WO2005000311A1

WO2005000311A1 - Substituted diketopiperazines for the treatment of benign prostatic hyperplasia

Info

Publication number: WO2005000311A1
Application number: PCT/EP2004/006815
Authority: WO
Inventors: David P Brooks
Original assignee: Glaxo Group Limited
Priority date: 2003-06-24
Filing date: 2004-06-22
Publication date: 2005-01-06
Also published as: GB0314733D0

Abstract

A method of treating or preventing benign prostatic hyperplasia which comprises administering to a mammal in need thereof of an effective amount of a compound of Formula (I) where R1, R2, R3 and R4 are defined as provided in claim 1.

Description

SUBSTITUDED DIKETOPIPERAZINES FOR THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA

This invention relates to the use of a class of di etopiperazine derivatives having a potent and selective antagonism of oxytocin for use in the treament of benign prostatic hyperplasia 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.0 WO99/47549 describes diketopiperazine derivatives including 3-benzyl-2,5 diketopiperazine derivatives as inhibitors of fructose 1,6-bisphospate (FBPase). WO99/38844 describes a method for preparing N-[aliphatic or aromatic) carbonyl]-2- aminoacetamide compounds and their cyclisation to give inter alia diketopiperazine5 derivatives.

WO99/37304 describes oxaheterocyclyl compounds including oxapiperazinyl compounds that are inhibitors of Factor Xa. 0 Prostate oxytocin levels are raised in dogs with benign prostatic hyperplasia and this increase is associated with increased 5 alpha-reductase activity (Nicholson & Jenkin, 1995, Adv Exp Med Biol, 395, 529-538). Oxytocin stimulates prostatic growth in the rat (Popovic et al, 1982, Lugoslav5 Pharmacol Acta 18, 95-106). Oxytocin is present in human prostate (Nicholson et al, 1985, J Endocinol, 104 (Suppl) 127)0 Oxytocin mRNA is present in the monkey prostate, suggesting local synthesis (Frayne & Nicholson, 1998, Molecular Human Reproduction. 4, 527-32)

5 We have found a class of diketopiperazine derivatives which exhibit a particularly useful level of activity as selective antagonists at the oxytocin receptor and thus are potentially useful in the treatment of benign prostatic hyperplasia 0 The present invention thus a method of treating or preventing benign prostatic hyperplasia which comprises administering to a mammal in need thereof of an effective amount of an oxytocin receptor antagonist compound of the formula (I).

and/or a physiologically acceptable derivative thereof, wherein:

R_\ represents aryl (Ci- ) 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 C^a-kyl (optionally substituted by a Ci-₂alkoxy, C₁-₂alklthio, di(C₁-₂alkyl) amino or a C -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 may be a carbocyclic group or it may contain up to 3 heteroatoms selected from O, S or N and one of the fused rings is benzene; R₄ represents OH or OCi-₄ alkyl (optionally substituted with C₁- alkylcarbonyloxy) or NRsRe;

R₅ represents hydrogen, Cμβalkyl (optionally substituted with

or C₃- cycloalkyl; R₆ represents hydrogen, C₁-₄alkoxy, C₃-₇cycloalkyl, C₁-₄alkyl [optionally substituted with one or more groups selected from, carboxyl, C₁-₄alkylsulphonyl, or C₁-₄alkoxycarbonyι], C₂-₄alkyl [optionally substituted with one or more groups selected from halogen, hydroxy,

or NR₇R₈ wherein R and R₈ 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 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 Cι-₃alkyl, hydroxy, -₃ alkoxy (optionally substituted by C ₃-₆ cycloalkyl or optionally subtituted phenyl), C ₃-₆cycloalkyl or NPv-R_d wherein R_e and R_d each independently represent a group selected from C ^alkyl (optionally substituted by C ₃-₆ cycloalkyl or optionally substituted phenyl ) or C ₃-₆ cycloalkyl)] 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- cycloalkyl or the group CH^CONRgR^ wherein R₉ represents hydrogen or ^a-kyl, R_to represents hydrogen, C^a-kyl optionally substituted by a 5 or 6 membered heteroaryl group or R_9; Rio 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

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- alkanoyl group or a

group or a Cι-₃ alkoxyC₂- alkyl [and which heterocyclic groups may be substituted by one or more halogen atoms or a group selected from Cι-₃alkyl, hydroxy, oxo, C ₃-₆cycloalkyl or NR_eRf wherein R_e and R_f each independently represent a group selected from C ^a-kyl (optionally substituted by C ₃-₆ cycloalkyl or optionally substituted phenyl ) or C ₃-₆ cycloalkyl].

A particularly useful class of compounds of formula (I) are those wherein R₁ 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

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 R_l5 R₂ and R₃ respectively and it is to be understood that formula (I) includes all possible stereoisomers and mixtures thereof. The substituent R₃ may exist in more than one tautomeric form and it is to be all understood that formula (I) includes all possible tautomeric forms and mixtures thereof.

The compounds of formula (I) wherein at least one of the groups R_l5 R₂,R₃ or K 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 prodrug e.g. ester or carbamate, or salt or solvate of such a prodrug, 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 that 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 l-(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 ₃.₆ cycloalkyl as a group or part of a group includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. The term C₃.₇cycloalkyl also includes cycloheptyl.

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,

(optionally substituted by 1-3 halogen atomsor NRgR [wherein R_g is hydrogen or C₁.₄ alkyl, R_h is hydrogen, d-₄ alkyl, or R_g and R 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]), Ci-₄ alkylsulphonyl, carboxyl, Cμ alkoxycarbonyl, di(Ci- ₄alkyl)aminocarbonyloxy, C₁-₄alkoxy (optionally substituted by 1-3 halogen atoms, amino, Cι-₄ alkylamino or di-(C₁-₄alkyl) amino), phenyl (optionally substituted by halogen or alkylaminosulphonyl), C₁- alkoxy, NR_aR_b [wherein R_a is hydrogen or C₁-₄ alkyl, R is hydrogen, Ci-₄ alkyl, Cι-₄ alkanoyl or Cμ alkylsulphonyl or R_a and R_b 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 ^a-kyl groups or may be spiro-fused to a dioxalane ring or may contain an additional heteroatom selected from nitrogen, oxygen or sulphur and may be substituted by 1 or 2 Ci-₄alkyl 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 aminosulphonyl group (wherein the substituents may be 1 or 2 CM alkyl groups) or a dihydroxyboryl 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, C_M alkyl , cycloalkyl, heteroaryl, saturated heterocyclic, or phenyl groups. Examples of such 5 membered heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, 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 C_M alkyl groups, or trifluoromethyl, or alkoxy groups. Examples of such groups include pyridyl, methylpyridyl, trifluoromethylpyridyl, pyrimidinyl and triazinyl.

When R₃ is a 5 or 6 membered heteroaryl group this is linked to the rest of the molecule via a carbon atom in the ring.

When R₃ is a fused bicyclic carbocyclic ring system this may be for example a naphthyl, tetrahydronaphthyl, indanyl or indenyl group.

When R₃ 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 C_M alkyl or halogen or haloalkyl and or may contain a carbonyl group. The said R₃ 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 R₃ 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 R₃ 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 C alky or halogen or haloalkyl and or may contain a carbonyl group. Examples of such 6, 5 bicyclic heteroaryl groups include benzofuranyl, benzothienyl, indolyl, benzo-oxadiazolyl, benzothiadiazolyl, benzo-oxazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, benzimidazolyl, indazolyl or benzotriazolyl and these groups may be substituted as described above.

When R₃ is a 6,6 or 6,5 bicyclic heterocyclic group and the hererocycle is partially saturated, this may contain 1 or 2 heteroatoms selected from O, S or N. Examples of such groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, 1,3- benzodioxolyl, benzopyrrolyl, 1,3-benzodithiolyl 1,4-benzodioxanyl, phthalyl, thiophthalyl, chromanyl or chromenyl and the groups may be substituted by one or more halogen or C₁.₄ alkyl groups, haloalkyl, or may contain a carbonyl group.

When R₃ is a fused bicyclic heteroaryl linked via the benzene ring therein then suitable examples of such a group include 6-quinolinyl, 4-isoindolinyl, 4-(N-methyl-isoindolinyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzimidazolyl benzoxazolyl, 2 methyl-benzo-oxazolyl, benzothiadiazolyl, benzotriazolyl and 1-methyl benzotriazolyl.

When R₃ is a fused bicyclic heteroaryl group linked via the heteroaryl ring this may be for example a 2-benzofuranyl, 2-benzothienyl or 2-N-methylindolyl group .

When R₃ is a 6,6 or 6,5 heterocyclic group wherein the heterocycle is partially saturated this is conveniently linked via the benzene ring therein and suitable examples include dihydrobenzofuran, dihydrobenzopyrrole, 1,3-benzodioxolyl, 2,2-difluoro-l,3- benzodioxolyl, and 1,4-benzodioxanyl.

When R₃ 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

-ahaloalkyl (trifluoromethyl), Cι-₃alkoxy (methoxy, ethoxy), haloalkoxy (trifluoromethoxy), aminoethoxy e.g. dimethylaminoethoxy, C_\. ₃ alkoxycarbonyl, carboxy, hydroxy, phenyl or phenyl (substituted by halogen or alkylaminosulphonyl), NR_aR_b [wherein R_a is hydrogen or Ci-₂alkyl and R is C₁-₂alkyl, CMalkanoyl, CMalkylsulphonyl, -aalkylaminocarbonyi] or NR_aRb represents a pyrrolidino or piperidino ring, which ring may be substituted by a C₁-₂alkyl, hydroxyl or a 2,2-1,3-dioxolane group or NR_aR_b represents a morpholino or a piperazino group which groups may be substituted by 1 or 2 C^alkyl groups or R_aR_b represents a 5 or 6 membered heteroaryl group containing from 1 to 4 nitrogen atoms (such as a 1- imidazolyl, 1,2-pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl substitutent), Ci- ₃alkylsulρhonyl, -salkylaminocarbonyl, -salkylaminosulphonyl, dihydroxyboryl or a 5 or 6 membered atom heteroaryl 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 C_M alkyl groups.

Examples of suitable R₃ groups wherein R 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- difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,5-difluoroρhenyl, 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-trifluorophenyl or 2,4,6-trifluorophenyl, 2- fluoro-4,5-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 2- fluoro-4 methoxyphenyl, 2- fluoro-4 hydroxyphenyl, 2-fluoro-4- dimethylaminomethylphenyl, 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-methyl-phenyl, 4- trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4- methoxycarbonylphenyl, 3-methoxycarbonyphenyl, 4-methylsulphonylphenyl, 4- methylaminocarbonylphenyl, 4- aminocarbonylphenyl, 4-methylaminosulphonylphenyl, 3-(3-pyrazyolyl)phenyl, 4-(3-pyrazolyl)phenyl, 4-(4-pyrazolyl)ρhenyl, 4-(3- pyridyl)phenyl, 4-(2-pyridylphenyl), 4-(2-imidazolyl)phenyl, 3-(2-imidazolyl)phenyl, 4- (l-t-butyl-tetrazol-5-yl)phenyl, 4-methylaminophenyl, 4-dimethylaminophenyl, 4- diethylaminophenyl, 4-acetylaminophenyl, 3-acetylaminophenyl, 4-hydroxy-3- acetylaminophenyl, 4-methylsulphonylaminophenyl, 4-N-methylpiperazinophenyl, 4-N- pyrrolidinophenyl, 2-fluoro-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- imidazolyl)phenyl, 4-(l-imidazolyl)phenyl, 4-(l-l,2,4-triazolyl)phenyl, 4-(l-l,2,3- triazolyl)phenyl, 4-(2-4,-t-butylthiazolyl)phenyl, 4-(5- 2-t-butyltetrazolyl)phenyl, 4-(4 spiro- 1 ,3-dioxolanyl)piperidinophenyl, 4-(4-fluorophenyl)phenyl, 4-(4- ethylaminosulphonylphenyl)phenyl, 4-dimethylaminoethoxyphenyl or 3-( dihydroxyboryl)phenyl.

When R₃ is a 5 or 6 membered heteroaryl group suitable examples of such groups include 2-furanyl, 3-thienyl, 3-furanyl, 2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5- chloro-2-thienyl, 3-fluoro-5-methyl-2-thienyl, 5-fluoro-2-thienyl, 5-methyl-2-thienyl, 5- methyl-2-furanyl, 5-bromo-2-furanyl, 4,5-dimethyl-2-furanyl, 2,3-dimethyl-5-thienyl, 5- trifluoromethyl-2-furanyl, 2-furanyl-4-carboxylic 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-oxazolyl, 2-cyclopropyl-4-oxazolyl, 2-trifluoromethyl-4-oxazolyl, 2,5-dimethyl- 4-oxazolyl, 4-thiazolyl, 2-methyl-4-thiazolyl, 2-trifluoromethyl-4-thiazolyl, 2- trifluoromethyl-5-thiazolyl, 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- piperazino)-5-thiazolyl.

When R₃ 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- benzotriazol-5-yl, 2,3-dihydro-l,4-benzodioxin-6-yl, 2,2-difluoro-l,3-benzodioxol-5-yl, 1 ,3-benzothiazol-6-yl, 1 -methyl- 1H- 1 ,2,3-benzotriazol-5-yl, 1 -methyl-lH- 1 ,2,3- benzotriazol-6-yl, l,2,3-benzotlιiadiazol-6-yl, 2-methyl-l,3-benzoxazol-5-yl, 2-methyl- l,3-benzoxazol-6-yl, l-benzofuran-5-yl, 1 -methyl- lH-lindol-5-yl, l-benzothien-5-yl, 1- benzofuran-6-yl, lH-indol-6-yl, l-methyl-lH-benzimidazol-6-yl, 1-methyl-lH- benzimidazol-5-yl, 3-methyl-l,2-benzoisoxazol-5-yl, 2-fluoro-l-benzofuran-5-yl, 1H- indol-5-yl, 2-methyl-lH-benzofuran-5-yl, lH-indazol-5-yl, lH-indazol-6-yl, 1- benzofuran-2-yl or l-methyl-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, trifluoromethyl, nitro, carboxyl, alkoxycarbonyl or carboxamido.

When the group Ri 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, trifluoromethyl, nitro, carboxyl, alkoxycarbonyl or carboxamido.

Examples of suitable Ri groups include phenethyl or indanyl optionally substituted by hydroxyl e.g. 2-indanyl, 1 -hydroxy -2-indanyl, 5 -hydroxy -2-indanyl. Examples of suitable R₂ groups include C -₄alkyl e.g. isopropyl, 1-methylpropyl or 2- methylpropyl ,C ₃.₆ cycloalkyl e.g cyclopentyl.

Conveniently R₄ is hydroxy , C _M alkoxy e.g. methoxy, propoxy, t-butoxy , 1- acetyloxyethoxy or NR R₆.

A preferred class of compounds of formula (I) are those wherein R-₄ represents hydroxy or the group NR₅R₆ or more preferably NR₅R₆.

A further preferred class of compounds is represented by formula (la)

(1a) wherein the groups Ri, R_2; R₃ and R- have the meanings defined for formula (I) Conveniently R is a group selected from 2-phenethyl or 2-indanyl optionally substituted by hydroxyl and more particularly 2-indanyl. Conveniently R₂ is a group selected from isopropyl, 1 -methyl propyl, 2-methylpropyl or cyclopentyl and more preferably R₂ is a group selected from 1-methylpropyl, or 2-methylpropyl.

Conveniently R₃ is a group selected from phenyl, halophenyl such as 2-fluorophenyl, 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-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 methoxyphenyl, 2- fluoro-4 hydroxyphenyl, 2-fluoro-4-dimethylaminomethylphenyl, 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- methyl-phenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl, 4- methoxyphenyl, 4-methoxycarbonylphenyl, 3-methoxycarbonyphenyl, 4- methylsulphonylphenyl, 4-methylaminocarbonylphenyl, 4- aminocarbonylphenyl, 4- methylaminosulphonylphenyl, 3-(3-pyrazyolyl)ρhenyl, 4-(3-pyrazolyl)phenyl, 4-(4- pyrazolyl)phenyl, 4-(3-pyridyl)phenyl, 4-(2-pyridylphenyl), 4-(2-imidazolyl)ρhenyl, 3-(2- imidazolyl)phenyl, 4-(l-t-butyl-tetrazol-5-yl)phenyl, 4-methylaminophenyl, 4- dimethylaminophenyl, 4-diethylaminophenyl, 4-acetylaminophenyl, 3- acetylaminophenyl, 4-hydroxy-3-acetylaminophenyl, 4-methylsulphonylaminophenyl, 4- N-methylpiperazinophenyl, 4-N-pyrrolidinophenyl, 2-fluoro-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-imidazolyl)phenyl, 4-(l-imidazolyl)phenyl, 4-(l-l,2,4- triazolyl)phenyl, 4-(l-l,2,3-triazolyl)phenyl, 4-(2-4,-t-butylthiazolyl)phenyl, 4-(5- 2-t- butyltetrazolyl)phenyl, 4-(4 spiro-l,3-dioxolanyl)piperidinophenyl, 4-(4- fluorophenyl)phenyl, 4-(4-ethylaminosulphonylphenyl)phenyl, 4- dimethylaminoethoxyphenyl,3-(dihydroxyboryl)phenyl, 2-furanyl, 3-thienyl, 3-furanyl, 2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chloro-2-tl ienyl, 3-fluoro-5-methyl- 2-thienyl, 5-methyl-2-thienyl, 5-methyl-2-furanyl, 5-bromo-2-furanyl, 4,5-dimethyl-2- furanyl, 5-trifluoromethyl-2-furanyl, 2-furanyl-4-carboxylic acid methylamide, 2-furanyl- 5-carboxylic acid methylamide, 2-pyridyl, 6-methyl-2-pyridyl, 6-methyl-3-pyridyl, 6- methoxy-3-pyridyl, 6-hydroxy-3-pyridyl, 6-trifluoromethyl-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-oxazolyl, 2,5-dimethyl-4-oxazolyl, 4- thiazolyl, 2-methyl-4-thiazolyl, 2-trifluoromethyl-4-thiazolyl, 2-trifluoromethyl-5- thiazolyl, l-methyl-4-pyrazolyl, l,3-dimethyl-5-pyrazolyl, 5-(2-pyridyl)-2-thienyl, 2,3- dihydro-l-benzofuran-5-yl, l,3-benzodioxol-5-yl, lH-l,2,3-benzotriazol-5-yl, 2,3- dihydro- 1 ,4-benzodioxin-6-yl, 2,2-difluoro- 1 ,3 -benzodioxol-5-yl, 1 ,3 -benzothiazol-6-yl, l-methyl-lH-l,2,3-benzotriazol-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- benzofuran-5-yl, l-methy-lH-lindol-5-yl, l-benzothien-5-yl, l-benzofuran-6-yl, 1H- indol-6-yl, 1 -methyl- lH-benzimidazol-6-yl, l-methyl-lH-benzimidazol-5-yl, 3-methyl- l,2-benzoisoxazol-5-yl, 2-fluoro-l-benzofuran-5-yl, lH-indol-5-yl, 2-methyl-lH- benzofuran-5-yl, lH-indazol-5-yl, lH-indazol-6-yl, l-benzofuran-2-yl or 1-methyl-lH- benzimidazol-2-yl.

Conveniently the group R₅ is hydrogen, Cμ-alkyl e.g. methyl or C₁-₄alkoxyC₂-₄alkyl e.g. 2-methoxyethyl and R₆ is a group selected from hydrogen,

e.g. methoxy, - ₄alkyl e.g. methyl, n-propyl, isopropyl or t-butyl, Cμ₄ alkyl substituted by 1 to 3 halogen atoms e.g. 2,2,2-trifluoroethyl or 2-fluoroethyl, substituted by alkoxycarbonyl or carboxyl e.g. methoxycarbonylmethyl or carboxymethyl, alkyl substituted by alkoxy e.g methoxyethyl, 2,2-dimethoxyethyl, alkyl substituted by hydroxy e.g. hydroxyethyl or alkyl substituted by dialkylamino e.g. dimethylaminoethyl, 2-benzyloxyphenyl, dimethoxybenzyl, optionally substituted heteroarylmethyl e.g. 2-pyridylmethyl, 3- pyridylmethyl, 4-pyridylmethyl, 3-methylimidazolylmethyl, heteroaryl such as thiazolyl e.g. 2-1,3-thiazolyl, alkyl substituted by NR R₈ [wherein NR₇R₈ form a 6-membered heterocyclic ring (e.g. piperidinoethyl or morpholinoethyl)], cycloalkyl e.g. cyclopropyl or cyclohexyl, or NRsR_δ represents, azetidino, 3-hydroxyazetidino, 3-methoxyazetidino, pyrrolidino, piperidino, 4-dimethylaminopiperidino, 4-methyl 1,4-diazepan-l-yl, morpholino, an optionally substituted piperazino ring e.g. N-methylpiperazino,N- methanesulphonylpiperazino, N-2-methoxyethylpiperazino, thiomorpholino or the sulphoxide or sulphone thereof.

A preferred class of compounds are those of formula (la) wherein Riis 2-indanyl, R₂ is a group selected from 1-methylpropyl or 2-methylpropyl and t is hydroxy and/or more particularly the group NR₅Re.

A further preferred class of compounds are those of formula (la) wherein R₅ is a group selected from hydrogen, C₁. alkyl e.g. methyl or C₁. alkoxyC₂-₄alkyl e.g. 2-methoxyethyl and R₆ is a group selected from hydrogen, Ci- alkoxy e.g. methoxy, C_Malkyl e.g. methyl, n-propyl, isopropyl or t-butyl, CM alkyl substituted by 1 to 3 halogen atoms e.g. 2,2,2- trifluoroethyl or 2-fluoroethyl,

substituted by alkoxycarbonyl or carboxyl e.g. methoxycarbonylmethyl or carboxymethyl, alkyl substituted by alkoxy e.g methoxyethyl, 2,2-dimethoxyethyl, alkyl substituted by hydroxy e.g. hydroxyethyl or alkyl substituted by dialkylamino e.g. dimethylaminoethyl, 2-benzyloxyphenyl, dimethoxybenzyl, optionally substituted heteroarylmethyl e.g. 2-pyridylmethyl, 3-pyridylmethyl, 4- pyridylmethyl, 3-methylimidazolylmethyl, heteroaryl such as thiazolyl e.g. 2-1,3- thiazolyl, alkyl substituted by NR₇R₈ [wherein NR₇R₈ form a 6-membered heterocyclic ring (e.g. piperidinoethyl or morpholinoethyl)], cycloalkyl e.g. cyclopropyl or cyclohexyl, or NR₅R₆ represents, azetidino, 3-hydroxy^'azetidino, 3-methoxyazetidino, pyrrolidino, piperidino, 4-dimethylaminopiperidino, 4-methyl 1,4-diazepan-l-yl, morpholino, an optionally substituted piperazino ring e.g. N-methylpiperazino, N- methanesulphonylpiperazino, N-2-methoxyethylpiperazino, thiomorpholino or the sulphoxide or sulphone thereof.

A yet further preferred class of compounds are those of formula (la) wherein R₃ is a group selected from phenyl, halophenyl such as 2-fluorophenyl, 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- difiuorophenyl, 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- trifluorophenyl or 2,4,6-trifluorophenyl, 2-fluoro-4,5-dimethoxyphenyl, 3-fluoro-4- methoxyphenyl, 4-fluoro-3-methoxyphenyl, 2-fluoro-4 methoxyphenyl, 2- fluoro-4 hydroxyphenyl, 2-fluoro-4-dimethylaminomethylphenyl, 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- methyl-phenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl, 4- methoxyphenyl, 4-methoxycarbonylphenyl, 3-methoxycarbonyphenyl, 4- methylsulphonylphenyl, 4-methylaminocarbonylphenyl, 4- aminocarbonylphenyl, 4- methylaminosulphonylphenyl, 3-(3-pyrazyolyl)phenyl, 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-yl)phenyl, 4-methylaminophenyl, 4- dimethylaminophenyl, 4-diethylaminophenyl, 4-acetylaminophenyl, 3- acetylaminophenyl, 4-hydroxy-3-acetylaminophenyl, 4-methylsulphonylaminophenyl, 4- N-methylpiperazinophenyl, 4-N-pyrrolidinophenyl, 2-fluoro-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-imidazolyl)phenyl, 4-(l-imidazolyl)phenyl, 4-(l-l,2,4- triazolyl)phenyl, 4-(l-l,2,3-triazolyl)phenyl, 4-(2-4,-t-butylthiazolyl)phenyl, 4-(5- 2-t- butyltetrazolyl)phenyl, 4-(4 spiro-l,3-dioxolanyl)piperidinophenyl, 4-(4- fluoroρhenyl)phenyl, 4-(4-ethylaminosulphonylphenyl)phenyl, 4- dimethylaminoethoxyphenyl,3-(dihydroxyboryl)phenyl, 2-furanyl, 3-thienyl, 3-furanyl, 2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chloro-2-thienyl, 3-fluoro-5-methyl- 2-thienyl, 5-methyl-2-thienyl, 5-methyl-2-furanyl, 5-bromo-2-furanyl, 4,5-dimethyl-2- furanyl, 5-trifluoromethyl-2-furanyl, 2-furanyl-4-carboxylic acid methylamide, 2-furanyl- 5-carboxylic acid methylamide, 2-pyridyl, 6-methyl-2-pyridyl, 6-methyl-3-pyridyl, 6- methoxy-3-pyridyl, 6-hydroxy-3-pyridyl, 6-trifluoromethyl-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-oxazolyl, 2,5-dimethyl-4-oxazolyl, 4- thiazolyl, 2-methyl-4-thiazolyl, 2-trifluoromethyl-4-thiazolyl, 2-trifluoromethyl-5- thiazolyl, l-methyl-4-pyrazolyl, l,3-dimethyl-5-pyrazolyl, 5-(2-pyridyl)-2-thienyl, 2,3- dihydro-l-benzofuran-5-yl, l,3-benzodioxol-5-yl, lH-l,2,3-benzotriazol-5-yl, 2,3- dihydro-1 ,4-benzodioxin-6-yl, 2,2-difluoro-l ,3-benzodioxol-5-yl, 1 ,3-benzothiazol-6-yl, 1 -methyl- 1 H- 1 ,2,3 -b enzotriazol-5 -yl, 1 -methyl- 1 H- 1 ,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- benzofuran-5-yl, l-methy-lH-lindol-5-yl, l-benzothien-5-yl, l-benzofuran-6-yl, 1H- indol-6-yl, l-methyl-lH-benzimidazol-6-yl, l-methyl-lH-benzimidazol-5-yl, 3-methyl- l,2-benzoisoxazol-5-yl, 2-fluoro-l-benzofuran-5-yl, lH-indol-5-yl, 2-methyl-lH- benzofuran-5-yl, lH-indazol-5-yl, lH-indazol-6-yl, l-benzofuran-2-yl or 1-methyl-lH- benzimidazol-2-yl.

Particular preferred compounds for use in the invention include: (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N,N-dimethylethanamide

(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N,N-dimethylethanamide (2R)-2-(4-fluorophenyl)-2-[(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 -yl] -N-isopropylethanamide.

(2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-2-[4-(4-hydroxypiperidin-l-yl)phenyl]ethanamide.

(2R)-2-{(3R,6R)-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-isoproρylethanamide.

(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-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -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- 1 -yl] ethanamide. (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-methylethanamide

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] ethanamide

(3R,6R)-l-[(lR)-l-(2,4-difluoroρhenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro- lH-inden-2-yl)-6-isobutylpiperazme-2,5-dione (3R,6R)-l-[(lR)-l-(2,4-difluorophenyl)-2-(3-hydroxyazetidin-l-yl)-2-oxoethyl]-3-(2,3- dihydro-lH-inden-2-yl)-6-isobutylpiperazine-2,5-dione

(3R,6R)-l-[(lR)-2-azetidin-l-yl-l-(2,4-difluorophenyl)-2-oxoethyl]-3-(2,3-dihydro-lH- inden-2-yl)-6-isobutylpiperazine-2,5-dione

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N-(2-hydroxyethyl)-N-methylethanamide

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-methyl-N-[2-(methylsulfonyl)ethyl]ethanamide

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-methyl-N-(2,2,2-trifluoroethyl)ethanamide (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N-methyl-N-(pyridin-2-ylmethyl)ethanamide

(3R,6R)- 1 - {(1R)- 1 -(2,4-difluoroρhenyl)-2-[4-(methylsulfonyl)piperazin- 1 -yl]-2- oxoethyl}-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutylpiperazine-2,5-dione

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-methoxy-N-methylethanamide

(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] ethanoic acid methyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5 dioxopiperazin- 1 -yl] ethanoate propyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] ethanoate l-(acetyloxy)ethyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-l-yl]ethanoate

(2R)-N-(tert-butyl)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-

[( 1 R)- 1 -methylpropyl] -2,5 -dioxopiperazin- 1 -yl} ethanamide

(2R)-N-(tert-butyl)-2-(2₅4-difluorophenyl)-2-{(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6- [(1S)-1 -methylpropyl]-2,5-dioxopiperazin-l -yl} ethanamide

(3R,6R)-l-[(lR)-l-(2,4-difluorophenyl)-2-mo holin-4-yl-2-oxoethyl]-3-(2,3-dihydro- lH-inden-2-yl)-6-[(l S)-l -methylpropyl]piperazine-2,5-dione.

(3R,6R)-l-[(lR)-l-(2,4-difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro- lH-inden-2-yl)-6-[(lR)-l-methylpropyl]piperazine-2,5-dione. (3R,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-2,5-dioxopiperazin-l-yl]-N- isopropyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide.

(2S)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxoρiperazin-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.

N,N-dimethyl-2-(2 -methyl- 1 ,3-oxazol-4-yl)ethanamide. (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]piperazine-2,5-dione.

(2S)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N,N- dimethyl-2-(5-methylthien-2-yl)ethanamide

(2S)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxoρiperazin-l-yl]-2-(3- fluoro-5-methylthien-2-yl)-N,N-dimethylethanamide

(2R)-2-(l-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N-isopropylethanamide.

(2R)-2-(l,2,3-benzothiadiazol-6-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-

2-yl)-6-isobutyl-2,5-dioxopiperazin- 1 -yl] ethanamide. (2R)-2-(2,3-dihydro-l-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-l-yl]-N-isopropylethanamide.

(2R)-2-(l,3-benzodioxol-5-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-

6-isobutyl-2,5-dioxopiperazin-l-yl]ethanamide.

(2R)-2-(benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N,N-dimethylethanamide.

N,N-dimethyl-2-(2-methyl- 1 -benzofuran-5 -yl)ethanamide. (2R)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]- N- isopropyl-2-(2-methyl- 1 -benzofiιran-5-yl)ethanamide.

(3R,6R)-3-(2,3-dihydro- lH-inden-2-yl)-6-isobutyl- 1-[(1R)- 1 -(2-methyl- 1 -benzofuran-5- yl)-2-moφholin-4-yl-2-oxoethyl]piperazin-2,5-dione.

(2R)-2-[(3R,6R)-3-(2₅3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-2-

(2-fluoro-l-benzofuran-5-yl)-N,N-dimethylethanamide.

(2R)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)^'-6-isobutyl-2,5-dioxopiperazin-l-yl]-2-

(2-fluoro-l-benzofuran-5-yl)-N-isopropylethanamide. (3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-l -[(1R)- 1 -(2-fluoro- 1 -benzofuran-5-yl)-2- morpholin-4-yl-2-oxoethyl]-6-isobutylpiperazine-2,5-dione.

( 1 H-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-l-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 (I) 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 of Pettibone et al, Drug Development Research 30. 129-142 (1993). The compounds of the invention also exhibit high affinity at the human recombinant oxytocin receptor in CHO cells and this may be conveniently demonstrated using the procedure described by Wyatt et al. Bioorganic & Medicinal Chemistry Letters, 2001 (11) pl301- 1305.

The compounds of formula (I)are therefore useful in the treatment or prevention of benign prostatic hyperplasia.

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 treating benign prostatic hyperplasia

According to a further aspect, the invention also provides for a method for treating or preventing benign prostatic hyperplasia which comprising administering to a patient in need thereof an effective amount of a compound of formula (I) and/or a physiologically acceptable salt thereof. According to a further aspect, the invention also provides for a method for treating or preventing benign prostatic cancer which comprising administering to a patient in need thereof an effective 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 benign prostatic hyperplasia and or benign prostatic cancer.

It will further be appreciated that the amount of a compound of the invention required for use in treatment will vary with the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician, hi general however doses employed for adult human treatment will typically be in the range of 2 to 800mg per day, dependent upon the route of administration.

Thus for parenteral 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 800mg, e.g. 20 to 150 mg per 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 formula (I) 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 for the treatment of benign prostatic hyperplasia comprising a compound of formula (I) or a pharmaceutically acceptable salt or non-toxic metabohcally 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 as 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 stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for 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 emulsions, 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.

For 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 formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for 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 i is the group NRsRg may be prepared by cyclisation of the compound of formula (II)

wherein R_ls R₂ and R₃ have the meanings defined in formula (I) R_π is hydrogen and R₁₂ is a C_halky! 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 R_π is hydrogen is conveniently prepared in-situ by treating a compound of formula (II) wherein Rπ is an acid labile nitrogen protecting group and R₁₂ is hydrogen or C^a-kyl, with an acid in a suitable solvent followed by treatment with a hydrohalic acid and methanol if R₁₂ 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 Rπ is an hydrogenolysable nitrogen protecting group and R₁₂ is - ₃alkyl in a suitable solvent such as methanol 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 R_{\ 1} include alkoxycarbonyl e.g. t- butyloxycarbonyl or an optionally substituted benzyloxycarbonyl group.

When R₁₂ is C^a-kyl 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 of formula (II) may be prepared by reaction of the mixed anhydride (III)

(»')

wherein R_\ and Rπ have the meanings defined above and wherein R₁₃ is a C straight or branched chain alkyl, optionally substituted phenyl or benzyl group, with the amine (IN)

wherein R₂, R₃, R₅ and R have the meanings defined above, and R₁₂ is hydrogen. The reaction is preferably carried out in an aprotic solvent such as an ether e.g. tefrahydrofuran 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) R, CH-C0₂H NHR„ (V)

wherein Ri and Rπ have the meanings defined above with the corresponding haloformate (VI; R₁₃CO₂X wherein R₁₃ 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- methylmorpholine and in an aprotic solvent e.g. an ether such as tefrahydrofuran or a hydrocarbon e.g. toluene.

The amine (IN) wherein R₅ is hydrogen may be prepared treating the amino acid (VII)

R₁₂0₂CCH(R₂)ΝH₂ (VII)

wherein R₂ has the meanings defined above and Rι₂ is hydrogen with the aldehyde (NIII; R₃CHO wherein R₃ 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; R₆Ν=C wherein R₆ has the meanings defined in formula I other than hydrogen). Alternatively, the compounds of formula (II) wherein R_\, R₂ and R₃ have the meanings given in formula (I) and Rπ is a nitrogen protecting group and R₁₃ is a carboxyl protecting group may be prepared by reacting the amino acid derivative (Nil) wherein R₂ has the meaning given in formula (I) and R₁₂ is a carboxyl protecting group with the aldehyde (NIII) wherein R₃ has the meaning given in formula (I) in a solvent such as an alkanol e.g. methanol or

2,2,2-trifluoroethanol followed by the sequential addition of the amino acid (N) wherein R_\ has the meanings given in formula (I) and Rπ is a carboxyl protecting group and the isonitrile (IX) wherein R₆ has the meanings given in formula (I).

Compounds of formula (II) wherein R₁₂ is a C^a-kyl group may also be prepared by reacting the carboxylic acid (X) or an activated derivative thereof

wherein R_ls R₂, R₃ and R_π have the meanings defined above and R₁₂ is a C^a-kyl group, with the amine NHR₅R₆ wherein R₅ 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- yloxytri-pyrrolidinophosphonium hexafluorophosphate in the presence of a suitable amine such as disopropylethylamine.

The carboxylic acid (X) may be prepared from the corresponding compound of formula (II) wherein R₅ represents hydrogen and R₆ represents the 2-hydroxyphenyl by reaction with carbonyldiimidazole or thiocarbonyldimidazole in a suitable solvent such as dichloromethane and subsequent reaction of the product thus formed with aqueous acetone.

Compounds of formula (II) wherein R₆ represents 2-hydroxyphenyl are conveniently prepared by catalytic hydrogenolysis (e.g. Pd/H₂) of the corresponding compound wherein R₆ is a 2-benyloxyphenyl 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 R is hydroxyl maybe prepared from a compound of formula (I) wherein I is the group NRsRβ and R₅ is hydrogen R₆ 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.

Compounds of formula (I) wherein R₅ is hydrogen and R₆ is 2-hydroxphenyl may be from the corresponding compound of formula (I) wherein R₆ is a 2-benyloxyphenyl group by hydrogenolysis using hydrogen and a palladium catalyst.

Compounds of formula (I) wherein R is the group NR₅R₆ may be prepared by reaction of the compound of formula (I) wherein R is hydroxyl or an activated derivative thereof with the amino NHRsRe wherein R₅ and R₆ have the meaning defined in formula (I) under the standard condition for preparing amides from a carboxylic acid and an amine such as NHR₅R₆. Thus the 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- tris(dimethylamino)phosphonium hexafluorophosphate),TBTU (2-(lH-benzotriazol-l - yl)-l,l,3,3-tetramethyluronium tetrafluoroborate), BOP-C1 (bis(2-oxo-3- oxazolidinyl)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 amine NHR₅R₆.

Alternatively compounds of formula (I) wherein Ri is the group NR₅R₆ may be prepared by reacting a compound of formula (I) wherein R₅ is hydrogen and R₆ 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 NHR₅R₆.

Compounds of formula (I) wherein Rj is OCM alkyl (optionally substituted with C_\.

₄alkylcarbonyloxy) may be prepared by reacting the corresponding carboxylic acid (1^ is OH) or an activated derivative thereof with the appropriate alcohol (R₄OH) or alkyl halide (R4iab.de) 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 the acid e.g. alkali meatal salts.

Compounds of formula (IN) maybe converted into other compounds of formula (IN) using standard procedures. Thus compound of formula (IN) wherein R₅ is hydrogen and R₆ is 2-benzyloxyphenyl may be converted into other compounds of formula (IN) wherein R₅ and R₆ 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 R_1} R₂ and R₃ is as shown in formula (la) may be prepared starting from the corresponding single isomers of the intermediates (III), (IN) and (Nil) and/or the various isomeric mixtures may be separated by conventional procedures.

The intermediates (N), (NI), (Nil), (NIII) 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). Physiologically acceptable salts of a compound of formula (I) wherein P is OH or one of the groups R_ls R₂, R or NR-^Rs has a basic or acidic centre may be prepared by treating the 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 (I) by conventional procedures for preparing such derivatives. Thus metabohcally 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.

General purification and analytical methods

Analytical HPLC was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID), eluting with 0.1% HCO₂H and 0.01 M ammonium acetate in water (solvent A), and 0.05%) HCO₂H 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 VG Platform spectrometer using electrospray positive [(ES+ve to give MH⁺ and M(NH )⁺ molecular ions] or electrospray negative [(ES-ve to give (M-H)^" molecular ion] modes on a Micromass series 2 or a Waters ZQ mass spectrometer. 1H NMR spectra were recorded using a Bruker DPX 400MHz spectrometer using tetramethylsilane as the external standard. Biotage™ chromatography 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 a HPLCABZ+ 5μm column (5cmxl0mm 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 NG 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 F₂₅ . Oasis™ refers to Waters^® Oasis™ HLB Extraction Cartridges, sold by

Waters Corporation®. Method 1

Example 1

(2R)-2-(4-fluorophenylV2-rr3R.6RV3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5- dioxopiperazin- 1 - yl] -N-isopropylethanamide

To a solution of (D)-leucine methyl ester hydrochlori.de (300mg) in methanol (4ml) was added triethylamine (230 μl) and 4-fluorobenzaldehyde (177μl). The mixture was stirred for 2.5 hours before (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-lH-inden-2- yl)ethanoic acid (481mg) and isopropylisocyanide (225μl) were sequentially added. After stirring for 16hr, the solvent was removed in vacuo 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 vacuo. The residue was dissolved in dichloromethane (2ml) and trifluoroacetic acid (5ml) and stirred for 3 hours at ambient temperature. After this time, the solvent was removed in vacuo 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 Biotage™ (90g, silica) eluting with toluene: ethyl acetate: cyclohexane (5: 3: 2) with 5% triethylamine to give r2R)-2-(4-fluorophenyl -2-r(3R.6RV3-(2.3- dihvdro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N-isopropylethanamide (149mg)

HPLC Rt = 3.42 minutes; m/z [M+H]⁺ = 480.

1H NMR (CDC1₃) δ 7.44 (m, 2H), 7.22 (m, 2H), 7.16 (m, 2H), 7.11 (t, 2H), 6.50 (d, IH), 5.60 (d, IH), 5.11 (s, IH), 4.10 (m, IH), 3.96 (m, 2H), 3.16 (dd, IH), 3.07 (d, IH), 2.91 (m, IH), 2.77 (m, IH), 1.84 (m, IH), 1.73 (m, IH), 1.42 (m, IH), 1.13 (d, 3H), 1.12 (d, 3H), 0.84 (d, 3H), 0.79 (d, 3H)

Similarly prepared

Example 2 (2R)-N-(tert-butyl -2-[(3R.6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -2-[4-(4-hvdroxypiperidin- 1 -vDphenyl] ethanamide. HPLC Rt = 3.27 minutes; m/z [M+H]⁺ = 575.

(CDCI₃) δ 7.3 (d,2H), 7.2 (m, 2H), 7.15 (m, 2H), 6.9 (d, 2H), 6.1 (d, IH), 5.5 (s, IH), 5.15 (s, IH), 3.95 (m, 2H), 3.9 (m, IH), 3.6 (m, 2H), 3.15 (m, IH), 3.1 (m, 2H), 3.0 (m, 2H), 2.9 (m, IH), 2.75 (m, IH), 2.0 (m, 2H), 1.75 (m, IH), 1.65 (m, 3H), 1.45 (m, IH), 1.3 (s, 9H), 0.8 (d, 3H), 0.7 (d, 3H). Example 3

(2R)-2-{(3R.6RV3-r2.3-dihvdro-lH-inden-2-ylV6-[riRVl-methv roPyll-2.5- dioxopiperazin- 1 -yll -2-(2-fluoro-4-morpholin-4-ylphenyl)-N-isoprop ylethanamide. HPLC Rt = 3.34 minutes; m/z [M+H]⁺ = 565

1HNMR (CDC1₃) δ 7.52 (t, IH), 7.22-7.11 (m, 4H), 7.04 (br s, IH), 6.66 (dd, IH), 6.56 (dd, IH), 5.07 (s, IH), 4.19-4.08 (m, 2H), 3.98 (dd, IH), 3.86-3.81 (4H, m), 3.21-2.91 (m, 8H), 2.80-2.73 (m, IH), 1.96-1.86 ( , IH), 1.72-1.61 (m, IH), 1.51-1.40 (m, IH), 1.19 (d, 3H), 1.16 (d, 3H), 1.06 (d, 3H), 0.92 (t, 3H).

Method 2

Example 4

(2RV2-r(3R,6R)-3-(2,3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5-dioxopiperazin-l-yl]-2- (4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide

Methyl (2R)-2-(r(lR.S)-2-{[2-(benzyloxy)phenyllamino}-l-r4-fluorophenyl)-2- oxoethyl][(2R -2-[(tert-butoxycarbonyl amino]-2-(2.3-dihydro-lH-inden-2- vDethanoyl] amino} -4-methylpentanoate

A mixture of 4-fluorobenzaldehyde (1.2g), (D)-leucine methyl ester hydrochloride (1.7g), triethylamine and methanol (56ml) was stirred at room temperature for 3 hours. 2- Benzyloxyphenylisocynanide (2.0g) and N-tert-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 vacuo. The resultant crude material was purified by column chromatography (eluting with 0.5% and 0.2%) methanol/ dichloromethane) to afford methyl (2R)-2-{[(lR,S)-2-{[2-(benzyloxy)phenyl]amino}-l-(4-fluorophenyl)-2- oxoethyl][(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-lH-inden-2- yl)ethanoyl]amino}-4-methylpentanoate (4.3g) HPLC Rt = 4.34 minutes, m/z [M+H]⁺ = 752

Methyl N-[(2RV2-r(tert-butoxycarbonyl)aminol-2-(2.3-dihvdro-lH-inden-2-yl)ethanoyll- N-{(lR,S)-l-(4-fluorophenyl)-2-[(2-hvdroxyphenyl)amino]-2-oxoethyl}-D-leucinate

A mixture of methyl (2R)-2-{[(lR,S)-2-{[2-(benzyloxy)ρhenyl]amino}-l-(4- fluorophenyl)-2-oxoethyl][(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-lH- inden-2-yl)ethanoyl]amino}-4-methylpentanoate (560mg), palladium on carbon (70mg) and ethanol (15ml) was stirred under an atmosphere of hydrogen for 5 hours. The mixture was filtered through Celite and the filtrate was evaporated in vacuo. 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- lH-inden-2-yl)ethanoyl]-N- {(1R,S 1 -(4-fluorophenyl)-2-[(2-hydroxyphenyl)amino]-2- oxoethyl} -D-leucinate.

HPLC Rt = 4.06 minutes, m/z [M+H]⁺ = 662

(2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-lH-inden-2- yl)ethanoyl][(lR)-l-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid.

Carbonyldiimidazole (558mg) was added to a solution of methyl N-[(2R)-2-[(tert- butoxycarbonyl)amino] -2-(2,3 -dihydro- 1 H-inden-2-yl)ethanoyl] -N- {(1 R,S)- 1 -(4- fluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-D-leucinate (2.0g) in dichloromethane (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 (60ml: 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 vacuo. Half of the material was taken to be used crude in further experiments. The second half was purified by Biotage™ (silica, 90g) eluting with methanol: dichloromethane: ammonia (1 : 98.5: 0.5 to 2.5: 86.5: 1). Evaporation of the appropriate fractions gave (2R)-{[(2R)-2-[(tert- butoxycarbonyl)amino]-2-(2,3-dihydro-lH-inden-2-yl)ethanoyl][(lR)-l- (methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid. (173mg). HPLC Rt = 3.91 minutes, m/z [M+H]⁺ = 571

(2RV2-r(3R.6R)-3-r2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5-dioxopiperazin-l-yll-2-

(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide

A solution of (2R {[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-lH-inden-2- yl)ethanoyl][(lR)-l-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid (73mg) in N,N-dimethylformamide (2ml) was sequentially treated with diisopropylethylamine (51μl), phosphorus¹ (l-hydroxy-lH-benzotriazolato-O)tri-l- pyrrolidinyl-(T-4)-hexafluorophosphate (80mg) and then after 2 minutes, 2,2,2- trifluoroethylamine (25 μl). 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 vacuo. The residue was dissolved in 4M hydrogen chloride in dioxane and stirred for 7 hours at room temperature. The reagent was removed in vacuo 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 vacuo. The crude material was purified by column chromatography (silica) eluting with methanol: dichloromethane (1% to 3%) to furnish f(2R)-2-r(3R,6RV3-(2.3-dihvdro-lH- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl1-2-(4-fluorophenylVN-(^"2.2.2- trifluoroethvpethanamide ( 1 Omg)

HPLC Rt = 3.4 minutes, m/z [M+H]⁺ = 520

1H NMR (CDC1₃) δ 7.42 (m, 2H), 7.34 (d, IH), 7.20-7.10 (m, 6H), 6.61 (t, IH), 5.28 (s,

IH), 4.08-3.96 (m, 3H), 3.88 (m, IH), 3.14 (dd, IH), 3.02 (m, 2H), 2.95-2.77 (m, 2H),

1.88-1.70 (m, 2H), 1.40 (ddd, IH), 0.85 (d, 3H), 0.79 (d, 3H).

The following compounds were prepared in a similar manner

Example 5 r2RV2-r4-fluorophenyl)-2-[(3R,6RV3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N,N-dimethylethanamide HPLC Rt = 3.37minutes, m/z [M+H]⁺ = 466 IH NMR (CDC13); δ 7.47-7.40 (m, 2H), 7.25-7.12 (m, 6H), 6.50 (d, IH), 6.47 (s, IH), 4.15 (dd, IH), 3.98 (dd, IH), 3.21-3.01 (m, 3H), 2.99 (s, 3H), 2.92-2.73 (m, 2H), 2.83 (m, 3H), 1.59-1.49 (m, IH), 1.42 (dt, IH), 0.66-0.57 (m, IH), 0.62 (d, 3H), 0.40 (d, 3H).

Example 6 r2R -2-r4-fluorophenyl)-2-[r3R.6R)-3-(2.3-dihvdro-lH-inden-2-vn-6-isobutyl-2,5- dioxopiperazin-l-yl]- morpholinamide

HPLC Rt = 3.32 minutes, m/z [M+H]⁺ = 508

1HNMR (CDC13); δ 7.44-7.39 (m, 2H), 7.26-7.12 (m, 6H), 6.87 (d, IH), 6.51 (s, IH),

4.12 (dd, IH), 4.00 (dd, IH), 3.73-3.62 (m, 3H), 3.60-3.54 (m, 2H), 3.37 (m, IH), 3.23 (m, IH), 3.20-3.02 (m, 4H), 2.91-2.75 (m, 2H), 1.60-1.50 (m, IH), 1.45 (dt, IH), 0.63 (d,

3H), 0.62-0.55 (m, IH), 0.42 (d, 3H).

The 2-fluoro-4-(mo holino)-benzaldehyde used in this synthesis was prepared by the following procedure.

2-Fluoro-4-(moφholmo)-benzonitrile

A solution of 2,4-difluorobenzonitrile (6.03g, 43.35mmol) and morpholine (8.3ml,

95.17mmol) in tetrahydrofuran (27ml) was stirred at room temperature for 24hr. The mixture was evaporated and the white solid purified by Biotage™ column (90g, silica) eluting with cyclohexane: ethyl acetate: (4: 1) to give 2-fluoro-4-(morpholino)- benzonitrile as a white solid (5.81g, 65%).

HPLC Rt = 2.83 minutes; m/z [M+H]⁺ = 207.

2-Fluoro-4-(morpholino)-benzaldehyde To a solution of 2-fluoro-4-(morpholino)-benzonitrile (2.82g, 13.7mmol) in tetrahydrofuran (27ml) under a nitrogen atmosphere was added dropwise a 1.5 M solution of DIBAL-H in toluene (18.3ml, 27.3mmol) during 13minutes and the resulting mixture stirred for 23.5hr at room temperature. The mixture was cooled to -50 °C and the excess DIBAL-H deastoyed by careful addition of methanol (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 (120ml) and water (120ml) and solid potassium carbonate added until the aqueous phase was pHlO. 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 cyclohexane: ethyl acetate: (7:3) to give 2-fluoro-4-(moφholino)-benzaldehyde (1.96g, 68%) as a white solid.

HPLC Rt = 2.63 minutes; m/z [M+H]⁺ = 210.

Method 3

Example 7

(2RV2-(2.4-difluorophenylV2-r(3R.6RV3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2,5- dioxopiperazin-l-yl]-N-isopropylethanamide

Methyl N-r(lR)-l-(2.4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-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 for 3 days, the suspension was cooled to -30°C and a solution of isopropylisocyanide (0.69 lg) 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 vacuo, the residue purified using a Biotage™ column (40g, silica) eluting with cyclohexane: ethyl acetate (gradient from 8:1 to 1:1). The required fractions were combined and concentrated in vacuo to furnish methyl N-[(lR)-l-(2,4- difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucinate (1.326g). 1H NMR (CDC1₃) d 7.32 (m, IH), 6.88 (m, IH), 6.82 (m, IH), 6.78 (m, IH), 4.42 (s, IH), 4.07 (m, IH), 3.69 (s, 3H), 3.18 (t, IH), 1.66 (m, IH), 1.49 (t, 2H), 1.18 (d, 3H), 1.15 (d, 3H), 0.88 (d, 3H), 0.77 (d, 3H)

N-[(lR)-l-(2,4-difluorophenyl)-2-(^'isopropylamino)-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 (294mg) in water (15ml). The reaction was rapidly stirred for 1.5 hours and then evaporated in vacuo. The residue was dissolved in water and neutralised using 2N hydrochloric acid. The resulting solid was collected by filtration and dried in vacuo. The filtrate was applied to 4 Oasis cartridges (6g), which were eluted with water (x2) and methanol (x2). The required fractions were combined and concentrated in vacuo to afford N-[(lR)-l-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine (1.01g). HPLC Rt = 2.51 minutes; m/z [M+H]⁺ = 343.

(2RV2-(2,4-difluorophenvn-2-r(3R.6R)-3-r2.3-dihvdro-lH-inden-2-vn-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N-isopropylethanamide.

To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-lH-inden-2-yl)ethanoic acid (291mg) in dry tetrahydrofuran (5ml) under a nitrogen atmosphere at -20°C was added N-methylmorpholine (lOlmg) and a solution of isopropylchloro formate in toluene (1.0M, 1ml). After 10 minutes, a solution of N-[(lR)-l-(2,4-difluorophenyl)-2- (isopropylamino)-2-oxoethyl]-L-leucine (342mg) in N,N-dimethylformamide/ tetrahydrofuran (5ml/ 10ml) was added and the resultant mixture was stirred at room temperature for 4 hours. The solvent was then removed in vacuo 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 vacuo 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-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N-isopropylethanamide; (0.137g) HPLC Rt = 3.47 minutes, m/z [M+H]⁺ = 498

1H NMR (CDC1₃) δ 7.68 (m, IH), 7.21 (m, 2H), 7.17 (m, 2H), 6.95 (m, IH), 6.89 (m, IH), 6.79 (d, IH), 5.91 (d, IH), 5.33 (s, IH), 4.12 (m, IH), 4.02 (m, IH), 3.92 (dd, IH), 3.16 (m, IH), 3.05 (m, 2H), 2.90 (m, IH), 2.78 (m, IH), 1.85 (m, IH), 1.79 (m, IH), 1.49 (m, IH), 1.17 (m, 6H), 0.88 (d, 3H), 0.82 (d, 3H)

Method 4

Example 8

(2R -2-(2.4-difluorophenylV2-[(3R.6RV3-C2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N,N-dimethylethanamide

Methyl N-[(lR)-2-{[2-(benzyloxy)phenyl]amino}-l-(2,4-difluorophenyl -2-oxoethyl]-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 -30°C for 2.5 hours and then allowed to warm to room temperature and stirred for a further 6 days. The solvent was removed in vacuo 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- (benzyloxy)phenyl] amino } - 1 -(2,4-difluorophenyl)-2-oxoethyl] -L-leucinate (5.06g). HPLC Rt=4.0 minutes, m/z [M-H]^" = 495

Methyl N--f(lR)-l-(2.4-difluorophenylV2-[(^'2-hvdroxyphenyl)amino]-2-oxoethyl}-L- leucinate

A mixture of palladium on carbon (10%, 300mg), methyl N-[(lR)-2-{[2- (benzyloxy)phenyl] amino } - 1 -(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-difluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl} -L-leucinate (2.179g). HPLC Rt=3.52 min, m/z [M-H]^" = 405

Methyl N-[l-r2,4-difluorophenyl)-2-(dimethylamino)-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,l'-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- Benzotriazolium, l-[bis(dimethylamino)methylene]-, tetrafluoroborate(l-), 3-oxide (TBTU, 321mg) and a solution of dimethylamine in tetrahydrofuran (0.5ml 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 (8:1 to 1:2 cyclohexane: ethyl acetate). The required fractions were combined and evaporated to furnish methyl N- [l-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (100mg). HPLC Rt = 3.16 minutes m/z [M+H]⁺ - 343

N-[l-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl1-L-leucine

To a solution of methyl N-[l-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L- leucinate (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- difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (95mg).

HPLC Rt = 2.23 minutes m/z [M+H]⁺ = 329

(2R)-2-r2.4-difluorophenylV2-r(3R.6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N.N-dimethylethanamide To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-lH-inden-2-yl)ethanoic acid (84mg) in dry tetrahydrofuran (6ml) at -20°C under a nitrogen atmosphere was added N-methylmorpholine (32D1) and a solution of isopropylchloroformate in toluene (1.0M, 290D1). After 10 minutes, a solution of N-[l-(2,4-difluorophenyl)-2- (dimethylamino)-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 furtherlδ hours. The solvent was then removed in vacuo and the residue was dissolved in dioxan (5ml) and to this was added triethylamine (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-difluoroρhenylV2-r(^'3R.6RV 3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N,N- dimethylethanamide (38mg .

HPLC Rt=3.5 minutes, m/z [M+H]⁺ = 484

1H NMR (CDC1₃) δ 7.42 (m, IH), 7.22 (m, 2H), 7.17 (m, 2H), 7.02-6.90 (m, 2H), 6.62 (s, IH), 6.37 (m, IH), 4.09 (m, IH), 3.98 (dd, IH), 3.20-3.02 (m, 3H), 2.99 (s, 3H), 2.87 (m, IH), 2.85 (s, 3H), 2.74 (m, IH), 1.55 (m, 2H), 0.70 (m, IH), 0.67 (d, 3H), 0.41 (d, 3H)

Similarly prepared

Example 9

(2R)-N-cyclopropyl-2-(2,4-difluorophenylV2-[(3R.6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6- isobutyl-2.5-dioxopiperazin-l-yl]ethanamide. HPLC Rt=3.41 minutes, m/z [M+H]⁺ = 496.

1H NMR (CDCI₃) δ 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, 6H), 1.88-1.70 (m, 2H), 1.48-1.38 (m, IH), 0.86 (s, 3H), 0.81-0.74 (m, 5H), 0.51-0.45 (m, 2H).

Example 10

(2RV2-(2.4-difluorophenyl)-2-r(3R6R)-3-r2,3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N,N-dimethylethanamide :

(2RSV2-r2.4-difluorophenylV2-r(3R.6RV3-r2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N-(2-benzyloxyphenyl)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 for 16 hours. N-tert-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 dichloromethane (ca. 20ml) and purified by Biotage™ flash column chromatography (2x90g silica cartridges on a Biotage Quad 3 system eluted with 1:9 ethyl acetate:cyclohexane) to afford methyl (2R)-2-{[(lR,S)-2-{[2-(benzyloxy)phenyl]amino}- 1 -(2,4-difluorophenyl)-2-oxoethyl] [(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro- lH-inden-2-yl)ethanoyl]amino}-4-methylpentanoate (5.100g) (HPLC Rt = 4.40 minutes m/z [M+H]⁺ = 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 methanol and excess of triethylamine were removed under reduced pressure. The crude product was purified by Biotage™ flash column chromatography (2x90g silica cartridges on a Biotage Quad 3 system eluted with 1 :2 ethyl acetate yclohexane) to yield (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- l-yl]-N-(2-benzyloxyphenyl)ethanamide (3.381g). HPLC Rt = 3.99 minutes, m/z [M+H]⁺ = 638

(2RS)-2-(2,4-difluorophenylV2-r(3R.6RV3-(2 -dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N-(2-hvdroxyphenyl)ethanamide

(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-(2-benzyloxyphenyl)ethanamide (3.38 lg) was dissolved in ethyl acetate (200ml) and hydro genated at atmospheric pressure over 10% palladium on carbon catalyst (0.980g of 10% 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-isobutyl-2,5-dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)ethanamide as a cream- coloured foam (2.650g).

HPLC Rt = 3.61 minutes, m/z [M-H⁺]^' = 546 (no [M+H}⁺ visible)

(2RS)-2-(2.4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -vfl-ethanoic acid.

(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)ethanamide (2.650g) was stirred in dichloromethane (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 then 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 (iii) ethyl acetate:methanol 9:1) to afford (2RS)-2-(2,4-difluorophenyl)- 2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-ethanoic acid.as a colourless solid 1.524g as a mixture of epimers. HPLC Rt = 3.44 and 3.58 minutes, both m/z [M+H⁺] = 457

(2RV2-(2.4-difluorophenylV2-[(3R.6RV3-r2.3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N,N-dimethylethanamide

The acid (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-l-yl]-ethanoic acid (0.747g) prepared as described above was dried over P₄Oio 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-Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride, dissolved in anhydrous dichloromethane :acetonitrile (1:1 v/v, 6ml) and treated with triethylamine (0.223ml) and BOP-Cl (bis(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 partitioned beween dichloromethane and 0.1M 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 the (2RV2-(2.4-difluorophenyl)-2-r(3R.6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl- 2,5 -dioxopiperazin- 1 -yl] -N.N-dimethylethanamide as a colourless solid 0.285g. HPLC Rt = 3.43 minutes, m/z [M+H]⁺ = 484 ^lH NMR (CDC1₃) δ 7.47 -7.40 (m, IH), 7.24-7.11 (m, 4H), 7.01-6.91 (m, 3H), 6.62 (s, IH), 4.09 (dd, IH), 3.98 (dd, IH), 3.19-3.01(m, 3H), 2.99 (3, 3H), 2.92-2.75 (m, 5H), 1.64-1.51 (m, 2H), 0.76-0.66 (m, 4H), 0.43 (d, 3H).

Method 5

Example 11

(2R)-2-r2.4-difluorophenylV2-[r3R.6RV3-(2.3-dihvdro-lH-inden-2-yl -6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N,N-dimethylethanamide

(2R)-[(benzyloxycarbonyl)amino1(2,3-dihvdro-lH-inden-2-yl)ethanoic acid R-Indanylglycine (1.91g) was suspended in dioxane (10ml) and water (10ml). To this was added triethylamine (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 vacuo to give (2R)- [(benzyloxycarbonyl)amino](2,3-dihydro-lH-inden-2-yl)ethanoic acid (3.06g). HPLC Rt = 3.35 minutes; m/z [M+H]⁺ = 326.

1H NMR (CDC1₃) δ 7.40-7.29 (m, 5H), 7.21-7.11 (m, 4H), 5.28 (d, IH), 5.11 (s, 2H), 4.57 (m, IH), 3.14-2.79 (m, 5H).

(2RS)-2-(2.4-difluorophenylV2-[(3R.6RV3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5- dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)ethanamide

To a solution of (D)-leucine methyl ester hydrochloride (1.45 g) in methanol (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)ethanoic acid (2.6g) and 2-benzyloxyphenylisocyanide (1.76g) were sequentially added. The reaction mixture was left to stand for 24 hours. The solvent was removed in vacuo 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 (3x100ml), saturated sodium bicarbonate solution, brine and dried over magnesium sulphate. The solvent was evaporated in vacuo. 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-(2,3-dihydro-lH-inden-2-yl)- 6-isobutyl-2,5-dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)ethanamide (2.0g). HPLC Rt = 3.59 minutes; m/z [M+H]⁺ = 548.

(2R)-2-(2,4-difluorophenyl)-2-rr3R.6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N,N-dimethylethanamide

Carbonyldiimidazole (4.80g, 1.54 equiv.) was suspended in anhydrous dichloromethane (40mL) 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-yl]-N-(2-hydroxyphenyl)ethanamide (10.50g, pre-dried in vacuo over P₄Oio 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 dichloromethane (200mL) and washed with IM hydrochloric acid (200mL). The organic phase was separated using a hydrophobic frit and was evaporated under reduced pressure to ca. 50mL. The crude product was applied to 4x90g silica Biotage™ columns on a Quad 3 system; each column being eluted with (i) 2:1 v/v ethyl acetate:cyclohexane (12x50mL fractions), (ii) ethyl acetate (12x50mL fractions), (iii) 9:1 v/v ethyl acetate:methanol to give (2RV2-r2.4-difluorophenyl)-2-[(3R.6RV3-(2.3-dihvdro-lH- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N,N-dimethylethanamide (5.753g, 62%) as a colourless solid.

HPLC Rt = 3.41 minutes, m/z [M+H]⁺ = 484 1H NMR (CDC1₃) δ 7.48 -7.38 (m, 2H), 7.24-7.11 (m, 4H), 7.01-6.90 (m, 2H), 6.62 (s, IH), 4.09 (dd, IH), 3.98 (dd, IH), 3.19-3.01(m, 3H), 2.99 (3, 3H), 2.92-2.75 (m, 5H), 1.64-1.51 (m, 2H), 0.76-0.66 (m, 4H), 0.43 (d, 3H).

Similarly prepared:

Example 12

(2RV2-(2,4-difluorophenylV2-r(3R.6RV3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5- dioxopiperazin- 1 - yl] -N-methylethanamide colourless solid, 41% HPLC Rt = 3.4 minutes, m/z [M+H]⁺ = 470

Example 13

(2RV2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5- dioxopiperazin- 1 -yl] ethanamide colourless solid, 36% HPLC Rt = 3.3 minutes, m/z [M+H]⁺ = 456

Example 14

(3R.6R)- 1-rriRVl -(2.4-difluorophenylV2-morpholin-4-yl-2-oxoethyll-3 -(2.3 -dihvdro- lH-inden-2-yl)-6-isobutylpiperazine-2.5-dione colourless solid, 61% HPLC Rt = 3.4 minutes, m/z [M+H]⁺ = 526

Example 15

(3R.6R)-l-r(lR)-l-(2.4-difluorophenylV2-(3-hvdroxyazetidin-l-yl)-2-oxoethyll-3-(2.3- dihvdro-lH-inden-2-yl -6-isobutylpiperazine-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 (3R.6R)-l-r(lR)-2-azetidin-l-yl-l-(2.4-difluorophenylV2-oxoethyll-3-(2.3-dihvdro-lH- inden-2-yl)-6-isobutylpiperazine-2,5-dione colourless solid, 46% HPLC Rt = 3.4 minutes, m/z [M+H]⁺ = 496 Example 17

(2R)-2-(2,4-difluorophenyl)-2-[(3R.6RV3-('2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N-(2-hydroxyethyl)-N-methylethanamide colourless solid, 59%) HPLC Rt = 3.3 minutes, m/z [M+H]⁺ = 514

Example 18

(2R -2-(2.4-difluorophenyl)-2-r(3R,6RV3-r2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin-l-yl]-N-methyl-N-[2-(methylsulfonyl)ethyl]ethanamide colourless solid, 22%

HPLC Rt = 3.2 minutes, m/z [M+H]⁺ = 576

Example 19

(2RV2-(2.4-difluoroρhenyl -2-r(3R.6RV3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N-methyl-N-(2,2,2-trifluoroethyl)ethanamide colourless solid, 11 % HPLC Rt = 3.5 minutes, m/z [M+H]⁺ = 552

(2,2,2-trifluoroethylmethylamine hydrochloride was prepared by the method of E R Bissell and M Finger; J. Org. Chem. 24 1256-1259 (1959))

Example 20

(2R)-2-(2,4-difluorophenyl -2-r(3R.6R -3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N-methyl-N-(pyridin-2- ylmethvDethanamide tan foam, 19%o HPLC Rt = 3.5 minutes, m/z [M+H]⁺ = 561

Example 21

(2R)-2-(2.4-difluorophenyl)-2-[(3R.6RV3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yll-N-methoxy-N-methylethanamide

HPLC Rt = 3.4 minutes, m/z [M+H]⁺ = 500

Example 22

(2R)-r2.4-difluorophenyl)[(3R,6R -3-(2,3-dihvdro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 - yl] ethanoic acid

Carbonyldiimidazole (1.42g, 1.6 equiv.) was suspended in anhydrous dichloromethane (10nιL)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-yl]-N-(2-hydroxyphenyl)ethanamide (3.00g) was then added and the 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 l:l(v/v) mixture of water and acetone (10 mL). The mixture was stirred for 2 hours, then the acetone was removed under reduced pressure and the residue was partitioned between dichloromethane and 0.1M HCl 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 acetate: cyclohexane, then ethyl acetate, then 1:1 (v/v) ethyl acetate methanol to give a mixture of diastereomers (2.61g). These were separated on a chiral reverse-phase column (Chiralcel OD, eluted with 15%> propan-2-ol/heptane containing O.P/oTFA) to give: (2RV(2.4-difluorophenvn (3R.6RV3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5- dioxopiperazin- 1 -yl] ethanoic acid (1.60g) HPLC Rt = 3.4 minutes, m/z [M+H]⁺ = 457

Example 23 methyl (2R)-(2.4-difluorophenyl)[(3R.6RV3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 - yl] ethanoate

Carbonyldiimidazole (0.324g, 1.6 equiv.) was suspended in anhydrous dichloromethane (4mL)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-yl]-N-(2-hydroxyphenyl)ethanamide (0.800g) 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 acetate: cyclohexane x5) to give:methyl (2R)-(2.4-difluoiOphenyl)[(3R.6R)-3-(2.3- dihvdro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]ethanoate (0.453g, 66%) HPLC Rt = 3.42 minutes, m/z [M+H]⁺ = 471

Similarly prepared:

Example 24 propyl (2RV(2.4-difluorophenvnr(3R.6RV3-(2.3-dihvdro-lH-inden-2-vn-6-isobutyl-2.5- dioxopiperazin- 1 -yl] ethanoate

HPLC Rt = 3.71 minutes, m/z [M+H]⁺ = 499

Example 25 l-(acetyloxy ethvU2R)-(2.4-difluoroρhenyl)r(3R.6R -3-(2.3-dihvdro-lH-inden-2-ylV6- isobutyl-2,5-dioxopiperazin-l-yl]ethanoate

(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1-yl] ethanoic acid (example 22) (0.130g) was stirred in anhydrous DMF (lmL) 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 DCM and IM HCl aq. (20 mL each). The organic phase was separated (hydrophobic 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) diethl ether x2, (iv) ethyl acetate x2, (v) methanol x2 to give l-(acetyloxy)ethyl (2R)- r2.4-difluorophenyl)rr3R.6R -3-(2 -dihvdro-lH-inden-2-ylV6-isobutyl-2.5- dioxopiperazin- 1 -yl] ethanoate (0.081 R) as a yellow foam. HPLC Rt = 3.5 minutes, m/z [M+H]⁺ = 543

Similarly prepared:

In the table below, Examples 26, 54-55, 66-104, 107-117, 124-131 were prepared via method 1. The t-butyl ester Example 39 was prepared via perchloric acid-catalysed transesterification 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.

Similarly prepared:

Hydroxylated metabolites of (2R)-2-(2.4-difluoroρhenyl)-2-F(3R,6R)-3-(2,3-dihvdro-lH- inden-2-yl)-6-isobutyl-2, 5 -dioxopiperazin- 1 -yll -N,N-dimethylethanamide were prepared as follows:

2 litres of growing cell cultures of Streptomyces rimosus BS33 was used to biotransform GW796679x. 500mg of GW796679X was added after 3 days growth and the broth harvested after another 5 days incubation. At harvest, 2 litres of methanol was added, then the cells removed by centrifugation. Methanol was removed from the supernatant by evaporation. The compounds were then extracted with ethyl acetate, evaporated to dryness, and purified by preparative HPLC to give examples 132,133,134 and 135.

Example 136

(2R)-2-(l-benzofuran-5-ylV2-[(3R.6R)-3-(2.3-dihvdro-lH-inden-2-vn-6-isobutyl-2,5- dioxopiperazin- 1 -yll-N-isopropylethanamide. Benzofuran-5-carboxaldehyde (215 mg, 1.47 mmol) and D-leucine t-butyl ester hydrochloride (329 mg, 1.47 mmol) were dissolved in methanol (1.5ml) and triethylamine (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 under 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 ml, 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 dichloromethane (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 dichloromethane 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 to 1 : 2 cyclohexane : ethyl acetate fractions inclusive were combined to give a pale yellow solid (336 mg). The solid was loaded in dichloromethane onto 6 preparative chromatography 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-(l-benzofuran-5-yl)-2-r(3R.6R)-3-(2.3-dihvdro- lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N-isopropylethanamide as a white solid (141mg, 0.28 mmol) HPLC Rt = 3.46 minutes; m/z [M+H]⁺ - 502. 1H NMR δ 7.95 (d, IH), 7.73 (d, IH), 7.68 (d, IH), 7.53 (d, IH), 7.37 (dd, IH), 7.16 (m, 4H), 6.79 (d, IH), 5.79 (d, IH), 5.37 (s, IH), 4.11 (m, IH), 4.03 (br dd, IH), 3.99 (dd,

IH), 3.16-2.97 (m, 3H), 2.95-2.78 (m, 2H), 1.79(m, IH), 1.69 (m, IH), 1.33 (m, IH), 1.09 (t, 6H), 0.78 (d, 3H), 0.67 (d, 3H).

Similarly prepared

Example 137

(2RV2-ri.2.3-benzothiadiazol-6-ylVN-rtert-butvn-2-[(3R.6R)-3-(2.3-dihvdro-lH-inden- 2-ylV6-isobutyl-2,5-dioxopiperazin-l-yl]ethanamide. HPLC Rt = 3.50 minutes; m/z [M+H]⁺ = 534. 1H NMR δ 8.66 (d, IH), 7.82 (d, IH), 7.67 (dd, IH), 7.20 (m, 4H), 6.72 (br d, IH), 6.13 (s, IH), 5.19 (s, IH), 4.06 (br dd, IH), 4.00 (dd, IH), 3.18 (m, IH), 3.07 (m, 2H), 2.92 (m, IH), 2.81 (m, IH), 1.86(m, IH), 1.80 (m, IH), 1.54 (m, IH), 1.36 (s, 9H), 0.85 (d, 3H), 0.78 (d, 3H).

Example 138 (2RV2-(2.3-dihvdro-l-benzofuran-5-yl)-2-[(3R.6RV3-(2,3-dihvdro-lH-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-l-yl]-N-isopropylethanamide. HPLC Rt = 3.34 minutes; m/z [M+H]⁺ = 504.

1H NMR δ 7.81 (br s, IH), 7.18 (m, 5H), 6.79 (d, IH), 6.44 (br d, IH), 5.50 (d, IH), 5.06 (s, IH), 4.61 (t, 2H), 4.08 (m, IH), 3.96 (m, 2H), 3.22 (t, 2H), 3.15 (m, IH), 3.07 (d, 2H), 2.90 (m, IH), 2.79 (dd, IH), 1.82(m, IH), 1.71 (m, IH), 1.42 (m, IH), 1.12 (dd, 6H), 0.83 (d, 3H), 0.77 (d, 3H).

Example 139

(2R)-2-(L3-benzodioxol-5-yl)-N-(tert-butyl)-2-r(3R.6R -3-(2,3-dihvdro-lH-inden-2-yl)- 6-isobutyl-2,5-dioxopiperazin- 1 -yl] ethanamide. HPLC Rt = 3.48; m/z [M+H]⁺ = 520

1H NMR (CDCI₃) δ 7.21 (m, 2H), 7.16 (m, 2H), 6.97 (d, IH), 6.88 (dd, IH), 6.82 (d, IH), 6.58 (m, IH), 6.06 (m, 2H), 5.64 (s, IH), 5.02 (m, IH), 3.95 (m, 2H), 3.16 (m, IH), 3.07 (m, 2H), 2.89 (m, IH), 2.77 (m, IH), 1.82 (m, IH), 1.71 (m, IH), 1.41 (m, IH), 1.32 (s, 9H), 0.83 (d, 3H), 0.79 (d, 3H)

Example 140

(2R -2-(benzofuran-5-ylV2-[(3R.6R -3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5- dioxopiperazin-l-yl]-N,N-dimethylethanamide

Methyl N-[(lR)-2-{[2-(benzyloxy)phenyl]amino}-l-(benzofuran-5-yl)-2-oxoethyl]-L- leucinate

To 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-benzyloxyphenylisonitrile (4.19g) in methanol (15ml). The reaction was stirred at -30°C for 2 hours and then allowed to warm to room temperature and stirred for a further 3 days. The solvent was removed in vacuo 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}- l-(benzofuran-5-yl)-2-oxoethyl]-L-leucinate (5.1 lg).

HPLC Rt=3.97 minutes, m/z [M+H]⁺ = 499 Methyl N-{(lR)-l-(benzofuran-5-yl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L- leucinate

A mixture of palladium on carbon (10%, 500mg), methyl N-[(lR)-2-{[2-

(benzyloxy)phenyl]amino}-l-(benzofuran-5-yl)-2-oxoethyl]-L-leucinate (5.1g) and ethyl acetate (60ml) 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-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (3.429g). HPLC Rt=3.49 min, m/z [M+H]⁺ = 411

Methyl N-[ 1 -(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate

A solution of methyl N-{(lR)-l-(benzofuran-5-yl)-2-[(2-hydroxyphenyl)amino]-2- oxoethyl} -L-leucinate (410mg) and l,l'-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, 71 Omg) 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- (benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (140mg). HPLC Rt = 2.70 minutes m/z [M+H]⁺ = 347

N-[l-(benzofuran-5-yl)-2-(dimethylamino -2-oxoethyl]-L-leucine

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). After 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™ cartridge (2x6g) and eluted with water (x2) and methanol (x2). The required fractions were combined and evaporated to afford N-[l- (benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (478mg).

HPLC Rt = 2.27 minutes m/z [M+H]⁺ = 333

(2R)-2-(benzofuran-5-yl)-2-r(3R.6R -3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N,N-dimethylethanamide

To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-lH-inden-2-yl)ethanoic acid (419mg) in dry tetrahydrofuran (5ml) at -20°C under a nitrogen atmosphere was added N-methylmoφholine (158μl) and a solution of isopropylchloroformate in toluene (1.0M, 1.44ml). After 10 minutes, a solution of N-[l-(benzofuran-5-yl)-2- (dimethylamino)-2-oxoethyl]-L-leucine (478mg) in dimethylformamide (5ml) 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 (13ml) was added and the reaction was left to stand for a further 18 hours. The solvent was then removed in vacuo and the residue was separated between dichloromethane and saturated sodium bicarbonate solution. The organic phase was evaporated in vacuo 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- (benzofυran-5-yl)-2-r(3R,6R)-3-(2,3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N,N-dimethylethanamide (5 lmg). HPLC Rt=3.36 minutes, m/z [M+H]⁺ = 488 1H NMR (D₆-DMSO) δ 8.47 (d, IH), 8.07 (d, IH), 7.71 (m, IH), 7.69 (d, IH), 7.38 (dd, IH), 7.21 (m, 2H), 7.12 (m, 2H), 7.03 (m, IH), 6.47 (s, IH), 3.88 (m, IH), 3.69 (dd, IH), 3.07-2.67 (m, 5H), 2.87 (s, 3H), 2.77 (s, 3H), 1.40-1.70 (m, 2H), 0.46 (m, IH), 0.42 (d, 3H), 0.02 (d, 3H)

Example 141 (2R)-2-r(3R,6R)-3 -(2,3-dihydro- 1 H-inden-2-yl)-6-isobutyl-2.5 -dioxopiperazin- 1 -yl] - N,N-dimethyl-2-(2-methyl-l-benzofuran-5-yl)ethanamide

(2RS)-2-(2-methyl-l-benzofuran-5-ylV2-r(3R.6RV3-(2.3-dihvdro-lH-inden-2-ylV6- isobutyl-2,5-dioxopiperazin-l-yl]-N-(2-hvdroxyphenyl)ethanamide

A mixture of 2-methyl-5-formylbenzofuran (1.26g), (D)-leucine methyl ester hydrochloride (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 vacuo. The residue was diluted with ethyl acetate (100ml) and acetic acid (10ml) and hydrogenated at atmospheric pressure over 10% 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 MgSO₄ 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 vacuo to give (2RS)-2-(2-methylbenzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-lH- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)ethanamide (1.58g). HPLC Rt = 3.60 minutes; m/z [M+H]⁺ = 566.

(2RV2-r(3R,6R -3-(2,3-dihvdro-lH-inden-2-yl -6-isobutyl-2.5-dioxopiperazin-l-vn- N,N-dimethyl-2-(2-methyl- 1 -benzofuran-5 -vDethanamide

Carbonyldiimidazole (92mg, 1.6 equiv.) was suspended in anhydrous dichloromethane (5mL) and the suspension was left at room temperature for 15 minutes. (2RS)-2-(2- mrthylbenzofuran-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. 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 18 hours. The reaction mixture was diluted with dichloromethane (2mL) and washed with IM hydrochloric acid (2mL). The organic phase was separated using a hydrophobic frit and was evaporated under reduced pressure to leave a brown gum. The crude product was applied to a silica cartridge (lOg). This was eluted with cyclohexane (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 vacuo to give (2R)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2- yl)-6-isobutyl-2,5-dioxopiperazin-l-yl1- N,N-dimethyl-2-(2-methyl-l-benzofuran-5- vDethanamide as an off-white solid (88mg). HPLC Rt = 3.40 minutes; m/z [M+H]⁺ = 502. 1H NMR (CDC1₃) δ 7.52 (d, IH), 7.43 (d, IH), 7.27-7.13 (m, 5H), 6.54 (s, IH), 6.38 (m, IH), 6.31 (d, IH), 4.24 (m, IH), 3.99 (dd, IH), 3.22-3.05 (m, 3H), 2.99 (s, 3H), 2.86 (m, IH), 2.82 (s, 3H), 2.75 (m, IH), 2.48 (m, 3H), 1.45 (m, IH), 1.36 (m, IH), 0.57 (m, IH), 0.51 (d, 3H), 0.19 (d, 3H).

Similarly prepared: -

Example 142

(2R)-2-r(3R.6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5-dioxopiperazin-l-yl]- N- isopropyl-2-(2-methyl-l-benzofuran-5-yl)ethanamide HPLC Rt = 3.40 minutes; m/z [M+H]⁺ = 516.

1HNMR (CDCI₃) δ 7.57 (m, IH), 7.41 (d, IH), 7.28-7.11 (m, 5H), 6.61 (m, IH), 6.37 (m, IH), 5.49 (d, IH), 5.23 (s, IH), 4.11 (m, IH), 4.02-3.93 (m, 2H), 3.19-3.05 (m, 3H), 2.92 (m, IH), 2.77 (m, IH), 2.48 (m, 3H), 1.79 (m, IH), 1.70 (m, IH), 1.38 (m, IH), 1.10 (m, 6H), 0.78 (d, 3H), 0.69 (d, 3H). Example 143

(3R.6RV3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-l-rriRVl-(2-methyl-l-benzofuran-5- ylV2-moφholin-4-yl-2-oxoethyl]piperazin-2.5-dione HPLC Rt = 3.38 minutes; m/z [M+H]⁺ = 544. 1H NMR (CDCI₃) δ 7.51 (d, IH), 7.45 (d, IH), 7.26-7.14 (m, 5H), 6.57 (s, IH), 6.39 (m, IH), 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 (m, IH), 2.75 (m, IH), 2.49 (m, 3H), 1.45 (m, IH), 1.37 (m, IH), 0.54 (m, IH), 0.51 (d, 3H), 0.20 (d, 3H).

Example 144

(2R -2-[(3R,6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yll-2- (2-fluoro- 1 -benzofuran-5-yl -N,N-dimethylethanamide HPLC Rt = 3.39 minutes; m/z [M+H]⁺ = 505.

1H NMR (CDCI3) δ 7.56 (d, IH), 7.45 (d, IH), 7.32 (dd, IH), 7.23 (m, 2H), 7.16 (m, 2H), 6.55 (s, IH), 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, IH), 0.58- 0.49 (m, 4H), 0.22 (d, 3H).

5-Bromo-2-fluoro-l-benzofuran 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 Selectflor (7.1g) 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- fluoro-1 -benzofuran (1.4g). 1H NMR (CDCI3) δ 7.61 (d, IH), 7.36 (dd, IH), 7.26 (d, IH), 5.84 (dd, IH).

2-Fluoro-5 -formyl- 1 -benzofuran

A slurry 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 the 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 dimethylformarnide (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 magnesium 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-fluoro-5-formyl-l -benzofuran (376mg). 1H NMR (CDCI₃) δ 10.05 (s, IH), 8.04 (m, IH), 7.83 (dd, IH), 7.54 (d, IH), 6.01 (dd, IH).

Example 145 (2R)-2-[(3R.6R)-3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5-dioxopiperazin-l-yll-2- (2-fluoro- 1 -benzofuran-5 -yl)-N-isopropylethanamide HPLC Rt = 3.42 minutes; m/z [M+H]⁺ = 520.

1HNMR (CDCI₃) δ 7.61 (d, IH), 7.42 (d, IH), 7.31 (dd, IH), 7.21 (m, 2H), 7.16 (m, 2H), 6.70 (d, IH), 5.89 (d, IH), 5.57 (d, IH), 5.18 (s, IH), 4.11 (m, IH), 3.98 (m, 2H), 3.16 (m, IH), 3.08 (m, 2H), 2.91 (m, IH), 2.78 (m, IH), 1.82 (m, IH), 1.73 (m, IH), 1.41 (m, IH), 1.12 (d, 3H), 1.10 (d, 3H), 0.81 (d, 3H), 0.72 (d, 3H).

Example 146

(3R.6RV3-(2.3-dihydro-lH-inden-2-yl)-l-r(lR)-l-(2-fluoro-l-benzofuran-5-yl)-2- moφholin-4-yl-2-oxoethyl]-6-isobutylpiperazine-2,5-dione HPLC Rt = 3.35 minutes; m/z [M+H]⁺ = 548.

1H NMR (CDCI₃) δ 7.55 (d, IH), 7.47 (d, IH), 7.31 (dd, IH), 7.27-7.14 (m, 4H), 6.58 (s, IH), 6.38 (d, IH), 5.91 (d, IH), 4.19 (m, IH), 4.00 (dd, IH), 3.73-3.50 (m, 5H), 3.39 (m, IH), 3.23-3.04 (m, 5H), 2.87 (m, IH), 2.76 (m, IH), 1.47 (m, IH), 1.40 (m, IH), 0.53 (d, 3H), 0.51 (m, IH), 0.24 (d, 3H).

Example 147

(2R)-2-[(3R.6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5-dioxopiperazin-l-vn-2-

(lH-indol-6-yl)-N,N-dimethylethanamide HPLC Rt = 3.38 minutes; m/z [M+H]⁺ = 487.

1H NMR (CDCI₃) δ 9.03 (s, IH), 7.66 (d, IH), 7.49 (d, IH), 7.30 (m, IH), 7.21 (m, IH),

7.18-7.10 (m, 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, 3H), 3.00 (s, 3H), 2.92-2.73 (m, 5H), 1.40 (m, IH), 1.33 (m, IH), 0.57 (m,

IH), 0.45 (d, 3H), 0.06 (d, 3H).

Example 148

(2R)-2-r(3R.6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5-dioxopiperazin-l-yl1-2-

(lH-indol-6-yl)-N-methyl-N-[2-(methylsulphonyl)ethyl]ethanamide

HPLC Rt = 3.20 minutes; m/z [M+H]⁺ = 579. 1H NMR (CDCI₃) δ 9.62 (s, IH), 7.64 (d, IH), 7.41 (d, IH), 7.30 (m, IH), 7.26-7.10 (m,

6H), 6.51 (m, IH), 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, 4H), 2.96-2.69 (m, 8H), 1.41 (m, 2H), 0.65 (m, IH), 0.47 (d, 3H), -0.10 (d,

3H).

Example 149

(2R)-2-(l-benzothien-5-vn -2-[(3R,6R)-3-(2 -dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N,N-dimethylethanamide (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-benzyloxyρhenyl)ethanamide

A mixture of 5-formylbenzothiophene (2.0g), (D)-leucine methyl ester hydrochloride (2.24g), triethylamine (1.72ml) and methanol (20ml) was stirred at room temperature for 24 hours. N-tert-butoxycarbonyl-(D)-indanylglycine (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 dichloromethane (30ml) and triethylamine (10ml) added. The mixture was stirred for 18 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 (2x100ml) and brine. The organic phase was dried over MgSO₄ and evaporated in vacuo to yield (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- benzyloxyphenyl)ethanamide as a brown foam (7.5g). HPLC Rt = 3.88 minutes, m/z [M+H]⁺ = 658.

(2RS)-2-(l-benzothien-5-yl)-2-rr3R.6RV3-(2.3-dihvdro-lH-inden-2-vn-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N-(2-hvdroxyphenyl)ethanamide

(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-benzyloxyphenyl)ethanamide (l.Og) was dissolved in dichloromethane (5ml) and to this was added dropwise a 1.0M 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 and evaporated in vacuo. The residue was purified by Biotage™ flash column chromatography, eluting with 3:2 ethyl acetate yclohexane. The required fractions were combined and evaporated in vacuo to give (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 (21 Omg).

HPLC Rt = 3.55 minutes, m/z [M+H]⁺ = 568.

(2R)-2-(l-benzothien-5-yl) -2-[(3R_<6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5- dioxopiperazin- 1 -yl] -N.N-dimethylethanamide Carbonyldiimidazole (lOOmg) was suspended in anhydrous dichloromethane (lmL) and the suspension was left 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 then left to stand at room temperature for 18 hours 15 minutes. The reaction mixture was evaporated under reduced pressure. The crude product was purified by silica column chromatography eluting with 1 : 1 v/v ethyl acetate yclohexane. The required fractions were combined and evaporated in vacuo to give (2R)-2-(benzothien-5-yl) -2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N,N-dimethylethanamide as a white solid (90mg). HPLC Rt = 3.35 minutes, m/z [M+H]⁺ = 504.

1H NMR (CDC1₃) δ 7.94 (d, IH), 7.89 (m, IH), 7.70 (d, IH), 7.54 (d, IH), 7.41 (m, IH), 7.35 (d, IH), 7.23 (m, IH), 7.13 (m, 3H), 6.63 (s, IH), 4.25 (m, IH), 4.02 (dd, IH), 3.23- 3.04 (m, 3H), 3.01 (s, 3H), 2.93-2.77 (m, 5H), 1.50-1.32 (m, 2H), 0.52 (m, IH), 0.49 (d, 3H), 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.

Example 176

(2R)-2-r(3R.6RV3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5-dioxopiperazin-l-yll-N- isopropyl-2-r5-(trifluoromethyl)-2-furyl]ethanamide

To a solution of 5-trifluoromethyl-furan-2-carbaldehyde (140mg)[prepared as in ref. Chem. Heterocycl. Compd. 13, 1977, 1280-1282 by RN.Grigorash, N.N.Lyalin, L.A.Alekseeva and L.M.Yagupol'skii: 5-Trifluoromethylfuran Derivatives] in methanol (1.1ml) was added triethylamine (118 μl) 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 (77.4μl) were sequentially added. The mixture, a yellow solution, was left to stand for 24 hours before the solvent was removed in vacuo. 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 vacuo. 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 vacuo. The residue was stirred in dioxane (9.5ml) containing triethylamine (0.5ml) and dichloromethane (5ml) for 4.75 hours. Then the mixture was evaporated in vacuo to leave a light brown solid. This crude material was purified by SPE column (lOg, silica Mega Bond Elut™) 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% diethyl 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 PK6F 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.6RV3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5-dioxopiperazin-l-yl]-N- isopropyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide (64mg), HPLC Rt = 3.59 minutes; m/z [M+H]⁺ = 520. 1H NMR (CDC1₃) δ 7.88 (d, IH), 7.16 (m, 4H), 6.85 (d, IH), 6.74 (d,lH), 6.30 (d,lH), 5.73 (s, H), 4.19 (dd, IH), 4.08 (m, IH), 3.97 (dd, IH), 3.14 (m, 2H), 3.01 (m, IH), 2.84 (m, 2H), 1.81 (m, IH), 1.68 (m, IH), 1.15 (d, 6H), 1.11 (m, IH), 0.82 (dd, 6H).

Similarly prepared

Example 177

(2S)-2-[(3R.6RV3-r2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5-dioxopiperazin-l-yl]-N- isopropyl-2-(5-methylthien-2-yl)ethanamide

By the procedure of Example 176 but using 5-methyl-thiophene-2-carbaldehyde HPLC Rt = 3.46 minutes; m/z [M+H]⁺ = 482.

1H NMR (CDCI₃) δ 7.21 (m, 2H), 7.16 (m, 2H), 6.94 (d, IH), 6.67 (d, IH), 6.63 (d, IH),

5.73 (d, IH), 4.94 (s, IH), 4.07 (m, IH), 3.93 (m, 2H), 3.16 (dd, IH), 3.05 (m, 2H), 2.93

(m, IH), 2.77 ( , IH), 2.47 (s, 3H), 1.96 (m, IH), 1.86 (m, IH), 1.72 (m, IH), 1.17 (d,

3H), 1.12 (d, 3H), 0.94 (d, 3H), 0.92 (d, 3H) Example 178

(2R)-2-r(3R,6R -3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5-dioxopiρerazin-l-yll- N.N-dimethyl-2- [ 5 -(trifluoromethv -2-furyl] ethanamide

N-[2-(benzyloxy phenyll-2-[(3R.6R)-3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5- dioxopiperazin-l-yl]-2-[5-(trifluoromethyl)-2-furyl]acetamide

A mixture of 5-trifluoromethyl-furan-2-carbaldehyde (351mg), (D)-leucine methyl ester hydrochloride (389mg), triethylamine (0.298ml) and methanol (2.2ml) was stirred at room temperature for 4 hours and then left to stand for 19 hours. N-tert-butoxycarbonyl- (D)-indanylglycine (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 41 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 18 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-(benzyloxy)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-2-[5-(trifluoromethyl)-2-furyl]acetamide as an orange solid (472mg).

HPLC Rt - 4.04 minutes, m/z [M+H]⁺ = 660.

2-[(3R.6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5-dioxopiperazin-l-yll-N-(2- hydroxyphenyl)-2-r5-(trifluoromethyl)-2-furyl]acetamide

N-[2-(benzyloxy)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-2-[5-(trifluoromethyl)-2-furyl]acetamide (469mg) was dissolved in ethyl acetate (10ml) and hydrogenated 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 vacuo 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- hydroxyphenyl)-2-[5-(trifluoromethyl)-2-furyl]acetamide (365mg). HPLC Rt = 3.64 minutes, m/z [M+H]⁺ = 570.

(2R)-2-r(3R,6RV3-(2.3-dihvdro-lH-inden-2-ylV6-isobutyl-2.5-dioxopiperazin-l-yll- N,N-dimethyl-2- [ 5 -(trifluoromethylA2-ftu. yl] ethanamide Carbonyldiimidazole (78mg, 1.6 equiv.) was suspended in anhydrous dichloromethane (lmL) and the suspension was left at room temperature for 15 minutes. (R)-N-(2- Hydroxy-phenyl)-2-((3R,6R)-3-indan-2-yl-6-isobutyl-2,5-dioxo-piperazin-l-yl)-2-(5- trifluoromethyl-furan-2-yl)-acetarnide (172mg) 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 (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 (2mL) and washed with IM hydrochloric acid (2mL). The organic ^• phase was separated using a hydrophobic frit and was evaporated under reduced pressure to leave a brown gum. The crude product was applied to 3 preparative chromatography plates, which were eluted with 1:1 v/v ethyl acetate yclohexane. The required band was extracted with ethyl acetate to give the (2RV2-[(3R.6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6- isobutyl-2.5-dioxopiperazin-l-yl -N,N-dimethyl-2-[5-(trifluoromethyl)-2- fury!] ethanamide as a pale yellow solid (87mg). HPLC Rt = 3.51 minutes, m/z [M+H]⁺ = 506.

1HNMR (CDC1₃) δ 7.19 (m, 5H), 6.86 (dd, IH), 6.64 (d, IH), 6.61 (s, IH), 4.25 (m, IH), 3.97 (dd, IH), 3.20-3.02 (m, 3H), 3.01 (s, 3H), 2.96 (s, 3H), 2.88 (m, IH), 2.80 (m, IH), 1.70 (m, IH), 1.67 (m, IH), 0.74 (d, 3H), 0.70 (m, IH), 0.63 (d, 3H).

Example 179

(2RV2-r(3R.6RV3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5-dioxopiperazin-l-yll-

N,N-dimethyl-2-(2-methyl-l,3-oxazol-4-yDethanamide

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

HPLC: Rt = 2.88 minutes ; m/z (M+H)⁺ = 453

(2R)-2-r(3R.6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5-dioxopiperazin-l-yll-N- (2-hydroxyphenyl)-2-(2 -methyl- 1 ,3-oxazol-4-yl)ethanamide

A mixture of 2-methyl-oxazole-4-carbaldehyde⁽¹⁾ (340mg), (D)-leucine methyl ester hydrochloride (568mg), triethylamine (0.435ml) and anhydrous methanol (20ml) was stirred at room temperature for 18 hours. N-benzyloxycarbonyl-(D)-indanylglycine

(1.015g) and 2-benzyloxy-phenylisocyanide (648mg) were then added sequentially and the mixture stirred for 12 days before being left to stand at room temperature for 10 days. The solvent was removed under reduced pressure to leave a dark orange gum which was dissolved in ethyl acetate (150mL) and washed with 2M hydrochloric acid (lOOmL), saturated sodium bicarbonate solution (lOOmL) and saturated sodium chloride solution (50mL) then dried over anhydrous magnesium sulphate and concentrated under reduced pressure to a volume of 5mL. This crude solution was diluted with ethanol (80mL) containing acetic acid (1.6mL) and added under vacuum to 10% palladium on carbon ( 50% water, 425mg). The resulting suspension was stirred under an atmosphere of hydrogen for 20 hours, filtered ( celite filteraid ) washed with ethanol (50mL) and the filtrate added under vacuum to a second quantity of 10% palladium on carbon (50% water, 670mg). The 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 (lOOmL) and dichloromethane (60mL), then the organic layer dried (hydrophobic frit) and the solvent removed under reduced pressure. Purification by Biotage flash chromatography (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-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-N-(2-hydroxyphenyl)- 2-(2-methyl-l ,3-oxazol-4-yl)ethanamide as a brown foam (197mg). HPLC : Rt = 3.28 minutes ; m/z (M+H)⁺ = 517 Ref(l) CAS 113732-84-6

Example 180 (3R.6R)-3-(2,3-dihvdro-lH-inden-2-yl)-6-isobutyl-l-[(lR)-l-(2-methyl-1.3-oxazol-4-yl)- 2-moφholin-4-yl-2-oxoethyl]piperazine-2,5-dione By the procedure of Example 179, using moφholine HPLC: Rt = 2.89 minutes ; m/z (M+H)⁺ = 495

Example 181

(2S)-2-[(3R.6R)-3-(2.3-dihvdro-lH-inden-2-vn-6-isobutyl-2.5-dioxoρiperazin-l-yll-N.N- dimethyl-2-(5-methylthien-2-yl)ethanamide

By the procedure of Example 180, using 5-methyl-thiophene -2-carb aldehyde

HPLC Rt = 3.25 minutes; m/z M ^' = 468.

Example 182

(2S)-2-r(3R,6R)-3-(2.3-dihvdro-lH-inden-2-yl)-6-isobutyl-2.5-dioxopiρerazin-l-yll-2-(3- fluoro-5-methylthien-2-yl)-N,N-dimethylethanamide

By the procedure of Example 178, using 3-fluoro-5-methyl-thiophene-2-carbaldehyde HPLC: Rt = 3.20 minutes ; m/z M⁺ = 486

2-(3-Bromo-5-methyl-thiophen-2-yl)-[l,3]dioxane

3-Bromo-5-methyl-2-tl iophenecarbaldehyde (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 acetate and the combined layers washed with brine, dried over magnesium sulphate, filtrated and concentrated to a yellow oil (lg).

Purification was performed by filtration on a SPE cartridge (Silica- lOg) using dichloromethane as eluent. The solution was eventually concentrated to yield 2-(3- bromo-5-methyl-thiophen-2-yl)-[l,3]dioxane as a yellow solid (1.18g). 1H-NMR (CDC1₃, 400MHz): 6.60ppm (s, IH); 5.72ppm (s, IH); 4.23ppm (m, 2H); 3.98ppm (m, 2H); 2.44ppm (d, 3H); 2.22ppm (m, IH); 1.42ppm (m, IH).

3-Fluoro-5-methyl-thiophene-2-carbaldehyde

To a solution of 2-(3-bromo-5-methyl-tlιiophen-2-yl)-[l,3]dioxane (1.16g) in dry tetrahydrofuran (10ml), under a nitrogen atmosphere, at -78 °C, 1.6M n-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 ether again (2x10ml), 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 temperature, over night. Neutralised with a saturated solution of sodium bicarbonate (10ml), 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. 1H-NMR (CDCI₃, 400MHz): δ 9.93ppm (s, IH); 6.62ppm (s, IH); 2.52ppm (m, 3H).

Similarly prepared:

Compounds 183 -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

Example 227

(3R.6RVl-r(lR)-l-(2,4-DifluorophenylV2-(3-fluoroazetidin-l-ylV2-oxoethyll-3-(2.3- dihydro- 1 H-inden-2-yl)-6-isobutylpiperazine-2.5 -dione

The azetidinol (Example 15) (57 mg) in anhydrous dichloromethane (2 mL) was stirred at -5°C and diethylaminosulfur trifluoride (50 μL, excess) was added in one portion. The mixture was left at room temperature overnight and saturated aqueous sodium hydrogen carbonate (3 mL) was added. The mixture was diluted with dichloromethane (10 mL) and the organic phase was separated using a hydrophobic frit and blown down with nitrogen. The crude reaction mixture was purified using the mass-directed autoprep system to give (3R,6R)-l-[(lR -l-(2.4-difluorophenylV2-(3-fluoroazetidin-l-ylV2- oxoethyl]-3-(2,3-dihvdro-lH-inden-2-yl)-6-isobutylpiperazine-2,5-dione (26 mg) as a white solid. HPLC Rt = 3.34 minutes, m/z [M+H]⁺ = 514 PharmcyExamples Tablets a) Compound of the invention 50.0mg Lactose ^• 70.0mg Microcrystalline Cellulose 70.0mg Cross-linked polyvinylpyrrolidone 8.0mg Magnesium Stearate 2.0mg Compression 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 50.0mg Lactose 120.0mg Pregelatinised Starch 20.0mg Cross-linked polyvinylpyrrolidone 8.0mg Magnesium Stearate 2.0mg Compression 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. Capsules a) Compound of the invention 50. Omg Lactose 148. Omg Magnesium Stearate 2.Omg 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 50. Omg Lactose 132. Omg Polyvinylpyrrolidone 8. Omg Cross-linked polyvinylpyrrolidone 8. Omg Magnesium Stearate 2.Omg 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. Injection 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 lmg/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 5mg/ml of the compound of the invention.

Measurement of Oxytocin 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 buffer. Test compounds were initially dissolved in DMSO (to lOmM) and diluted in DMSO (Beckman Biomek FX). lμl of compound was transferred to black 384 assay plates (NUNC) using a Biomek FX. 20μl of lnM Bodipy TMR Oxytocin (Perkin Elmer) in assay buffer was added to all wells (Labsystems Multidrop) then 20μl membrane added to all wells (Multidrop). Plates were incubated at room temp for 60 min.

Polarisation was read on LJL Analyst (λEx^SSSnm, λEm=580nM, λDichroic=555nm). Data were fitted to a 4 parameter logistic equation. An estimated Ki was calculated as IC50/5.

In the above test compounds of formula (I) in general have a pKi value within the range of 7 to 11 . Thus the compounds of examples 1 to 227 have a pKi within the range 8.5 to 10.8.

The compounds of formula (I) are essentially non toxic at therapuetically active doses. Thus compound of the example 10 has been administered to rats at doses of up to 300mg/kg p.o for 4 days, and no adverse toxicological effects were observed.

Claims

1. A method of treating or preventing benign prostatic hypeφlasia which comprises administering to a mammal in need thereof of an effective amoimt of a compound of the formula (I)

and/or a physiologically acceptable derivative thereof, wherein: Ri represents aryl (C_1- ) 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 d-βalkyl (optionally substituted by a C₁-₂alkoxy, C^alklthio, 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 may be a carbocyclic group or it may contain up to 3 heteroatoms selected from O, S or N and one of the fused rings is benzene; i represents OH or OCi- alkyl (optionally substituted with C₁- alkylcarbonyloxy) or NRsRδ;

R₅ represents hydrogen, -βalkyl (optionally substituted with Ci- alkoxy) or C₃- ₇cycloalkyl; R₆ represents hydrogen, methyl, Ci-₄alkoxy, C₃-₇cycloalkyl, C -₄alkyl [optionally substituted with one or more groups selected from: carboxyl, C₁-₄alkylsulphonyl, or C_\. ₄alkoxycarbonyl], C₂- alkyl [optionally substituted with one or more groups selected from halogen, hydroxy, C^alkoxy or NR₇R₈ wherein R₇ and R₈ independently represent hydrogen or Ci- alkyl 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 C^a-kyl, hydroxy, -₃ alkoxy (optionally substituted by C ₃- 6 cycloalkyl or optionally subtituted phenyl), C ₃-₆cycloalkyl or NR_<-R_d wherein R_e and each independently represent a group selected from C i^alkyl (optionally substituted by C 3-₆ cycloalkyl or optionally substituted phenyl ) or C ₃.₅ cycloalkyl)] 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 CH₂CONR₉Rio wherein R represents hydrogen or Ci-₄alkyl, R₁₀ represents hydrogen, Ci-₄alkyl optionally substituted by a 5 or 6 membered heteroaryl group or R_9; Rio 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 or Ci-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 ^alkyl or a C₁-₄alkanoyl group or a C₁-₄alkylsulphonyl group or a Ci-₃ alkoxyC₂-₄ alkyl [and which heterocyclic groups may be substituted by one or more halogen atoms or a group selected from Cι-₃alkyl, hydroxy, oxo, C ₃-₆cycloalkyl or NR_eR_f wherein _e and R_f each independently represent a group selected from C ι-₃alkyl (optionally substituted by C ₃-₆ cycloalkyl or optionally substituted phenyl ) or C ₃-₆ cycloalkyl.].

2. ^• A method as claimed in claim 1 wherein R₁ is a 2-indanyl group and R₂, R₃ and _t have the meanings defined in claim 1.

3. A method as claimed in claim 1 or claim 2 wherein R₄ is hydroxy or the group NR5R6.

4. A method as claimed in any of claims 1 to 3 wherein the compounds have the stereochemistry as defined in formula (la).

da) wherein the groups Ri, R_2;j R₃ and R-t have the meanings defined for formula (I).

5. A method as claimed in any of claims 1 to 4 wherein R₂ is a group selected from 1-methylpropy lor 2-methylpropyl .

6. A method as claimed in any of claims 1 to 5 wherein R₃ is an optionally substituted phenyl group.

7. A method as claimed in any of claims 1 to 6 wherein R₃ is a 5 or 6 membered hetero aryl group.

8. A method as claimed in any of claims 1 to 7 wherein R₃ is a fused bicyclic ring system containing 9-10 ring members which may be a carbocyclic group or it may contain up to 3 heteroatoms selected from O, S or N and one of the fused rings is benzene.

9. A method as claimed in any of claims 1 to 8 wherein R₃ is a group selected from phenyl, 2-fluorophenyl, 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- dichlorophenyl, 3,4-dichlorophenyl, 2 fluoro-4-bromophenyl, 4-chloro-3-fmorophenyl 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 methoxyphenyl, 2- fluoro-4 hydroxyphenyl, 2-fluoro-4-dimethylaminomethylphenyl, 2- fluoro-4-hydroxymethylphenyl, 3-fluoro-4-(4-moφholino)phenyl, 3-fluoro-4- carboxymethyloxyphenyl, 3-fluoro-4-t-butyloxycarbonylmethyloxyphenyl, 3-fluoro-4- dimethylaminocarbonyloxyphenyl, 3-chloro-4 trifluoromethoxyphenyl, 2,3-difluoro-4- methyl-phenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl, 4- methoxyphenyl, 4-methoxycarbonylphenyl, 3-methoxycarbonyphenyl, 4- methylsulphonylphenyl, 4-methylaminocarbonylphenyl, 4- aminocarbonylphenyl, 4- methylaminosulphonylphenyl, 3-(3-pyrazyolyl)phenyl, 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-yl)phenyl, 4-methylaminophenyl, 4- dimethylaminophenyl, 4-diethylaminophenyl, 4-acetylaminophenyl, 3- acetylaminophenyl, 4-hydroxy-3 -acetylaminophenyl, 4-methylsulphonylaminophenyl, 4- N-methylpiperazinophenyl, 4-N-pyrrolidinophenyl, 2-fluoro-4-(4-moφholino)phenyl, 4- (4-moφholino)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-imidazolyl)phenyl, 4-(l-imidazolyl)phenyl, 4-(l-l,2,4- triazolyl)phenyl, 4-(l-l,2,3-triazolyl)phenyl, 4-(2-4,-t-butylthiazolyl)phenyl, 4-(5- 2-t- butyltetrazolyl)phenyl, 4-(4 spiro-l,3-dioxolanyl)piperidinophenyl, 4-(4- fluorophenyl)phenyl, 4-(4-ethylaminosulphonylphenyl)phenyl, 4- dimethylaminoethoxyphenyl,3-(dihydroxyboryl)phenyl, 2-furanyl, 3-thienyl, 3-furanyl, 2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chloro-2-thienyl, 3-fluoro-5-methyl- 2-thienyl, 5-methyl-2-thienyl, 5-methyl-2-furanyl, 5-bromo-2-furanyl, 4,5-dimethyl-2- furanyl, 5-trifluoromethyl-2-furanyl, 2-furanyl-4-carboxylic acid methylamide, 2-furanyl- 5-carboxylic acid methylamide, 2-pyridyl, 6-methyl-2-pyridyl, 6-methyl-3-pyridyl, 6- methoxy-3-pyridyl, 6-hydroxy-3-pyridyl, 6-trifluoromethyl-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-oxazolyl, 2,5-dimethyl-4-oxazolyl, 4- thiazolyl, 2-methyl-4-thiazolyl, 2-trifluoromethyl-4-thiazolyl, 2-trifluoromethyl-5- thiazolyl, l-methyl-4-pyrazolyl, l,3-dimethyl-5-pyrazolyl, 5-(2-pyridyl)-2-thienyl, 2,3- dihydro-l-benzofuran-5-yl, l,3-benzodioxol-5-yl, lH-l,2,3-benzotriazol-5-yl, 2,3- dihydro- 1 ,4-benzodioxin-6-yl, 2,2-difluoro- 1 ,3 -benzodioxol-5-yl, 1 ,3 -benzothiazol-6-yl, l-methyl-lH-l,2,3-benzotriazol-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- benzofuran-5-yl, l-methy-lH-lindol-5-yl, l-benzothien-5-yl, l-benzofuran-6-yl, 1H- indol-6-yl, 1 -methyl- lH-benzimidazol-6-yl, l-methyl-lH-benzimidazol-5-yl, 3-methyl- l,2-benzoisoxazol-5-yl, 2-fluoro-l-benzofuran-5-yl, lH-indol-5-yl, 2-methyl-lH- benzofuran-5-yl, lH-indazol-5-yl, lH-indazol-6-yl, l-benzofuran-2-yl or 1-methyl-lH- benzimidazol-2-yl.

10. A method as claimed in any of claims 1 to 9 wherein R₅ is a group selected from hydrogen, C^alkyl, Cι-₄alkoxyC₂.₄alkyl and R₆ is a group selected from hydrogen, Ci- alkoxy, C^a-kyl, Cι- alkyl substituted by 1 to 3 halogen atoms, Cι-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 NRsR_ό represents, azetidino, 3- hydroxyazetidino, 3-methoxyazetidino, pyrrolidino, piperidino, 4- dimethylaminopiperidino, 4-methyl 1,4-diazepan-l-yl, moφholino, an optionally substituted piperazino ring, thiomoφholino or the sulphoxide or sulphone thereof.

11. A method as claimed in any of claims 1 to 10 wherein the compound of formula (I) is selected from:-

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N,N-dimethylethanamide

(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N,N-dimethylethanamide

(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]- moφholinamide

(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl]-N-isopropylethanamide. (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -2-[4-(4-hydroxypiperidin- 1 -yl)phenyl] ethanamide.

(2R)-2-{(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-[(lR)-l-methylpropyl]-2,5- dioxopiperazin- 1 -yl} -2-(2-fluoro-4-moφholin-4-ylphenyl)-N-isopropylethanamide.

(2R)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiρerazin-l-yl]-2- (4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide.

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-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]ethanamide.

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-methylethanamide (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] ethanamide

(3R,6R)-l-[(lR)-l-(2,4-difluorophenyl)-2-moφholin-4-yl-2-oxoethyl]-3-(2,3-dihydro- lH-inden-2-yl)-6-isobutylpiperazine-2,5-dione

(3R,6R)-l-[(lR)-l-(2,4-difluorophenyl)-2-(3-hydroxyazetidin-l-yl)-2-oxoethyl]-3-(2,3- dihydro-lH-inden-2-yl)-6-isobutylpiperazine-2,5-dione

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N-(2-hydroxyethyl)-N-methylethanamide (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-methyl-N-[2-(methylsulfonyl)ethyl]ethanamide

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N-methyl-N-(2,2,2-trifluoroethyl)ethanamide

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] -N-methyl-N-(pyridin-2-ylmethyl)ethanamide

(3R,6R 1 - {( 1 R)- 1 -(2,4-difluorophenyl)-2-[4-(methylsulfonyl)piperazin- 1 -yl]-2- oxoethyl}-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutylpiperazine-2,5-dione

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-methoxy-N-methylethanamide (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] ethanoic acid methyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1 -yl] ethanoate propyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin- 1-yl] ethanoate l-(acetyloxy)ethyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-l-yl]ethanoate

[( 1 R)- 1 -methylpropyl] -2, 5 -dioxopiperazin- 1 -yl} ethanamide (2R)-N-(tert-butyl)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-

[(lS)-l-methylpropyl]-2,5-dioxopiperazin-l-yl}ethanamide

(3R,6R)-l-[(lR)-l-(2,4-difluorophenyl)-2-moφholin-4-yl-2-oxoethyl]-3-(2,3-dihydro- lH-inden-2-yl)-6-[(lS)-l-methylpropyl]piperazine-2,5-dione

(3R,6R)-l-[(lR)-l-(2,4-difluorophenyl)-2-moφholin-4-yl-2-oxoethyl]-3-(2,3-dihydro- 1 H-inden-2-yl)-6- [( 1 R)- 1 -methylpropyl]piperazine-2, 5 -dione

(3R,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-2,5-dioxopiperazin-l-yl]-N- isopropyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide

(2S)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-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

N,N-dimethyl-2-(2-methyl-l,3-oxazol-4-yl)ethanamide

(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-l-[(lR)-l-(2-methyl-l,3-oxazol-4-yl)- 2-moφholin-4-yl-2-oxoethyl]piperazine-2,5-dione

(2S)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-2-(3- fluoro-5-methylthien-2-yl)-N,N-dimethylethanamide (2R)-2-(l-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-l-yl]-N-isopropylethanamide.

2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]ethanamide.

(2R)-2-(2,3-dihydro-l-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-l-yl]-N-isopropylethanamide.

6-isobutyl-2,5-dioxopiperazin-l-yl]ethanamide.

(2R)-2-(benzofuran-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-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-l-yl]-

N,N-dimethyl-2-(2-methyl- 1 -benzofuran-5 -yl)ethanamide

(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-benzoftxran-5-yl)ethanamide

(3R,6R)-3-(2,3-dihydro- lH-inden-2-yl)-6-isobutyl- 1 -[(1R)- 1 -(2-methyl- 1 -benzofuran-5- yl)-2-moφholin-4-yl-2-oxoethyl]piperazin-2,5-dione

(2-fluoro- 1 -benzofuran-5-yl)-N,N-dimethylethanamide

(2-fluoro-l-benzofuran-5-yl)-N-isopropylethanamide (3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-l-[(lR)-l-(2-fluoro-l-benzofuran-5-yl)-2- moφholin-4-yl-2-oxoethyl]-6-isobutylpiperazine-2,5-dione

(2R)-2-[(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-6-isobutyl-2,5-dioxoρiρerazin-l-yl]-2-

(lH-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

12. A pharmaceutical composition comprising a compound of formula (1) as defined in claim 1 or claim 2 together with one or more pharmaceutically acceptable carriers.

13. The use of compound of formula (1) as defined in claim 1 for the manufacture of a medicament for treating benign prostatic hypeφlasia