OA12756A - 3-(Imidazolyl)-2-alkoxypropanoic acids as tafia inhibitors. - Google Patents

Abstract

Compounds according to formula (I) wherein n is 0-3, R<1> is optionally substituted C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, Heterocycle, Aromatic heterocycle, Aryl or hydrogen and R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8> and R<9> are each independently selected from hydrogen and optionally substituted C 1-6 alkyl, or R<5> and R<8> are an alkylene chain, are novel. They are useful in the treatment of thrombotic conditions and other pathologies associated with fibrin deposition.

Description

Λ 012756

3-(IMIDAZOLYL)-2-ALKOXYPROPANOIC ACIDS AS TAFIA INHIBITORS

The présent invention relates to a sériés of novel 3-(imidazolyl)-2-(<û-aminoalkyloxy)-propanoic acid dérivatives that are inhibitors of TAFIa inhibitors and are useful in thetreatment of disease.

Background

Sophisticated mechanisms hâve evolved in mammals to repair the body in the eventof vascular injury and so maintain hemostasis. The injured biood vessel constrictsto reduce the blood flow to the area, piateiets aggregate to reduce the loss of bioodfrom the area, and fibrinogen is cleaved to produce fibrin which then polymerisesand forms a clôt. This ciot covers the area of vascular damage, preventing bloodloss. Polymerised fibrin also provides a provisional matrix which enhances thesubséquent repair process. Once the blood vessel has been repaired the clôtdissolves. The process leading to the formation of the clôt is the coagulationcascade, and the process leading to its dissolution is the fibrinolysis cascade.Imbalances in the blood coagulation process are thought to be at the origin of a largeand disparate number of disease conditions, which are linked by an unwanted buildup of fibrin. The scale of fibrin build up is determined by the délicate equilibriumbetween the two biochemical cascades in the human body. Agents that canmodulate the balance between coagulation and fibrinolysis are therefore potentiallyvaluable in the treatment of these disease conditions.

Studies hâve shown that coagulation and fibrinolysis are linked through thegénération of α-thrombin. a-Thrombin is the final product of the blood coagulationcascade and is responsable for the conversion of fibrinogen into fibrin. In addition tomediating coagulation, α-thrombin also reduces the rate at which blood clots arebroken down by the serine protease plasmin. The protein that médiates thisantifibrinolytic effect of α-thrombin is TAFI (Thrombin Activatable FibrinolysisInhibitor). TAFI is a 60kDa glycoprotein found in human plasma. It is also known asprocarboxypeptidase B, carboxypeptidase B, plasma carboxypeptidase B, 012756 2 carboxypeptidase U and carboxypeptidase R. Following initiation of the coagulationcascade it is transformed into an activated form, TAFIa, whereupon it acts upon thefibrin matrix of the developing blood ciot to prevent its dissolution. TAFI circulâtes innormal plasma at a concentration of about 75nM in an inactive form. Thrombinconverts the inactive zymogen to the active TAFI (TAFIa), a reaction that isaugmented about 1250-fold by thrombomodulin. Once activated, TAFIa cleavesboth C-terminal arginine and lysine residues from the developing fibrin clôt. Theremoval of these dibasic amino acids from the surface of the fibrin matrix atténuâtesclôt lysis by inhibiting the bindîng of the key mediators of fibrinolysis: tissueplasminogen activator (tPA) and its substrate, plasminogen, which is the precursor ofplasmin. Both tPA and plasminogen contain a structural motif called a kringledomain which binds tightiy to C-terminal lysine residues. The removal of thesebindîng sites prevents the formation of a ternary complex between tPA, plasminogenand fibrin and this inhibits the conversion of plasminogen to plasmin, thus protectingthe clôt from rapid dégradation.

In the presence of a TAFIa inhibitor, TAFIa will not be able to act upon a developingfibrin clôt as described above to inhîbit fibrinolysis of the clôt. Thus a TAFIa inhibitorshould serve to enhance fibrinolysis.

It can be seen that, in pathologies where the normal equilibrium between coagulationand fibrinolysis is disturbed in favour of coagulation, there will be a larger amount offibrin présent than normal. This makes it more likely that the subjects will developone or more of the conditions in which thrombus build up is implicated.—Süehsubjects can be expected to benefit from treatment with a pro-fibrinolytic agent.McKay et al. (Biochemistry 1978, 17,401 ) disclose the testing of a number ofcompounds as compétitive inhibitors of bovine carboxypeptidase B of pancreaticorigin. Inhibition was measured by the inhibitor’s efficiency in protecting the activecentre tyrosine and glutamic acid of bovine carboxypeptidase B from irréversiblealkylation by bromoacetyl-D-arginine or bromoacetamidobutylguanidine. It issuggested that such inhibitors could act as bradykinin potentiators. Bovine enzymesof pancreatic origin are very different to those found in human plasma, so one wouldnot expect inhibitors of one to inhibit the other. Moreover, such inhibitors aredirected towards a very different utility. Accordingly this disclosure provides no 012756 3 îeaching of TAFIa inhibitors or their utility.

Redlitz et al. (J. Clin. Invest. 1995, 96,2534) teach the involvement of plasmacarboxypeptidase B (pCPB, or TAFI) in the formation of clots. The lysis of bloodclots was followed in the absence and presence of pCPB, whereupon it was foundthat the presence of pCPB slowed clôt lysis. To confirm that pCPB was responsibletwo control reactions were run; one where the lysis experiment was repeated in thepresence of pCPB and potato carboxypeptidase inhibitor, PCI, and a second wherethe lysis reaction was conducted in the presence of plasma from which pCPB wasremoved. In both cases lysis proceeded uninhibited.

Boffa et al. (J. Biol. Chem. 1998,273,2127) compare plasma and recombinant TAFIand TAFIa with respect to glycosylation, activation, thermal stability and enzymaticproperties. Inhibition constants for three compétitive inhibitors were determined:ε-aminocaproic acid (ε-ACA), 2-guanidinoethyImercaptosuccinic acid (GEMSA) andpotato carboxypeptidase inhibitor (PCI).

There are large numbers of carboxypeptidases (i.e. enzymes that cleave theC-terminal amino acid from a peptide). They may be classified as acidic, neutral orbasic, depending on the type of amino acid they cleave. Basic carboxypeptidasescleave arginine, lysine and histidine. TAFIa is a member of a spécifie subset of thebasic carboxypeptidases. In terms of the présent invention, the inhibitors disclosedabove by Redlitz et al. and Boffa et al. are too weak, non-specific or otherwiseunsuitable to be considered as suitable TAFIa inhibitors for therapeutic application.Further, whilst the rôle of TAFIa in clôt lysis is explained, there is no suggestion thatTAFIa inhibitors can be used to treat disease. US-A-5993815 teaches the use of a peptide that binds to the TAFI zymogen, therebyinhibiting its activation, to treat those disorders where a C-terminal lysine or arginineis cleaved from an intact peptide. Suitable disorders are arthritis, sepsis,thrombosis, strokes, deep vein thrombosis and myocardial infarctions. The peptideused is an antibody or a functionally active fragment. The peptide should be used inan amount to promote fibrinolysis In vivo. 012756 4 WO00/66550 and WOOO/66557 disclose broad classes of compounds useful asinhibitors of carboxypeptidase U. Inhibitors of carboxypeptidase U are postulated tofacilitate fibrinolysis and thus the compounds are taught as useful in the treatment of 5 thrombotic conditions. There is no data to support this assertion, though details of asuitable assay are given. WOOO/66152 discloses formulations containing a carboxypeptidase U inhibitor and athrombin inhibitor. Suitable carboxypeptidase U inhibitors are those of 10 WO00/66550. The formulations are taught as primarily useful in treating thromboticconditions. WO01/19836 discloses a sériés of phosphonate esters and analogues thereof ascarboxypeptidase B inhibitors that are suitable for the treatment or prévention of 15 thrombotic diseases. WO02/14285 discloses a sériés of a-imidazolylmethyl-û>aminocarboxylic acids andA/“-(û>aminoalkyl)-histidine dérivatives that are inhibitors of TAFIa. The compoundsare considered to be potentially useful in the treatment of a number of conditions. 20

The présent invention discloses a further class of TAFIa inhibitors.

Description of the Invention

In a first aspect, the présent invention provides compounds according targeneral25 formula (I)

(I) 072756 wherein: n is 0,1,2 or 3; R1 is selected from (a) an optionally substituted straight chain or branched Chain Cv6 alkyl group, (b) an optionally substituted straight Chain or branched chain C2-6 alkenyl group, (c) an optionally substituted straight chain or branched chain C2.6alkynyl group, (d) Aryl, (e) Aromatic heterocycle, (f) Heterocycle, and (g) hydrogen; where the optional substituents in groups (a), (b) and (c) above are selected from:C3-7 cycloalkyl, Aryl, Aromatic heterocycle, Heterocycle, OR10, NRWR11, S(O)PRW,OC(O)R11, CO2R’°, CONR10R11, SO2NRwR11, halo and NHSO2R10, and where p is 0,1 or 2; R2, R3, R4, R6, R7 and R9 are each independently selected from hydrogen andstraight chain or branched chain Ci-6 alkyl optionally substituted by OR10 or halo; R5 and R8 are each independently selected from hydrogen and straight chain orbranched chain C1-6 alkyl optionally substituted by OR10 or halo, or together are a C2.e alkylene chain; R10 and R11 are each independently selected from hydrogen and straight chain orbranched chain Cve alkyl;

Aryl is a 6-14 membered aromatic monocyclic or fused polycyclic carbocycîic groupoptionally substituted with one or more groups selected from R12, halo, OR13,NR13R14, NR13CO2R12, CO2R13, NR13SO2R12, CN, haloalkyl, O(haloalkyl), SR13,S(O)R12, SO2R12, 0C(O)R13, SO2NR13R14, C(O)NR13R14, C3.7 cycioakyl, O(C3.7cycloalkyl), R15 and OR15, where R12 is straight chain or branched chain C^e alkyl, R13 and R14 are each independently selected from hydrogen and straight chain orbranched chain Cve alkyl, and R15 is phenyl optionally substituted by R12, OR13, haloor haloalkyl;

Aromatic heterocycle is a 5 to 7 membered aromatic ring containing from 1 to 3heteroatoms, each independently selected from O, S and N, said ring beingoptionally substituted with one or more groups selected from OR13, NR13R14, CO2R13,NR13CO2R12, R12, halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12,OC(O)R13, NR13SO2R12, SO2NR13Ru and C(O)NR13RU; and 07275g

Heterocycle is a 3 to 8 membered ring containing from 1 to 3 heteroatoms, eachindependently selected from O, S and N, said ring being saturated or partiallysaturated, said ring further being optionally substituted with one or more groups selected from OR13, NR13R14, CO2R13, NR13CO2R14, R12, halo, CN, haloalkyl,O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12, SO2NR13R14 andC(O)NR13R14, or a tautomer thereof, or a pharmaceutically acceptable sait or solvaté of saidcompound or said tautomer.

As used herein: i) Halo includes fluoro, chloro, bromo and iodo groups. ii) Haloalkyl includes monohaloalkyl, polyhaloalkyl and perhaloalkyl, such as2-bromoethyl, 2,2,2-trifluoroethyl, chlorodifluoromethyl and trichloromethyl. iii) Unless otherwise indicated, afkyl includes straight Chain and branched Chain alkyl.

It wîll be understood that, in the compounds according to general formula (I), the R1group and C(R2)(R3)(amino acid) group may be attached at any atom of theimidazole ring that is available to form a covalent bond, and that it is not intended /^-positions, nor the C(R2)(R3)(amino acid) group to the C4- and expositions. It wîll

of the imidazole ring, and that only one of the nitrogen atoms (by convention designated N1) of the imidazole ring is available to form a covalent bond—Thus the possible substitution patterns are 1,2-; 1,4-; 1,5-; 2,4- and 2,5-. When the imidazoleis 2,4- or 2,5-substituted then there is a hydrogen atom attached at the ΛΖ’-position.

Certain compounds according to formula (I) may exist in more than one tautomericform. If the imidazole of general formula (I) is substituted at the 2- and 4-positionsthe 2,4-disubstituted imidazole can tautomerise to form the corresponding 2,5-disubstituted imidazole. Furthermore, where a compound includes an Aromaticheterocyle that is substituted with a hydroxyl group it may exist as the ‘keto’tautomer. The tautomeric relationship between 2-hydroxypyridine and 2-pyridone isa well known example of this phenomenon. Ail such tautomers of compounds of 012756 formula (I), including mixtures thereof, are included in the scope of the présentinvention.

The compounds of formula (I) contain one or more asymmetric carbon atoms (chiralcenters) and can therefore exist in two or more optical stereoisomeric forms such asenantiomers, diastereomers and epimers. Where the compounds of formula (I)contain a carbon-carbon double bond, cis (Z) / trans (E) stereoisomerism may alsooccur. Ail such individual stereoisomers of the compounds of formula (I) andmixtures thereof, including racemates, are included in the scope of the présentinvention.

Individual stereoisomers may be separated from mixtures by conventionaitechniques such as, for example, by fractional crystallization or by chromatographyof the mixture of compounds or of a suitable sait or dérivative thereof. In particular,individual enantiomers of the compounds of formula (I) may be prepared byresolution, such as by H.P.LC. of the corresponding racemate using a suitable chiralsupport or by fractional crystallisation of the diastereoisomeric salts formed byreaction of the corresponding racemate with a suitable optical,y active acid or base,as appropriate. The individual enantiomers may also be obtained from acorresponding optically pure intermediate prepared by such a resolution method.These general principles are discussed in more detail by J. Jacques and A. Collet(“Enantiomers, Racemates and Résolutions", Wiley, NY, 1981) and by W. Liu(“Handbook of Chiral Chemicals", D. Ager (ed.), M. Dekker, NY, 1999; chapter 8).

It will be appreciated that the compounds of formula (I) hâve both acidic and basicfunctional groups. Therefore, in addition to the uncharged form depicted in thegeneral formula, they may exist as interna, salts (zwitterions). Furthermore, theymay form pharmaceutically acceptable salts with acids and bases. Such zwitterionsand salts are included within the scope of the invention. A pharmaceutically acceptable sait of a compound of the formula (l) may be readilyprepared by mixing together solutions of a compound of the formula (I) and thedesired acid or base, as appropriate. The sait may precipitate from solution and becollected by filtration or may be recovered by évaporation of the solvent. Salts may 012756 also be prepared by ion exchange, such as by equiiibrating a solution of a compoundof formula (I) with an appropriate ion exchange resin. Ion exchange may also beused to convert one sait form of a compound of formula (I), such as a sait with anacid or base that is not pharmaceutically acceptable, to another sait form. Thesemethods are generally well known in the art. Suitable acid addition salts are formedfrom acids which form non-toxic salts and examples are the hydrochloride,hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate,saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate,p-toluenesulphonate and pamoate salts. Suitable base salts are formed from baseswhich form non-toxic salts and examples are the sodium, potassium, aluminium,calcium, magnésium, zinc and diethanolamine salts. For a review ofpharmaceutically acceptable salts see Berge étal. (J. Pharm. Soi., 1977, 66,1).

The compounds of formula (I) may form pharmaceutically acceptable solvatés(including hydrates). These solvatés are also included in the scope of the présentinvention.

The compounds of formula (I) may exist in one or more crystalline forms. Thesepolymorphs, including mixtures thereof are also included within the scope of theprésent invention.

The scope of the présent invention further includes prodrugs of compounds offormula (I), i.e. pharmaceutically acceptable dérivatives of the compourïds-inwhichone or more of the functional groups explicitly recited above hâve been modifiedsuch that they are converted to the parent compounds in vivo. Suitable prodrugsare discussed in Drugs of Today 1983, 19,499-538 and Annual Reports in MédicinalChemistry 1975, 10, 306-326.

The absolute stereochemistry of the compounds of formula (I) may be as depicted informula (IA) or formula (IB) below. By convention the absolute stereochemistry atthe chiral center of (IA) is designated as ‘S and that of (IB) is ‘R. The compoundsof formula (IA) are particularly preferred. 012756

Preferred compounds of formula (I) include those where the imidazole is substitutedat the C2 or C4 positions by the C(R2)(R3)(amino acid) group to give compounds offormulae (IC) and (ID) respectively. Particularly preferred are those compounds of 5 formula (1) where R1 is attached at the C* position of the imidazole moiety and theC(R2)(R3)(amino acid) group is attached at the C2 position so as to give the2,4-disubstituted imidazole of formula (IC1) or where R1 is attached at the N1 positionof the imidazole moiety and the C(R2)(R3)(amino acid) group is attached at the C4position so as to give the 1,4-disubstituted imidazole of formula (ID1). Most 10 preferred are those compounds of formula (I) where R1 is attached at the N1 positionof the imidazole moiety and the C(R2)(R3)(amino acid) group is attached at the C4position so as to give the 1,4-disubstituted imidazole of formula (ID1).

(ID) 012756

Preferably n is O or 1. More preferably n is 0.

Preferably R1 is hydrogen, Aryl, or a Cve alkyl or C2-6 alkenyl group optionallysubstituted by one or more groupe selected from C3.7 cycloalkyl, Aryl, Aromaticheterocycle, Heterocycle, OR10, NR10R11, S(O)PR10, OC(0)R11, CO2R10, CONR10R11,SO2NR10R11, halo and NHSO2R10. More preferably R1 is hydrogen, Aryl, C2.6 alkenylor a Ci-6alkyl group optionally substituted by one or more groups selected from C3.7cycloalkyl, Aryl, Aromatic heterocycle, OR10, CO2R10, halo and NHSO2R10. Yet morepreferably R1 is hydrogen, Aryl or a Ci-6alkyl group optionally substituted by a groupselected from C3-7 cycloalkyl, Aryl, Aromatic heterocycle, OR10, CO2R10 andNHSO2R10. Yet more preferably R1 is hydrogen, Aryl or a Ci-6 alkyl group optionallysubstituted by a group selected from cyclohexyl and Aryl. Yet more preferably R1 ishydrogen or C1-3 alkyl. Most preferably R1 is hydrogen.

Preferably R2 and R3 are each independently selected from hydrogen and Ci.6 alkyl.More preferably R2 and R3 are hydrogen.

Preferably R4 is hydrogen or Ci-6 alkyl. More preferably R4 is hydrogen.

Preferably R6, R7 and R9 are each independently selected from hydrogen and C1.6alkyl. More preferably R6, R7 and R9 are each independently selected fromhydrogen and (^.3 alkyl. Yet more preferably R6, R7 and R9 are each independentlyselected from hydrogen and methyl. Most preferably R6, R7 and R9 are ail hydrogen. 012756 11

When R5 and R8 do not constitute a C2-6 alkylene link then R5 is preferabiy hydrogenor Ci-6 alkyl, more preferabiy hydrogen or Cv3 alkyl, yet more preferabiy hydrogen ormethyl, and most preferabiy methyl, and R8 is preferabiy hydrogen or Cve alkyl, morepreferabiy hydrogen or Ci-3 alkyl, yet more preferabiy hydrogen or methyl, and mostpreferabiy hydrogen.

When R5 and R8 constitute a C2-e alkylene link then the link is preferabiy a C2.3alkylene link and more preferabiy it is a C2 alkylene link.

Preferabiy R10 and R11 are each independently selected from hydrogen and C1.3alkyl. More preferabiy R10 and R11 are each independently selected from hydrogenand methyl.

Aryl includes optionally substituted phenyl, naphthyl, anthracenyl and phenanthrenyl.Preferabiy Aryl is phenyl or naphthyl optionally substituted by 1 >3 groups selectedfrom R12, halo, OR13, NR13R14, NR13CO2R12, CO2R13, NR13SO2R12, CN, haloalkyl,O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, SO2NR13R14, C(O)NR13R14, C3-7cycloakyl, O(C3-7 cycloalkyl), R15 and OR15. More preferabiy Aryl is phenyl optionallysubstituted by Ci.6 alkyl, halo, 0(Cv6 alkyl), CF3, C3.7 cycloakyl, 0(03-7 cycloalkyl), R1S or OR15 and R15 is phenyl optionally substituted by Ci.6 alkyl, halo, Ο(Ονβ alkyl)or CF3. Yet more preferabiy Aryl is phenyl optionally substituted by Ci-e alkyl, CF3,cyclohexyl, O(cyclohexyl), R15 or OR15 and R15 is phenyl optionally substituted by Ci-ealkyl, Cl, F, O(Ci-e alkyl) or CF3. Most preferabiy Aryl is phenyl. -

Preferabiy Aromatic heterocycle is a 5 or 6 membered aromatic ring containing 1 or 2heteroatoms each independently selected from O, S and N, including optionallysubstituted furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyland triazinyl, optionally substituted by 1-3 groups selected from OR13, NR13R14,CO2R13, NR13CO2R12, R12, halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12,OC(O)R13, NR13SO2R12, SO2NR13Ru, C(O)NR13R14. More preferabiy Aromaticheterocycle is a 5 or 6 membered aromatic ring containing from 1 to 3 heteroatoms,each independently selected from O, S and N, optionally substituted by 1-3 groupsselected from OR13, NR13RU, CO2R13, NR13CO2R12, R12, halo, CN, haloalkyl, 012756 12 O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12, SO2NR13R14,C(O)NR13R14. Most preferably Aromatic heterocycle is an unsubstituted 5 or 6membered aromatic ring contaîning 1 or 2 heteroatoms, each independentiy selectedfrom O, S and N.

Preferably, Heterocycle is a 3 to 8 membered ring contaîning 1 or 2 heteroatoms,each independentiy selected from O, S and N, said ring being saturated or partiallysaturated, optionally substituted by 1 to 3 groups selected from OR13, NR13R14,CO2R13, NR13CO2R12, R12, halo, CN, haloalkyl, O(haloatkyl), SR13, S(O)R12, SO2R12,OC(O)R13, NR13SO2R12, SO2NR13RU, C(O)NR13R14. More preferably, Heterocycle isa 5 or 6 membered ring contaîning 1 or 2 heteroatoms, each independentiy selectedfrom O, S and N, said ring being saturated or partially saturated, optionallysubstituted by 1 to 3 groups selected from OR13, NR13R14, CO2R13, NR13CO2R12, R12,halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12,SO2NR13R14, C(O)NR13R14. Most preferably, Heterocycle is an unsubstituted 5 or 6membered ring contaîning 1 or 2 heteroatoms, each independentiy selected from O,S and N, said ring being saturated or partially saturated, including oxiranyl, azetidinyl,tetrahydrofuranyl, thiolanyl, pyrrolidinyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl,morpholinyl, piperidinyl and piperazinyl.

Preferred compounds of the présent invention are: (2S)-(-)-2-(2-aminoethoxy)-3-(1-phenyl-1 W-imidazol-4-yl)propanoic acid (Example 6);(2S)-2-{[(1 fi)-2-amino-1 -methylethyl]oxy}-3-[1-(2-cyclohexylethyl)-1 H-imidazol-4-yl]-prôpanoic acid (Example 15); "—~ (2S)-2-{[( 1 fl)-2-amino-1 -methylethyl]oxy}-3-(1 -phenyl-1 W-imidazol-4-yl)propanoicacid (Example 17); (2S)-2-{((2S)-2-aminopropyI]oxy)-3-[1-(2-cyclohexylethyl)-1H-imidazol-4-yl]propanoicacid (Example 34); (2S)-2-(2-aminoethoxy)-3-(1 W-imidazoi-4-yl)propanoic acid (Example 50); (2S)-2-{[(1 fi)-2-amino-1-methylethyl]oxy}-3-(1 tf-imidazol-4-yl)propanoic acid(Exampie 51); and (2S)-2-{[(1 R)-2-amino-1 -methylethyl]oxy}-3-[1 -(2-pyridinyl)-1 H-imidazol-4-yl]-propanoic acid (Example 52). 012756 13

Particularly preferred is (2S)-2-{[(1f?)-2-amino-1-methyleihyl]oxy}-3-(1/-/-imÎdazo!-4-yl)propanoic acid (Example 51).

The compounds of formula (I) are inhibitors of TAFIa. Inhibition of TAFIa can bedemonstrated using an assay based on the method of Boffa et al. (J. Biol. Chem.1998, 273,2127) as further described below. The activity of the compounds ischaracterized by a calculated Kf value. Generally the compounds of the présentinvention hâve a Ki value of 10μΜ or less. Better compounds hâve a Kj value of1 μΜ or less, or even 100nM or less. The most potent compounds hâve a Kf value of25nMorless.

The compounds of formula (I) are sélective for TAFIa over other carboxypeptidases,and particularly carboxypeptidase N (CPN). Unwanted inhibition of CPN isconsidered to be the most likely cause of undesirable side effects in clinical use.Selectivity can be expressed as the ratio of the K, for TAFIa to the K| for CPN.Generally the compounds of the présent invention hâve a selectivity ratio of at least5. Better compounds hâve a selectivity ratio of at least 10. The most sélectivecompounds hâve a selectivity ratio of at least 50.

The compounds of formula (I) may be prepared according to the general methodswhich are described below and in the Examples and Préparations section. Thesemethods provide a further aspect of the présent invention. Nevertheless, the skilledman wiil appreciate that the compounds of the invention could be made byimethodsother than those herein described, by adaptation of the methods herein describedand/or adaptation of a plethora of methods known in the art. It is to be understoodthat the synthetic transformation methods specifically mentioned herein may becarried out in various different sequences in order that the desired substances canbe efficiently assembled. The skilled chemist wiil exercise his judgement and skillas to the most efficient sequence of reactions for the synthesis of a given targetsubstance.

It wiil be apparent to those skilled in the art that sensitive functional groups may needto be protected and deprotected during the synthesis of a substance of the invention. 012756 14

This may be achieved by conventional techniques, for example as described by T. W.Greene and P. G. M. Wuts (“Protective Groups in Organic Synthesis”, 3RD édition,Wiley-lnterscience, NY, 1999). 5 Compounds of formula (I) may be prepared from the corresponding esters of formula(II) (wherein P1 is a lower alkyl group, a benzyt group or any other carboxyl protectinggroup).

P1 is preferably a lower alkyl group such as methyl or ethyl, in which case suitable 10 conditions for this step include treatment with NaOH in dioxan for 1 -3 days.

Compounds of formula (II) may be prepared from the corresponding protectedamines of formula (III) (wherein P2 is a ferf-butyloxycarbonyl, benzyloxycarbonyl orfluorenylmethyloxycarbonyl group, or any other amine protecting group). Where R9 15 is H then the préparation involves only a deprotection step. Where R9 is other thanF+then a further step is necessary to introduce R9, such as a reductive aminationreaction.

012756 15

Alternatively, compounds of formula (III) may be converted to the correspondingacids (IV) prior to deprotecting the amine to give the compounds of formula (I).

Compounds of formula (III) may be prepared from imidazoleacetic acid dérivatives of5 formula (V), wherein X is a leaving group such as a chlorine, bromine or iodine atom, or a methanesulphonate or trifluoromethanesulphonate group, by reaction with aalcohol of formula (VI).

(III) 012756 16

Compounds of formula (V) may be prepared from the corresponding hydroxyaciddérivatives of formula (VII) or, where X is Br, by direct halogénation of the esters offormula (VIII).

5 Compounds of formula (VI), (VII) and (VIII) are known or may be prepared bymethods analogous to those used for the préparation of such known compounds.

Compounds of formula (III) may alternatively be prepared from a-hydroxyimidazole-acetic acid dérivatives of formula (Vil) by reaction with a compound of formula (IX) 10 wherein Y is a leaving group such as a chlorine, bromine or iodine atom, or amethanesulphonate or trifluoromethanesulphonate group.

(III)

Compounds of formula (II) where neither of R8 and R9 are hydrogen may also beprepared from compounds of formula (X). When R3 is hydrogen the transformation 15 may be accomplished by hydrogénation in the presence of a suitable catalyst.

When R3 is other than hydrogen the transformation may be accomplished using areagent such as R3-M, where M is a métal such as lithium or magnésium, in thepresence of a copper(l) sait. 012756 17

Compounds of formula (X) may be prepared from compounds of formula (XI) bydéhydration. The transformation may be accomplished using, for example,methanesulfonyl chloride and a tertiary amine.

Compounds of formula (XI) may be prepared by an aldol-type reaction betweenalkoxy-esters of formula (XII) and aldéhydes or ketones of formula (XIII) irithepresence of a strong base, such as lithium diisopropylamide.

(XII)

(XI) 10 Compounds of formula (XIII) are generally known, or may be prepared by methods 012756 18 analogous to published methods. Compounds of formula (XII) may be prepared byreacting the corresponding amino-alcohols R8R9NC(R6)(R7)(CH2)nC(R4)(R5)OH with abromoacetate BrCHzCC^P1 in the presence of a base such as sodium hydride. 5 Compounds of formula (I) wherein R9 is hydrogen may alternatively be prepared bythe hydrolysis of lactams of formula (XIV).

Compounds of formula (XIV) may be prepared from the corresponding unsaturatedcompounds of formula (XV). When R3 is hydrogen the transformation may be 10 accomplished by hydrogénation in the presence of a suitable catalyst. When R3 isother than hydrogen the transformation may be accomplished using a reagent suchas R3-M, where M is a métal such as lithium or magnésium, in the presence of acopper(l) sait.

15 Compounds of formula (XV) may be prepared by déhydration of alcohois of formula(XVI). 012756 10 15

Compounds of formula (XVI) may be prepared by reacting an aldéhyde or ketone offormula (XIII) with a lactam of formula (XVII) in the presence of a strong base, suchas lithium diisopropylamide.

Compounds of formula (XVII) may be prepared from aminoalcohols of formula (XVIII)by reaction with chloroacetyl chloride. Compounds of formula (XVIII) are generallyknown, or may be prepared by adaptation of generally known methods.

When R8 is H, the foregoing method can be problematic, particularly at the stepinvolving the reaction of compounds of formula (XIII) and (XVII). It is generallyconvenient in this case to use a protected aminoalcohol of formula (XVIIIa), where P3is a nitrogen protecting group. A particularly useful embodiment of P3 is the4-methoxybenzyl group. This may be removed following the élaboration ofintermediate (XlVa) by treatment with ceric ammonium nitrate. 012756

When R1 is H it may be necessary or convenient to protect the imidazole as îts trityldérivative. Accordingly, when R1 is H, compounds of formula (XIX), (XX) or (XXI)may be elaborated by the foregoing methods to provide compounds of formula (XXII) 5 which, upon deprotection, give compounds of formula (III).

(XXI)

This route may also be useful for the préparation of certain compounds according toformula (I) wherein R1 is attached at the N1 position of the imidazole ring.Compounds of formula (III) wherein R1 is H may be alkylated or arylated to give 10 compounds of formula (III) wherein R1 is other than H and is attached at the N1position. 21 012756

(XXII) (III, R1 = H) (III, R1 at N1)

When R1 is an alkyl, alkenyl or alkynyl group it may be introduced in an alkylationréaction. Suitable conditions for this step include treatment with 1.1 eq of césiumcarbonate and 1.1 eq of an alkylating agent in N.N-dimethylformamide, or withsodium hydride and 1.1 eq of an alkylating agent in THF. Suitable alkylatingreagents include R1-CI, R1-Br, R1-I, R1-OSO2CH3 and R1-OSO2CF3. When R1 is Arylor Aromatic heterocycle it may be introduced in an arylation reaction. Suitableconditions for this step include treatment with 2eq of AryI-B(OH)2 or Aromaticheterocycle-B(OH)2 in the presence of 1.5 eq of copper acetate, 2eq of pyridine, airand 4À molecular sieves.

For the compounds of formula (I) wherein the imidazole is 2,4- or 2,5-disubstituted, itmay also be convenient or necessary to use a protecting group at the N1 position.

The compounds of formula (I) are useful as therapeutic agents. The compounds willgenerally be formulated so as to be amenable to administration to the subject by thechosen route. In a further aspect, therefore, the présent invention provides for apharmaceutical composition comprising a compound of formula (I) or a stereoisomer,tautomer or pharmaceutically acceptable sait, solvaté or prodrug thereof and apharmaceutically acceptable excipient, diluent or carrier selected with regard to theintended route of administration and standard pharmaceutical practice. Forexample, the compounds of formula (I) can be administered orally, buccally orsublingually in the form of tablets, capsules, ovules, élixirs, solutions or suspensions.These formulations may contain flavouring or colouring agents, and may be adaptedfor immédiate-, delayed-, modified-, sustained-, pulsed- or controlled-releaseapplications. 012756 22

Tablets may contain excipients such as microcrystalline cellulose, lactose, sodiumcitrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants suchas starch (preferably corn, potato or tapioca starch), sodium starch glycollate,croscarmellose sodium and certain complex silicates, and granulation binders suchas polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropyl-cellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents suchas magnésium stéarate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of a similar type may also be employed as fillers in gelatincapsules. Preferred excipients in this regard include lactose, starch, cellulose anddérivatives thereof, milk sugar and high molecular weight polyethylene glycols.

For solutions, suspensions and élixirs, the compounds of formula (I) may becombined with various sweetening or flavouring agents, colouring matter or dyes,with emulsifying and/or suspending agents, and with diluents such as water, éthanol,propylene glycol and glycerin, and combinations thereof.

The compounds of formula (I) may also be administered in the form of a solution- orsuspension-filled soft or hard gelatin capsule. Such capsules are generally made ofgelatin, glycerin, water and sorbitol. Hard capsules are distinguished from softcapsules by containing less water and thus having a correspondingly stronger Shell.Additional excipients suitable for use in such capsules include propylene glycol,éthanol, water, glycerol and edible oils. "— --

The compounds of formula (I) can also be administered parenterally, for example,intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly,intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously. Suchadministration may be as a single bolus injection or as a short- or long-durationinfusion. For such parentéral administration the compounds are preferablyformulated as a stérile solution in water or another suitable solvent or mixture ofsolvents. The solution may contain other substances such as: salts, particularlysodium chloride, and sugars, particularly glucose or mannitol, to make the solutionisotonie with blood; buffering agents such as acetic, citric and phosphoric acids and 012756 23 their sodium salts, such that the pH of the solution is preferably between 3 and 9;and preservatives. The préparation of suitable parentéral formulations under stérileconditions is readily accomplished by standard pharmaceutical techniques wellknown to those skilled in the art.

The compounds of formula (I) can also be administered intranasally or by inhalationand are conveniently delivered in the form of a dry powder inhaler or an aérosolspray présentation from a pressurised container, pump, spray, atomiser or nebuliser,with or without the use of a suitable propeüant such as dichlorodifluoromethane,trichlorofluoromethane, dichiorotetrafluoroethane, a hydrofluoroaikane such as 1,1,1,2-tetrafluoroethane (HFA134A™) or 1,1,1,2,3,3,3-heptafluoropropane (HFA227EA™), carbon dioxide or other suitable gas. In the case of a pressurisedaérosol, the dosage unit may be determined by providing a valve to deliver ametered amount. The pressurised container, pump, spray, atomiser or nebulisermay contain a solution or suspension of the active compound, e.g. using a mixture oféthanol and the propellant as the solvent, which may additionally contain a lubricant,e.g. sorbitan trioleate. Capsules and cartridges (made, for exampie, from gelatin)for use in an inhaler or insufflator may be formulated to contain a powder mix of acompound of the formula (I) and a suitable powder base such as lactose or starch.

Alternatively, the compounds of formula (I) can be administered by the vaginal orrectal routes in the form of a suppository or pessary, or The compounds of formula(I) may also be administered dermally or transdermally, for example, by the use of askin patch.

Alternatively, the compounds of formula (I) can be applied topically in the form of agel, hydrogel, lotion, solution, cream, ointment or dusting powder. Suitableointments may contain the active compound suspended or dissolved in, for example,a mixture with one or more of the following: minerai oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound,emulsifying wax and water. Suitable lotions or creams may contain the activecompound suspended or dissolved in, for example, a mixture of one or more of thefollowing: minerai oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol 012756 24 and water.

Alternative^, the compounds of formula (I) may be administered by the ocular route.For ophthalmic use, the compounds can be formulated as micronised suspensions inisotonie, pH adjusted, stérile saline, or, preferably, as solutions in isotonie, pHadjusted, stérile saline, optionaliy in combination with a preservative such as abenzylalkonium chloride. Alternatively, they may be formulated in an ointment suchas petrolatum.

The compounds of formula (I) may also be used in combination with a cyclodextrin.Gyclodextrins are known to form inclusion and non-inclusion complexes with drugmolécules. Formation of a drug-cyclodextrin complex may modify the solubility,dissolution rate, bioavailability and/or stability property of a drug molécule. Drug-cyclodextrin complexes are generally useful for most dosage forms andadministration routes. As an alternative to direct complexation with the drug thecyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent orsolubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used andsuitable examples are described in WO91/11172, WO94/02518 and WO98/55148.

Because the compounds of formula (I) are inhibitors of TAFIa they are useful astherapeutic agents in pathologies in which inhibition of TAFIa is bénéficiai. In afurther aspect, therefore, the présent invention provides for a compound of formula(I) or a stereoisomer, tautomer, solvaté, pharmaceutically acceptable sait or prodrugthereof for use as a médicament. In particular, the présent invention provides forthe use of a compound of formula (I) or a stereoisomer, tautomer, solvaté,pharmaceutically acceptable sait or prodrug thereof in the préparation of amédicament for the treatment or prévention of a condition selected from thromboticconditions, atherosclerosis, adhesions, dermai scarring, cancer, fibrotic conditions,inflammatory diseases and those conditions which benefit from maintaining orenhancing bradykinin levels in the body. The utility of TAFIa inhibitors for thetreatment of thrombotic conditions dérivés from their potential to promote fibrinolysiswhile not interfering with coagulation. In most clinically relevant situations thrombusformation is sub-acute, i.e. the thrombus forms slowly. Conventional anti-thromboticagents block the coagulation pathway and so prevent thrombus growth, but as an 012756 25 unavoidable conséquence they also block the clotting response to vascular damage,which results în an increased incidence of hemorrhaging. By promoting fibrinolysis,TAFIa inhibitors accelerate the dissolution of the developing thrombus withoutinterfering w'rth the clotting response. Accordingly, one preferred embodiment of the 5 présent invention provides for the use of a compound of formula (I) or a pharmaceutically acceptable sait, solvaté or prodrug thereof in the préparation of amédicament for the treatment of a thrombotic condition selected from myocardialinfarction, deep vein thrombosis, stroke, young stroke, cérébral infarction, cérébralthrombosis, cérébral embolism, peripheral vascular disease, angina and other forms 10 of acute coronary syndromes, disseminated intravascular coagulation, sepsis,pulmonary embolism, embolie events secondary to cardiac arrhythmias and theprévention of cardiovascular events following surgical revascularisation orintervention, or for improving the outcome of organ transplantation by reducing bloodclotting and so preserving organ function. Cardiovascular events following 15 intervention surgery include conditions such as restenosis or reocclusion followinginterventions such as percutaneous transluminal coronary angioplasty, grafting, stentin-placement, coronary bypass surgery or any other forms of surgical revascularisation or intervention. Disseminated intravascular coagulation includesail conditions resulting from intravascular activation of the coagulation process. This 20 might occur acutely through the reiease of procoagulant substances (eg. obstetricemergencies, snakebite, crush injury malignancy), by abnormal contact of the blood(eg. infections, burns, extracorporeal circulation, grafts) or though génération ofprocoagulants in the blood (transfusion reactions, leukemia); or chronically, (eg.toxemia, malignant hypertension, severe liver cirrhosis). Deep vein thrombosis also 25 encompasses what is known as ‘economy Cass syndrome’, where clots form insubjects forced to endure cramped conditions for a period of time, such as thosesitting in the economy class seats of an aéroplane. A rôle for thrombus formation in the pathophysiology of atherosclerosis has recently 30 been highlighted by several independent groups. Non-occlusive thrombi not ontyrestrict blood flow leading to myocardial ischemia and angina pectoris but also, dueto incomplète endogenous lysis, may be incorporated into the arterial wall assolidified plaque material enhancing the atherosclerotic process. Long-termadministration of a TAFIa inhibitor promûtes the lysis of developing thrombi and 012756’ 26 therefore provides a safe and efficacious treatment which alleviates the symptoms ofangina pectoris while impairing the progression of the underlying disease.Conventional treatment of myocardial ischaemia in clinically stable coronary arterydisease is predominately designed to reduce cardiac workload and enhance bloodflow. Such approaches clearly reduce myocardial ischaemia thus increasing quaiityof life. However, these strategies hâve little effect on the pathogenesis of coronaryatherosclerosis which is a chronic process of continuous remodeling of the vasculartree in response to varying degrees of vascular injury. Accordingly, anotherpreferred embodiment of the présent invention provides for the use of compounds offormula (I) and pharmaceutically acceptable salts, solvatés and prodrugs thereof inthe préparation of a médicament for the treatment or prévention of atherosclerosis,including atherosclerosis as a conséquence of peripheral vascular disease, insulinrésistance and Syndrome X, and further including myocardial ischaemia and anginapectoris resulting from atherosclerosis. Atherosclerosis is taken to include bothprimary and secondary coronary artery disease, in which atherosclerosis restricts theblood supply to the heart. Primary prévention of coronary artery disease meanspreventing the onset of ischémie complications such as myocardial infarction inpatients with no history of coronary artery disease but who hâve one or more riskfactors. Secondary prévention of coronary artery disease means preventing ischémiecomplications in patients with established coronary artery disease, such as patientswho hâve had a previous myocardial infarction. Syndrome X is a term often used togroup together a number of interrelated diseases. The first stage of syndrome Xconsists of insulin résistance, abnormal cholestérol and triglycéride levels, obesityand hypertension. Any one of these conditions may be used to diagnose-the start ofSyndrome X. The disease may then progress with one condition leading to thedevelopment of another in the group. For example insulin résistance is associatedwith high lipid levels, hypertension and obesity. The disease then cascades, withthe development of each additional condition increasing the risk of developing moreserious diseases. This can progress to the development of diabètes, kidneydisease and heart disease. These diseases may lead to stroke, myocardialinfarction and organ failure. Atherosclerosis is common in patients with SyndromeX. TAFIa inhibitors are also effective in preventing the formation of adhesions in the 012756 27 body. Most surgical procedures and physical traumas resuit in bleeding into thecavities between tissues. The blood which collects at these sites then clots formingfibrin-rich thrombi. These thrombi bridge the gaps between adjacent tissues and actas foci for the accumulation of inflammatory cells and fibroblasts. Invadingfibroblasts lay down a collagen-rich extracellular matrix which strengthens theadhesion of the tissues producing a firm bond which may then restrict movement.Adhesions hâve been characterised according to their location and may resuitfollowing any surgery, e.g. abdominal, orthopaedic, neurological, cardiovascular andocular surgery. This inappropriate adhesion of tissues post-surgery or trauma is amajor issue which can lead to various outcomes, e.g. "aches and pains", "twinges”,local inflammation, restriction in mobility, pain, intestinal obstruction and sometimes,in the most severe cases, death. In the case of gynaecological surgery, infertilitymay resuit. Additionally clots forming fibrin-rich thrombi are implicated in dermalscarring and restenosis. Without being bound by any theory, it is believed thatadhesion formation may be enhanced when a deficiency in fibrinolysis résulte inenhanced and maintained clôt formation. Treatment with a TAFIa inhibitor aroundand/or after surgical intervention may enhance fibrinolysis of the fibrin-rich thrombiand hence inhibit thrombus formation, accretion and stabilization, thereby inhibitingadhesion formation. A TAFIa inhibitor given either locally as a topical application orsystemically may be seen to be of benefit in a range of surgical procedures. Inaddition, administration of a TAFIa inhibitor may be used to treat adhesions resultingfrom other forms of non-surgical physical trauma where this has caused internaibleeding. Examples of such trauma might include sporting injuries or anÿthing elseresulting in a tear, eut, bruise or induration of the body. Accordingly, anotherpreferred embodiment of the présent invention provldes for the use of compounds offormula (I) and pharmaceutically acceptable salts, solvatés and prodrugs thereof inthe préparation of a médicament for the treatment or prévention of a médicament forthe treatment or prévention of adhesions or dermal scarring. TAFIa inhibitors are also effective in inhibiting tumour maturation, progression andmetastasis. Without being bound by any theory, it is believed that the hemostaticSystem is involved at several levels of cancer pathology, including neovascularisation, shedding of cells from the primary tumour, invasion of the bloodsupply, adhérence to the vessel wall and growth at the metastatic site. It is thought 012756 28 that the efficacy of TAFJa inhibitors stems from an ability to reduce fibrin dépositionaround solid tumours and thereby inhibit the above processes. Accordingly, anotherpreferred embodiment of the présent invention provides for the use of compounds offormula (i) and pharmaceutically acceptable salts, solvatés and prodrugs thereof inthe préparation of a médicament for the treatment or prévention of cancer. TAFIa inhibitors are efficacious in treatment of any condition in which fibrosis is acontributing factor. Suitable fibrotic conditions include cystic fibrosis, pulmonaryfibrotic diseases such as chronic obstructive pulmonary disease (COPD), adultrespiratory distress syndrome (ARDS), fibromuscular dysplasia and fibrotic lungdisease, and fibrin déposition in the eye during opthalmic surgery. Accordingly,another preferred embodiment of the présent invention provides for the use ofcompounds of formula (I) and pharmaceutically acceptable salts, solvatés andprodrugs thereof in the préparation of a médicament for the treatment or préventionof fibrotic disease, and in particular for the treatment or prévention of a fibroticcondition selected from cystic fibrosis, pulmonary fibrotic diseases, chronicobstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS),fibromuscular dysplasia, fibrotic lung disease and fibrin déposition in the eye duringopthalmic surgery. TAFIa inhibitors are efficacious in the treatment of inflammation, inflammatorydiseases such as asthma, arthritis, endometriosis, inflammatory bowel diseases,psoriasis and atopie dermatitis and neurodegenerative diseases such as Alzheimer’sdisease and Parkinson’s disease. Accordingly, another preferred embediment ofthe présent invention provides for the use of compounds of formula (I) andpharmaceutically acceptable salts, solvatés and prodrugs thereof in the préparationof a médicament for the treatment or prévention of inflammation, inflammatorydiseases such as asthma, arthritis, endometriosis, inflammatory bowel diseases,psoriasis and atopie dermatitis and neurodegenerative diseases such as Alzheimer’sdisease and Parkinson’s disease. TAFIabinds to and breaks down bradykinin (Tan étal., Biochemistry 1995, 34, 5811). There are many conditions which are known to benefit from maintaining orenhancing levels of bradykinin such as hypertension, angina, heart failure, 012756 29 pulmonary hypertension, rénal failure and organ failure. Accordingly, anotherpreferred embodiment of the présent invention provides for the use of compounds offormula (I) and pharmaceutically acceptable salts, solvatés and prodrugs thereof inthe préparation of a médicament for the treatment or prévention of conditions whichbenefit from maintaining or enhancing levels of bradykinin.

In a further aspect, the présent invention provides a method of treating or preventingthrombotic conditions, atherosclerosis, adhesions, dermal scarring, cancer, fibroticconditions, inflammatory diseases and those conditions which benefit frommaintaining or enhancing bradykinin levels in the body which comprisesadministering a therapeutically effective amount of a compound of formula (I) or astereoisomer, tautomer or pharmaceutically acceptable sait, solvaté or prodrugthereof to a patient in need of such treatment.

One preferred embodiment of the présent invention provides for a method of treatingor preventing thrombosis, particularly myocardial infarction, deep vein thrombosis,stroke, young stroke, cérébral infarction, cérébral thrombosis, cérébral embolism,peripheral vascular disease, angina and other forms of acute coronary syndromes,disseminated intravascular coagulation, sepsis, pulmonary embolism, embolie eventssecondary to cardiac arrhythmias and preventing cardiovascular events followingintervention surgery which comprises administering a therapeutically effectiveamount of a compound of formula (I) or a stereoisomer, tautomer orpharmaceutically acceptable sait, solvaté or prodrug thereof to a patient îr need ofsuch treatment. Subjects with thrombotic conditions who are suitable for treatmentby the présent invention include those having conditions associated withhypercoagulability, such as factor V mutation, antithrombin III deficiency, heparincofactor II deficiency, protein C deficiency, protein S deficiency and polycythemiavera, and those exhibiting homocystinaemia or homocystinuria.

Another preferred embodiment of the présent invention provides for a method oftreating or preventing atherosclerosis which comprises administering atherapeutically effective amount of a compound of formula (I) or a stereoisomer,tautomer or pharmaceutically acceptable sait, solvaté or prodrug thereof to a patientin need of such treatment. 012756 30

Another preferred embodiment of the présent invention provides for a method oftreating or preventing adhesions or dermal scarring which comprises administering atherapeutically effective amount of a compound of formula (I) or a stereoisomer,tautomer or pharmaceutically acceptable sait, solvaté or prodrug thereof to a patientin need of such treatment.

Another preferred embodiment of the présent invention provides for a method oftreating or preventing cancer which comprises administering a therapeuticallyeffective amount of a compound of formula (I) or a stereoisomer, tautomer orpharmaceutically acceptable sait, solvaté or prodrug thereof to a patient in need ofsuch treatment.

Another preferred embodiment of the présent invention provides for a method oftreating or preventing a fibrotic condition such as cystic fibrosis, pulmonary fibroticdiseases, chronic obstructive pulmonary disease (COPD), adult respiratory distresssyndrome (ARDS), fibromuscular dysplasia, fibrotic lung disease and fibrindéposition in the eye during ophthalmic surgery which comprises administering atherapeutically effective amount of a compound of formula (I) or a stereoisomer,tautomer or pharmaceutically acceptable sait, solvaté or prodrug thereof to a patientin need of such treatment.

Another preferred embodiment of the présent invention provides for a method oftreating or preventing an inflammatory disease such as asthma, arthritisr "endometriosis, inflammatory bowel diseases, psoriasis or atopie dermatitis or aneurodegenerative disease such as Alzheimer’s disease or Parkinson's diseasewhich comprises administering a therapeutically effective amount of a compound offormula (I) or a stereoisomer, tautomer or pharmaceutically acceptable sait, solvatéor prodrug thereof to a patient in need of such treatment.

Another preferred embodiment of the présent invention provides for a method oftreating or preventing conditions which benefit from maintaining or enhancing levelsof bradykinin which comprises administering a therapeutically effective amount of acompound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable 012756 31 sait, solvaté or prodrug thereof to a patient in need of such treatment.

It is to be appreciated that ali references herein to treatment include curative,palliative and prophylactic treatment. The amount of compound administered andthe frequency of administration will be determined by the attending physicien takinginto account the characteristics of the patient, such as âge, weight and State ofhealth, and the degree of inhibition of TAFIa desired. The total daily dose for atypical 70kg adult will generally be between 1 mg and 5g, preferably between 10mgand 1g, more preferably between 50mg and 750mg. The total dose may be givenas a single or divided dose.

The compounds of the présent invention may be used alone or in combination withother therapeutic agents. When used in combination with another therapeutic agentthe administration of the two agents may be simultaneous or sequential.Simultaneous administration includes the administration of a single dosage form thatcomprises both agents and the administration of the two agents in separate dosageforms at substantially the same time. Sequential administration includes theadministration of the two agents according to different schedules provided that thereis an overlap in the periods during which the treatment is provided. Suitable agentswith which the compounds of formula (I) can be co-administered includeantithrombotics, including antiplatelet agents, anticoagulants and profibrinolytics.Suitable antithrombotics include: aspirin, Plavix™, ticlopidine, warfarin (Coumadin™),unfractionated heparin, hirudin (Lepirudin™), streptokinase, urokinase, recombinanttissue plasminogen activator (tPA), dipyridamole, Reopro™, Aggrastat™, andIntegrilin™. The compounds of formula (I) can also be administered together withantihypertensive agents and with agents to treat dyslipidaemia such as statins egLipitor™. Further suitable drug classes for co-administration include Factor Xinhibitors and antiarrhythmics such as amiodarone or digoxin. Accordingly, in afurther aspect, the présent invention provides for the use of a compound of formula(I) or a stereoisomer, tautomer or pharmaceutically acceptable sait, solvaté orprodrug thereof in combination with an antithrombotic agent for the préparation of amédicament for the treatment of thrombosis. In a preferred embodiment theantithrombotic is an profibrinolytic. In a more preferred embodiment theantithrombotic is recombinant tissue plasminogen activator (tPA). 012756 32

In a further aspect, the présent invention provides for a method of treating orpreventing thrombosis, which comprises administering a therapeutically effectiveamount of a compound of formula (I) or a stereoisomer, tautomer orpharmaceutically acceptable sait, solvaté or prodrug thereof in combination with anantithrombotic to a patient in need of such treatment. In a preferred embodimentthe antithrombotic is a profibrinolytic. In a more preferred embodiment theantithrombotic is recombinant tissue plasminogen activator (tPA).

In a further aspect, the présent invention provides for a kit comprising: a) a composition comprising a compound of formula (I) or a stereoisomer,tautomer or pharmaceutically acceptable sait, solvaté or prodrug thereofas disclosed herein and a pharmaceutically acceptable diluent or carrier; b) a composition comprising an antithrombotic and a pharmaceuticallyacceptable diluent or carrier; and c) a container

The components of this kit may be administered separately, simultaneously orsequentialiy.

The présent invention also provides for the use a compound of formula (I) or astereoisomer, tautomer or pharmaceutically acceptable sait, solvaté or prodrugthereof as a coating on intravascular devices such as indweliing cathéters fordialysis, replacement heart valves or arterial stents; and as a coating on extra-corporeal blood circulation devices such as heart, lung and kidney dialysis machines,to prevent thrombosis, particularly myocardial infarction, deep vein thrombosis,stroke, young stroke, cérébral infarction, cérébral thrombosis, cérébral embolism,peripheral vascular disease, angina and other forms of acute coronary syndromes,disseminated intravascular coagulation, sepsis, pulmonary embolism, embolie eventssecondary to cardiac arrhythmias and the prévention of cardiovascular events suchas restenosis foilowing intervention surgery such as percutaneous transluminalcoronary angioplasty, grafting, stent in-placement, coronary bypass surgery or anyother forms of surgical revascularisation or intervention.

The invention provides for intravascular devices, of which the intravascular portion is 012756 33 coated with a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable sait, solvaté or prodrug thereof; and extra corporéalblood circulation devices such as heart, lung and kidney dialysis machines, wherethe portion coming into contact with the subjects blood is coated with a compound offormula (I) or a stereoisomer, tautomer or pharmaceutically acceptable sait, solvatéor prodrug thereof.

The compounds of the présent invention are TAFIa inhibitors, whose utility is basedupon preventing the reaction between a developing thrombus and TAFIa. It hasbeen found that the compounds of the présent invention are also capable of bindingto the unactivated TAFI molecule, at the site implicated in the reaction betweenTAFIa and the developing clot. The use of TAFIa inhibitors as described above interms of scope and utility, includes such TAFIa inhibitors which bind to TAFI.

The invention is further illustrated by the following, non-limiting examples.

Melting points were determined on a Gallenkamp melting point apparatus usingglass capillary tubes and are uncorrected. Unless otherwise indicated ail reactionswere carried out under a nitrogen atmosphère, using commercially availableanhydrous solvents. Ό.88 Ammonia’ refers to commercially-available aqueousammonia solution of about 0.88 spécifie gravity. Thin-layer chromatography wasperformed on glass-backed pre-coated Merck si,ica gel (60 F254) plates, and si,icagel column chromatography was carried out using 40-63//m silica gel (Merck silicageL60). Ion exchange chromatography was performed using with the spëcified ionexchange resin which had been pre-washed with deionised water. Proton NMRspectra were measured on a Varian Inova 300, Varian Inova 400, or Varian Mercury400 spectrometer in the solvents specified. ,n the NMR spectra, only non-exchangeable protons which appeared distinct from the solvent peaks are reported.Low resolution mass spectra were recorded on either a Fisons Trio 1000, usingthermospray positive ionisation, or a Finnigan Navigator, using electrospray positiveor négative ionisation. High resolution mass spectra were recorded on a BrukerApex II FT-MS using electrospray positive ionisation. Combustion analyses wereconducted by Exeter Analytical UK. Ltd., Uxbridge, Middlesex. Optical rotationswere determined at 25°C using a Perkin Elmer 341 polarimeter using the solvents 012756 34 and concentrations specified. Example compounds designated as (+) or (-) opticalisomers are assigned based on the sign of optical rotation when determined in asuitable solvent. 5 Abbreviations and Définitions Arbocel™Amberlyst® 15atm Biotage™ Filtration agent, from J. Rettenmaier &amp; Sohne, Germany Ion exchange resin, available from Aldrich Chemical CompanyPressure in atmosphères (1 atm = 760 Torr = 101.3 kPa)Chromatography performed using Flash 75 silica gel cartridge,from Biotage, UK BOC fert-Butyloxycarbonyl group br Broad c Concentration used for optical rotation measurements in g per100 ml (1 mg/ml is c0.10) cat Catalytic d Doublet dd Degussa® 101 Doublet of doublets 10 wt% palladium on activated carbon, Degussa type E101available from Aldrich Chemical Company Dowex® Ion exchange resin, from Aldrich Chemical Company ee Enantiomeric excess HRMS High Resolution Mass Spectrocopy (electrospray ionisationpositive scan) Hyflo™ liq LRMS Hyflo supercel®, from Aldrich Chemical Company liquid Low Resolution Mass Spectroscopy (electrospray or thermosprayionisation positive scan) LRMS (ES') Low Resolution Mass Spectroscopy (electrospray ionisationnégative scan) m m/z MCI™ gel Multiplet Mass spectrum peak High porous polymer, CHP20P 75-150μιη, from Mitsubishi 35 012756

Chemical Corporation psi Pounds per square inch (1 psi = 6.9 kPa) q Quartet

Rf Rétention factor on TLC s Singlet

Sep-Pak® Reverse phase C18 silica gel cartridge, Waters Corporation t Triplet TLC Thin Layer Chromatography δ Chemical shift

Example 1 (2S)-(-)-2-(2-Aminoethoxy)-3-( 1 -propyl-1 H-imidazol-4-vl)propanoic acid

A solution of the compound of Préparation 88 (437mg, 1.96mmol) in 6M hydrochloricacid (35ml) was heated at reflux for 72 hours, then allowed to cool and concentratedunder reduced pressure. The residue was dissolved in water (2ml) and the solutionwas purified by column chromatography on Dowex® 50WX8-200 ion exchange resin 10 using an elution gradient of water:0.88 ammonia (100:0 to 98:2). The productcontaining fractions were combined and evaporated under reduced pressure, andthe product was freeze-dried to afford the title compound, 456mg. 1H-NMR (CDCI3,400MHz) δ: 0.82 (t, 3H), 1.70 (m, 2H), 2.80 (m, 1H), 3.01 (m, 3H), 3.44 (m, 1H), 3.78(m, 3H), 3.89 (dd, 1 H), 6.70 (s, 1H), 7.35 (s, 1 H). LRMS: m/z (ES+) 264 [MNa4]. 15 Microanalysis found: C, 49.04; H, 8.17; N, 15.51. CnH19N3O3;1.6H2O requires C,49.04; H, 8.28; N, 15.60%. [a]o = -33.43 (c = 0.193, methanol). 012756 36

Examples 2 to 4

The following compounds of general formula

were prepared from the corresponding morpholinone compounds following the5 procedure of Example 1.

Ex R Yield (%) Data 2 37 sticky solid 'H-NMR (D2O, 400MHz) δ: 0.76 (t, 3H), 1.10 (m, 2H), 1.60 (m, 2H), 2.75 (dd, 1H), 2.82 (dd, 1H), 3.00 (m, 2H), 3.55(m, 2H), 3.62 (t, 2H), 3.90 (dd, 1H), 6.83(s, 1 H), 7.48 (s, 1 H). LRMS: m/z (TSP+)256.2 [MH4]. Microanalysis found: C,53.59; H, 8.35; N, 15.57. Οΐ2Η2ΐΝ3Ο3;0.75Η2Ο requires C, 53.62; H, 8.44; N, 15.63%. 3 48 sticky gum ’H-NMR (D2O, 300MHz) δ: 0.82 (m, 2H), 1.05 (m, 4Η), 1.57 (m, 7H), 2.77-2.97 (m,2Η), 3.05 (m, 2Η), 3.59 (m, 2H), 3.95 (m,3Η), 6.94 (s, 1H), 7.59 (s, 1H). LRMS:m/z (ES4) 310 [MH4]. " 4 or" 61 1H-NMR (CDCI3, 400MHz) δ: 2.80 (dd, 1H), 2.99 (m, 5Η), 3.42 (m, 1H), 3.80 (m,1H), 3.92 (m, 1H), 4.02 (t, 2H), 6.64 (s, 1H), 7.01 (d, 2H), 7.20 (m, 4H). LRMS:m/z (ES4) 304 [MH4]. Microanalysisfound: C, 58.93; H, 7.17; N, 12.82. Ci6H2iN3O3;1.27H2O requires C, 58.91; H, 7.27; N, 12.88%. 37 012758

Example 5 (2SI-(-)-2-(2-Aminoethoxv)-3-f 1 -(2-cvclohexvlethvl)-1 Wmidazpl-4-vnpropanoic acid

A solution of the compound of Préparation 133 (72mg, 0.25mmol) in concentratedhydrochloric acid (5ml) was heated at 110°C for 18 hours, then allowed to cool andconcentrated under reduced pressure. The residue was dissolved in water and thesolution was purified by column chromatography on Dowex® 50WX8-200 ionexchange resin using an elution gradient of water.0.88 ammonia:methanol (95:5:0 to90:5:5). The product was dissolved in water (5ml) and freeze-dried to afford the titlecompound as a sticky gum, 45mg. 1H-NMR (CD3OD, 400MHz) δ: 0.99 (m, 2H), 1.21(m, 4H), 1.61-1.78 (m, 7H), 2.86 (dd, 1H), 3.02 (m, 3H), 3.58-3.70 (m, 2H), 3.98 (m,3H), 6.93 (s, 1H), 7.50 (s, 1H). LRMS: m/z (ES+) 310 [MH*]. Microanalysis found:C, 59.56; H, 8.76; N, 12.91. C16H27N3O3;0.75H2O requires C, 59.51; H, 8.90; N, 13.01 %. [a]D ~ -23.34 (c = 0.102, methanol).

Example 6

The title compound was obtained as a fawn solid in 87% yield from the morpholinoneof Préparation 104, following the procedure of Example 5. 1H-NMR (D20,400MHz)δ: 2.88 (dd, 1H), 3.00 (dd, 1H), 3.10 (t, 2H), 3.62 (t, 2H), 4.02 (m, 1 H), 7.30 (s, 1H),7.39 (m, 1H), 7.45 (m, 4H), 7.98 (s, 1H). LRMS: m/z (ES*) 298 [MNa*].

Microanalysis found: C, 59.15; H, 6.39; N, 14.71. Ci4H17N3O3;0.5H2O requires C,59.14; H, 6.38; N, 14.78%. [<xJD = -16.8 (c = 0.10, methanol).

Example 7 (2S)-2-(2-Aminoethoxy)-3-f 1 -f3.5-bis(trifluoromethvl)phenvn-1 H-imidazol-4-yl)- 38 012756

The title compound was obtained as a white solid in 45% yield from themorpholinone of Préparation 106, following the procedure of Example 5. 1H-NMR 5 (CD3OD, 400MHz) δ: 3.00-3.18 (m, 3H), 3.65 (m, 1 H), 3.75 (m, 1 H), 4.04 (m, 2H),7.58 (s, 1H), 7.98 (s, 1H), 8.22 (s, 2H), 8.30 (s, 1H). LRMS: m/z (ES) 410 [M-H'].Microanalysis found: C, 43.95; H, 3.79; N, 9.99. C16Hi5FeN3O3;1.25H2O requires C,44.30; H, 4.07; N, 9.69%. 10 Example 8 (2ffS)-2-r(2-(Methvlamino)ethoxvl-3-(1 -propyl-1 H-imidazol-4-yl)propanoic acid

The title compound was obtained from the morpholinone of Préparation 51, followingthe procedure of Example 1. ’H-NMR (D2O, 400MHz) δ: 0.70 (t, 3H), 1.62 (m, 2H), 15 2.56 (s, 3H), 2.76 (dd, 1 H), 2.84 (dd, 1 H), 3.05 (m, 2H), 3.53-3.63 (m, 2H), 3.80 (t,2H), 3.94 (dd, 1H), 6.84 (s, 1H), 7.50 (s, 1H). LRMS: m/z (TSP+) 256.2 [MH*].

Example 9 (2/?S)-2-lï2-(Dimethvlamino)ethoxv1-3-( 1 -propyl-1 H-imidazol-4-yl)propanoic acid

A solution of the protected acid of Préparation 142 (200mg, 0.62mmol) intrifluoroacetic acid (5ml) and dichloromethane (5ml) was stirred at room températurefor 18 hours, then concentrated under reduced pressure. The residue was 012756 39 dissolved in water and the solution was purified by column chromatography onDowex® 50WX8-200 ion exchange resin using water:0.88 ammonia (96:4) as eluant.The product containing fractions were concentrated under reduced pressure and theresidue was dissolved in water and freeze-dried to afford the title compound as a 5 sticky gum, 100mg. 1H-NMR (D2O,400MHz) δ: 0.66 (t, 3H), 1.60 (m, 2H), 2.60-2.78(m, 7H), 2.82 (dd, 1H), 3.14 (m, 2H), 3.57 (m, 1H), 3.61 (m, 1H), 3.78 (t, 2H), 3.92(m, 1 H), 6.82 (s, 1 H), 7.48 (s, 1 H). LRMS: m/z (TSP+) 270.2 [MH*]. Microanalysisfound: C, 54.41; H, 8.72; N, 14.58. Ci3H23N3O3;H2O requires C, 54.34; H, 8.77; N,14.62%. 10

Example 10 (2RS)-3-( 1 -Fropyl-1 Wmidazol-4-vl)-2-f(3ffl-Pvrrolidin-3-vloxvlpropanoic acid

Concentrated hydrochloric acid (3ml) was added to a solution of the protected amino 15 acid of Préparation 143 (232mg, O.55mmol) in dioxan (2ml), and the mixture wasstirred at room température for 18 hours, then concentrated under reduced pressure.The residue was dissolved in water (1ml) and the solution was purified by columnchromatography on Dowex® 50WX8-2Q0 ion exchange resin using an elutiongradient of water:0.88 ammonia (100:0 to 98:2). The product was freeze-dried to 20 afford the title compound as a white solid, 67mg. 1H-NMR (D20,400MHz) (mixtureof diastereoisomers) δ: 0.72 (m, 3H), 1.63 (m, 2H), 1.80,1.98,2.08 (3xm, 2H), 2,65,2.84 (2xm, 3H), 3.03-3.38 (m, 3H), 3.81 (m, 2H), 3.94 (m, 1H), 4.14 (m, 1H), 6.89(m, 1 H), 7.53 (m, 1 H). LRMS: m/z (ES+) 290 [MNa+], 012756 40

Example 11 i2ffS)-2-(2-Aminoethoxv)-3-f1-i2"f4l-ethviri .r-biphenvl1-4-vl)ethvlÎ-1 H-imidazol-4-vll· propanoic acid

5 A mixture of the compound of Préparation 121 (170mg, 0.43mmol) and concentratedhydrochloric acid (2ml) was heated at 110°C for 18 hours, then allowed to cool andconcentrated under reduced pressure. The residue was azeotroped with éthanol,methanol and dichloromethane, then purified by column chromatography on Dowex®50WX8-200 ion exchange resin using an elution gradient of water:0.88 ammonia 10 (100:0 to 98:2) to afford the title compound, 15mg. 1H-NMR (CD3OD, 400MHz) δ: 1.22 (t, 3H), 2.62 (q, 2H), 2.82 (m, 1H), 2.98 (m, 3H), 3.02 (t, 2H), 3.50-3.62 (m, 2H), 3.90 (m, 1 H), 4.18 (t, 2H), 6.86 (s, 1H), 7.14 (d, 2H), 7.20 (d, 2H), 7.30 (s, 1H), 7.43(m, 4H). Microanalysis found: C, 64.05; H, 6.99; N, 9.35. C25H29N3O3;2.7H2Orequires C, 64.28; H, 7.21; N, 8.99%. 15

Examples 12 to 14

The following compounds of general formula

were prepared from the corresponding morpholinones following the procedure of20 Example 11. 012756 41

Ex R Yield (%) Data 12 35 whïte solid 1H-NMR (CD3OD, 400MHz) δ: 2.15 (m, 2H), 2.62 (t, 2H), 2.90 (dd, 1H), 3.02 (m,3H), 3.60 (m, 1H), 3.66 (m, 1H), 3.98 (m,3H), 6.96 (s, 1H), 7.25 (m, 3H), 7.40 (m,2H), 7.54 (m, 3H), 7.58 (d, 2H). LRMS:m/z (ES') 392 [M-H'J. 13 H3C 17 white foam 1H-NMR (CD3OD, 400MHz) Ô: 2.09 (m, 2H), 2.34 (s, 3H), 2.59 (m, 2H), 2.86 (m,1H), 3.00 (m, 3H), 3.60 (m, 2H), 3.97 (m,3H), 6.96 (s, 1H), 7.19 (m, 4H), 7.40-7.60(m, 5H). LRMS: m/z (ES*) 430 [MNa*]. 14 21 yeliow solid 'H-NMR (CD3OD, 400MHz) δ: 2.18 (m, 2H), 2.78 (t, 2H), 2.88 (dd, 1H), 3.02 (m,3H), 3.58-3.72 (m, 2H), 3.97 (m, 3H), 6.95 (s, 1H), 7.40 (m, 2H), 7.50 (s, 1H),7.60 (s, 1H), 7.78 (m, 3H). LRMS: m/z(ES') 366 [M-H'J.

Example 15 ' (25k2-ff ( 1 /7)-2-Amino-1 -methvleth νΠοχν)-3-Γ 1 -(2-cvclohexylethvl)-1 H-imiàazol-4-νΠ- propanoic acid

The title compound was obtained in 45% yield from the morpholinone of Préparation92, following the procedure of Example 11. 1H-NMR (CD3OD, 400MHz) 5:0.94 (m,4H), 1.18 (m, 4H), 1.59-1.76 (m, 7H), 2.72 (m, 2H), 2.96 (m, 1H), 3.03 (m, 1H), 3.26(m, 1 H), 3.55 (m, 1H), 3.98 (m, 3H), 6.88 (s, 1H), 7.48 (s, 1H). LRMS: m/z (ES+) 42 012756 324 [MNa*]. Microanalysis found: C, 58.97; H, 9.01 ; N, 11.85. C17H29N3O3;1 .2H2Orequires C, 59.18; H, 9.17; N, 12.18%.

Example 16

A solution of the compound of Préparation 99 (70mg, 0.27mmol) in concentratedhydrochloric acid (2ml) was heated at 110°C for 18 hours, then allowed to cool andconcentrated under reduced pressure. The residue was azeotroped with water,then purified by column chromatography on Dowex® 50WX8-200 ion exchange resinusing water:0.88 ammonia (95:5) as eluant to afford the title compound as a paleyellow solid, 50mg. 1H-NMR (CD3OD, 400MHz) δ: 2.93-3.14 (m, 3H), 3.24 (m, 1 H),3.59-3.73 (m, 2H), 4.00 (m, 1 H), 7.35 (m, 2H), 7.45 (m, 4H), 7.98 (s, 1 H). LRMS:m/z (ES+) 298 [MNa4].

Example 17 (2S)-2-ff(1 fî)-2-Amino-1 -methvlethvnoxv)-3-(1 -phenyl-1 H-imidazol-4-yl)propanoic

The title compound was obtained in 75% yield from the morpholinone of Préparation109, following the procedure of Example 16, except that an elution gradient ofmethanol:water:0.88 ammonia (20:80:5 to 30:65:5) was used for the ion exchangechromatography. 1H-NMR (D2O, 400MHz) δ: 0.90 (d, 3H), 2.80 (m, 2H), 3.00 (m,2K), 3.59 (m, 1H), 4.14 (dd, 1H), 7.26 (s, 1H), 7.37 (m, 1H), 7.42 (m, 4H), 7.96 (s,1H). LRMS: m/z (ES ) 288 [M-H‘]. Microanalysis found: C, 58.76; H, 6.72; N, 13.37. C15H19N3O3;H2O requires C, 58.63; H, 6.89; N, 13.67%. [a]D = -83.0 (c =0.1, methanol). 012756 43

Example 18 (251-2-(1/1 ffl-2-Amino-t -methvlethvl1oxv)-3-f 1 -(3'.4'-dichlorof 1.1 '-biphenvll-3-νΠ-Ι H-

The title compound was obtained as a white foam from the morpholinone ofPréparation 115, following the procedure of Example 17, except that an elutiongradient of water:methanol:0.88 ammonia (75:20:5 to 15:80:5) was used for the ionexchange chromatography. 1H-NMR (CD3OD, 400MHz) δ: 1.00 (d, 3H), 2.77 (dd, 10 1H), 2.92 (m, 2H), 3.15 (dd, 1H), 3.59 (m, 1H), 4.10 (m, 1H), 7.42 (s, 1H), 7.50-7.627(m, 5H), 7.78 (s, 1H), 7.86 (s, 1H), 8.10 (s, 1H). LRMS: m/z (ES*) 434, 436 [MH*].

Example 19 (25)-2-(i(1R)-2-Amino-1-methvlethvnoxv)-3-F1-(4-phenoxvphenvl)-1H-imidazol-4-vl1-

A solution of the morpholinone of Préparation 111 (130mg, 0.36mmol) inconcentrated hydrochloric acid (10ml) was heated at 1102C for 18 hours, thenallowed to cool and concentrated under reduced pressure. The residue was purified 20 by column chromatography on Dowex® 50WX8-200 ion exchange resin usingwater:methanol:0.88 ammonia (70:30:5) as eluant. The product was dissolved inwater and freeze-dried to afford the title compound as an off-white powder, 70mg.’H-NMR (CD3OD, 400MHz) δ: 1.00 (d, 3H), 2.78 (dd, 1H), 2.86-3.00 (m, 2H), 3.17(dd, 1H), 3.60 (m, 1 H), 4.15 (dd, 1H), 7.02 (d, 2H), 7.08 (d, 2H), 7.17 (m, 1H), 7.30 012756 44 (s, 1H), 7.39 (m, 2H), 7.50 (d, 2H), 7.95 (s, 1H). LRMS: m/z (ES*) 404 [MNa-1].Microanalysis found: C, 62.70; H, 6.22; N, 10.30. C2iH23N3O4;1.2H2O requires C,62.58; H, 6.35; N, 10.43%. [cc]D = -50.9 (c = 0.117, methanol). 5 Examples 20 to 31

The following compounds of general formula

were prepared by heating a solution of the corresponding morpholinone (0.2 to0.4mmol) in concentrated hydrochloric acid (2ml) at reflux for 18 hours, concentrating 10 the cooled solution, and azeotroping the residue with éthanol, ethyl acetate anddichloromethane.

Ex R Y Data 20 /CH3 q -(CH2)2- ’H-NMR (CD3OD, 400MHz) δ: 1.22 (d, 6H), 2.90 (m, 1H), 3.10-3.22 (m, 6H),3.78 (m, 2H), 4.36 (m, 1H), 4.45 (t, 2H),7.18 (d, 2H), 7.24 (d, 2H), 7.44 (m, 3H),7.52 (d, 2H), 8.62 (s, 1H). Microanalysis found: C, 56.65; H, 7.03; N, 7.92. C25H3iN3O4;2HCI;2H2O_ - requires C, 56.60; H, 7.03; N, 7.92%. 21 y -(CH2)2- 1H-NMR (CD3OD, 400MHz) δ: 3.18 (m, 5H), 3.78 (m, 3H), 4.15-4.38 (m, 1H),4.44 (m, 2H), 7.21 (m, 3H), 7.50 (m, 4H), 7.63 (m, 1H), 8.58-8.65 (m, 1H).LRMS: m/z (ES*) 432, 434 [MH*]. 012756 45

Ex R Y Data 22 RC -(CH2)2- 1H-NMR (CD3OD, 400MHz) δ: 3.10- 3.30 (m, 4H), 3.78 (m, 4H), 4.30 (m, 1H), 4.46 (m, 2H), 7.24 (m, 2H), 7.50(m, 1H), 7.60 (m, 2H), 7.74 (m, 4H), 8.62 (m, 1H). Microanalysis found: C, 50.27; H, 5.39; N, 7.34. C23H24F3- N3O3;2HCI;1.7H2O requires C, 50.14; H, 5.38; N, 7.63%. 23 F3C A -(CH2)2- 1H-NMR (CD3OD, 400MHz) δ: 3.18 (m, 3H), 3.21 (m, 2H), 3.76 (m, 0.5H), 3.80(m, 2H), 4.20 (m, 0.5H), 4.32 (m, 1H),4.48 (m, 2H), 7.20 (m, 4H), 7.30 (d, 1H), 7.50 (m, 2H), 7.60 (m, 1H), 7.76(m, 1H), 8.60 (m, 1H). HRMS: m/z(ES*) 448.1842 [MH*]. 24 -(CH2)2- 1H-NMR (CD3OD, 400MHz) δ: 3.18 (m, 2H), 3.20 (m, 2H), 3.74 (m, 1 H), 3.80(m, 2H), 4.20 (m, 1H), 4.35 (m, 1H), 4.48 (t, 2H), 7.21 (m, 2H), 7.26-7.40(m, 4H), 7.48 (m, 1H), 7.52 (m, 1H),8.59-8.65 (m, 1 H). Microanalysisfound: C, 50.18; H, 5.15; N, 7.32. C22H23Cl2N3O3;2HCI;H2O requires C, 50.02; H, 5.11; N, 7.61%. 25 H_C ch3 MeO * -(CH2)2- ^-NMR (CD3OD, 400MHz) δ: 1.20 (m, 6H), 2.81 (m, 1H), 3.17 (m, 6H), 3.70(m, 2H), 3.78 (m, 2H), 4.18 (m, 1H), 4.30 (m, 1H), 4.46 (m, 2H), 6.78-7.16(m, 5H), 7.39 (d, 1H), 7.44 (m, 2H), 8.60 (m, 1H). 012756 46

Ex R r Y Data 26 "K -(CH2)2- fH-NMR (CDgOD, 400MHz) δ: 3.17 (m, 4H), 3.78 (m, 3H), 4.18 (m, 1H), 4.30(m, 1H), 4.45 (m, 2H), 7.20 (m, 2H), 7.40 (m, 2H), 7.56 (m, 5H), 8.61 (m, 1 H). Microanalysis found: C, 52.64; H, 5.82; N, 7.91. CazH^CINaOaÆHChhfeO requires C, 52.34; H, 5.59; N, 8.32%. 27 HA ,CH3 -(CH2)2- 1H-NMR (CD3OD, 400MHz) δ: 2.24 (d, 6H), 3.07-3.22 (m, 5H), 3.77 (m, 3H),4.30 (m, 1H), 4.42 (m, 2H), 7.23 (d, 1H), 7.30 (s, 1H), 7.45 (m, 3H), 8.60(2xs, 1 H). Microanalysis found: C, 57.44; H, 6.74; N, 8.02. CW-fegNaCb;-2HCI;1;3H2O requires C, 57.21; H, 6.72; N, 8.34%. 28 « h3c λ -(CH2)2- ’H-NMR (CD3OD, 400MHz) δ: 3.12- 3.23 (m, 8H), 3.75 (m, 1H), 3.80 (m, 2H), 4.32 (m, 1H), 4.45 (m, 2H), 6.90(m, 1H), 6.99 (m, 1H), 7.10 (m, 1H), 7.19 (m, 4H), 7.50 (s, 1H), 8.61 (m, 1 H). Microanalysis found: C, 54.72; H, 6.14; N, 7.96. CjaHzeFNaOa^HCI;- 1.2H2O requires C, 54.59; H, 6.06/N, 8.30%. 29 HgC-^ Λ "(CH2)2- 1H-NMR (CD3OD, 400MHz) δ: 1.00 (t, 3H), 2.56 (q, 2H), 3.19 (m, 5H), 3.80(m, 2H), 4.19 (m, 1H), 4.30 (m, 1H), 4.46 (m, 2H), 7.04 (d, 1H), 7.19 (m, 7H), 7.50 (m, 1H), 8.62 (2xs, 1H) 012756 47

Ex R Y Data 30 -(CH2)3- VNMR (CD3OD, 400MHz) Ô: 2.23 (m, 2H), 2.70 (t, 2H), 3.17 (m, 3H), 3.21 (m, 1 H), 3.80 (t, 2H), 4,22 (m, 2H), 4.30 (m,1H), 7.25 (m, 2H), 7.40 (d, 2H), 7.48-7.64 (m, 5H0, 8.62 (m, 1H). Microanalysis found: C, 51.77; H, 5.72; N, 7.61. C23H26CIN3O3;2HCI;2H2Orequires C, 51.46; H, 6.01; N, 7.83%. 31 3 -(CH2)3- 'H-NMR (CD3OD, 400MHz) δ: 2.23 (m, 2H), 2.74 (m, 2H), 3.17 (m, 4H), 3.80(m, 2H), 4.22 (m, 3H), 7.05 (m, 1H), 7.18 (m, 2H), 7.29 (m, 2H), 7.44 (m, 2H), 7.58-7.70 (m, 1H), 8.82 (s, 1H).Microanalysis found: C, 50.15; H, 5.38; N, 7.39. CaaHssFzNaOa^HCI^.SHaOrequires C, 50.46; H, 5.89; N, 7.68%.

Example 32 (2fîS)-2-(2-Aminoethoxy)-3-ri-(3-f1.1 ‘-biphenvn-3-ylpropvl)-l /7-imidazol-4-vP- propanoic acid dihvdrochloride

The title compound was obtained as an off-white foam from the compound ofPréparation 145, following the procedure of Example 20. 1H-NMR (CD3OD,400MHz) δ: 2.25 (m, 2H), 2.75 (m, 2H), 3.14 (m, 2H), 3.27 (m, 1 H), 3.74 (m, 1 H), 3.78 (m, 2H), 4.22 (m, 3H), 7.18 (m, 1H), 7.25-7.42 (m, 6H), 7.45 (s, 1H), 7.58 (d, 10 2H), 8.80 (s, 1H). LRMS: m/z (ES*) 394 [MH4]. Microanalysis found: C, 54.03; H,6.73; N, 8.09. C23H27N3O3;2HCI;2.4H2O requires C, 54.21 ; H, 6.68; N, 8.24%. 012756 48

Example 33 (2f?S)-2-(2-Aminoethoxv)-3-f1-(3-f1.r-biphenvn-2-vlpropyl)-1 H-imidazol-4-νΠ- propanoic acid dihvdrochloride

5 The tïtle compound was obtained as an off-white foam in 30% yield from thecompound of Préparation 146, following the procedure of Example 20. 1H-NMR(CD3OD, 400MHz) 8; 1.96 (m, 2H), 2.60 (t, 2H), 3.05-3.23 (m, 4H), 3.79 (m, 2H), 4.02 (t, 2H), 4.48 (m, 1H), 7.14 (d, 1H), 7.19-7.30 (m, 6H), 7.36 (m, 3H), 8.62 (s, 1H).Microanalysis found: C, 54.89; H, 6.24; N, 8.35. 023Η27Ν303;2ΗΟ;2Η2Ο requires C, 10 54.98; H, 6.62; N, 8.36%.

Example 34 (25)-2-{ί(251-ΑπΊίηορΓθρνΠοχνΐ-3-Γ1-(2-ονοΙοΐΊ8χνΙβ1ΐΊνΟ-1Η-ΐΓηΐά3ζοΙ-4-νΠρΓορ3ηοΐο

The title compound was obtained in 64% yield from the morpholinone of Préparation95, following the procedure of Example 20. 1H-NMR (CD3OD, 400MHz) δ: 0.80-1.32(m, 9H), 1.60-1.80 (m, 7H), 3.20 (m, 1H), 3.57 (m, 3H), 3.80 (m, 1H), 4.20 (m, 2H), 4.35 (m, 1 H), 7.48 (s, 1 H), 8.86 (s, 1 H). HRMS: m/z (ESI) 324.2280 [MH+], 20 012756 49

Example 35 (2ffl-2-ff(2R)-Aminopropvlloxv)-3T1-(2-cvclohexvlethvn-1 H-imidazol-4-yllpropanoic

5 The title eompound was obtained from the morpholinone of Préparation 96, followingthe procedure of Example 20. ^-NMR (CD3OD, 400MHz) δ: 0.80-1.32 (m, 9H), 1.60-1.80 (m, 7H), 3.20 (m, 1H), 3.57 (m, 3H), 3.80 (m, 1H), 4.20 (m, 2H), 4.35 (m, 1 H), 7.48 (s, 1 H), 8.86 (s, 1 H). HRMS: m/z (ESI) 324.2275 [MH4]. 10 Example 36 (2fîS)-2-(2-Aminoethoxv)-3-n -(2-methvlphenvn-l Wmidazol-4-vnpropanoic acid

A solution of the morpholinone of Préparation 100 (100mg, 0.37mmol) in15 concentrated hydrochloric acid (2ml) was heated at 110°C for 36 hours, then cooled and. concentrated under reduced pressure. The residue was azeotroped wfthmethanol and dichloromethane to afford the title eompound. 1H-NMR (CD3OD,400MHz) 8: 2.10 (s, 3H), 3.19 (m, 2H), 3.26 (m, 1H), 3.39 (m, 1H), 3.82 (t, 2H), 4.42(m, 1H), 7.40 (m, 2H), 7.46 (m, 2H), 7.62 (s, 1H), 9.14 (s, 1H). HRMS: m/z 20 290.1502 [MH4]. 012756 50

Example 37 (2ffl-2-flï1 S)-2-Amino-1 -methvlethvnoxv1-3-n-(2-cyclohexvlethvn-l H-irnidazol-4-νΠ- propanoic acid dihvdrochloride

5 The title compound was obtained from the morpholinone of Préparation 91, followingthe procedure of Example 20. 1H-NMR (CD3OD, 400MHz) δ: 1.01 (m, 5H), 1,21 (m,4H), 1.74 (m, 7H), 2.93-3.14 (m, 3H), 3.25 (m. 1H), 3.79 (m, 1H), 4.21 (t, 2H), 4.38(m. 1 H), 7.55 (s, 1 H), 8.90 (s, 1 H). LRMS: m/z (ES') 322 [M-H']. Microanalysisfound: C. 47.73; H, 7.85; N, 9.66. C17H28N3O3;2HCI;1.6H2O requires C. 48.02; H. 10 8.11; N, 9.88%.

Example 38 f2S1-2-fi(1ffl-2-Amino-1-methvlethynoxv1-3-f1-f2-f4.4-dimethvlcyclohexvl)ethvn-l/7- imidazol-4-vnpropanoic acid dihvdrochloride

The title compound was obtained in 83% yield from the morpholinone of Préparation93ffollowing the procedure of Example 20. 1H-NMR (CD3OD, 400MHz) 5.-0:88 (s,6H). 1.04 (d, 3H), 1.17-1.34 (m, 5H). 1.40 (m, 2H), 1.60 (m, 2H), 2.97-3.18 (m, 3H), 3.30 (m, 1H). 3.81 (m, 1 H), 4.24 (m, 2H), 4.40 (m, 1H), 7.58 (s, 1H), 8.94 (s, 1H). 20 HRMS: m/z (ES4) 374.2484 [MNa4]. 012756 51

Example 39 (2S)-2-(fi1 fl)-2-Amino-1-methviethvl1oxv)-3-ri-(3-cvclohexvl-3-methvlt)utvl)-1H- imidazol-4-vnpropanoic acid dihvdrochloride

5 The title compound was obtained from the morpholinone of Préparation 94, followingthe procedure of Example 20. 1H-NMR (CD3OD, 400MHz) δ: 0.94 (s, 6H), 0.98-1.30(m, 10H), 1.62 (m, 1H), 1.78 (m, 6H), 2.90-3.15 (m, 3H), 3.78 (m, 1H), 4.20 (m, 2H),4.38 (m, 1 H), 7.52 (s, 1 H), 8.90 (s, 1 H). LRMS: m/z (ES+) 366 [MH*]. 10 Example 40 2-(2-Aminoethoxy)-3-f1 -(3-phenoxvphenvB-t B-imidazol-4-vHpropanoic acid dihvdrochloride

A solution of the morpholinone of Préparation 102 (25mg, 0.07mmol) in concentrated15 hydrochloric acid (5ml) was heated at 110°C for 18 hours, then cooled and concentrated under reduced pressure. The residue was dissolved in water andfreeze-dried to afford the title compound as a fawn solid, 35mg. 1H-NMR (D2O,400MHz) δ: 3.04 (m, 3H), 3.18 (dd, 1H), 3.63 (t, 2H), 4.19 (m, 1H), 6.98 (d, 2H), 7.06(m, 3H), 7.19 (d, 1H), 7.46 (dd, 2H), 7.50 (dd, 1H), 7.54 (s, 1H), 8.87 (s, 1H). 20 LRMS: m/z (ES*) 368 [MH*]. 012756 52

Examples 41 to 44

The following compounds of general formula

were prepared from the corresponding morpholinones following the procedure of5 Example 40

Ex R Data 41 w ’H-NMR (D2O, 400MHz) δ: 3.01-3.20 (m, 4H), 3.65 (m, 2H), 4.21 (m, 1H), 7.10 (m, 2H), 7.25(s, 1H), 7.32 (m, 3H), 7.54 (m, 3H), 7.61 (m, 1 H), 8.59 (s, 1 H). LRMS: m/z (ES*) 352[MH*]; 374 [MNa*]. 42 1H-NMR (D2O, 400MHz) Ô: 3.Î8-3.35 (m, 4H), 3.80 (t, 2H), 4.30 (dd, 1H), 7.60 (m, 3H), 7.77(s, 1H), 7.98 (m, 2H), 8.04 (m, 2H), 9.06 (s, 1 H). LRMS: m/z (ES+) 348 [MNa*].Microanalysis found: C, 49.16; H, 5.60; N, 9.54. Ci8Hi9N3O3;2HCl;2.3H2O requires C, 49.18; H, 5.65; N, 9.58%. 43 P Cl ^H-NMR (D2O, 400MHz) δ: 3.17-3.35 (m, 4H), 3.79 (m, 2Η), 4.30 (m, 1 H), 7.40 (m, 2H), 7.52(m, 2H), 7.60 (m, 2H), 7.70 (m, 3H), 9.027s, 1 H). LRMS: m/z (ES+) 386 [MH4]. 44 (y Cl Cl ^H-NMR (D2O, 400MHz) δ: 3.20-3.35 (m, 4H), 3.80 (m, 2H), 4.30 (t, 1H), 7.42-7.75 (m, 8H),9.05 (s, 1H). LRMS: m/z (ES+) 420, 422[MH*]. 012756 53

Example 45 (2S)-(-)-2-(2-Aminoethoxv)-3-i1 -(4-te/f-butvlphenvl)-1 /7-imidazol-4-vllpropanoic acid dihvdrochloride

5 The title compound was obtained as a fawn solid from the morpholinone of

Préparation 105, following the procedure of Example 40. 1H-NMR (D2O, 400MHz) δ:1.20 (s, 9H), 3.04-3.35 (m, 4H), 3.78 (m, 2H), 4.38 (m, 1H), 7.41 (m, 2H), 7.58 (m,2H), 7.61 (s, 1H), 8.98 (s, 1H). LRMS: m/z (ES*) 332 [MH4]. Microanalysis found:C, 49.58; H, 6.75; N, 9.84. C1BH25N3O3;2HCI;1.75H2O requires C, 49.58; H, 7.06; N, 10 9.64%. [<x]D = -2.00 (c = 0.30, methanol).

Examples 46 to 48

The following compounds of general formula

15 were prepared from the corresponding morpholinones following the procedure ofExample 40 :

Ex R Data 46 ^H-NMR (D20,400MHz) δ: 1.00 (d, 3H), 1.16- 1.42 (m, 6H), 1.64 (m, 1H), 1.78 (m, 3H), 2.59(m, 1H), 2.89-3.17 (m, 4H), 3.68 (m, 1H), 4.30(m, 1H), 7.44 (m, 4H), 7.66 (s, 1H), 8.98 (s, 1 H). LRMS: m/z (ES+) 372 [MH*]. Microanalysis found: C, 52.74; H, 7.27; N, 8.54. C2iH29N3O3;2HCI;2H2O requires C, 52.50; H, 7.34; N, 8.75%. 012756 54

Ex R Data /=\ 1H-NMR (D2O, 400MHz) δ: 0.98 (d, 3H), 2.90 M (m, 1H), 3.05 (m, 2H), 3.24 (m, 1H), 3.78 (m, 1H), 4.38 (m, 1H), 7.02 (d, 2H), 7.15 (m, 3H), 47 7.26 (d, 1H), 7.38 (m, 2H), 7.48 (m, 1H), 7.62 O (s, 1 H), 8.99 (s, 1 H). LRMS: m/z (ES4) 382 [MH4]. [a]D = -72.0 (c = 0.05, methanol) *H-NMR (D2O, 400MHz) δ: 1.01 (d, 3H0,2.98 (m, 1H), 3.15 (m, 2H), 3.29 (m, 1H), 3.79 (m, 1H), 4.37 (m, 1H), 7.40 (m, 2H), 7.58 (d, 2H), 48 7.62 (m, 2H), 7.75 (m, 3H), 9.05 (s, 1H). LRMS: m/z (TSP4) 400.2 [MH4]. y Microanalysis found: C, 47.90; H, 5.48; N, Cl 7.90. C2iH22CIN3O3;2HCI;3H2O requires C, 47.88; H, 5.74; N, 7.98%.

Example 49 (2S)-2-ff(1 ffl-2-Amino-1 -methylethvl1oxy)-3-{1 -r4-fcyclohexvloxv)phenvlM /7-imidazol- 4-vl)propanoic acid

A solution of the protected amino acid of Préparation 120 in a mixture of 2Nhydrochloric acid (1ml), water (1ml) and dioxan (1ml) was stirred at roomtempérature for 2 hours, then concentrated under reduced pressure. The residuewas dissolved in water and purified by column chromatography on Dowex® 50WX8- 10 200 ion exchange resin using water:methanol:0.88 ammonia (48:48:4) as eluant.The product was dissolved in water and freeze-dried to afford the title compound,25mg. ’H-NMR (D2O, 400MHz) δ: 0.94 (d, 3H), 1.35 (m, 4H), 1.55 (m, 3H), 1.72-2.01 (m, 3H), 2.78-2.97 (m, 2H), 3.10 (m, 2H), 3.60 (m, 1H), 4.01 (m, 1H), 4.21 (m, 1 H), 6.92 (d, 2H), 7.01 (s, 1 H), 7.20 (d, 2H), 7.62 (s, 1 H). LRMS: m/z (ES4) 388 012756 55 [MH4]. Microanalysis found: C, 59.33; H, 7.65; N, 9.80. CsiHggNsO^hfeO requiresC, 59.56; H, 7.85; N, 9.92%.

Exemple 50 (2S)‘2-(2-Aminoethoxv)-3-(1 H-imidazol-4-v))propanoic acid dihvdrochloride

A suspension of the morpholinone of Préparation 118 (90mg, 0.24mmol) and lithiumhydroxide (32mg, 1.33mmol) in a mixture of water (2ml) and tetrahydrofuran (1ml)was stirred at room température for 18 hours, then concentrated under reducedpressure. The residue was suspended in concentrated hydrochloric acid (3ml) andthe mixture was heated at 110°C for 18 hours, then cooled and concentrated underreduced pressure. The residue was triturated with acetone and the resulting solidwas collected and dried, then recrystallised from methanol/acetone to afford the titlecompound as a white solid, 12mg. 1H-NMR (CD3OD, 400MHz) Ô: 3.20 (m, 2H), 3.30(m, 2H), 3.83 (m, 2H), 4.37 (m, 0.5H), 4.41 (m, 0.5H), 7.41 (s, 1H), 8.81 (s, 1H).LRMS: m/z (ES ) 198 [M-H'].

Example 51 (2S)-24F(1 /?)-2-Amino-1-methylethvnoxv)-3-(1 H-imidazol-4-vl)propanoic acid

A solution of the morpholinone of Préparation 105 (320mg, 1.64mmol) inconcentrated hydrochloric acid (5ml) was heated at 110°C for 18 hours, then allowedto cool and diluted with water (80ml). The resulting solution was purified by columnchromatography on Dowex® 50WX8-200 ion exchange resin using an elutiongradient of water:0.88 ammonia (100:0 to 95:5). The product was dissolved in waterand freeze-dried to afford the title compound as a colourless foam, 290mg. 1H-NMR(D2O, 400MHz) δ: 0.90 (d, 3H), 2.80 (dd, 2H), 2.98 (dd, 2H), 3.57 (m, 1H), 4.04 (m, 012756 56 1 H), 6.84 (s, 1 H), 7.60 (s, 1 H). LRMS: m/z (ES+) 236 [MNa4]. Microanalysis found:C, 46.00; H, 7.41 ; N, 17.81. C9H15N3O4;1.25H2O requires C, 45.85; H, 7.48; N, 17.82%. [aÎD = -94.62 (c = 1.72, water).

Alternative svnthesis A mixture of the protected lactone of Préparation 55a (1.58g, 4.42mmol) andmethanesulphonic acid (6.5ml) was heated at 70°C for 2.5 hours. The cooledsolution was diluted with ether (40ml), the mixture was stirred, and the ether wasdecanted off. This process was repeated twice. Water was added and the mixturewas stirred vigorously then filtered. The filtrate was allowed to stand at roomtempérature for 24 hours then purified by column chromatography on Dowex®50WX8-200 ion exchange resin using water.0.88 ammonia (95:5) as eluant, and thefractions obtained were evaporated under reduced pressure (with water-bathtempérature below 33°C). The product obtained was dissolved in concentratedhydrochloric acid (5ml), and the solution was heated at 100°C for 18 hours, thencooled and diluted with water (30ml). This solution was purified by columnchromatography on Dowex® 50WX8-200 ion exchange resin using water.0.88ammonia (95:5) as eluant. The product was stirred in acetonitrile (10ml) for 1 hour,filtered and dried in vacuo for 18 hours. Microanalysis found: C, 46.58; H, 7.50; N,17.98. C9H15N3.1H2O requires C, 46.75; H, 7.41; N. 18.17%.

Example 52 . (2S)-2-(i(1 fî)-2-Amino-1-methvlethvHoxv)-3-f1 -(2-pyridinyl)-1 H-imidazol-4-νΠ- propanoic acid dihydrochloride

A solution of the morpholinone of Préparation 152 (72mg, 0.26mmol) in concentratedhydrochloric acid (3ml) was heated at 100°C for 18 hours, then allowed to cool,diluted with water, and concentrated under reduced pressure. The residue waspurified by column chromatography on Dowex® 50WX8-200 ion exchange resin 57 01 2756 using an elution gradient of water:0.88 ammonia (100:0 to 95:5). The product wasdissolved in 2N hydrochloric acid and the resulting solution was concentrated underreduced pressure. The residue was dissolved in water (10ml) and freeze-dried toafford the title compound as a solid, 58mg. 1H-NMR (D20,400MHz) (mixture of 5 imidazole regioisomers) δ: 0.79, 0.99 (2xd, 3H), 2.56, 2.92 (2xm, 1 H), 3.02-3.44 (m,3H), 3.58, 3.78 (2xm, 1K), 7.55 (m, 1H), 7.71 (m, 1H), 7.96-8.19 (m, 2H), 8.52, 8.61(2xm, 1 H), 9.03, 9.38 (2xs, 1 H). LRMS: m/z (ES+) 291 [MH+].

Example 53 10 (2S)-2-(i(1/:?)-2-Amino-1-methvlethvlloxv)-3-(1-propvl-1/-/-imidazol-4-v0propanoic acid

A solution of the compound of Préparation 157 (560mg, 2.36mmol) in concentratedhydrochloric acid (10ml) was stirred at 110°C for 18 hours. The cooled solution wasconcentrated under reduced pressure and the residue was purified by column 15 chromatography on ion-exchange resin (Dowex® 50WX8-200) using an elutiongradient of water:0.88 ammonia (100:0 to 95:5) to afford the title compound as afoam, 350mg. 1H-NMR (D20,400MHz) δ: 0.66 (t, 3H), 0.81 (d, 3H), 1.60 (m, 2H), 2.60-2.78 (m, 2H), 2.80-2.98 (m, 2H), 3.45 (m, 1H), 3.78 (t, 2H), 3.98 (dd, 1H), 6.82(s, 1 H), 7.43 (s, 1 H). LRMS: m/z (ES*) 278 [MNa4]. Microanalysis found: C, 53.44; 20 H, 8.13; N, 15.40 Ci2H21N3O3;0.8H2O requires C, 53.44; H, 8.45; N, 15.58%. [aJD =-86.93° (c = 0.11, methanol) 012756 58

Example 54 (2fî)-2-(f(1 R)-2-Amino-1-methvlethvnoxvl-3-f1 Wmidazol-4-yl)propanoic acid

A mixture of the lactam of Préparation 158 (80mg, 0.50mmol) and 2N hydrochloricacid (2ml) was heated at 110°C for 16 hours, then allowed to cool and diluted withwater (10ml). This solution was purified by column chromatography on Dowex®50WX8 resin, using water:0.88 ammonia (95:5) as eluant. The product wastriturated with acetone and the resulting solid was dried in vacuo to afford the titlecompound as a brown solid, 68mg. 1H-NMR (D20,400MHz) δ: 1.00 (d, 3H), 2.76(dd, 2H), 2.83 (m, 2H), 3.60 (m, 1H), 3.86 (m, 1K), 6.79 (s, 1H), 7.57 (s, 1H).

Préparation 1 1 -n-Propyl-1 H-imidazole-4-carboxaldehvde

lmidazole-4-carboxaldehyde (30g, 0.31 mol) was added portionwise to a solution ofsodium hydride (13.9g, 60% dispersion in minerai oil, 0.348mol) in tetrahydrofuran(450ml), and the solution was stirred for 45 minutes. n-Propyl bromide (3.1.2ml,0.344mol) was then added portionwise, foliowed by 18-crown-6 (150mg), and themixture was heated under reflux for 18 hours. Aqueous ammonium chloridesolution was added to the cooled solution, and the mixture was extracted with ethylacetate (2x) and dichloromethane (2x). The combined organic extracts were dried(MgSO4), filtered, and concentrated under reduced pressure. The crude productwas purified by column chromatography on silica gel, eluting with ethyl acetate:pentane (40:60), to give the title compound, 20.2g, 47% yield. 1H-NMR (DMSO-d6,400MHz) δ : 0.80 (t, 3H), 1.76 (m, 2H), 3.98 (t, 2H), 7.84 (s, 1H), 8.04 (s, 1H), 9.70(s, 1H). LRMS: m/z (TSP+) 277.3 [2M+H]+ 012756 59

Préparation 2 1 -n-Butvl-1 /-/-imidazole-4-carboxaldehvde

The title compound was obtained in 28% yield from imidazole-4-carboxaldehyde andn-butyl bromide, following a similar procedure to that described in Préparation 1.1H-NMR (CDCI3, 300MHz) δ: 0.97 (t, 3H), 1.37 (m, 2H), 1.80 (m, 2H), 4.00 (t, 2H),7.55 (s, 1H), 7.62 (s, 1 H), 9.88 (s, 1H). LRMS: m/z (TSP+) 153.3 [MH*].

Préparation 3 1 -(2-Cyclohexviethvl)-1 H-imidazole-4-carboxaldehyde

lmidazoie-4-carboxaldehyde (4.8g, 50mmol) was added portionwise to a suspensionof sodium hydride (2.20g, 60% dispersion in minerai oii, 55mmol) in tetrahydrofuran(150ml), and the mixture was then stirred at room température for 1 hour. 2-Cyclohexylethyl bromide (8.6mi, 55mmol) was added, and the mixture was heatedunder reflux for 18 hours. The cooled mixture was evaporated under reducedpressure and the residue was partitioned between water (500ml) and dichloromethane (500ml). The layers were separated, and the organic phase wasdried (MgSO4) and evaporated under reduced pressure. The crude prodûct waspurified by column chromatography on silica gel using an elution gradient oftoluene'.ethy, acetate (100:0 to 96:4) to afford the title compound, 1.78g. 1H-NMR(CDCI3, 400MHz) δ: 0.98 (m, 2H), 1.20 (m, 4H), 1.68 (m, 7H), 4.00 (t, 2H), 7.4 (s, 1 H), 7.60 (s, 1 H), 9.80 (s, 1 H). LRMS: m/z (TSP+) 207.2 [MH*].

Préparation 4 1 -(2-Phenylethvl)-1 H-imidazole-4-carboxaldehyde

__ /=N 012756 60 lmidazole-4-carboxaldehyde (6.73g, 70mmol) was added portionwise to asuspension of sodium hydride (1.68g, 60% dispersion in minerai oil, 70mmol) intetrahydrofuran (280ml), and the mixture was then stirred at room température for 30minutes. (2-Bromoethyi)benzene (9.56ml, 70mmoi) was added, and the mixturewas stirred at room température for 72 hours. The mixture was evaporated underreduced pressure and the residue was partitioned between water (300ml) anddichloromethane (500ml), and the layers were separated. The organic phase wasdried (MgSO4) and evaporated under reduced pressure. The crude product waspre-adsorbed onto silica gel, and purified by column chromatography on silica gelusing an elution gradient of ethyl acetate:pentane (50:50 to 100:0) to afford the titlecompound, 1.44g. 1H-NMR (CDCI3, 400MHz) δ: 3.16 (t, 2H), 4.23 (t, 2H), 7.02 (d,2H), 7.28 (m, 3H), 7.36 (s, 1H), 7.50 (s, 1H), 9.83 (s, 1H). LRMS: m/z (ES+) 223[MNa*].

A solution of trityl chloride (9.5g, 34.3mmol) in Ν,Ν-dimethylformamide (50ml) wasadded dropwise to an ice-cooled solution of imidazole-4-carboxaldehyde (3g,31.2mmol) and triethylamine (17ml, 125mmol) in Ν,Ν-dimethylformamide (30ml) andthe solution was stirred for 2 hours. The reaction was then allowed to warm to roomtempérature, and was stirred for a further 18 hours. Water (200ml) was added, andthe resulting pink solid was collected and dried, then dissolved in dichloromethane(200ml). The resulting solution was washed with water (2x100ml), dried (MgSO4)and evaporated under reduced pressure. The product was recrystallised frométhanol to afford the title compound as a solid, 7.8g. 1H-NMR (CDCI3, 400MHz) δ:7.06 (m, 6H), 7.32 (m, 9H), 7.48 (s, 1H), 7.58 (s, 1H), 9.82 (s, 1H). Microanalysisfound: C, 81.54; H, 5.37; N, 8.24. C23H18N2O requires C, 81.63; H, 5.36; N, 8.28%. 61 012756

Préparation 6 2-f(4-Methoxvbenzvl)amino1ethanol

Acetic acid (ca. 150ml) was added to a solution of p-anisaldehyde (58.2g, 0.42mol)and ethanolamine (152ml, 2.52mol) in methanol (1L), to achieve a pH of 6. Sodiumtriacetoxyborohydride (100g, 0.47mol) was added portionwise, and once additionwas complété, the mixture was stirred at room température for 72 hours. Themixture was concentrated under reduced pressure, basified using 1N sodiumhydroxide solution and extracted with dichloromethane (10x300ml). The combinedextracts were evaporated and the crude product was purified by columnchromatography on silica gel using an elution gradient of dichloromethane:methanol(98:2 to 90:10) to afford the title compound, 42g. 1H-NMR (CDCI3,400MHz) δ: 2.78(t, 2H), 3.62 (t, 2H), 3.75 (m, 5H), 4.24 (s, 2H), 6.81 (d, 2H), 7.22 (d, 2H). LRMS:m/z (ES*) 182 [MH*].

Préparation 7 (2ffl-1-f(4-Methoxybenzvnaminol-2-propanol

A solution of (fl)-(-)-1-amino-2-propanol (9.00g, 0.12mol) in tetrahydrofuran (40ml)and acetic acid (5ml) was added dropwise to a solution of p-anisaldehyde (5.45g,0.04mol) in tetrahydrofuran (40ml), and once addition was complété, the solutionwas stirred at room température for 2 hours. The solution was cooled in an ice-bâth, and sodium triacetoxyborohydride (9.50g, 0.0.045mol) was added portionwise,and then the mixture was stirred at room température for 18 hours. The reactionmixture was concentrated under reduced pressure and the residue was partitionedbetween dichloromethane (150ml) and sodium hydroxide solution (150ml, 0.5N). Thelayers were separated and the aqueous phase was saturated with sodium chloride,then extracted with further dichloromethane (3x30ml). The combined organicsolutions were dried (MgSO*) and evaporated under reduced pressure. The residue βζ 012756 was purified by chromatography on silica gel (gradient elution 98:2:0.2 to 97:3:0.3dichloromethane:methanol:0.88 NH3) to afford an orange oil (4.9g). 1H-NMR(CDCIa, 400MHz) δ: 1.12 (d, 3H), 2.39 (dd, 1H), 2.70 (dd, 1H), 3.62-3.79 (m, 6H),6.82 (d, 2H), 7.19 (d, 2H). LRMS: m/z (ES4) 196 [MH4].

Préparation 8 (2S)-1-f(4-Methoxvbenzvl)aminol-2-propanol

A mixture of (S)-(+)-1 -amino-2-propanol (9g, 0.12mol), p-anisaldehyde (5.45g,0.04mol), acetic acid (5ml), and sodium triacetoxyborohydride (9.5g, 0.045mol) inmethanol (80ml) was stirred at room température for 72 hours. The reaction mixturewas concentrated under reduced pressure and the residue was partitioned betweendichloromethane (150ml) and sodium hydroxide solution (100ml, 0.5N). The layerswere separated, and the aqueous phase was extracted with further dichloromethane(4x30ml). The combined organic solutions were dried (MgSO4) and concentratedunder reduced pressure. The residual yellow oil was purified by columnchromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (98:2:0.2 to 95:5:0.5) to afford the titlecompound, 6.2g. 1H-NMR (CDCI3, 400MHz) δ: 1.10 (d, 3H), 2.24-2.40 (m, 2H), 2.65(dd, 1H), 3.62-3.80 (m, 6H), 6.82 (d, 2H), 7.19 (d, 2H). LRMS: m/z (ES4) 218[MNa4]

Préparation 9 (2fî)-2-r(4-Methoxybenzvl)amino1-1-propanol

(H)-(-)-2-Amino-1-propanol (10.36ml, 133mmol) was added dropwise to a solution ofp-anisaldehyde (5.85g, 42.9mmol) in methanol (90ml), and the solution was cooledin an ice-bath. Acetic acid (2.5ml) and sodium triacetoxyborohydride (10.0g,47.2mmol) were added and the réaction mixture was allowed to warm to room 012756 63 température over an hour. The solution was warmed to 40°C and stirred for afurther 48 hours then concentrated under reduced pressure. The residue waspartitioned between saturated sodium bicarbonate solution (50ml) anddichloromethane (100ml) and the layers were separated. The aqueous phase was 5 extracted with further dichloromethane (10x50ml), and the combined organic solutions were dried (MgSO4) and evaporated under reduced pressure. The residuewas purified twice by column chromatography on silica gel using an elution gradientof dichloromethane:methanol:0.88 ammonia (97:3:0.3 to 90:10:1) to afford the titlecompound, 6.0g. 1H-NMR (CDCfe, 400MHz) δ: 1.04 (d, 3H), 2.80 (m, 1 H), 322 (dd, 10 1 H), 3.58 (dd, 1 H), 3.62 (d, 1 H), 3.78 (m, 4H), 6.82 (d, 2H), 7.20 (d, 2H). LRMS:m/z (ES+) 196 [MH+J. [a]D = -34.85 (c = 0.137, methanol)

Préparation 10 i2S)-2-f(4-Methoxvbenzyl)amino1-1-propanol

The title compound was obtained in 67% yield from (S)-(+)-2-amino-1-propanol andp-anisaldehyde, following the procedure described in Préparation 9. 1H-NMR(CDCfe, 400MHz) δ: 1.08 (d, 3H), 2.83 (m, 1H), 3.30 (dd, 1H), 3.59 (dd, 1H), 3.66 (d,1 H), 3.77 (s, 3H), 3.82 (d, 1 H), 4.08 (bs, 2H), 6.82 (d, 2H), 7.22 (d, 2H). [ct]D = 20 +39.19 (c = 0.146, methanol) -

25 A solution of sodium hydroxide (7.08g, 0.177mol) in water (150ml) was added to asolution of the amino alcohol of Préparation 6 (32g, 0.177mol) in dichloromethane(250ml), and the mixture was cooled to 0°C. A solution of chloroacetyl chloride 012756 64 (14.3ml, 0.177mol) in dichloromethane (50ml) was added dropwise over 30 minutes,and the mixture was stirred at room température for 18 hours. The phases wereseparated, and the organic layer was washed with sodium hydroxide (2N, 150ml), 2Nhydrochloric acid (150ml), and brine (50ml), then dried (MgSC>4) and concentratedunder reduced pressure. The residual oil was dissolved in éthanol (200ml), asolution of potassium hydroxide (9.93g, 0.177mol) in éthanol (200ml) was added andthe mixture was stirred at room température for 18 hours. The mixture was filtered,the filtrate was evaporated under reduced pressure, and the residue was trituratedwith diethyl ether/pentane to afford the title compound as a white powder, 26g. 1H-NMR (CDCI3, 400MHz) δ: 3.20 (t, 2H), 3.78 (m, 5H), 4.19 (s, 2H), 4.54 (s, 2H), 6.82(d, 2H), 7.18 (d, 2H). LRMS: m/z (ES+) 244 [MNa*].

Préparation 12 (6fl)-4-(4-Methoxybenzvl)-6-methvl-3-morpholinone

The title compound was obtained in 76% yield from the alcohol of Préparation 7 andchloroacetyl chloride, following a similar procedure to that described in Préparation11, except, the compound was additionally purified by column chromatography onsilica gel using dichloromethane:methanol:0.88 ammonia (98:2:0.2) as eiuant. 1H-NMR (CDCIs, 400MHz) δ: 1.18 (d, 3H), 2.99-3.14 (m, 2H), 3.79 (m, 4H),-4-.-17 (d, 1H),4.25 (d, 1H), 4.38 (d, 1H), 4.61 (d, 1 H), 6.82 (d, 2H), 7.17 (d, 2H). LRMS: m/z (ES+)258 [MNa4]

Préparation 13 (6S)-4-(4-Methoxvbenzvt)-6-methvl-3-morphoiinone

O 65 012756

The title compound was obtained as a yellow oil in 61% yield from the amino aicoholof Préparation 8, following the procedure described in Préparation 11. ’H-NMR(CDCI3i 400MHz) δ: 1.18 (d, 3H), 2.98-3.10 (m, 2H), 3.78 (m, 4H), 4.18 (d, 1H), 4.25(d, 1 H), 4.38 (d, 1H), 4.60 (d, 1H), 6.61 (d, 2H), 7.17 (d, 2H). LRMS: m/z (ES+) 258[MNa4]

Préparation 14 (5S)-4-(4-Methoxvbenzvl)-5-methvl-3-morpholinone

A solution of chloroacetyl chioride (2.34ml, 29mmol) in dichloromethane (25ml) wasadded dropwise over 10 minutes to a stirred ice-cooled mixture of the amino aicoholof Préparation 10 (5.6g, 28.7mmol) in sodium hydroxide solution (1,16g, 29mmol inwater (20ml)) and dichloromethane (50ml). The mixture was stirred at roomtempérature for 18 hours, and then the layers were separated. The organic phasewas washed with 1N sodium hydroxide solution (25ml), 2M hydrochloric acid (20ml)and brine (20ml), then dried (MgSO,») and evaporated under reduced pressure. Theresidue was dissolved in éthanol (40ml) the solution was cooled in an ice-bath, and asolution of potassium hydroxide (1,63g, 29mmol) in éthanol (40ml) was addeddropwise over 5 minutes. The mixture was then aliowed to warm to roomtempérature and was stirred for a further 18 hours. The resulting precipjtate wasfiltered off, the filtrate was concentrated under reduced pressure, and the residuewas dissolved in dichloromethane (150ml). This solution was dried (MgSC>4) andevaporated under reduced pressure. The crude product was purified by coiumnchromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (97:3:0.3 to 95:5:0.5) to afford the titlecompound, 4g. 1H-NMR (CDCfe,400MHz) δ: 1.26 (d, 3H), 3.37 (m, 1 H), 3.62 (dd,1H), 3.70 (dd, 1H), 3.80 (s, 3H), 3.90 (d, 1H), 4.20 (d, 1H), 4.24 (d, 1H), 5.33 (d, 1H),6.83 (d, 2H), 7.19 (d, 2H). [a]D= -109.66 (C = 0.139, methanol) 012756 66

Préparation 15 (5fl)-4-(4-Methoxvbenzvl)-5-methvl-3-morpholinone

The title compound was obtained in 49% yield from the alcohol of Préparation 9 5 following a similar procedure to that described in Préparation 14. 1H-NMR (CDCI3,400MHz) 5:1.24 (d, 3H), 3.30 (m, 1H), 3.60 (dd, 1H), 3.70 (dd, 1H), 3.78 (s, 3H),3.85 (d, 1H), 4.18 (d, 1H), 4.22 (d, 1H), 5.28 (d, 1H), 6.81 (d, 2H), 7.18 (d, 2H).

Préparation 16 10 4-Methvl-3-morpholinone ^CH3

O A solution of chloroacetyl chloride (3.81ml, 50mmol) in dichloromethane (100ml) wasadded dropwise over 30 minutes to a suspension of 2-(methylamino)ethanol (4ml,50mmol) and sodium hydroxide (2g, 50mmol) in dichloromethane (50ml) and water 15 (50ml), and the mixture was stirred at room température for 72 hours then evaporated under reduced pressure. The residue was dissolved in éthanol (100ml),potassium hydroxide (2.8g, 50mmol) was added, and the mixture was stirred at 40°Cfor 18 hours then filtered, and the filtratê was concentrated under reduced pressure.The crude product was purified by column chromatography on silica gel using an 20 elution gradient of pentane:ethyl acetate (100:0 to 50:50 to 0:100), to afford the titlecompound, 3.42g. 1H-NMR (CDCI3, 400MHz) δ: 2.98 (s, 3H), 3.34 (t, 2H), 3.84 (t,2H), 4.14 (s, 2H). Found: C, 51.55; H, 8.02; N, 12.01. C5H9NO2;0.1H2O requires C,51.36; H, 7.93; N, 11.98%. 012756 67

Préparation 17 tert-Butvl Γ2-( dimethvlamino)ethoxv1acetate

CH. CH3 Ν,Ν-Dimethylethanolamine (5.02ml, 50mmol) was added dropwise over 5 minutes toan ice-cooled suspension of sodium hydride (2.2g, 60% dispersion in minerai oil,55mmol) in tetrahydrofuran (100ml), and the solution was stirred for 30 minutes.ferf-Butyl bromoacetate (7.38ml, 50mmol) was added dropwise over 5 minutes, thenthe mixture was allowed to warm to room température and stirred for a further 18hours. The mixture was pre-adsorbed onto silica gel, and purified by columnchromatography on silica gel using an elution gradient of pentane:ethylacetateimethanol (50:50:0 to 0:100:0 to 0:80:20) to afford the title compound as ayellow oil, 1.46g. 1H-NMR (CDCI3, 400MHz) δ: 1.50 (s, 9H), 2.30 (s, 6H), 2.59 (t,2H), 3.64 (t, 2H) 4.00 (s, 2H). LRMS: m/z (ES*) 204 [MH*)

Préparation 18 tert-Butvl (3fl)-3-(2-fert-butoxv-2-oxoethoxy)pyrrolidine-1 -carboxvlate H.

Sodium hydride (704mg, 60% in minerai oil, 17.6mmol) was added to an ice-cooledsolution of tert-butyl (3fî)-3-hydroxypyrrolidine-1-carboxylate (J. Med. Chem. 1998,41(25), 4983) (5g, 26.7mmol) in tetrahydrofuran (100ml), and the mixture wasallowed to warm to room température and stirred for 20 minutes. ferf-Butylbromoacetate (5.2g, 26.7mmol) was added and the mixture was heated under refluxfor 18 hours, then cooied and concentrated under reduced pressure. The residuewas partitioned between ethyl acetate and water and the phases separated. Theorganic layer was dried (MgSO4) and evaporated under reduced pressure. Thecrude product was purified by column chromatography on silica gel using an elutiongradient of ethyl acetate:pentane (0:100 to 20:80) to afford the title compound, 68 01 2756 1.95g. Ή-NMR (CDCIa, 400MHz) δ: 1.42 (s, 9H), 1.44 (s, 9H), 1.85-2.05 (m, 2H), 3.40 (m, 4H), 3.94 (m, 2H), 4.10 (m, 1H). LRMS: mZz (ES+) 324 [MNa-*]

Préparation 19

Ethyl 3-cvclohexvl-3-methvlbutanoate H„c CH,

ch3

Trimethylsilyl chloride (1.3ml, 10.2mmol), copper (I) chloride (30mg, 0.3mmol) andcyclohexylmagnesium chloride (4.6ml, 2N in diethyl ether, 9.2mmol) were addedslowly to an ice-cooled solution of ethyl 3,3-dimethylacrylate (1g, 8.5mmol) intetrahydrofuran (10ml). The solution was stirred for 10 minutes, then allowed towarm to room température and stirred for an hour. Saturated aqueous ammoniumchloride solution (10ml) was added and the mixture was partitioned between water(10ml) and diethyl ether (20ml). The layers were separated and the aqueous phasewas extracted with diethyl ether (2x10ml). The combined organic extracts weredried (MgSO4) and concentrated under reduced pressure. The crude product waspurified by column chromatography on silica gel using ethyl acetate:pentane(5:95) aseluant to afford the title compound, 1.2g. 1H-NMR (CDCI3, 400MHz) Ô: 0.75 (m, 8H),1.05-1.28 (m, 7H), 1.62 (m, 1H), 1.78 (m, 4H), 2.20 (s, 2H), 4.10 (q, 2H).

Préparation 20 3-Cvclohexvl-3-methvl-1 -butanol ΌΗ

Lithium borohydride (1.23g, 56.6mmol) was added to a solution of the ester ofPréparation 19 (4g, 18.9mmol) in tetrahydrofuran (30ml), and the mixture was stirredat 50°C for 18 hours. Aqueous ammonium chloride solution (15ml) was addedcarefully to the cooled solution, and the mixture was extracted with ethyl acetate(3x30ml). The combined organic extracts were washed with brine, dried (MgSO4)and evaporated under reduced pressure. The crude product was purified by column 012756 69 chromatography on silica gel using ethyl acetate:pentane (20:80) as eluant to affordthe title compound, 1g. 1H-NMR (CDCI3,400MHz) δ: 0.80 (s, 6H), 0.88-1.18 (m,6H), 1.50 (t, 2H), 1.60 (m, 1H), 1.70 (m, 4H), 3.64 (m, 2H).

Préparation 21 (3-Bromo-1.1 -dimethvlpropvOcvclohexane

Triphenylphosphine (1.8g, 7.1mmol) was added portionwise to an ice-cooled solutionof the alcohol of Préparation 20 (1g, 5.9mmol) and carbon tetrabromide (2.9g,8.8mmol) in dichloromethane (15ml), and once addition was complété, the mixturewas stirred at room température for 72 hours. The solution was concentrated underreduced pressure and the residue was suspended in a mixture of pentane:ethylacetate (5:1, by volume). The resulting precipitate was filtered ofï through a pad ofsilica gel and washed with pentane:ethyl acetate (5:1, by volume, 300ml). Thecombined filtrâtes were concentrated under reduced pressure, and the product waspurified by column chromatography on silica gel using pentane as eluant to affordthe title compound, 1.1g. 1H-NMR (CDCI3, 400MHz) δ: 0.80 (2xs, 6H), 0.90-1.20 (m,6H), 1.62 (m, 3H), 1.75 (m, 2H), 1.81 (m, 2H), 3.36 (m, 2H).

Préparation 22 4-(2-Bromoethvl)-1.1 -dimethvlcvclohexane

A mixture of 2-(4,4-dimethylcyclohexyl)ethanol (WO99/59971) (2g, 12.8mmol),concentrated sulphuric acid (750μΙ) and 48% hydrobromic acid (3ml) was stirred at90°C for 7 hours. The cooled mixture was then carefully quenched by the additionof water (25ml), and the mixture was extracted with dichloromethane (3x30ml). Thecombined organic extracts were washed with 2M sodium carbonate solution andbrine (30ml), then dried (MgSO4) and concentrated under reduced pressure. Theresidual black gum was purified by distillation to afford the title compound, 330mg. 012756 70 1H-NMR (CDCI3, 400MHz) δ: 0.82 (2xs, 6H), 1.02-1.20 (m, 4H), 1.35 (m, 3H), 1.50(m, 2H), 1.78 (m, 2H), 3.40 (t, 2H).

Préparation 23 2-fHvdroxv( 1 -propvl-1 H-imidazol-4-vl)methvn-4-(4-methoxvbenzvl)-3-morpholinone

A solution of the compound of Préparation 11 (13g, 58.7mmol) in tetrahydrofuran(100ml) was added dropwise to a solution of lithium diisopropylàmide (35.3ml, 2M intetrahydrofuran/heptane/ethylbenzene, 70.5mmol) at -78°C, and the solution wasstirred at -78°C for 20 minutes. The aldéhyde of Préparation 1 (9.75g, 70.5mmol)was added dropwise and the mixture was atlowed to warm to room température,then stirred for 1.5 hours. Ammonium chloride solution (100ml) was added and themixture was diluted with water (100ml) and tetrahydrofuran (300ml). The layerswere separated, the aqueous phase was extracted with tetrahydrofuran (250ml), andthe combined organic solutions were dried (MgSO4) and evaporated under reducedpressure. The crude product was purified by column chromatography on silica gelusing an elution gradient of ethyl acetate:dichloromethane:methanol:0.88 ammonia(100:0:0:0 to 0:95:5:0.5) to afford the title compound, 14g. 1H-NMR (CDCI3,400MHz) (mixture of diastereoisomers) δ: 0.90 (t, 3H), 1.76 (m, 2H), 3.00 (m, 1H),3.32-3.43 (m, 1H), 3.61-3.81 (m, 6H), 3.98 (m, 1H), 4.42-4.58 (m, 3H), 4.75 (m,0.5H), 5.03 (m, 0.5H), 6.81 (m, 3H), 7.15 (m, 2H), 7.38 (s, 1H). LRMSfWz (ES+)360.0 (MH4]

Préparation 24 2-FHvdroxv(1-propyi-1H-imidazol-4-vl)methvn-4-methvl-3-morpholinone

Lithium diisopropylàmide (17.4ml, 2M in heptane/tetrahydrofuran/ethylbenzene,34.8mmol) was added over 10 minutes to a cooled (-78°C) solution of the compound 012756 71 of Préparation 10 (3.42g, 29mmol) in tetrahydrofuran (100ml), and the resultingsolution was stirred for 20 minutes. The aldéhyde of Préparation 1 (4.81 g,34.8mmol) was added and the mixture was allowed to warm slowly to roomtempérature, then stirred for 18 hours. Aqueous ammonium chloride solution (20ml)was added, and the mixture was evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel using an elution gradient ofpentane:ethyl acetate:methanol:diethylamine (50:50:0:0 to 0:100:0:0 to 0:90:5:5) toafford the title compound as a yellow gum, 5.47g. 1H-NMR (CDCI3,400MHz)(mixture of diastereoisomers) δ: 0.90 (t, 3H), 1.78 (m, 2H), 2.98 (2xs, 3H), 3.10 (m,1H), 3.57 (m, 2H), 3.80 (m, 3H), 3.98-4.08 (m, 1 H), 4.39, 4.49, 4.86, 4.98, 5.22 (5xm,2H), 6.88 (s, 1 H), 7.38 (s, 1 K). LRMS: m/z (TSP+) 254.2 [MH*]

Préparation 25 2-ff 1 -Butvl-1 H-imidazol-4-vl)(hvdroxv)methvtl-4-(4-methoxvbenzvl)-3-morpholinone OH o A solution of the compound of Préparation 11 (3.63g, 16.4mmol) in tetrahydrofuran(40ml) was added dropwise over 5 minutes to a solution of lithium diisopropylamide(9.8ml, 2M in tetrahydrofuranZheptane/ethylbenzene, 19.7mmol) at-78°C, and thesolution was stirred at -78°C for 30 minutes. The aldéhyde of Préparation 2 (3.0g, 19.7mmol) was added dropwise and the mixture was allowed to warm to roomtempérature, then stirred for 18 hours. The mixture was partitioned betweenammonium chloride solution and ethyl acetate (300ml). The iayers were separated,and the organic solution was dried (MgSC>4) and evaporated under reducedpressure. The crude product was purified by column chromatography on silica gelusing an elution gradient of ethyl acetate:methanol: (100:0 to 90:10) to afford the titlecompound, 4.35g. 1H-NMR (CDCI3,400MHz) (mixture of diastereoisomers) δ: 0.96(t, 3H), 1.35 (m, 2H), 1.78 (m, 2H), 3.03 (m, 1 H), 3.42 (m, 1 H), 3.66-3.80 (m, 5H),3.87 (m, 2H), 4.00 (m, 1H), 4.50 (m, 0.5H), 4.57 (m, 2.5H), 4.83 (m, 0.5H), 5.06 (m, 0.5H), 6.90 (m, 3H), 7.20 (m, 2H), 7.41 (s, 1H). LRMS: m/z (TSP+) 374.0 [MH*] 72

Préparation 26 2-iï1-(2-Cvclohexylethvl)-1W-imidazol“4-vll(hvdroxv)methvn-4-(4-methoxvbenzvl)-3- morpholinone 012756

5 The title compound was obtained as a sticky gum in 66% yield from the compound ofPréparation 11 and the aldéhyde of Préparation 3, following a similar procedure tothat described in Préparation 25. 1H-NMR (CDCI3,400MHz) (mixture ofdiastereoisomers) δ: 0.98 (m, 2H), 1.22 (m, 4H), 1.58-1.78 (m, 7H), 3.03 (m, 1 H),3.38-3.50 (m, 1 H), 3.70-3.82 (m, 4H), 3.90 (m, 2H), 4.01 (m, 1H), 4.50 (d, 0.5H), 10 4.58 (m, 2.5H), 4.87 (m, 0.5H), 5.08 (m, 0.5H), 6.82-6.95 (m, 3H), 7.19 (m, 2H), 7.41(s, 1 H). LRMS: m/z (TSP+) 428.1 [MH4]

Préparation 27 2-fHvdroxvf 1 -(2-phenylethyl)-1 /7-imidazol-4-vnmethvn-4-(4-methoxybenzvl)-3- 15 morpholinone

The title compound was obtained in 54% yield from the compound of Préparation 11and the aldéhyde of Préparation 4, following a similar procedure to that described inPréparation 25, except pentanerethyl acetate:methanol (50:50:0 to 0:100:0 to 20 0:87:13) was used as the elution gradient. 1H-NMR (CDCI3, 400MHz) (mixture ofdiastereoisomers) δ: 3.02 (m, 3H), 3.42 (m, 1H), 3.74 (m, 4H), 3.95-4.05 (m, 1H), 4.12 (m, 2H), 4.45 (m, 0.5H), 4.58 (m, 2.5H), 4.81 (m, 0.5H), 5.06 (d, 0.5H), 6.84 (m,3H), 7.07 (d, 2H), 7.19 (m, 2H), 7.27 (m, 4H). LRMS: m/z (ES4) 422 [MH4] 73 012756

Préparation 28 2-[Hvdroxv( 1 -tritvl-1 H-imidazol-4-vl)methvn-4-(4-methoxvbenzvl)-3-morpholinone

A solution of lithium diisopropylamide (88.5ml, 1.5M in cyclohexane, 133mmol) and5 tetrahydrofuran (100ml) was cooled to -78°C. A solution of the compound of

Préparation 11 (26g, 118mmol) in tetrahydrofuran (100ml) was added dropwise, andthe solution was stirred for 30 minutes. A solution of the imidazole of Préparation 5(39.9g, 118mmol) in tetrahydrofuran (350ml) was added dropwise over 1 hour, andonce addition was complété, the reaction was altowed to warm slowly to room 10 température with stirring, over 3 hours. Saturated ammonium chloride solution(200ml) and water (100ml) were added, the phases were separated, and theaqueous layer was extracted with ethyl acetate (100ml). The combined organicsolutions were dried (MgSO4) and evaporated under reduced pressure. Theresidual orange oil was dissolved in ethyl acetate/methanol, the solution was 15 sonicated, and the resulting white precipitate was filtered off, washed with diethylether and dried, to give the title compound, 21 g. The filtrate was evaporated underreduced pressure and the residue was purified by column chromatography on si,icagel using ethyl acetate:methanol (96:4) as eluant to afford additional prûdûct, 28g.1H-NMR (CDCb, 400MHz) (mixture of diastereoisomers) δ: 2.98 (m, 1 H), 3.35 (m, 20 1H), 3.66 (m, 1.H), 3.73 (s, 3H), 3.96 (m, 1H), 4.40 (d, 1H), 4.54 (s, 1H), 4.60 (d, 1H),5.21 (m, 1H), 6.79 (m, 3H), 7.08 (m, 6H), 7.15 (m, 2H), 7.26 (m, 9H), 7.37 (s, 1H).LRMS: m/z (TSP+) 560.2 [MH4] 012756 74

Préparation 29 (6R)-2-fHydroxv(1-tritvl-1H-imidazol-4-vnmethvn-4-(4-methoxvbenzvl)-6-methvi-3- morpholinone

5 The title compound was obtained in 62% yield from the morpholinone of Préparation12 and the imidazole of Préparation 5, following a similar procedure to that describedin Préparation 28. 1H-NMR (CDCI3,400MHz) (mixture of diastereoisomers) Ô: 1.00,1.06 (2xm, 3H), 2.87-3.04 (m, 2H), 3.76 (m, 3H), 3.80-4.74 (m, 4H), 4.98-5.21 (m,1H), 6.78 (m, 3H), 7.05-7.20 (m, 8H), 7.23-7.40 (m, 10H). LRMS: m/z (ES+) 574 10 [MH+]

Préparation 30 (65)-2-rHvdroxv(1-trityl-1 H-imidazol-4-vl)rnethvn-4-(4-methoxvbenzvl)-6-rnethyl-3- morpholinone

The title compound was obtained as a yellow foam in 53% yield from themorpholinone of Préparation 13 and the imidazole of Préparation 5, following asimilar procedure to that described in Préparation 28. 1H-NMR (CDCI3, 400MHz)(mixture of diastereoisomers) δ: 1.00,1.05 (2xm, 3H), 2.85-3.04 (m, 2H), 3.76 (m, 20 3H), 3.80-3.96 (m, 1H), 4.39-4.70 (m, 3K), 4.98-5.20 (m, 1K), 6.78 (m, 3H), 7.05-7.20 (m, 8H), 7.25 (m, 9H), 7.39 (m, 1H). LRMS: m/z (ES+) 574 [MH*] 012756 75

Préparation 31 (5S)-2-rHvdroxv( 1 -tritvl-1 H-imidazol-4-vl)methvl1-4-(4-methoxvbenzvl)-5-methvl-3- morpholinone

5 The title compound was obtained in 57% yield from the morpholinone of Préparation14 and the imidazole of Préparation 5, following a similar procedure to that describedin Préparation 28. 1H-NMR (CDCI3,400MHz) (mixture of diastereoisomers) δ: 1.03-1.19 (m, 3H), 2.99-4.83 (m, 8H), 5.02-5.38 (m, 2H), 6.78-6.88 (m, 3H), 7.10-7.21 (m,8K), 7.22-7.42 (m, 10H). 10

Préparation 32 (5fl)-2-fHvdroxy( 1 -tritvl-1 H-imidazol-4-vl)methvlî-4-(4-methoxybenzvl)-5-methyl-3- morpholinone

15 The titfe compound was obtained as a yeilow foam in 80% yield from the morpholinone of Préparation 15 and the imidazole of Préparation 5, following asimilar procedure to that described in Préparation 28. 1H-NMR (CDCI3,400MHz)(mixture of diastereoisomers) δ: 1.00-1.16 (m, 3H), 3.16-4.94 (m, 8H), 5.00-5.37 (m,2H), 6.72-6.83 (m, 3H), 7.04-7.19 (m, 8H), 7.21-7.40 (m, 10H). 20 012756 76

Préparation 33 tert-Butyl 2-[2-(άίιτΐ6ΐηνΐ3ηηΐηο)θΐΚοχν1-3-ΚνάΓθχν-3-(1 -propyl-1 H-imidazol-4-

5 Lithium diisopropylamide (4.3ml, 2M in heptane/tetrahydrofuran/ethylbenzene,8.6mmol) was added dropwise over 5 minutes to a solution of the amine ofPréparation 17 (1.46g, 7.2mmol) in tetrahydrofuran (20ml) and the solution wasstirred at -78°C for 20 minutes. The aldéhyde of Préparation 1 (1.18g, 8.6mmoi)was added and the mixture was stirred for 3 hours then allowed to warm to -20°C. 10 Water was added, and the mixture pre-adsorbed onto silica gel. The product waspurified by column chromatography on silica gel using an elution gradient of ethylacetate:methanol:diethylamine (100:0:0 to 96:2:2) to afford the title compound, 1.36g. 1H-NMR (CDCI3l 400MHz) (mixture of diastereoisomers) δ: 0.88 (m, 3H), 1.35(2xs, 9H), 1.75 (m, 2H), 2.22 (s, 6H), 2.42 (m, 1H), 2.58 (m, 1H), 3.55 (m, 1H), 3.80 15 (m, 2H), 3.90 (m, 1H), 4.17 (m, 1H), 4.82, 5.00 (m, 1H), 6.90 (2xs, 1H), 7.35 (2xs, 1 H). LRMS: m/z (TSP+) 342.2 [MH4] - Préparation 34 -_ ferf-Butyl (3S)-3-(1-terf-butoxycarbonvl-2-hvdroxv-2-(1 -propyl-1 H-imidazol-4-vD- 20 ethoxvlpyrrolidine-1 -carboxylate

A solution of the compound of Préparation 18 (5.67g, 18.8mmol) in tetrahydrofuran 77 0 1 2756 (20ml) was added dropwise to a solution of lithium diisopropylamide (11,3ml, 2M inheptane/tetrahydrofuran/ethylbenzene, 22.6mmol) at -78°C, and the solution wasstirred at -78°C for 20 minutes. The aldéhyde of Préparation 1 (3.12g, 22.6mmol)was added portionwise, and the mixture was allowed to warm to room températurethen stirred for 18 hours. Ammonium chloride solution (50ml) was added carefullyand the mixture was extracted with tetrahydrofuran (2x200ml). The combinedorganic solutions were dried (MgSO4) and evaporated under reduced pressure. Theresidual orange oil was purified by column chromatography on silica gel using anelution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0: to 90:10:1) toafford the title compound, 3.7g. 1H-NMR (CDCfe, 400MHz) (mixture ofdiastereoisomers) Ô: 0.92 (t, 3H), 1.42 (s, 18H), 1.79 (m, 2H), 1.94-2.14 (m, 1H),2.75-3.50 (m, 5H), 3.84 (m, 2H), 4.03-4.35 (m, 2H), 4.81-5.08 (m, 2H), 6.88 (m, 1H),7.39 (s, 1 H). LRMS: m/z (ES+) 440 [MH+]

Préparation 35 (2EZ)-4-(4-Methoxvbenzyl)-2-ÎY 1 -propyl-1 H-imidazol-4-vhmethvlidene1-3-

Triethylamine (9.19ml, 65.9mmol) was added to a solution of the alcohol ofPréparation 23 (15.8g, 44.0mmol) in dichloromethane (300ml). The solution wascoolêd in ice, methanesulphonyl chloride (5.1ml, 65.9mmol) was added, and thesolution was stirred for 2 hours at room température. Additional triethylamine(3.06ml, 22mmol) was added, and the mixture was stirred at 40°C for 18 hours thencooled. The mixture was diluted with dichloromethane (1000ml) and washed withsodium bicarbonate solution (200ml). The aqueous wash was extracted withdichloromethane (400ml), and the combined organic solutions were dried (MgSO4)and evaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using an elution gradient of ethyl acetate:dichloromethan^:methanol:0.88 ammonia (100:0:0:0 to 0:95:5:0.5 to0:90:10:1) to afford the fltle compound, 8.3g. 1H-NMR (CDCI3,400MKz) (mixture of i 78 012756 géométrie isomers) δ: 0.90 (t, 3H), 1.78 (m, 2H), 3.39 (t, 2H), 3.77 (s, 3H), 3.83 (t, 2H), 4.15 (t, 2H), 4.61 (s, 2H), 6.81 (d, 2H), 7.00 (s, 1H), 7.19 (d, 2H), 7.28 (s, 1 H), 7.41 (s, 1 H). LRMS: m/z (ES+) 342 [MH4] 5 Préparation 36 (2EZ)-4-(4-Methoxvbenzvl)-2-f(1 -tritvl-1 Wmidazol-4-vl)rnethvlidene1-3-morpholinone

The title compound was obtained in 77% yield as a yellow foam from the alcohol ofPréparation 28 foliowing the procedure described in Préparation 35. 1H-NMR 10 (CDCI3,400MHz) (mixture of géométrie isomers) δ: 3.34 (t, 2H), 3.78 (s, 3H), 4.00 (t,2H), 4.59 (s, 2H), 6.80 (d, 2H), 6.98 (s, 1H), 7.10 (m, 6H), 7.17 (d, 2H), 7.28 (m, 10H), 7.39 (s, 1 H). LRMS: m/z (ES4) 542 [MH4]

Préparation 37 15 f2EZ.6R)-4-(4-Methoxvbenzvl)-6-methvl-2-[(1-tritvl-lH-imidazol-4-vl)methvlidene1-3- morpholinone

The title compound was obtained in 57% yield as a pale yellow foam, from thealcohol of Préparation 29, foliowing the procedure described in Préparation 35. 1H- 20 NMR (CDCI3, 400MHz) (mixture of géométrie isomers) δ: 1.02 (d, 3H), 3.08 (dd, 1H),3.20 (dd, 1H), 3.77 (S, 3H), 4.10 (m, 1H), 4.50 (d, 1H), 4.60 (d, 1H), 6.80 (d, 2H),6.99 (s, 1 H), 7.14 (m, 8H), 7.28 (m, 10H), 7.38 (s, 1 H). LRMS: m/z (ES4) 556 [MH4] 79 012756

Préparation 38 (2EZ.6S]-4-(4-Methoxvbenzvl)-6-methvl-2-f(1 -tritvl-1 /7-imidazol-4-yl)methviidene1-3- morpholinone

5 Methanesulphonyl chloride (911 μΙ, 11.78mmol) was added dropwise to an ice-cooiedsolution of the alcohol of Préparation 30 (4.5g, 7.85mmol) in dichloromethane (40ml)and triethylamine (1.64ml, 11.78mmol), and the solution was stirred at roomtempérature for 1 hour. Additional triethylamine (546μΙ, 3.93mmol) was added, andthe mixture was stirred at 40°C for 18 hours. The cooled mixture was partitioned 10 between dichloromethane (50ml) and water (50ml) and the layers were separated.The organic phase was dried (MgSO4) and concentrated under reduced pressure.The residual orange oil was purified by column chromatography on silica gel usingan elution gradient of dichloromethane:methanol:0.88 ammonia (99:1:0.1 to98:2:0.2) to afford the titie compound as a yellow foam, 2.5g. 1H-NMR (CDCI3, 15 400MHz) (mixture of géométrie isomers) δ: 1.02 (d, 3H), 3.05 (m, 1 H), 3.20 (m, 1 H), 3.78 (s, 3H), 4.06 (m, 1 H), 4.47-4.63 (m, 2H), 6.80 (d, 2H), 6.98 (s, 1 H), 7.12 (m, 8H), 7.27 (m, 10H), 7.38 (s, 1H). LRMS: m/z (ES+) 556 [MH*]

Préparation 39 20 (2£'Z.5S)-4-(4-Methoxybenzvl)-5-methvl-2-r( 1 -tritvl-1 H-imidazol-4-vhmethvlidene]-3- morpholinone

O 80 01 27 56

The title compound was obtained in 28% yield from the alcohol of Préparation 31following a similar procedure to that described in Préparation 38. 1H-NMR (CDCfe,400MHz) (mixture of géométrie isomers) δ: 1.22 (d, 3H), 3.38 (m, 1H), 3.78 (s, 3H),3.81 (d, 1H), 3.95 (m, 2H), 5.28 (d, 1H), 6.80 (d, 2H), 6.95 (s, 1H), 7.10-7.19 (m, 9H),7.28 (m, 9H), 7.40 (s, 1H).

Préparation 40 (2EZ,5R)-4-(4-Methoxvbenzvl)-5-methvl-2-ff1-trityl-1 /•/•imidazol-4-vl)methvlidene1-3- morphotinone

The title compound was obtained in 27% yield from the alcohol of Préparation 32following a similar procedure to that described in Préparation 38. 1H-NMR (CDCI3,400MHz) (mixture of géométrie isomers) δ: 1.25 (d, 3H), 3.41 (m, 1H), 3.78 (s, 3H),3.83 (dd. 1H). 3.98 (m, 2H), 5.30 (d, 1H), 6.82 (d, 2H), 6.98 (s, 1 H). 7.18 (m, 9H),7.32 (m, 9H), 7.41 (s, 1H).

Préparation 41 (2EZ1-2-K1 -Butyl-1 rt-imidazol-4-vl)methvlidene1-4-(4-methoxybenzyl)-3-morpholinone

Triethylamine (1.78ml, 12.8mmol) was added to a solution of the alcohol ofPréparation 25 (4.34g, 11.6mmol) in dichloromethane (50ml). The solution wascooled in ice and methanesulphonyl chloride (990μΙ, 12.8mmol) was added. Thesolution was stirred for 30 minutes, additional triethylamine (1.78ml, 12.8mmol)added, and the mixture was stirred at room température for 18 hours. The mixturewas concentrated under reduced pressure and the residue was purified by column 012755 81 chromatography on siiica gel using an elution gradient of dichloromethane:ethylacetate:methanol (100:0:0 to 0:90:10) to afford the title compound as a sticky gum,1.12g. 1H-NMR (CDCI3,400MHz) (mixture of géométrie isomers) δ: 0.95 (t, 3H),1.34 (m, 2H), 1.78 (m, 2H), 3.42 (t, 2H), 3.80 (s, 3H), 3.94 (t, 2H), 4.19 (t, 2H), 4.63(s, 2H), 6.84 (d, 2H), 7.02 (s, 1H), 7.22 (d, 2H), 7.32 (s, 1H), 7.44 (s, 1H). LRMS:m/z (TSP4) 356.2 [MH4]

Préparation 42 (2E2)-2-f f 1 -(2-Cyclohexvlethvl)-1 H-imidazoi-4-vllmethviidene)-4-f4-methoxvbenzyi)- 3-morpholinone

The title compound was obtained as a sticky gum in 57% yield from the alcohol ofPréparation 26 following the procedure described in Préparation 41. 1H-NMR(CDCI3,400MHz) (mixture of géométrie isomers) δ: 0.94 (m, 2H), 1.18 (m, 4H), 1.64(m, 7H), 3.40 (t, 2H), 3.78 (s, 3H), 3.90 (t, 2H), 4.17 (t, 2H), 4.61 (s, 2H), 6.81 (d,2H), 6.99 (s, 1H), 7.20 (d, 2H), 7.25 (s, 1H), 7.40 (s, 1H). LRMS: m/z (TSP+) 410.1[MH4]

Préparation 43 (2£2l-4-(4-Methoxvbenzvl)-2-ff1-(2-phenvlethyl)-1 H-imidazol-4-vnmethylidene)-3- morpholinone

Triethylamine (0.98ml, 7.03mmoi) was added to a solution of the alcohol ofPréparation 27 (1.41 g, 3.35mmol) in dichloromethane (15ml). The solution wascooled in ice, methanesulphonyl chloride (311μΙ, 4.02mmol) was added, and themixture was warmed to 40°C and stirred for 18 hours, then concentrated underreduced pressure. The residue was purified by column chromatography on siiica gel 82 using an elution gradient of pentanerethyl acetatermethanol (75:25:0 to 0:100:0 to 0:95:5) to afford the title compound as an orange oil, 449mg. 1H-NMR (CDCb, 400MHz) (mixture of géométrie isomers) δ: 3.03 (t, 2H), 3.42 (t, 2H), 3.80 (s, 3H), 4.18 (m, 4H), 4.63 (s, 2H), 6.85 (d, 2H), 7.02 (s, 1H), 7.06 (d, 2H), 7.25 (m, 7H). 5 LRMS: m/z (ES+) 404 [ΜΗΠ 012756

Préparation 44 terf-Butvl (2EZ)-2-f2-(dimethvlamino)ethoxvf-3-( 1 -propyi-1 H-imidazol-4-vB-2- 10

Methanesulphonyl chloride (340μΙ, 4.4mmol) was added dropwise to an ice-cooiedsolution of the alcohol of Préparation 33 (1.36g, 4.0mmol) and triethylamine (616μΙ,4.4mmol) in dichloromethane (20ml). The solution was stirred at room températurefor 1 hour, additional triethylamine (616μΙ, 4.4mmol) was added, and the solution 15 was stirred at room température for 18 hours. TLC analysis showed startingmaterial remaining, so the solution was heated to reflux and stirred for a further 3hours. The cooled mixture was pre-adsorbed onto silica gel and purified by columnchromatography on silica gel using an elution gradient of ethyl acetate:diethylamine:methanol (100:0:0 to 96:2:2) to afford the title compound, 20 650mg. 1H-NMR (CDCI3,400MHz) (mixture of géométrie isomers) δ: 0^8 tt, 3H),1.56 (s, 9H), 1.84 (m, 2H), 2.34 (s, 6H), 2.65 (t, 2H), 3.94 (t, 2H), 4.04 (t, 2H), 7.08(s, 1 H), 7.44 (s, 1 H), 7.98 (s, 1 H). LRMS: m/z (TSP+) 324.2 [MH+] °’275fi

Préparation 45 terf-Butvl (3S)-3-fiYEZ)-1 -( fert-butoxvcarbonvl)-2-( 1 -propvi-1 B-imidazol-4- vl)ethenvl1oxvlpvrrolidine-1-carboxvlate

The title compound was obtained as an orange oil in 36% yield from the alcohol ofPréparation 34 following the procedure described in Préparation 44. 1H-NMR(CDCh, 400MHz) (mixture of géométrie isomers) δ: 0.93 (t, 3H), 1.35-1.56 (m, 18H),1.80 (m, 2H), 1.98 (m, 1H), 2.17 (m, 1H), 3.26-3.66 (m, 4H), 3.86 (m, 2H), 5.15 (m,1H), 7.06, 7.15 (2xs, 1H), 7.35, 7.39 (2xs, 1H), 7.41 (s, 1H). LRMS: m/z (ES+) 422[MH*]

Préparation 46 (2EZ)-4-Methvl-2-f(1 -propyl-1 H-imidazol-4-vl)methvlidene]-3-morpholinone

Triethyiamine (3.32ml, 23.8mmol) was added to a solution of the alcohol ofPréparation 24 (5.47g, 21.6mmol) in dichloromethane (80ml), and the solution wascooled in ice. A solution of methanesulphonyl chloride (1.84ml, 23.8mmol) indichloromethane (3ml) was added over 5 minutes, and the solution was stirred atroom température for 1 hour. The mixture was evaporated under reduced pressure,the residue was dissolved in Ν,Ν-dimethyIformamide (15ml), triethyiamine (3.32ml,23.8mmol) was added, and the solution was heated at reflux and stirred for 20minutes. The cooled solution was concentrated under reduced pressure and theresidue was dissolved in methanol (100ml) then adsorbed onto silica gel and purifiedby column chromatography on silica gel using an elution gradient of ethylacetate:methanol:diethylamine (100:0:0 to 95:5:0.5) to afford the title compound, w »^/56 84 2.5g. 1H-NMR (CDCI3,400MHz) (mixture of géométrie isomers) δ: 0.98 (t, 3H), 1.82(m, 2H), 3.14 (s, 3H), 3.59 (t, 2H), 3.90 (t, 2H), 4.26 (t, 2H), 7.00 (s, 1H), 7.35 (s, 1H), 7.45 (s, 1 H). LRMS: m/z (TSP*) 236.2 [MH*] 5 Préparation 47 (-)-(2S)-4-(4-Methoxvbenzvl)-2-IY1-propvl-t A7-imidazol-4-vl)rnethvn-3-morpholinone

A mixture of the alkene of Préparation 35 (8.3g, 24.3mmol) and 10% PdZC(Degussa® 101) (800mg) in éthanol (240ml) was hydrogenated at 100psi (690kPa) 10 and 50°C for 18 hours, then cooled and filtered through Arbocel®. The filtrate wasevaporated under reduced pressure to give an orange oil. This product was purifiedbÿ column chromatography on a Chiralcel® OJ column, using hexane: isopropylalcohokdiethylamine (70:30:0.5) as eluant, to afford enantiomer 1,1.65g, followed byenantiomer 2, the title compound, 1.54g. 1H-NMR (CDCI3, 400MHz) δ: 0.92 (t, 3H), 15 1.78 (m, 2H), 3.07 (m, 2H), 3.38 (m, 2H), 3.74 (m, 1H), 3.79 (m, 5H), 3.98 (m, 1H),4.52 (m, 3H), 6.72 (s, 1H), 6.82 (d, 2H), 7.18 (d, 2H), 7.38 (s, 1H). LRMS: m/z (ES*)344 [MH*]. [a]D = -66.10, (c = 0.368, methanol)

Préparation 48 20 (2RS)-2-f(1 -Butyl-1 H-imidazol-4-yt)methvn-4-(4-methoxvbenzvl)-3-morpholinone

A mixture of the alkene of Préparation 41 (2.5g, 6.96mmol) and 10% Pd/C(Degussa® 101) (250mg) in éthanol (100ml) was hydrogenated at 50°C and 60 psi(41 OkPa) for 18 hours. The cooled mixture was filtered through Arbocel® and the 25 filtrate was evaporated under reduced pressure to afford the tille compound as anoil, 2.44g. ’H-NMR (CDCI3, 400MHz) δ: 0.95 (t, 3H), 1.32 (m, 2H), 1.73 (m, 2H),3.04 (m, 2H), 3.34-3.42 (m, 2H), 3.73 (m, 1H), 3.78 (s, 3H), 3.82 (t, 2H), 3.98 (m, 012756 85 1 H), 4.45-4.60 (m, 3H), 6.74 (s, 1 H), 6.82 (d, 2H), 7.18 (d, 2H), 7.38 (s, 1 H). LRMS:m/z (TSP+) 358.2 [MH*]

Préparations 49 to 50 5 The compounds of the following general formula

were prepared from the appropriate alkene (Préparations 42 and 43), following asimilar procedure to that described in Préparation 48.

Prep. No. R Yield (%) Data 491 75, sticky gum ^H-NMR (CDCb 400MHz) δ: 0.96 (m, 2H), 1.20 (m, 4H), 1.68 (m, 7H), 3.04 (m, 2H), 3.40 (m, 2H), 3.74 (m, 1H), 3.80 (s, 3H), 3.86 (s, 3H), 3.98 (m, 1H), 4.55 (m, 2H), 6.74 (s, 1H), 6.84 (d, 2H), 7.18 (d, 2H), 7.38(s, 1H). LRMS: m/z (TSP+) 412.2 [MH*J 50 (Χ" 91 orange oil fH-NMR (CDCfe, 400MHz) δ: 3.00-3.10 (m, 4H), 3.35 (dd, 1H), 3.40 (dd, 1H), 3.70 (m,1H), 3.79 (s, 3H), 3.98 (m, 1H), 4.08 (t, 2H),4.45 (m, 1H), 4.55 (m, 2H), 6.69 (s;1H), 6.68 (d, 2H), 7.06 (d, 2H), 7.18 (d, 2H), 7.25(m, 4H). LRMS: m/z (ES+) 406 [MH*] 10 1 = purified by column chromatography on silica gel using an elution gradient of ethylacetateimethanol (100:0 to 90:10) 012756 86

Préparation 51 (2RS)-4-Methvl-2-f(1-propvl-1H-irnidazol-4-vl)methvn-3-morpholinone

CH3

O A mixture of the alkene of Préparation 46 (2.5g, 1.06mmol) and 10% Pd/O(Degussa® 101) (250mg) in éthanol (50ml) was hydrogenated at 50°C and 60 psi(41 OkPa) for 18 hours. The cooled mixture was filtered through Arbocel® and thefiltrate was evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel using an elution gradient of ethylacetate:methanol:diethyiamine (100:0:0 to 96.5:1.75:1.75) to afford the titlecompound as a colourless oil, 2.08g. 1H-NMR (CDCI3, 400MHz) δ: 0.95 (t, 3H), 1.80(m, 2H), 3.00 (m, 4H), 3.18 (m, 1H), 3.37 (m, 1H), 3.57 (m, 1H), 3.82 (m, 3H), 4.03(m, 1 H), 4.46 (dd, 1 H), 6.78 (s, 1 H), 7.39 (s, 1 H). LRMS: m/z (ES+) 238 [MH*]

Préparation 52 (2RS)-2-f(1 HJmidazol-4-v0methvll-4-(4-methoxvbenzvl)-3-rnorpholinone CH.

HN A mixture of the protected imidazole of Préparation 36 (25g, 46mmol) and Pd/CDegussa® 101 catalyst (2.5g) in éthanol (500ml) was hydrogenated at 5020-and 60psi (410kPa) for 18 hours. TLC analysis showed starting material remaining, so themixture was filtered through Arbocel® and the filtrate was hydrogenated using freshcatalyst (2.5g) in ethano, (500ml) at 50°C and 60 psi (410kPa) for a further 18 hours.The mixture was filtered through Arbocel® and the filtrate was evaporated underreduced pressure. The product was purified by column chromatography on silicagel using an elution gradient of dichloromethane:methanol:0.88 ammonia (98:2:0.2to 95:5:0.5) to afford the title compound as a white foam, 9g. 1H-NMR (CDGb,400MHz) δ: 3.01 (m, 1H), 3.18 (m, 2H), 3.38 (m, 1H), 3.70 (dd, 1H), 3.78 (s, 3H),3.97 (dd, 1H), 4.32 (m, 1H), 4.50 (dd, 2H), 6.81 (d, 2H), 6.86 (s, 1H), 7.02 (d, 2H), 012756 87 7.46 (s, 1 H). LRMS: m/z (ES+) 302 [MH*]

Préparation 53 (-)-i2S)-2-iil A/-lmidazol-4-vl)methvll-4-i4-methoxvbenzyl)-3-morpholinone and

Préparation 54 (+l·(2Rl·2-f(1H-lmidazol-4-vΠmethvl1-4-(4-methoxvbenzvll·3-morpho^inonΘ

The racemic compound of Préparation 52 was further purified by HPLC using aChiralpak® OD column, and hexane:isopropyl alcohol (80:20) as eluant to afford thetitle compound of préparation 53, >99%ee. 1H-NMR (CDCb, 400MHz) δ: 3.01 (m,1H), 3.18 (m, 2H), 3.38 (m, 1H), 3.70 (dd, 1H), 3.78 (s, 3H), 3.97 (dd, 1H), 4.32 (m,1H), 4.50 (dd, 2H), 6.81 (d, 2H), 6.86 (s, 1H), 7.02 (d, 2H), 7.46 (s, 1H). LRMS: m/z(ES*) 324 [MNa*]. [a]D = -529.3 (c = 0.05, methanoi).

Further elution gave the title compound of préparation 54, >99%ee. 1H-NMR(CDCI3,400MHz) δ: 3.01 (m, 1H), 3.18 (m, 2H), 3.38 (m, 1H), 3.66-3.79 (m, 4H),3.97 (dd, 1H), 4.32 (t, 1H), 4.50 (dd, 2H), 6.81 (d, 2H), 6.86 (s, 1H), 7.02 (d, 2H), 7.46 (s, 1 H). LRMS: m/z (ES*) 324 [MNa*]

Préparation 55a (2S,6/7F2-r(1 Wmidazol-4-yl)rnethvn-4-(4-methoxvbenzvh-6-methyl-3-morpholinone and

A mixture of the alkene of Préparation 154 (41g, 131mmol) and 10% palladium oncarbon (Degussa type 101) (8g) in ethanoi (500ml) was hydrogenated at 50 psi(345kPa) and 60°C for 24 hours. The mixture was filtered through Arbocel®, thefiltrate was concentrated under reduced pressure and the residue was azeotroped 88 0T2756 with dichloromethane. The crude product was purified by column chromatographyon siiica gel using a Biotage column, eiuting with a solvent gradient ofdichloromethane:methanol:0.88 ammonia (97.5:2.5:0.1 to 90:10:1 ). The higherrunning, major product was repurified by column chromatography on siiica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.25) to afford the title compound ofpréparation 55a as a white foam. 1H-NMR (CDCI3,400MHz) δ: 1.19 (d, 3H), 2.97- 3.22 (m, 4H), 3.78' (s, 3H), 3.84 (m, 1H), 4.32 (t, 1H), 4.40 (d, 1H), 4.50 (d, 1H), 6.80(d, 2H), 6.86 (s, 1 H), 7.00 (d, 2H), 7.46 (s, 1H). LRMS: m/z (ES") 314 [M-H]’

The lower running, minor product was further purified by column chromatography onsiiica gel using ether:methanol:0.88 ammonia (90:10:1) as eluant and the productwas azeotroped with dichloromethane to afford the title compound of préparation 55bas a white foam, 220mg. 1H-NMR (CDCfe, 400MHz) 5:1.19 (d, 3H), 2.97-3.22 (m,4H), 3.78 (s, 3H), 3.84 (m, 1H), 4.32 (t, 1H), 4.40 (d, 1H), 4.50 (d, 1H), 6.80 (d, 2H),6.86 (s, 1 H), 7.00 (d, 2H), 7.46 (s, 1 H).

Préparation 56 (2fl.6S)-2“f(1H-lmidazol-4-vl)methvn-4-(4-methoxvbenzvl)-6-methvl-3-morpholinone

The title compound was obtained in 20% yield from the protected alkene ofPréparation 38 following the procedure described in 52. 1H-NMR (CDCU ^OOMHz)δ: 1.19 (d, 3H), 2.99 (m, 2H), 3.17 (m, 2H), 3.78 (s, 3H), 3.83 (m, 1H), 4.30 (m, 1H),4.44 (dd, 2H), 6.80 (d, 2H), 6.85 (s, 1H), 7.00 (d, 2H), 7.45 (s, 1H). LRMS: m/z(ES+) 316 [MH]+

Préparation 57 (2S,55)-2-f(1H-lmidazol-4-vl)methvn-4-(4-methoxybenzvl)-5-methvl-3-morpholinone

O 0 >2756 89

The title compound was obtained in 47% yieid from the protected alkene ofPréparation 39 following a similar procedure to that described in Préparation 52. 1HNMR (CDCI3, 400MHz) (—3:1 mixture of depicted C-2 stereoisomer) δ: 1.15 (d, 3H), 3.22 (m, 3H), 3.48, 3.70-4.00 (2xm, 6H), 4.38 (m, 1H), 5.18-5.37 (m, 1H), 6.83 (d,2H), 6.98 (m, 1H), 7.18 (d, 2H), 7.62 (s, 1 H). LRMS: m/z (ES') 314 [M-H']

Préparation 58 i2R.5ffl-2-f(1H-lmidazoi-4-vl)methvn-4-(4-methoxvbenzvl)-5-methvl-3-morpholinone

The title compound was obtained in 67% yieid from the protected imidazole ofPréparation 40 following a similar procedure to that described in Préparation 52. 1HNMR (CDCfe, 400MHz) (-3:1 mixture of depicted C-2 stereoisomer) δ: 1.16 (d, 3H), 3.22 (m, 3H), 3.46, 3.70-3.98 (2xm, 6H), 4.35, 4.39 (2xm, 1H), 5.20, 5.30 (2xd, 1H),6.82,6.94 (2xm, 3H), 7.18 (d, 2H), 7.53 (2xs, 1H). LRMS: m/z (ES') 314 [M-H']

Préparation 59 (2RS)-(( 1 -f2-(4-Bromophenvi)ethvn-1 H-imidazol-4-vnmethvl)-4-(4-methoxvbenzvn-3- morpholinone

Sodium hydride (836mg, 60% dispersion in minerai oii, 20.9mmol) was addedportionwise to an ice-cooled solution of the imidazole of Préparation 52 (5g, 19.9mol)in tetrahydrofuran (100ml), and the solution was stirred for 15 minutes. 4-Bromophenylethyl methanesulphonate (Bioorg. Med. Chem. 1996; 4(5); 645) (6.1g,21.9mmol) was then added, and the mixture was stirred at room température for 3days. The reaction was quenched with water (50ml), and the mixture was extractedwith ethyl acetate (2x100ml). The combined organic extracts were dried (MgSCfe)and evaporated under reduced pressure. The crude product was purified by column „ <”2756 chromatography on silica gel using an elution gradient of dichloromethane:methanoi:0.88 ammonia (99:1:0.1 to 95:5:0.5) to afford the title compound, 4.4g. 1H-NMR (CDCI3,400MHz) δ: 2.97 (t, 2H), 3.04 (m, 2H), 3.36 (m, 2H), 3.70 (m, 1H), 3.78 (s, 3H), 3.97 (m, 1H), 4.03 (t, 2H), 4.45 (m, 1H), 4.54 (dd, 5 2H), 6.62 (s, 1 H), 6.82 (d, 2H), 6.90 (d, 2H), 7.18 (d, 2H), 7.20 (s, 1 H), 7.39 (d, 2H).

Préparation 60 (-)-(2S)-2-ff 1 -(2-Cvclohexylethvh-1 /7-imidazol-4-vllmethvl)-4-(4-methoxvbenzvn-3- morpholinone

A mixture of the compound of Préparation 53 (400mg, 1.32mmol), césium carbonate(472mg, 1.45mmol), and 2-cyclohexylethyl bromide (227μΙ, 1.45mmol) in N.N-dimethylformamide (4ml) was stirred at 80°C for 18 hours. The cooled mixture waspartitioned between ethyl acetate (250ml) and water (100ml), and the layers were 15 separated. The organic phase washed with water (3x100ml), dried (MgSO4) andevaporated under reduced pressure. The crude product was purified twice bycolumn chromatography on silica gel using first an elution gradient ofdichloromethane:methanol:0.88 ammonia (100:0:0 to 95:5:0.5), then using an elutiongradient of ethyl acetate:diethylamine (100:0 to 95:5), to afford the title compound, 20 as a colourless gum, 191 mg. 1H-NMR (CDCb, 400MHz) δ: 0.90 (m, 2H), 1.04-1.24(m, 4H), 1.60 (m, 7H), 3.02 (m, 2H), 3.26-3.40 (m, 2H), 3.70 (m, 1H), 378 (s, 3H),3.81 (t, 2H), 3.97 (m, 1H), 4.42-4.58 (m, 3H), 6.68 (s, 1H), 6.80 (d, 2H), 7.14 (d, 2H), 7.35 (s, 1 H). LRMS: m/z (ES+) 412 [MH+J. [a)D = -50.37, (c = 0.112 in methanol) 012756 91

Préparation 61 (2fî.65f)-2-ii1-i2-Cvclohexvlethvl)-1/-/-imidazol-4-vnmethvl)-4-(4-methoxvbenzvl)-6-

A mixture of the compound of Préparation 56 (200mg, 0.635mmol), césiumcarbonate (248mg, 0.762mmol) and 2-cyclohexylethyl bromide (109μΙ, 0.70mmoi) inΝ,Ν-dirnethylformamide (8ml) was stirred at 70°C for 18 hours. The cooled mixturewas partitioned between ethyl acetate (10ml) and water (10ml), and the layers wereseparated. The organic phase washed with water (2x20ml) and brin© (20ml), thendried (MgSO4) and evaporated under reduced pressure. The crude product waspurified by coiumn chromatography on silica gel using an elution gradient ofdichloromethane:methanol:0.88 ammonia (99:1:0.1 to 98:2:0.2) to afford the titlecompound as a colourless gum, 120mg. 1H-NMR (CDCI3,400MHz) δ: 0.90 (m, 2H),1.18 (m, 7H), 1.62 (m, 7H), 2.94-3.08 (m, 3H), 3.32 (dd, 1H), 3.78 (s, 3H), 3.80 (m,3H), 4.43 (m, 3H), 6.66 (s, 1H), 6.80 (d, 2H), 7.14 (d, 2H), 7.32 (s, 1H). LRMS: m/z(ES+) 426 (MH*]

Préparation 62 (2S,6fl)-2-(f 1 -(2-Cvciohexvlethvl)-1 Wmidazol-4-vnmethvl}-4-(4-methoxvbenzv0-6- methvl-3-morpholinone

The title compound was obtained as a colourless oil in 38% yield from the imidazoleof Préparation 55 and 2-cyclohexylethyl bromide following the procedure describedin Préparation 61. 'H-NMR (CDCI3, 400MHz) δ: 0.90 (m, 2H), 1.17 (m, 7H), 1.61 (m,7H), 2.94-3.08 (m, 3H), 3.32 (dd, 1H), 3.78 (s, 3H), 3.81 (m, 3H), 4.43 (m, 3H), 6.66(s, 1H), 6.80 (d, 2H), 7.12 (d, 2H), 7.32 (s, 1H). LRMS: m/z (ES*) 448 [MNa*] 012756 92

Préparation 63 (2S,5S)-2-(f 1 -(2-Cvclohexvlethvl)-1 Wmidazol-4-vHmethvl)-4-(4-methoxvbenzvB-5- methvl-3-morphoiinone

The title compound was obtained in 21% yîeld from the imidazole of Préparation 57foltowing a similar procedure to that described in Préparation 61, except that ethylacetate:methanol:diethylamine (98:1:1) was used as the column eluant. 1H-NMR(CDCI3,400MHz) (mixture of C-2 diastereoisomers) δ: 0.98 (m, 2H), 1.20 (m, 7H), 10 1.68 (m, 7H), 3.05-3.98 (m, 11H), 4.50 (m, 1H), 5.22-5.40 (m, 1H), 6.76, 6.84 (s andm, 3H), 7.14, 7.20 (2xd, 2H), 7.39 (m, 1 H). LRMS: m/z (ES*) 426 [MH*]

Préparation 64 (2R,5fl)-2-ff1-(2-Gvclohexylethvl)-1 Wmidazol-4-vl1rnethvl)-4-(4-methoxvbênzvl)-5- 15 methvl-3-morpholinone

The title compound was obtained in 40% yield from the imidazole of Préparation 58foTlowing a similar procedure to that described in Préparation 61. 1H-NMR (CDCI3,400MHz) (mixture of C-2 diastereoisomers) δ: 0.90 (m, 2H), 1.18 (m, 7H), 1.63 (m, 20 7H), 3.01-3.33 (m, 3H), 3.61-3.90 (m, 8H), 4.42 (m, 1H), 5.22 (m, 1H), 6.72 (s, 1H),6.80 (d, 2H), 7.16 (d, 2H), 7.35 (s, 1H). LRMS: m/z (ES*) 426 [MH*] 93 012756

Préparation 65 (2S.6fî)-2-ff 1 -(3-Cvclohexvl-3-methvlbiitvB-1 H-imidazol-4-vnmethvl)-4-(4- methoxvbenzv0-6-methvl-3-morpholinone

A mixture of the bromide of Préparation 21 (420mg, 1.8mmol), the imidazole ofPréparation 55 (470mg, l.5mmol) and césium carbonate (586mg, 1.8mmol) in N,N-dimethylformamide (5ml) was stirred at 70°C for 18 hours. The cooled mixture wasconcentrated under reduced pressure and partitioned between ethyl acetate (20ml)and water (20ml) and the layers were separated. The aqueous phase was extractedwith ethyl acetate (3x15ml), and the combined organic solutions were washed withbrine (15ml), dried (MgSO4) and evaporated under reduced pressure. The crudeproduct was purified by column chromatography using a Biotage® silica column andtoluene:diethylamine (99:1 to 85:15) as eluant to afford the title compound, 60mg.1H-NMR (CDCfe, 400MHz) δ: 0.82 (s, 6H), 0.90-1.10 (m, 8H), 1.63 (m, 3H), 1.78 (m,5H), 2.94-3.06 (m, 3H), 3.30 (dd, 1H), 3.79 (m, 6H), 4.40-4.55 (m, 3H), 6.68 (s, 1H),6.80 (d, 2H), 7.10 (d, 2H), 7.32 (s, 1H). LRMS: m/z (ES+) 468 (MH*]

Préparation 66 (2S,6fl)-2-{( 1 -r2-(4,4-Dimethvlcvclohexvl)ethvn-1 A7-8midazol-4-yllmethvl)-4-(4-

The title compound was obtained in 10% yield from the bromide of Préparation 22and the imidazole of Préparation 55 foliowing a similar procedure to that described inPréparation 65. 1H-NMR (CDCI3, 400MHz) δ: 0.84 (2xs, 6H), 1.16 (m, 8H), 1.37 (m,2H), 1.50 (m, 2H), 1.63 (m, 2H), 2.97-3.10 (m, 3H), 3.35 (dd, 1H), 3.79 (s, 3H), 3.85 012756 94 (m, 3H), 4.48 (m, 3H), 6.70 (s, 1H), 6.82 (d, 2H), 7.16 (d, 2H), 7.35 (s, 1H). LRMS:m/z (ES+) 454 [MH+]

Préparation 67 (2RS)-2-ff 1 -i(2gZ-3-Brorno-2-propenvl1-1 H-imidazol-4-vl}methv0-4-(4-

Sodium hydride (133mg, 60% dispersion in minerai oil, 3.32mmo!) was added to anice-cooled solution of the morphoiinone of Préparation 52 (1g, 3.32mmol) intetrahydrofuran (10ml). 1,3-Dibromo-1-propene (mixture of cis and trans) (332μΙ,3.32mmol) was added dropwise over 5 minutes then the mixture was allowed towarm to room température and stirred for 2 hours. The mixture was partitionedbetween water (50ml) and ethyl acetate (50ml), and the phases were separated.The aqueous layer was extracted with ethyl acetate (10ml), and the combinedorganic solutions were dried (Na2SO4) and evaporated under reduced pressure.The crude product was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (98:2:0.2) as eluant to afford the titlecompound as a colourless oil, 1.1g. 1H-NMR (CDCb, 400MHz) (mixture ofgéométrie isomers) δ: 3.02 (m, 2H), 3.26-3.40 (m, 2H), 3.68 (m, 1 H), 3.78 (s, 3H),3.96 (m, 1 H), 4.40 (d, 1H), 4.42-4.55 (m, 3H), 4.60 (m, 1H), 6.22 (m, 1H), 6.70 (2xs,1 H), 6.80 (m, 3H), 7.15 (m, 2H), 7.38 (2xs, 1 H). LRMS: m/z (ES+) 4207422 [MH4]

Préparation 68 (2RS)-4-(4-MethoxybenzvO-2-lY 1 -phenyl-1 H-imidazol-4-vl)methvll-3-morpholinone

4Â Molecular sieves, copper (il) acetate (452mg, 2.49mmol) and benzeneboronicacid (405mg, 3.32mmol) were added to a solution of the imidazole of Préparation 52 „012756 (500mg, 1.66mmol) and pyridine (269μΙ, 3.32mmol)in dichloromethane (20mlj, andthe solution was stirred at room température for 18 hours. Compressed air was thenbubbled through the solution for 10 hours. The solvent was retained by using a“coid finger". The solution was then stirred under a nitrogen atmosphère for afurther 18 hours. A solution of ethylenediaminetetraacetic acid (800mg) in saturatedsodium bicarbonate solution (35ml) was added and the mixture was stirred for 20minutes, then extracted with dichloromethane (70ml). The aqueous phase wasfurther was extracted with dichloromethane (20ml) and the combined organicsolutions were washed with water (10ml), dried (MgSCU) and concentrated underreduced pressure. The residual black soiid was purified by column chromatographyon silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia(98:2:0.2 to 97:3:0.3) to afford the title compound as a pale yellow oil, 175mg. 1H-NMR (CDCI3,400MHz) δ: 3.02 (m, 1H), 3.18 (m, 1H), 3.38 (m, 2H), 3.70-3.79 (m, 4H), 3.99 (m, 1H), 4.42 (d, 1H), 4.50 (m, 1H), 4.60 (d, 1H), 6.77 (m, 2H), 7.10 (m, 3H), 7.32 (m, 3H), 7.41 (m, 2H), 7.78 (bs, 1H). LRMS: m/z (ES+) 400 [MNa4]

Préparation 69 (2RS)-2-ff 1 -(2-methvlphenvl)-1 H-imidazol-4-vllmethvl)-4-(4-Methoxvbenzvl)-3- morpholinone

The title compound was obtained in 16% yield from the imidazole of Préparation 52and 2-methylbenzeneboronic acid following the procedure described in Préparation68. 1H-NMR (CDCI3, 400MHz) δ: 2.15 (s, 3H), 3.02 (m, 1H), 3.18 (m, 1H), 3.38 (m,2H), 3.77 (m, 4H), 3.98 (m, 1H), 4.54 (m, 3H), 6.78 (d, 2H), 6.85 (bs, 1H), 7.15 (m,3H), 7.21 (s, 1H), 7.25 (m, 2H), 7.45 (bs, 1H). LRMS: m/z (TSP+) 470.2 [MH4] 012756 96

Préparation 70 (2RS)-2-{f 1 -(3-phenoxyphenvD-1 /7-imidazol-4-vl1methvl}-4-(4-Methoxvbenzvl)-3- morpholinone

4Â Molecular sieves (50mg), copper (II) acetate (174mg, 0.96mmol) and 3-phenoxyphenylboronic acid (J. Chem. Soc. 1970; 488) (350mg, 1.6mmol) wereadded to a solution of the imidazole of Préparation 52 (240mg, 0.8mmol) andpyridine (130μΙ, 1.6mmol) in dichloromethane (2ml). Compressed air was thenbubbled through the solution, maintained at 20-25°C using a water bath, for 7 hours,and the solvent was retained by using a “cold finger”. The solution was then stirredunder a nitrogen atmosphère for a further 18 hours. The mixture was partîtionedbetween dichloromethane (80ml) and a solution of ethylenediaminetetraacetic acidtetrasodium sait (1g) in saturated sodium bicarbonate solution (30ml) and the phaseswere separated. The organic layer was dried (MgSO-i) and concentrated underreduced pressure. The residue was purified by column chromatography on silica ge,using an elution gradient of ethyl acetate:diethylamine (100:0 to 95:5). The productwas further purified by column chromatography using a Biotage® silica gel column,and an elution gradient of toluene:diethylamine (100:0 to 88:12) to afford the titlecompound as a pale yellow gum, 120mg. 1H-NMR (CDCI3, 400MHz) δ: 3.01 (m,tH), 3.15 (dd, 1H), 3.38 (m, 2H), 3.72 (m, 4H), 3.97 (m, 1H), 4.45 (d~TM),'4.50 (m,1H), 4.58 (d, 1H), 6.77 (d, 2H), 6.90 (m, 1H), 6.97 (m, 1H), 7.00-7.18 (m, 7H), 7.37(m, 3H), 7.75 (s, 1 H). LRMS m/z (TSP+) 470.2 {MH4]

Préparations 71 to 73

The following compounds of general structure

were prepared from the morpholinone of Préparation 52 and the appropriate boronic 97 01275e acids, foliowing a similar procedure to that described in Préparation 70.

Prep R Yield (%) Data 71 % 8 1H-NMR (CDCIa, 400MHz) δ: 3.00 (m, 2H), 3.26 (m, 2H), 3.62 (m, 1H), 3.75 (s, 3H), 3.90(m, 1H), 4.38 (m, 1H), 4.48 (s, 2H), 6.61 (s, 1H), 6.78 (d, 2H), 7.02 (m, 2H), 7.14 (d, 2H),7.22 (m, 4H), 7.30 (m, 1H), 7.40 (m, 3H). LRMS: m/z (ES+) 454 [MH+] 72 ca 19 orange oil *H-NMR (CDCIa, 400MHz) δ: 3.06 (m, 1H), 3.22 (m, 1H), 3.41 (m, 2H), 3.62 (s, 3H), 3.79(m, 1 H), 4.01 (m, 1 H), 4.46 (d, 1 H), 4.59 (m, 1H), 4.62 (d, 1H), 6.78 (d, 2H), 7.15 (d, 2H), 7.24 (m, 1H), 7.50 (m, 3H), 7.79 (s, 1H), 7.84(dd, 1H), 7.95 (m, 2H). LRMS: m/z (ES+) 450[MNa+] 73 "Or 20 colour- less oil ’H-NMR (CDCIa, 400MHz) δ: 3.05 (m, 1H), 3.18 (dd, 1H), 3.40 (m, 2H), 3.77 (m, 4H), 4.00(m, 1H), 4.48 (d, 1H), 4.55 (m, 1 H), 4.62 (d, 1H), 6.80 (d, 2H), 7.14 (d, 2H), 7.21-7.37 (m, 3H), 7.45 (m, 1H), 7.54 (s, 1H), 7.78 (s, 1H).LRMS: m/z (TSP+) 457.7 [MH4]

Préparations 74 to 76

The foliowing compounds of general structure

were prepared from the morpholinone of Préparation 53 and the appropriate boronicacids, foliowing a similar procedure to that described in Préparation 70. 012756 98

Prep R Yield (%) Data 74 σ 30 solid 1H-NMR (CDCI3, 400MHz) δ: 3.02 (m, 1H), 3.18 (dd, 1H), 3.39 (m, 2H), 3.72 (m, 4H), 3.98(m, 1H), 4.43 (d, 1H), 4.52 (m, 1H), 4.60 (d, 1H), 6.75 (d, 2H), 7.10 (m, 3H), 7.31 (m, 3H),7.42 (dd, 2H), 7.78 (s, 1 H). LRMS: m/z(TSP+) 378.1 [MH4]. [a]D = -34.8, (c = 0.10,methanol) 75 h3c^i H3C^CH3 9 oil 1H-NMR (CDCI3, 400MHz) δ: 1.37 (s, 9H), 3.04 (m, 1H), 3.19 (dd, 1H), 3.40 (m, 2H), 3.76 (m,4H), 4.00 (m, 1H), 4.46 (d, 1H), 4.58 (m, 1H),4.62 (d, 1H), 6.78 (d, 2H), 7.14 (m, 3H), 7.26(d, 2H), 7.44 (d, 2H), 7.77 (s, 1 H). LRMS: m/z(TSP+) 434.2 [MH4] 76 cf3 12 gum 'H-NMR (CDCI3, 400MHz) δ: 3.10 (m, 1H), 3.19 (dd, 1H), 3.41 (m, 2H), 3.78 (m, 4H), 4.00(m, 1H), 4.58 (m, 3H), 6.80 (d, 2H), 7.17 (d, 2H), 7.20 (s, 1H), 7.80 (s, 2H), 7.83 (d, 2H).LRMS: m/z (TSP+) 514.0 [MH4]. [a]D = -28.96, (c = 0.096, methanol)

Préparations 77 to 80

The following compounds of general structure

5 were prepared from the morpholinone of Préparation 55 and the appropriate boronicacids, following a similar procedure to that described in Préparation 70. 99

Prep R Yield (%) Data 77 ’O' 33 sticky gum 1H-NMR (CDCI3,400MHz) δ:Ί .18 (d, 3H), 2.98-3.18 (m, 3H), 3.35, 3.38 (2xd, 1H), 3.70(m, 3H), 3.85 (m, 1H), 4.41 (d, 1H), 4.52 (m, 1H), 4.58 (d, 1H), 6.77 (d, 2H), 7.05 (m, 4H),7.20-7.34 (m, 1H), 7.42 (d, 1H), 7.47 (s, 1H),7.75 (s, 1 H). LRMS: m/z (TSP+) 470.1,472.0[MH4] 78 σ 28 1H-NMR (CDCI3,400MHz) δ: 1.19 (d, 3H), 3.00 (dd, 1H), 3.05-3.22 (m, 2H), 3.40 (dd, 1H), 3.75 (s, 3H), 3.92 (m, 1H), 4.42 (d, 1H), 4.57(m, 1H), 4.60 (d, 1H), 6.78 (d, 2H), 7.10 (m, 3H), 7.34 (m, 3H), 7.43 (m, 2H), 7.78 (s, 1H).LRMS: m/z (ES+) 392 [MH4] 791 9 11 1H-NMR (CDCia, 400MHz) δ: 1.18 (d, 3H), 3.00 (dd, 1H), 3.04-3.19 (m, 2H), 3.38 (dd, 1H), 3.76 (S, 3H), 3.87 (m, 1H), 4.42 (d, 1H), 4.55(m, 1H), 4.58 (d, 1H), 6.78 (d, 2H), 6.96 (m, 2H), 7.02-7.18 (m, 7H), 7.38 (m, 3H), 7.76 (s, 1 H). LRMS: m/z (ES4) 484 [MH4] 80 9 u 41 white foam ’H-NMR (CDCI3, 400MHz) Ô: 1.19 (d, 3H), 3.00 (dd, 1 H), 3.07-3.20 (m, 2H), 3.40 (dd, 1 H), 3.77 (s, 3H), 3.90 (m, 1H), 4.42 (d, 1H), 4.55(m, 1H), 4.60 (dd, 1H), 6.78 (d, 2H), 7.01-7.18(m, 8H), 7.26 (d, 2H), 7.38 (dd, 2H), 7.72 (s, 1 H). LRMS: m/z (ES4) 484 [MH4] 1 = 3-phenoxyphenylboronic acid (J.Chem.Soc. 1970; 488) was used 012756 100

Préparation 81 (2S,6/7)-2-f Γ 1 -(4-Cvclohexvlphenvl)-1 H-imidazol-4-vi1methvl)-4-(4-methoxvbenzvn-6- methvl-3-morpholinone ÇHa ch,

O A mixture of copper (II) acetate (398mg, 2.2mmol), 4-cyclohexyibenzeneboronic acid(980mg, 4.8mmol), the imidazole of Préparation 55 (790mg, 2.4mmol) and pyridine(390μΙ, 4.8mmol) in dichloromethane (20ml) was stirred at room température whilecompressed air was bubbled through the solution for 8 hours, and the solvent wasretained by using a “cold finger”. The solution was then stirred under a nitrogenatmosphère for a further 18 hours. The mixture was partitioned betweendichloromethane (200ml) and water (200ml) containing ethylenediaminetetraaceticacid tetrasodium sait (1 g) and aqueous sodium bicarbonate solution (35ml) and thelayers were separated. The organic phase was dried (MgSCM and concentratedunder reduced pressure. The residue was purified by column chromatography usinga Biotage® silica gel column and an elution gradient of toluene:diethylamine (95:5 to92:8) to afford the title compound, 140mg. 1H-NMR (CDCI3,400MHz) δ: 1.15-1.47(m, 9H), 1.72-1.94 (m, 4H), 2.55 (m, 1H), 2.99 (dd, 1H), 3.03-3.20 (m, 2H), 3.39 (dd,1H), 3.73 (s, 3H), 3.90 (m, 1H), 4.42 (d, 1H), 4.56 (m, 2H), 6.78 (d, 2H), 7.02-7.19 (m, 5H), 7.20 (m, 2H), 7.74 (s, 1 H). LRMS: m/z (ES+) 474 [MH+]

Préparation 82 4-(Cvclohexvloxv)phenvlboronic acid A solution of 4-(cyclohexyloxy)phenylbromide (J. Am. Chem. Soc. 1978; 3559) intetrahydrofuran (40ml) was degassed then cooled to -78°C. n-Butyl lithium(13.47ml, 1.45M in hexanes, 19.5mmol) was added dropwise, and the mixture wasstirred for 30 minutes. Triisopropyl borate (5.01ml, 26.6mmol) was added dropwise 012756 101 over 10 minutes, and the mixture was allowed to warm slowly, with stirring, to roomtempérature, then poured into sodium hydroxide solution (0.25M, 300ml). Thismixture was stirred for 15 minutes then extracted with diethyl ether (2x150ml). Theaqueous layer was acidified to pH 1 using concentrated hydrochloric acid and 5 extracted with dichloromethane (2x150ml). These combined organic extracts weredried (MgSC>4) and evaporated under reduced pressure to give the title compound asa white solid, 3.1g. 1H-NMR (CDCI3, 400MHz) δ: 0.88-1.62 (m, 7H), 1.80 (m, 2H),2.00 (m, 2H), 4.39 (m, 1 H), 6.98 (d, 2H), 8.17 (d, 2H). 10 Préparation 83 (25.6f^-2-((1-f4-(Cvclohexvloxvbhenvn-1 H-imidazol-4-vl)methvi)-4-(4-

The title compound was obtained in 41% yield from the imidazole of Préparation 5515 and the boronic acid of Préparation 82 following a simiiar procedure to that described in Préparation 81. 1H-NMR (CDCfe, 400MHz) δ: 1.19 (d, 3H), 1.38 (m, 3H), 1.57 (m,3H), 1.80 (m, 2H), 1.99 (m, 2H), 2.99 (dd, 1H), 3.04-3.20 (m, 2H), 3.39 (dd, 1H), 3.77(s, 3H), 3.88 (m, 1H), 4.22 (m, 1H), 4.42 (d, 1H), 4.56 (m, 1H), 4.60 (d, 1H), 6.79 (d,2H), 6.96 (d, 2H), 7.02 (s, 1H), 7.10-7.28 (m, 4H), 7.65 (s, 1H). LRMS: m/z (ES4) 20 490 [MH4] 102 012756

Préparation 84 (2RS)2-ff 1 -(4'-Chloroi 1.1 '-biphenvll-3-vl)-1 H-imidazol-4-vnmethvll-4-f4-

5 A mixture of the bromide of Préparation 73 (200mg, 0.44mmol), 4-chlorophenyl-boronic acid (207mg, 1.32mmol), lithium chloride (56mg, 1.32mmol), césiumcarbonate (433mg, 1.32mmol) and tetrakis(triphenylphosphîne)palladium(0) (51 mg,0.044mmol) in water (2ml) and tetrahydrofuran (5ml) was stirred at 75°C for 18hours. The cooled mixture was partitioned between dichloromethane and 2M 10 sodium carbonate solution containing 6% v/v 0.88 ammonia. The organic phasewas separated, dried (MgSO4) and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel using an eiutiongradient of toluene:diethylamine (95:5 to 93:7) to afford the title compound as a paieyellow oil, 150mg. 1H-NMR (CDCfe, 400MHz) δ: 3.05 (m, 1 H), 3.20 (dd, 1H), 3.42 15 (m, 2H), 3.72 (s, 3H), 3.78 (m, 1 H), 4.00 (m, 1 H), 4.48 (d, 1 H), 4.58 (dd, 1 H), 4.62 (d, 1H), 6.78 (d, 2K), 7.14 (d, 2H), 7.20 (s, 1H), 7.35-7.59 (m, 8H), 7.82 (s, 1H). z Préparation 85 -__ (2S,6R)-2-ff 1 -O'-Chlorof 1 ,r-biphenvn-3-vt)-1 H-imidazol-4-vnmethvl)-4-(4- 20 methoxybenzyl)-6-methvl-3-morpholinone

The title compound was obtained as a white solid in 63% yield from the bromide of 012756 103

Préparation 77 and 3-chlorobenzeneboronic acid following a similar procedure to thatdescribed in Préparation 84. 1H-NMR (CDCfe, 400MHz) δ: 1.20 (d, 3H), 3.00 (dd,1H), 3.07-3.21 (m, 2K), 3.41 (dd, 1H), 3.72 (s, 3H), 3.90 (m, 1H), 4.44 (d, 1H), 4.58(m, 2H), 6.78 (d, 2H), 7.13 (d, 2H), 7.20-7.58 (m, 9H), 7.82 (s, 1 H). LRMS: m/z(ES4) 502, 504 [MH4]

Préparation 86 (2RS]-2-f[1 -O'.^-DichioroM ,1 '-biphenvn-3-vl)-1 /-/-imidazol-4-vnmethvl)-4-(4- methoxvbenzvl)-3-morpholinone

A mixture of the bromide of Préparation 73 (200mg, 0.44mmoi), 3,4-dichloro-benzeneboronic acid (102mg, 0.53mmol), lithium chloride (56mg, 1.32mmol), césiumcarbonate (433mg, 1.32mmol) and tetrakis(triphenylphosphine)palladium(0) (26mg,0.022mmol) in water (2ml) and tetrahydrofuran (5ml), was stirred at 75°C for 2.5hours. TLC analysis showed starting materia, remaining, so additional 3,4-dichlorobenzeneboronic acid (204mg, 1.06mmol) and tetrakis(triphenylphosphine)-palladium(O) (26mg, 0.022mmol) were added and the mixture was heatedjor afurther 18 hours at reflux. The cooled mixture was partitioned betweendichloromethane and 2M sodium carbonate solution containing 6% v/v 0.88ammonia. The organic phase was separated, dried (MgSCX») and concentratedunder reduced pressure. The residue was purified by column chromatography onsilica gel using an elution gradient of toluene:diethylamine (95:5 to 93:7) to afford thetitle compound as a crystalline solid, 165mg. 1H-NMR (CDCI3,400MHz) δ: 3.06 (m,1H), 3.20 (dd, 1H), 3.41 (m, 2H), 3.75 (m, 4H), 4.00 (m, 1H), 4.48 (d, 1H), 4.58 (m,1H), 4.62 (d, 1H), 6.58 (2xs, 2H), 7.18 (m, 3H), 7.40 (m, 2H), 7.52 (m, 4H), 7.65 (s,1H),7.82(s, 1H). LRMS: m/z (ES4) 522, 524 [MH4] 012756 104

Préparation 87 (2S,6H)-2-([ 1 -(3',4-Dichloror 1.1 '-biphenvn-3-vh-l H-irnidazol-4-vHmethvl)-4-(4- methoxvbenzvl)-6-methvl-3-morpholinone

A mixture of the bromide of Préparation 77 (200mg, 0.425mmol), 3,4-dichloro-benzeneboronic acid (243mg, 1.27mmol), lithium chloride (54mg, 1.27mmol), césiumcarbonate (416mg, 1.32mmol) and tetrakis(triphenylphosphine)palfadium(0) (23mg,0.02mmol) in water (2ml) and tetrahydrofuran (5ml) was stirred at 75°C for 3 hours.The cooled mixture was partitioned between ethyl acetate (100ml) and water (50ml).The organic phase was separated, dried (MgSO4) and concentrated under reducedpressure. The residue was purified by column chromatography on silica gel usingan elution gradient of pentane:ethyl acetateimethanol (50:50:0 to 0:100:0 to 0:95:5)to give a white foam. This was further purified by column chromatography using aBiotage® silica gel column, and an elution gradient of ethyl acetate:methanol (100:0to 93:7) to afford the title compound as a white foam, 140mg. 1H-NMR (CDCi3,400MHz) δ: 1.20 (d, 3H), 3.00-3.21 (m, 3H), 3.40 (m, 1H), 3.75 (s, 3H), 3.90 (m, 1H), 4.42 (m, 1 H), 4.59 (m, 2H), 6.78 (d, 2H), 7.13 (d, 2H), 7.19 (s, 1 H), 7.38 (m, 1 H),-7.40 (m, 1H), 7.50 (m, 4H), 7.65 (s, 1H), 7.81 (s, 1H). LRMS: m/z (ES-+> 536, 538[MH4]

Préparation 88 (2S)-2-f(1 -Propyl-1 H-imidazol-4-yl)methvn-3-morpholinone

Ammonium cérium (IV) nitrate (4.55g, 8.30mmol) was added to a solution of thecompound of Préparation 47 (1.43g, 4.15mmol) in acetonitrile (9ml) and water (9ml) 012756 105 and the mixture was stirred at room température for 18 hours then concentratedunder reduced pressure and the residue was dissolved in methanol. This solutionwas purified by column chromatography on silica gel using an elution gradient ofdichloromethane:methanoi:0.88 ammonia (95:5:0.5 to 90:10:1) to afford an orangeoil. This was further purified by column chromatography on Dowex® 50WX8-200 ionexchange resin, using an elution gradient of water:0.88 ammonia (100:0 to 98:2) toafford the title compound, 522mg. 1H-NMR (CDCi3, 400MHz) δ: 0.88 (t, 3H), 1.75(m, 2H), 3.00 (dd, 1H), 3.23 (m, 2H), 3.50 (m, 1 H), 3.74 (m, 1H), 3.79 (t, 2H), 4.00(m, 1H), 4.43 (dd, 1 H), 5.94 (bs, 1 H), 6.73 (s, 1 H), 7.36 (s, 1 H). LRMS: m/z (ES+)224 [MH4]

Préparation 89 (2RS)-2-f (1 -Butvl-1 H-imidazol-4-vl)methvll-3-morpholinone

Ammonium cérium (IV) nitrate (5.7g, 10.4mmol) was added to a solution of thecompound of Préparation 48 (1.87g, 5.2mmoi) in acetonitrile (50ml) and water(50ml), and the mixture was stirred at room température for 18 hours. The solventswere evaporated under reduced pressure and the residue was purified using aDowex® 50WX8-200 ion-exchange column and 5% 0.88 ammonia as eluant. Thisproduct was further purified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to affordthe title compound, 300mg. 1H-NMR (CDCI3, 400MHz) δ: 0.96 (t, 3H), 1.34 (m, 2H), 1.75 (m, 2H), 3.02 (dd, 1H), 3.28 (m, 2H), 3.56 (m, 1H), 3.78 (m, 1H), 3.82 (t, 2H),4.02 (m, 1H), 4.48 (dd, 1H), 5.98 (bs, 1H), 6.77 (s, 1H), 7.38 (s, 1H). LRMS: m/z(ES4) 238 [MH4] 012756 106

Préparation 90 (2RS)-2-(f 1 -(2-Cvclohexvlethvl)-1 H-tmidazol-4-vl1methvi)-3-morpholinone

Ammonium cérium (IV) nitrate (1.1g, 2.0mmol) was added to a solution of thecompound of Préparation 49 (411 mg, I.Ommol) in acetonitrile (5ml) and water (5ml),and the mixture was stirred at room température for 18 hours then concentratedunder reduced pressure. The residue was pre-adsorbed onto silica gel and purifiedby column chromatography on silica ge, using an elution gradient of ethylacetate:dichloromethane:methanol:0.88 ammonia (100:0:0:0 to 75:0:25:0 to0:90:10:1 ). The product was further purified by column chromatography on reversephase polystyrène gel, using an elution gradient of water:methanol (100:0 to 0:100)to afford the title compound, 522mg. 1H-NMR (CD3OD, 400MHz) δ: 1.01 (m, 2H), 1.24 (m, 4H), 1.76 (m, 7H), 3.22 (m, 3H), 3.40 (m, 1H), 3.80 (m, 1 H), 4.02 (m, 1H), 4.22 (m, 2K), 4.38 (m, 1H), 7.43 (s, 1H), 8.85 (s, 1H). LRMS: m/z (TSP+) 292.2[MH4]

Préparation 91 (2fl,65)-2-(f 1 -(2-Cvclohexvlethyl)-1 /7-imidazol-4-vl1methvl)-6-methyl-3-morpholinone

Ammonium cérium (IV) nitrate (387mg, 0.758mmol) was added to a solution of thecompound of Préparation 61 (120mg, 0.283mmol) in acetonitrile (8ml) and water(5ml) and the mixture was stirred at 40°C for 18 hours then concentrated underreduced pressure. The residue was pre-adsorbed onto silica gel and purified bycolumn chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (98:2:0.2 to 95:5:0.5) to afford the titlecompound as a colourless oil, 66mg. 1H-NMR (CDCI3, 400MHz) δ: 0.92 (m, 2H), 012756 107 1.18 (m, 7H), 1.62 (m, 7H), 2.98 (dd, 1H), 3.18 (m, 2H), 3.23 (dd, 1H), 3.83 (m, 3H),4.41 (m, 1 H), 6.19 (bs, 1H), 6.70 (s, 1 H), 7.30 (s, 1 H). LRMS: m/z (ES+) 328 [MNa4]

Préparation 92 Îf2S.6ffl-2-if1-i2-Cvclohexvlethvl)-1/-/-imidazol-4-vnmethvi)-6-methvl-3-morphoiinone

The titie compound was obtained as a pale yellow solid in 63% yield from theprotected morpholinone of Préparation 62 following the procedure described inPréparation 91. 1H-NMR (CDCI3,400MHz) δ: 0.92 (m, 2H), 1.18 (m, 7H), 1.62 (m,7H), 2.98 (dd, 1H), 3.19 (m, 2H), 3.23 (dd, 1H), 3.83 (m, 3H), 4.41 (m, 1H), 6.03 (bs,1H), 6.70 (s, 1H), 7.34 (s, 1H). LRMS: m/z (ES4) 328 [MNa4]

Préparation 93 (2S.6fft-2-(f 1 -î2-(4.4-Dimethvlcvclohexvhethvn-1 H-imidazol-4-vl)methvi~)-6-methvl-3-

The titie compound was obtained in 53% yield from the protected morpholinone ofPréparation 66 following a similar procedure to that described in Préparation 91,except that ethyl acetate:methanol:diethyiamine (99:0.5:0.5 to 95:2.5:2.5) was usedas the column eluant. 1H-NMR (CDCI3, 400MHz) δ: 0.82 (2xs, 6H), 1.10 (d, 3H),1.18-1.38 (m, 8H), 1.48 (m, 1H), 1.63 (m, 2H), 2.98 (m, 1H), 3.19 (m, 2H), 3.23 (dd,1H), 3.84 (m, 3H), 4.41 (m, 1H), 6.97 (bs, 1H), 7.21 (s, 1H), 7.34 (s, 1H). LRMS:m/z (ES4) 334 [MH4]

Préparation 94 (2S,6fl)-2-[f 1 -(3-Cvclohexvl-3-methvlbutv0-1 W-imidazol-4-vl1methyl}-6-methvl-3- 012756 108 morpholinone

NH

O

The title compound was obtained in 52% yield from the protected morpholinone ofPréparation 65 following a similar procedure to that described in Préparation 91, 5 except that dichloromethane:methanol:0.88 ammonia (99:1:0.1 to 93:7:0.7) wasused as the column eluant. 1H-NMR (CD3OD, 400MHz) δ: 0.86 (s, 6H), 1.00 (m,2H), 1.03-1.28 (m, 7H), 1.70 (m, 7H), 2.90 (m, 1H), 3.03 (m, 1H), 3.18 (m, 2H), 3.82(m, 1H), 3.95 (m, 2H), 4.36 (m, 1H), 5.42 (s, 1 H), 6.86 (s, 1H), 7.50 (s, 1H). LRMS:m/z (ES+) 348 [MH*] 10

Préparation 95 (2S.5S)-2-ff1-(2-Cyclohexvlethvl)-1H-imidazol-4-vHmethvl}-5-methvl-3-morpholinone A mixture of the protected morpholinone of Préparation 63 (170mg, 0.4mmol) and15 ammonium cérium (IV) nitrate (550mg, 1 .Ommol) in water (1ml) and acetonitrile (1 ml) was stirred at 40°C for 18 hours then concentrated under reduced pressure. Theresidue was purified by column chromatography using a Biotage® silica gel columnand an elution gradient of ethyl acetate:diethylamine (95:5 to 80:20) to afford thetitle compound, 18mg. 1H-NMR (CDCI3, 400MHz) δ: 0.97 (m, 2H), 1.20 (m, 7H), 20 1.66 (m, 7H), 3.06 (dd, 1 H), 3.25 (dd, 1 H), 3.58 (m, 1 H), 3.65 (dd, 1 H), 3.83 (m, 3H), 4.43 (dd, 1 H), 6.15 (bs, 1 H), 6.78 (s, 1 H), 7.38 (s, 1 H). 012756 109

Préparation 96 (2ft.5ffl-2-fl1-(2-Cvclohexvlethvl)-1AAimidazol-4-vl1methvfl-5-rnethvl-3-morpholinone

The title compound was obtained in 34% from the protected morpholinone of5 Préparation 64 following the procedure described in Préparation 95. 1H-NMR (CDCI3, 400MHz) δ: 0.78-0.98 (m, 2H), 1.03-1.22 (m, 7H), 1.62 (m, 7H), 3.02 (m,1H), 3.18 (dd, 1H), 3.55 (m, 1H), 3.61 (dd, 1H), 3.77 (dd, 1H), 3.82 (t, 2H), 4.38 (m,1 H), 6.24 (bs, 1 H), 6.73 (s, 1 H), 7.37 (s, 1 H). 10 Préparation 97 (2RS)-2-(f 1 -(2-Fhenylethyll· 1 H-imidazol-4-vnmethvn-3-morpholinone

Ammonium cérium (IV) nitrate (883mg, 1.6mmol) was added to a solution of thecompound of Préparation 50 (326mg, 0.81 mmol) in acetonitrile (2.4ml) and water 15 (2.4ml) and the mixture was stirred at room température for 5 days, then concentrated under reduced pressure. The residue was dissolved in methano, andadsorbed onto silica gei, then purified by column chromatography on silicigel usingan elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1)to afford the title compound as an orange oil, 97mg. 1H-NMR (CDCI3) 400MHz) 20 δ: 3.02 (m, 3H), 3.26 (m, 2H), 3.52 (m, 1H), 3.77 (m, 1H), 4.00 (m, 1H), 4.10 (t, 2H), 4.43 (dd, 1H), 5.99 (bs, 1 H), 6.70 (s, 1 H), 7.05 (d, 2H), 7.24 (m, 4H). LRMS: m/z(ES+) 286 [MH*] 012756 110

Préparation 98 (2RS)-2-f( 1 -r2-(4-Bromophenyi)ethvn-1 H-imidazol-4-y|}methvl)-3-morpholinone

A solution of ammonium cérium (IV) nitrate (1.35g, 2.48mmol) in water (5ml) was 5 added to a solution of the bromide of Préparation 59 (600mg, 1.24mmol) inacetonitrile (10ml) and the mixture was stirred at 40°C for 18 hours. TLC analysisshowed starting material remaining, so additional ammonium cérium (IV) nitrate(308mg, 0.56mmol) was added and the mixture was stirred at 40°C for a further 2hours. The cooled mixture was concentrated under reduced pressure and the 10 residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (98:2:0.2 to 95:5:0.5) to affordthe title compound, 250mg. 1H-NMR (CDCI3, 400MHz) δ: 2.98 (t, 2H), 3.03 (m, 1H), 3.25 (m, 2H), 3.52 (m, 1H), 3.77 (m, 1H), 4.00 (m, 1H), 4.05 (t, 2H), 4.42 (m, 1 H),5.99 (bs, 1H), 6.65 (s, 1H), 6.93 (d, 2H), 7.22 (s, 1H), 7.40 (d. 2H). 15

Préparations 99 to 101

The following compounds of general structure

were prepared from the corresponding protected morpholinones following a similar20 procedure to that described in Préparation 98. 012756 111

Ex R Yieid (%) Data 99 σ 58 3H-NMR (CDCI3, 400MHz) Ô: 3.10 (dd, 1H), 3.25 (m, 1H), 3.37 (m, 1H), 3.58 (m, 1H), 3.78 (m, 1 H), 4.02 (m, 1H), 4.54 (m, 1H), 5.83 (bs, 1 H), 7.15 (s, 1H), 7.33 (m, 3H), 7.42 (m, 2H), 7.78 (s, 1 H). LRMS: m/z (ES*)280 [MNa*J 100 a. 74 *H-NMR (CDCIa, 400MHz) δ: 2.20 (s, 3H), 3.16 (dd, 1H), 3.30 (m, 1H), 3.38 (dd, 1H), 3.58 (m, 1H), 3.80 (m, 1H), 4.04 (m, 1H), 4.56 (dd, 1H),6.18(bs, 1H), 6.90 (s, 1H),7.20-7.35 (m, 4H), 7.50 (s, 1H). HRMS: m/z272.1394 [MH*] 1011 % 1H-NMR (CD3OD, 400MHz) δ: 2.92 (dd, 1H), 3.05 (m, 1H), 3.19 (m, 1H), 3.63 (m, 1H), 3.86 (m, 1H), 4.22 (m, 1H), 6.82 (s, 1H), 7.10(m, 2H), 7.30 (m, 3H), 7.40 (m, 1H), 7.50 (m,4K). LRMS m/z (ES*) 356 [MNa*] 1 = ethyl acetate:methanol:diethylamine (100:0:0 to 90:5:5) used as the columneluant

Préparation 102 5 (2RS)-2-f f 1 -(3-Phenoxyphenvl)-1 H-imidazol-4-vPmethyl)-3-morpholinone

A solution of ammonium cérium (IV) nitrate (350mg, 063mmol) in water (2ml) wasadded to a solution of the protected morpholine of Préparation (120mg, 0.256mmol)in acetonitrile (2ml), and the mixture was stirred at 40°C for 18 hours. TLG analysis 10 showed starting material remaining, so additional ammonium cérium (IV) nitrate 012756 112 (500mg, 0.91 mmol) was added, and the mixture was stirred at 40°C for a further 8hours. The mixture was evaporated under reduced pressure and the residue waspartitioned between dichloromethane (50ml) and a solution of ethytenediamine-tetraacetic acid (1g) in saturated sodium bicarbonate solution (50ml). The phaseswere separated and the organic layer was dried (MgSO4) and evaporated underreduced pressure. The crude product was purified by column chromatography onsilica gel using an elution gradient of ethyl acetate:methanol:diethylamine (100:0:0 to96:2:2) to afford the title compound, 25mg. 1H-NMR (CDCI3,400MHz) δ: 3.05 (dd,1H), 3.21-3.18 (m, 2H), 3.57 (m, 1H), 3.77 (m, 1H), 4.00 (m, 1H), 4.48 (dd, 1H), 6.15(bs, 1 H), 6.90 (d, 1H), 6.98 (s, 1H), 7.02 (m, 3H), 7.14 (m, 2H), 7.37 (m, 3H), 7.74 (s,1 K). LRMS: m/z (TSP*) 350.0 [MH*]

Préparation 103 (2RS)-2-([ 1 -(2-NaphthvD-1 /7-imidazol-4-vllmethvl)-3-morpholinone

The title compound was obtained as a yellow gum in 56% yield from the protectedmorpholinone of Préparation 72, following a similar procedure to that described inPréparation 102, except that dichloromethane:methanol:0.88 ammonia (100:0:0 to90:10:1 ) was used as the column eluant. 1H-NMR (CDCI3, 400MHz) δ: 3.15 (dd,1H), 3.23 (m, 1H), 3.38 (dd, 1H), 3.58 (m, 1H), 3.78 (m, 1H), 4.02 (m.JH), 4.53 (dd,1 H), 6.01 (bs, 1 H), 7.22 (d, 2H), 7.48 (m, 3H), 7.75-7.94 (m, 4H). LRMS: m/z (ES+)308 [MH*]

Préparation 104 (-)-(2S)‘2-ff1-Phenvl-1H-imidazol-4-vnmethvl)-3-morpholinone

Ammonium cérium (IV) nitrate (1.43g, 2.61 mmol) was added to a solution of the 012756 113 proiectecf morpholinone of Préparation 74 (330mg, 0.87mmol) in water (2ml) andacetonitrile (2ml), and the mixture was stirred at 40°C for 4 hours. TLC analysisshowed starting material remaining, so additional ammonium cérium (IV) nitrate(1.43g, 2.61 mmol) was added, and the mixture was stirred at 40°C for a further 2hours. The mixture was partitioned between dichloromethane (200ml) and asolution of ethylenediaminetetraacetic acid (1g) in saturated sodium bicarbonatesolution (50ml). The phases were separated and the organic layer was dried(MgSO4) and evaporated under reduced pressure. The crude product was purifiedby column chromatography on silica gel using an elution gradient of ethylaçetate:methanol:diethylamine ( 100:0:0 to 96:2:2). The product was azeotropedwith toluene and dichloromethane to afford the title compound as an oil, 173mg. 1H-NMR (CDCI3, 400MHz) δ: 3.14 (dd, 1H), 3.28 (m, 1H), 3.38 (dd, 1H), 3.58 (m, 1H),3.80 (m, 1H), 4.05 (m, 1H), 4.56 (dd, 1H), 5.98 (bs, 1H), 7.17 (s, 1H), 7.37 (m, 3H),7.45 (m, 2H), 7.79 (s, 1 H). LRMS: m/z (TSP+) 258.1 {MH4] [a]D = -70.59, (c = 0.104, methanol)

Préparation 105 (2S)-2-(ri-(4-terf-Butvlphenvl)-1H-imidazol-4-vnmethyl)-3-morpholinone

Ammonium cérium (IV) nitrate (297mg, 0.55mmol) was added to a solution of theprotected morpholinone of Préparation 75 (94mg, 0.22mmol) in water (2ml) andacetonitrile (2ml), and the mixture was stirred at 40°C for 15 hours. Ethylene-diaminetetraacetic acid (0.5g) in saturated sodium bicarbonate solution (5ml) wasadded and the mixture was extracted with dichloromethane (2x50ml). Thecombined organic extracts were dried (MgSO4) and evaporated under reducedpressure. The crude product was purified by column chromatography on silica gelusing an elution gradient of ethyl acetate.methanohdiethylamine (98:1:1 to 94:3:3), toafford the title compound as an oil, 22mg. 1H-NMR (CDCI3,400MHz) δ: 1.37 (s, 9H), 3.12 (dd, 1 H), 3.26 (m, 1H), 3.38 (dd, 1H), 3.58 (m, 1H), 3.79 (m, 1H), 4.04 (m, 1H),4.55 (m, 1H), 6.22 (bs, 1H), 7.10 (s, 1H), 7.25 (d, 2H), 7.42 (d, 2H), 7.77 (s, 1H). 012756 114 LRMS: m/z (TSP+) 314.1 [MH4]

Préparation 106 i-)-(2S)-2-(f 143.5-Bis(trifluoromethvhphenvl1-1 H-imidazol-4-vl)methvl)-3-

The title compound was obtained as a solid in 81% yield from the protectedmorpholinone of Préparation 76 following the procedure described in Préparation105. 1H-NMR (CDCI3, 400MHz) δ: 3.18 (dd, 1H), 3.30 (m, 1 H), 3.39 (dd, 1 H), 3.60(m, 1H), 3.80 (m, 1H), 4.06 (m, 1H), 4.55 (m, 1H), 5.88 (bs, 1H), 7.20 (s, 1H), 7.81(s, 2H), 7.84 (s, 1 H), 7.87 (s, 1 H). LRMS: m/z (TSP+) 394.0 [MH4]. [<x)D = -40.35, (c= 0.116, methanol)

Préparation 107 (2RS)-2-[f1-(4l-Chloro[1.1 ‘-biphenvn-3-vl)-1 H-imidazol-4-vl1methyl)-3-morpholinone

The title compound was obtained as a solid in 91% yield from the protectedmorpholinone of Préparation 84 following the procedure described in Préparation105. 1H-NMR (CDCI3, 400MHz) δ: 3.10 (dd, 1H), 3.25 (m, 1H), 3.38 (dd, 1H), 3.57(m, 1H), 3.78 (m, 1H), 4.02 (m, 1H), 4.52 (dd, 1H), 5.96 (bs, 1H), 7.17 (s, 1H), 7.37(m, 3H), 7.42 (m, 1 H), 7.50 (m, 3H), 7.57 (s, 1 H), 7.80 (s, 1 H). LRMS: m/z (ES') 366(M-H')

Préparation 108 (2RS)-2-[f 1 -(3‘.4'-Dichloro[ 1,1 '-biphenyll-S-vD-l /7-imidazol-4-vnmethvl}-3- 012756 115 morpholinone

The title compound was obtained in 49% yield from the protected morpholinone ofPréparation 86 following the procedure described in Préparation 105. 1H-NMR 5 (CDCfe, 400MHz) δ: 3.10 (dd, 1 H), 3.25 (m, 1 H), 3.38 (dd, 1 H), 3.57 (m, 1 H), 3.78(m, 1H), 4.02 (m, 1H), 4.52 (dd, 1H), 5.86 (bs, 1H), 7.18 (S, 1H), 7.37 (m, 2H), 7.50(m, 4H), 7.62 (s, 1 H), 7.80 (s, 1 H). LRMS: m/z (ES+) 402,404 (MH+)

Préparations 109 to 114 10 The following compounds of the general structure

were prepared from the appropriate protected morpholinones, following a similarprocedure to that described in Préparation 105.

Prep R Yield (%) Data 109 σ 50 ’H-NMR (CDCI3i 400MHz) δ: 1.22 (d, 3H), 3.08 (dd, 1H), 3.22 (m, 2H), 3.38 (dd, 1H), 3.92 (m, 1 H), 4.50 (m, 1 H), 6.62 (bs, 1 H), 7.16 (s, 1H), 7.37 (m, 3H), 7.42 (m, 2H), 7.78(S,1H). 012756 116

Prep R Yield (%) Data 110 σ° 25 1H-NMR (CDCI3,400MHz) &amp; 1.20 (d, 3H), 3.02 (dd, 1H), 3.20 (m, 2H), 3.34 (dd, 1H), 3.88 (m, 1H), 4.44 (m, 1H), 6.05 (bs, 1H), 6.90 (d, 1H), 6.98 (s, 1H), 7.02 (m, 4H), 7.14(m, 1H), 7.36 (m, 3H), 7.70 (s, 1 H). LRMS:m/z (ES+) 364 [ MH*] 111 9 •χχ 44 sticky gum 1H-NMR (CDCfe, 400MHz) δ: 1.24 (d, 3H), 3.09 (dd, 1H), 3.22 (m, 2H), 3.39 (dd, 1H), 3.95 (m, 1H), 4.50 (m, 1H), 5.86 (bs, 1H), 7.03 (m, 4H), 7.18 (m, 2H), 7.36 (m, 4H), 7.70 (s, 1 H). LRMS: m/z (ES+) 364 [MH*] 1121 J 44 1H-NMR (CDCIa, 400MHz) δ: 1.23 (d, 3H), 3.10 (dd, 1H), 3.22 (m, 2H), 3.39 (dd, 1H), 3.94 (m, 1H), 4.55 (m, 1H), 5.84 (bs, 1H), 7.20 (s, 1H), 7.39 (m, 3H), 7.42-7.60 (m, 5H),7.80 (s, 1K). 1131 40 solid 1H-NMR (CDCI3, 400MHz) δ: 1.22 (m, 5H), 1.40 (m, 4H), 1.70-1.90 (m, 4H), 2.55 (m, 1H), 3.09 (dd, 1H), 3.21 (m, 2H), 3.38.(dd, 1H), 3.92 (m, 1H), 4.50 (m, 1H), 6.00 (bs, 1H), 7.10 (s, 1H), 7.27 (m, 4H), 7.74 (s, 1H).LRMS: m/z (ES+) 354 [MH4] 012756 117

Prep R Yield (%) Data 1142 9 'Û 34 1H-NMR (CDCI3, 400MHz) δ: 0.88-1.15 (m, 2H), 1.22 (d, 3H), 1.38 (m, 3H), 1.58 (m, 1H)1.80 (m, 2H), 1.99 (m, 2H), 3.06 (dd, 1H), 3.22 (m, 2H), 3.39 (dd, 1H), 3.92 (m, 1H), 4.22 (m, 1H), 4.50 (m, 1H), 5.84 (bs, 1H), 6.97 (d, 2H), 7.05 (s, 1H), 7.22 (d, 2H), 7.64(s,1H). 1 - Acetonitrile:water (3:1, by volume) was used as the reaction solvent 2 = Acetonitrile:water (2:1, by volume) was used as the reaction solvent

Préparation 115 5 (2g,6f?)-2-ff 1 -(3’.4'-Dichlorof 1.1 '-biphenvn-3-vl)-1 H-imidazol-4-vllmethvn-6-methyl-3-

The title compound was obtained as a white foam in 63% yield from the protectedmorpholînone of Préparation 87 following a similar procedure to that described in 10 Préparation 105. 1H-NMR (CDCfe, 400MHz) δ: 1.24 (d, 3H), 3.14 (dd, 1 H), 3.23 (m,2H), 3.40 (dd, 1H), 3.97 (m, 1H), 4.56 (dd, 1H), 5.80 (bs, 1H), 7.10 (s, 1H), 7.40 (m,2H), 7.55 (m, 4H), 7.68 (s, 1H), 7.81 (s, 1H). LRMS: m/z (TSP4) 416.1,420.1 [MH4]

Préparation 116 15 (2S)-2-(1H-lmidazol-4-vlmethyl)-3-morpholinone

012756 118 A mixture of the protected morpholinone of Préparation 53 (500mg, 1.66mmol), andammonium cérium (IV) nitrate (2.5g, 4.5mmol) in water (6ml) and acetonitrile (6ml)was stirred at 40°C for 18 hours. Potassium carbonate (1.5g) was added and themixture was stirred for 10 minutes then adsorbed onto silica gel. The product wasisolated by column chromatography on silica gel using ethyl acetate:methanol:diethylamine (96:2:2 to 80:10:10) and was further purified bycolumn chromatography on silica gel using dichloromethane-.methanol (90:10 to85:15) to afford the title compound, 240mg. 1H-NMR (CD3OD, 400MHz) δ: 3.02-3.42 (m, 4H), 3.78 (m, 1H0, 4.00 (m, 1H), 4.38 (m, 1H), 6.75 (s, 1H), 7.78 (s, 1K).HRMS: m/z (ES+) 182.0924 [MH*]

Préparation 117 (-)-(2S.6R)-2-(1/7-imidazol-4-vlmethvl)-6-methyl-3-morpholinone

A mixture of the protected morpholinone of Préparation 55 (1g, 3.2mmol) andammonium cérium (IV) nitrate (5.2g, 9.6mmol) in water (20ml) and acetonitrile (30ml)was stirred at 40°C for 18 hours. The solvent was evaporated under reducedpressure. The residue was suspended in a mixture of dichloromethane:methanol:0.88 ammonia (99:1:0.1 by volume) and purified twice bycolümn chromatography on silica gel using an elution gradient of — 'dichloromethane:methanol:0.88 ammonia (90:10:1). The resulting oil wasazeotroped with diethyl ether to afford the title compound as a colourless foam,380mg. 1H-NMR (CD3OD, 400MHz) δ: 1.21 (d, 3H), 3.02 (m, 2H), 3.19 (m, 2H), 3.90 (m, 1H), 4.36 (m, 1H), 6.81 (s, 1H), 7.54 (s, 1H). LRMS: m/z (ES*) 196 [MH*].[a]D = -104.56 (c = 0.19, methanol) 012756 119

Préparation 118 fert-Butvl (2SV2-U1 -(fert-butoxvcarbonvl)-1 H-imidazol-4-vNmethvl)-3-oxo-4- morphoiinecarboxvlate

A solution of the morpholinone of Préparation 116 (70mg, 0.39mmol), dimethylaminopyridine (3mg) and di-fert-butyl dicarbonate (354mg, 1.62mmol) inaoetonitrile (5ml) was stirred at room température for 42 hours. The mixture wasconcentrated under reduced pressure and the residue was purified by columnchromatography on silica gel using an elution gradient of

dichloromethane:methanol:0.88 ammonia (99:1:0.1 to 95:5:0.5) to afford the titlecompound, 96mg. 1H-NMR (CDCI3,400MHz) δ: 1.58 (s, 9H), 1.61 (s, 9H), 3.04 (dd,1H), 3.35 (dd, 1H), 3.78 (m, 3H), 4.05 (m, 1H), 4.50 (m, 1H), 7.20 (s, 1 H), 8.00 (s,1H). HRMS: m/z (ES+) 382.1972 [MH+J

Préparation 119 fert-Butvl (25,6ffl-2-((1 -r4-(cvclohexvloxv)phenvll-1 H-imidazol-4-yl}methv0-6-methvl- 3-oxomorpholine-4-carboxvlate

0.8mmol) were added to a solution of the morpholinone of Préparation 114 (135mg,O.37mmol) in aoetonitrile (5ml), and the mixture was stirred at room température for 5hours. TLC analysis showed starting material remaining, so additional di-fert-butyldicarbonate (87mg, 0.4mmol) was added, and the mixture was stirred at roomtempérature for a further 18 hours. The reaction mixture was concentrated underreduced pressure and the residue was purified by column chromatography on silicagel using ethyl acetate as eluant, to give the title compound, 95mg. LRMS: m/z 012756 120 (ES+) 470 [ΜΗ*]

Préparation 120

Lithium (2S)-2-({(1 /7)-2-[ί^βζΐ-άυΐοχνο3ώοηνΠ3πιΐηοΜ -methvlethvnoxv)-3-f1-f4- (cvclohexvloxv)phenvn-1H-imidazol-4-vl)propanoate

A mixture of the protected morpholinone of Préparation 119 (87mg, 0.19mmoJ) andlithium hydroxide (24mg, 0.56mmol) in tetrahydrofuran (0.5ml) and water (1 ml) wasstirred at room température for 18 hours. The reaction mixture was evaporatedunder reduced pressure to afford the title compound. 1H-NMR (D20,400MHz)δ: 0.60 (m, 2H), 1.00-1.38 (m, 16H), 1.50 (m, 2H), 1.70 (m, 2H), 2.58 (m, 1 H), 2.80(m, 2H), 2.94 (m, 1H), 3.30 (m, 1H), 3.82 (m, 1 H), 4.00 (m, 1H), 6.63 (d, 2H), 6.82 (s,1 H), 7.00 (d, 2H), 7.56 (s, 1 H). LRMS: m/z (ES ) 486 [M-H]'

Préparation 121 » (2RS)-2-(f 1 -r2-(4'-EthvlF1.1 '-biphenvIH-vDethvn-l /7-imidazol-4-vnmethvh-3- morpholinone

A mixture of the bromo compound of Préparation 98 (250mg, 0.69mmol), 4-ethylbenzeneboronic acid (154mg, 1.03mmol), tetrakis(triphenylphosphine)-palladium(O) 78mg, 0.068mmol) and sodium carbonate solution (411 μΙ, 2M,0.823mmol) in water (1 ml) and dioxan (5ml) was heated at 100°C for 3 hours. Thecooled reaction mixture was diluted with water (10ml), and the mixture was extractedwith ethyl acetate (3x15ml). The combined organic extracts were dried (MgSÛ4)and evaporated under reduced pressure. The crude product was purified by columnchromatography on silica gel using an elution gradient of 012756 121 dichloromethane:methanol:0.88 ammonia (99:1:0.1 to 95:5:0.5) to afford the titlecompound, 170mg. 1H-NMR (CDCI3,400MHz) Ô: 1.22 (t, 3H), 2.64 (q, 2H), 3.02 (m,3H), 3.22 (m, 2H), 3.44 (m, 1H), 3.72 (m, 1H), 3.98 (m, 1H), 4.10 (t, 2H), 4.42 (m, 1H), 5.90 (bs, 1H), 6.70 (s, 1H), 7.08 (d, 2H), 7.22 (m, 3H), 7.44 (m, 4H).

Aryt boronic acids (R-B(OH)2), (0.74mmol) were added to solutions of the bromocompound of Préparation 98 (180mg, 0.49mmol) tetrakis(triphenylphosphine)- 10 palladium(0) (56mg, 0.051 mmol) and sodium carbonate solution (295μΙ, 2M, 0.593mmol) in water (1 ml) and dioxan (5ml). The reaction mixtures were heated to100°C for 4 hours, then allowed to cool. Water (15ml) was added, and the mixtureswere extracted with ethyl acetate (3x15ml). The combined organic extracts weredried (MgSO4) and evaporated under reduced pressure. The crude products were 15 purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (97:3:0.3 to 95:5:0.5) to afford the desiredproducts, shown in the following table.

Prep R Yield (%) Data 122 CHa 63 1H-NMR (CDCI3i 400MHz) δ: 1.28 (d, 6H), 2.95 (m, 1H), 3.02 (m, 3H), 3.24 (m, 2H), 3.52 (m, 1H), 3.75 (m, 1H), 4.00 (m, 1H), 4.12 (t, 2H), 4.44 (m, 1H), 5.92 (bs, 1H), 6.75(bs, 1H), 7.14 (d, 2H), 7.28 (m, 3H), 7.50 (m,4H). LRMS: m/z (ES*) 404 [MH*J 123 Xi 78 ^-NMR (CDCIa, 400MHz) δ: 3.04 (m,3H), 3.26 (m, 2H), 3.54 (m, 1 H), 3.76 (m, 1H), 4.00 (m, 1H), 4.15 (t, 2H), 4.44 (m, 1H), 6.06(bs, 1H), 6.75 (s, 1H), 7.14 (d, 2H), 7.19 (dd,1H), 7.24 (s, 1H), 7.40 (m, 3H), 7.59 (d, 1H). 122

ο 1275 S

Prep R Yield (%) Data 124 ,fu 61 1H-NMR (CDCI3, 400MHz) Ô: 3.06 (m, 3H), 3.25 (m, 2H), 3.54 (m, 1H), 3.77 (m, 1H), 4.01 (m, 1H), 4.15 (t, 2H), 4.44 (m, 1H), 5.83(bs, 1H), 6.77 (s, 1H), 7.17 (d, 2H), 7.24 (s,1H), 7.55 (d, 2H), 7.66 (m, 4H). LRMS: m/z(ES4) 452 [MNa4] 125 Qf 66 1H-NMR (CDCI3, 400MHz) δ: 3.05 (m, 3H), 3.26 (m, 2H), 3.55 (m, 1H), 3.77 (m, 1H), 4.00 (m, 1H), 4.17 (t, 2H), 4.45 (m, 1H), 5.96(bs, 1H), 6.74 (s, 1H), 7.09 (d, 2H), 7.20-7.34(m, 4H), 7.42 (dd, 1H), 7.57 (dd, 1H), 7.75 (d, 1 H). Microanalysis found: C, 62.77; H, 5.21 ;N, 9.46. C23H22N3O2F3:0.5H2O requires C, 63.01; H, 5.29; N, 9.58%. 126 Cl 56 ’H-NMR (CDCI3, 400MHz) δ: 3.02 (m, 3H), 3.22 (m, 2H), 3.50 (m, 1H), 3.74 (m, 1H), 4.00 (m, 1H), 4.14 (t, 2H), 4.42 (dd, 1H), 5.95(s, 1H), 6.74 (s, 1H), 7.08 (d, 2H), 7.19-7.35(m, 5H), 7.42 (s, 1 H). LRMS: m/z (ES+) 430,432 [MH4] 127 H3C\ 0 Y HaC^C^ 70 1H-NMR (CDCb, 400MHz) δ: 1.25 (d, 6H), 2.90 (m, 1H), 3.05 (m, 3H), 3.22 (m, 2H), 3.44 (m, 1H), 3.75 (m, 4H), 4.00 (m, 1H), 4.15 (t, 2H), 4.44 (m, 1H), 5.86 (s, 1H), 6.78(s, 1H), 6.92 (d, 1H), 7.15 (m, 4H), 7.35 (s, 1 H), 7.44 (d, 2H). LRMS: m/z (ES+) 456[MNa4] 012756 123

Prep R Yield (%) Data 128 X. 1H-NMR (CDCI3, 400MHz) δ: 3.02 (m, 3H), 3.22 (m, 2H), 3.47 (m, 1H), 3.70 (m, 1H), 3.98 (m, 1K), 4.09 (t, 2H), 4.42 (dd, 1H), 5.82(s, 1H), 6.74 (s, 1H), 7.10 (d, 2H), 7.22 (s, 1H), 7.38 (d, 2H), 7.44 (m, 4H). HRMS: m/z396.147 [MH*] 129 :χχ 36 ’H-NMR (CDCI3, 400MHz) Ô: 2.35 (2xs, 6H), 3.06 (m, 3H), 3.30 (m, 2H), 3.55 (m, 1H), 3.78 (m, 1H), 4.02 (m, 1H), 4.17 (t, 2H), 4.46/dd, 1H), 5.83 (bs, 1H), 6.78 (s, 1H), 7.15 (d,2H), 7.21 (d, 1H), 7.30 (m, 3H), 7.53 (d, 2H).LRMS: m/z (ES+) 391 [MH*] 130 "'θ' 62 1H-NMR (CDCl3,400MHz) S: 2.20 (s, 3H), 3.02 (m, 3H), 3.22 (m, 2H), 3.50 (m, 1H), 3.75 (m, 1H), 4.00 (m, 1H), 4.10 (m. 2H), 4.42 (m, 1H), 5.81 (s, 1H), 6.72 (m, 2H),7.02-7.25 (m, 7H). LRMS: m/z (ES+) 395[MH*] 131 ^ch3 σ 52 fH-NMR (CDCIa, 400MHz) δ: 1.04 (t, 3H), 2.55 (q, 2H), 3.01 (m, 3H), 3.22 (m, 2H), 3.48(m, 1H), 3.72 (m, 1H), 3.98 (m, 1H). 4ÎI0 (t,2H), 4.42 (dd, 1H), 6.10 (s, 1H), 6.74 (s, 1H),7.06 (d, 2H), 7.10 (d, 1H), 7.19 (m, 3H), 7.25(m, 3H). Microanalysis found: C, 70.93; H,7.15; N, 10.39. C24H27N3O2;H2O requires C, 70.74; H, 7.17; N, 10.31%. 012756 124

Préparation 132 (2RS)-2-((1 -F (2EZ)-3-Bromo-2-propenvll-1 H-imidazol-4-vl)methvh-3-morpholinone

A mixture of ammonium cérium (IV) nitrate (2.6g, 4.75mmol) and the compound ofPréparation 67 (1g, 2.38mmol) in acetonitrile (10ml) and water (5ml) was stirred at40°C for 18 hours. TLC analysis showed starting material remaining, so additionalammonium cérium (IV) nitrate (650mg, 1.19mmol) was added and the mixture wasstirred for a further 3 hours at 40°C. The mixture was concentrated under reducedpressure and azeotroped with methanol. The crude product was pre-adsorbed ontosilica gel and purified twice by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol:0.88 ammonia (99:1:0.1 to 95:5:0.5) to affordthe title compound, 370mg. 1H-NMR (CDCI3,400MHz) (mixture of géométrieisomers) Ô: 3.00 (m, 1H), 3.23 (m, 2H), 3.50 (m, 1H), 3.74 (m, 1H), 4.00 (m, 1H), 4.42 (m, 2H), 4.62 (d, 1H), 5.98 (bs, 1H), 6.26 (m, 1.5H), 6.42 (d, 0.5H), 6.75 (2xs, 1 H), 7.40 (2xs, 1 H). LRMS: m/z (ES+) 300, 302 [MH*]

Préparation 133 f-)-(2S)-2-f f 1 -(2-Cyclohexvlethyl)-1 H-imidazol-4-vnmethvi)-3-morpholinone

Ammonium cérium (IV) nitrate (482mg, 0.88mmol) and water (1ml) were added to asolution of the compound of Préparation 60 (181mg, 0.44mmol) in acetonitrile (1ml)and the mixture was stirred at 40°C for 18 hours. TLC analysis showed startingmaterial remaining, so additional ammonium cérium (IV) nitrate was added (250mg,0.46mmol) and the mixture was stirred at 40°C for a further 5 hours. The mixturewas partitioned between dichloromethane (75ml) and a solution of ethylenediamine-tetraacetic acid (1g) in aqueous sodium bicarbonate (30ml), and the phases wereseparated. The organic layer was dried (MgSO4) and evaporated under reduced 012756 125 pressure. The crude product was purified by column chromatography on silica gelusing an eiution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to94:6:0.6) to afford the title compound as a sticky gum, 80mg. 1H-NMR (CDCI3,400MHz) Ô: 0.97 (m, 2H), 1.20 (m, 4H), 1.63 (m, 7H), 3.02 (dd, 1H), 3.26 (m, 2H),3.56 (m, 1H), 3.78 (m, 1H), 3.86 (t, 2H), 4.02 (m, 1H), 4.45 (m, 1H), 5.83 (bs, 1H), 6.76 (s, 1 H), 7.38 (s, 1 H). LRMS: m/z (TSP+) 292.1 [MH+]. [ct]D = -60.01, (c = 0.05,methanol)

Préparation 134 (2RS)-2-(( 1 -IY2EZ)-3-i1 ,r-Biphenyl1-4-vl-2-propenvn-1 H-imidazol-4-vl)methyl)-3- morphoiinone

A mixture of the bromo compound of Préparation 132 (185mg, 0.62mmol), 4-biphenylboronic acid (183mg, 0.925mmol), tetrakis(triphenylphosphine)palladium(0)(72mg, 0.062mmol) and sodium carbonate (78mg, 0.74mmol) in water (3ml) anddioxan (6ml) was heated at 100°C for 3 hours, then cooled and partitioned betweenwater (20ml) and ethyl acetate (20ml). The layers were separated and the aqueousphase was extracted with ethy, acetate (10ml). The combined organic extracts weredried (MgSO4) and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel using an eiution gradient ofdichloromethane:methanol:0.88 ammonia (99:1:0.1 to 98:2:0.2) to afford the titlecompound as a white foam, 100mg. 1H-NMR (CDCI3,400MHz) (mixture ofgéométrie isomers) δ: 3.00 (m, 1H), 3.22 (m, 2H), 3.54 (m, 1H), 3.75 (m, 1H), 4.00(m, 1H), 4.44 (m, 1 H), 4.62 (m, 1H), 4.78 (m, 1H), 5.80,6.26 (2xm, 1 H), 5.93 (bs,1H), 6.54,6.66-6.80 (2xm, 2H), 7.23-7.60 (m, 10H). LRMS: m/z (ES+) 374 [MH*] 012756 126

Préparations 135 to 137The following compounds of general structure

were prepared from the bromide of Préparation 132 and the appropriate boronic5 acid, following similar procedures to that described in Préparation 134.

Prep R Yield (%) Data 135 σα. 36 white foam 1H-NMR (CDCb, 400MHz) (mixture of géométrie isomers) δ: 3.00 (m, 1H), 3.20-3.35 (m, 2H), 3.50 (m, 1H), 3.62 (m, 1 H), 3.98 (m, 1 H), 4.42 (m, 1H), 4.62 (m, 1 H), 4.78 (m, 1H), 5.75 (bs, 1H), 5.82, 6.30 (2xm,1H), 6.57, 6.78 (2xm, 2H), 7.18-7.58 (m, 10H). LRMS: m/z (ES+) 374 [MH4] 1361 σ? 41 white foam ’H-NMR (CDCI3, 400MHz) (mixture of géométrie isomers) δ: 2.98 (dd, 1H), 3.22 (m,2H), 3.50 (m, 1H), 3.74 (m, 1H), 4.00 (m, 1H), 4.42 (m, 1H), 4.54 (m, 2H), 5.66, 6.18(2xm, 1H), 5.82 (bs, 1H), 6.50-6.72 (m, 2H),7.22-7.42 (m, 10H). LRMS: m/z (ES4) 396[MNa4] "— " 137 œ. 51 white foam 'H-NMR (CDCI3, 400MHz) (mixture of géométrie isomers) δ: 3.00 (m, 1 H), 3.20-3.35 (m, 2H), 3.50 (m, 1H), 3.75 (m, 1H), 4.00 (m, 1H), 4.44 (m, 1H), 4.64 (m, 1H), 4.80 (m, 1H), 5.78 (bs, 1H), 5.84, 6.38 (2xm, 1H), 6.62-6.85 (m, 2H), 7.30-7.82 (m, 8H).LRMS: m/z (ES4) 348 [MH4] 1 = isolated without column chromatography 012756 127

Préparation 138 (2RS)-2-(( 1 -f(2£Z)-3-(4-BromophenvB-2-propenvn-1 B-imidazol-4-vl)methvh-3-

The title compound was obtained in 42% yield from the compound of Préparation 67and 4-bromobenzeneboronic acid foilowing the procedure described in Préparation134. 1H-NMR (CDCI3,400MHz) (mixture of géométrie isomers) Ô: 3.00 (m, 1H), 3.25(m, 2H), 3.54 (m, 1H), 3.76 (m, 1H), 4.00 (m, 1H), 4.43 (m, 1H), 4.59-4.79 (m, 2H),5.80, 6.22 (2xm, 2H), 6.40, 6.62 (2xm, 1H), 6.72, 6.78 (2xs, 1H), 7.06 (d, 1H), 7.19(d, 1H), 7.38-7.58 (m, 3H). LRMS: m/z (TSP+) 376.1, 378.1 [MH*]

Préparation 139 (2RS)-2-((1-f(2£Z)-3-(4,-Methvlf1 .T-biphenvn-4-yl)-2-propenvn-1 H-imidazol-4-

A mixture of the bromo compound of Préparation 138 (132mg, 0.35mmol), 4-methylbenzeneboronic acid (72mg, O.53mmol), tetrakis(triphenylphosphine)-palladium(O) (50mg, 0.04mmoi) and sodium carbonate (270μΙ, 2M, 0.53mmol) indioxan (6ml) was heated at 100°C for 1.5 hours. The cooled reaction mixture waspartitioned between water (20ml) and ethyi acetate (20ml) and the layers wereseparated. The aqueous phase was extracted with ethyi acetate (10ml) and thecombined organic extracts were dried (MgSÛ4) and evaporated under reducedpressure. The residual yellow oil was purified by column chromatography on silicagel using an elution gradient of dichloromethane:methanol:0.88 ammonia (99:1:0.1to 98:2:0.2) to afford the title compound as a white foam, 77mg. 1H-NMR (CDCI3, 012756 128 400MHz) (mixture of géométrie isomers) δ: 2.38 (2xs, 3H), 3.00 (m, 1H), 3.25 (m,2H), 3.54 (m, 1H), 3.75 (m, 1H), 4.00 (m, 1H), 4.43 (m, 1 H), 4.62 (m, 1H), 4.78 (m,1H), 5.78,6.28 (2xm, 2H), 6.55,6.68-6.80 (2xm, 2H), 7.22 (m, 3H), 7.38-7.63 (m,6H). LRMS: m/z (ES*) 388 [MH*]

Préparation 140 (2RS)-2-(i1-r(2£Z)-3-(4l-Chloroi1.r-biphenvn-4-vl)-2-propenvl]-1H-imidazol-4-vl)-

A mixture of the bromo compound of Préparation 138 (100mg, 0.27mmol), 4-chlorobenzeneboronic acid (63mg, 0.4mmoi), tetrakis(triphenylphosphine)-palladium(O) (31 mg, 0.027mmol) and sodium carbonate solution (400μΙ, 2M,0.79mmol) in éthanol (1 ml) and toluene (4ml) was heated at 100°C for 3 hours. TLCanalysis showed starting material remaining, so dioxan (3ml), additional 4-chlorobenzeneboronic acid (21 mg, 0.13mmol) and tetrakis(triphenylphosphine)-paliadium(O) (15mg, 0.013mmol) were added, and the mixture was stirred at 100°Cfor a further 6 hours. The cooled reaction mixture was partitioned between water(10ml) and ethyl acetate (20ml) and the layers were separated. The aqueous phasewas extracted with ethyl acetate (10ml) and the combined organic extracts weredried (MgSO-O and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (98:2:0.2) as eluant to afford the titlecompound as a white solid, 60mg. 1H-NMR (CDCb, 400MHz) (mixture of géométrieisomers) δ: 3.02 (m, 1H), 3.27 (m, 2H), 3.57 (m, 1H), 3.78 (m, 1H), 4.02 (m 1 H), 4.47(m, 1H), 4.65, 4.79 (2xd, 2H), 5.82, 6.32 (m, 1H), 6.18 (bs, 1H), 6.57, 6.82 (2xm, 2H), 7.30 (d, 1 H), 7.39-7.79 (m, 8H). LRMS: m/z (ES+) 430 [MNa*] 012756 129

Préparation 141 (2RS)-2-({ 1 -f(2£Z)-3-f2'.5'-Difluoro[1.1 '-όΐρΚθηνΠ-4-νΠ-2-ΡΓ0ΡθηνΠ-1 H-imidazol-4- vl)methvl)-3-morpholinone

5 The title compound was obtained from the compound of Préparation 138 and 2,5-difluorobenzeneboronic acid foilowing the procedure deseribed in Préparation 140.1H-NMR (CDCb, 400MHz) (mixture of géométrie isomers) δ: 3.02 (m, 1 H), 3.28 (m,2H), 3.57 (m, 1H), 3.78 (m, 1H), 4.00 (m, 1H), 4.45 (m, 1H), 4.63 (d, 1H), 4.79 (d, 1H), 5.82, 6.36 (m, 1H), 6.14 (bs, 1H), 6.58, 6.79 (2xm, 2H), 7.00 (m, 1H), 7.14 (m, 10 2H), 7.32 (d, 1 H), 7.40-7.70 (m,4H). LRMS: m/z (ES*) 432 [MNa4]

Préparation 142 terf-Butyl (2F?S)-2-f2-(dimethvlamino)ethoxvl-3-(1 -propyl-1 Wmidazol-4-vhpropanoate

15 A mixture of the alkene of Préparation 44 (650mg, 2.01 mmol) and 10% palladium oncharcoal (Degussa® 101) (60mg) in éthanol (20ml) was hydrogenated at 50°C and60 psi (41 OkPa) for 18 hours. The cooled mixture was fiitered through Arbocel® andthe filtrate was evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel using an elution gradient of ethyl 20 acetate:diethylamine:methanol (100:0:0 to 97:1.5:1.5) to afford the title compound,502mg. 1H-NMR (CDCI3, 400MHz) δ: 0.92 (t, 3H), 1.42 (s, 9H), 1.77 (m, 2H), 2.21(s, 6H), 2.48 (t, 2H), 2.90-3.03 (m, 2H), 3.42 (m, 1H), 3.70 (m, 1H), 3.80 (t, 2H), 4.08(m, 1H), 6.79 (s, 1H), 7.37 (s, 1H). LRMS: m/z (TSP+) 326.2 [MH4] 012756 130

Préparation 143 fert-Butvl (35)-3-((1 RS)-2-tert-butoxy-2-oxo-1 -f( 1 -propyl-1 H-imidazol-4- v0methvllethoxv)-1“PvrroIidinecarboxvtate h3c

o ch3 5 A mixture of the alkene of Préparation 45 (1.19g, 2.83mmol) and Degussa® 101catalyst (120mg) in éthanol (12ml) was hydrogenated at 50°C and 60 psi (410kPa)for 18 hours. TLC analysis showed starting material remaining, so additionalcatalyst (120mg) was added and the mixture was hydrogenated at 50°C and 60 psi(41 OkPa) for a further 48 hours. The mixture was filtered through Arbocel®, the 10 catalyst was washed with éthanol, and the combined filtrâtes were evaporated underreduced pressure. The residual oil was purified by column chromatography on silicagel using ethyl acetate as the eluant to afford the title compound as a colourless oil,227mg. ’H-NMR (CDCI3, 400MHz) δ: 0.92 (t, 3H), 1.42 (m, 18H), 1.79 (m, 2H),2.00-2.30 (m, 2H), 2.80-2.95 (m, 1H), 3.00-3.48 (m, 5H), 3.84 (t, 2H), 4.05-4.20 (m, 15 2H), 6.75 (m, 1 H), 7.50 (m, 1 H). LRMS: m/z (ES+) 424 [MH4]

Préparation 144 (2RS)-2-(f 1 -(3-f1,1 '-Biphenvn-4-ylpropvl)-1 H-imidazol-4-vllmethvl)-3-môrpholinone

,NH 20 A mixture of the alkene of Préparation 134 (100mg, 0.268mmol) and Degussa® 101catalyst (15mg) in éthanol (12ml) was hydrogenated at 50°C and 60 psi (410kPa) for6 hours. TLC analysis showed starting material remaining, so additional Degussa® 012756 131 101 catalyst (20mg) was added and the mixture was hydrogenated fora further 18hours. The reaction mixture was filtered through Arbocel®, the catalyst was washedwith éthanol, and the comblned filtrâtes were evaporated under reduced pressure.The residue was purified by coiumn chromatography on silica gel using an elution 5 gradient of dichloromethane:methanoi:0.88 ammonia (99:1:0.1 to 98:2:0.2) to affordthe title compound as a colourless oil, 70mg. 1H-NMR (CDCI3, 400MHz) δ: 2.10 (m,2H), 2.61 (t, 2H), 3.02 (dd, 1H), 3.23 (m, 2H), 3.49 (m, 1H), 3.74 (m, 1H), 3.86 (t,2H), 4.00 (m, 1H), 4.42 (m, 1H), 6.20 (bs, 1H), 7.20 (d, 2H), 7.29 (m, 1H), 7.39 (m,4H), 7.50 (d, 2H), 7.54 (d, 2H). LRMS: m/z (ES+) 398 [MNa4] 0

Préparations 145 to 150The following compounds of general structure

were prepared from the appropriate alkenes, following similar procedures to that15 described in Préparation 144.

Prep R Yield (%) Data 1451 0 70 TH-NMR (CDCI3, 400MHz) δ: 2.17 (m, 2H), 2.68 (t, 2H), 3.02 (m, 1H), 3.24 (m, 2H), 3.50(m, 1H), 3.74 (m, 1H), 3.90 (t, 2H), 4:00 (m,1H), 4.43 (m, 1H), 6.50 (bs, 1H), 6.78 (s, 1H),7.16 (d, 1H), 7.32-7.48 (m, 7H), 7.58 (d, 2H).LRMS: m/z (ES4) 377 [MH4] 146 σ1? 71 1H-NMR (CDCI3, 400MHz) δ: 1.82 (m, 2H), 2.58 (t, 2H), 2.97 (dd, 1H), 3.22 (m, 2H), 3.50(m, 1H), 3.60-3.77 (m, 3H), 3.99 (m, 1H), 4.40 (m, 1H), 5.82 (bs, 1H), 6.55 (s, 1H), 7.20 (m, 7H), 7.38 (m, 3H). LRMS: m/z(ES4) 398 [MH4] 012756 132

Prep R Yield (%) Data 147 (/ yj HSC 65 1H-NMR (CDCI3, 400MHz) Ô: 2.10 (m, 2H), 2.38 (s, 3H), 2.61 (t, 2H), 3.02 (dd, 1H), 3.23(m, 2H), 3.50 (m, 1H), 3.75 (m, 1H), 3.83 (t,2H), 4.00 (m, 1 H), 4.42 (m, 1H), 5.82 (bs, 1H), 6.77 (s, 1H), 7.19 (m, 4H), 7.38 (s, 1H),7.45 (m, 4H). LRMS: m/z (ES+) 412 [MNa*] 148 (7 yy a 57 1H-NMR (CDCI3, 400MHz) δ: 2.10 (m, 2H), 2.60 (t, 2H), 3.02 (dd, 1H), 3.25 (m, 2H), 3.50(m, 1H), 3.74 (m, 1H), 3.85 (t, 2H), 4.00 (m,1H), 4.42 (m, 1H), 6.05 (bs, 1H), 6.77 (s, 1H),7.19 (d, 2H), 7.38 (m, 3H), 7.45 (m, 4H).LRMS: m/z (ES+) 432 [MNa*] 149 F 76 1H-NMR (CDCI3, 400MHz) δ: 2.08 (m, 2H), 2.60 (t, 2H), 3.02 (dd, 1H), 3.23 (m, 2H), 3.50(m, 1H), 3.74 (m, 1H), 3.85 (t, 2H), 4.00 (m,1H), 4.42 (m, 1H), 6.00 (bs, 1 H), 6.75 (s, 1H),6.96 (m, 1H), 7.05 (m, 2H), 7.20 (d, 2H), 7.38(s, 1 H), 7.42 (d, 2H). LRMS: m/z (ES+) 434[MNa+î 150 70 1H-NMR (CDCI3, 400MHz) δ: 2.20 (m, 2H), 2.78 (t, 2H), 3.06 (dd, 1H), 3.30 (m, 2H)' 3.54(m, 1H), 3.75 (m, 1H), 3.90 (t, 2H), 4.03 (m,1H), 4.48 (m, 1H), 5.89 (bs, 1H), 6.78 (s, 1H),7.28 (d, 1H), 7.39 (s, 1 H), 7.45 (m, 2H), 7.59(s, 1 H), 7.80 (m, 3H). LRMS: m/z (ES+) 372[MNa*] 1 = isolated without column chromatography

Préparation 151 (2S.6/7)-4-(4-Methoxybenzvl)-6-methvl-2-fri-(2-pvridinvl)-1/-/-imidazol-4-yl1methvl}-3- 012756 morpholinone

A mixture of the imidazole of Préparation 55 (566mg, 1.8mmol), copper (I) oxide(20mg, 0.14mmol) and potassium carbonate (372mg, 2.7mmol) in 2-bromopyridine(1ml) was heated at 100°C for 18 hours. The cooled mixture was purified byBiotage® column chromatography on silica gel using an elution gradient oftoluene:diethylamine (93:7 to 86:14) to afford the title compound as a foam, 482mg.1H-NMR (CDCb, 400MHz) (5:1 mixture of regioisomers) δ: 0.94,1.20 (2xd, 3H), 2.83- 3.23 (m, 4H), 3.63,3.78 (2xs, 3H), 3.97 (m, 1K), 4.16,4.22 (2xd, 1H), 4.50-4.82 (m,2H), 6.64,6.82 (2xd, 2H), 7.00,7.18 (2xd, 2H), 7.35,7.44 (2xm, 1H), 7.59 (m, 2H),7.96 (m, 1 H), 8.40-8.57 (m, 2H). HRMS: m/z (ES*) 393.1926 [MH*]

Préparation 152 (2S.6ff)-6-Methvl-2-ff1-f2-pyridinvl)-1H-imidazol-4-vnmethvl)-3-morpholinone

A mixture of the protected morpholinone of Préparation 151 (454mg, 1.16mmol) andammonium cérium (IV) nitrate (1.585g, 2.9mmol) in water (8ml) and acetonitrile(16ml) was heated at 40°C for 6 hours. The cooled mixture was diluted withmethanol (100ml), and the solution was adsorbed onto silica gel. The product wasisolated by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:1) as eluant and further purified byBiotage® column chromatography on silica gel using toluene:diethy,amine (92:8) thendichloromethane:methanol:0.88 ammonia (95:5:1) as eluant to afford the titlecompound, 204mg. 1H-NMR (CD3OD, 400MHz) (7:1 mixture of regioisomers)δ: 1.01, 1.21 (2xd, 3H), 2.92-336 (m, 4H), 3.78, 3.93 (2xm, 1H), 4.27, 4.46 (2xm, 1H),7.37, 7.45 (2xm, 1H), 7.58-7.70 (m, 2H), 7.96, 8.00 (2xm, 1H), 8.40-8.18 (m, 2H). 012756 134

Préparation 153 (6F?)-2-fHvdroxv( 1 -propyl-1 H-imidazol-4-vl)rnethvn-4-(4-methoxvbenzvl)-6-methvl-3- morpholinone

A solution of the compound of Préparation 12 (6.81g, 29.0mmol) in tetrahydrofuranwas added dropwise to a solution of lithium diisopropylamide (23.2ml, 1.5M incyclohexanes, 34.8mmol) at -78°C, and the solution was stirred for a further 20minutes at -78°C. A solution of the aldéhyde of Préparation 1 (4g, 29.0mmol) intetrahydrofuran (80ml total volume) was then added dropwise, and the mixture wasallowed to warm slowly to room température. Saturated ammonium chloridesolution (50ml) was added, followed by water (100ml), and the mixture was extractedwith ethyl acetate. The combined organic extracts were dried (MgSO4) andconcentrated under reduced pressure. The residual orange oil was purified bycolumn chromatography on silica gel using an elution gradient of ethylacetate:methano, (98:2 to 95:5) to afford the title compound as an orange oil, 5.71g. : 1H-NMR (CDCI3, 400MHz) (mixture of diastereoisomers) δ: 0.92 (m, 3H), 1.14 (m,3H), 1.58 (m, 2H), 2.96-3.18 (m, 2H), 3.78-4.00 (m, 6H), 4.22-4.76 (m, 3H), 5.06- 5.30 (m, 1H), 6.81-6.95 (m, 3H), 7.18 (m, 2H), 7.42 (d, 1H). LRMS: m/z (ES4) 374[MH4] ’—-

Préparation 154 (2EZ.6R)-4-(4-Methoxybenzvl)-6-methvl-2-f(1H-imidazol-4-vl)methvlidenel-3- morpholinone

A mixture of the compound of Préparation 37 (91g, 164mmol) and water (90ml) in 012756 135 glacial acetic acid (900ml) was heated at 40°C for 1 hour. The cooled mixture wasconcentrated under reduced pressure, diluted with water (400ml) and the resultingprecipitate filtered off. The filtrate was washed with ether (2x400ml), thenneutralised using sodium bicarbonate and extracted with ethyl acetate (1000ml).This organic solution washed with water, dried (Na2SO4) and evaporated underreduced pressure to afford the title compound as a gum, 46.4g. 1H-NMR (CDCI3,400MHz) δ: 1.41 (d, 3H), 3.24 (dd, 1H), 3.38 (dd, 1H), 3.80 (s, 3H), 4.34 (m, 1H),4.58 (d, 1H), 4.68 (d, 1H), 6.84 (d, 2H), 6.97 (s, 1H), 7.20 (d, 2H), 7.30 (s, 1H).

Préparation 155 (2£Z6ff)-4-(4-Methoxvbenzvl)-6-methvl-2-f(1-propvl-1H-imidazol-4-vl)methylidenel- 3-morpholinone

Triethy,amine (3ml, 21.75mmol) was added dropwise to a solution of the alcohol ofPréparation 153 (5.41g, 14.50mmol) in dichloromethane (60ml), and the solution wascooled to 0°C. Methanesulphonyl chloride (1.68ml, 21.75mmol) was added, and themixture was allowed to warm to room température, then stirred for a further 2 hours.Additional triethylamine (2ml, 14.50mmol) was added, and the mixture was warmedto 35°C, then stirred for 18 hours. The solution was washed with water (1O0ml),sodium bicarbonate solution (100ml) and brine (50ml), then dried (MgSO4) andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (99:1:0.1 to 98:2:0.2) to afford one isomerof the title compound as an orange oil, 1,8g, and the second isomer, 260mg. 1H-NMR (CDCI3,400MHz, major isomer) δ: 0.96 (t, 3H), 1.38 (d, 3H), 1.80 (m, 2H), 3.20(dd, 1H), 3.32 (dd, 1H), 3.78 (s, 3H), 3.86 (t, 2H), 4.25 (m, 1H), 4.57 (d, 1H), 4.65 (d, 1 H), 6.84 (d, 2H), 7.02 (s, 1H), 7.20 (d, 2H), 7.35 (s, 1H), 7.46 (s, 1 H). LRMS: m/z(ES*) 356 [MH*]. Microanalysis found: C, 63.99; H, 6.88; N, 11.00 CaoHasNsOsîHzOrequires C, 64.32; H, 7.29; N, 11.25%. 136 012756

Préparation 156 (2S,6 R)-4-(4-Methoxybenzvn-6-methvi-2-f(1 -propyl-1 H-imidazol-4-vÎ)methvn-3- morpholinone CH3

CH. A mixture of the alkene of Préparation 155 (1.8g, 5.07mmol) and 10% palladium oncharcoal (Degussa type 101) (200mg) in éthanol (50ml) was hydrogenated at 60 psi(410kPa) and 50°C for 18 hours. TLC analysis showed starting material remaining.The mixture was filtered, the filtrate was evaporated under reduced pressure, andthe residue was re-dissolved in éthanol (50ml). 10% Palladium on charcoal(Degussa type 101) (200mg) was added and the mixture was hydrogenated at 60psi(410kPa) and 50°C for 18 hours, then filtered. The filtrate was evaporated underreduced pressure and the residue was purified by column chromatography on silicagel using dichloromethane:methanol:0.88 ammonia (98:2:0.2) to afford the titlecompound as a colourless oil, 1.35g. 1H-NMR (CDCI3, 400MHz) δ: 0.92 (t, 3H), 1.19(d, 3H), 1.78 (m, 2H), 2.98-3.16 (m, 3H), 3.58 (dd, 1H), 3.82 (m, 6H), 4.50 (m, 3H),6.75 (s, 1H), 6.82 (d, 2H), 7.18 (d, 2H), 7.58 (s, 1H). LRMS: m/z (ES+) 358 [MH4].Microanalysis found: C, 62.12; H, 7.58; N, 10.89 C2oH27N303;1.5H20 requires C,62.48; H, 7.86; N, 10.93%.

Préparation 157 (2S,6/7)-6-Methvl-2-i(1-propvl-1/V-imidazol-4-yl)methvn-3-rnorpholinone CHg H,

NH A solution of the compound of Préparation 156 (1.2g, 3.36mmol) in methane-sulphonic acid (5ml) was stirred at 70°C for 2 hours. The cooled mixture waswashed with ether (2x20ml) by décantation. Water (20ml) was added and the 012756 137 mixture was basified using 0.88 ammonia, then washed with ethyl acetate (20ml).The aqueous phase was evaporated under reduced pressure, the residue wassuspended in acetonitrile, and this mixture was heated to 50°C. The acetonitriiesolution was separated by décantation and evaporated under reduced pressure togive an oil. This was purified by column chromatography on silica gel using anelution gradient of dichioromethane:methanol:0.88 ammonia (98:2:0.2 to 96:4:0.4) toafford the title compound as a colourless oil, 560mg. 1H-NMR (CDCI3i 400MHz) δ:0.94 (t, 3H), 1.22 (d, 3H), 1.59 (m, 2H), 3.04 (dd, 1H), 3.18-3.37 (m, 3H), 3.85 (m,3H), 4.42 (m, 1H), 6.50 (s, 1H), 6.79 (s, 1H), 7.68 (s, 1H). LRMS: m/z (ES4) 238[MH4]

Préparation 158 (2ff,6fî)-2-f(1 H-lmidazol-4-vl)methvll-6-methvl-3-morpholinone

Ammonium cérium (IV) nitrate (1.1g, 2mmol) was added to a solution of theprotected lactam of Préparation 55b (200mg, 0.63mmol) in water (4ml) andacetonitrile (4ml) and the mixture was stirred at room température for 3 hours. Thesolution was diluted with acetonitrile (5ml) and 0.88 ammonia (4ml), and the mixturewas filtered through Arbocel®, washing through with a solution of acetonitrile:water(50:50,10ml). The filtrate was concentrated under reduced pressure and theaqueous residue was washed with ether, then evaporated under reduced pressure.The crude product was purified by column chromatography on silica gel using anelution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.25 to 92:8:0.4)to afford the title compound as a foam, 88mg. 1H-NMR (D20,400MHz) δ: 1.20 (d,3H), 3.02-3.30 (m, 6H), 4.01 (m, 1 H), 4.40 (dd, 1 H), 6.86 (s, 1 H), 7.58 (s, 1 H).

The compounds of the présent invention may be tested using the following assay,which is based on that disclosed in Boffa et al., J. Biol. Chem. 1998,273,2127. Thecompounds are incubated with activated TAFI and a standard substrate for TAFIa, 012756 138 the rate of hydrolysis of the substrate is determined and compared to the rate ofhydrolysis in the absence of the compounds, and the amount of inhibition expressedin terms of Kh

Assav for TAFIa inhibition, i) TAFI activation

Human TAFI (recombinant or purified) was activated by incubating 20μΙ of stocksolution (360pg/ml) with 1ΟμΙ of human thrombin (10NIH units/ml), 10μΙ of rabbitthrombomodulin (30pg/ml), 6μΙ calcium chloride (50mM) in 50μΙ of 20mM HEPES (N-[2-hydroxyethyl]piperazine-N-[2-ethanesulfonic acid]) buffer containing 150mMsodium chloride and 0.01% TWEEN 80 (polyoxyethylene-sorbitan monooleate) pH 7.6 for 20 minutes at 22°C. At the end of the incubation period, thrombin wasneutralised by the addition of 10μΙ_ of PPACK (D-Phe-Pro-Arg chloromethyl ketone)(100nM). The resulting TAFIa solution was stored on ice for 5 minutes and finallydiluted with 175μΙ of HEPES buffer. ii) K| Détermination (TAFIa)

Calculated K, A number of different dilutions of the test compound in water were made up. To20μΙ of each dilution was added 150μΙ of HEPES buffer and 10μΙ of TAFIa, whichwas then pre-incubated for 15 minutes at 248C. To each dilution was then added20μΙ furylacryloyl-alanyl-lysine (FAAL) at a standard concentration. Substrateturnover was measured by reading the absorbance of the reaction mixture at 330nmevéry 15 seconds for 30 minutes. The reaction was performed at 24sC~5hd sampleswere mixed for 3 seconds prior to each absorbance reading. A graph of % inhibition against test compound concentration was then plotted; fromwhich was calculated the IC50 value. The Kj value was then calculated using theCheng-Prusoff équation.

Two Controls, positive and négative, were used to check the accuracy of the resultsin each case. For the first control, the assay was performed as above, but with 20μΙof water rather than a dilution of the test compound. This showed minimal inhibition. 012756 139

For the second control, the assay was performed as above, but with an effectiveamount of a non spécifie carboxypeptidase inhibitor rather than a dilution of the testcompound. This showed maximal inhibition. When the two Controls did notdemonstrate minimal and maximal inhibition respectively then the results were 5 discounted and the test compound was reanalysed.

Using the above assay the compounds of the Examples were found to be potent andsélective inhibitors of TAFIa. Ail the compounds tested had a Kj value less than20μΜ. The spécifie Kj values of certain compounds are detailed below: 10

Compound of Example: 4 5 40 49 51

Kj (TAFIa)10 nM10 nM14 nM9nM26 nM

The selectivity of the compounds of the présent invention for TAFIa over CPN wasdetermined by calculating the Ki of the compounds of the présent invention for CPN,then comparing it to the Kj for TAFIa. The Kj was calculated using the assay for the 15 calculation of TAFIa Kj, but substituting 10μΙ of human CPN for 10μΙ of TAFIa.

Those compounds of the présent invention tested exhibited a strong selectivity forTAFIa over CPN of the order of >50:1. The spécifie Ki values and calculatedselêctivities of certain compounds are detailed below: 20

Compound of Example: 5 51 K, (CPN)>10 μΜ>10 μΜ

Selectivity >1000 >380

Claims (29)

1. Claims 012756 1 A compound according to formula (I)

   wherein: nisO, 1,2 or 3; R1 is selected from (a) an optionally substituted straight Chain or branched Chain Ci-6 alkyl group, (b) an optionally substituted straight chain or branched Chain C2-6 alkenylgroup, (c) an optionally substituted straight chain or branched chain C2.6 alkynylgroup, (d) Aryl, (e) Aromatic heterocycle, (f) Heterocycle, and (g) hydrogen; where the optional substituents in groups (a), (b) and (c) aboveltre’selectedfrom: C3-7cycloalkyl, Aryl, Aromatic heterocycle, Heterocycle, OR10,NR10R11, S(O)PR10, OC(O)R11, CO2R10, CONR10R11, SO2NR10R11, halo andNHSO2R10, and where p is 0,1 or 2; R2, R3, R4, R6, R7 and R9 are each independently selected from hydrogen andstraight chain or branched chain Ci.6 alkyl optionally substituted by OR10 orhalo; R5 and R8 are each independently selected from hydrogen and straight chain orbranched chain Ci-6 alkyl optionally substituted by OR10 or halo, or togetherare a C2.6 alkylene chain; » 012756 R10 and R11 are each independently selected from hydrogen and straight chainor branched Chain Cve alkyl; Aryl is a 6-14 memberad aromatic monocyclic or fused polycyclic carbocyciicgroup optionaliy substituted with one or more groups selected from R12, halo,OR13, NR13R14, NR13CO2R12, COzR13,NR13SO2R12, CN, haloalkyl,O(haloalkyl), SR13, S(O)R12, SO2R12,0C(0)R13, SO2NR13R14, C(O)NR13R14,C3.7 cycloakyl, O(C3-7 cycloalkyl), R15 and OR15, where R12 is straight chain orbranched chain Cm alkyl, R13 and R14 are each independently selected fromhydrogen and straight chain or branched chain Cm alkyl, and R15 is phenyloptionaliy substituted by R12, OR13, halo or haloalkyl; Aromatic heterocycle is a 5 to 7 membered aromatic ring containing from 1 to 3heteroatoms, each independently selected from O, S and N, said ring beingoptionaliy substituted with one or more groups selected from OR13, NR13R14,CO2R13, NR13CO2R12, R12, halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12,SQ2R12, OC(O)R13, NR13SO2R12, SO2NR13R14 and C(O)NR13R14; and Heterocycle is a 3 to 8 membered ring containing from 1 to 3 heteroatoms, eachindependently selected from O, S and N, said ring being saturated or partiallysaturated, said ring further being optionaliy substituted with one or moregroups selected from OR13, NR13R14, CO2R13, NR13CO2R14, R12, halo, CN,haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12,SO2NR13R14 and C(O)NR13R14, or a tautomer thereof, or a pharmaceutically acceptable sait of said compoundor said tautomer.
2. 2 * A compound according to Claim 1 wherein the substitution pattern of theimidazole is as depicted in formula (ID1) 142 012756

   (ID1)
3. 3 A compound according to Claim 1 wherein the stereochemistry is as depicted informula (IA)
4. 4 A compound according to any preceding Claim wherein n is O or 1.
5. 5 A compound according to Claim 4 wherein n is 0.
6. 6- A compound according to any preceding Claim wherein R1 is hydrogen, Aryl,C2-6 alkeny, or a Ci-6 alkyl group optionally substituted by one or more groupsselected from C3.7 cycloalkyl, Aryl, Aromatic heterocycle, OR10, CO2R10, haloand NHSO2R10.
7. 7 A.compound according to Claim 6 wherein R1 is hydrogen, Aryl or a C^s alkylgroup optionally substituted by a group selected from cyclohexyl and Aryl R1 ishydrogen, Aryl or Ci-6 alkyl optionally substituted by cyclohexyl or Aryl.
8. 8 A compound according to Claim 7 wherein R1 is hydrogen or C^ alkyl.
9. 9 A compound according to Claim 8 wherein R1 is hydrogen. 012756 143
10. 10 A compound according to any preceding Claim wherein R2 and R3 are eachindependently hydrogen or Cve alkyl.
11. 11 A compound according to Claim 10 wherein R2 and R3 are both hydrogen.
12. 12 A compound according to any preceding Claim wherein R4 is hydrogen or Cvsalkyl.
13. 13 A compound according to Claim 12 wherein R4 is hydrogen.
14. 14 A compound according to any preceding Claim wherein R6, R7 and R9 are eachindependently hydrogen or Cv3 alkyl.
15. 15 A compound according to Claim 14 wherein R6, R7 and R9 are eachindependently hydrogen or methyl.
16. 16 A compound according to Claim 15 wherein R®, R7 and R9 are ail hydrogen.
17. 17 A compound according to any preceding Claim wherein R5 is hydrogen or Ci-3alkyl.
18. 18 A compound according to Claim 17 wherein R5 is hydrogen or methyl.
19. 19 A compound according to Claim 18 wherein R5 is methyl.
20. 20 A compound according to any of Claims 17,18 and 19 wherein R® is hydrogenor methyl.
21. 21 A compound according to Claim 20 wherein R8 is hydrogen.
22. 22 - A compound according to Claim 1, selected from: (2S)-(-)-2-(2-aminoethoxy)-3-(1 -phenyl-1 W-imidazol-4-yl)propanoic acid;(2S)-2-{[(1 fî)-2-amino-1 -methylethyl]oxy}-3-[1 -(2-cyclohexylethyl)-1 /Y-imidazol-4-yljpropanoic acid; (2S)-2-{[(1 fî)-2-am in o-1 -methylethyl]oxy}-3-(1 -phenyl-1 H-imidazol-4-yl)-propanoic acid; (2S)-2-{i(2S)-2-aminopropyl]oxy}-3-[1 -(2-cyclohexylethyl)-1 H-imidazol-4-yl]-propanoic acid; (2S)-2-(2-aminoethoxy)-3-(1 W-imidazol-4-yl)propanoic acid; (2S)-2-{[ ( 1 fî)-2-amino-1 -methylethyl]oxy}-3-(1 H-imidazol-4-yl)propanoic acid; 012756 144 and (2S)-2-{[(1 F?)-2-amino-1 -methylethyl]oxy}-3-[1 -(2-pyridinyl)-1 /7-imidazol-4-ylJ-propanoic acid, and pharmaceutically acceptable salts thereof.
23. 23 A compound according to any of Claims 1 to 22 for use as a médicament.
24. 24 A compound according to any of Claims 1 to 22 for use as a médicament for thetreatment of a condition selected from thrombotic conditions, atherosclerosis,adhesions, dermal scarring, cancer, fibrotic conditions, inflammatory diseasesand those conditions which benefit from maintaining or enhancing bradykininlevels in the body.
25. 25 A pharmaceutical composition comprising a compound according to any ofClaims 1 to 22 and a pharmaceutically acceptable carrier.
26. 26 The use of a compound according to any of Claims 1 to 22 for the préparationof a médicament for the treatment of a condition selected from thromboticconditions, atherosclerosis, adhesions, dermal scarring, cancer, fibroticconditions, inflammatory diseases and those conditions which benefit frommaintaining or enhancing bradykinin levels in the body.
27. 27 A use according to Claim 26 wherein the médicament is for the treatment of athrombotic condition.
28. 28 a process for the préparation of a compound according to formula (I) 012756 145

    wherein: n is 0,1,2 or 3; R1 is selected from (a) an optionally substituted straight Chain or branched Chain Cve alkyl group, (b) an optionally substituted straight chain or branched chain C2-ealkenylgroup, (c) an optionally substituted straight chain or branched chain C2.6 alkynylgroup, (d) Aryl, (e) Aromatic heterocycle, (f) Heterocycle, and (g) hydrogen; where the optional substituents in groups (a), (b) and (c) above are selectedfrom: C3-7cycloalkyl, Aryl, Aromatic heterocycle, Heterocycle, OR10,NR10R11, S(O)pR10, OC(O)R11, CO2R10, CONR10R11, SO2NR1?R11, halo andNrtSO2R10, and where p is 0,1 or 2; R2, R3, R4, R6, R7 and R9 are each independently selected from hydrogen andstraight chain or branched chain Cv6 alkyl optionally substituted by OR10 orhalo; R5 and R8 are each independently selected from hydrogen and straight chain orbranched chain C1-6 alkyl optionally substituted by OR10 or halo, or togetherare a C2.6 alkylene chain; R10 and R11 are each independently selected from hydrogen and straight chainor branched chain Cve alkyl; Aryl is a 6-14 membered aromatic monocyclic orfused polycyclic carbocyclic 146 012756 group optionaliy substituted with one or more groups selected from R**, halo,OR13, NR13R14, NR13CO2R12, CO2R13, NR13SO2R12, CN, haloalkyl,O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, SO2NR13R14, C(O)NR13R14,C3.7 cycloakyl, O(C3-7 cycloalkyl), R15 and OR15, where R12 is straight Chain orbranched chain C1.6 alkyl, R13 and R14 are each independently selected fromhydrogen and straight chain or branched chain Ci-6 alkyl, and R15 is phenyloptionaliy substituted by R12, OR13, halo or haloalkyl; Aromatic heterocycle is a 5 to 7 membered aromatic ring containing from 1 to 3heteroatoms, each independently selected from O, S and N, said ring beingoptionaliy substituted with one or more groups selected from OR13, NR13R14,CO2R13, NR13CO2R12, R12, halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12,SO2R12, OC(O)R13, NR13SO2R12, SO2NR13R14 and C(O)NR13R14; and Heterocycle is a 3 to 8 membered ring containing from 1 to 3 heteroatoms, eachindependently selected from O, S and N, said ring being saturated or partiallysaturated, said ring further being optionaliy substituted with one or moregroups selected from OR13, NR13R14, CO2R13, NR13CO2R14, R12, halo, CN,haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12,SO2NR13R14 and C(O)NR13R14, or a tautomer thereof, comprising the steps of; (i) preparing a compound according to formula (II)

    wherein: P1 is an optionaliy substituted Cv6 alkyl group, an optionaliy substituted C4-7cycloalkyl group, an optionaliy substituted benzyl group or a tri(Ci-e alkyl)silylgroup; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined for formula (I); and 147 012756 (ii) treating said compound of formula (II) with a reagent or combination ofreagents suitable for removing the P1 group.
29. 29. A process for the préparation of a compound according to formula (I)

    wherein: nisO, 1,2or3; R1 is selected from (a) an optionally substituted straight chain or branched Chain Cve alkyl group, (b) an optionally substituted straight chain or branched Chain C2-6 alkenylgroup, (c) an optionally substituted straight chain or branched chain C2.6 alkynylgroup, (d) Aryl, (e) Aromatic heterocycle, (f) Heterocycle, and (g) hydrogen; where the optional substituents in groups (a), (b) and (c) above are selectedfrom: C3.7cycloalkyl, Aryl. Aromatic heterocycle, Heterocycle, OR10,NRWR11, S(O)pR10, OC(O)R11, CO2R10, CONR10R11, SO2NR10R11, haloand NHSO2R10, and where p is 0,1 or 2; R2, R3, R4, R6 and R7 are each independently selected from hydrogen andstraight chain or branched chain Ci.6 alkyl optionally substituted by OR10 orhalo; R5 and R8 are each independently selected from hydrogen and straight chain orbranched chain C1-6 alkyl optionally substituted by OR10 or halo, or together 148 012756 are a C2-e alkylene Chain; R9 is hydrogen; R10 and R11 are each independently selected from hydrogen and straight chainor branched chain C^ alkyl; Aryl is a 6-14 membered aromatic monocyclic or fused poiycyclic carbocyclicgroup optionally substituted with one or more groupe selected from R12, halo,OR13, NR13R14, NR13CO2R12, CO2R13, NR13SO2R12, CN, haloalkyl,O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, SO2NR13R14, C(O)NR13R14,C3-7 cycloakyl, O(C3-7 cycloalkyl), R15 and OR15, where R12 is straight chain orbranched chain alkyl, R13 and R14 are each independently selected fromhydrogen and straight chain or branched chain Ci-β alkyl, and R15 is phenyloptionally substituted by R12, OR13, halo or haloalkyl; Aromatic heterocycle is a 5 to 7 membered aromatic ring containing from 1 to 3heteroatoms, each independently selected from O, S and N, said ring beingoptionally substituted with one or more groups selected from OR13, NR13R14,CO2R13, NR13CO2R12, R12, halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12,SO2R12, OC(O)R13, NR13SO2R12, SO2NR13R14 and C(O)NR13R14; and Heterocycle is a 3 to 8 membered ring containing from 1 to 3 heteroatoms, eachindependently selected from O, S and N, said ring being saturated or partial,ysaturated, said ring further being optionally substituted with one or moregroups selected from OR13, NR13R14, CO2R13, NR13CO2R14, R12, halo, CN,haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12,SO2NR13R14 and C(O)NR13R14, or a tautomer thereof, comprising the steps of: (i) preparing a compound according to formula (XIV)

    wherein: R1, R2, R3, R4, R5, R6, R7, R8 and n are as defined for formula (I); and 012756 149 (h) treating said compound of formula (II) with a reagent or combinationof reagents suitable for hydrolyzing the amide bond of the lactamring.