HK1117541B

HK1117541B - Template-fixed peptidomimeticsas inhibitors of serine proteases

Info

Publication number: HK1117541B
Application number: HK08107766.9A
Authority: HK
Inventors: D．奥布莱希特; J．A．罗宾逊; A．德施库尔斯
Original assignee: 波利弗尔有限公司; 苏黎士大学
Filing date: 2008-07-15
Publication date: 2012-12-28

Description

Template-fixed peptidomimetics as serine protease inhibitors

The present invention provides template-fixed beta-hairpin peptidomimetics (peptidomimetics) incorporating a template-fixed chain of 7 or 11 alpha-amino acid residues, which residues are Gly, or Pro, or certain species, depending on their position in the chain, as defined below. These template-fixed beta-hairpin peptidomimetics are useful as inhibitors of proteases. They are particularly valuable as inhibitors of various serine proteases such as trypsin, human cathepsin G, and thrombin. In addition, the present invention provides an efficient method such that these compounds can be prepared in library form as desired. The library method provides an efficient novel tool for identifying specific serine protease inhibitors.

Protease inhibitors arise because of their promising therapeutic use in the treatment of diseases such as cancer (r.p. beckett, a.davidson, a.h. drummond, m.whittaker, Drug disc.today 1996, 1, 16-26; l.l.johnson, r.dyer, d.j.hupe, curr.opin.chem.biol.1998, 2, 466-71; d.leung, g.abbenante, and d.p.fairlie, j.med.chem.2000, 43, 305-341), parasites, fungi, and viral infections [ such as schistosomiasis (m.m.becker, s.a.harrop, j.p.dalton, b.h.kalina, d.p.mcnus, d.p.p.mendy, j.billey, j.billem.496.1995, bril.501); malaria (A.M.Silva, A.Y.Lee, S.V.Gulnik, P.Maier, J.Collins, T.N.Bhat, P.J.Collins, R.E.Cachau, K.E.Luker, I.Y.Gluzman, S.E.Francis, A.Oksman, D.E.Goldberg, J.W.Erikson, Proc.Natl.Acad.Sci.U.S.A 1996, 93, 10034-9), Candida albicans (C.Abad-Zappetero, R.Goldman, S.W.Muchmore, C.Hutchins, K.Stewart, J.Navaza, C.D.Payne, T.L.ray, protein, 1996, 5, HIV-52, HIV (A.Y.Leysson, J.S.S.Scholk.S.J.S.H.J.S.S.S.J.H.S.S.J.S.S.S.S.D.S.D.C.C.D.D.J.D.D.D.D.C.D.D.D.D.D.C.D.D.C.D.Y.A.A.protein, protein, 5, HIV (A.52), HIV (A.S.S.S.S.S.S.S.D.D.D.D.D.D.D.D.52), HIV (C.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.H.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.H.H.D.D.D.D.D.D.H.D.D.D.D.D., cardiovascular diseases (m.t.stubbs, w.a.bode, thromb.res.1993, 69, 1-58), and neurodegenerative defects, including alzheimer's disease (r.vassar, b.d.bennett, s.babu-Kahn, s.kahn, e.a.mendizaz, science, 1999, 286, 735-41).

Since most proteases bind to their substrates in an extended or beta-chain conformation, a good inhibitor must therefore be able to mimic this conformation. The B-hairpin mimetic is therefore ideally suited for locking to peptide sequences in extended conformation.

Among proteases, serine proteases are important therapeutic targets. Serine proteases are classified as trypsin-like (positively charged residues Lys/Arg, preferably on P1), elastase-like (small hydrophobic residues Ala/Val on P1), or chymotrypsin-like (large hydrophobic residues Phe/Tyr/Leu on P1) depending on their substrate specificity, in particular depending on the kind of residues present on P1. Serine proteases for which protease-inhibitor X-ray crystal data can be obtained on the PDB database (PDB: www.rcsb.org/PDB) include trypsin, alpha-chymotrypsin, gamma-chymotrypsin, human neutrophilic elastase, thrombin, subtilisin, human cytomegalovirus, protease A, colorless bacteria, human cathepsin G, glutamate specific protease, carbopeptidase D, blood coagulation factor VIIa, porcine factor 1XA, mesenterioppetedase, HCV protease, and thermitase. Other serine proteases of therapeutic value include tryptase, complement convertase, hepatitis C-NS3 protease. Inhibitors of thrombin (e.g. J.L.Metha, L.Y.Chen, W.W.Nichols, C.Mattsson, D.Gustaffson, T.G.P.Saldeen, J.Cardiovasc.Pharmacol.1998, 31, 345-51; C.Lila, P.Gloanec, L.cadet, Y.Herve, J.Fournier, F.Leborgene, T.J.Verben, G.Dennteruil, Synth.Comm.1998, 28, 4419-29) and factor Xa (e.g. J.Vacca, Annu.Rep.Med.Chem.1998, 33, 81-90) are evaluated as antithrombotic agents, elastase (J.Williams, R.C.Falone, C.Knee, R.L.Valnem.51, R.Thr.R.R.R.31, R.R.R.R.R.R.R.Valley, R.R.R.C.Valneme, R.R.R.K.K.7, R.R.R.R.R.R.S. Val.51, R.R.R.R.R.R.7, R.R.E.E.R.R.E.E.R.E.R.R.A.R.A.R.A. Val.3-3, R.S. Leu, R.D.3, R.3, R.R.S. Val.S. Tr.R.R. Finally, cathepsin G and elastase are intimately involved in the regulation of the activity of cytokines and their receptors. In particular at the site of inflammation, the release of high concentrations of cathepsin G, elastase and protease 3 from infiltrating polymorphonuclear cells is closely correlated in time with the elevated levels of inflammatory cytokines, which clearly suggests that these proteases are involved in the control of cytokine bioactivity and availability (u.bank, s.ansorge, j.leukc.biol.2001, 69, 177-90). Inhibitors of thrombin and cathepsin G are therefore valuable targets for new drug candidates.

Among the many protein serine protease inhibitors that exist, one is a14 amino acid cyclic peptide from sunflower seed, called sunflower trypsin inhibitor (SFTI-1) (stt，R.Santiago Garcia，J.J.Barker，A.V.Konarev，P.R.Shewry，A.R.Clarke，R.L.Brady，J.Mol.Biol.1999，290，525-533；Y.-Q.Long，S.-L.Lee，C.-Y.Lin，I.J.Enyedy，S.Wang，P.Li，R.B.Dickson，P.P.Roller，Biorg.&Med.chem.lett.2001, 11, 2515-containing 2519) which showed sequence and conformation similarity with the trypsin-reactive loop of the Bowman-Birk family serine protease inhibitors. The inhibitor adopts a beta-hairpin conformation when bound to the active site of bovine beta-trypsin. SFTI-1 inhibits beta-trypsin (K)_i< 0.1nM), cathepsin G, elastase (K)_iAbout 105. mu.M), chymotrypsin (K)_iAbout 7.4. mu.M) and thrombin (K)_iAbout 136 mM).

We propose herein an inhibitor design approach that involves grafting the β -hairpin loop from a naturally occurring peptide onto a hairpin inducing template. Based on the well-defined 3D-structure of the beta-hairpin mimetics, libraries of compounds can be designed, and novel inhibitors with different specificity profiles for several classes of proteases can be finally obtained.

Template-bound hairpin mimetics have been described in the literature (D, Obrecht, M.Altorfer, J.A.Robinson, adv.Med.chem.1999, 4, 1-68; J.A.Robinson, Syn.Lett.2000, 4, 429-441), but these molecules have previously been evaluated for the development of peptides that inhibit proteases and that constitute mimetics of extended peptide conformations. However, the ability to generate β -hairpin peptidomimetics using combinatorial and parallel synthetic methods has been established (L.Jiang, K.Moehle, B.Dhanapaal, D.Obrecht, J.A.Robinson, Helv.Chim.acta.2000, 83, 3097-. This technology enables the rapid synthesis of protease inhibitor libraries and the development of key residues that determine specificity for a given serine protease.

The beta-hairpin peptidomimetics of the invention are compounds having the general formula

Wherein

Is a radical of one of the formulae

Wherein

Is a residue of an L-alpha-amino acid, wherein B is of the formula-NR²⁰CH(R⁷¹) -or an enantiomer of one of the groups a1-a69 as defined below;

is a radical of one of the formulae

R¹Is H; a lower alkyl group; or aryl-lower alkyl;

R²is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；-(CH₂)_m(CHR⁶¹)_sOCONR³³R⁷⁸；

-(CH₂)_m(CHR⁶¹)_sNR²⁰CONR³³R⁷⁸；-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；

-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；-(CH₂)_o(CHR⁶¹)_sSO₂R⁶²；

Or- (CH)₂)_o(CHR⁶¹)_sC₆H₄R⁸；

R³Is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

-(CH₂)_o(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_o(CHR⁶¹)_sC₆H₄R⁸；

R⁴Is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_p(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_p(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_p(CHR⁶¹)_sPO(OR⁶⁰)₂；

-(CH₂)_p(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_o(CHR⁶¹)_sC₆H₄R⁸；

R⁵Is an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；-(CH₂)_m(CHR⁶¹)_sOCONR³³R⁷⁸；

-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；-(CH₂)_o(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_o(CHR⁶¹)_sC₆H₄R⁸；

R⁶Is H; an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R⁷Is an alkyl group; chainAn alkenyl group; - (CH)₂)_q(CHR⁶¹)_sOR⁵⁵；-(CH₂)_q(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_r(CHR⁶¹)_sCOOR⁵⁷；

-(CH₂)_r(CHR⁶¹)_sCONR⁵⁸R⁵⁹；-(CH₂)_r(CHR⁶¹)_sPO(OR⁶⁰)₂；

-(CH₂)_r(CHR⁶¹)_sSO₂R⁶²(ii) a Or

-(CH₂)_r(CHR⁶¹)_sC₆H₄R⁸；

R⁸Is H; cl; f; CF (compact flash)₃；NO₂(ii) a A lower alkyl group; a lower alkenyl group; an aryl group; aryl-lower alkyl; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；-(CH₂)_o(CHR⁶¹)NR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sOCONR³³R⁷⁸；-(CH₂)_o(CHR⁶¹)_sNR²⁰CONR³³R⁷⁸；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；-(CH₂)_o(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_o(CHR⁶¹)_sCOR⁶⁴；

R⁹Is an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sS⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R¹⁰Is an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R¹¹Is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；-(CH₂)_m(CHR⁶¹)_sOCONR³³R⁷⁸；

Or- (CH)₂)_o(CHR⁶¹)_sC₆H₄R⁸；

R¹²Is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；-(CH₂)_r(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_r(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_r(CHR⁶¹)_sPO(OR⁶⁰)₂；-(CH₂)_r(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_r(CHR⁶¹)_sC₆H₄R⁸；

R¹³Is an alkyl group; an alkenyl group; - (CH)₂)_q(CHR⁶¹)_sOR⁵⁵；-(CH₂)_q(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_q(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_q(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_q(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_q(CHR⁶¹)_sPO(OR⁶⁰)₂；

-(CH₂)_q(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_q(CHR⁶¹)_sC₆H₄R⁸；

R¹⁴Is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_q(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_q(CHR⁶¹)_sCONR⁵⁸R⁵⁹；-(CH₂)_q(CHR⁶¹)_sPO(OR⁶⁰)₂；

-(CH₂)_q(CHR⁶¹)_sSOR⁶²(ii) a Or- (CH)₂)_q(CHR⁶¹)_sC₆H₄R⁸；

R¹⁵Is an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)₈COOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R¹⁶Is an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R¹⁷Is an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_q(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_q(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_q(CHR⁶¹)_sPO(OR⁶⁰)₂；

R¹⁸Is an alkyl group; an alkenyl group; - (CH)₂)_p(CHR⁶¹)_sOR⁵⁵；-(CH₂)_p(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_p(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_p(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_p(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_p(CHR⁶¹)_sPO(OR⁶⁰)₂；

R¹⁹Is a lower alkyl group; - (CH)₂)_p(CHR⁶¹)_sOR⁵⁵；-(CH₂)_p(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_p(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_p(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_p(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_p(CHR⁶¹)_sPO(OR⁶⁰)₂；

-(CH₂)_p(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_o(CHR⁶¹)_sC₆H₄R⁸(ii) a Or

R¹⁸And R¹⁹Together may form: - (CH)₂)_2-6-；-(CH₂)₂O(CH₂)₂-；-(CH₂)₂S(CH₂)₂-; or

-(CH₂)₂NR³⁴(CH₂)₂-；

R²⁰Is H; an alkyl group; an alkenyl group; or aryl-lower alkyl;

R²¹is H; an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R²²Is H; an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R²³Is an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R²⁴Is an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R²⁵Is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R²⁶Is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；-(CH₂)_o(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_o(CHR⁶¹)_sC₆H₄R⁸(ii) a Or

R²⁵And R²⁶Together may form: - (CH)₂)_2-6-；-(CH₂)_rO(CH₂)_r-；-(CH₂)_rS(CH₂)_r-; or

-(CH₂)_rNR³⁴(CH₂)_r-；

R²⁷Is H; an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R²⁸Is an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_s-OR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R²⁹Is an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R³⁰Is H; an alkyl group; an alkenyl group; or aryl-lower alkyl;

R³¹is H; an alkyl group; an alkenyl group; - (CH)₂)_p(CHR⁶¹)_sOR⁵⁵；-(CH₂)_p(CHR⁶¹)_sNR³³R³⁴；

R³²Is H; a lower alkyl group; or aryl-lower alkyl;

R³³is H; alkyl, alkenyl; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_m(CHR⁶¹)_sNR³⁴R⁶³；-(CH₂)_m(CHR⁶¹)_sOCONR³⁴R⁷⁸；

-(CH₂)_m(CHR⁶¹)_sNR²⁰CONR³⁴R⁷⁸；-(CH₂)_o(CHR⁶¹)_sCOR⁶⁴；

-(CH₂)_o(CHR⁶¹)_s-CONR⁵⁸R⁵⁹，-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；-(CH₂)_o(CHR⁶¹)_sSO₂R⁶²；

Or- (CH)₂)_o(CHR⁶¹)_sC₆H₄R⁸；

R³⁴Is H; a lower alkyl group; aryl, or aryl-lower alkyl;

R³⁵is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_p(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_p(CHR⁶¹)_sCONR⁵⁸R⁵⁹；-(CH₂)_p(CHR⁶¹)_sPO(OR⁶⁰)₂；

-(CH₂)_p(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_p(CHR⁶¹)_sC₆H₄R⁸；

R³⁶Is H, alkyl; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_p(CHR⁶¹)_sNR³³R³⁴；

R³⁷Is H; f; br; cl; NO₂；CF₃(ii) a A lower alkyl group; - (CH)₂)_p(CHR⁶¹)_sOR⁵⁵；

-(CH₂)_p(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R³⁸Is H; f; br; cl; NO₂；CF₃(ii) a An alkyl group; an alkenyl group; - (CH)₂)_p(CHR⁶¹)_sOR⁵⁵；

-(CH₂)_p(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R³⁹Is H; an alkyl group; an alkenyl group; or aryl-lower alkyl;

R⁴⁰is H; an alkyl group; an alkenyl group; or aryl-lower alkyl;

R⁴¹is H; f; br; cl; NO₂；CF₃(ii) a An alkyl group; an alkenyl group; - (CH)₂)_p(CHR⁶¹)_sOR⁵⁵；

-(CH₂)_p(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R⁴²Is H; f; br; cl; NO₂；CF₃(ii) a An alkyl group; an alkenyl group; - (CH)₂)_p(CHR⁶¹)_sOR⁵⁵；

-(CH₂)_p(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂；

R⁴³Is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；

R⁴⁴Is an alkyl group; an alkenyl group; - (CH)₂)_r(CHR⁶¹)_sOR⁵⁵；-(CH₂)_r(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_r(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_r(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_r(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_r(CHR⁶¹)_sPO(OR⁶⁰)₂；

-(CH₂)_r(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_r(CHR⁶¹)_sC₆H₄R⁸；

R⁴⁵Is H; an alkyl group; an alkenyl group; - (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；-(CH₂)_o(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_o(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_s(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_s(CHR⁶¹)_sPO(OR⁶⁰)₂；

-(CH₂)_s(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_s(CHR⁶¹)_sC₆H₄R⁸；

R⁴⁶Is H; an alkyl group; an alkenyl group; or- (CH)₂)_o(CHR⁶¹)_pC₆H₄R⁸；

R⁴⁷Is H; an alkyl group; an alkenyl group; or- (CH)₂)_o(CHR⁶¹)_sOR⁵⁵；

R⁴⁸Is H; a lower alkyl group; a lower alkenyl group; or aryl-lower alkyl;

R⁴⁹is H; an alkyl group; an alkenyl group; - (CHR)⁶¹)_sCOOR⁵⁷；(CHR⁶¹)_sCONR⁵⁸R⁵⁹；(CHR⁶¹)_sPO(OR⁶⁰)₂；

-(CHR⁶¹)_sSOR⁶²(ii) a Or- (CHR)⁶¹)_sC₆H₄R⁸；

R⁵⁰Is H; a lower alkyl group; or aryl-lower alkyl;

R⁵¹is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_pPO(OR⁶⁰)₂；-(CH₂)_p(CHR⁶¹)_sSO₂R⁶²(ii) a Or- (CH)₂)_p(CHR⁶¹)_sC₆H₄R⁸；

R⁵²Is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_pPO(OR⁶⁰)₂；

R⁵³Is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sSR⁵⁶；

-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)_sCOOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

-(CH₂)_o(CHR⁶¹)_pPO(OR⁶⁰)₂；

R⁵⁴Is H; an alkyl group; an alkenyl group; - (CH)₂)_m(CHR⁶¹)_sOR⁵⁵；-(CH₂)_m(CHR⁶¹)_sNR³³R³⁴；

-(CH₂)_o(CHR⁶¹)COOR⁵⁷；-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹(ii) a Or- (CH)₂)_o(CHR⁶¹)_sC₆H₄R⁸；

R⁵⁵Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl;

-(CH₂)_m(CHR⁶¹)_sOR⁵⁷；

-(CH₂)_m(CHR⁶¹)_sNR³⁴R⁶³；-(CH₂)_o(CHR⁶¹)_s-COR⁶⁴；-(CH₂)_o(CHR⁶¹)COOR⁵⁷；

or- (CH)₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

R⁵⁶Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl;

-(CH₂)_m(CHR⁶¹)_sOR⁵⁷；

-(CH₂)_m(CHR⁶¹)_sNR³⁴R⁶³；-(CH₂)_o(CHR⁶¹)_s-COR⁶⁴(ii) a Or

-(CH₂)_o(CHR⁶¹)_sCONR⁵⁸R⁵⁹；

R⁵⁷Is H; a lower alkyl group; a lower alkenyl group; aryl lower alkyl; or heteroaryl lower alkyl;

R⁵⁸is H; a lower alkyl group; a lower alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; or heteroaryl-lower alkyl;

R⁵⁹is H; a lower alkyl group; a lower alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; or heteroaryl-lower alkyl; or

R⁵⁸And R⁵⁹Together may form: - (CH)₂)_2-6-；-(CH₂)₂O(CH₂)₂-；-(CH₂)₂S(CH₂)₂-; or- (CH)₂)₂NR³⁴(CH₂)₂-；

R⁶⁰Is H; a lower alkyl group; a lower alkenyl group; an aryl group; or aryl-lower alkyl;

R⁶¹is an alkyl group; an alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CH)₂)_mOR⁵⁵；

-(CH₂)_mNR³³R³⁴；-(CH₂)_oCOOR³⁷；-(CH₂)_oNR⁵⁸R⁵⁹(ii) a Or- (CH)₂)_oPO(COR⁶⁰)₂；

R⁶²Is a lower alkyl group; a lower alkenyl group; aryl, heteroaryl; or aryl-lower alkyl;

R⁶³is H; a lower alkyl group; a lower alkenyl group; aryl, heteroaryl; aryl-lower alkyl;

heteroaryl-lower alkyl;

-COR⁶⁴；-COOR⁵⁷；-CONR⁵⁸R⁵⁹；-SO₂R⁶²(ii) a OR-PO (OR)⁶⁰)₂；

R⁶⁴Is H; a lower alkyl group; a lower alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl;

-(CH₂)_p(CHR⁶¹)_sOR⁶⁵；-(CH₂)_p(CHR⁶¹)_sSR⁶⁶(ii) a Or- (CH)₂)_p(CHR⁶¹)_sNR³⁴R⁶³；

R⁶⁵Is H; a lower alkyl group; a lower alkenyl group; aryl, aryl-lower alkyl; heteroaryl-lower alkyl; -COR⁵⁷；

-COOR⁵⁷(ii) a or-CONR⁵⁸R⁵⁹；

R⁶⁶Is H; a lower alkyl group; lower alkenyl(ii) a An aryl group; aryl-lower alkyl; heteroaryl-lower alkyl; or-CONR⁵⁸R⁵⁹；

m is 2 to 4; o is 0 to 4; p is 1 to 4; q is 0 to 2; r is 1 or 2; s is 0 or 1;

z is a chain of N alpha-amino acid residues, N is an integer 7 or 11, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, such that these amino acid residues are (depending on their position in the chain) Gly, or Pro, or have the formula-A-CO-, or one of the following classes

C： -NR²⁰CH(R⁷²)CO-；

D： -NR²⁰CH(R⁷³)CO-；

E： -NR²⁰CH(R⁷⁴)CO-；

F： -NR²⁰CH(R⁸⁴)CO-；and

H： -NR²⁰-CH(CO-)-(CH₂)_4-7-CH(CO-)-NR²⁰-；

-NR²⁰-CH(CO-)-(CH₂)_pSS(CH₂)_p-CH(CO-)-NR²⁰-；

-NR²⁰-CH(CO-)-(-(CH₂)_pNR²⁰CO(CH₂)_p-CH(CO-)-NR²⁰-；and

-NR²⁰-CH(CO-)-(-(CH₂)_pNR²⁰CONR²⁰(CH₂)_p-CH(CO-)-NR²⁰-；

R⁷¹Is H; a lower alkyl group; a lower alkenyl group; - (CH)₂)_p(CHR⁶¹)_sOR⁷⁵；

-(CH₂)_p(CHR⁶¹)_sSR⁷⁵；-(CH₂)_pNR⁷⁸R⁷⁹；

-(CH₂)_o(CHR⁶¹)_sCOOR⁷⁵；-(CH₂)_pCONR⁷⁸R⁷⁹；-(CH₂)_pPO(OR⁶²)₂；

-(CH₂)_pSO₂R⁶²(ii) a Or

-(CH₂)_o-C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶；

R⁷²Is H; a lower alkyl group; a lower alkenyl group; - (CH)₂)_p(CHR⁶¹)_sOR⁸⁵(ii) a Or

-(CH₂)_p(CHR⁶¹)_sSR⁸⁵；

R⁷³Is- (CH)₂)_oR⁷⁷；-(CH₂)_rO(CH₂)_oR⁷⁷；-(CH₂)_rS(CH₂)_oR⁷⁷(ii) a Or

-(CH₂)_rNR²⁰(CH₂)_oR⁷⁷；

R⁷⁴Is- (CH)₂)_pNR⁷⁸R⁷⁹；-(CH₂)_pC(＝NR⁸⁰)NR⁷⁸R⁷⁹；-(CH₂)_pC(＝NOR⁵⁰)NR⁷⁸R⁷⁹；

-(CH₂)_pC(＝NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹；-(CH₂)_pNR⁸⁰C(＝NR⁸⁰)NR⁷⁸R⁷⁹；-(CH₂)_pC₆H₄NR⁷⁸R⁷⁹；

-(CH₂)_pC₆H₄C(＝NR⁸⁰)NR⁷⁸R⁷⁹；-(CH₂)_pC₆H₄C(＝NOR⁵⁰)NR⁷⁸R⁷⁹；

-(CH₂)_pC₆H₄C(＝NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹；-(CH₂)_pC₆H₄NR⁸⁰C(＝NR⁸⁰)NR⁷⁸R⁷⁹；

-(CH₂)_rO(CH₂)_mNR⁷⁸R⁷⁹；-(CH₂)_rO(CH₂)_pC(＝NR⁸⁰)NR⁷⁸R⁷⁹；-

(CH₂)_rO(CH₂)_pC(＝NOR⁵⁰)NR⁷⁸R⁷⁹；

-(CH₂)_rO(CH₂)_pC(＝NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹；-(CH₂)_rO(CH₂)_mNR⁸⁰C(＝NR⁸⁰)NR⁷⁸R⁷⁹；

-(CH₂)_rO(CH₂)_pC₆H₄CNR⁷⁸R⁷⁹；-(CH₂)_rO(CH₂)_pC₆H₄C(＝NR⁸⁰)NR⁷⁸R⁷⁹；

-(CH₂)_rO(CH₂)_pC₆H₄C(＝NOR⁵⁰)NR⁷⁸R⁷⁹；-(CH₂)_rO(CH₂)_pC₆H₄C(＝NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹；

-(CH₂)_rO(CH₂)_pC₆H₄NR⁸⁰C(＝NR⁸⁰)NR⁷⁸R⁷⁹；-(CH₂)_rS(CH₂)_mNR⁷⁸R⁷⁹；

-(CH₂)_rS(CH₂)_pC(＝NR⁸⁰)NR⁷⁸R⁷⁹；-(CH₂)_rS(CH₂)_pC(＝NOR⁵⁰)NR⁷⁸R⁷⁹；

-(CH₂)_rS(CH₂)_pC(＝NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹；-(CH₂)_rS(CH₂)_mNR⁸⁰C(＝NR⁸⁰)NR⁷⁸R⁷⁹；

-(CH₂)_rS(CH₂)_pC₆H₄CNR⁷⁸R⁷⁹；-(CH₂)_rS(CH₂)_pC₆H₄C(＝NR⁸⁰)NR⁷⁸R⁷⁹；

-(CH₂)_rS(CH₂)_pC₆H₄C(＝NOR⁵⁰)NR⁷⁸R⁷⁹；-(CH₂)_rS(CH₂)_pC₆H₄C(＝NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹；

-(CH₂)_rS(CH₂)_pC₆H₄NR⁸⁰C-(＝NR⁸⁰)NR⁷⁸R⁷⁹；-(CH₂)_pNR⁸⁰CONR⁷⁸R⁷⁹(ii) a Or

-(CH₂)_pC₆H₄NR⁸⁰CONR⁷⁸R⁷⁹；

R⁷⁵Is a lower alkyl group; a lower alkenyl group; or aryl-lower alkyl;

R⁷⁶is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl; - (CH)₂)_oOR⁷²；

-(CH₂)_oSR⁷²；-(CH₂)_oNR³³R³⁴；

-(CH₂)_oCOOR⁷⁵；-(CH₂)_oCONR⁵⁸R⁵⁹；-(CH₂)_oPO(OR⁶⁰)₂；-(CH₂)_pSO₂R⁶²(ii) a Or

-(CH₂)_oCOR⁶⁴；

R⁷⁷is-C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶(ii) a Or a heteroaryl group having one of the following formulae

R⁷⁸Is H; a lower alkyl group; an aryl group; or aryl-lower alkyl;

R⁷⁹is H; a lower alkyl group; an aryl group; or aryl-lower alkyl; or

R⁷⁸And R⁷⁹When taken together may be- (CH)₂)_2-7-；-(CH₂)₂O(CH₂)₂-; or- (CH)₂)₂NR³³(CH₂)₂-；

R⁸⁰Is H; or lower alkyl;

R⁸¹is H; a lower alkyl group; or aryl-lower alkyl;

R⁸²is H; a lower alkyl group; an aryl group; a heteroaryl group; or aryl-lower alkyl;

R⁸³is H; a lower alkyl group; an aryl group; or-NR⁷⁸R⁷⁹；

R⁸⁴Is- (CH)₂)_m(CHR⁶¹)_sOH；-(CH₂)_pCONR⁷⁸R⁷⁹；-(CH₂)_pNR⁸⁰CONR⁷⁸R⁷⁹；-(CH₂)_pC₆H₄CONR⁷⁸R⁷⁹；-(CH₂)_pCOOR⁸⁰Or- (CH)₂)_pC₆H₄NR⁸⁰CONR⁷⁸R⁷⁹；

R⁸⁵Is a lower alkyl group; or lower alkenyl;

provided that in said chain Z of n alpha-amino acid residues

-if n is 7, then the amino acid residues at positions 1-7 are:

p1: class C or class F or class D;

p2: class E or class C or class D or class F;

p3: class F or class C, or the residue is Gly or Pro;

p4: class C or class D or class F, or the residue is Gly or Pro;

p5: class F or has the formula-A-CO-, or the residue is Gly or Pro;

p6: class C or class E or having the formula-A-CO-, or the residue is Pro;

p7: class C or class F or class D;

if n is 11, then the amino acid residues at positions 1-11 are:

p1: class E or class F or class C;

p2: class C or class F or class E;

p3: class C or class F;

p4: species E or species C or species D or species F, or the residue is Gly or Pro;

p5: class F or class C, or the residue is Gly or Pro;

p6: class C or class D or class F, or the residue is Gly or Pro;

p7: class F or has the formula-A-CO-, or the residue is Gly or Pro;

p8: class C or class E or having the formula-A-CO-, or the residue is Gly or Pro;

p9: class C or class F;

p10: class F or class C;

p11: class D or class E or class F or class C; or

P2 and P10 together may form a H-like group;

and pharmaceutically acceptable salts thereof.

According to the invention, these β -hairpin peptidomimetics can be made by a method comprising:

(a) the appropriately functionalized solid support is brought into contact with the desired end productⁿ/₂+¹/₂Orⁿ/₂-¹/₂Coupling of a suitable N-protected derivative of an amino acid at position, any functional group that may be present in said N-protected amino acid derivative being likewise suitably protected;

(b) removing the N-protecting group from the product thus obtained;

(c) coupling the product thus obtained with a suitable N-protected derivative of an amino acid located one position closer to the N-terminal amino acid residue in the desired end product, any functional groups that may be present in said N-protected amino acid derivative being likewise suitably protected;

(d) removing the N-protecting group from the product thus obtained;

(e) repeating steps (c) and (d) if necessary until the N-terminal amino acid residue has been introduced;

(f) coupling the product thus obtained to a compound of the general formula

Wherein

X is an N-protecting group, or, if defined above

Is the above group (a1) or (a2), alternatively,

(fa) coupling the product obtained in step (d) or (e) with a suitable N-protected derivative of an amino acid of the general formula

HOOC-B-H III or HOOC-A-H IV

Wherein B and A are as defined above, any functional groups which may be present in the N-protected amino acid derivative are likewise suitably protected;

(fb) removing the N-protecting group from the product thus obtained; and

(fc) coupling of the product thus obtained with suitable N-protected derivatives of amino acids having the general formulae IV and III above, respectively, any functional groups which may be present in said N-protected amino acid derivatives being likewise suitably protected;

(g) removing the N-protecting group from the product obtained in step (f) or (fc);

(h) coupling the product thus obtained to a suitable N-protected derivative of the amino acid at position N in the desired end product, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;

(i) removing the N-protecting group from the product thus obtained;

(j) coupling the product thus obtained to a suitable N-protected derivative of an amino acid one position further than the N-position in the desired end product, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;

(k) removing the N-protecting group from the product thus obtained;

(l) Repeating steps (j) and (k) if necessary until all amino acid residues have been introduced;

(m) if desired, selectively deprotecting one or several protective functional groups present in the molecule and appropriately substituting the reactive groups thus released;

(o) separating the product thus obtained from the solid support;

(p) cyclizing the cleaved product from the solid support;

(q) if desired, forming interchain linkages between the side chains of appropriate amino acid residues at opposite positions in the β -strand region;

(r) removing any protecting groups present on the functional groups of any component of the chain of amino acid residues and, if desired, any protecting groups that may additionally be present in the molecule; and

(r) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting the pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different pharmaceutically acceptable salt.

The term "alkyl" as used in the present specification, alone or in combination, denotes a saturated, straight-chain or branched hydrocarbon radical having up to 24, preferably up to 12, carbon atoms. Similarly, the term "alkenyl" denotes straight-chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms and containing at least one or, depending on the chain length, up to four olefinic double bonds. The term "lower" denotes groups and compounds having up to 6 carbon atoms. Thus, for example, the term "lower alkyl" denotes a saturated, straight-chain or branched hydrocarbon group having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and the like. The term "aryl" denotes an aromatic carbocyclic hydrocarbon radical comprising one or two six-membered rings, such as phenyl or naphthyl, which may be substituted by up to three substituents such as Br, Cl, F, CF₃，NO₂Lower alkyl or lower alkenyl. The term "heteroaryl" denotes an aromatic heterocyclic group comprising one or two five-and/or six-membered rings, wherein at least one ring comprises up to three heteroatoms selected from O, S and N and the rings are optionally substituted; representative examples of such optionally substituted heteroaryl groups are as defined above for R⁷⁷Is given in the following.

The structural component-A-CO-represents an amino acid structural unit, which together with the structural component-B-CO-forms the templates (a1) and (a 2). Templates (a) - (p) constitute building blocks with the N-and C-termini oriented in space such that the distance between the two groups can be 4.0-5.5A. The peptide chain is linked to the C-terminus and N-terminus of templates (a) - (p) via the respective N-and C-termini, such that the templates and chain form a cyclic structure, such as the one described in structural formula I. In case the distance between the N-and C-termini of the template is 4.0-5.5A as here, the template will induce the H-bond network required for the formation of the beta-hairpin conformation in the peptide chain Z. The template and peptide chain thus form a β -hairpin mimetic.

The beta-hairpin conformation is highly relevant for the protease inhibitory activity of the beta-hairpin mimetics of the invention. The β -hairpin stabilized conformational properties of the templates (a) - (p) play a crucial role not only for protease inhibitory activity but also for the synthetic process as defined above, since the introduction of the template near the middle of the linear protective peptide precursor significantly increases the cyclization reaction yield.

The structural units A1-A69 belong to the class of amino acids, the N-terminus of which is a secondary amine forming part of a ring. Among the amino acids encoded by the gene, only proline falls into this class. The structural units A1-A69 are in configuration (D) and they are combined with the structural unit in configuration (L) -, -B-CO-. A preferred combination of templates (a1) is-^DA1-CO-^LB-CO-to^DA69-CO-^LB-CO-. Thus, for example,^DPro-^Lpro constitutes a prototype of template (a 1). Less preferred, but possible wherein the template (a2) is^LA1-CO-^DB-CO-to^LA69-CO-^DA combination of B-CO-. Thus, for example,^LPro-^Dpro constitutes a less preferred prototype of template (a 2).

It is understood that the structural unit in which A has the (D) -configuration-A1-CO-to-A69-CO-carries the group R in the alpha-position relative to the N-terminus¹。R¹Are H and lower alkyl, most preferred R¹The values are H and methyl. It will be understood by those skilled in the art that A1-A69 is shown in the (D) -configuration if R is¹H and methyl correspond to the (R) -configuration. According to the Cahn, Ingold and Prelog-rules, this configuration can also be due to R¹Must be represented as (S) in preference to other values.

Except that R¹The structural units-A1-CO-to-A69-CO-may also carry further units known as R²-R¹⁷A substituent of (1). The other substituent may be H, and if it is not H, it is preferably a small to medium size aliphatic or aromatic group. R²-R¹⁷Examples of preferred values of (c) are:

-R²: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_mOCONR³³R⁷⁸(wherein R is³³: a lower alkyl group; or lower alkenyl; r⁷⁸: h; or lower alkyl); (CH)₂)_mNR²⁰CONR³³R⁷⁸(wherein R is²⁰: h or lower alkyl; r³³: a lower alkyl group; or lower alkenyl; r⁷⁸: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: low grade; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R³: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_mNR³³R³⁴(whereinR³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁴: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h or lower alkyl); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: is low inA lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁵: a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_mOCONR³³R⁷⁸(wherein R is³³: a lower alkyl group; or lower alkenyl; r⁷⁸: h; or lower alkyl); (CH)₂)_mNR²⁰CONR³³R⁷⁸(wherein R is²⁰: h or lower alkyl; r³³: a lower alkyl group; or lower alkenyl; r⁷⁸: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: an alkyl group; an alkenyl group; an aryl group; and aryl-lower alkyl; heteroaryl-lower alkyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁶: h; a lower alkyl group; lower chainAn alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁷: a lower alkyl group; a lower alkenyl group; (CH)₂)_qOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_qSR⁵⁶(wherein R is⁵⁶: h or lower alkyl; or lower alkenyl); (CH)₂)_qNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_qN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_rCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_qCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_rPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_rSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h or lower alkyl); (CH)₂)_oOCONR³³R⁷⁸(wherein R is³³: a lower alkyl group; or lower alkenyl; r⁷⁸: h; or lower alkyl); (CH)₂)_oNR²⁰CONR³³R⁷⁸(wherein R is²⁰: h or lower alkyl; r³³: a lower alkyl group; or lower alkenyl; r⁷⁸: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (a)CH₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁹: a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R¹⁰: a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: lower alkylA group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R¹¹: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_mOCONR³³R⁷⁸(wherein R is³³: a lower alkyl group; or lower alkenyl; r⁷⁸: h; or lower alkyl); (CH)₂)_mNR²⁰CONR³³R⁷⁸(wherein R is²⁰: h; or lower alkyl; r³³: a lower alkyl group; or lower alkenyl; r⁷⁸: h; or lower alkyl); (CH)₂)_mNR²⁰COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R¹²: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_rCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_rCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_rPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R¹³: a lower alkyl group; a lower alkenyl group; (CH)₂)_qOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_qSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_qNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or is low inAlkyl groups); (CH)₂)_qN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_rCOO⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_qCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_rPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_rSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R¹⁴: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; a lower alkyl group; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R¹⁵: a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); of particular interest are NR²⁰CO lower alkyl (R)²⁰H; or lower alkyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰(ii) a A lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R¹⁶: a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R¹⁷: a lower alkyl group; a lower alkenyl group; (CH)₂)_qOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_qSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_qNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_qN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_rCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_qCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_rPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_rSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

Among the structural units A1-A69, the following are preferred: wherein R is²A5, A8, A22, A25 being H, wherein R²A38, A42, A47, and A50 for H. Most preferred are structural units of the A8' and A8 "types:

wherein R is²⁰Is H or lower alkyl; and R⁶⁴Is an alkyl group; an alkenyl group; an aryl group; aryl-lower alkyl; or heteroaryl-lower alkyl; and R⁷⁵Is a lower alkyl group; a lower alkenyl group; or aryl-lower alkyl; especially wherein R⁷⁵Are allyl (A8' -1) and R⁶⁴Are those of n-hexyl group (A8 '' -1).

The structural unit A70 belongs to the class of open-chain alpha-substituted alpha-amino acids, the structural units A71 and A72 to the corresponding beta-amino acid analogs, and the structural units A73-A104 to the cyclic analogs of A70. These amino acid derivatives have been shown to confine small peptides in a well-defined reverse-turn or U-shaped conformation (C.M. Venkatachalam, biopolymer, 1968, 6, 1425-one 1434; W.Kabsch, C Sander, biopolymer (Biopolymers), 1983, 22, 2577). These building blocks or templates are ideally suited for stabilizing the beta-hairpin conformation in the peptide loop (D.Obrecht, M.Altorfer, J.A.Robinson, "novel peptide mimetic structures and strategies for efficient guidance of searches", adv.Med Chem.1999, Vol.4, 1-68; P.Balaram, "non-canonical amino acids in peptide design and protein engineering", curr.Opin.struct.biol.1992, 2, 845-.

It has been found that the corresponding isomers of structural elements A70-CO-to A104-CO-bound to the L-configured structural element B-CO-effectively stabilize and induce beta-hairpin conformations (D.Obrecht, M.Altorfer, J.A.Robinson, "novel peptide mimetic structural elements and strategies for efficient guided search", Adv.Med Chem.1999, Vol.4, 1-68; D.Obrecht, C.Spiegler, P.Sch. nholzer, K.M muller, H.Heimgartner, F.Stierli, Helv.Chim.Acta 1992, 75, 1666. 1696; D.Obrecht. Buchdall, U.Bohdal, J.Daly, C.Lehmann, P.Schhol. zer, K.M. Heter, Tex. Shunholz, C.Schhol. Aczer, 1995, Sphuhder, C.Sphuhder, C.7. Sphuhder, C.S.35, H.S.Okahrysson, H.7, H.35, H.S.C.35, H.E.S.C.H.H.H.E.C.35, 703-714).

Thus, for the purposes of the present invention, the template (A1) may also consist of the structural element-A70-CO-to A104-CO-, in which the structural elements A70 to A104 are in the (D) -or (L) -configuration, in combination with the structural element-B-CO-in the (L) -configuration.

R in A70-A104²⁰Preferred values of (b) are H or lower alkyl, with methyl being most preferred. R in the structural units A70 to A104¹⁸，R¹⁹And R²¹-R²⁹Preferred values of (a) are as follows:

-R¹⁸: lower alkyl

-R¹⁹: a lower alkyl group; a lower alkenyl group; (CH)₂)_pOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_pSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_pNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_pN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl;R⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_pCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_pCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_pSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_oC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R²¹: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or is low inAlkoxy groups).

-R²²: a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸: h; f; cl; CF; a lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R²³: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); of particular interest are NR²⁰CO lower alkyl (R)²⁰H; or lower alkylRadical); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R²⁴: a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); of particular interest are NR²⁰CO lower alkyl (R)²⁰H; or lower alkyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a Low gradeAn alkyl group; a lower alkenyl group; or lower alkoxy).

-R²⁵: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R²⁶: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹：H；Lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-alternatively, R²⁵And R²⁶When taken together may be- (CH)₂)_2-6-；-(CH₂)₂O(CH₂)₂-；-(CH₂)₂S(CH₂)₂-; or- (CH)₂)₂NR³⁴(CH₂)₂-；

-R²⁷: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R²⁸: a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R²⁹: a lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); particularly advantageousIs NR²⁰CO lower alkyl (R)²⁰H; or lower alkyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

For templates (b) - (p), such as (b1) and (c1), preferred values for the various symbols are as follows:

-R⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; (CH)₂)_oOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_oSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; or lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl) (ii) a Or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R²⁰: h; or lower alkyl

-R³⁰: h, methyl

-R³¹: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_pOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_pNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_pN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_rC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy); most preferred is CH₂CONR⁵⁸R⁵⁹(R⁵⁸: h; or lower alkyl; r⁵⁹: a lower alkyl group; or lower alkenyl).

-R³²: h, methyl

-R³³: a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_mOCONR³³R⁷⁸(wherein R is³³: a lower alkyl group; or lower alkenyl; r⁷⁸: h; or lower alkyl); (CH)₂)_mNR²⁰CONR³³R⁷⁸(wherein R is²⁰: h or lower alkyl; r³³: a lower alkyl group; or lower alkenyl; r⁷⁸: h; or lower alkyl); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl).

-R³⁴: h; or a lower alkyl group.

-R³⁵: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl).

-R³⁶: a lower alkyl group; a lower alkenyl group; or aryl-lower alkyl.

-R³⁷: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_pOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_pNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_pN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R³⁸: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_pOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_pNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_pN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R³⁹: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl).

-R⁴⁰: a lower alkyl group; a lower alkenyl group; or aryl-lower alkyl.

-R⁴¹: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_pOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_pNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_pN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl) (ii) a Or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁴²: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_pOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_pNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_pN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁴³: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mSR⁵⁶(wherein R is⁵⁶: a lower alkyl group; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); (CH)₂)_oPO(OR⁶⁰)₂(wherein R is⁶⁰: a lower alkyl group; or lower alkenyl); (CH)₂)_oSO₂R⁶²(wherein R is⁶²: a lower alkyl group; or lower alkenyl); or (CH)₂)_qC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁴⁴: a lower alkyl group; a lower alkenyl group; (CH)₂)_pOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_pSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_pNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_pN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_pCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_pCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); or (CH)₂)_oC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁴⁵: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_sOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_sSR⁵⁶(wherein R is⁵⁶: h; or is low inAn alkyl group; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); or (CH)₂)_sC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁴⁶: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_sOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_sSR⁵⁶(wherein R is⁵⁶: h; or lower alkyl; or lower alkenyl); (CH)₂)_oNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_oN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); or (CH)₂)_sC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁴⁷: h; OR OR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl).

-R⁴⁸: h; or a lower alkyl group.

-R⁴⁹: h; a lower alkyl group; (CH)₂)_oCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_oCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); or (CH)₂)_sC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁵⁰: h; methyl radical

-R⁵¹: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_pCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_pCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); or (CH)₂)_rC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁵²: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or is low inAlkyl groups); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_pCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_pCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); or (CH)₂)_rC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁵³: h; a lower alkyl group; a lower alkenyl group; (CH)₂)_mOR⁵⁵(wherein R is⁵⁵: a lower alkyl group; or lower alkenyl); (CH)₂)_mNR³³R³⁴(wherein R is³³: a lower alkyl group; or lower alkenyl; r³⁴: h; or lower alkyl); (CH)₂)_mN(R²⁰)COR⁶⁴(wherein: R²⁰: h; or lower alkyl; r⁶⁴: a lower alkyl group; or lower alkenyl); (CH)₂)_pCOOR⁵⁷(wherein R is⁵⁷: a lower alkyl group; or lower alkenyl); (CH)₂)_pCONR⁵⁸R⁵⁹(wherein R is⁵⁸: a lower alkyl group; or lower alkenyl; and R⁵⁹: h; lower alkyl); or (CH)₂)_rC₆H₄R⁸(wherein R is⁸：H；F；Cl；CF₃(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).

-R⁵⁴: a lower alkyl group; a lower alkenyl group; or aryl-lower alkyl.

Among the structural units a70 to a104, the following are preferred: wherein R is²²A74, A75, A76 being H, wherein R²²A77, a78 and a79 for H.

The structural units-B-CO-in templates (a1) and (a2) represent L-amino acid residues.Preferred values for B are: -NR²⁰CH(R⁷¹) -and wherein R²A5, A8, A22, A25 being H, wherein R²Is the enantiomer of a38, a42, a47, and a50 of H. Most preferred is

Ala L-alanine

Arg L-arginine

Asn L-asparagine

Cys L-cysteine

Gln L-Glutamine

Gly glycine

His L-histidine

Ile L-isoleucine

Leu L-leucine

Lys L-lysine

Met L-methionine

Phe L-phenylalanine

Pro L-proline

Ser L-serine

Thr L-threonine

Trp L-Tryptophan

Tyr L-tyrosine

Val L-valine

Cit L-citrulline

Orn L-Ornithine

tBuA L-tert-butylalanine

Sar sarcosine

t-BuG L-tert-butylglycine

4AmPhe L-p-aminophenylalanine

3AmPhe L-m-aminophenylalanine

2AmPhe L-o-aminophenylalanine

Phe(mC(NH₂) (NH) L-m-amidinophenylalanine

Phe(pC(NH₂) (NH) L-p-amidinophenylalanine

Phe(mNHC(NH₂) (NH) L-m-guanidinobenzenePhenylalanine radical

Phe(pNHC(NH₂) (NH) L-p-guanidinophenylalanine

Phg L-phenylglycine

Cha L-Cyclohexylalanine

C₄al L-3-Cyclobutylalanine

C₅al L-3-Cyclopentylalanine

Nle L-norleucine

2-Nal L-2-naphthylalanine

1-Nal L-1-naphthylalanine

4Cl-Phe L-4-chlorophenylalanine

3Cl-Phe L-3-chlorophenylalanine

2Cl-Phe L-2-chlorophenylalanine

3，4Cl₂-Phe L-3, 4-dichlorophenylalanine

4F-Phe L-4-fluorophenylalanine

3F-Phe L-3-fluorophenylalanine

2F-Phe L-2-fluorophenylalanine

Tic L-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid

Thi L-beta-2-thienylalanine

Tza L-2-Thiazolylalanine

Mso L-methionine sulfoxide

AcLys L-N-acetyl lysine

Dpr L-2, 3-diaminopropionic acid

A₂Bu L-2, 4-diaminobutyric acid

Dbu (S) -2, 3-diaminobutyric acid

Abu gamma-aminobutyric acid (GABA)

Aha epsilon-aminocaproic acid

Aib alpha-aminoisobutyric acid

Y (Bzl) L-O-benzyltyrosine

Bip L-Biphenylalanine (L-Biphenylalanine)

S (Bzl) L-O-benzylserine

T (Bzl) L-O-benzylthreonine

hHa L-high cyclohexyl alanine

hCys L-homocysteine

hSer L-homoserine

hArg L-homoarginine

hPhe L-homophenylalanine

Bpa L-4-benzoylphenylalanine

Pip L-pipecolic acid

OctG L-octyl glycine

MePhe L-N-methylphenylalanine

Menle L-N-Methylnorleucine

MeAla L-N-methylalanine

MeIle L-N-methylisoleucine

MeVal L-N-methylvaline (L-N-Methvaline)

MeLeu L-N-methylleucine

In addition, the most preferred values of B also include groups of the type A8' ″ in the (L) -configuration:

A8″’

wherein R is²⁰Is H or lower alkyl, R⁶⁴Is an alkyl group; an alkenyl group; an aryl group; aryl-lower alkyl; or heteroaryl-lower alkyl; especially wherein R⁶⁴Those which are n-hexyl (A8' -1).

The peptide chain Z of the β -hairpin mimetics described herein is generally defined by amino acid residues belonging to one of the following classes:

the class C-NR²⁰CH(R⁷²) CO-; hydrophobic: small to medium size

The species D-NR²⁰CH(R⁷³) CO-; hydrophobic: large aromatic or heteroaromatic compounds

The species E-NR²⁰CH(R⁷⁴) CO-; "polar-cationic" and "urea-derived

Class F-NR²⁰CH(R⁸⁴) CO-; "polar-uncharged" and "anionic"

The species H-NR²⁰-CH(CO-)-(CH₂)_4-7-CH(CO-)-NR²⁰-；

-NR²⁰-CH(CO-)-(CH₂)_pSS(CH₂)_p-CH(CO-)-NR²⁰-；

-NR²⁰-CH(CO-)-(-(CH₂)_pNR²⁰CO(CH₂)_p-CH(CO-)-NR²⁰-; and

-NR²⁰-CH(CO-)-(-(CH₂)_pNR²⁰CONR²⁰(CH₂)_p-CH(CO-)-NR²⁰-；

"interchain bond

In addition, the amino acid residues in the chain Z can also have the formula-A-CO-, wherein A is as defined above.

Class C includes those according to the para-substituent R⁷²Is defined as an amino acid residue having small to medium size hydrophobic side chain groups. Hydrophobic residues refer to amino acid side chains that are uncharged at physiological pH and are repelled by aqueous solutions. In addition, these side chains generally do not contain hydrogen bond donor groups such as, but not limited to, primary and secondary amides, primary and secondary amines and their corresponding protonated salts, thiols, alcohols, phosphonates, phosphates, ureas or thioureas. They may contain hydrogen bond acceptor groups such as ethers, thioethers, esters, tertiary amides, alkyl-or arylphosphonates and phosphates or tertiary amines. Gene-encoded small to medium-sized amino acids include alanine, isoleucine, leucine, methionine and valine.

Class D includes those according to the substituent R⁷³Have aromatic and heteroaromatic side chain groups. An aromatic amino acid residue refers to a hydrophobic amino acid having a side chain comprising at least one ring with a conjugated pi-electron system (aromatic group). They may additionally contain hydrogen bond donor groups such as, but not limited to, primary and secondary amides, primary and secondary amines and their corresponding protonated salts, thiols, alcohols, phosphonates, phosphate esters, ureas or thioureas, and hydrogen bond acceptor groups such as, but not limited to, ethers, thioethers, esters, tertiary amides, alkyl-or arylphosphonate-and phosphates or tertiary amines. Aromatic amino acids encoded by the gene include phenylalanine and tyrosine.

Heteroaromatic amino acid residues are referred to in terms of the para-substituent R⁷⁷Has a side chain comprising at least one ring having a conjugated pi-system into which at least one heteroatom such as, but not limited to, O, S and N is introduced. In addition, they may contain hydrogen bond donor groups such as, but not limited to, primary and secondary amides, primary and secondary amines and their corresponding protonated salts, thiols, alcohols, phosphonates, phosphate esters, ureas or thioureas, and hydrogen bond acceptor groups such as, but not limited to, ethers, thioethers, esters, tertiary amides, alkyl-or arylphosphonate-and phosphate esters or tertiary amines. The gene encodes heteroaromatic amino acids including tryptophan and histidine.

Class E includes those according to the para-substituent R⁷⁴Contains amino acids with side chains of polar-cationic and urea-derived residues. Polar-cationic refers to a basic side chain that is protonated at physiological pH. The polar-cationic amino acids encoded by the gene include arginine, lysine and histidine. Citrulline is an example of an amino acid comprising a urea-derived residue.

Class F includes the substituents R⁸⁴Comprises amino acids having side chains with polar-uncharged or anionic residues. Polar-uncharged or anionic residues refer to hydrophilic side chains that are, respectively, uncharged and anionic at physiological pH (including carboxylic acids), but are not repelled by aqueous solutions. These side chains typically contain hydrogen bond donor groups such as, but not limited to, primary and secondary amides, carboxylic acids and esters, primary and secondary amines, thiols, alcohols, phosphonates, phosphates, ureas or thioureas. These groups can form a hydrogen bonding network with water molecules. They may additionally also contain hydrogen bond acceptor groups such as, but not limited to, ethers, thioethers, esters, tertiary amides, carboxylic acids and carboxylates, alkyl-or arylphosphonate-s and phosphate esters or tertiary amines. The polar-uncharged and anionic amino acids encoded by the gene include asparagine, cysteine, glutamine, serine and threonine, and aspartic acid and glutamic acid.

Class H comprises side chains of preferably (L) -amino acids in opposite positions of the beta-strand region that may form interchain bonds. The most common bond is the disulfide bond formed by cysteine and homocysteine located at opposite positions of the β -chain. Various methods are known for forming disulfide bonds, including those described below: tam et al, Synthesis (Synthesis), 1979, 955-957; stewart et al, solid phase peptide synthesis, 2d Ed., Pierce Chemical Company, III., 1984; ahmed et al, J.biol.chem.1975, 250, 8477-8482; and Pennington et al, Peptides (Peptides), pages 164-. Most advantageously, for the scope of the present invention, disulfide bonds can be prepared as described below in the relevant example (procedure 3) using an acetamidomethyl (Acm) -protecting group (for cysteine). One well-established interchain bond is the formation of a linkage between ornithine and lysine, respectively, and glutamic and aspartic acid residues at opposite beta-strand positions, respectively, by amide bonds. The preferred protecting group for the side chain amino groups of ornithine and lysine is allyloxycarbonyl (Alloc), while the preferred protecting group for aspartic and glutamic acids is allyl ester. Finally, interchain linkages may also be established by bonding the amino groups of lysine and ornithine at the opposite β -strand positions to a reagent such as N, N-carbonylimidazole to form a cyclic urea.

As described above, the interchain bonds are located as follows:

-if n ═ 11: the P2 and P10 bits are together.

These interchain linkages are known to stabilize the beta-hairpin conformation and thus constitute an important structural component for the design of beta-hairpin mimetics.

The most preferred amino acid residues in the chain Z are those derived from natural alpha-amino acids. The following list of amino acids, or residues thereof, suitable for use in the present invention, wherein the abbreviations correspond to commonly used conventions:

three letter code		Single letter code
			AlaArgAsnAspCysGluGlnGlyHisIleLeuLysMetPhePro^DProSerThrTrpTyrVal	L-alanine L-arginine L-asparagine L-aspartic acid L-cysteine L-glutamic acid L-glutamine glycine L-histidine L-isoleucine L-leucine L-lysine L-methionineAcid L-phenylalanine L-proline D-proline L-serine L-threonine L-tryptophan L-tyrosine L-valine	ARNDCEQGHILKMFP^DPSTWYV

Other α -amino acids, or residues thereof, suitable for use in the present invention include:

CitOrntBuA

l-citrulline L-ornithine L-tert-butylalanine

SarPent-BuG4AmPhe3AmPhe2AmPhePhe(mC(NH₂)＝NH)Phe(pC(NH₂)＝NH)Phe(mNHC(NH₂)＝NH)Phe(pNHC(NH₂)＝NH)PhgChaC₄alC₅alNle2-Nal1-Nal4Cl-Phe3Cl-Phe2Cl-Phe3，4Cl₂-Phe4F-Phe3F-Phe2F-PheTicThiTzaMso

Sarcosine L-penicillamine L-tert-butylglycine L-p-aminophenylalanine L-m-aminophenylalanine L-o-aminophenylalanine L-m-amidinophenylalanine L-p-amidinophenylalanine L-m-guanidinophenylalanine L-p-guanidinophenylalanine L-phenylglycine L-cyclohexylalanine L-3-cyclobutylalanine L-3-cyclopentylalanine L-norleucine L-2-naphthylalanine L-1-naphthylalanine L-4-chlorophenylalanine L-3-chlorophenylalanine L-2-chlorophenylalanine LL-3, 4-dichlorophenylalanine L-4-fluorophenylalanine L-3-fluorophenylalanine L-2-fluorophenylalanine 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid L-beta-2-thienylalanine L-2-thiazolylalanine L-methionine sulfoxide (L-Methioninenesulfonide)

AcLySDprA₂BuDbuAbuAhaAibY(Bzl)BipS(Bzl)T(Bzl)hChahCyshSerhArghPheBpa4-AmPyrr14-AmPyrr24-PhePyrr14-PhePyrr25-PhePyrr15-PhePyrr2Pro(4-OH)1Pro(4-OH)2Pip^DPipOctGMePhe

N-acetyl lysine 2, 3-diaminopropionic acid 2, 4-diaminobutyric acid (S) -2, 3-diaminobutyric acid γ -aminobutyric acid (GABA) epsilon-aminocaproic acid α -aminoisobutyric acid L-O-benzyltyrosine L- (4-phenyl) phenylalanine L-O-benzylserine L-O-benzylthreonine L-homocyclohexylalanine L-homocysteine L-homoserine L-homoarginine L-homophenylalanine L-4-benzoylphenylalanine (2S, 4S) -4-amino-pyrrolidine-L-carboxylic acid (2S, 4R) -4-amino-pyrrolidine-L-carboxylic acid (2S, 5R) -4-phenyl-pyrrolidine-L-carboxylic acid (2S, 5S) -4-phenyl-pyrrolidine-L-carboxylic acid (2S, 5R) -5-phenyl-pyrrolidine-L-carboxylic acid (2S, 5S) -5-phenyl-pyrrolidine-L-carboxylic acid (4S) -L-hydroxyproline (4R) -L-hydroxyproline L-pipecolic acid D-pipecolic acid L-octylglycine L-N-methylphenylalanine

MeNleMeAlaMeIleMeValMeLeu

L-N-Methylnorleucine L-N-Methylalanine L-N-Methylisoleucine L-N-Methylvaline L-N-Methylleucine

Particularly preferred residues of class C are:

AlaIleLeuMetValtBuAt-BuGChaC₄alC₅alNlehChaOctGMePheMeNleMeAlaMeIleMeValMeLeu

l-alanine L-isoleucine L-leucine L-methionine L-valine L-tert-butylalanine L-tert-butylglycine L-cyclohexylalanine L-3-cyclobutylalanine L-3-cyclopentylalanine L-norleucine L-homocyclohexylalanine L-octylglycine L-N-methylphenylalanine L-N-methylnorleucine L-N-methylalanine L-N-methylisoleucine L-N-methylvaline L-N-methylleucine

Particularly preferred residues of class D are:

His	l-histidine

PheTrpTyrPhg2-Nal1-Nal4Cl-Phe3Cl-Phe2Cl-Phe3，4Cl₂-Phe4F-Phe3F-Phe2F-PheThiTzaY(Bzl)BipS(Bzl)T(Bzl)hPheBpa

L-phenylalanine L-tryptophan L-tyrosine L-phenylglycine L-2-naphthylalanine L-1-naphthylalanine L-4-chlorophenylalanine L-3-chlorophenylalanine L-2-chlorophenylalanine L-3, 4-dichlorophenylalanine L-4-fluorophenylalanine L-3-fluorophenylalanine L-2-fluorophenylalanine L-beta-2-thienylalanine L-2-thiazolylalanine L-O-benzyltyrosine L-biphenylalanine L-O-benzylserine L-O-benzylthreonine L-homophenylalanine L-4-benzoylphenylalanine.

Particularly preferred residues of class E are

ArgLysOrnDprA₂BuDbu

L-arginine L-lysine L-ornithine L-2, 3-diaminopropionic acid L-2, 4-diaminobutyric acid (S) -2, 3-diaminobutyric acid

Phe(pNH₂)Phe(mNH₂)Phe(oNH₂)hArgPhe(mC(NH₂)＝NH)Phe(pC(NH₂)＝NH)Phe(mNHC(NH₂)＝NH)Phe(pNHC(NH₂)＝NH)Cit

L-p-aminophenylalanine L-m-aminophenylalanine L-o-aminophenylalanine L-homoarginine L-m-amidinophenylalanine L-p-amidinophenylalanine L-m-guanidinophenylalanine L-p-guanidinophenylalanine L-citrulline

Particularly preferred residues of class F are

AspAsnCysGluGlnSerThrCitPenAcLyshCyshSer

L-aspartic acid L-asparagine L-cysteine L-glutamic acid L-glutamine L-serine L-threonine L-citrulline L-penicillamine L-N^ε-acetyl lysine L-homocysteine L-homoserine

Typically, the peptide chain Z within the β -hairpin mimetics of the invention comprises 7 or 11 amino acid residues (n ═ 7 or 11). P of each amino acid residue in the chain Z¹-PⁿThe bits are explicitly defined as follows: p¹Represents the first amino acid in the chain Z coupled at its N-terminus to the C-terminus of the group-B-CO-in template (B) - (P) or template (a1), or of the group-A-CO-in template (A2), and PⁿRepresents the last amino acid in chain Z coupled at its C-terminus to the N-terminus of template (B) - (p) or of group-A-CO-in template (a1) or of group-B-CO-in template (A2). P¹-PⁿThe bits preferably each comprise one or two or three species belonging to the above classes C-F, or ProAmino acid residues, as shown below:

-if n is 7, the amino acid residues in positions 1-7 are preferably:

p1: class C or class F;

p2: class E or class D or class C;

p3: class F or class C;

p4: class C or class F or class D;

p5: class F, or residue is Pro;

p6: class C or class E, or the residue is Pro;

p7: class C or class F;

-if n is 11, the amino acid residues in positions 1-11 are preferably:

p1: class E or class F;

p2: class C or class F;

p3: class C;

p4: class E or class D or class C;

p5: class F or class C;

p6: class C, or class D;

p7: class F, or residue is Pro;

p8: class C or class E, or the residue is Pro;

p9: class C or class F;

p10: class F or class C;

p11: class D or class E; or

P2 and P10, taken together, may form a group of the kind H;

particularly preferred β -peptide mimetics of the present invention include those described in examples 1, 4, 7, 8 and 15.

The methods of the invention can advantageously be performed as parallel array synthesis, resulting in a library of template-fixed β -hairpin peptidomimetics having the general formula I above. These parallel syntheses can yield arrays of many (usually 24-192, typically 96) compounds of formula I in high yields and specified purity, with minimal formation of dimer and polymer by-products. For functionalized solid supports (i.e., solid support plus linker molecule), proper selection of template and cyclization reaction sites therefore plays an important role.

The functionalized solid support is suitably derived from the use of, preferably from 1 to 5%, divinylbenzene-crosslinked polystyrene; coated with polyethylene glycol spacer (Tentagel)^R) The polystyrene of (4); and polyacrylamide resins (see also Obrecht, d.; villgordo, j. -M, "solid-supported combinations and parallel syntheses of libraries of small molecular weight compounds", tetrahedron organic chemistry, vol.17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized with a linker, i.e. a bifunctional spacer molecule comprising an immobilization group at one end for attachment to the solid support and a selectively cleavable functional group at the other end for subsequent chemical conversion and cleavage steps. For the purposes of the present invention, the linker must be designed to ultimately release the carboxyl group under mildly acidic conditions that do not affect the protecting groups present on any of the functional groups in the various amino acid side chains. Linkers suitable for use in the present invention form acid labile esters with the carboxyl group of amino acids, typically acid labile benzyl, benzhydryl and trityl esters; examples of such linker structures include 2-methoxy-4-hydroxymethylphenoxy (Sasrin)^RLinker), 4- (2, 4-dimethoxyphenyl-hydroxymethyl) -phenoxy (Rink linker), 4- (4-hydroxymethyl-3-methoxyphenoxy) butanoic acid (HMPB linker), trityl and 2-chlorotrityl.

Preferably, the support is derived from polystyrene cross-linked with most preferably 1-5% divinylbenzene and functionalized with a 2-chlorotrityl linker.

If performed as a parallel array synthesis, the process of the invention may advantageously be performed as described below, but it will be immediately apparent to the skilled person how to make necessary modifications to the procedure when the synthesis of a single compound of formula I above is required.

The number of reaction vessels (generally 24-192, typically 96) is equal to the total number of compounds to be synthesized by the parallel process, to which 25-1000mg, preferably 100mg, of a suitable functionalized solid support, preferably 1-3% cross-linked polystyrene or tentagel resin, are loaded.

The solvent to be used must be capable of swelling the resin and includes, but is not limited to, Dichloromethane (DCM), Dimethylformamide (DMF), N-methylpyrrolidinone (NMP), dioxane, toluene, Tetrahydrofuran (THF), ethanol (EtOH), Trifluoroethanol (TFE), isopropyl alcohol and the like. Solvent mixtures comprising a polar solvent as at least one component (e.g. 20% TFE/DCM, 35% THF/NMP) are beneficial for ensuring high reactivity and solvation of resin-bound peptide chains (Fields, G.B., Fields, C.G., J.Am.chem.Soc.1991, 113, 4202-.

Significant progress has been made in the synthesis of protected peptide segments with the development of various linkers that release a C-terminal carboxylic acid group under mild acidic conditions that do not affect the acid labile groups protecting the functional groups in the side chains. 2-methoxy-4-hydroxybenzyl alcohol-derived linker (Sasrin)^RThe linker, Mergler et al, Tetrahedron letters (Tetrahedron Lett.), 1988, 294005-4008) can be cleaved with dilute trifluoroacetic acid (0.5-1% TFA in DCM) and stabilized against Fmoc deprotection conditions during peptide synthesis, where the Boc/tBu-group attachment of a protecting group is compatible with the protection scheme. Other linkers suitable for use in the process of the invention include the superacid labile 4- (2, 4-dimethoxyphenyl-hydroxymethyl) -phenoxy linker (Rink linker, Rink, H. tetrahedron communication, 1987, 28, 3787-mer 3790) where removal of the peptide requires 10% acetic acid (in DCM) or 0.2% trifluoroacetic acid (in DCM); 4- (4-hydroxymethyl-3-methoxyphenoxy) butanoic acid derived linker (HMPB-linker, Fl rsheimer)&Riniker, Peptides (Peptides), 1991, 1990131). It was also cleaved with 1% TFA/DCM to give a peptide stretch containing all acid-labile side chain protecting groups; and, in addition, a 2-chlorotrityl chloride linker (Barlos et al, tetrahedron letters, 1989, 30, 3943-.

Protecting groups which are applicable to amino acids and to residues thereof, respectively, are, for example,

for amino groups (e.g. also present in the side chain of lysine)

Cbz benzyloxycarbonyl

Boc tert-butyloxycarbonyl

Fmoc 9-fluorenylmethoxycarbonyl

Alloc allyloxycarbonyl radical

Teoc trimethylsilyl ethoxycarbonyl

Tc Trichloroethoxycarbonyl

Nps o-nitrophenylsulfonyl;

trt triphenylmethyl or trityl

For carboxyl groups (as also present in the side chains of aspartic and glutamic acids), where reaction with the alcohol component converts to esters

tBu tert-butyl

Bn benzyl group

Me methyl group

Ph phenyl

Pac phenacyl

Allyl radical

Tse Trimethylsilylethyl group

Tce trichloroethyl;

for guanidino groups (as present in the side chain of arginine)

Pmc 2, 2, 5, 7, 8-pentamethyl chroman-6-sulfonyl

Ts tosyl (i.e. p-tosyl)

Cbz benzyloxycarbonyl

Pbf pentamethyl dihydrobenzofuran-5-sulfonyl

For hydroxyl groups (as present in the side chains of threonine and serine)

tBu tert-butyl

Bn benzyl group

Trt trityl radical

And for thiol groups (as present in the side chain of cysteine)

Acm acetylaminomethyl

tBu tert-butyl

Bn benzyl group

Trt trityl radical

Mtr 4-methoxytrityl.

The 9-fluorenylmethoxycarbonyl- (Fmoc) -protected amino acid derivative is preferably used as a building block for the construction of template-fixed beta-hairpin loop mimetics of formula I. For deprotection, i.e. cleavage of the Fmoc group, 20% piperidine (in DMF) or 2% DBU/2% piperidine (in DMF) may be used.

The amount of reactants (i.e., amino acid derivatives) is generally 1-20 equivalents based on the milliequivalents/gram (meq/g) loading of functionalized solid support initially weighed into the reaction tube (typically 0.1-2.85meq/g for polystyrene resins). Other equivalents of reactants may be used if desired to drive the reaction to completion within a reasonable time. The reaction tubes, as well as the clamp block and manifold, are reinserted into the reservoir block and the device is secured together. A gas flow is initiated through the manifold to provide a controlled environment, such as nitrogen, argon, air, and the like. The air flow may also be heated or cooled before flowing through the manifold. Heating or cooling of the reaction well is achieved by heating the reaction block or external cooling with isopropanol/dry ice and the like to achieve the desired synthesis reaction. Agitation is achieved by shaking or magnetic stirring (within the reaction tube). Preferred workstations, but not limited to, are the Labsource's Combi-chemstation and MultiSyn Tech's-Syro synthesizers.

Amide bond formation requires activation of the alpha-carboxyl group for the acylation step. If the activation is carried out using a conventional carbodiimide such as dicyclohexylcarbodiimide (DCC, Sheehan & Hess, J.Am.chem.Soc.1955, 77, 1067-. In a variant of the carbodiimide process, 1-hydroxybenzotriazole (HOBt, K _ nig & Geiger, chem. Ber 1970, 103, 788-. HOBt prevents dehydration, inhibits racemization of activated amino acids and acts as a catalyst to promote slow coupling reactions. Certain Phosphonium reagents have been used as direct coupling reagents, such as benzotriazol-1-yl-oxy-tris- (dimethylamino) -Phosphonium hexafluorophosphate (BOP) (Castro et al, tetrahedron letters, 1975, 14, 1219-; these phosphene reagents are also suitable for forming HOBt esters in situ with protected amino acid derivatives. More recently, diphenoxyphosphoryl azide (DPPA) or O- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TATU) or O- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU)/7-aza-1-hydroxybenzotriazole (HOAt, Carpino et al, tetrahedron letters, 1994, 35, 2279-.

Since near quantitative coupling reactions are necessary, it is desirable to have experimental evidence of reaction completion. The ninhydrin test (Kaiser et al, analytical biochemistry, 1970, 34, 595) can be performed easily and quickly after each coupling step, with a positive colorimetric response to an aliquot of the resin-bound peptide qualitatively indicating the presence of a primary amine. Fmoc chemistry enables spectrophotometric detection of Fmoc chromophores upon their release with base (Meienhofer et al, int.J. peptide protein Res.1979, 13, 35-42).

The resin bound intermediates within each reaction tube are washed free of excess residual reagents, solvents, and byproducts by repeated exposure to pure solvents by one of two methods:

1) the reaction well was filled with solvent (preferably 5ml), the reaction tube and the clamp block and manifold were immersed and stirred for 5-300 minutes, preferably 15 minutes, and then drained by gravity, followed by applying air pressure through the manifold inlet (while closing the outlet) to expel the solvent;

2) the manifold is removed from the clamp block and an aliquot (preferably 5ml) of the solvent is dispensed through the top of the reaction tube and discharged by gravity through a filter into a receiving container such as a test tube or vial.

The above two washing procedures are repeated up to about 50 times (preferably about 10 times) with the efficiency of reagent, solvent, and byproduct removal being checked by methods such as TLC, GC, or inspection of the washings.

For each successive conversion, the procedure described above for reacting the resin-bound compound with the reagent in the reaction well followed by removal of excess reagent, byproducts and solvent is repeated until the final resin-bound fully protected linear peptide is prepared.

Before the fully protected linear peptide is detached from the solid support,if desired, one or more of the protecting functional groups present in the molecule may be selectively deprotected and the reactive groups so liberated suitably substituted. To this end, the functional group must initially be protected by a protecting group which can be selectively removed without affecting the remaining protecting groups present. Alloc (allyloxycarbonyl) is an example of such a protecting group for an amino group, which can for example make use of Pd⁰And phenylsilane at CH₂Cl₂Is selectively removed without affecting the remaining protecting groups present in the molecule, such as Fmoc. The reactive groups so released may then be treated with a reagent suitable for introducing the desired substituent. Thus, for example, an amino group can be acylated with an acylating agent corresponding to the acyl substituent to be introduced.

The detachment of the fully protected linear peptide from the solid support is achieved by immersing the reaction tube, as well as the clamp block and manifold, in a reaction well containing a solution of the cleaving reagent (preferably 3-5 ml). Gas flow, temperature control, agitation, and reaction detection were performed as described above and the detachment reaction was performed as needed. The reaction tubes, as well as the clamp block and manifold, are detached from the reservoir block and raised above the solution level but below the upper lip of the reaction wells, and then air pressure is applied through the manifold inlet (while the outlet is closed) to effectively drain the final product solution into the reservoir wells. The resin remaining in the reaction tube is then washed 2-5 times as above with 3-5ml of an appropriate solvent to extract (wash out) as much of the liberated product as possible. The product solutions thus obtained were combined, taking care to avoid cross-mixing. Each solution/extract is then treated as necessary to isolate the final compound. Typical treatments include, but are not limited to, evaporation, concentration, liquid/liquid extraction, acidification, basification, neutralization or other reactions in solution.

The solution containing the fully protected linear peptide derivative which has been excised from the solid support and neutralized with a base is evaporated. The cyclization reaction is then carried out in solution using solvents such as DCM, DMF, dioxane, THF and the like. Various coupling reagents mentioned earlier may be used for the cyclization reaction. The duration of the cyclization reaction is about 6 to 48 hours, preferably about 24 hours. The reaction is followed, for example, by RP-HPLC (reverse phase high performance liquid chromatography). The solvent is then removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a water-immiscible solvent, such as DCM, and the solution is extracted with water or a mixture of water-miscible solvents to remove any excess coupling reagent.

Interchain bonds may be formed between side chains of appropriate amino acid residues at opposite positions of the β -chain region, if desired, before the protecting group is removed from the fully protected cyclic peptide. Interchain bonds and their formation have been discussed above in explaining the class H groups, and may be, for example, disulfide bonds formed by cysteine and homocysteine at opposite positions of the β -chain, or glutamic and aspartic acid residues linked to ornithine and lysine, respectively, at opposite β -chain positions by amide bond formation. The formation of these interchain bonds can be carried out by methods well known in the art.

Finally, fully protected peptide derivatives of class I were treated with 95% TFA, 2.5% H₂O, 2.5% TIS or another scavenger combination to effect cleavage of the protecting group. The cleavage reaction time is usually 30 minutes to 12 hours, preferably about 2 hours. Most of the TFA was then evaporated and the product was precipitated with ether/hexane (1: 1) or other solvent suitable for this purpose. After careful removal of the solvent, the cyclic peptide derivative obtained as the final product can be isolated. Depending on its purity, the peptide derivative can be used directly in the biological analysis, or it must be further purified, for example by preparative HPLC.

The fully deprotected product thus obtained may then be converted into a pharmaceutically acceptable salt or the pharmaceutically acceptable or unacceptable salt thus obtained may be converted into the corresponding free compound of structural formula I or into a different pharmaceutically acceptable salt, as described above, if desired. Any of these manipulations can be performed by methods well known in the art.

The starting materials for the process of the present invention, the pre-starting materials used therein, and the preparation of these starting and pre-starting materials will now be discussed in detail.

Building blocks of class A can be synthesized according to literature procedures described below. The corresponding amino acids have been described as unprotected or as Boc-or Fmoc-protected racemates, (D) -or (L) -isomers. It will be appreciated that the unprotected amino acid building blocks can be readily converted to the corresponding Fmoc-protected amino acid building blocks required for the present invention by standard protecting group treatment. An overview describing the general process for synthesizing alpha-amino acids includes: r. Duthaler, tetrahedron (reported) 1994, 349, 1540-1650; r.m. williams, "synthesis of optically active α -amino acids", tetrahedral Organic Chemistry Series (Tetrahedron Organic Chemistry Series), vol.7, j.e. baldwin, p.d. magnus (Eds.), Pergamon press, Oxford 1989. A particularly useful method for the synthesis of optically active alpha-amino acids relevant to the present invention involves kinetic resolution using hydrolases (M.A. Verhovskaya, I.A. Yamskov, Russian chem.Rev.1991, 60, 1163-Ack 1179; R.M.Williams, "Synthesis of optically active alpha-amino acids", tetrahedral organic chemistry series, Vol.7, J.E.Baldwin, P.D.Magnus (Eds.), Pergamon Press, Oxford1989, Chapter 7, p.257-279). Hydrolytic enzymes include amide and nitrile hydrolysis by aminopeptidases or nitrilases, cleavage of the N-acyl group by acyltransferases, and ester hydrolysis by lipases or proteases. It is fully demonstrated that some enzymes specifically lead to pure (L) -enantiomers, while others yield the corresponding (D) -enantiomers (e.g., R. Duthaler, tetrahedron reports 1994, 349, 1540-1650; R. M. Williams, "optically active alpha-amino acid synthesis", tetrahedron organic chemistry series, Vol.7, J.E. Baldwin, P.D. Magnus (Eds.), Pergammon Press, Oxford 1989).

A1: see D.BeN-Ishai, tetrahedron, 1977, 33, 881-; sato, A.P.Kozikowski, tetrahedron communication, 1989, 30, 4073-; baldwin, c.n.farthing, a.t.russell, c.j.schofield, a.c.spirey, tetrahedron communication, 1996, 37, 3761-; baldwin, r.m.adlington, n.g.robinson, j.chem.soc.chem.commun.1987, 153-; p.wipf, y.uto, tetrahedron communication, 1999,40, 5165-; baldwin, R.M.Adlington, A.O 'Neil, A.C.Spirey, J.B.Sweeney, J.chem.Soc.chem.Commun.1989, 1852-E.Baldwin, R.M.Adlington, A.O' Neil, J.C.Spirey, J.B.Sweeney, J.chem.Soc.chem.Commun.1989, 1852-E.1854 (for R.¹＝H，R²＝H)；T.Hiyama，Bull.Chem.Soc.Jpn.1974，47，2909-2910；T.Wakamiya，K.Shimbo，T.Shiba，K.Nakajima，M.Neya，K.Okawa，Bull.Chem.Soc.Jpn.1982，55，3878-3881；I.Shima，N.Shimazaki，K.Imai，K.Hemmi，M.Hashimoto，Chem.Pharm.Bull.1990，38，564-566；H.Han，J.Yoon，K.D.Janda，J.Org.Chem.1998，63，2045-2048(R¹＝H，R²＝Me)；J.Legters，G.H.Willems，L.Thijs，B.Zwannenburg，Recl.Trav.Chim.Pays-Bas1992，111，59-68(R¹＝H，R²Hexyl); legters, l.thijs, b.zwannenburg, recl.trav.chim.pays-Bas 1992, 111, 16-21; G.A. Molander, P.J.Stengel, J.org.chem.1995, 21, 6660-¹＝H，R²Ph); funaki, L.Thijs, B.Zwannenburg, tetrahedron, 1996, 52, 9909-¹＝H，R²＝Bn)；A.S.Pepito，D.C.Dittmer，J.Org.Chem.1997，62，7920-7925；(R¹＝H，R²＝CH₂OH)；M.Egli，A.S.Dreiding，Helv.Chim.Acta 1986，69，1442-1460(R²＝CH(OH)CH₂OH); m.carduccu, s.fioravanti, m.a.loreto, l.pellacani, p.a.tardella, tetrahedron communication, 1996, 37, 3777-; lakner, l.p.hager, tetrahedron: asymmetry 1997, 21, 3547-3550 (R)¹＝Me，R²H, Me); g.a. molander, p.j.stenel, tetrahedron, 1997, 26, 8887-; loreto, F.Pompei, P.A.Tardella, D.Tofani, tetrahedron, 1997, 53, 15853-one 15858 (R.A.Loreto, F.Pompei, P.A.Tardella, D.Tofani, tetrahedron, 1997, 53, 15853-one)¹＝Me，R²＝CH₂SiMe₃)；H.Shao，J.K.Rueter，M.Goodman，J.Org.Chem.1998，63，5240-5244(R¹＝Me，R²＝Me)。

A2: see a.rao, m.k.gurj _ r, v.vivarr, Tetrahedron: asymmetry 1992, 3, 859-862; R.L.Johnson, G.Rayakumar, K.L.Yu, R.K.Misra, J.Med.chem.1986, 29, 2104-2107 (R.L.Johnson, G.Rayakumar, K.L.Yu, R.K.Misra, J.Med.chem.1986)¹＝H，R²＝H)；J.E.Baldwin，R.M.Adlington, R.H.Jones, C.J.Schofield, C.Zarcostas, J.chem.Soc.chem.Commun.1985, 194-196; J.E.Baldwin, R.M.Adlington, R.H.Jones, C.J.Schofield, C.Zarcostas, tetrahedron, 1986, 42, 4879-¹＝H，R²＝CH₂OH，CH₂CHO，CH₂CH₂COOH，CH₂CH₂OH)；A.P.Kozikowski，W.Tueckmantel，I.J.Reynolds，J.T.Wroblewski，J.Med.Chem.1990，33，1561-1571；A.P.Kozikowski，W.Tueckmantel，Y.Liao，H.Manev，S.IkonomovicJ.T.Wroblenski，J.Med.Chem.1993，36，2706-2708(R¹＝H，R²＝CH₂OH，CHCONH₂，CONHCH₂COOH，COOtBu)；D.Seebach，T.Vettiger，H.-M.Müller，D.Plattner，W.Petter，Liebigs Ann.Chem.1990，687-695(R¹Aryl CH (OH), R²＝H)；D.Seebach，E.Dziadulewicz，L.Behrendt，S.Cantoreggi，R.Fitzi，Liebigs Ann.Chem.1989，1215-1232(R¹＝Me，Et，R²＝H)。

A3: see A.P.Kozikowski, Y.Liao, W.Tueckmantel, S.Wang, S.Pshsenichkin, bioorg.Med.chem.Lett.1996, 6, 2559-¹＝H；R²＝CHCHO，CH₂OH，CH₂CH₂OH，CH₂COOH，COOH)；Isono，J.Am.Chem.Soc，1969，91，7490(R¹＝H；R²＝Et)；P.J.Blythin，M.J.Green，M.J.Mary，H.Shue，J.Org.Chem.1994，59，6098-6100；S.Hanessian，N.Bernstein，R.-Y.Yang，R.Maquire，Bioorg.Chem.Lett.1994，9，1437-1442(R¹＝H；R²＝Ph)。

A4: see e.emmer, tetrahedron, 1992, 48, 7165-; M.P.Meyer, P.L.Feldman, H.Rapoport, J.org.chem.1985, 50, 5223-¹＝H；R²＝H)；A.J.Bose，M.S.Manhas，J.E.Vincent，I.F.Fernandez，J.Org.Chem.1982，47，4075-4081(R¹＝H；R²＝NHCOCH₂OPh)；D.L.Boger，J.B.Meyers，J.Or g.Chem.1991，56，5385-5390(R¹＝H；R²＝NHCOCH₂Ph); K. kampe, tetrahedron communication, 1969, 117-¹＝CH₂OH；R²＝Ph)；M.D.Andrews，M.G.Maloney，K.L.Owen，J.Chem.Soc.Perkin Trans.1，1996，227-228(R¹＝CH₂OH；R²＝H)。

A5: see c.bi sang, c.weber, j.inglis, c.a.schiffer, w.f.van Gunsteren, j.a.robinson j.am.chem.soc.1995, 117, 7904 (r.bi sang, c.weber, j.inglis, c.a.schiffer, w.f.van Gunsteren, j.a.robinson j.am.chem.¹＝CH₃；R²H); S.Takano, M.Morija, Y.Iwabuki, K.Ogasawara, tetrahedron letters, 1989, 30, 3805-¹＝H；R²＝COOH)；M.D.Bachi，R.Breiman，H.Meshulam，J.Org.Chem.1983，48，1439-1444(R¹＝H；R²Ch (et) COOH); D.S.Kemp, T.P.Curran, tetrahedral communication, 1988, 29, 4931-4934; D.S.Kemp, T.P.Curran, W.M.Davies, J.org.chem.1991, 56, 6672-¹＝H；R²＝CH₂OH)；F.Manfre，J.-M.Kern，J.-F.Biellmann，J.Org.Chem.1992，57，2060-2065(R¹＝H；R²＝H，CH＝CH₂，CCH)；B.W.Bycroft，S.R.Chabra，J.Chem.Soc.Chem.Commun.1989，423-425(R¹＝H；R²＝CH₂COOtBu；Y.Xu，J.Choi，M.I.Calaza，S.Turner，H.Rapoport，J.Org.Chem.1999，64，4069-4078(R¹＝H；R²3-pyridyl); e.m.khalil, w.j.ojala, a.pradham, v.d.nair, w.b.gleason, j.med.chem.1999, 42, 628 637; khalil, N.L. Subasinge, R.L. Johnson, tetrahedron communication, 1996, 37, 3441-¹Allyl; r²H); dennicola, j. -l. luche, tetrahedral communication, 1992, 33, 6461-; S.Thaisrivong, D.T.pals, J.A.Lawson, S.Turner, D.W.Harris, J.Med.chem.1987, 30, 536-541; khalil, N.L.Subasinge, R.L.Johnson, tetrahedron communication, 1996, 37, 3441-; lewis, J.Wilkie, T.J.Rutherford, D.Gani, J.chem.Soc.Perkin Trans.1, 1998, 3777-3794 (R.¹＝Me；R²＝H)；A.Lewis，J.Wilkie，T.J.Rutherford，D.Gani，J.Chem.Soc.Perkin Trans.1，1998，3777-3794(R¹＝CH₂COOMe；R²H); subasinge, E.M.Khalil, R.L.Johnson, tetrahedron letters 1997, 38, 1317-¹＝CH₂CHO；R²＝H)；D.J.Witter，S.J.Famiglietti，J.C.Gambier，A.L.Castelhano，Bioorg.Med.Chem.Lett.1998，8，3137-3142；E.H.Khalil，W.H.Ojada，A.Pradham，V.D.Nair，W.B.Gleason，J.Med.Chem.1999，42，628-6 37(R¹＝CH₂CH₂CHO；R²＝H)。

A6: see DeNardo, Farmaco Ed.Sci.1977, 32, 522-529 (R)¹＝H；R³H); floris, n.terhiuis, h.hiemstra, n.w.speckamp, tetrahedron, 1993, 49, 8605-; S.Kanemasa, N.Tomoshige, O.Tsuge, Bull.chem.Soc.Jpn.1989, 62, 3944-¹＝H；R³＝H)；Sucrow，Chem.Ber.1979，112，1719。

A7: see Fichter, j.prak t.chem.1906, 74, 310 (R)¹＝Me；R⁴＝Ph)。

A8: see l.lapansanis, g.milias, k.froussios, m.kolovos, synthesis, 1983, 641-673; H.Nedev, H.Naharicoa, tetrahedral communication, 1993, 34, 4201-4204; d.y.jackson, c.quan, d.r.artis, t.rawson, b.blackburn, j.med.chem.1997, 40, 3359-3368; konopinska, H.Bartosz-Bechowski, G.Rosinski, W.Sobotka, Bull.pol.Acad.Sci.chem.1993, 41, 27-40; J.Hondrelis, G.Lone rgan, S.Voliotis, J.Matsukas, tetrahedron, 1990, 46, 565-; T.Nakamura, H.Matsuyama, H.Kanigata, M.Iyoda, J.org.chem.1992, 57, 3783-; c.e.o' Connell, k.ackermann, c.a.rowell, a.garcia, m.d.lewis, c.e.schwartz, bioorg.med.chem.lett.1999, 9, 2095-; lowe, T.Vilaivan, J.chem.Soc.Perkin Trans.1997, 547-554; bellier, I.McCort-Trancepain, B.Ducos, S.Danascimenta, H.Mundal, J.Med.Chem.1997, 40, 3947-; M.Peterson, R.VinceJ. Med. chem.1991, 34, 2787-; e.m. Smith, g.f. Swiss, b.r.neus tadt, e.h.gold, j.a.sommer, j.med.chem.1988, 31, 875-; E.Rubibi, C.Gilon, Z.Selinger, M.Chorev, tetrahedron, 1986, 42, 6039-¹＝H；R⁵＝OH)；C.R.Noe，M.Knollmueller，H.Voellenkle，M.Noe-Letschnig，A.Weigand，J.Mühl，Pharmazie，1996，51，800-804(R¹＝CH₃；R⁵＝OH)；J.Kitchin，R.C.Berthell，N.Cammack，S.Dolan，D.N.Evans，J.Med.Chem.1994，37，3703-3716；D.Y.Jackson，C.Quan，D.R.Artis，T.Rawson，B.Blackburn，J.Med.Chem.1997，40，3359-3368(R¹＝H；R⁵OBn); baldwin, a.r.field, c.c.lawrence, k.d.merrit, c.j.schofield, tetrahedron communication, 1993, 34, 7489-7492; K.Hashimoto, Y.Shima, H.Shirahama, Heterocycles (Heterocycles), 1996, 42, 489-¹＝H；R⁵OTs); t.r.webb, c.eignebrot, j.org.chem.1991, 56, 3009-; cafferty, C.A.Slate, B.M.Nakhle, H.D.Graham, T.L.Anstell, tetrahedron, 1995, 51, 9859-¹＝H；R⁵＝NH₂)；T.R.Webb，C.Eigenbrot，J.Org.Chem.1991，56，3009-3016(R¹＝H；R⁵＝CH₂NH₂) (ii) a J.K. Thittathil, J.L.Monoot, tetrahedron communication, 1986, 27, 151-¹＝H；R⁵＝Ph)；K.Plucinska，T.Kataoka，M.Yodo，W.Cody，J.Med.Chem.1993，36，1902-1913(R¹＝H；R⁵＝SBn)；J.Krapcho，C.Turk，D.W.Cushman，J.R.Powell，J.Med.Chem.1988，31，1148-1160(R¹＝H；R⁵＝SPh)；A.J.Verbiscar，B.Witkop，J.Org.Chem.1970，35，1924-1927(R¹＝H；R⁵＝SCH₂(4-OMe)C₆H₄)；S.I.Klein，J.M.Denner，B.F.Molino，C.Gardner，R.D′Alisa，Bioorg. Med. Chem. Lett. 1996，6，2225-2230(R¹＝H；R⁵＝0(CH₂)₃Ph); R.Zhang, F.Brownewell, J.S.Madalengoita, tetrahedron communication, 1999, 40, 2707-¹＝H；R⁵＝CH₂COOBn)。

A9: see Blake, j.am. chem. soc.1964, 86，5293-5297；J.Cooper，R.T.Gallagher，D.T.Knight，J.Chem.Soc.Chem.Perkin Trans.1，1993，1313-1318；D.W.Knight，A.W.Sibley，J.Chem.Soc.Perkin Trans.1，1997，2179，2188(R¹＝H；R⁶H); blake, J.Am.chem.Soc.1964, 86, 5293-5297; Y.Yamada, T.Ishii, M.Kimura, K.Hosaka, tetrahedron letters, 1981, 1353-¹＝H；R⁶＝OH)；Y.Umio，Yakugaku Zasshi，1958，78，727(R¹＝H；R⁶＝iPr)；Miyamoto，YakugakuZasshi，1957，77，580-584；Tanaka，Proc.Jpn.Acad.1957，33，47-50(R¹＝H；R⁶＝CH(CH₃)CH₂N(CH₃)₂)；L.E.Overman，B.N.Rodgers，J.E. Tellew，W. C. Trenkle，J. Am. Chem. Soc. 1997，119，7159-7160(R¹＝H；R⁶Allyl); ohki, chem.pharm.Bull.1976, 24, 1362-¹＝CH₃；R⁶＝H)。

A10: see J.Mulzer, A.Meier, J.Buschmann, P.Luger, Synthesis, 1996, 123-132 (R)¹＝H；R⁷＝CH＝CH₂)；J.Cooper，P.T.Gallagher，D.W.Knight，J.Chem.Soc.Chem.Commun.1988，509-510；E.G_tschi，C.Jenny，P.Reindl，F.Ricklin，Helv.Chim.Acta 1996，79，2219-2234(R¹＝H；R⁷OH); sasaki, R.Pauli, C.Fontaine, A.Chiaroni, C.Riche, P.Potier, tetrahedron letters 1994, 35, 241-¹＝H；R⁷COOH); R.Cotton, A.N.C.Johnstone, M.North, tetrahedron, 1995, 51, 8525-8544 (R.¹＝H；R⁷COOMe); J. S.Sabol, G.A.Flynn, D.Friedrich, E.W.Huber, tetrahedron letters 1997, 38, 3687-¹＝H；R⁷＝CONH₂) (ii) a P.P.Waid, G.A.Flynn, E.W.Huber, J.S.Sabol, tetrahedron communication, 1996, 37, 4091-¹＝H；R⁷＝(4-Bno)C₆H₄) (ii) a Sasaki, R.Pauli, P.Potier, tetrahedron letters, 1994, 35, 237-¹＝H；R⁷＝SO₂Ph)；R.J.Heffner，J. Jiang，M.Jouillié，J.Am.Chem.Soc.1992，114，10181-10189；U.Schmidt，H.Griesser，A.Lieberknecht，J.H_usler，Angew.Chem.1981，93，272-273(R¹＝H；R⁷Aryl ═ O); H.Mosberg, A.L.Lomize, C.Wang, H.Kroona, D.L.Heyl, J.Med.chem.1994, 37, 4371-one 4383 (R.¹＝H；R⁷＝4-OHC₆H₄)；S.A.Kolodziej，G.V.Nikiforovich，R.Sceean，M.-F.Lignon，J.Martinez，G.R.Marshall，J.Med.Chem.1995，38，137-149(R¹＝H；R⁷＝SCH₂(4-Me)C₆H₄)。

A11: see Kuhn, Osswald, chem. Ber. 1956, 89, 1423-; patchett, Witkop, J.Am.chem.Soc.1957, 79, 185-189; benz, Helv.Chim. Acta 1974, 57, 2459-; p, Wessig, Synlett, 1999, 9, 1465-1467; E.M.Smit, G.F.Swiss, B.R.Neustadt, E.H.gold, J.A.Sommer, J.Med.chem.1988, 31, 875-; krapcho, c. turk, d.w.cushman, j.r.powell, j.m.deftreset, j.med.chem.1988, 31, 1148 (R)¹＝H；R⁶H); D.BenIshai, S.Hirsh, tetrahedron, 1988, 44, 5441-5450 (R)¹＝H；R⁶＝CH₃)；M.W.Holladay，C.W.Lin，C.S.Garvey，D.G.Witte，J.Med.Chem.1991，34，455-457(R¹＝H；R⁶Allyl); barralough, P.Hudhomme, C.A.Spray, D.W.Young, tetrahedron, 1995, 51, 4195-¹＝H；R⁶Et); baldwin, m.rudolf, tetrahedron communication, 1994, 35, 6163-; J.E.Baldwi n, S.J.BamHord, A.M.Fryer, M.Rudolf, M.E.Wood, tetrahedron, 1997, 53, 5233-¹＝H；R⁶＝CH₂COOtBu)；P. Gill，W. D. Lubell，J. Org. Chem. 1995，60，2658-2659(R¹＝H；R⁶＝CH₃(ii) a Bn; an allyl group; CH (CH)₂COOMe)；M.J.Blanco，F.J.Sardina，J.Org.Chem.1998，63，3411-3466(R¹＝H；R⁶＝OCH₂OMe)。

A12: see Ahmed, Cheeseman, tetrahedron, 1977, 33,2255-2257；J.S.New，J.P.Yevich，J.Heterocycl.Chem.1984，21，1355-1360；R.Kikumoto，Y.Tamao，K.Ohkubo，T.Tezuka，S.Tonomura，J.Med.Chem.1980，23，1293-1299；C.J.Blankley，J.S.Kaltenbronn，D.E.DeJohn，A.Werner，L.R.Bennett，J.Med.Chem.1987，30，992-998；S.Klutcho，C.J.Blankley，R.W.Fleming，J.M.Hinkley，R.E.Werner，J.Med.Chem.1986，29，1953-1961(R¹＝H；R⁸h); beeley, C.J.M.Rockwell, tetrahedron letters, 1990, 31, 417-¹＝COOEt；R⁸＝H)。

A13: see g.flowet, w.brieher, t.majewski, k.mahan, j.med.chem.1991, 43, 2089-; g.galienda, p.grieco, e.perissuti, v.santagada, faraco, 1996, 51, 197-; mcconsey, m.j.hawkins, p.andrade-Gordon, m.f.addo, b.e.maryanoff, bioorg.med.chem.lett.1999, 9, 1423-; g.b.jones, s.b.heaton, b.j. Chapman, m. Guzel, Tetrahedron: asymmetry 1997, 8, 3625-; m.asami, h.watanabe, k.honda, s.inoue, Tetrahedron: asymmetry1998, 9, 4165-; k.gross, Y.M.Yun, P.Beak, J.org.chem.1997, 62, 7679-¹＝H；R⁶＝H；R⁸＝H)；K.Gross，Y.M.Yun，P.Beak，J.Org.Chem.1997，62，7679-7689(R¹＝H；R⁶＝H；R⁸＝6-Cl)；Ch.Noe，M.Knollmueller，C.Schoedl，M.L.Berger，Sci.Pharm.1996，64，577-590；E.Reiman，W.Erdle，H.Unger，Pharmazie，1994，54，418-421(R¹＝H；R⁶＝CH₂COOH；R⁸H); collot, M.Schmitt, A.K.Marwah, B.Norberg, J.J.Bourgignon, tetrahedron letters 1997, 38, 8033-¹＝H；R⁶＝Ph；R⁸H); L.V.Dunkerton, H.Chen, B.P.McKillican, tetrahedron communication, 1988, 29, 2539-¹＝C(CH₃)₂CH＝CH₂；R⁶＝H；R⁸＝H)；E.J.Corey，J.Am.Chem.Soc.1970，92，2476-2488；Neunhoeffer，Lehmann，Chem.Ber.1961，94，2960-2963(R¹＝CH₃；R⁶＝H；R⁸＝H)。

A14: amino acids of class a14 can be made according to scheme 1.

Scheme 1

i：NaH，BrCH(R¹)COOMe，DMF；ii：LiOHx1H₂O，MeOH，H₂O; iii: polyphosphoric Acid (PPA); iv: NaH, ClCOOMe, THF; v: enzymatic resolution (e.g., lipase); vi: NaOH, MeOH, H₂O, heating; vii: fmocosu, Na₂CO₃Aqueous solution, dioxane

A15: see D.S. Perlow, J.M.Erb, N.P.Gould, R.D.Tung, R.M.Freidinger, J.org.chem.1992, 57, 4394-; D.Y.Jackson, C.Quan, D.R.Artis, T.Rawson, B.Blackburn, J.Med.chem.1997, 40, 3359-3368 (R.Y.Jackson, C.Quan, D.R.Artis, T.Rawson, B.Blackburn, J.Med.chem.1997, 40, 3359-3368)¹＝H；R²H); H.H.Wasserman, K.Rodrigues, K.Kucharczyk, tetrahedron communication, 1989, 30, 6077-¹＝H；R²＝COOH)。

A16: see Beyerman, Boekee, Recl.Trav.Chim.Pays-Bas, 1959, 78, 648-; free, a.r.day, j.org.chem.1960, 25, 2105-; d.r. adams, p.d. bailey, i.d. collier, j.d. heferman, s.strokes, j.chem.soc.chem.commun.1996, 349-; baldwin, r.m.adlington, c.r.a.godfrey, d.w.collins, j.d.vaughan, j.chem.soc.chem.commu.1993, 1434-; Y.Matsumura, Y.Takeshima, H.Ohita, Bull.chem.Soc.Jpn.1994, 67, 304-306 (R)¹＝H；R⁶＝H)；C. Herdeis，W.Engel，Arch.Pharm.1991，324，670(R¹＝COOMe；R⁶＝CH₃)。

A17, a 18: see c.r.davies, j.s.davies, j.chem.soc.perkintrans 1, 1976, 2390-; bevan, j.chem.soc.c, 1971, 514-522; umezawa, K.Nakazawa, Y.Ikeda，H.Naganawa，S.Kondo，J.Org.Chem.1999，64，3034-3038(R¹＝R³＝H)；P.D.Williams，M.G.Bock，R.D.Tung，V.M.Garsky，D.S.Parlow，J.Med.Chem，1992，35，3905-3918；K.Tamaki，K.Tanzawa，S.Kurihara，T.Oikawa，S.Monma，Chem.Pharm.Bull.1995，43，1883-1893(R¹＝R⁵＝H；R³COOBn); k.j.hale, j.cai, v.delisser, s.manavazar, s.a.peak, tetrahedron, 1996, 52, 1047-; M.H.Chen, O.P.Goel, J. -W.Hyun, J.Magano, J.R.Rubin, bioorg.Med.chem.Lett.1999, 9, 1587-¹＝R⁵＝H；R³COOtBu); R.Bainteli, I.Brun, P.Hall, R.Metterich, tetrahedron letters, 1999, 40, 2109-¹＝R⁵＝H；R³COR); K.J.Hale, N.Jogiya, S.Manavizar, tetrahedron, 1998, 39, 7163-¹＝H；R³＝COOBn；R⁵＝OBn)；T. Kamenecka，S.J.Danishewsky，Angew.Chem.Int.Ed.Engl.1998，37，2995-2998(R¹＝H；R³＝COO(CH₂)₂SiMe₃；R⁵＝OSiMe₂tBu。

A19: see Beilstein, registration number 648833 (R)¹＝R⁴＝R⁸H). Such compounds can be made according to scheme 2.

Scheme 2.

i：NaH，CH₂(COOMe)₂，DMSO；ii：NaH，R¹-X, DMSO; iii: aqueous NaOH, MeOH, 75 degrees; iv: DBU, Mel, DMF; v: LDA, BocN ═ NBoc; vi: TFA, CH₂Cl₂；vii：CbzCl，Na₂CO₃Aqueous solution, dioxane; viii: enzymatic resolution (e.g., lipase); followed by DBU, Mel, DMF; ix: NaH, R⁴-X，THF；x：Pd/C，H₂，EtOH；xi：LiOHx1H₂O，MeOH，H₂O；xii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A20: see D.Hagiwara, H.Miyake, N.Igari, M.Karino, Y.Maeda, J.Med.chem.1994, 37, 2090-¹＝H；R⁹＝OH)；Y.Arakawa，M.Yasuda，M.Ohnishi，S.Yoshifuji，Chem.Pharm.Bull.1997，45，255-259(R¹＝H；R⁹COOH); mur ray, I.D. Starkey, tetrahedron communication, 1996, 37, 1875-membered 1878 (R)¹＝H；R⁹＝(CH₂)₂NHCOCH₂Ph); clinch, A.Vasella, R.Schauer, tetrahedron letters, 1987, 28, 6425-¹＝H；R⁹＝NHAc)。

A21: see, a.golubev, n.sewald, k.burger, tetrahedron letters, 1995, 36, 2037-; machetti, F.M.Cordero, F.DeSario, A.Guarna, A.Brandi, tetrahedron letters, 1996, 37, 4205-; ornstein, d.d.schoepp, m.b.arnold, j.d.leaner, d.lodge, j.med.chem.1991, 34, 90-97; r¹＝R⁶＝H)；P.D.Leeson，B.J.Williams，R.Baker，T.Ludduwahetty，K.W.Moore，M.Rowley，J.Chem.Soc.Chem.Commun.1990，1578-1580；D.I.C.Scopes，N.F.Hayes，D.E.Bays，D.Belton，J.Brain，J.Med.Chem.1992，35，490-501；H.Kessler，M.Kuehn，T.L_schner，Liebigs Ann.Chem.1986，1-20(R¹＝R⁶＝H)；C.Herdeis，W.Engel，Arch.Pharm.1992，7，419-424(R¹＝R⁶＝Bn)；C.Herdeis，W.Engel，Arch.Pharm.1992，411-418(R¹＝COOMe；R⁶＝H)；C.Herdeis，W.Engel，Arch.Pharm.1992，419-424(R¹＝COOMe；R⁶＝Bn)。

A22: see P.D.Leeson, B.J.Williams, R.Baker, T.Ladduwahetty, K.W.Moore, M.Rowley, J.chem.Soc.chem.Comm.1990, 1578-1580 (R.D.Leeson, B.J.Williams, R.Baker, T.Ladduwahetty, K.W.Moore, M.Rowley, J.chem.Soc.chem.Comm¹＝H；R¹⁰＝NHOBn)。

A23: see Beyerman, Boekee, Recl.Trav.Chim.Pays-Bas 1959, 78, 648-; d.r.adams, p.d.bailey，I.D.Collier，J.D.Heffernan，S.Stokes J.Chem.Soc.Chem.Commun.1996，349-350；J.E.Baldwin，R.M.Adlington，C.Godfrey，D.W.Collins，J.G.Vaughan，J.Chem.Soc.Chem.Comm.1993，1434-1435(R¹＝R⁶＝H)；C.Herdeis，W.Engel，Arch. Pharm. 1993，297-302(R¹＝COOMe；R⁶＝H)。

A24: see Plieninger, Leonh _ user, chem. Ber. 1959, 92, 1579-; D.W.Knight, N.Lewis, A.C.Share, D.Haigh, J.chem.Soc.Perkin Trans.11998, 22, 3673-; drummond, g.johnson, d.g.nickel, d.f.ortwine, r.f.bruns, b.welbaum, j.med.chem.1989, 32, 2116-; M.P.Moyer, P.L.Feldman, H.Rapoport, J.org.chem.1985, 50, 5223-¹＝R⁶＝H)；McElvain，Laughton，J.Am.Chem.Soc.1951，73，448-451(R¹＝H；R⁶＝Ph)；McElvain，Laughton，J.Am.Chem.Soc.1951，73，448-451(R¹＝Ph；R⁶＝H)；

A25: see l.y.hu, t.r.ryder, s.s.nikam, e.millerman, b.g.szoke, m.f.rafferty, bioorg.med.chem.lett.1999, 9, 1121-; lumma, r.d.hartman, w.s. Saari, e.l.engelhardt, v.j.lotti, c.a.stone, j.med.chem.1981, 24, 93-101; hosten, m.j.o.antenenuis, ball.soc.chim.belg.1988, 97, 48-50; c.f. bigge, s.j.hays, p.m.novak, j.t.drummond, g.johnson, t.p.bovski, tetrahedral communication, 1989, 30, 5193-; aebishcher, P.Frey, H. -P.Haerter, P.L.Herrling, W.Muller, Helv.Chim.acta 1989, 72, 1043-; hoeckstra, b.e.maryanoff, b.p.damiano, p.andrade-Gordon, j.h.cohen, m.j.constanzo, b.j.haertlein, l.r.hecker, b.l.hulshizer, j.a.kauffman, p.keane, j.med.chem.1999, 42, 5254-¹＝H；R¹¹＝H)；B.D.Dor sey，R.B.Levin，S.L.McDaniel，J.P.Vacca，J.P.Guare，J.Med.Chem.1994，37，3443-3451；M.Cheng，B. De，S.Pikul，N.G.Almstaed，M.G.Natchus，M.V.Anastasio，S.J.McPhail，C.J.Snider，Y.O.Taiwo，L.Chen，C.M.Dunaway，J.Med.Chem.2000，43，369-380；R.Kuwano，Y.Ito，J.Org.Chem.1999，64，1232-1237(R¹＝H；R¹¹＝COOtBu)；J.Kitchin，R.C.Bethell，N.Cammack，S.Dolan，D.N.Evans，J.Med.Chem.1994，37，3707-3716(R¹＝H；R¹¹＝COOPh)；C.F.Bigge，S.J.Hays，P.M.Novak，J.T.Drummond，G.Johnson，T.P.Bobovski，J.Med.Chem.1990，33，2916-2924(R¹＝H；R¹¹＝COOtBu；(CH₂)₃COOEt；(CH₂)₃PO(Me)OH；CH₂PO(OH)₂；(CH₂)₂PO(OEt)₂；(CH₂)₂PO(OH)₂)。

Compounds of class a25 may also be prepared according to scheme 3:

scheme 3

i: lawesson reagent, toluene, 80 degrees; ii: DBU, Mel, DMF; iii: NaBH₄Or NaCNBH₃，MeOH；iv：Boc₂O，THF；v：LiOHx1H₂O，MeOH，H₂O；vi：Pd/C，H₂，EtOH；vii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A26: see Koegel, j.biol.chem.1953, 201, 547 (R)¹＝R¹²＝H)。

A27: see g.makara, g.r.marshall, tetrahedron communication, 1997, 38, 5069-; r.n. patel, a.banerjee, r.l.hanson, d.b.brzowski, l.w.parker, l.j.szarka, Tetrahedron: asymmetry1999, 10, 31-36 (R)¹＝H；R¹³＝OH，OtBu)；J.E.Johanson，B.D.Christie，H.Rapoport，J.Org.Chem.1981，46，4914-4920；N.Moss，J.-S.Duceppe，J.-M-Ferland，J.Gauthier，J.Med.Chem.1996，39，2178-2187(R¹＝H；R¹³CONHMe); g.m.makara, g.r.marshall, tetrahedronCommunication, 1997, 38, 5069-5072 (R)¹＝H；R¹³＝SCH₂(4-MeO)C₆H₄)。

A28: see, a.golubev, n.sewald, k.burger, tetrahedron letters, 1995, 36, 2037-; ornstein, d.d.schoepp, m.b.arnold, j.d.leaner, d.lodge, j.med.chem.1991, 34, 90-97 (r.l.ornstein, d.d.schoepp, m.b.arnold, j.d.leaner, d.lodge, j.med.chem.1991, 34, 90-97 (r.d.¹＝R⁶＝H)；P.D.Leeson，B.J.Williams，R.Baker，T.Ladduwahet ty，K.W.Moore，M.Rowley，J.Chem.Soc.Chem.Commun.1990，22，1578-1580；C.Herdeis，W.Engel，Arch.Pharm.1991，324，670(R¹＝H；R⁶＝Me)；C.Herdeis，W.Engel，Arch.Pharm.1991，324，670(R¹＝COOMe；R⁶＝H，Me)。

A29: see Kawase, Masami, chem.Pharm.Bull. 1997, 45, 1248-1253; I.G.C.Coutts, J.A.Hadfield, P.R.Huddleston, J.chem.Res.Miniprint, 1987, 9, 2472-; I.G.C.Coutts, J.A.Hadfield, P.R.Huddleston, J.chem.Res.Miniprint, 1987, 9, 2472-; v.j.hrubi, w.l.cody, a.m.castrucci, m.e.hadley, collection.czech.chem.commu.1988, 53, 2549-; r.t.shuman, r.b.rothenberger, c.s.campbell, g.f.smith, d.s.gifford-Moore, p.d.gesellchen, j.med.chem.1993, 36, 314-; M.Kawase, Y.Okada, H.Miyamae, heterocycles, 1998, 48, 285-294 (R)¹＝R⁸＝H)；Kawase，Masami，Chem.Pharm.Bull.1997，45，1248-1253(R¹＝H；R⁸＝6，7-(MeO₂)；D.F.Ortwine，T.C.Malone，C.F.Bigge，J.T.Drummond，C.Humblet，J.Med.Chem.1992，35，1345-1370(R¹＝H；R⁸＝7-CH₂PO(OEt)₂) (ii) a Corey, D.Y.gin, tetrahedron communication, 1996, 37, 7163-¹＝CH₂SCOOtBu)；P.Dostert，M.Varasi，A.DellaTorre，C.Monti，V.Rizzo，Eur.J.Med.Chim.Ther.1992，27，57-59(R¹＝Me；R⁸＝6，7-(OH)₂)；Z.Czarnocki，D.Suh，D.B.McLean，P.G.Hultin，W.A.Szarek，Can.J.Chem.1992，70，1555-1561；B.Sch_nenberger，A.Brossi，Helv.Chim.Acta 1986，69，1486-1497(R¹＝Me；R⁸＝6-OH；7-MeO)；Hahn，Stiel，Chem.Ber.1936，69，2627；M.Chrzanowska，B.Sch_nenberger，A.Brossi，J.L.FlippeN-Ander son，Helv.Chim.Acta 1987，70，1721-1731；T.Hudl icky，J.Org.Chem.1981，46，1738-1741(R¹＝Bn；R⁸＝6，7-(OH)₂) (ii) a Meyers, M.A.Gonzalez, V.Struzka, A.Akahane, J.Guiles, J.S.Warmus, tetrahedron letters, 1991, 32, 5501-¹＝CH₂(3, 4-methylenedioxy) C₆H₃；R⁸＝6，7-(OMe)₂)。

A30 and a31 can be prepared according to schemes 4 and 5.

Scheme 4

i: NaH, N-benzoyl glycine tert-butyl ester, DMF; ii: NaH, pd (o), toluene; iii: TFA, CH₂Cl₂(ii) a iv: a polyphosphoric acid; v: aqueous NaOH, MeOH, 75 degrees; followed by aqueous HCl; vi: DBU, Mel, DMF; vii: lithium hexamethyl-dililazide, THF, chlorotrimethylsilane, -78 degrees; then R¹-X; viii: enzymatic resolution (e.g., lipase); subsequent isolation into the methyl ester: DBU, Mel, DMF; ix: aqueous NaOH, MeOH, heating; x: fmocosu, Na₂CO₃Aqueous solution, dioxane

Scheme 5

i：Boc₂O，Na₂CO₃Aqueous solution, dioxane; ii: DBU, Mel, DMF; iii: lithiumhexamethylisilazide, THF, chlorotrimethylsilane, -78 degrees: then R²-X；iv：LiOHx 1H₂O，MeOH，H₂O；v：TFA，CH₂Cl₂；vi：FmocDSu，Na₂CO₃Aqueous solution, dioxane

A32 can be prepared according to the following: p.w.schiller, g.weltrowska, t.m. -d.nguyen, c.lemieux, n.nga, j.med.chem.1991, 34, 3125-; v.s.goodfellow, m.v.marathon, k.g.kuhlman, t.d.fitzpatrick, d.cuadrato, j.med.chem.1996, 39, 1472-; G.Caliendo, F.Fiorino, P.Grieco, E.Perissutt, S.Deluca, A.Guiliano, G.Santelli, D.Califono, B.Severino, V.Santagada, Farmaco, 1999, 54, 785-; V.S.Goodfellow, M.V.Marathe, K.G.Kuhlman, T.D.Fitzpatrick, D.Cuadro, J.Med.chem.1996, 39, 1472-¹＝R⁸H); tourwe, E.Mannekens, N.T.Trang, P.Verheyden, H.Jaspers, J.Med.chem.1998, 41, 5167-5176; A. szardnings, M.Gordeev, D.V.Patel, tetrahedron communication, 1996, 37, 3635-; W.Wiczk, K.Stachywarik, P.Skurski, L.Lankiewicz, A.Michniewicz, A.Roy, J.am.chem.Soc.1996, 118, 8300-; K.Verschuren, G.Toth, D.Tourwe, M.Lebl, G.van Binst, V.Hrubi, Synthesis, 1992, 458-¹＝H；R⁸＝6-OH)；P.L.Ornstein，M.B.Arnold，N.K.Augenstein，J.W.Paschal，J.Org.Chem.1991，56，4388-4392(R¹＝H；R⁸＝6-MeO)；D.Ma，Z.Ma，A.P.Kozikowski，S.Pshenichkin，J.T.Wroblenski，Bioorg.Med.Lett.1998，8，2447-2450(R¹＝H；R⁸＝6-COOH)；U.Sch_llkopf，R.Hinrichs，R.Lonsky，Angew.Chem.1987，99，137-138(R¹＝Me；R⁸H); B.O.Kammermeier, U.Lerch, C.Sommer, Synthesis, 1992, 1157-an-1160 (R.¹＝COOMe；R⁸＝H)；T.Gees，W.B.Schweizer，D.Seebach，Helv.Chim.Acta 1993，76，2640-2653(R¹＝Me；R⁸＝6，7-(MeO₂)。

A33: see Hinton, Mann, J.chem.Soc.1959, 599-.

A34: see g.p. zecchini, m.p. paradisi, J.Heterocyclic chem.1979, 16, 1589-; S.Cerrini, J.chem.Soc.Perkin Trans.1, 1979, 1013-; P.L.Ornstein, J.W.Pascal, P.D.Gesellchen, J.org.chem.1990, 55, 738-741; G.M.Kscan, A.M.Yan, C.G.Diefenbacher, J.L.Stanton, J.Med.chem.1985, 28, 1606-1611; J.A.Robl, D.S.Karanewsky, M.M.Asaad, tetrahedron communication, 1995, 36, 1593-; s.katayama, n.ae, r.nagata, Tetrahedron: asymmetry1998, 9, 4295-¹＝R⁸＝H)；K.Hino，Y.Nagai，H.Uno，Chem.Pharm.Bull.1988，36，2386-2400(R¹＝Me；R⁸＝H)。

A35: see Beilstein registration number: 530775, 883013 (R)¹＝R⁸＝H)。

A36: see r.w.carling, p.d.leeson, a.m.moseley, r.baker, a.c.foster, j.med.chem.1992, 35, 1942-1953; S.Kano, T.Ebata, S.Shibuya, J.chem.Soc.Perkin Trans.1, 1980, 2105-¹＝R⁸＝H)；R.W.Carling，P.D.Leeson，A.M.Moseley，R.Baker，A.C.Foster，J.Med.Chem.1992，35，1942-1953(R¹＝H；R⁸＝5-Cl；7-Cl)。

A37: see Nagarajan, Indian J.chem.1973, 11, 112 (R)¹＝CH₂COOMe；R⁸＝H)。

A38: see r.pauly, n.a.sasaki, p.potire, tetrahedral communication, 1994, 35, 237-; J.Podlech, D.Seebach, Liebigs Ann.org.Bioorg.chem.1995, 7, 1217-; nicolaou, G. -Q.Shi, K.Namoto, F.Bernal, J.Chem.Soc.Chem.Commun.1998, 1757-¹＝H；R²＝H)。

A39: see Beilstein, registration number 782885.

A40: see F.P.J.C.Rutjes, N.M.Terhiuis, H.Hiemstra, N.W.Speckamp, tetrahedron, 1993, 49, 8605-substituted 8628 (R.P.J.C.Rutjes, N.M.Terhiemstra, N.W.Speckamp¹＝H；R³Bn); such compounds can be prepared according to scheme 6.

Scheme 6

i：BocNHNH₂，NaCNBH₃，MeOH，AcOH；ii：CbzCl，Et₃N，CH₂Cl₂；iii：TFA，CH₂Cl₂(ii) a Then pyridine, DMAP, heating; iv: resolution (e.g., lipase); v: DBU, Mel, DMF; vi: lawesson reagent, toluene, 75 degrees; vii: DBU, Mel, DMF; viii: NaBH₄Or NaCNBH₃MeOH; ix: introduction of R by reductive amination, alkylation or acylation³；x：LiOHx1H₂O，MeOH，H₂O；xi：Pd/C，H₂，EtOH；xii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A41: such compounds can be prepared according to scheme 7.

Scheme 7

i: resolution (e.g., lipase); subsequent isolation into the methyl ester: DBU, Mel, DMF; ii: NaH, R⁴-X，THF；iii：LiOHx1H₂O，MeOH，H₂O；iv：Pd/C，H₂，EtOH；v：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A42-A46: such compounds may be prepared according to schemes 8-12. Important intermediates 34 and alpha-amino acid syntheses involving this building block include: R.M.Williams, M. -N.im, tetrahedral communication, 1988, 29, 6079-; R.M.Williams, M. -N.im, J.am.chem.Soc.1991, 113, 9276-; dellaria, b.d.santarsiero, tetrahedral communication, 1988, 29, 6079-; delllaria, b.d.santarsiero, j.org.chem.1989, 54, 3916-; baldwin, v.lee, c.j.schofield, Synlett 1992, 249-; baldwin, v.lee, c.j.schofield, heterocycles, 1992, 34, 903-906.

Scheme 8

i: lithium hexamethyl-dililazide, THF, chlorotrimethylsilane, -78 degrees; then R⁵-X; ii: HBr; iii: DBU, Mel, DMF; iv: DIBAL-H, THF; v: EtOH, p-pyridinium tosylate, molecular sieve 4A; vi: lithium hexamethyl-dililazide, THF, -78 degrees, 33; vii: Pd/C, H₂EtOH; followed by DBU, Mel, DMF; followed by TFA, CH₂Cl₂(ii) a viii: aqueous HCl, THF; then Na (OAc)₃BH, AcOH, dichloroethane; ix: liohx1H₂O，MeOH，H₂O；x：FmocOSu，Na₂CO₃Aqueous solution, dioxane

Scheme 9

i: lithium hexamethyl-dililazide, THF, chlorotrimethylsilane, -78 degrees; then R⁶-X; ii: HBr; iii: DBU, Mel, DMF; iv: DIBAL-H, THF; v: EtOH, p-pyridinium tosylate, molecular sieve 4A; vi: lithium hexamethyl-dililazide, THF, -78 degrees, 39; vii: Pd/C, H₂EtOH; followed by DBU, Mel, DMF; followed by TFA, CH₂Cl₂(ii) a viii: aqueous HCl, THF; then Na (OAc)₃BH, AcOH, difluoroethane; viii: boc₂O，Et₃N，CH₂Cl₂；ix：Bu₄NFx10H₂O, THF; ix: pyridinium chlorochromate (cClO); x: liohx1H₂O，MeOH，H₂O；xi：TFA，CH₂Cl₂；xii：FmocOSu，Na₂CO₃Aqueous solution ofAlkane

Scheme 10

i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: BtOH, p-toluenesulfonic acid pyridine _, molecular sieve 4A; v: lithium hexamethyl-dililazide, THF, -78 degrees, 43; vi: Pd/C, H₂EtOH; followed by DBU, Met, DMF; followed by TFA, CH₂Cl₂(ii) a vii: aqueous HCl, THF; then Na (OAc)₃BH, AcOH, dichloroethane; viii: liohx1H₂O，MeOH，H₂O；ix：FmocOSu，Na₂CO₃Aqueous solution, dioxane

Scheme 11

i: HBr; ii: DBU, Mel, DMF; ii i: DIBAL-H, THF; iv: EtOH, p-pyridinium tosylate, molecular sieve 4A; v: lithium hexamethyl-dililazide, THF, -78 degrees, 47; vi: Pd/C, H₂EtOH; followed by DBU, Met, DMF; followed by TFA, CH₂Cl₂(ii) a vii: aqueous HCl, THF; then Na (OAc)₃BH, AcOH, dichloroethane; viii Boc₂O，Et₃N，CH₂Cl₂；ix：Bu₄NFx10H₂O, THF; x: pyridinium chlorochromate (cClO); xi: liohx1H₂O，MeOH，H₂O；xii：TFA，CH₂Cl₂；xiii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

Scheme 12

i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, p-pyridinium tosylate, molecular sieve 4A; v: lithium hexamethyl-dililazide, THF, -78 degrees, 51; vi: Pd/C, H₂EtOH; then DBU, Me), DMF; followed by TFA, CH₂Cl₂(ii) a vii: aqueous HCl, THF; then Na (OAc)₃BH, AcOH, dichloroethane; viii: boc₂O，Et₃N，CH₂Cl₂；ix：Bu₄NFx10H₂O, THF; x: pyridinium chlorochromate (cClO); xi: liohx1H₂O，MeOH，H₂O；xii：TFA，CH₂Cl₂；xiii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A47: see P.Barraclough, R.D.Farrant, D.Kettle, S.Smith, J.chem.Res.Miniprint 1991, 11, 2876-2884 (R.Barraclough, R.D.Farrant, D.Kettle, S.Smith, J.Chem.Res.Miniprint 1991, 11, 2876)¹＝R¹¹＝H，Bn，(CH₂)₂PO(OEt)₂)。

A48: see A.Nouvet, M.Binard, F.Lamatoy, J.Martinez, R.Lazaro, tetrahedron, 1999, 55, 4685-4698 (R)¹＝R¹²＝H)。

A49: see m.y.kolleganov, i.g.kolleganova, m.d.mitrofanova, l.i.martynnko, p.p.nazarov, v.i.spitsyn, bull.acad.sci.ussr div.chem.sci (engl.trans.)1983, 32, 1293-materials 1299; akad Nauk SSSR Ser. Khim 1983, 6, 1293-1299; V.P.Vasilev, T.D.Orlova, S.F.Ledenkov, J.Gen.chem.USSR (Engl. Trans.1989, 59, 1629-¹＝H；R¹²＝CH(COOH)CH₂COOH). Compounds of class a49 may also be prepared according to scheme 13.

Scheme 13

i：NaH，CbzNH(CH₂)₂Br，THF；ii：Pd/C，H₂，EtOH；iii：EDCl，CH₂Cl₂Diisopropylethylamine; iv: NaH, R¹²-X，THF；v：LiOHx1H₂O，MeOH，H₂O；vi：TFA，CH₂Cl₂；vii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A50 and a 51: these classes of compounds can be prepared according to schemes 14 and 15.

Scheme 14

i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, p-pyridinium tosylate, molecular sieve 4A; v: lithium hexamethyl-dililazide, THF, -78 degrees, 59; vi: Pd/C, H₂EtOH; followed by DBU, Mel, DMF; followed by TFA, CH₂Cl₂(ii) a vii: aqueous HCl, THF; then Na (OAc)₃BH, AcOH, dichloroethane; viii: liohx1H₂O，MeOH，H₂O；ix：FmocOSu，Na₂CO₃Aqueous solution, dioxane

Scheme 15

i: HBr; ii: DBU, Mel, DMF; iii: DIBAH, THF; iv: EtOH, p-pyridinium tosylate, molecular sieve 4A; v: lithium hexamethyl-dililazide, THF, -78 degrees, 63 vi: Pd/C, H₂EtOH; followed by DBU, Mel, DMF; followed by TFA, CH₂Cl₂(ii) a vii: aqueous HCl, THF; then Na (OAc)₃BH, AcOH, dichloroethane; viii: boc₂O，Et₃N，CH₂Cl₂；ix：Bu₄NFx10H₂O, THF; x: perfluorochromic acid pyridinePyridine A; xi: liohx1H₂O，MeOH，H₂O；xii：TFA，CH₂Cl₂；xiii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A53: see P.Barraclough, R.D.Farrant, D.Kettle, S.Smith, J.chem.Res.Miniprint 1991, 11, 2876-2884 (R.Barraclough, R.D.Farrant, D.Kettle, S.Smith, J.Chem.Res.Miniprint 1991, 11, 2876)¹＝R¹¹＝H；R¹＝H；R¹¹＝Bn，(CH₂)₃PO(OH)₂)；(CH₂)₃PO(Et)₂)；J.I.Levin，J.F.DiJoseph，L.M.Killar；A.Sung，T.Walter，Bioorg.Med.Chem.Lett.1998，8，2657-2662(R¹＝H；R¹¹＝4CF₃OC₆H₄CO)。

A52 and a 54: such compounds may be prepared according to schemes 16 and 17.

Scheme 16

i: iBuMgCl, THF; ii: NaH, THF; iii: lithium hexamethyl-dililazide, THF, chlorotrimethylsilane, -78 degrees; then R⁶-X; iv: aqueous NaOH, MeOH, 75 degrees; followed by aqueous HCl; v: DBU, Mel, DMF; vi: lithium hexamethyl-dililazide, THF, chlorotrimethylsilane, -78 degrees; then R¹-X; vii: resolution (e.g., lipase); followed by DBU, Mel, DMF; viii: liohx1H₂O，MeOH，H₂O；ix：TFA，CH₂Cl₂；x：FmocOSu，Na₂CO₃Aqueous solution, dioxane

Scheme 17

i：NaN₃，DMSO；ii：NaH，THF，CH₂＝CHCOOBn；iii：Pd/C，H₂，EtOH；iv：EDCl，CH₂Cl₂Diisopropylethylamine; v: NaH, R¹²-X，THF；vi：LiOHx1H₂O，MeOH，H₂O；vii：TFA，CH₂Cl₂；viii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A55 and a 56: such compounds may be prepared according to schemes 18 and 19.

Scheme 18

i：NaH，THF，CbzNH(CH₂)₃Br；ii：Pd/C，H₂EtOH; then toluene is heated; iii: resolution (e.g., lipase); iv: DBU, Mel, DMF; v: NaH, R¹²-X，THF；vi：LiOHx1H₂O，MeOH，H₂O；vii：TFA，CH₂Cl₂；viii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

Scheme 19

i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, p-phenylphosphonic acid pyridine _, molecular sieve 4A; v: lithium hexamethyl-dililazide, THF, -78 degrees, 86; vi: Pd/C, H₂EtOH; followed by DBU, Mel, DMF; followed by TFA, CH₂Cl₂(ii) a vii: aqueous HCl, THF; then Na (OAc)₃BH, AcOH, dichloroethane; viii: liohx1H₂O，MeOH，H₂O；ix：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A57: such compounds may be prepared according to scheme 20.

Scheme 20

i: NaOMe, MeOH; ii: NaH, THF; iii: aqueous NaOH, MeOH, 75 degrees; followed by aqueous HCl; iv: DBU, Mel, DMF; v: lithium hexamethyl-dililazide, THF, chlorotrimethylsilane, -78 degrees; then R¹-X; vi: resolution (e.g., lipase); the methyl ester was then isolated: DBU, Mel, DMF; vii: liohx1H₂O，MeOH，H₂O；viii：TFA，CH₂Cl₂；ix：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A58: see C. -H.Lee, H.Kohn, J.org.chem.1990, 55, 6098-¹＝R⁸＝H)。

A59: can be prepared according to scheme 21.

Scheme 21

i: NaOMe, MeOH; ii: NaH, THF; iii: aqueous NaOH, MeOH, 75; followed by aqueous HCl; iv: DBU, Mel, DMF; v: lithium hexamethyl-dililazide, THF, chlorotrimethylsilane, -78 degrees; then R¹-X; vi: resolution (e.g., lipase); the methyl ester was then isolated: DBU, Mel, DMF; vii: liohx1H₂O，MeOH，H₂O；viii：TFA，CH₂Cl₂；ix：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A60: such compounds may be prepared according to scheme 22.

Scheme 22

i: NaH, DMSO; ii: aqueous NaOH, MeOH, 75; followed by aqueous HCl; iii: DBU, Mel, DMF; iv: NaOMe (2.2equiv.), R¹-X；v：Raney-Ni，H₂，EtOH；vi：CbzCl，Et₃N，CH₂Cl₂；vii：NaH，Br(CH₂)₂Br, THF; viii: resolution (e.g., lipase); followed by DBU, Mel, DMF; ix: Pd/C, H₂，EtOH；x：NaH，R¹⁴-X，THF；xi：LiOHx1H₂O，MeOH，H₂O；xii：TFA，CH₂Cl₂；xiii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A61: see d.r.armour, k.m.morriss, m.s.congreve, a.b.

Hawcock，Bioorg.Med.Chem.Lett.1997，7，2037-2042(R¹＝R¹²＝H)。

A62: such compounds may be prepared according to scheme 23.

Scheme 23

i: resolution (e.g., lipase); followed by DBU, Mel, DMF; ii: lithium hexamethyl-dililazide, THF, chlorotrimethylsilane, -78 degrees; then R⁶-X；iii：LiOHx1H₂O，MeOH，H₂O；iv：TFA，CH₂Cl₂；v：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A63: see s.e. gibson, n.guillo, r.j.middleton, a.thuilliez, m.j.tozer, j.chem.soc.perkin trans.1, 1997, 4, 447-456; S.E.Gibson, N.Guillo, S.B.Kalindjan, M.J.Tozer, bioorg.Med.chem.Lett, 1997, 7, 1289-one 1292 (R.E.Gibson, N.Guillo., S.B.Kalindjan, M.J.Tozer, Med.chem.Lett, 1997, 7, 1289-one)¹＝H；R⁸＝H)；Beilstein registration number: 459155 (R)¹＝H；R⁸＝4，5-MeO₂)。

A64: such compounds may be prepared according to scheme 24.

Scheme 24

i：NaH，DMSO；ii：Pd/C，H₂EtOH; iii: iBuOCOCl, diisopropylethylamine, CH₂Cl₂(ii) a Followed by diazomethane; iv: HBr, CH₂Cl₂(ii) a v: NaH, THF; vi: aqueous NaOH, MeOH, 75 degrees; followed by aqueous HCl; vii: DBU, Mel, DMF; viii: lithium diisopropylamide, THF, chlorotrimethylsilane, -78 degrees; then R¹-X; ix: resolution (e.g., lipase); the methyl ester was then isolated: DBU, Mel, DMF; x: liohx1H₂O，MeOH，H₂O；xi：TFA，CH₂Cl₂；xii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A65 and a 67: these classes of compounds can be prepared according to schemes 25 and 26.

Scheme 25

i：NaH，DMSO，BrCH(R¹)COOMe；ii：LiOHx1H₂O，MeOH，H₂O; iii: polyphosphoric acid; iv: NaH, ClCOOMe, THF; v: resolution (e.g., lipase); subsequent isolation into the methyl ester: DBU, Mel, DMF; vi: liohx1H₂O，MeOH，H₂O；vii：TFA，CH₂Cl₂；viii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

Scheme 26

i：NaH，THF，CH₂I₂；ii：NaH，DMSO；iii：Bu₄NFx10H₂O, THF; iv: methanesulfonyl chloride, Et₃N，CH₂Cl₂(ii) a Followed by NaH, THF; v: aqueous NaOH, MeOH, 75 degrees; followed by aqueous HCl; vi: DBU, Mel, DMF; vii: lithium hexamethonium-dililazide, THF, chlorotrimethylsilane, -78 degrees; then R¹-X；viii：Pd/C，H₂，EtOH；ix：NaH，THF，R¹⁴-X; x: resolution (e.g., lipase); the methyl ester was then isolated: DBU, Mel, DMF; xi: liohx1H₂O，MeOH，H₂O；xii：TFA，CH₂Cl₂；xiii：FmocOSu，Na₂CO₃Aqueous solution, dioxane

A66: see G.L.Grunewald, L.H.Dahanukar, J.Heterococcus.chem.1994, 31, 1609-¹＝H；R⁸＝H，8-NO₂；C(1)＝0)。

A68: see Griesbeck, H.Mauder, I.Muller, chem.Ber.1992, 11, 2467-2476; (R)¹＝R⁸＝H；C(1)＝0)。

A69：R. Kreher，W. Gerhardt，Liebigs Ann. Chem. 1981，240-247(R¹＝R⁸＝H)。

As mentioned above, the structural unit A70 belongs to the open-chain α -substituted α -amino acids, A71 and A72 to the corresponding β -amino acid analogs and A73-A104 to the cyclic analogs of A70.

Building blocks of the species A70 and A73-A104 have been synthesized by several different general methods: by [2+2] cycloaddition of enones to imines (I. Ojima, H.J.C.Chen, X.Quin, tetrahedron letters, 1988, 44, 5307-; synthesis of chiral aldol condensation reaction (Y.Ito, M.Sawamura, E.Shirakawa, K.Hayashikazi, T.Hayashi, tetrahedron letters, 1988, 29, 235-FIG. 238; synthesis of chiral aldol condensation reaction by the oxazolidinone method (J.S.Amato, L.M.Weinstock, S.Karady, US 4508921A; M.Gander-Coqoz, D.Seebach, Helv.Chim.acta 1988, 71, 224-FIG. 236; A.K.Beck, D.Seebach, Chimia1988, 42, 142-Vit 144; D.Seebach, J.D.Aebi, M.Gander-Coqoz, R.Naebach, Helv.acta 7, 70, Sch4. Seebach, D.Seebach, A.1248, Gerder-Coqoz, R.Nav.C.68, Helv.acta.7, Schizok + N.K.K.K.K.K.K.K.K.D.C.D.J.C. K.S.S.S.S.S. K. 1988, C. K., chem.Soc.Perkin Trans.1, 1988, 305-; M.Kolb, J.Barth, Liebigs Ann.Chem.1983, 1668-1688); by di-lactonamide ether synthesis (U.S. Sch. kllkkopf, R.Hinrichs, R.Lonsky, Angew. chem.1987, 99, 137-; resolution of racemic amino acids by the microbial resolution (K.Sakashita, I.Watanabe, JP 62/253397A 2) and by the hydantoin method with chiral auxiliaries derived from L-phenylalanine amide (D.Obrecht, C.Spiegler, P.Sch. nholzer, K.M muller, H.Heimgartner, F.Stierli, Helv.Chim.acta 1992, 75, 1666. 1696; D.Obrecht, U.Bohdal, J.Daly, C.Lehmann, P.Schholnzer, K.M muller, tetrahedron, 1995, 51, 10883-, D.Obrecht, C.Lehmann, C.ruffiex, P.Schholnzer, K.M. Acuit, Buffer, C.7. C.Leffmann, C.S. Henhaget, C.S.7, Spieche-, C.S.7, Offechhol, C.S.7, C.E.7. Kelvier, C.S.S.S.S.C.E.S.D.7, C.7, C.E.7, C.E.S. Kelvier, C.S. Kelvier, C.S.S.S.S. K. K. The latter process is particularly useful for preparing enantiomers in pure form of the building blocks of the classes A70 (see scheme 27) and A73-A104 (see scheme 28).

Scheme 27

i：KCN，(NH₄)₂CO₃，EtOH/H₂O；ii：Ba(OH)₂，H₂O; iii: aqueous NaOH, PhCOCl, dioxane; then DCC, CH₂Cl₂；iv：NaH，DMF，R¹⁸-X or R¹⁹-X; v: l-phenylalanine cyclohexylamide, N-methylpyrrolidone, 70 degrees; vi: CH3SO3H, MeOH, 80 degrees; vii: 6N HCl aqueous solution, dioxane, 100 ℃; viii: me₃SiCl，DIEA，CH₂Cl₂(ii) a Followed by FmocCl

The method depicted in scheme 27 comprises reacting the appropriate ketone 126 with KCN, (NH)₄)₂CO₃Treatment in an ethanol/water mixture (E.Ware, J.chem.Res.1950, 46, 403; L.H.Goodson, I.L.Honigberg, J.J.Lehmann, W.H.Burton, J.Org.chem.1960, 25, 1920; S.N.Rastogi, J.S.Bindra, N.Anand, Ind.J.chem.1971, 1175) gives the corresponding hydantoin 127 which is then treated with Ba (OH)₂Hydrolysis in water at 120-. Schotten-Baumann acylation (Houben-Weyl, 'Methoden der Organischen Chemie', volume XI/2, Stickstoff-Verbindungen II und III ', GeorgTieme Verlag, Stuttgart, pp 339), followed by cyclization with N, N' -dicyclohexylcarbodiimide to give azlactone 129(D.Obrecht, U.Bohdal, C.Broger, D.Burc.Lehmann, R.Ruffiex, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 5631; D.Obrechnu. C.Spiegler, P.Sch _ nzelner, K.M, H.Hegainer, F.Stierli, Acv.1666, Chi 96). Alternatively, azlactone 129 can be prepared starting from amino acids 130 and 131, Schotten-Baumann acylAlkylation and cyclization with N, N' -dicyclohexylcarbodiimide to azlactone 132 and 133 and alkylation to 129(D.Obrecht, U.Bohdal, C.Broger, D.Burr, C.Lehmann, R.Ruffeux, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-580; D.Obrecht, C.Spiegler, P.Sch _ nholzer, K.M muller, H.Heimgartner, F.Stierli, Helv.Chim.acta 1992, 75, 1666-1696) (see scheme 1). 129 was treated with L-phenylalanine cyclohexylamide (D.Obrecht, U.Bohdal, C.Broger, D.Burr, C.Lehmann, R.Ruffieux, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-. 134 and 135 were treated with methanesulfonic acid in methanol at 80 deg. to give esters 136a and 136b, which were then converted to the corresponding Fmoc-protected final building blocks 137a and 137 b.

Scheme 28

i：KCN，(NH₄)₂CO₃，EtOH/H₂O；ii：Ba(OH)₂，H₂O; iii: aqueous NaOH, PhCOCl, dioxane; then DCC, CH₂Cl₂(ii) a iv: l-phenylalanine cyclohexylamide, N-methylpyrrolidone, 70 degrees; v: CH (CH)₃SO₃H, MeOH, 80 degrees; vi: 6N HCl aqueous solution, dioxane, 100 ℃; vii: me₃SiCl，DIEA，CH₂Cl₂；FmocCl

According to the general method described in scheme 28 (D.Obrecht, U.Bohdal, C.Broger, D.Burr, C.Lehmann, R.Ruffeioux, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-580; D.Obrecht, C.Spiegler, P.Sch _ nholzer, K.M uller, H.Heimgartner, F.Stierli, Helv.Chim.acta 1992, 75, 1666-1696), A73-A104 can be prepared starting from the corresponding ketone 138, hydantoin formation (139) (E.Ware, J.Chem.Res.1950, 46, 403; L.H.Goodson, I.L.Honig.berg, j.j.lehmann, w.h.burton, j.org.chem.1960, 25, 1920; s.n.rastogi, j.s.bindra, n.anand, ind.j.chem.1971, 1175; D.Obrecht, U.Bohdal, C.Broger, D.Burr, C.Lehmann, R.Ruffieux, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-₂) Racemic amino acid 140 is obtained, which is then cyclized with N, N' -dicyclohexylcarbodiimide by Schotten-Baumann-acylation to give azlactone 141. Reaction with L-phenylalanine cyclohexylamide (D.Obrecht, U.Bohdal, C.Broger, D.Burr, C.Lehmann, R.Ruffieux, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-. Treatment of 142 and 143 with methanesulfonic acid in methanol at 80 ° gives esters 144a and 144b, which are then converted into the corresponding appropriately protected amino acid precursors 145a and 145b, which can be used for peptide synthesis.

A71: such amino acid building blocks (see formula 147) can be conveniently prepared from the corresponding disubstituted succinate 146 by the Curtius-rearrangement shown in scheme 29.

Scheme 29

i: diphenylphosphoryl azide, toluene, 80 degrees; subsequent benzyl alcohol

A71: see D.Seebach, S.Abele.T.Sifferlen, M.Haenggi, S.Gruner, P.Seiler, Helv.Chim.acta 1998, 81, 2218-¹⁸And R¹⁹Forming: - (CH)₂)₂-；-(CH₂)₃-；-(CH₂)₄-；-(CH₂)₅-；R²⁰＝H)；L.Ducrie，S.Reinelt，P.Seiler，F.Diederich，D.R.Bolin，R.M.Campbell，G.L.Olson，Helv.Chim.Acta 1999，82，2432-2447；C.N.C.Drey，R.J.Ridge，J.Chem.Soc.Perkin Trans.1，1981，2468-2471；U.P.Dhokte，V.V.Khau，D.R.Hutchinson, M.J. Martinelli, tetrahedron letters, 1998, 39, 8771-8774 (R)¹⁸＝R¹⁹＝Me；R²⁰＝H)；D.L.Varie，D.A.Hay，S.L.Andis，T.H.Corbett，Bioorg.Med.Chem.Lett.1999，9，369-374(R¹⁸＝R¹⁹＝Et)；Testa，J.Org.Chem.1959，24，1928-1936(R¹⁸＝Et；R¹⁹＝Ph)；M.Haddad，C.Wakselman，J.FluorineChem.1995，73，57-60(R¹⁸＝Me；R¹⁹＝CF₃；R²⁰＝H)；T.Shono，K.Tsubata，N.Okinaga，J.Org.Chem.1984，49，1056-1059(R¹⁸＝R¹⁹＝R²⁰＝Me)；K.Ikeda，Y.Terao，M.Sekiya，Chem.Pharm.Bull.1981，29，1747-1749(R¹⁸And R¹⁹Forming: - (CH)₂)₅-；R²⁰＝Me)。

Amino acid building block species a72 can be conveniently prepared according to scheme 30 by Arndt-eisert C1-homologation of compounds of species a 70.

Scheme 30

i: iBuOCOCl, diisopropylethylamine, CH₂Cl₂(ii) a Subsequently diazomethane, hv or Cu (I)

A72: see Y.V.zeifman, J.Gen.chem.USSR (Engl. Trans.)1967, 37, 2355-¹⁸＝R¹⁹＝CF₃)；W.R.Schoen，J.M.Pisano，K.Pendergast，M.J.Wyvratt，M.H.Fisher，J.Med.Chem.1994，37，897-906；S.Thaisrivongs，D.T.Pals，D.W.DuCharme，S.Turner，G.L.DeGraaf，J.Med. Chem.1991，34，655-642；T.K.Hansen，H.Thoegersen，B.S.Hansen，Bioorg. Med.Chem.Lett.1997，7，2951-2954；R.J.DeVita，R.Bochis，A.J.Frontier，A.Kotliar，M.H.Fisher，J.Med.Chem.1998，41，1716-1728；D.Seebach，P.E.Ciceri，M.Overhand，B.Jaun，D.Rigo，Helv.Chim.Acta 1996，79，2043-2066；R.P.Nargund，K.H.Barakat，K.Cheng，W.Chan，B.R.Butler，A.A.Patchett，Bioorg.Med.Chem.Lett.1996，6，1265-1270(R¹⁸＝R¹⁹＝Me)；E.Altmann，K.Nebel，M.Mutter，Helv.Chim.Acta 1991，74，800-806(R¹⁸＝Me；R¹⁹＝COOMe)。

A73: such compounds may be prepared according to the following: mapeli, G.Tarocy, F.Schwitzer, C.H.Stammer, J.org.chem.1989, 54, 145-149 (R.²¹＝4-OHC₆H₄)；F.Elrod，E.M.Holt，C.Mapelli，C.H.Stammer，J.Chem.Soc.Chem.Commun.1988，252-253(R²¹＝CH₂COOMe)；R.E.Mitchell，M.C.Pirrung，G.M.McGeehan，Phytochemistry1987，26，2695(R²¹＝CH₂OH)，J.Bland，A.Batolussi，C.H.Stammer，J.Org.Chem.1988，53，992-995(R²¹＝CH₂NH₂). Other derivatives of A73 have been described in T.Wakamiya, Y.Oda, H.Fujita, T.Shiba, tetrahedron letters, 1986, 27, 2143-; U.S. Sch _ llkopf, B.Hupfeld, R.Gull, Angew.chem.1986, 98, 755-; baldwin, r.m.adlington, b.j.rawlings, tetrahedral communication, 1985, 26, 481-; D.Kalvin, K.Ramalinggram, R.Woodard, Synth.Comm.1985, 15, 267-272 and L.M.Izquierdo, I.Arenal, M.Bernabe, E.Alvarez, tetrahedron letters, 1985, 41, 215-220.

A74: such compounds can be prepared according to the general procedure described in scheme 28 starting from the corresponding cyclobutanone.

A75 and a 76: such compounds can be prepared using the following methods: hughes, J.Clardy, J.org.chem.1988, 53, 4793-; e.a. bell, m.y.qureshi, r.j.pryce, d.h.janzen, p.lemke, j.clardy, j.am.chem.soc.1980, 102, 1409; y. gaioni, tetrahedral communication, 1988, 29, 1591-; allan, J.R.Haurahan, T.W.Hambley, G.A.R.Johnston, K.N.Mewett, A.D.Mitrovic, J.Med.chem.1990, 33, 2905-²³COOH); G.W.Fleet, J.A.Seijas, M.Vasquez Tato, tetrahedron, 1988, 44, 2077-²³＝CH₂OH)。

A77: such compounds may be prepared according to J.H.Burckhalter, G.Schmied, J.Pharm.Sci.1966, 55, 443-²³Aryl).

A78: such compounds may be prepared according to J.C. Watkins, P.Kroosgard-Larsen, T.Honner é, TIPS 1990, 11, 25-33; trigalo, d.brisson, r.azerad, tetrahedron letters, 1988, 29, 6109 (R)²⁴COOH).

A79: such compounds can be prepared according to the general procedure described in scheme 28 starting from the corresponding pyrrolidin-3-one.

A80-A82: such compounds can be prepared according to d.m. walker, e.w. logusch, tetrahedral communication, 1989, 30, 1181-1184; morimoto, K.Achiwa, chem.pharm.Bull.1989, 35, 3845-3849; J.Yoshimura, S.Kondo, M.Ihara, H.Hashimoto, Carbohydrate research (Carbohydrate Res.), 1982, 99, 129-142.

A83: such compounds can be prepared according to the general procedure described in scheme 28 starting from the corresponding pyrazolin-4-one.

A84: such compounds may be prepared according to R.M. Pinder, B.H.Butcher, D.H.Buxton, D.J.Howells, J.Med.chem.1971, 14, 892-893; D.Obrecht, U.Bohdal, C.Broger, D.Burr, C.Lehmann, R.Ruffieux, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-.

A85: such compounds can be prepared according to the general procedure described in scheme 28 starting from the corresponding indan-1, 3-dione.

A86: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding indan-2-one.

A87: such compounds and analogs thereof may be prepared according to c.cativiela, m.d.diaz deVillegas, a.avenoza, j.m.peregrina, tetrahedron, 1993, 47, 10987-; cativiela, p.lopez, j.a.mayoral, tetrahedron, Assymmetry 1990, 1, 379; cativiela, j.a.mayoral, a.avenoza, m.gonzalez, m.a.rey, synthesis, 1990, 1114.

A87 and a 88: such compounds may be prepared according to l.munda, j.chem.soc.1961, 4372; J.Ansell, D.Morgan, H.C.price, tetrahedron letters, 1978, 47, 4615-one 4616.

A89: such compounds can be prepared according to the general procedure described in scheme 28 starting from the corresponding piperidin-3-one.

A90: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding tetrahydrothiopyran-3-one.

A91: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding tetrahydropyran-3-one.

A92: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding piperidine-2, 5-dione.

A93: such compounds can be prepared according to the general procedure described in scheme 28 starting from the corresponding cyclohexanone.

A94: such compounds may be prepared according to j.org.chem.1990, 55, 4208.

A95: such compounds can be prepared according to N.J.Lewis, R.L.Inlos, J.Hes, R.H.Matthews, G.Milo, J.Med.chem.1978, 21, 1070-.

A96: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding tetrahydropyran-4-one.

A97: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding piperidine-2, 4-dione.

A98: such compounds can be prepared according to the general procedure described in scheme 28 starting from the corresponding 1-tetralone (D.Obrecht, C.Spiegler, P.Sch. nholzer, K.M muller, H.Heimgartner, F.Stierli, Helv.Chim. acta 1992, 75, 1666-.

A99: such compounds can be prepared according to the general procedure described in scheme 28 starting from the corresponding 1, 2, 3, 4-tetrahydronaphthalene-1, 4-dione mono-diethyl acetal.

A100: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding tetrahydroquinolin-4-one.

A101: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding tetrahydroquinoline-2, 4-dione.

A102: such compounds may be prepared according to the following: ishizumi, N.Ohashi, N.Tanno, J.org.chem.1987, 52, 4477-; D.Obrecht, U.Bohdal, C.Broger, D.Burr, C.Lehmann, R.Ruffieux, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-; obrecht, C.Spiegler, P.Sch _ nholzer, K.M muller, H.Heimgartner, F.Stierli, Helv.Chim.acta 1992, 75, 1666-; D.R.Haines, R.W.Fuller, S.Ahmad, D.T.Vistica, V.E.Marquez, J.Med.chem.1987, 30, 542-; t.decks, p.a.crooks, r.d.waigh, j.pharm.sci 1984, 73, 457-; blair, L.N.Mander, Austr.J.chem.1979, 32, 1055-.

The general description of the structural units of species (b) to (p) is: S.Hanessian, G.McNaughton-Smith, H.G.Lombart, W.D.Lubell, tetrahedron, 1997, 38, 12789-; obrecht, M.Altorfer, J.A.Robinson, "novel peptide mimetic building blocks and strategies for efficient guided search", adv.Med.chem.1999, Vol.4, 1-68

Templates of species (b1) may be prepared according to schemes 31 and 32.

Scheme 31

i: 150 is treated with a dehydrating reagent such as thionyl chloride in methanol at elevated temperature, suitably under reflux.

ii: for example, Boc is introduced using di-tert-butyl dicarbonate (di-tert. -butyl dicarbanate) and triethylamine in a suitable solvent such as dichloromethane; any other suitable N-protecting group (not shown in reaction scheme 31) can be introduced in a similar manner.

iii: the product formed was reacted with phthalimide, diethyl diazodicarboxylate and triphenylphosphine (triphenylphoshine) under standard Mitsunobu conditions (Mit Sunobu, O.; Wada, M.; Sano, T.J.J.J.Am.chem.Soc.1972, 94, 672) to give 151, suitably.

iv: 151 was treated with trifluoroacetic acid in dichloromethane.

v: 152 was coupled with Cbz-Asp (tBu) OH in DMF using reagents such as HBTU and 1-hydroxybenzotriazole (HOBt) and a base such as diisopropylethylamine under standard peptide coupling conditions to afford 153.

vi: suitably by using H₂And a catalyst such as palladium on charcoal, in a solvent such as ethanol, DMF and ethyl acetate to remove the Cbz-group.

vii: the phthalimide group is suitably prepared by treatment with hydrazine in a suitable solvent such as ethanol at elevated temperature, suitably at about 80 ℃ and subjecting the product formed to treatment with trifluoroacetic acid in CH₂Cl₂To be broken down from the resulting product.

viii: the amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 154, see Bisang, c.; weber, c.; robinson, J.A.Helv.Chim.acta 1996, 79, 1825-.

Scheme 32

i: 150 is treated with a dehydrating reagent such as thionyl chloride in a suitable solvent such as methanol at elevated temperature, suitably under reflux.

ii: the resulting amino acid ester is N-protected for introduction of the Cbz-group under standard conditions, for example using benzyloxycarbonyl chloride and triethylamine in a suitable solvent such as dichloromethane.

iii: the Cbz-protected amino acid methyl ester is treated with trimethylsilyl chloride and a base such as triethylamine in a solvent such as tetrahydrofuran, cooled, suitably to about-78 ℃, and then reacted with a strong base such as lithium diisopropylamide or lithium hexamethyldisilylazide (lithohexamethyldisilylazide) and tert-butyl bromoacetate to give 155 as a mixture of diastereomers, see bishang, c.; jiang, l.; freund, e.; emery, f.; bauch, C.; matile, H,; pluschke, g.; robinson, J.A.J.am.chem.Soc.1998, 120, 7439-7449; emery, f.; bisang, c.; favre, m.; jiang, l.; robinson, J.A.J.chem.Soc.chem.Commun.1996, 2155-2156.

iv: 155 with phthalimide, diethyl diazodicarboxylate and triphenylphosphine under standard Mitsunobu conditions (Mitsunobu, O.; Wada, M.; Sano, T.J.J.J.am.chem.Soc.1972, 94, 672).

v: the resulting product used H₂And a suitable catalyst such as palladium on charcoal, in a solvent such as ethyl acetate, DMF or ethanol; the diastereomer was subsequently separated and 156 was obtained.

vi: 156 are coupled with Fmoc-Asp (allyl) OH under standard peptide coupling conditions using reagents such as HATU, HOAt and bases such as diisopropylethylamine in a suitable solvent such as DMF.

vii: cyclization with DBU in DMF suitably gives 157.

viii: the phthalimide group is suitably cleaved from the resulting product by hydrazinolysis, e.g. treatment with methylhydrazine in a suitable solvent such as DMF.

ix: the product formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or mixture of solvents such as dioxane and water or dichloromethane using a base such as sodium carbonate or triethylamine to give 158.

x: standard removal of allyl ester groups using, for example, palladium (O) as a catalyst gives 159.

(b2) Type templates can be prepared according to scheme 33.

Scheme 33

i: 160 (available from vitamin C as described in Hubschwerlen, C. (Synthesis, 1986, 962) was treated with phthalimide, diethyl diazodicarboxylate and triphenylphosphine under standard Mitsunobu conditions (Mitsunobu, O.; Wada, M.; Sano, T.J.J.J.Am.chem.Soc.1972, 94, 672).

ii: the phthalimide group is suitably cleaved from the product by hydrazinolysis, for example by treatment with methylhydrazine in a suitable solvent such as DMF.

iii: the amino group is protected by treatment with a benzoylating reagent such as benzoic anhydride or benzoyl chloride and a base such as triethylamine or 4-dimethylaminopyridine in a suitable solvent such as dichloromethane or DMF.

iv: for example with K₂S₂O₈And Na₂HPO₄The 2, 4-dimethoxybenzyl group is removed in aqueous acetonitrile at elevated temperature, such as at about 80 ℃.

v: the tert-butoxycarbonyl group is introduced in a suitable solvent such as dichloromethane using, for example, di-tert-butyloxycarbonyl dicarbonate (di-tert. -butyloxycarbonyl dicarbonate), triethylamine and a catalytic amount of 4-dimethylaminopyridine.

vi: with aqueous sodium carbonate in tetrahydrofuran, followed by acidification.

vii: the carboxylic acid group is conveniently esterified with diazomethane in a suitable solvent such as diethyl ether to give 161.

Viii: suitably by using H₂Hydrogenation in the presence of a catalyst such as palladium on charcoal in a solvent such as DMF to remove the Cbz-group gives 161, see Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.

ix: 161 was coupled with Cbz-asp (tbu) OH under standard peptide coupling conditions in DMF using reagents such as HBTU and 1-hydroxybenzotriazole using bases such as diisopropylethylamine to give 162, see Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.

x: by using, for example, H₂And a catalyst such as palladium on charcoal, hydrogenated under standard conditions to remove the Cbz-group, yielding 163, see Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.

xi: tert-butyl ester and tert-butyloxycarbonyl groups are cleaved using trifluoroacetic acid in dichloromethane or 4N hydrochloric acid in dioxane, as appropriate.

xii: the intermediate free amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 164, see Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.

(c1) Type templates can be prepared according to schemes 34-37.

Scheme 34

i: 166 was synthesized from 165 according to p.waldmeier, "solid-supported synthesis of highly substituted xanthene-derived templates for the synthesis of β -turn stabilized cyclic peptide libraries" (bosch paper, university of zurich, 1996). To cleave the phthalimide group, 166 is suitably subjected to hydrazinolysis, such as with hydrazine hydrate in a suitable solvent such as ethanol at elevated temperature, such as at about 80 ℃.

ii: the intermediate aminonitrile is suitably saponified under basic conditions, for example using aqueous sodium hydroxide in a suitable solvent such as ethanol at elevated temperature, suitably under reflux, to give 167.

iii: the intermediate free amino acids formed are suitably protected with reagents such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in an appropriate solvent or mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine 168, see p.waldmeier, "solid supported synthesis of highly substituted xanthene derived templates for the synthesis of β -turn stabilized cyclic peptide libraries" (bosch paper, university of zurich, 1996).

iv: the regioselective bromination of 167 is preferably carried out using bromine in acetic acid and dichloromethane. In a similar manner, R³⁷＝NO₂Can be prepared by using HNO₃Treated in acetic acid to introduce and R³⁷＝CH₂NPht by treatment with hydroxymethylphthalimide in H₂SO₄Is introduced by middle treatment.

v: the amino group is suitably Cbz-protected with a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide.

vi: the carboxylic acid groups are preferably esterified using DBU and methyl iodide in DMF to afford 169.

vii: suitably by palladium (O) -catalysed Stille- (Stille, j.k.angelw.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, t.; mijaura, n.; suzuki, A.J.org.chem.1993, 58, 2201) to introduce lower alkyl, substituted lower alkyl and aryl substituents (R³⁷). Any other functionalization known for aryl bromides can be used to introduce the substituent R³⁷。

viii: for example by using H₂And a catalyst such as palladium on charcoal, in a suitable solvent such as ethanol, DMF and ethyl acetate to remove the Cbz-group.

ix: the ester group is suitably hydrolysed under acidic conditions, e.g. using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, preferably at about 100 ℃.

x: the intermediate free amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 170.

Scheme 35

i: the bis-ortho-bromination of 171 is preferably carried out in acetic acid and dichloromethane using an excess of bromine. In a similar manner, R³⁷＝R³⁸＝NO₂Can be prepared by using HNO₃Introduced by treatment in acetic acid, R³⁷＝R³⁸＝CH₂-NPht can be obtained by reacting hydroxymethylphthalimide with H₂SO₄Is introduced by middle treatment.

ii: the amino group is protected, suitably Cbz-protected, using a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide.

iii: the carboxylic acid group is preferably esterified using DBU and methyl iodide in DMF to give 172.

iv: lower alkyl, substituted lower alkyl and aryl substituents (R.sub.alkyl, and aryl substituents) are introduced, for example, by palladium (O) -catalyzed Stille- (Stille, J.K.Angew.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, T.; Mijaura, N.; Suzuki, A.J.org.chem.1993, 58, 2201)³⁷＝R³⁸). Any other functionalization known for aryl bromides can be used to introduce the substituent R³⁷And R³⁸。

v: for example by using H₂And a catalyst such as palladium on charcoal, in a suitable solvent such as ethanol, DMF or ethyl acetate to remove 173 Cbz-groups.

vi: the ester group is suitably hydrolysed under acidic conditions, for example using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, suitably at about 100 ℃.

vii: the intermediate free amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 174.

Scheme 36

i: the methoxy group of 166 is preferably cleaved by treatment with an excess of boron tribromide in a suitable solvent such as dichloromethane.

ii: the cyano group is hydrolysed under acidic conditions, preferably using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, suitably at about 100 ℃.

iii: the resulting acid is treated with a dehydrating agent such as thionyl chloride in a suitable solvent such as dioxane to afford 175.

iv: 175 with a suitable triflating reagent, preferably trifluoromethanesulfonic anhydride, in the presence of a base such as 2, 6-di-tert-butyl-pyridine in a suitable solvent such as dichloromethane.

v: the intermediate is suitably heated in a suitable solvent such as methanol.

vi: introduction of lower alkyl or aryl-lower alkyl (R) by alkylation³⁵) 177 is obtained. Any other functionalization known for phenolic groups can be used for introducing the substituent R³⁵。

vii: lower alkyl or aryl groups (R.sub.H.sub.R.sub.H.sub.R.sub.H.sub.R.sub.H.sub.T.; Mijaura N.sub.J.org.chem.1993, 58, 2201) are suitably introduced by palladium (O) -catalysed Suzuki-coupling (Oh-e.T.; Mijaura, N.sub.A.J.Org.chem.1993, 58, 220³⁶) To obtain 178. Any other functionalization known for aryl bromides can be used to introduce the substituent R³⁶。

viii: the ester group is hydrolysed under acidic conditions, suitably with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane, at elevated temperature, for example at about 100 ℃.

ix: the phthalimido group is suitably cleaved by hydrazinolysis, e.g. using hydrazine hydrate in a suitable solvent such as ethanol.

x: the intermediate free amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 179.

Scheme 37

i: 175 are brominated using a reagent such as bromine in a mixture of acetic acid and dichloromethane at a temperature of from about 0 deg.c to about room temperature.

ii: the hydroxyl group is benzoylated to give 180 using a suitable acylating agent such as benzoyl chloride or benzoic anhydride, a base such as pyridine or triethylamine and a suitable solvent such as dichloromethane.

iii: 180 with methanol and a catalytic amount of an acidic catalyst such as camphorsulfonic acid under heating.

iv: introduction of lower alkyl or aryl-lower alkyl (R) by alkylation with a base such as sodium hydride or potassium tert-butoxide in a solvent such as tetrahydrofuran, dimethoxyethane or DMF³⁵) To obtain 181.

v: lower alkyl, substituted lower alkyl and aryl substituents (R)³⁸) Such as by palladium (O) -catalyzed Stille- (Stille, j.k.angelw.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, t.; mijaura, n.; suzuki, a.j.org.chem.1993, 58, 2201). Any other functionalization known for aryl bromides can be used to introduce the substituent R³⁸。

vi: to cleave the benzyloxy group, the intermediate is suitably heated with sodium cyanide and methanol adsorbed on alumina.

vii: treatment with an appropriate triflating reagent, preferably trifluoromethanesulfonic anhydride, in the presence of a base such as 2, 6-di-tert-butyl-pyridine in an appropriate solvent such as dichloromethane.

viii: lower alkyl and aryl substituents (R.J.Org.Chem.1993, 58, 2201) are introduced, for example, by palladium (O) -catalysed Stille- (Stille, J.K.Angew.Chem.1986, 68, 504) and Suzuki-coupling (Oh-e, T.; Mijaura, N.; Suzuki, A.J.Org.Chem.1993, 58, 2201)³⁶) Yielding 182. Any other functionalization known for aryl bromides can be used to introduce the substituent R³⁶。

ix: bromination is carried out under standard conditions such as with bromine in acetic acid and dichloromethane at temperatures of about 0 ℃ to about room temperature.

x: lower alkyl, substituted lower alkyl and aryl substituents (R)³⁷) For example by palladium (0) -catalyzed Stille- (Stille, j.k.angelw.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, t.; mijaura, n.; the process is carried out by Suzuki,chem.1993, 58, 2201) to obtain 184. Any other functionalization known for aryl bromides can be used to introduce the substituent R³⁷。

xi: the ester group is hydrolysed under acidic conditions, suitably using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, for example at about 100 ℃.

xii: the phthalimido group is cleaved, for example, by hydrazinolysis, suitably using hydrazine hydrate in a suitable solvent such as ethanol.

xiii: the intermediate free amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to afford 185.

(c2) Type templates can be prepared as shown in schemes 38 and 39.

Scheme 38

i: according to Muller, K.; obrecht, d.; kniersinger, a.; spiegler, c.; bannwarth, w.; trzeciak, a.; englert, g.; labhardt, a.; schnholzer, p. medicinal chemical prospection, Editor Testa, b.; kyburz, e.; fuhrer, w.; giger, r., Weinheim, New York, Basel, Cambridge: verlag Helvetica Chimica Acta, 1993, 513-; bannwarth, w.; gerber, f.; grieder, a.; kniersinger, a.; muller, K.; obrecht.d.; trzeciak, a.can.pat.appl.ca2101599 (page 131) 3, 7-dimethoxyphenothiazine 186 was prepared and converted to 187. The benzyl radical is suitably prepared, for example, by reacting with H₂And a catalyst such as palladium on charcoal, hydrogenated in a suitable solvent such as ethanol, DMF or ethyl acetate to break at 187.

ii: by makingWith a suitable alkylating agent (R)⁴³-X'; x' ═ OTf, Br, I) and a strong base such as sodium amide in liquid ammonia or sodium hydride in tetrahydrofuran, dioxane or DMF in the presence of a phase transfer catalyst such as TDA-I to introduce lower alkyl groups (R)⁴³). In a similar manner, substituted lower alkyl (R) groups may be introduced⁴³) (ii) a Thus, for example, R⁴³＝CH₂COOR⁵⁵And CH₂CH₂COOR⁵⁵Can be introduced by treatment with the appropriate 2-haloacetic acid and 3-halopropionic acid derivatives, respectively. Any other functionalization known for diarylamines can be used to introduce the substituent R⁴³。

iii: the methoxy group of 188 is suitably cleaved by treatment with an excess of boron tribromide in a suitable solvent, such as dichloromethane, at a temperature of from about-20 ℃ to about room temperature.

iv: for introducing lower alkyl, substituted lower alkyl or aryl-lower alkyl substituents (R)³⁹And R⁴⁰) The intermediate diphenol derivative is suitably reacted with a compound of formula R³⁹-and R⁴⁰The reagent of-X '(X' ═ OTf, Br, I) is reacted in the presence of a strong base such as sodium hydride in tetrahydrofuran, dioxane or DMF in the presence of a phase transfer catalyst such as TDA-I. Any other functionalization known for phenolic groups can be used for introducing the substituent R³⁹And R⁴⁰。

v: the cyano groups of 188 and 189, respectively, are suitably hydrolyzed under acidic conditions, such as with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane, at elevated temperature, such as at about 100 ℃.

vi: the phthalimide group of the intermediate is suitably cleaved by hydrazinolysis, e.g. using hydrazine hydrate in a suitable solvent such as ethanol.

vii: the free amino group is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 190 and 191 respectively.

Scheme 39

i: the cyano group of 188 is suitably hydrolysed under acidic conditions, e.g. using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, e.g. at about 100 ℃.

ii: the phthalimide group of the intermediate is suitably cleaved by hydrazinolysis, e.g. using hydrazine hydrate in a suitable solvent such as ethanol, to give 192.

iii: 192 is preferably carried out in acetic acid and dichloromethane using an excess of bromine. In a similar manner, R⁴¹＝R⁴²＝NO₂Can be prepared by using HNO₃Treated in acetic acid to introduce and R⁴¹＝R⁴²＝CH₂By reacting with hydroxymethylphthalimide at H₂SO₄Is introduced by middle treatment. Any other functionalization known for electrophilic aromatic substitution can be used to introduce the substituent R⁴¹And R⁴²。

iv: the amino group is protected, suitably Cbz-protected, using a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide.

v: the carboxylic acid group is preferably esterified using DBU and methyl iodide in DMF to give 193.

vi: 192 is preferably carried out using bromine in acetic acid and dichloromethane. In a similar manner, R⁴¹＝NO₂Can be prepared by using HNO₃Is introduced by treatment in acetic acid and R⁴¹＝CH₂NPt can be prepared by reacting hydroxymethylphthalimide with H₂SO₄Is introduced by the intermediate treatment. Any other functionalization known for electrophilic aromatic substitution can be used to introduce the substitutionSubstituent R⁴¹。

vii: the amino group is suitably Cbz-protected using a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide.

viii: the carboxylic acid group is preferably esterified using DBU and methyl iodide in DMF to give 194.

ix：194(R⁴¹) And 193 (R)⁴¹And R⁴²) The lower alkyl, substituted lower alkyl and aryl substituents of (a) are suitably prepared by palladium (0) -catalyzed Stille- (Stille, j.k.angelw.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, t.; mijaura, n.; suzuki, a.j.org.chem.1993, 58, 2201). Any other functionalization known for aryl bromides can be used to introduce the substituent R⁴¹And R⁴²。

x: for example by using H₂And a catalyst such as palladium on charcoal, in a suitable solvent such as ethanol, DMF and ethyl acetate to remove the Cbz-group.

xi: the ester group is suitably hydrolysed under acidic conditions, e.g. using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, preferably at about 100 ℃.

xii: the intermediate free amino acids formed are suitably protected with reagents such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide by use of a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to give 195 and 196.

(c3) Type templates can be prepared as in schemes 40 and 41.

Scheme 40

Resorufin

i: according to Muller, K.; obrecht, d.; kniersinger, a.; spiegler, c.; bannwarth, w.; trzeciak, a.; englert, g.; labhardt, a.; schnholzer, p. medicinal chemical prospection, Editor Testa, b.; kyburz, e.; fuhrer, w.; giger, r., Weinheim, New York, Basel, Cambridge: verlag Helvetica Chimica Acta, 1993, 513-53 l; bannwarth, w.; gerber, f.; grieder, a.; kniersinger, a.; muller, K.; obrecht.d.; trzeciak, a.can.pat.appl.ca2101599 (page 131), 197 can be prepared from commercial resorufin and converted to 198. For cleavage of the benzyl group 198 is expediently used, for example, for H₂And a catalyst such as palladium on charcoal, in a suitable solvent such as ethanol, DMF or ethyl acetate.

ii: by using a strong base such as sodium amide in liquid ammonia or sodium hydride in tetrahydrofuran, dioxane or DMF in the presence of a phase transfer catalyst such as TDA-I⁴³-X '(X' ═ OTf, Br, I) alkylation to introduce lower alkyl (R)⁴³)199 is obtained. In a similar manner, substituted lower alkyl (R)⁴³) Can be introduced; thus, for example, R⁴³＝CH₂COOR⁵⁵And CH₂CH₂COOR⁵⁵Can be introduced by treatment with the appropriate 2-haloacetic acid and 3-halopropionic acid derivatives, respectively. Any other functionalization known for diarylamino groups can be used to introduce the substituent R⁴³。

iii: 199 are suitably cleaved by treatment with an excess of boron tribromide in dichloromethane at a temperature of from about-20 ° to about room temperature.

iv: the intermediate di-phenol derivative is preferably reacted with R³⁹And R⁴⁰-X '(X' ═ OTf, Br, I) is reacted in the presence of a strong base such as sodium hydride in tetrahydrofuran, dioxane or DMF in the presence of a phase transfer catalyst such as TDA-I. Any other functionalization for the phenol group can be used for introducing the substituent R³⁹And R⁴⁰。

v: 199 and 200 are each hydrolyzed under acidic conditions, such as with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, suitably about 100 ℃.

vi: the phthalimide group is suitably cleaved by hydrazinolysis, e.g. using hydrazine hydrate in a suitable solvent such as ethanol.

vii: the free amino group is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 201 and 202 respectively.

Scheme 41

i: the cyano group of 199 is suitably hydrolysed under acidic conditions, e.g. using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, e.g. at about 100 ℃.

ii: the phthalimide group of the intermediate is suitably cleaved by hydrazinolysis, e.g. using hydrazine hydrate in a suitable solvent such as ethanol, to give 203.

iii: the bis-ortho-bromination of 203 is preferably carried out in acetic acid and dichloromethane using excess bromine. In a similar manner, R⁴¹＝R⁴²＝NO₂Can be prepared by using HNO₃Treated in acetic acid to introduce and R⁴¹＝R⁴²＝CH₂-NPht can be obtained by reacting hydroxymethylphthalimide with H₂SO₄Is introduced by middle treatment. Any other functionalization known for electrophilic aromatic substitution can be used to introduce the substituent R⁴¹And R⁴²。

v: the carboxylic acid group is preferably esterified using DBU and methyl iodide in DMF to give 204.

vi: the regioselective bromination of 203 is preferably carried out using bromine in acetic acid and dichloromethane. In a similar manner, R⁴¹＝NO₂Can be prepared by using HNO₃Is introduced by treatment in acetic acid and R⁴¹＝CH₂-NPht can be obtained by reacting hydroxymethylphthalimide with H₂SO₄Is introduced by the middle treatment

vii: the amino group is suitably protected by Cbz-using a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide.

viii: the carboxylic acid group is preferably esterified using DBU and methyl iodide in DMF to give 205.

ix: 205 (R.J.org.chem.1993, 58, 2201) is suitably introduced by palladium (O) -catalysed Stille- (Stille, J.K.Angew.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, T.; Mijaura, N.; Suzuki, A.J.org.chem.1993, 58, 2201)⁴¹) And 204 (R)⁴¹And R⁴²) Substituted lower alkyl and aryl substituents of (a). Any other functionalization known for aryl bromides can be used to introduce the substituent R⁴¹And R⁴²。

xii: the intermediate free amino acids formed are suitably protected by a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 206 and 207.

Template (d) can be prepared according to D.Obrecht, U.Bohdal, C.Lehmann, P.Sch _ nholzer, K.M uller, tetrahedron, 1995, 51, 10883; D.Obrecht, C.Abrecht, M.Altorfer, U.Bohdal, A.Grieder, M.Kleber, P.Pfyffer, K.Muller, Helv.Chim.acta 1996, 79, 1315-.

Templates (e1) and (e 2): see r.mueller, l.revesz, tetrahedron communication, 1994, 35, 4091; H. lubell, w.d.lubell, j.org.chem.1996, 61, 9437; l.colombo, m.digiacomo, g.papeo, o.carogo, c.scolaticco, l.manzoni, tetrahedron communique, 1994, 35, 4031.

Template (e 3): see s.hanessian, b.ronan, a.laoui, bioorg.med.chem.lett.1994, 4, 1397.

Template (e 4): see s.hanessian, g.mcnaughton-Smith, bioorg.med.chem.lett.1996, 6, 1567.

Template (f): see t.p.curran, p.m.mcenay, tetrahedron communication, 1995, 36, 191-charge 194.

Template (g): see D.Gramber g, C.Weber, R.Beeli, J.Inglis, C.Bruns, J.A.Robinson, Helv.chem.acta 1995, 78, 1588-; kim, J.P.Dumas, J.P.Germanas, J.org.chem.1996, 61, 3138-.

Template (h): see s.de Lombart, l.blanchard, l.b.stamford, d.m.specbeck, m.d.grim, t.m.jenson, h.r.rodriguez, tetrahedron letters 1994, 35, 7513-.

Template (i 1): see J.A.Robl, D.S.Karanewski, M.M.Asaad, tetrahedron letters, 1995, 5, 773-.

Template (i 2): see t.p.burkholder, t.b.le, e.l.giroux, g.a.flynn, bioorg.med.chem.let t.1992, 2, 579.

Templates (i3) and (i 4): see l.m.simpkins, j.a.robl, m.p.cimatersi, d.e.ryono, j.stevenson, c.q.sun, e.w.petrillo, d.s.karanewski, m.m.a.saad, j.e.bird, t.r.schaeffer, n.c. tripppodo, abstract of the paper, 210^th Am.Chem.Soc Meeting，Chicago，I11，MEDI 064(1995)。

Template (k): see d.benishai, a.r.mcmurray, tetrahedron, 1993, 49, 6399.

Template (l): see, e.g., von Roedern, H.Kessler, Angew.chem.int.Ed.Engl.1994, 33, 687-.

Template (m): see R.Gonzalez-Munizz, M.J.Dominguez, M.T.Garcia-Lopez, tetrahedron, 1992, 48, 5191-.

Template (n): see f.esser, a.copy, h.briem, h.k _ pen, k. -h.pook, int.j.pept.res.1995, 45, 540-.

Template (o): see n.de la fig, i.alkorta, t.garcia-Lopez, r.herranz, r.gonzalez-Muniz, tetrahedron, 1995, 51, 7841.

Template (p): see U.S. Slomcynska, D.K. Chalmers, F.Cornille, M.L.Smythe, D.D.Benson, K.D.Moeller, G.R.Mar shall, J.org.Chem.1996, 61, 1198-.

Medicaments comprising a β -hairpin mimetic of the general formula I, its solvates or salts are likewise subject matter of the present invention, as are processes for the manufacture of these medicaments, which comprise bringing one or more of the compounds mentioned and, if desired, one or more other therapeutically valuable substances into a galenical dosage form.

To control or prevent known diseases that can be treated by protease inhibitors, the β -hairpin mimetics of the invention can be administered individually, as a mixture of several β -hairpin mimetics, in combination with other inhibitors of the protease enzyme or in combination with other pharmaceutically active agents. The beta-hairpin mimetics of the invention may be administered as such or as a pharmaceutical composition. The dosage of the active substance, i.e. the compound of formula I, can vary within wide limits and will of course be adapted to the requirements which differ in each particular case. In general, in the case of oral or parenteral (e.g., intravenous or subcutaneous) administration, an administration dose of about 0.1 to 29mg/kg, preferably about 0.5 to 5mg/kg per day should be appropriate for an adult, but the upper limit given above may also be increased or decreased as necessary.

Pharmaceutical compositions comprising the beta-hairpin peptidomimetics of the invention can be manufactured using conventional mixing, dissolving, granulating, tablet-making, polishing, emulsifying, encapsulating, entrapping or lyophilizing processes. The pharmaceutical compositions can be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active β -hairpin peptidomimetics into pharmaceutically acceptable preparations. The appropriate formulation will depend on the method of administration chosen.

Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.

For injection, the β -hairpin peptidomimetics of the invention can be formulated in aqueous solution, preferably in a physiologically compatible buffer such as Hink's solution, Ringer's solution, or physiological saline buffer. The solution may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the β -hairpin peptidomimetics of the invention may be in powder form for admixture with a suitable carrier, e.g., sterile pyrogen-free water, prior to use.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation, as is known in the art.

For oral administration, the compounds can be readily formulated by combining the active β -hairpin peptidomimetics of the invention with pharmaceutically acceptable carriers well known in the art. These carriers enable the beta-hairpin peptidomimetics of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, soft gels, suspensions and the like, for oral ingestion by a patient to be treated. For oral formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, for example lactose, sucrose, mannitol and sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agent; and a binder. If desired, disintegrating agents, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added. If desired, the solid dosage form may be sugar coated or enteric coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, and the like. In addition, flavoring agents, preservatives, coloring agents and the like may be added.

For oral administration, the compositions may be in the form of tablets, lozenges, etc., formulated as conventional.

For administration by inhalation, the β -hairpin peptidomimetics of the invention are suitably delivered as an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a β -hairpin peptidomimetic of the invention and a suitable powder base such as lactose or starch.

These compounds may also be formulated in rectal or vaginal compositions such as suppositories, with suitable suppository bases such as cocoa butter or other glycerides.

In addition to the previously described formulations, the β -hairpin peptidomimetics of the invention can also be formulated as stock formulations. These long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. To make these depot formulations, the β -hairpin peptidomimetics of the invention can be formulated with suitable polymers or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as a nearly insoluble salt.

In addition, other drug delivery systems such as liposomes and emulsions well known in the art may be used. Certain organic solvents such as dimethyl sulfoxide may also be used. In addition, the β -hairpin peptidomimetics of the invention can be delivered using a sustained release system, such as a semipermeable matrix of a solid polymer containing the therapeutic agent. Various sustained release materials are established and are well known to those skilled in the art. Sustained release capsules can release the compound for weeks to over 100 days depending on its chemical nature. Other strategies for protein stabilization may be used depending on the chemical nature and biological stability of the therapeutic agent.

Because the β -hairpin peptidomimetics of the invention may contain charged residues, they may be included in any of the above formulations as a free base or as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than the corresponding free base forms.

The β -hairpin peptidomimetics of the invention, or compositions thereof, are generally used in amounts effective to achieve the intended purpose. It will be appreciated that the amount depends on the particular application.

For use in treating or preventing diseases that respond to protease inhibitor therapy, the β -hairpin peptidomimetics of the invention or compositions thereof are administered or administered in a therapeutically effective amount. A therapeutically effective amount is an amount effective to ameliorate symptoms of, or ameliorate, treat or prevent a disease associated with protease activity. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in view of the detailed description provided herein.

The starting dose can also be determined based on in vivo data, such as animal models, using techniques well known in the art. Administration to humans can be readily optimized by one of ordinary skill in the art based on animal data.

The dosage and time interval can be individually adjusted to provide plasma levels of the beta-hairpin peptidomimetics of the invention sufficient to maintain the therapeutic effect. A typical patient dose for administration by injection is about 0.1-5 mg/kg/day, preferably about 0.5-1 mg/kg/day. Therapeutically effective serum levels can be achieved by administering multiple doses per day.

The amount of β -hairpin peptidomimetic to be administered will of course depend on the subject to be treated, the weight of the subject, the severity of the disease, the mode of administration and the judgment of the prescribing physician.

Generally, therapeutically effective doses of the β -hairpin peptidomimetics described herein provide therapeutic benefit without causing substantial toxicity.

Toxicity of the beta-hairpin peptidomimetics of the invention can be determined here by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD₅₀(50% lethal dose of population) or LD₁₀₀(the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index. Compounds with high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used to calculate a range of doses that are not toxic for human use. The dosage of the beta-hairpin peptidomimetics of the invention is preferably within a range of circulating concentrations that includes an effective dose with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be selected by the individual physician according to the patient's condition (see, e.g., Fingl et al, 1975: pharmacological basis for therapy, Ch.1, p.1).

Compounds of formula I containing a free thiol group, i.e. containing a compound of formula- (CH)₂)_m(CHR⁶¹)_sSR⁵⁶(wherein R is⁵⁶Is H) as residue of R²-R⁶，R⁸-R¹⁰，R¹²，R¹³，R¹⁵-R¹⁹，R²¹-R²⁹，R³³Or R⁶⁴The compounds of (a) can be immobilized on gold-coated sheets (powers) and the interaction with ligands can be determined using so-called Surface Plasmon Resonance (SPR) biosensor analysis (see m.fivash, e.m.towler and r.j.fisher, curr. opin. in biotechnol.1998,9, 97-101; and r.l.rich and d.g.myszka, curr.opin.in biotechnol.2000, 11, 54-61).

The following examples illustrate the invention in more detail, but are not intended to limit its scope in any way. The following abbreviations are used in these examples:

HBTU: 1-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate salt

(Knorr et al, tetrahedron communication, 1989, 30, 1927-

HOBt: 1-hydroxybenzotriazoles

DIEA: diisopropylethylamine

HOAT: 7-aza-1-hydroxybenzotriazoles

HATU: o- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

Carpino et al, tetrahedron communication, 1994, 35, 2279-

Examples

1. Peptide synthesis

Coupling of the 1 st protected amino acid residue

0.5g of 2-chlorotrityl chloride resin (Barlos et al, tetrahedron letters, 1989, 30, 3943-. Suspending the resin in CH₂Cl₂(2.5ml) and swollen at room temperature under constant stirring. The resin was treated with 0.415mMol (4eq) of the first suitably protected amino acid residue (see below) and 284. mu.l (4eq) of Diisopropylethylamine (DIEA) in CH₂Cl₂(2.5ml), the mixture was shaken at 25 ℃ for 15 minutes, poured onto the pre-swollen resin and stirred at 25 ℃ for 18 hours. The resin color turned purple and the solution remained yellow. The resin was thoroughly washed (CH)₂Cl₂/MeOH/DIEA：17/2/1；CH₂Cl₂，DMF；CH₂Cl₂；Et₂O，3 times each) and dried under vacuum for 6 hours.

The loading is typically 0.6-0.7mMol/g

The following pre-loaded resins were prepared: Fmoc-Ser (tBu) O-chlorotrityl resin and Fmoc-AlaO-chlorotrityl resin.

1.1. Procedure 1

The synthesis was carried out using a Syro-peptide synthesizer (Multisyntech) using 24 to 96 reaction vessels. In each container, more than 60mg (weight of resin before loading) of resin was placed. The following reaction cycles were programmed and performed:

step (ii) of	Reagent	Time
			1234567	CH₂Cl₂Washing and swelling (manual) DMF, washing and swelling 40% piperidine/DMFDMF, washing 5 equivalents Fmoc amino acid/DMF +5 eq.hbtu +5 eq.hobt +5 eq.dieamdmf, washing CH₂Cl₂Washing (at the end of the synthesis)	3×1min.1×5min1×5min.5×2min.1×120min.4×2min.3×2min.

Steps 3-6 were repeated to add each amino acid.

Fragmentation of fully protected peptide fragments

After the synthesis is complete, the resin is addedSuspension of TFA in 1ml (0.39mMol) in CH₂Cl₂(v/v) in 1% solution for 3 min, filtered and the filtrate was extracted with 1ml (1.17mMol, 3eq.) of DIEA in CH₂Cl₂(v/v) neutralization of the 20% solution. This procedure was repeated twice to ensure completion of the fracture. The filtrate was evaporated to dryness and the product was fully deprotected to passage through reverse phase-HPLC (column C)₁₈) Analysis was performed to examine the efficiency of linear peptide synthesis.

Cyclization reaction of linear peptide

100mg of the fully protected linear peptide was dissolved in DMF (9ml, conc.10 mg/ml). 41.8mg (0.110mMol, 3eq.) of HATU, 14.9mg (0.110mMol, 3eq.) of HOAt and 1ml (0.584mMol) of 10% DIEA in DMF (v/v) were then added and the mixture was vortexed at 20 ℃ for 16h and then concentrated under high vacuum. The residue is in CH₂Cl₂And H₂O/CH₃And CN (90/10: v/v). CH (CH)₂Cl₂The phases are evaporated to give the fully protected cyclic peptide.

Deprotection and purification of cyclic peptides:

the resulting cyclic peptide was dissolved in 1ml of a cleavage mixture comprising 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% Triisopropylsilane (TIS). The mixture was left at 20 ℃ for 2.5 hours and then concentrated under vacuum. Dissolving the residue in H₂O/acetic acid (75/25: v/v) and the mixture was extracted with di-isopropyl ether.

The aqueous phase was dried under vacuum and the product was subsequently purified by preparative reverse phase HPLC.

After lyophilization, a product was obtained as a white powder and analyzed by ESI-MS. Analytical data including HPLC residence time and ESI-MS are given in Table 1.

Examples ex.1-11(n ═ 7) are shown in table 1. The peptide was synthesized starting with amino acid P3 coupled to the resin. The starting resins were Fmoc-Ser (tBu) O-chlorotrityl resin and Fmoc-AlaO-chlorotrityl resin, prepared as above. Linear peptide on solid support according to procedure 1The following synthesis sequence is as follows: P4-P6-P7-^DPro-Pro-P1-P2-P3-resin, cleaved, cyclized, deprotected and purified as described.

Examples ex.12 and 13(n ═ 7) are also given in table 1. The peptide was synthesized starting with amino acid P3 grafted onto the resin. The starting resin was Fmoc-Ser (tBu) O-chlorotrityl resin, prepared as above. Linear peptides were synthesized on solid supports according to procedure 1 in the following order: P4-P5-P6-P7-^DPro- (A8' -1) -P1-P2-P3-resin (ex 12) and P4-P5-P6-P7-^DPro- (A8 "-1) -P1-P2-P3-resin (ex.13), cleaved, cyclized, deprotected and purified as described.

Example ex.14(n ═ 7) is also given in table 1. The peptide was synthesized starting with amino acid P3 grafted onto the resin. The starting resin was Fmoc-Ser (tBu) O-chlorotrityl resin, prepared as above. Linear peptides were synthesized on solid supports according to procedure 1 in the following order: P4-P5-P6-P7- (c1-1) -P1-P2-P3-resin, cleaved, cyclized, deprotected and purified as described.

The structural unit (c1-1) is described below.

Example ex.15(n ═ 11) is likewise given in table 1. The peptide was synthesized starting with amino acid P5 coupled to the resin. The starting resin was Fmoc-Ser (tBu) O-chlorotrityl resin, prepared as above. Linear peptides were synthesized on solid supports according to procedure 3 (see below) in the following order: P6-P7-P8-P9-P10-P11-^DPro-Pro-P1-P2-P3-P4-P5-resin, cleaved, cyclized, oxidized, deprotected and purified as described.

Table 1: examples ex.1 to 15

a) A Vydac C-18-column; gradient: 5% MeCN/H₂O+0.1％CF₃COOH 2 min.; followed by 50% MeCN/H₂O+0.1％CF₃COOH 15min and 50-100% MeCN/H₂O+0.1％CF₃COOH 4min.

b) A Vydac C-18-column; gradient: 5-60% MeCN/H₂O+0.1％CF₃COOH 20min.

c) Nd: without measurement

1.2. Procedure 2

Example ex.13 was also synthesized using procedure 2.

Peptide synthesis was performed by solid phase method using standard Fmoc chemistry on a peptide synthesizer-ABI 433A.

The first amino acid, Fmoc-Ser (tBu) -OH (0.68g, 1.2 equivalents) in CH₂Cl₂DIEA (1.12mL, 4 equivalents) in (20mL) was coupled to 2-chlorotrityl chloride resin (Barlos et al, tetrahedron letters, 1989, 30, 3943-. The resin is subsequently coated with 3 XCH₂Cl₂/MeOH/DIEA(17∶2∶1)，3×CH₂Cl₂，2×DMF，2×CH₂Cl₂2 × MeOH. Finally, the resin was dried under vacuum and the substitution level was measured as weight gain (about 0.6 mmol/g).

If it is desired to use different acylating agents, resins with synthetic linear peptides, Ile-Lys (Boc) -Pro-Pro-Ile-^DPro-212-Thr (tBu) -Lys (Boc) -Ser (tBu) -resin, preferably divided into equal parts and placed in different reaction vessels to perform the acylation reaction in parallel. The coupling and deprotection reactions in the following steps were detected by Kaiser's assay (Kaiser et al, analytical biochemistry, 1970, 43, 595).

Removal of Alloc protecting groups:

to a linear peptide resin (100 mg/reaction vessel) was added Pd (PPh) under argon₃)₄(15mg, 0.5 eq), followed by the addition of anhydrous CH₂Cl₂(10mL) and phenylsilane (17. mu.L, 30 equiv.). The reaction mixture was left in the dark for 1 hour, filtered and the resin was washed with CH₂Cl₂DMF, and CH₂Cl₂And washing twice.

Acylation of 4-amino-proline groups

The corresponding acylating agent (usually a carboxylic acid (R) is added to the resin at room temperature in DMF (2mL)⁶⁴' COOH, 3 equivalents), HBTU (22.3mg, 4 equivalents), HOBt (8mg, 4 equivalents) and DIEA (125. mu.L, 6 equivalents) for 1.5-2 hrs. The resin was filtered and washed with 2 XDMF, 3 XCH₂Cl₂2 XDMF washing.

N^α-deprotection of the Fmoc group:

deprotection of the Fmoc-group was achieved by treating the resin with 20% piperidine in DMF for 20 min. The resin was then filtered and washed with DMF, and CH₂Cl₂Washed three times with DMF, and CH₂Cl₂And washing twice.

Cleavage of the peptide from the resin:

linear side chain protected peptides were prepared by using AcOH: TFE: CH at room temperature₂Cl₂(2: 6, v/v/v)2 hrs. The resin was filtered and washed twice with a mixture of AcOH: TFE: DCM and with CH₂Cl₂And washing once. The filtrate was then diluted with hexane (14 fold by volume) and concentrated. Two repeated evaporations with hexanes were used to remove traces of AcOH. The residue was dried under vacuum. The yield of linear protective peptide is generally about 40-50 mg.

Cyclization reaction of linear protection peptide:

the cyclization reaction was carried out in DMF at a concentration of 5mg/mL using HATU (13.12mg, 3 equivalents), HOAT (4.7mg, 3 equivalents), DIEA (153. mu.L, 6 equivalents). The reaction mixture was stirred at room temperature for 16hrs and the completion of the reaction was checked by HPLC. After evaporation of DMF, CH₃CN/H₂O (90/10, v/v) was added to the residue and extracted with DCM. The organic layer was washed once with water and evaporated to dryness. Drying under vacuum.

Cleavage of side chain protecting groups:

final deprotection of the side chain protecting groups was achieved by reacting the peptide with TFA: triisopropylsilane: H₂O (95: 2.5, v/v/v) was treated at room temperature for 3 hrs. TFA was then evaporated and the residue triturated with cold ether.

And (3) purification:

the crude peptide thus obtained was used by HPLC on a VYDAC C18 preparative column with 5-60% CH within 30min₃CN/H₂O + 0.1% TFA was analyzed and purified as a gradient with a flow rate of 10 ml/min. The purity of the final peptide was checked by analytical HPLC and ESI-MS.

1.3. Procedure 3

Procedure 3 describes the synthesis of β -hairpin mimetics with β -chain disulfide bonds.

n is 11: : the peptide was synthesized according to procedure 1 starting with amino acid P5 coupled to the resin. Linear peptides were synthesized on solid supports according to procedure 1 in the following order: P6-P7-P8-P9-P10-P11-^DPro-Pro-P1-P2-P3-P4-P5-resin, wherein Fmoc-Cys (Acm) OH or Fmoc-Cys (Tr) OH is introduced at positions P2 and P10. The linear peptide was cleaved and cyclized as described in procedure 1.

If Cys (Acm) is introduced as a protected building block, the cyclized side chain protected β -hairpin mimetic is dissolved in methanol (0.5 mL) and a solution of iodine in methanol (1N, 1.5 equiv.) is added dropwise thereto at room temperature. The reaction mixture was stirred at room temperature for 4 hours and the solvent was evaporated. The crude product was then deprotected and purified as described in step 1.

If Cys (Tr) is introduced as a protected cysteine building block, a cyclic fully protected beta-hairpin mimetic is used comprising trifluoroacetic acid/phenylthiomethane/phenol/H₂A mixture of O/ethane-dithiol/triisopropylsilane (82.5: 5: 2.5) was treated at room temperature for 2 hours. The reduced peptide was subjected to air oxidation by stirring in ammonium acetate buffer for 30 minutes and purified according to procedure 1.

2. Synthesis of the template

2.1 Synthesis of (2S, 4S) -4- [ (allyloxy) carbonylamino ] -1- [ (9H-fluoren-9-yl) methoxycarbonyl ] -proline (212) and (2S, 4R) -4- [ (allyloxy) carbonylamino ] -1- [ (9H-fluoren-9-yl) methoxy-carbonyl ] proline (217) is shown in schemes 42 and 43.

Scheme 42

i：SOCl₂，MeOH；ii：Boc₂O，DMAP，Et₃N；iii：pNO₂C₆H₄SO₂Cl，Et₃N；iv：NaN₃，DMF；v：SnCl₂Di-alkyl/H₂O；vi：ClCOOCH₂CH＝CH₂Aqueous NaHCO₃Di-alkane: vii: LiOH, MeOH, H₂O；viii：TFA，CH₂Cl₂；ix：Fmoc-OSu，DIBA

(2S, 4S) -4- [ (allyloxy) carbonylamino ] -1- [ (9H-fluoren-9-yl) methoxycarbonyl ] -proline (212)

i, ii: to a solution of (2S, 4R) -4-hydroxyproline (30g, 0.18mol) in anhydrous methanol (300ml) was added thionyl chloride (38ml, 2.5eq, 0.45mol) dropwise at 0 ℃. The solution was heated to reflux under nitrogen and stirred for 3 h. The solution was then concentrated by rotary evaporation and the ester was precipitated by addition of diethyl ether. After filtration, the white solid is washed with diethyl ether and subsequently dried under HV: (2S, 4R) -4-hydroxyproline-methyl ester-hydrochloride, a white solid (29.9g, 90%). %). TLC (CH)₂Cl₂MeOH/water 70: 28: 2): r_f0.82。IR(KBr)：3378s(br.)，2950m，2863w，1745s，1700s，1590m，1450s，1415s，1360s，1215s，1185s，1080m，700m。¹H-NMR(300MHz，MeOH-d₄)4.66-4.55(m，2H，H-C(4)，H-C(2))；3.85(s，3H，H₃C-O)；3.45(dd，J＝12.2，3.8，1H，H-C(5))；3.37-3.25(m，1H，H-C(5))；2.44-2.34(m，1H，H-C(3))，2.27-2.12(m，1H，H-C(3))。¹³C-NMR(75MHz，MeOH-d₄)：170.8(s，COOMe)；70.8(d，C(4))；59.6(d，C(2))；55.2(t，C(5))；54.2(q，Me)；38.7(t，C(3))。CI-MS(NH₃)：146.1([M-Cl]⁺)。

The above intermediate (30g, 0.17mmol) was dissolved in CH₂Cl₂(300ml), cooled to 0 ℃ and triethylamine (45ml, 1.5eq, 0.25mol) was added dropwise. Then added in CH₂Cl₂Di-tert-butyl dicarbonate (54.0g, 1.5eq, 0.25mmol) and 4-N, N-dimethylaminopyridine (2.50g, 0.1eq, 17mmol) in (15ml) and the solution was stirred at room temperature overnight. The solution was then treated with 1N aqueous citric acid, saturated NaHCO₃Washed with an aqueous solution and dried (Na)₂SO₄) The residue was evaporated and dried under high vacuum: (2S, 4R) -4-hydroxy-1- [ (tert-butoxy) carbonyl]Proline-methyl ester (209), a white solid (39.6g, 78%). TLC (CH)₂Cl₂/MeOH 9∶1)：Rf 0.55。[α]²⁴ _D＝-55.9(c＝0.983，CHCl₃)。IR(KBr)：3615w，3440w(br.)，2980m，2950m，2880m，1750s，1705s，1680s，1480m，1410s，1370s，1340m，1200s，1160s，1130m，1090m，1055w，960w，915w，895w，855m，715m。¹H-NMR(300MHz，CDCl₃)：4.47-4.37(m，2H，H-C(4)，H-C(2))；3.73(s，3H，H₃C-O))；3.62(dd，J＝11.8，4.1，1H，H-C(5))；3.54-3.44(m，1H，H-C(5))；2.32-2.25(m，1H，H-C(3))；2.10-2.03(m，1H，H-C(3))；1.46+1.41(2s，9H，tBu)。¹³C-NMR(75MHz，CDCl₃)：173.6(s，COOMe)；154.3+153.9(2s，COOtBu)；80.3(s，C-tBu)；70.0+69.3(2d，C(4))；57.9+57.4(2d，C(2))；54.6(t，C(5))；51.9(q，Me)；39.0+38.4(2t，C(3))；28.1+27.6(2q，tBu)。CI-MS：246.2([M+H]⁺)；190.1([M-tBu+H]⁺)；146.1([M-BOC+H]⁺)。

iii, iv: (39g, 0.16mol)209 was dissolved in CH at 0 deg.C₂Cl₂(300ml), followed by addition of 4-nitrobenzenesulfonyl chloride (46g, 1.3eq, 0.21mol) and Et₃N (33ml, 1.5eq, 0.24 mol). The solution was then stirred overnight and gradually brought to room temperature with 1N hydrochloric acid, saturated NaHCO₃Aqueous solution washing and drying (Na)₂SO₄). The solvent was evaporated and the crude product was purified by filtration over silica gel with (2: 1) hexane/AcOEt. The product was crystallized from hexane/AcOEt: (2S, 4S) -4- [ (p-nitrobenzyl) sulfonyloxy]-1- [ (tert-butoxy) carbonyl]Proline methyl ester, a white crystal (46.4g, 65%). TLC (Hexane/AcOEt 1: 1): r_f 0.78.M.p.：93-95℃。[α]²⁰ _D＝-32.3°(c＝0.907，CHCl₃)。IR(KBr)：3110w，3071w，2971w，1745s，1696s，1609s，1532s，1414s，1365s，1348m，1289m，1190m，1173m，1122w，1097w，1043w，954w，912w，755w，578w.¹H-NMR(600MHz，CDCl₃)：8.42-8.34(m，2H，H-C(Nos))；8.11-8.04(m，2H，H-C(Nos))；5.14(s，1H，H-C(4))；4.39-4.28(m，1H，H-C(2))；3.70-3.56(m，5H，H₂-C(5)，H₃C-O)；2.58-2.38(m，1H，H-C(3))；2.25-2.11(m，1H，H-C(3))；1.37+1.33(2s，9H，tBu)。¹³C-NMR(150MHz，CDCl₃)：172.4+172.2(2s，COOMe)；153.6+153.0(2s，COOtBu)；150.8+142.0(2s，C(Nos))；129.0+124.6(2d，C(Nos))；80.4(s，C-tBu)；80.8+79.9(2d，C(4))；57.1+56.9(2d，C(2))；52.2+51.7(2t，C(5))；52.3(q，Me)；37.1+35.9(2t，C(3))；28.0(q，tBu)。ESI-MS(MeOH+NaI)：453.0([M+Na]⁺)。

The above intermediate (38g, 88mmol) was dissolved in DMF (450ml) and subsequently purified by addition of sodium azide (34g, 6eq,0.53mol) was heated to 40 ℃ and the solution was stirred overnight. DMF was evaporated and the solid was suspended in diethyl ether. The suspension was washed with water and dried (Na)₂SO₄). The solvent was evaporated and the product was dried under high vacuum: (2S, 4S) -4-azido-1- [ (tert-butoxy) carbonyl]Proline methyl ester (210), yellow oil (21.1g, 88%). [ alpha ] to]²⁰ _D＝-36.9(c＝0.965，CHCl₃)。¹H-NMR(600MHz，CDCl₃)：4.46-4.25(2m，1H，H-C(2))；4.20-4.10(m，1H，H-C(4))；3.80-3.65(m，4H，H-C(5)，H₃C-O)；3.53-3.41(m，1H，H-C(5))；2.54-2.39(m，1H，H-C(3))；2.21-2.12(m，1H，H-C(3))；1.47+1.41(2s，9H，tBu)。¹³C-NMR(150MHz，CDCl₃)：172.2+171.9(2s，COOMe)；153.9+153.4(2s，COOtBu)；80.5(s，C-tBu)；59.2+58.2(2d，C(4))；57.7+57.3(2d，C(2))；52.4+52.2(2q，Me)；51.2+50.7(2t，C(5))；36.0+35.0(2t，C(3))；28.3+28.2(2q，tBu)。EI-MS(70ev)：20.1([M]⁺)；227.1([M-CO₂+H]⁺)；169.1([M-BOC+H]⁺)；。

v, vi: dissolve (21.1g, 78mmol) of the above intermediate in a (3: 1) -mixture of dioxane/water (500ml) and SnCl₂(59.2g, 4eq, 0.31mol) was added at 0 ℃ and the solution was stirred for 30min and gradually brought to room temperature and stirred for a further 5h. In the presence of solid NaHCO₃After adjusting the pH to 8, allyl chloroformate (41.5ml, 5eq, 0.39mol) was added and the solution was stirred at room temperature overnight. The reaction mixture was evaporated and extracted with AcOEt. The organic phase was washed with brine and dried (Na)₂SO₄) The solvent was evaporated and the product was dried under high vacuum: (2S, 4S) -4- [ (allyloxy) carbonylamino group]-1- [ (tert-butoxy) carbonyl]Proline methyl ester (211), a clear thick oil (22.3g, 87%). [ alpha ] to]²⁰ _D＝-30.2°(c＝1.25，CHCl₃)。¹H-NMR(300MHz，CDCl₃)：5.98-5.77(m，1H，H-C(β)(Alloc))；5.32-5.12(m，2H，H₂-C(γ)(Alloc)；4.59-4.46(m，2H，H₂-C(α)(Alloc))；4.40-4.16(m，2H，H-C(4)，H-C(2))；3.80-3.53(m，4H，H-C(5)，H₃C-O)；3.53-3.31(m，1H，H-C(5))；2.54-2.17(m，1H，H-C(3))；1.98-1.84(m，1H，H-C(3))；1.41+1.37(2s，9H，tBu)。ESI-MS(MeOH+CH₂Cl₂)：351.2([M+Na]⁺)；229.0([M-BOC+H]⁺)。

vii-ix: 22g, 67mmol) of 211 were dissolved in a methanol/water (4: 1) -mixture (100ml) and LiOH (5g, 2eq, 134mmol) was added at room temperature, and the solution was stirred for 3.5 h. The reaction mixture was evaporated and extracted with 1N hydrochloric acid (100ml) and AcOEt. The solvent was removed and the resulting solid was dissolved in 1: 1 TFA/CH₂Cl₂(200ml) and stirred for 2 h. The solvent was evaporated and the product was dried under high vacuum: (2S, 4S) -4- [ (allyloxy) carbonylamino group]Proline, a clear oil (21g, 96%)¹H-NMR(600MHz，MeOH-d₄)：5.98-5.85(m，1H，H-C(β)(Alloc))；5.30(dd，J＝17.1，1.5Hz，1H，H-C(γ)(Alloc))；5.12(d，J＝10.7Hz，1H，H-C(g)(Alloc))；4.54(d，J＝4.4Hz，2H，H₂-C(α)(Alloc))；4.44(t，J＝8.9Hz，1H，H-C(2))；4.36-4.27(m，1H，H-C(4))；3.58(dd，J＝12.2，7.3Hz，1H，H-C(5))；3.34-3.32(m，1H，H-C(5))；2.73(ddd，J＝13.6，8.7，7.2Hz，1H，H-C(3))；2.23-2.15(m，1H，H-C(3))。¹³C-NMR(150MHz，MeOH-d₄)：171.3(s，COOMe)；158.3(s，COOAllyl)；134.1(d，C(β)(Alloc))；118.0(t，C(γ)(Alloc))；66.8(t，C(α)(Alloc))；59.7(d，C(2))；51.3(d，C(4))；51.1(t，C(5))；34.9(t，C(3))。ESI-MS(DCM+MeOH)：237.0([M+Na]⁺)；215.0([M+H]⁺)。

The above intermediate (15g, 70mmol) and 9-fluorenylmethoxycarbonylsuccinimide (28g, 1.2eq, 84mmol) were dissolved in DCM (700ml) and DIEA (48ml, 6eq, 0.42mol) was added and the solution was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in AcOEt, then washed with 1N hydrochloric acid and dried (Na)₂SO₄). After evaporation, the crude product was purified by filtration on silica gel using a (3: 1) hexane/AcOEt to AcOEt gradient. The solvent is evaporated and the residue is taken up inCrystallization from hexane at-20 ℃. The product was dried under high vacuum: (2S, 4S) -4- [ (allyloxy) carbonylamino group]-1- [ (9H-fluoren-9-yl) methoxycarbonyl]-proline (212), a white solid (23.8mg, 78%) [ alpha ]]²⁰ _D＝-27.0(c＝1.1，CHCl₃)。IR(KBr)：3321w(br.)，3066w，2953w，1707s，1530m，1451s，1422s，1354m，1250m，1205m，1173m，1118m，1033m，977m，936m，759m，739s，621m，597w，571w，545s.¹H-NMR(300MHz，MeOH-d₄)：7.88-7.78(m，2H，H-C(4‘)(Fmoc))；7.71-7.61(m，2H，H-C(1‘)(Fmoc))；7.49-7.29(m，4H，H-C(3‘)(Fmoc)，H-C(2‘)(Fmoc))；6.08-5.68(m，1H，H-C(β)(Alloc))；5.41-5.17(m，2H，H₂-C(γ)(Alloc)；4.58(s，2H，H₂-C(α)(Alloc))；4.74-4.17(m，5H，H₂-C(10‘)(Fmoc)，H-C(9‘)(Fmoc)，H-C(4)，H-C(2))；3.94-3.73(m，1H，H-C(5))；3.41-3.26(m，1H，H-C(5))；2.74-2.54(m，1H，H-C(3))；2.12-1.92(m，1H，H-C(3))。ESI-MS(DCM+MeOH)：459.3([M+Na]⁺)；437.3([M+H]⁺)。

Scheme 43

i：Ac₂O，AcOH；ii：SOCl₂，MeOH；iii：Boc₂O，DMAP，Et₃N；vi：pNO₂C₆H₄SO₂Cl，Et₃N；v：NaN₃，DMF；vi：SnCl₂Di-alkyl/H₂O；vii：ClCOOCH₂CH＝CH₂Aqueous NaHCO₃Di-alkane: viii: LiOH, MeOH, H₂O；ix：TFA，CH₂Cl₂；x：Fmoc-OSu，DIEA

(2R, 4S) -4- [ (allyloxy) carbonylamino ] -1- [ (9H-fluoren-9-yl) methoxycarbonyl ] -proline (217)

i: acetic anhydride (1.02kg, 5.3eq, 10mol) in glacial acetic acid (31) were heated to 50 ℃ and (2S, 4R) -4-hydroxyproline (208) (247g, 1.88mol) was added in one portion. The solution was refluxed for 5.5h, cooled to room temperature and the solvent was removed under reduced pressure to give a thick oil. The oil was then dissolved in 2N hydrochloric acid (3.51) and heated at reflux for 4h, then treated with charcoal and filtered through Celite (Celite). As the solution was evaporated, a white needle was formed, which was then filtered. Product drying under high vacuum: (2R, 4R) -4-hydroxyproline-hydrochloride (213), white crystal needle (220.9g, 70%). M.p.: 117 deg.c. [ alpha ] to]²⁰ _D+19.3 ° (c-1.04, water). IR (KBr): 3238s 3017s, 2569m, 1712s, 1584m, 1376s, 1332m, 1255s, 1204m, 1181w, 1091w, 1066w, 994w, 725m, 499s.¹H-NMR(600MHz，MeOH-d₄)：9.64(s，1H，H-N)；8.89(s，1H，H-N)；4.55-4.53(m，1H，H-C(4))；4.51(dd，J＝10.4，3.6Hz，1H，H-C(2))；3.44-3.35(m，2H，H₂-C(5))；2.54-2.48(m，1H，H-C(3))；2.40-2.34(m，1H，H-C(3))。¹³C-NMR(150MHz，MeOH-d₄)：171.9(s，COOH)；70.3(d，C(4))；59.6(d，C(2))；55.0(t，C(5))；38.5(t，C(3))。EI-MS(NH₃)：132.1([M-Cl]⁺). The filtrate was further concentrated to give an additional 59.5g (19%).

ii, iii: thionyl chloride (38ml, 2.5eq, 0.45mol) was added dropwise to a solution of 213(30g, 0.18mol) in dry methanol (550ml) at 0 ℃. The solution was refluxed for 3h under nitrogen atmosphere. The solution was evaporated and the ester hydrochloride salt precipitated by addition of diethyl ether. After filtration, the white solid was washed with diethyl ether and dried under high vacuum: (2R, 4R) -4-hydroxyproline methyl ester-hydrochloride as a white solid (29g, 89%). [ alpha ] to]²⁰ _D＝+8.6°(c＝0.873，MeOH)。IR(KBr)：3388s(br.)，2980s(br.)，1730s，1634m，1586s，1384s，1248s，1095s，1064s，1030m，877m。¹H-NMR(300MHz，MeOH-d₄)：4.59-4.44(m，2H，H-C(4)，H-C(2))；3.81(s，3H，H₃C-O)；3.37-3.31(m，2H，H₂-C(5))；2.50-2.37(m，1H，H-C(3))，2.37-2.27(m，1H，H-C(3))。¹³C-NMR(75MHz，MeOH-d₄)：170.9(s，COOMe)；70.2(d，C(4))；59.8(d，C(2))；55.1(t，C(5))；))；54.1(q，C(Me))；38.4(t，C(3))。EI-MS(NH₃)：146.1([M-Cl]⁺)。

The above intermediate (10g, 55mmol) was dissolved in CH₂Cl₂(100ml), cooled to 0 ℃ and triethylamine (15.2ml, 2eq, 0.11mol) was added dropwise. Then added in CH₂Cl₂Di-tert-butyl dicarbonate (18.0g, 1.5eq, 83mmol) and 4-N, N-dimethylaminopyridine (0.67g, 0.1eq, 5mmol) in (10ml) and the solution was stirred at RT overnight. The solution was treated with 1M aqueous citric acid and saturated aqueous NaHCO₃The solution is washed and dried (Na)₂SO₄) The solvent is evaporated and dried under high vacuum: (2R, 4R) -4-hydroxy-1- [ (tert-butoxy) -carbonyl]Proline methyl ester (214), a white solid (13g, 97%). [ alpha ] to]²⁰ _D＝+13.0°(c＝1.06，CHCl₃)。IR(KBr)：3466s(br.)，2985s，2930m，1729s，1679s，1424s，1283m，1262m，1122s，1089s，969m，770m。¹H-NMR(300MHz，CDCl₃)：4.43-4.26(m，2H，H-C(4)，H-C(2))；3.80+3.79(2s，3H，H₃C-O))；3.76-3.47(m，2H，H₂-C(5))；2.44-2.24(m，1H，H-C(3))；2.16-2.03(m，1H，H-C(3))；1.47+1.43(2s，9H，tBu)。ESI-MS：268.1([M+Na]⁺)。

iv, v: 214(12.2g, 50mmol) was dissolved in CH₂Cl₂(130ml), cooled to 0 ℃ and added 4-nitrobenzenesulfonyl chloride (14.3g, 1.3eq, 65mmol) and Et₃N (10.3ml, 1.5eq, 75 mmol). The reaction mixture was stirred overnight and gradually brought to room temperature. The solution was treated with 1N hydrochloric acid and saturated aqueous NaHCO₃The solution is washed and dried (Na)₂SO₄) The solvent was evaporated and the crude product was purified by filtration on silica gel using a (2: 1) -mixture of hexane/AcOEt: 18g (84%). The product was then recrystallized from hexane/AcOEt: (2R, 4R) -4- [ (p-nitrobenzyl) sulfonyloxy]-1- [ (tert-butoxy) carbonyl]Proline-methyl ester, a white crystal (13.7g, 64%). TLC (Hexane/AcOEt 11)：Rf 0.76.M.p.：113-115℃。[α]²⁰ _D＝+21.6°(c＝0.924，CHCl₃)。IR(KBr)：3112s(br.)，2981s，2955s，2882m，1755s，1683s，1532s，1413s，1375s，1348s，1192s，928s，911s，759m，745s，610s.¹H-NMR(600MHz，CDCl₃)：8.45-8.35(m，2H，H-C(Nos))；8.15-8.06(m，2H，H-C(Nos))；5.27-5.16(m，1H，H-C(4))；4.53-4.32(m，1H，H-C(2))；3.75-3.60(m，5H，H₂-C(5)，H₃C-O)；2.59-2.35(m，2H，H₂-C(3))；1.42+1.39(2s，9H，tBu)。¹³C-NMR(150MHz，CDCl₃)：171.8+171.6(s，COOMe)；153.8+153.4(s，COOtBu)；151.0+142.6(s，C(Nos))；129.2+124.7(d，C(Nos))；81.0(s，C-tBu)；80.8+79.7(d，C(4))；57.4+57.1(d，C(2))；52.6+52.5+52.3+51.8(t，C(5)，q，Me)；37.2+36.3(t，C(3))；28.5+28.3(q，tBu)。ESI-MS(DCM+MeOH+NaI)：453.2([M+Na]⁺)。

The above intermediate (13g, 30mmol) was dissolved in DMF (200ml), heated to 40 ℃ and sodium azide (14.3g, 6eq, 180mmol) was added, then the reaction mixture was stirred overnight. The reaction mixture was evaporated and the residue was suspended in diethyl ether. The suspension was filtered, the filtrate was washed with water and the organic phase was dried (Na)₂SO₄). The solvent was evaporated and the product was dried under high vacuum: (2R, 4S) -4-azido-1- [ (tert-butoxy) carbonyl]Proline methyl ester (215), a yellow oil (8.15g, 99%). [ alpha ] to]²⁰ _D＝+42.8 °(c＝1.05，CHCl₃)。¹H-NMR(300MHz，CDCl₃)：4.58-4.37(m，1H，H-C(2))；4.34-4.23(m，1H，H-C(4))；3.92-3.51(m，5H，H₂-C(5)，H₃C-O)；2.52-2.33(m，1H，H-C(3))；2.33-2.20(m，1H，H-C(3))；1.56+1.51(2s，9H，tBu)。CI-MS(NH₃)：288.2([M+NH₄]⁺)；271.1([M+H]⁺)。

vi, vii: 215(8g, 30mmol) was dissolved in a (3: 1) -mixture of dioxane/water (400ml), cooled to 0 ℃ and SnCl was added₂(22.4g, 4eq, 120mmol) and then reactingThe mixture was stirred at 0 ° for 30min, gradually warmed to room temperature and stirred for an additional 5h. In the presence of solid NaHCO₃After adjusting the pH of the solution to 8, allyl chloroformate (15.7ml, 5eq, 150mmol) was added. The reaction mixture was stirred at room temperature overnight, evaporated and extracted with AcOEt, then the organic phase was washed with brine. In the dry organic phase (Na)₂SO₄) Thereafter, the solvent was evaporated and the product was dried under high vacuum: (2R, 4S) -4- [ (allyloxy) carbonylamino group]-1- [ (tert-butoxy) carbonyl]Proline-methyl ester, a clear thick oil (216) (8.7g, 89%). [ alpha ] to]²⁰ _D＝+41.9°(c＝0.928，CHCl₃)。¹H-NMR(300MHz，CDCl₃)：5.98-5.87(m，1H，H-C(β)(Alloc))；5.34-5.02(m，2H，H₂-C(γ)(Alloc)；4.62-4.49(m，2H，H₂-C(α)(Alloc))；4.41-4.23(m，2H，H-C(4)，H-C(2))；3.82-3.66(m，4H，H-C(5)，H₃C-O)；3.43-3.20(m，1H，H-C(5))；2.33-2.07(m，2H，H₂-C(3))；1.43+1.39(2s，9H，tBu)。CI-MS(NH₃)：329.1([M+H]⁺)。

vii-x: 216(8.4g, 25mmol) were dissolved in a methanol/water (4: 1) -mixture (100ml) at room temperature, LiOH (2.2g, 2eq, 50mmol) was added and the solution was stirred overnight. Methanol was evaporated and the residue poured into 1N hydrochloric acid (100ml) and extracted with AcOEt. The solvent was removed and the residue was dissolved in TFA/CH₂Cl₂Was neutralized and stirred for 2h (1: 1) -mixture (2O0 ml). The solvent was evaporated and the product was dried under high vacuum: (2R, 4R) -4- [ (allyloxy) carbonylamino group]Proline, a clear oil (5.2g, 96%)¹H-NMR(300MHz，MeOH-d₄)：6.04-5.88(m，1H，H₂-C(B)(Alloc))；5.38-5.19(m，2H，H₂-C(γ)(Alloc)；4.64-4.54(m，3H，H₂-C(α)(Alloc)，H-C(4))；4.39-4.22(m，1H，H-C(2))；3.71-3.60(m，1H，H-C(5))；3.45-3.32(m，1H，H-C(5))；2.51-2.41(m，2H，H₂-C(3))。CI-MS(NH₃)：215.1([M+H]⁺)。

The intermediate (200mg, 0.86mmol) and 9-fluorenylmethyloxyAlkylcarbonyl succinimide (440mg, 1.5eq, 1.3mmol) dissolved in CH₂Cl₂(10ml) and DIEA (466. mu.l, 4eq, 3.44mmol) was added, and the solution was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in AcOEt, washed with 1N hydrochloric acid and dried (Na)₂SO₄). After evaporation, the crude product was purified by filtration on silica gel using a (3: 1) hexane/AcOEt to AcOEt gradient. Solvent and CH₂Cl₂Co-evaporation and drying of the product under high vacuum: (2R, 4S) -4- [ (allyloxy) carbonylamino group]-1- [ (9H-fluoren-9-yl) methoxy-carbonyl]-proline (217), white solid (90mg, 33%) [ alpha ]]²⁰ _D＝+29.3°(c＝1.08，CHCl₃)。IR(KBr)：3314s(br.)，3066s(br.)，2952s(br.)，1708s(br.)，1536m，1424s，1353s，1126m，1030m，909m，759m，738s，620m。¹H-NMR(300MHz，CDCl₃)：8.74(s，1H，H-N)；7.7 9-7.66(m，2H，H-C(4‘)(fmoc))；7.6 2-7.4 9(m，2H，H-C(1‘)(fmoc))；7.44-7.22(m，4H，H-C(3‘)(fmoc)，H-C(2‘)(fmoc))；6.03-5.74(m，1H，H-C(β)(Alloc))；5.41-5.07(m，2H，H₂-C(γ)(Alloc)；4.74-4.17(m，7H，H₂-C(10‘)(fmoc)，H-C(9‘)(fmoc)，H-C(4)，H-C(2)，H₂-C(α)(Alloc))；3.91-3.76(m，1H，H-C(5))；3.48-3.25(m，1H，H-C(5))；2.45-2.08(m，2H，H₂-C(3))。ESI-MS(MeOH)：437.3([M+H]⁺)；ESI-MS(MeOH+Na)：459.1([M+Na]⁺)。

2.3. Starting from derivatives 210 and 215, important precursors 219a and 221a can be prepared according to scheme 44.

R⁶⁴: n-hexyl (219a, 221 a).

Scheme 44

i：SnCl₂Di-alkyl/H₂O；ii：R⁶⁴COCl, diisopropylethylamine, CH₂Cl₂；iii：LiOHx1H₂O，MeOH，H₂O；iv：TFA，CH₂Cl₂；v：FmocOSu，Na₂CO₃Aqueous solution, dioxane

i, ii: typical procedure:

to 78mmol of azide 210 and 215 in a (3: 1) -mixture of dioxane/water (500ml) at 0 deg.C was added SnCl₂(59.2g, 4eq, 0.31mol) and the solution was stirred for 30 minutes. The reaction mixture was gradually warmed to room temperature and stirred for another 5 hours. In the presence of solid NaHCO₃After adjusting the pH to 8, the reaction mixture was treated with CH₂Cl₂Extraction, drying of the organic fraction (MgSO)₄) Evaporated and the residue dried under reduced pressure. Dissolving the residue in CH₂Cl₂(300ml), cooled to 4 ℃ with an ice bath, followed by the addition of DIEA (20.0 ml, 117mmol) and the appropriate acid chloride R at 4 ℃⁶⁴` COCl (101.0mmol) in CH₂Cl₂(50 ml). The reaction mixture was stirred at 4 ℃ for 1 hour and at room temperature for 18 hours with HCl aq. (0.5N, 200mL) and CH₂Cl₂And (4) extracting. The organic fraction was dried (MgSO)₄) Evaporating and condensing the residue on SiO₂Chromatography over a gradient of ethyl acetate/hexane afforded 218a and 220a, which were then converted to the final products 219a and 221a as described for 216 to 217. The overall yield is 50-60%.

Template (b 1):

synthesis of (2S, 6S, 8aR) -8a- { [ (tert-butyl) oxycarbonyl ] methyl } perhydro-5, 8-dioxo- { [ (9H-fluoren-9-yl) methoxycarbonyl ] amino } -pyrrolo [1, 2-a ] pyrazine-6-acetic acid (222):

to a solution of 250mg (0.414mmol) of { (2S, 6S, 8aR) -8a- [ (tert-butyl) oxycarbonyl group under argon]Methyl } perhydro-5, 8-dioxo- { [ (9H-fluoren-9-yl) methoxycarbonyl]Amino } -pyrrolo [1, 2-a)]A stirred solution of allyl pyrazine-6-acetate in a degassed dichloromethane/methanol mixture (9: 1, 3 ml) was added with 25mg (0.0216mmol) of tetrakis (triphenylphosphine) palladium, 0.05 ml of acetic acid and 0.025 ml of N-methylmorpholine. The reaction mixture was stirred at room temperature for 48 hours and then poured onto water and dichloromethane. The organic phase was dried (MgSO)₄) Evaporating and dissolving the residue in SiO₂Chromatography on dichloromethane/methanol (9: 1) gave 180mg (77%) (2S, 6S, 8aR) -8a- { [ (tert-butyl) oxycarbonyl]Methyl } perhydro-5, 8-dioxo- { [ (9H-fluoren-9-yl) -methoxycarbonyl]Amino } -pyrrolo [1, 2-a)]Pyrazine-6-acetic acid (222), a white powder.

¹H-NMR(300MHz，DMSO-d₆)：8.30(s，1H)；7.88(d，J＝7.2，2H)；7.67(d，J＝7.4，2H)；7.62(br.s，1H)；7.41(t，J＝7.2，2H)；7.33(t，J＝7.4，2H)；4.35-4.2(m，5H)；3.55(br.d，J＝6.3，2H)；2.8-2.55(m，3H)；2.45-2.25(m，2H)；2.1-1.95(m，1H)；1.35(s，9H)；MS(ESI)：586.1(M+Na)⁺，564.1(M+H)⁺。

Template (c 1):

the experimental procedures are described in w.bannwarth, a.knierzinger, k.muller, d.obrecht, a.trzeciak, EP 0592791 a2, 1993.

3. Biological methods

3.1. Enzyme assay

The active enzyme concentration was calculated using the formula described by Hendersen (P.J.F.Hendersen, biochem.J.1972, 127, 321-333). Inhibitor concentrations were determined by quantitative amino acid analysis. All analyses were repeated in quadruplicate.

Determination of antitrypsin Activity

The solution of trypsin was incubated with increasing concentrations of inhibitor for 5 minutes. Assay at 20 ℃ with 10mM CaCl₂In Tris-HCl buffer (pH7.8, 100 mM). The substrate was N- α -benzoyl-L-arginine-4-nitroaniline (3.2mM) and the initial reaction rate was monitored at 405nm over 30 minutes.

Determination of anti-Elastase Activity

As above, except that the substrate was N-succinyl-L-alanyl-L-prolyl-L-phenylalanine-4-nitroaniline (1.6 mM).

Apparent Ki values were calculated by fitting the initial rate data to the following equation, assuming competitive tight binding inhibition (j.f. williams, j.f. morrison, Methods enzymol.1979, 63, 437 467):

determination of anti-cathepsin G Activity

10mL of a solution of cathepsin G (0.2U/mL, corresponding to about 2. mu.M, from Calbiochem) was incubated with increasing concentrations of inhibitor for 15 minutes. Analysis of 700ml total volume containing 0.05mol/L CaCl at 37 deg.C₂In HEPES buffer (pH 7.5; 0.1 mol/L). Then, 70. mu.l of substrate (N-succinyl-L-alanyl-L-prolyl-L-phenylalanine-4-nitroaniline, 20mM in DMSO) was added. The release of p-nitroanilide was monitored at 405nm to determine the initial rate of reaction. Each measurement was repeated three times (A.J. Barrett, Methods in Enzymology, 1981, 80, 561-.

3.2. Results

Examples	Ki (nM) trypsin	Ki (nM) chymotrypsin	Ki (nM) cathepsin G
				Ex.1	100	＞10’000	100’000
Ex.2	1500	Nd	Nd
				Ex.3	＞10’000	Nd	Nd
Ex.4	700	Nd	Nd
				Ex.5	1900	Nd	Nd
Ex.6	＞25’000	Nd	Nd
				Ex.7	110	Nd	Nd
Ex.8	710	Nd	Nd
				Ex.9	＞25’000	4400	Nd
Ex.10	＞20’000	1400	Nd
				Ex.11	＞20’000	4700	Nd
Ex.15	21	3800	10’000

Nd: without measurement

Sequence listing

<110>POLYPHOR LTD

<120> template-fixed peptidomimetics as serine protease inhibitors

<130>P927PCT

<140>PCT/EP 01/14528

<141>2001-12-11

<160>15

<170>PatentIn Ver.2.1

<210>1

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<400>1

Thr Lys Ser Ile Pro Pro Ile Xaa Pro

1 5

<210>2

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<400>2

Ala Lys Ser Ile Pro Pro Ile Xaa Pro

1 5

<210>3

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<400>3

Thr Ala Ser Ile Pro Pro Ile Xaa Pro

1 5

<210>4

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<400>4

Thr Lys Ala Ile Pro Pro Ile Xaa Pro

1 5

<210>5

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<400>5

Thr Lys Ser Ala Pro Pro Ile Xaa Pro

1 5

<210>6

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<400>6

Thr Lys Ser Ile Ala Pro Ile Xaa Pro

1 5

<210>7

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<400>7

Thr Lys Ser Ile Pro Ala Ile Xaa Pro

1 5

<210>8

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<400>8

Thr Lys Ser Ile Pro Pro Ala Xaa Pro

1 5

<210>9

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<400>9

Thr Tyr Ser Ile Pro Pro Ile Xaa Pro

1 5

<210>10

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<400>10

Thr Trp Ser Ile Pro Pro Ile Xaa Pro

1 5

<210>11

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<400>11

Thr Phe Ser Ile Pro Pro Ile Xaa Pro

1 5

<210>12

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa at position 8 is D-Pro; xaa at position 9 is

4- (allyloxycarbonylamino) -Pro

<400>12

Thr Lys Ser Ile Pro Pro Ile Xaa Xaa

1 5

<210>13

<211>9

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa at position 8 is D-Pro; xaa at position 9 is

4- (n-hexylcarbonylamino) -Pro

<400>13

Thr Lys Ser Ile Pro Pro Ile Xaa Xaa

1 5

<210>14

<211>8

<212>PRT

<213> Artificial sequence

<220>

<223> Xaa is a divalent radical of 5-aminomethyl-9, 9-dimethyl-3, 6-dimethoxyxanthene-4-acetic acid

<220>

<223> Artificial sequence description: template-fixed peptidomimetics incorporating a chain of 7 amino acid residues

<400>14

Thr Lys Ser Ile Pro Pro Ile Xaa

1 5

<210>15

<211>13

<212>PRT

<213> Artificial sequence

<220>

<223> Artificial sequence description: cyclic peptides

<220>

<223> Xaa is D-Pro

<220>

<221> disulfide bond

<222>(2)..(10)

<400>15

Arg Cys Thr Lys Ser Ile Pro Pro Ile Cys Phe Xaa Pro

1 5 10

Claims

1. A compound having the following general formula (I) or a pharmaceutically acceptable salt thereof

Wherein

Is a group^DPro-^LPro；

Z is a chain of N α -amino acid residues, N being the integer 7 or 11, the positions of the amino acid residues in the chain being counted starting from the N-terminal amino acid; and also

-n is 7; and the amino acid residues at positions 1-7 are:

●P1：Thr；

●P2：Lys；

●P3：Ser；

●P4：Ile；

●P5：Pro；

●P6：Pro；

● P7: ile; or

●P1：Thr；

●P2：Lys；

●P3：Ala；

●P4：Ile；

●P5：Pro；

●P6：Pro；

● P7: ile; or

●P1：Thr；

●P2：Lys；

●P3：Ser；

●P4：Ile；

●P5：Pro；

●P6：Ala；

● P7: ile; or

●P1：Thr；

●P2：Lys；

●P3：Ser；

●P4：Ile；

●P5：Pro；

●P6：Pro；

●P7：Ala；

Or

-n is 11; and the amino acid residues at positions 1-11 are:

●P1：Arg；

●P2：Cys；

●P3：Thr；

●P4：Lys；

●P5：Ser；

●P6：Ile；

●P7：Pro；

●P8：Pro；

●P9：Ile；

●P10：Cys；

●P11：Phe，

the two Cys residues form a disulfide bond.

2. A pharmaceutical composition comprising a compound or salt according to claim 1 and a pharmaceutically inert carrier.

3. Use of a compound or salt according to claim 1 for the manufacture of a medicament for inhibiting a serine protease.

4. A process for the manufacture of a compound or salt according to claim 1, which process comprises

(a) Coupling a suitably functionalized solid support with a suitably N-protected derivative of an amino acid at position N/2+1/2 or N/2-1/2 in the desired end product, any functional groups that may be present in said N-protected amino acid derivative being likewise suitably protected;

(b) removing the N-protecting group from the product thus obtained;

(c) coupling the product thus obtained with a suitable N-protected derivative of an amino acid in the desired end product at a position close to the N-terminal amino acid residue, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;

(d) removing the N-protecting group from the product thus obtained;

(e) repeating steps (c) and (d) until the N-terminal amino acid residue has been introduced;

(f) coupling the product thus obtained to a compound of the general formula

Wherein

As defined above and X is an N-protecting group, or, alternatively,

(fa) reacting the product obtained in step (d) or (e) with^LCoupling of an appropriately N-protected derivative of Pro;

(fb) removing the N-protecting group from the product thus obtained; and

(fc) reaction of the product thus obtained with^DCoupling of an appropriately N-protected derivative of Pro;

(i) removing the N-protecting group from the product thus obtained;

(j) coupling the product thus obtained to a suitable N-protected derivative of an amino acid one position further than the N-position in the desired end product, any functional groups that may be present in said N-protected amino acid derivative being likewise suitably protected;

(k) removing the N-protecting group from the product thus obtained;

(l) Repeating steps (j) and (k) until all amino acid residues have been introduced;

(m) detaching the product thus obtained from the solid support;

(n) cyclizing the product cleaved from the solid support;

(o) removing any protecting groups present on the functional groups of any component of the chain of amino acid residues and any protecting groups that may otherwise be present in the molecule.

5. The method of claim 4, further comprising, between step (1) and step (m), the steps of: selectively deprotecting one or several protected functional groups present in the molecule and appropriately substituting the reactive groups thus released.

6. The method according to claim 4 or 5, wherein between step (n) and step (o) further comprising the steps of: interchain linkages are formed between the side chains of the appropriate amino acid residues at opposite positions in the β -strand region.

7. The method according to claim 4 or 5, wherein the following step is further included after step (o): converting the product obtained in step (o) into a pharmaceutically acceptable salt or converting the pharmaceutically acceptable or unacceptable salt obtained in step (o) into the corresponding free compound of formula I or into a different pharmaceutically acceptable salt.