyl)-2-furyl]acetamide(365mg). HPLC Rl - 3.64 minutes, m/z [M+H]+ = 570. (2RI-2-£(3_Rj6RV 3-(213 -dihydro- 1 H-inden-2-vl)-6-isobutYl-2.5-dioxopiperazin- 1 -yll- l]et Carbonyldiimidazole (78rng» 1.6 equiv.) was suspended in anhydrous dichloromethane (ImL) and the suspension was left at room temperature for 15 minutes. (R)-N-(2-l-lydroxy-phenyl)-2-((3R)6R)-3-indan-2-yl-6-isobutyl-2J5-dioxo-piperazin-l-yl)-2-(5-trifluoromethyl-ti.iran-2-yl)-acetamide (172rng) was then added and the mixture was stirred at room temperature for 5 hours 20 minutes. The resulting brown solution was then treated with a 2.0M solution of dimethyl amine in tetrahydrofuran (0.9mL, 6 equiv,)and the resulting mixture was stirred for 30 minutes and then left to stand at room temperature for 18 hours 15 minutes. The reaction mixture was diluted with dichloromethane (2inL) and washed with 1M hydrochloric acid (2mL). The organic phase was separated using a hydrophobic frit and was evaporated under reduced pressure lo leave u brown gum. The crude product was applied to 3 preparative chromatography plates, which were eluted with l:lv/v ethyl acetate:cyclohexane. The required band was extracted with ethyl acetate to give the (2RV2-[(3R,6RV3-(2,3-dihvdro-lH-inden-2-yl)-6-jgojjutyl-215-dioxQpipera2in-l-vl]-N,N '11 NMR (CDCb) 5 7.19 (m, 5H), 6.86 (dd, 1H), 6.64 (d, 1H), 6.61 (s, 1H), 4.25 (m, 1H), 3,97 (dd, 111), 3.20-3.02 (m, 3H), 3.01 (s, 3H), 2.96 (s, 3H), 2.88 (m, 1H), 2.80 (m, 1H), 1.70 (m, 111), 1.67 (m, 1H), 0.74 (d, 311), 0.70 (m, 1H), 0.63 (d, 3H). Example 179 (2l^-2.-[(3R,6l^ N j^yrneJhyl-2-(2-met.hyl-l,3-oxazol-4-vl)ethananiide By the procedure of Example 178, using (2R)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)- 6 isobutyl-2,5-dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)-2-(2-methyl-l,3-oxazol-4- yl)ethanamide , l-JPLC: Ut = 2.88 minutes ; m/z (M+H)+ = 453 JlRVH(3R,6R)-3-(23-d^ (^:liydjiQxyphenyl)-2-(2-methyl-1.3-QxazQl-4-vl)ethanarnide A mixture ot 2-nietliyl-oxazole-4-carbaldehyde<:i methyl ester liydrochloride triethylamine and anhydrous methanol was stirred at room temperature for hours. n-benzyloxycarbonyl- were then added sequentially the mixture days before being left to stand days. solvent removed under reduced pressure leave a dark orange gum which dissolved in ethyl acetate washed with hydrochloric acid saturated sodium bicarbonate solution chloride dried over magnesium sulphate concentrated volume of this crude diluted ethanol> containing acetic acid (1 .6mL) and added under vacuum to 10% palladium on carbon ( 50% water, 425rng). The resulting suspension was stirred under an atmosphere of hydrogen for 20 hours, filtered ( celite tllteraid ) washed with ethanol (50mL) and the filtrate added under vacuum lo a second quantity of 10% palladium on carbon (50% water, 670nig). Hie suspension was stirred under an atmosphere of hydrogen for 2 hours, the hydrogenation apparatus was then evacuated and refilled with hydrogen and the suspension stirred for a further 20 hours. The suspension was filtered ( celite filteraid ) washed with ethanol (200mL) and the combined filtrates concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate solution (1 OOmL) and dichloromethane (60mL), then the organic layer dried (hydrophobic frit) and the solvent removed under reduced pressure. Purification by Biotage flash cinematography (40g silica) eluting with ethyl acetate : cyclohexane (3:1, 300mL ) ethyl acetate (300mL) then ethyl acetate : methanol (20:1, 600mL) gave (2R)-2-[(3R,6R)-3-(2,3-i:lihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)-2- (2-mctbyl- 1 ,3-oxazol-4-yl)ethanamide as a brown foam (197mg). I il'LC : Rt - 3.28 minutes ; m/z (M+H)+ = 517 Rcf (1) CAS 113732-84-6 Example 180 {3Ji^R)r3-&3^ 2-inQrpholin-4-yl-2-()xoethvl1piperazine-2.5-dione By the procedure of Example 1 79, using morpholine lil'LC: Rt - 2.89 minutes ; m/z (M+H)"1' = 495 Example 181 QSji2^:[(3RJ6R)-3-(2,3-clihydro-lH-inden-2-yn-6-isobutvl-2,5-dioxopiperazin-l^ ditnct hyl -2-(5 -mellvy lthien-2-vnethanarnide By the procedure of Example 180, using 5-methyl-thiophene -2-carbaldehyde HPLC Rt - 3.25 minutes; m/z M1' = 468. Example 182 I2SVM(3R16R)-3-(2,3-dihydro-lH-inden-2-vn-6-isobutvl-2,5-dioxopiperazin-l-vl]-2-(3- jluoro:5-inethylthien-2-yl)-N.N-dimethylemanamide By the procedure of Example 178, using 3-fluoro-5-methyl-thiophene-2-carbaldehyde JjPLC: Rt- 3. 20 minutes; m/zMf = 3-Hromo-5-methyl-2-thiophenecarbaldehyde (l.OOg) was dissolved in dry 1,4-dioxane (8ml). Molecular sieves (4 Angstrom, 2g), 1,3-propandiol (9ml), p-toluene sulphonic acid (362mg) were added and the mixture was stirred under a nitrogen atmosphere, at room temperature, over night. Molecular sieves were removed by filtration and the filtrate evaporated. The residue was taken up with ethyl acetate and washed with saturated solution of sodium carbonate. The aqueous was extracted with more ethyl ,'icetate and the combined layers washed with brine, dried over magnesium sulphate, filtrated and concentrated to a yellow oil (Ig). Purification was performed by filtration on a SPE cartridge (Silica-lOg) using dichloromethane as eluent. The solution was eventually concentrated to yield 2-(3-hronK>-5~methyJ~thiophen-2-yl)-[l,3]dioxane as a yellow solid (1.18g). 'II-NMR (CDC1:K 1 -Flu»ro-5-methyl-thiophene-2-carbaldehyde ID a solution of 2-(3-bromo-5-methyl-thiophen-2-yl)-[l,3]dioxane (1.16g) in dry letrahydrofuran (10ml), under a nitrogen atmosphere, at-78 °C, 1.6M«-butyl lithium in hexane (3.30ml) was added dropwise. After 15 minutes stirring,N-fluoro-benzene-sulfonyl-imide (1.66g) was added portionwise. The solution was stirred at -78 °C for further 10 minutes, allowed to warm to room temperature and then stirred for a further 60 minutes. The reaction was quenched with water (5ml), diluted with diethyl ether (20ml) and washed with IN sodium hydroxide (30ml). The aqueous was extracted with diethyl oilier again (2x1 Oml), the combined organic layers were dried over magnesium sulphate, filtrated and evaporated. The residue was redissolved in 1,4-dioxane (15ml) and water (10), p-toluene sulphonic acid (837mg) was added and the solution was stirrer at room lempcrature. over night. Neutralised with a saturated solution of sodium bicarbonate (I Oml), then extracted with ether twice. The organic was dried over magnesium sulphate and evaporated at reduced pressure (200mbar). The residual dioxane was removed by distillation at reduced pressure, the residue further purified by flash chromatography (petroleum ether / dichloromethane 55/45), giving 3-fluoro-5-methyl-thiophene-2-carbaldehyde as a colourless oil (366mg), approximately 70% pure. ' IJ-NMR (CDCh, 400MHz): 5 9.93ppm (s, 1H); 6.62ppm (s, 1H); 2.52ppm (m, 3H). Similarly prepared: Compounds 1S3 -206,213,215,218,222-225 were prepared via method 1. Compounds 207,208,216, were prepared via method 2. Compounds 209-212, 214,217,219-221 and 226 were prepared via method 5. (Table Removed) Phnrnicy Examples Tablets a) Compound of the invention SO.Omg Lactose 70.0mg Microcrystallirie Cellulose 70.0mg Cross-linked polyvinylpyrrolidone S.Omg Magnesium Stearate 2.0mg ("oinpression weight 200.0mg The compound of the invention, microcrystalline cellulose, lactose and cross-linked polyvinylpyrrolidone are sieved through a 500 micron sieve and blended in a suitable mixer. The magnesium stearate is sieved through a 250 micron sieve and blended with the active blend. The blend is compressed into tablets using suitable punches. b) Compound of the invention SO.Omg Lactose 120.0mg 1'regelutinised Starch 20.0mg Cross-linked polyvinylpyrrolidone S.Omg Magnesium Stearate 2.0mg (.'(impression weight 200.0mg The compound of the invention, lactose and pregelatinised starch are blended together and granulated with water. The wet mass is dried and milled. The magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granule. The resultant blend is compressed using suitable tablet punches. . a) Compound of the invention SO.Omg Lactose 148.0mg Magnesium Stearate 2.0mg Fill weight 200.0mg The compound of the invention and pregelatinised starch are screened through a 500 micron mesh sieve, blended together and lubricated with magnesium stearate, (meshed through a 250 micron sieve). The blend is filled into hard gelatine capsules of a suitable .size'. b) Compound of the invention SO.Omg Lactose 132.0mg Polyvinylpyrrolidone S.Omg Cross-linked polyvinylpyrrolidone S.Omg Magnesium Stearate 2.0mg Fill weight 200.0mg The compound of the invention and lactose are blended together and granulated with a solution of polyvinylpyrrolidone. The wet mass is dried and milled. The magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granules. The resultant blend is filled into hard gelatine capsules of a suitable size. In) ection Formulation % w/v Compound of the invention 0.10 Water for injections B.P. to 100.00 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the compound of the invention using dilute acid or alkali or by the addition of suitable buffer salts. Solubilisers, such as cosolvents, may also be added to facilitate solution of the compound of the invention. Antioxidants and metal chelating salts may also be included. The solution is clarified, made up to final volume with water and the pH remeasured and adjusted if necessary, to provide Img/ml of the compound of formula (I). The solution may be packaged for injection, for example by filling and sealing in ampoules, vials or syringes. The ampoules, vials or syringes may be aseptically filled (e.g. the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions) and/or terminally sterilised (e.g. by heating in an autoclave using one of the acceptable cycles). The solution may be packed under an inert atmosphere of nitrogen. Preferably the solution is filled into ampoules, sealed by fusion of the glass and terminally sterilised. further sterile formulations are prepared in a similar manner containing 0.05, 0.20 and 0.5% w/v of the compound of the invention, so as to provide respectively 0.5, 2 and .Sing/ml of the compound of the invention. Measurement of C')xytQ_pin. Antagonist Activity Assay Buffer used throughout the assay: 50mM HEPES, lOmM MgC12, 0.125mg/ml BSA, pH adjusted to 7.4 with KOH. hOT-CHO membranes were prepared at a concentration of 0.3mg protein/ml in assay uiffer. Test compounds were initially dissolved in DMSO (to lOmM) and diluted in )MSO (Beckman Biomek FX). lu.1 of compound was transferred to black 384 assay ilat.es (NUNC) using a Biomek FX. 20ul of InM Bodipy TMR Oxytocin (Perkin Elmer) 11 assay buffer was added to all wells (Labsystems Multidrop) then 20i.il membrane idded to all wells (Multidrop). Plates were incubated at room temp for 60 min. 'olarisation was read on LJL Analyst (AJBx=535nm, XEm=580ilM, A.Dichroic=555nm). )ata were fitted to a 4 parameter logistic equation. An estimated Ki was calculated as C50/5. n the above test compounds of the invention in general have a pKi value within the range if 7 to 11 . Thus the compounds of examples 1 to 227 have a pKi within the range 8.5 o 10.8. 'he compounds of the invention are .essentially non toxic at therapuetically active doses, lius compound of the example 10 has been administered to rats at doses of up to OOmg/kg p.o for 4 days, and no adverse toxicological effects were observed. WE CLAIM: 1. A diketopiperazine compound of formula (I): (Formula Removed) and/or a physiologically acceptable derivative thereof, wherein: R1 represents aryl (C1-4) alkyl or a 5-7 membered cycloalkyl group optionally substituted with one or more hydroxyl groups which, is fused to an optionally substituted benzene ring; R2 represents C1-6alkyl (optionally substituted by a C1-2alkoxy, C1-2alklthio, di(C1-2alkyl) amino or a C3-6 cycloalkyl group) or C3-6cycloalkyl, or 5-6 membered heterocyclic group containing a single hetero atom selected from O, S or N, which, nitrogen atom carries a hydrogen atom or a methyl or ethyl group; R3 represents optionally substituted phenyl, a 5 or 6 membered hetero aryl group or a fused bicyclic ring system containing 9-10 ring members which is a carbocyclic group or it contains up to 3 heteroatoms selected from O, S or N and one of the fused rings is benzene; R4 represents OH or OC1-4 alkyl (optionally substituted with C1-4alkylcarbonyloxy) or NR5R6; R5 represents hydrogen, C1-6alkyl (optionally substituted with C1-4alkoxy) or C3-7cycloalkyl; R6 represents hydrogen, methyl, C1-4alkoxy', C3-7cycloaIkyl, C2-4alkyl [optionally substituted with, one or more groups selected from: carboxyl, C1-4alkylsulphonyl, or C1-4alkoxycarbonyl]3 C2-4-alkyl [optionally substituted with one ormore groups selected from halogen, hydroxy, C1-4alkoxy or NR7R8 wherein R7 and Rs independently represent hydrogen or C1-4alkyl or together with the nitrogen atom to which they are attached to form a 3-7 membered saturated heterocyclic ring which contain an additional heteroatom selected from O, S or N (and which heterocyclid group is substituted by 1 to 3 groups selected from C1-3alkyl, hydroxy, C1-3 alkoxy (optionally substituted by C3-6 cycloalkyl or optionally subtituted phenyl), C 3-6cycloalkyl or NRcRd wherein Rc and Rd each independently represent a group selected from C1-3alkyl (optionally substituted by C3-6 cycloalkyl or optionally substituted phenyl) or C3-6cycloalkyl)] or R6 represents a phenyl or benzyl group (optionally substituted by one or more methoxy or benzyloxy groups) or an optionally substituted heteroarylmethyl group or a heteroaryl group or C3-7 cycloalkyl or the group CH2CONR9R10 wherein R9 represents hydrogen or C1-4alkyl, RI0 represents hydrogen, C1-4alkyl optionally substituted by a 5 or 6 membered heteroaryl group or R9, R10 and the nitrogen atom to which they are attached together form a 5 or 6 membered saturated heterocyclic ring and wherein the 6 membered heterocyclic group may contain an additional heteroatom selected from oxygen, sulphur or nitrogen and the additional nitrogen atom either carries a hydrogen atom or a C1-4alkyl orC1-4alkanoyl group; or R5 and R6 together with the nitrogen atom to which they are attached form a 3 to 7 membered saturated heterocyclic ring which heterocycle may contain an additional heteroatom selected from oxygen, sulphur and nitrogen and wherein the sulphur atom may be in an oxidised form e.g. SO2 and the additional nitrogen atom either carries a hydrogen atom or a C1-4alkyl or a C1-4alkanoyl group or a C1-4alkylsulphonyl group or a C1-3 alkoxyC2-4 alkyl [and which heterocyclic groups may be substituted by one or more halogen atoms or a group selected from C1-3alkyl, hydroxy, oxo, C 3-6cycloalkyI or NR-Rf wherein Re and Rf each independently represent a group selected from C1-3alkyl (optionally substituted by C3-6 cycloalkyl or optionally substituted phenyl) or C3-5 cycloalkyl.] 2. The compound as claimed in claim 1 wherein R1 is a 2-indanyl group and R2, R3 and R4 are as defined above. 3. The compound of formula (I) as claimed in claim 1 wherein R4 is hydroxy or the group NR5R6 wherein R5 and R6 are as defined in claim 1. 4. The compound of formula (I) as claimed in any of claims 1 and 2 wherein the compounds have the stereoisomers as defined in formula (la): (Formula Removed) wherein the groups R1, R2, R3 and R4 have the meanings defined for formula (I). 5. The compound of formula (I) as claimed in any of claims 1 to 4 wherein R2 is a group selected from 1-methylpropyl or 2-methylpropyl. 6. The compound of formula (I) as claimed in any of claims 1 to 5 wherein R3 is an optionally substituted phenyl group. 7. The compound of formula (I) as claimed in any of claims 1 to 6 wherein R3 is a 5 or 6 membered hetero aryl group. 8. The compound of formula (I) as claimed in any of claims 1 to 7 wherein R3 is a fused bicyclic ring system containing 9-10 ring members which is a carbocyclic group or it contains up to 3 heteroatoms selected from O, S or N and one of the fused rings is benzene. 9. The compound of formula (I) as claimed in any of claims 1 to 8 wherein R3 is a group selected from phenyl, 2-fluorophenyI, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichloroph.enyl, 3,4-dichlorophenyl, 2 fluoro-4-bromophenyl, 4-chloro-3-fluorophenyl 2,3,4-trifluorophenyI 2,4,5-trifluorophenyl or 2,4,6-trifluorophenyl, 2-:nuoro-4,5-dimethoxyphenyl, 3-fliioro-4-metb.oxyphenyl, 4-fluoro-3-methoxyphenyl, 2-fluoro-4 metlioxyphenyl, 2- fluoro-4 hydroxyphenyl, 2-fluoro-4-dimethylaminomethylphenyl, 2-fluoro-4-hydroxymeth.ylph.enyl, 3-fluoro-4-(4-morpholino)phenyl, 3-fluoro-4-carboxymeth.yloxyph.enyl, 3-fluoro-4-t-butyloxyearbonylmethyloxyphenyl, 3-fluoro-4-dimethyIaminocarbonyloxyphenyl, 3-chIoro-4 trifluoromethoxyphenyl, 2,3-difluoro-4-methyl-phenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-metlioxycarbonylphenyl, 3-methoxycarbonyphenyl, 4-methylsulphonylphenyl, 4-methylaminocarbonylphenyl, 4- aminocarbonylphenyl, 4-methylaminosulphonylphenyl, 3-(3-pyrazyolyl)phenyi, 4-(3-pyrazolyl)phenyl, 4-(4-pyrazolyl)phenyl, 4-(3-pyridyl)phenyl, 4-(2-pyridylphenyl), 4-(2-imidazolyl)phenyl, 3-(2-imidazolyl)phenyl, 4-(l-t-butyl-tetrazol-5-yI)phenyl, 4-methylaminophenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-acetylaminophenyl, 3-acetylaminophenyl, 4-hydroxy-3-acet3'laminophenyl, 4-methyIsulphonylaminophenyI, 4-N-methylpiperazinophenyl, 4-N-pyrrolidinophenyl, 2-fluoro-4-(4-moipholino)phenyl, 4-(4-morph.olino)phenyl, 4-(4-hydroxypiperidino)phenyI, 2-fluoro-4-(4~hydroxypiperidino)phenyl, 3-(l-pyrazolyl)phenyl, 4-(l-pyrazoIyl)phenyl,, 4-(l-3,5 di-t-butylpyrazolyl)phenyl, 3-(l-imidazolyl)phenyl, 4-(l-imidazolyl)phenyl, 4-(l-l,2>4-triazolyl)phenyl, 4-(l-l,2,3-triazolyl)phenyl, 4-(2-4,-t-butyltMazolyl)phenyl, 4-(5- 2-t-buryltetrazolyl)phenyI, 4-(4 spiro-l,3-dioxolanyl)piperidinophenyl, 4-(4-fluorophenyl)phenyl, 4-(4-eth3daminosulphonylpheny])phenyl?4-dimethylaminoethoxyphenyl,3-(dmydroxyboryl)phenyl, 2-furanyI, 3-tbienyl, 3-furanyl, 2-thienyI, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chIoro-2-thienyl, 3-fluoro-5-methyl-2-thienyl, 5-methyl-2-thienyI, 5-methyl-2-furanyl, 5-bromo-2-furanyl, 4,5-dimethyl-2-furanyl, 5-trifluoromethyl-2-furanyl, 2-furanyl-4-carboxylic acidmethylamide, 2-furanyl-5-carboxylic acid methylamide, 2-pyridyl, 6-methyl-2-pyridyl, 6-methyl-3-pyridyl, 6-methoxy-3-pyridyI, 6-hydroxy-3-pyridyl, 6-trifluorometh.yl-3-pyridyl, 3-pyridyl, 4-pyridyl, 3,5-pyrimidinyl, 2-thiazolyl,, 2-methyl-4-oxazolyl, 2-ethyl-4-oxazolyl, 2-cyclopropyl-4-oxazolyl, 2- trifluoromethyl-4-oxazoly], 2,5-dimethyl-4-oxazolyl, 4-thiazolyl, 2-methyl-4-thiazolyl, 2-trifiuoromethyl-4-thiazoly-i, 2-frifluoromethyI-5-thiazolyl, l-methyl-4-pyrazolyl, 1,3-dimethyl-5-pyrazolyI, 5-(2-pyridyl)-2-thieny], 2,3-dihydro-l-benzofuran-5-yl, 1,3-benzodioxol-5-yl, lH-l,2,3-benzotriazol-5-yl, 2,3-dihydro-l,4-benzodioxin-6-yl, 2,2-difiuoro-l,3-benzodioxoI-5-yl, l,3-benzothiazol-6-yl, l-methyl-lH-l,2,3-benzotriazol-5-yl,1-methyl-1H-1,2,3-benzotriazol-6-yl, l,2,3-ben2othiadiazol-6-yl, 2-methyl-l,3-benzoxazol-5-yl, 2-methyI-l,3-benzoxazol-6-yl, l-benzofuran-5-yl, l-rnetb.y-lH-lindol-5-yl, l-benzothien-5-yL 1 -benzofuran-6-yl, lH-indol-6-yl, l-methyl-lH-benzimidazol-6-yI, l-methyl-lH-benzimidazol-5-yI, 3-methyI-l,2-betizoisoxazoI-5-yl, 2-fluoro-l-benzofuran-5-yl, lH-indol-5-yl, 2-methyl-lH-benzofuran-5-yl, lH-indazoI-5-yI, 1H-indazol-6-yI, l-benzofuran-2-yl or l-methyl-lH-benzimidazol-2-yl. 10. The compound of formula (1) as claimed in any of claims 1 to 9 wherein R5 is a group selected from hydrogen, C1-4alkyl, C1-4alkoxyC2-4aIkyl and R6 is a group selected from hydrogen, C1-4alkoxy, C1-4alkyl, C1-4 alkyl substituted by 1 to 3 halogen atoms, C1-4alkyl substituted by alkoxycarbonyl or carboxyl, alkyl substituted by alkoxy, alkyl substituted by hydroxy, alkyl substituted by dialkylamino, 2-benzyloxyphenyl, dimethoxybenzyl, optionally substituted heteroarylmethyl, heteroaryl, alkyl substituted by NR7R8 wherein NR7R8 form a 6-membered heterocyclic ring, cycloalkyl,or NR5R6 represents, azetidino, 3-hydroxyazetidino, 3-methoxyazetidino, pyrrolidine, pipeiidino, 4-dirnethylaminopiperidino, 4-methyI 1,4-diazepan-l-yl, moipholino, an optionally substituted piperazino ring, thiomorpholino or the sulphoxide or sulphone thereof. 11. The compound of formula I as claimed in claim 1 selected from:- (2R)-2-(2J4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin.-l-yl]-N,N-dimetliyletlianamide (2R)-2-(4-fluorophenyl)-2-[(3R>6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2J5- dioxopiperazin-1 -yl]-N,N-dimethylethanarnide (2R)-2-(4-fIuorophenyl)-2-f(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]- morpholinamide (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1 -yi]-N-isopropylethanamide. (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyI-2,5- dioxopiperazin-l-yl]-2-[4-(4-hydroxypiperidin-l-yl)phenyl]ethanamide. (2R)-2-{(3Rs6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-[(lR)-l-methylpropyl]-2,5- dioxopiperazin-1 -yl} -2-(2-fluoro-4-morpholin-4-ylphenyl)-N-isopropylethanarnide. (2R)-2-[(3R36R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-2- (4-f1uorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide. (2R.)-2-(2,4-difluorophenyI)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1 -yI]-N-isopropylethanamide. (2R)-N-cyclopropyl-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-l-yl]ethanarmde. (2R)-2-(2!4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2>5- dioxopiperazin-1 -yl]-N-methy'Iethanamide (2R)-2-(2,4-difluorophenyl)-2-[(3R)6R)-3-(2>3-dihydro-lH-inden-2-yJ)-6-isobutyl-2,5- dioxopiperazin-1-yl]ethanamide (3R,6R)-1 -[(1R)-1 -(2,4-difluorophenyl)-2-morpholin-4-yi-2-oxoetliyl]-3-(2,3-dihydro- 1 H-inden-2-yl)-6-isobutylpiperazine-2,5-dione (3RJ6R)-l-[(lR)-l-(2J4-difluorophenyl)-2-(3-hydroxyazetidin-l-yl)-2-oxoethyI]-3-(2,3- dihydro-lH-inden-2-yl)-6-isobutylpiperazine-2,5-dione (3R>6R)-l-[(lR)-2-azetidm-l-yl-l-(2,4-difluorophenyI)-2-oxoethyl]-3-(2,3-dihydro-lH- inden-2-yl)-6-isobutylpiperazine-2,5-dione (2R)-2-(2,4-difluoroplienyI)-2-[(3Rs6R)-3-(253-dihydro-lH-inden-2-yl)-6-isobutyl-2>5- dioxopiperazin-l-yl]-N-(2-hydroxyethyl)-N-methylethanamide (2R)-2-(2,4 dioxopiperazin-l-yl]-N-methyl-N-[2-(methylsulfony])efliyl]ethanamide (2R)-2-(2,4-difluorophenyl)-2-[(3RJ6R)-3-(2a3-dihydro-lH-inden-2-yl)-6-isobutyl-2>5- dioxopiperazin-l-yI]-N-m6tb.yl-N-(2>2,2-1rifIuoroetihyl)ethanamide (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1 -yI]-N-methyl-N-(pyridin-2-ylmethyl)ethanamide (3R;6R)-l-{(lR)-l-(2;4-difluorophenyl)-2-[4-(methylsulfonyl)piperazin-l-yl]-2- oxoethyl}-3-(2,3-dihydro-lH-inden-2-yl)-6-isobulylpiperazine-255-dione (2R)-2-(2>4-difluorophenyl)-2-[(3R,6R)-3-(2?3-dih.ydro-lH-inden-2-yl)-6-isobutyl-2,5- d i oxopiperazin-1 -yI]-N-raetIioxy-N-methylethanamide (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-diIiydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]ethanoic acid methyl (2R)-(2,4-difluorophenyl)r(3R,6R)-3-(2,3-dihydro-lH-inden-2-yI)-6-isobutyl-2,5- dioxopiperazin-1-yl]ethanoate propyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yI)-6-isobuty]-2,5- di oxopiperazin-1 -yl] ethanoate ] -(acetyloxy)ethyi (2R)-(2a4-difluoroplienyl)[(3R,6R)-3-(2,3-dihydro- lH-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-l-yI]ethanoate (2R)-N-(tert-butyl)-2-(2,4-difluorophenyI)-2-{(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6- [(lR)-l-methylpropyl]-2,5-dioxopiperazin-l-yl}ethanamide (2R)-N-(tert-butyl)-2-(2)4-difluorophenyl)-2-{(3Rs6R)-3-(2J3-dihydro-lH-inden-2-yl)-6- [(1 S)-l -rnethylpropyl]-2,5-dioxopiperazin-l -yl} ethanamide (3R,6R)-l-[(lR)4-(2,4-difluoropbenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro- lH~ir±den-2-yl)-6-[(I S)-l -metbylpiopyl]piperazine-2,5-dione (3R,6R)-l-[(lR)-l-(2J4-dif3uorophenyl)-2-morpliolm-4-yl-2-oxoethyl]-3-(2>3-dihydro- 1 H-inden-2-yl)-6-[(l R)-1-methylpropyl]piperazine-235-diorie (3R,6R)-l-[(lR)-l-(2,4-difluorophenyl)-2-(3-fluoroazetidin-l-yl)-2-oxoethyl]-3-(2,3- dihydro-lH-inden-2-yl)-6-isobutyIpiperazine-2,5-dione (2R)-2-[(3R,6R)-3-(2J3-dihydro-lH-inden-2-yl)-6-isobutyl-2>5-dioxopiperazin-l-yl]-N- isopropyl-2-[5-(trifluoromethyl)-2-fiirylJethanamide (2S)-2-[(3R,6R)-3-(2>3-dihydro-lH-inden-2-yl)-6-isobutyl-2)5-dioxopipera2in-l-yl]-N- isopropyl-2-(5-methylthien-2-yl)ethanamide (2R)-2-[(3R,6R)-3-(2>3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]- N,N-dimethyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide (2R)-24(3R,6R)-3-(2J3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopipera2dn-l-ylJ- N3N-dimethyl-2-(2-metliyl-1,3 -oxazol-4-yl)ethanamide (3R56R)-33-dihydro-lH-inden-2-yl)-6-isobutyl-l-[(lR)-l-(2-metliyl-l,3-oxa2ol-4-yl)- 2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione (2S)-2-[(3R36R)-3-(2)3-dihydro4H-inden-2-yl)-6-isobutyI-2,5-dioxopiperaziri-l-yl]-N,N- dimethyl-2-(5-methylthien-2-yl)ethanamide (2S)-2-[(3RJ6R)-3-(2)3-dihydro-lH-inden-2-yl)-6-isobutyl-2J5-dioxopiperazin-l-yl]-2-(3- fluoro-S-metliylthien-2-yl)-N,N-dimethylethanamide (2R)-2-(l-benzofuran-5-yl)-2-[(3RJ6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobu1yl-2,5- dioxopiperazin-l-yl]-N-isopropyletiianamide. (2R)-2-(lJ2)3-benzotbiadiazol-6-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2J3-dihydro-lH-inden- 2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]ethanamide. (2R)-2 isobtity]-2,5-dioxopiperazin-l-yl]-N-isopropylethanamide. (2R)-2-(l)3-benzodioxol-5-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2J3-dihydro-lH-inden-2-yI)- 6-isobutyl-2,5-dioxopiperazin-1 -yl]ethanamide. (2R)-2-(benzofuran-5-yl)-2-[(3RJ6R)-3-C2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yI]-N,N-dimethylethanamide. (2R)-2-[(3RJ6R)-3-(2,3-dihydro-lH-mden-2-yl)-6-i5obutyl-235-dioxopiperazin-l-ylJ- N,N-diniethyl-2-(2-methyl-1 -benzofuran.-5-yl)ethanamide (2R)-2-[(3R>6R)-3-(2,3-dihydro-lH-mden-2-yI)-6-isoburyI-2,5-dioxopiperazin-l-yl]-N- isopropyl-2-(2-dihydro-lH4nden-2-yI)-6-isobirtyl-l-[(lR)-l-(2-methyl-l-benzofuran-5- yl)-2-morphoIin-4-methyI-l-benzoftffan-5-yl)ethanamide (3R)6R)-3-(2J3-yl-2-oxoethyljpiperazin-2,5-dione (2R)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyi-235-dioxopiperazin-l-y]]-2- (2-fluoro-l-benzofuran-5-yl)-N3N-dimetbyIethanamide (2R)-2-[(3R36R)-3-(233-dihydro-lH-mden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l--yl]-2- (2-fluoro-l-benzofuran-5-yI)-N-isopropylethanamide (3R,6R)-3-(2,3-dihydro4H-inden-2-yl)-l-[(lR)-l-(2-fluoro-l-be!nzoruran-5-yl)-2- moiph.olin-4-yl-2-oxoethyl]-6-isobutylpiperazine-235-dione (2R)-2-[(3R,6R)-3-(233-dihydro-lH-inden-2-yl)-6-isobu1yl-2,5-dioxopiperazin-l-yl]-2- (1 H-indol-6-yl)-N5N-dimethylethanamide (2R)-2-(l-benzothien-5-yl)-2-[(3R36R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1 -yl3-N,N-dimethylethanamide 12. A pharmaceutical composition comprising 30 to 95 % of a compound of formula (I) as claimed in claim 1 together with one or more pharmaceutical acceptable carriers. 13. A process for the preparation of compounds of formula (I) as claimed in claim 1 wherein R4 is the group NR5R6 which comprises: (a) cyclisation of the compound of formula (II) (Formula Removed) wherein R1, R2 and R3 have the meanings defined in formula (I) R11 is hydrogen and R22 is a C1-3alkyl group in a suitable solvent

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1570-DELNP-2004-Abstract-(03-09-2008).pdf

1570-DELNP-2004-Abstract-(04-08-2008).pdf

1570-delnp-2004-abstract.pdf

1570-DELNP-2004-Claims-(03-09-2008).pdf

1570-DELNP-2004-Claims-(04-08-2008).pdf

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1570-delnp-2004-description (complete)-04-08-2008.pdf

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1570-DELNP-2004-Form-1-(03-09-2008).pdf

1570-DELNP-2004-Form-1-(04-08-2008).pdf

1570-delnp-2004-form-1.pdf

1570-delnp-2004-form-18.pdf

1570-DELNP-2004-Form-2-(03-09-2008).pdf

1570-DELNP-2004-Form-2-(04-08-2008).pdf

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Description (Complete)-(03-09-2008).tif