WO2012016595A1

WO2012016595A1 - β-HAIRPIN PEPTIDOMIMETICS

Info

Publication number: WO2012016595A1
Application number: PCT/EP2010/061445
Authority: WO
Inventors: Daniel Obrecht; Frank Otto Gombert; John Anthony Robinson; Krystyna Patora-Komisarska
Original assignee: Polyphor AG; Zurich Universitaet Institut fuer Medizinische Virologie
Current assignee: Zurich Universitaet Institut fuer Medizinische Virologie; Spexis AG
Priority date: 2010-08-05
Filing date: 2010-08-05
Publication date: 2012-02-09
Anticipated expiration: 2013-02-05
Also published as: US8895499B2; US20130189363A1

Abstract

β-Hairpin peptidomimetics of the general formula Cyclo (-Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹- Xaa¹²-Xaa¹³-Xaa¹⁴-), enantiomers and pharmaceutically acceptable salts thereof, with Xaa¹ - Xaa¹⁴ being amino acid residues of certain types which are defined in the description and the claims, have anti-infective activity, e.g. to selectively inhibit the growth of or to kill microorganisms such as Bacillus subtilis and/or Shigella boydii. They can be used as medicaments to treat or prevent infections or as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials. These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

Description

β-Hairpin peptidomimetics

The present invention provides β-hairpin peptidomimetics having selective anti-infective activity.

The β-hairpin peptidomimetics of the invention are Cyclo (-Xaa^Xaa^Xaa^Xaa^-Xaa^Xaa^Xaa^Xaa^Xaa'-Xaa^-Xaa¹¹- Xaa¹²-Xaa¹³-Xaa¹⁴-) , and pharmaceutically acceptable salts thereof, with Xaa¹ to Xaa¹⁴ being as described herein below.

In addition, the present invention provides an efficient synthetic process by which these compounds can, if desired, be made in parallel library-format. These β-hairpin peptidomimetics show a significantly enhanced ratio between anti-infective activity on the one hand, and reduced hemolysis of red blood cells and reduced or no cytotoxicity on the other.

A major cause of death worldwide and a leading cause of mortality in developed countries are infectious diseases. They result from the presence of pathogenic microbial agents including pathogenic viruses and pathogenic bacteria. The growing problem of bacterial resistance to established antibiotics has stimulated intense interest in developing novel antimicrobial agents with new modes of action (D. Obrecht, J. A. Robinson, F. Bernadini, C. Bisang, S.J. DeMarco, K . Moehle, F.O. Gombert, Curr. Med. Chem. 2009, 16, 42-65; H. Breithaupt, Nat. Biotechnol. 1999, 27, 1165-1169). One emerging class of antibiotics is based on naturally occurring cationic peptides (T. Ganz, R.I. Lehrer, Mol. Medicine Today 1999, 5, 292-297; R.M. Epand, H.J. Vogel, Biochim. Biophys . Acta 1999, 1462, 11-28) . These include disulfide-bridged β-hairpin and β-sheet peptides (such as the protegrins [V.N. Kokryakov, S.S.L. Harwig, E.A. Panyutich, A. A. Shevchenko, G.M. Aleshina, O.V. Shamova, H.A. Korneva, R.I. Lehrer, FEBS Lett. 1993, 327, 231-236], tachyplesins [T. Nakamura, H. Furunaka, T. Miyata, F. Tokunaga, T. Muta, S. Iwanaga, M. Niwa, T. Takao, Y. Shimonishi, J. Biol. Chem. 1988, 263, 16709-16713], and the defensins [R.I. Lehrer, A.K. Lichtenstein, T. Ganz, Annu . Rev. Immunol. 1993, 11, 105-128], amphipathic a-helical peptides (e.g. cecropins, dermaseptins, magainins, and mellitins [A. Tossi, L. Sandri, A. Giangaspero, Biopolymers 2000, 55, 4-30]), as well as other linear and loop- structured peptides. Although the mechanisms of action of antimicrobial cationic peptides are not yet fully understood, their primary site of interaction is the microbial cell membrane (H.W. Huang, Biochemistry 2000, 39, 8347-8352) . Upon exposure to these agents, the cell membrane undergoes permeabilization, which is followed by rapid cell death. However, more complex mechanisms of action, for example, involving receptor-mediated signaling, cannot presently be ruled out (M. Wu, E. Maier, R. Benz, R.E. Hancock, Biochemistry 1999, 38, 7235-7242) .

Unlike most antibiotics, antiviral agents do not destroy the target viruses but they are able to inhibit the development of viral pathogens at different stages of their replication cycle, for example, by preventing the entry of the viruses to the target cells or by blocking essential steps during the viral synthesis within the target cells. Common diseases caused by viruses are, for example, influenza, avian influenza, swine influenza, severe acute respiratory syndrome (SARS) , or acquired immune deficiency syndrome (AIDS) . Encephalitis, meningitis, pharyngitis parotitis, gingivostomatitis, hepatitis, myelitis, gastroenteritis, pancreatitis, certain skin infections or cardiovascular diseases as well as pneumonia or sexually transmitted diseases can be caused by viral infections. In the compounds described below, a new strategy is introduced to stabilize β-hairpin conformations in backbone- cyclic cationic peptide mimetics exhibiting selective anti- infective activity. This involves transplanting the hairpin sequence onto a template, whose function is to restrain the peptide loop backbone into a hairpin geometry.

Template-bound hairpin mimetic peptides 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) and the ability to generate β-hairpin peptidomimetics using combinatorial and parallel synthesis methods has now been established (L. Jiang, K. Moehle, B. Dhanapal, D. Obrecht, J. A. Robinson, Helv. Chim. Acta. 2000, 83, 3097-3112) . Antibacterial template-fixed peptidomimetics and methods for their synthesis have been described in International Patent applications WO02/070547 Al, WO2004/018503 Al and WO2007/079605 A2 but these molecules do not show high potency and selectivity against Bacillus subtilis and/or Shigella boydii.

The β-hairpin peptidomimetics of the present invention are compounds of the general formula Cyclo ( -Xaa¹-Xaa²-Xaa -Xaa⁴- Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are:

Xaa¹ : amino acid residue of type C, or of type D,

as described herein below;

Xaa²: amino acid residue of type E,

as described herein below;

Xaa³: amino acid residue of type C, or of type F,

as described herein below;

Xaa⁴: amino acid residue of type C, or of type E,

as described herein below; Xaa⁵: amino acid residue of type C,

as described herein below;

Xaa⁶: amino acid residue of type E, as described herein below; or the D-isomer of an amino acid residue of type E, as described herein below;

Xaa⁷: amino acid residue of type F,

as described herein below, or Gly;

Xaa⁸: amino acid residue of type E,

as described herein below;

- Xaa⁹: amino acid residue of type E,

as described herein below;

Xaa¹⁰: amino acid residue of type C, or of type F,

as described herein below;

Xaa¹¹: amino acid residue of type E, or of type F,

as described herein below;

Xaa¹²: amino acid residue of type C, or of type E,

or of type F, as described herein below;

Xaa¹³: amino acid residue of formula -A-CO-,

as described herein below;

- Xaa¹⁴: amino acid residue of formula -B-C0-,

as described herein below;

with the proviso that if

Xaa⁹ is an amino acid residue of type E,

as described herein below,

then Xaa⁹ is Dab; and/or if

Xaa¹² is an amino acid residue of type F, as described herein below,

then Xaa¹² is Gin; and/or

at least two of the amino acid residues of Cyclo ( -Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹- Xaa¹ -Xaa¹³-Xaa¹⁴-) are non-canonical amino acid residues, as described herein below; or compounds of the general formula Cyclo ( -Xaa¹-Xaa²-Xaa³- Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are: - Xaa¹: amino acid residue of type D,

as described herein below;

Xaa²: amino acid residue of type E,

as described herein below;

Xaa³: amino acid residue of type C, or of type F,

as described herein below;

Xaa⁴: amino acid residue of type E,

as described herein below;

Xaa⁵: amino acid residue of type C,

as described herein below;

- Xaa⁶: amino acid residue of type E, or the D-isomer of an amino acid residue of type E,

as described herein below;

Xaa⁷: amino acid residue of type C, or of type D,

or of type E, or of type F,

as described herein below, or Gly;

Xaa⁸: amino acid residue of type F,

as described herein below;

Xaa⁹: amino acid residue of type E,

as described herein below;

- Xaa¹⁰: amino acid residue of type C, or of type D,

or of type F, as described herein below;

Xaa¹¹: amino acid residue of type E, or or type F,

as described herein below;

Xaa¹²: amino acid residue of type C or of type E,

as described herein below;

Xaa¹³: amino acid residue of formula -A-CO-,

as described herein below;

Xaa¹⁴: amino acid residue of formula -B-CO-,

as described herein below;

with the proviso that if

Xaa⁷ is an amino acid residue of type F, as described herein below,

then Xaa⁷ is Gin or Thr; and/or if

Xaa¹⁰ is an amino acid residue of type F, as described herein below,

then Xaa¹⁰ is Ser; and/or

at least one of the amino acid residues Cyclo (-Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^-Xaa¹ Xaa¹²-Xaa¹³-Xaa¹⁴- ) is a non-canonical amino acid residue, as described herein below; or compounds of the general formula Cyclo (-Xaa¹-Xaa²-Xaa³- Xaa -Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa -Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are:

Xaa¹: amino acid residue of type D,

as described herein below;

Xaa²: amino acid residue of type E,

as described herein below;

Xaa³: amino acid residue of type C,

as described herein below;

Xaa⁴: amino acid residue of type E,

as described herein below;

- Xaa⁵: amino acid residue of type C,

as described herein below;

Xaa⁶: amino acid residue of type E, as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below;

- Xaa⁷: amino acid residue of type F,

as described herein below;

Xaa⁸: amino acid residue of type D,

as described herein below;

Xaa⁹: amino acid residue of type E,

as described herein below; amino acid residue of type F

as described herein below;

amino acid residue of type E

as described herein below;

amino acid residue of type E

as described herein below;

amino acid residue of formul

as described herein below;

amino acid residue of formul

as described herein below; or compounds of the general formula Cyclo ( -Xaa¹-Xaa²-Xaa³- Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are:

Xaa¹ : amino acid residue of type D,

as described herein below;

- Xaa²: amino acid residue of type E,

as described herein below;

Xaa³: amino acid residue of type E,

as described herein below;

Xaa⁴: amino acid residue of type E,

as described herein below;

Xaa⁵: amino acid residue of type C,

as described herein below, or Gly;

Xaa⁶: amino acid residue of type E, or of type F,

as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below, or -B-CO-, as described herein below or

Gly;

Xaa⁷: amino acid residue of type E, as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below, or Gly; Xaa⁸: amino acid residue of type F,

as described herein below, or Gly;

Xaa⁹: amino acid residue of type E,

as described herein below;

- Xaa¹⁰: amino acid residue of type F,

as described herein below;

Xaa¹¹: amino acid residue of type E,

as described herein below;

Xaa¹²: amino acid residue of type E,

as described herein below;

Xaa¹³: amino acid residue of formula -A-C0-,

as described herein below;

Xaa¹⁴: amino acid residue of formula -B-C0-,

as described herein below;

with the proviso that at least one of the amino acid residues of Cyclo (-Xaa^Xaa^Xaa^Xaa^Xaa^ aa^Xaa'-Xaa⁸- Xaa⁹-Xaa¹⁰-Xaa^1:L-Xaa¹²-Xaa¹³-Xaa¹⁴- ) is a non-canonical amino acid residue, as described herein below; or compounds of the general formula Cyclo (-Xaa¹-Xaa²-Xaa³- Xaa -Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaaⁿ-Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are:

Xaa¹: amino acid residue of type E,

as described herein below;

Xaa²: amino acid residue of type E,

as described herein below;

- Xaa³: amino acid residue of type C, or of type F,

as described herein below;

Xaa⁴: amino acid residue of type E,

as described herein below;

Xaa⁵: amino acid residue of type C, or of type F,

as described herein below; Xaa⁶: amino acid residue of type E, as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below;

Xaa⁷: Gly;

Xaa⁸: amino acid residue of type E, or of type F,

as described herein below;

Xaa⁹: amino acid residue of type E,

as described herein below;

Xaa¹⁰: amino acid residue of type C, or of type F,

as described herein below;

Xaa¹¹: amino acid residue of type E,

as described herein below;

Xaa¹²: amino acid residue of type E,

as described herein below;

Xaa¹³: amino acid residue of formula -A-CO-,

as described herein below;

Xaa¹⁴: amino acid residue of formula -B-CO-,

as described herein below;

with the proviso that at least two of the amino acid residues of Cyclo ( -Xaa^Xaa^Xaa^Xaa^ aa^Xaa^Xaa^Xaa⁸- Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹²-Xaa¹³-Xaa¹⁴- ) are non-canonical amino acid residues; or compounds of the general formula Cyclo ( -Xaa¹-Xaa²-Xaa³- Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaaⁿ-Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are:

Xaa¹: amino acid residue of type E,

as described herein below;

Xaa²: amino acid residue of type C, or of type F,

as described herein below;

Xaa³: amino acid residue of type E,

as described herein below;

- Xaa⁴: amino acid residue of type E,

as described herein below; Xaa⁵: amino acid residue of type C,

as described herein below;

Xaa⁶: amino acid residue of type E,

as described herein below;

- Xaa⁷: Gly;

Xaa⁸: amino acid residue of type F,

as described herein below;

Xaa⁹: amino acid residue of type E,

as described herein below;

- Xaa¹⁰: amino acid residue of type E, or of type F,

as described herein below;

Xaa¹¹: amino acid residue of type E, or of type F,

as described herein below;

Xaa¹²: amino acid residue of type E,

as described herein below;

Xaa¹³: amino acid residue of formula -A-C0-,

as described herein below;

Xaa¹⁴: amino acid residue of formula -B-CO-,

as described herein below;

- the amino acid residues Xaa² and Xaa¹¹, taken together, can form an amino acid residue of type H,

as described herein below;

with the proviso that at least one of the amino acid residues of Cyclo (-Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa⁸- Xaa⁹-Xaa¹⁰-Xaaⁿ-Xaa¹²-Xaa¹³-Xaa¹⁴-) are non-canonical amino acid residues; or compounds of the general formula Cyclo (-Xaa^Xaa^Xaa³- Xaa -Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa^u-Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are:

Xaa¹: amino acid residue of type, E or of type F,

as described herein below; : amino acid residue of type C, or of type D, or of type E, or of type F, as described herein below;

Xaa³: amino acid residue of type E, as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below, or Gly;

Xaa⁴: amino acid residue of type C, or of type D, or of type E, or of type F, as described herein below;

^— Xaa⁵: amino acid residue of type E,

as described herein below;

^— Xaa⁶: amino acid residue of type E, or of type F,

as described herein below, or Gly;

Xaa⁷: amino acid residue of type D, or of type E, or of type F, as described herein below, or Gly;

Xaa⁸: amino acid residue of type E,

as described herein below;

Xaa⁹: amino acid residue of type D, or of type E,

as described herein below;

Xaa¹⁰: amino acid residue of type C, or of type D, or of type E, or of type F, as described herein below; Xaa¹¹: amino acid residue of type D, or of type E, or of type F, as described herein below, or Gly;

Xaa¹²: amino acid residue of type C, or of type D, or of type E, or of type F, as described herein below; Xaa¹³: amino acid residue of formula -A-C0-,

as described herein below;

Xaa¹⁴: amino acid residue of formula -B-CO-,

as described herein below;

the amino acid residues Xaa² and Xaa¹¹, taken together, can form an amino acid residue of type H,

as described herein below;

with the proviso that at least two of the amino acid residues of Cyclo (-Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸- Xaa⁹-Xaa¹⁰-Xaa^u-Xaa¹²-Xaa¹³-Xaa¹⁴-) are non-canonical amino acid residues; -B-CO- is Gly, NMeGly or the residue of an L-a-amino acid with B being a residue of formula -NR²⁰CH (R⁷¹) -, or - NR²⁰CH (R⁷²) or -NR²⁰CH (R⁷³) -, or -NR²⁰CH (R⁷⁴ ) - , or -NR²⁰CH (R⁸⁴) - , or the enantiomer of one of the groups Al to A69 as defined hereinafter;

A of -A-CO- is a group of one of the formulae

A1 A2 A3 A4

A5 A6 A7 A8 A9

A10 A11 A12 A13 A14

A15 A16 A17 A18 A19

R¹ is H; lower alkyl; lower cycloalkyl; lower alkyl-aryl or aryl-lower alkyl;

R² is H; alkyl; alkenyl; - (CH₂) _p (CHR⁶¹) _sOR⁵⁵;

- (CH₂)_P(CHR⁶¹) _SSR⁵⁶;

- (CH₂) _p (CHR⁶¹) _SNR³³R³⁴; - (CH₂) _p (CHR⁶¹) _sOCONR³³R⁷⁵;

- (CH₂) p (CHR⁶¹) _SNR²⁰CONR³³R⁸²; - (CH₂) ₀ (CHR⁶¹) _sCOOR⁵⁷;

- (CH₂) o (CHR⁶¹) _sCONR⁵⁸R⁵⁹; - (CH₂) ₀ (CHR⁶¹) _sPO (OR⁶⁰) ₂;

- (CH₂)₀(CHR⁶¹) _sS0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SR⁷⁷;

R³ is alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵⁶;

- (CH₂)₀(CHR⁶¹)_SNR³³R³⁴;

- (CH₂) ₀ (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂) o (CHR⁶¹) sCOOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

- (CH₂)_o(CHR⁶¹) _sPO(OR⁶⁰)₂;

- (CH₂)₀(CHR⁶¹) _S S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R⁴ is H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵; - (CH₂) _m (CHR⁶¹) _SSR⁵⁶

- (CH₂ )_m(CHR⁶¹) _SNR³³R³⁴;

- (CH₂ )_m(CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) _m (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂ ) (CHR⁶¹) sCOOR⁵⁷; - (CH₂ ) _p (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

- (CH₂ )_P(CHR⁶¹) _SPO(OR⁶⁰)₂;

- (CH₂ )_P(CHR⁶¹) s S0₂R⁶²; or - (CH₂)₀(CHR⁶¹) ₅C₆H₄R⁸;

⁵ is H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵;

- (CH₂) (CHR⁶¹) sSR⁵⁶;

- (CH₂) i_m(CHR⁶¹) _SNR³³R³⁴; - (CH₂) _m (CHR⁶¹) _sOCONR³³R⁷⁵;

- (CH₂) _m (CHR⁶¹ ) _SNR²⁰CONR³³R⁸²; - (CH₂) ₀ (CHR⁶¹) _sCOOR⁵⁷ ;

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

- (CH₂) o(CHR⁶¹) S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

,⁶ is H; alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵;

- (CH₂) (CHR⁶¹) _SSR⁵⁶; - (CH₂) ₀ (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) o (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂) o (CHR⁶¹) _sCOOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂;

-(CH₂)o(CHR⁶¹)_s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

7 is alkyl; alkenyl; - (CH₂) _q (CHR⁶¹) _sOR⁵⁵; - (CH₂) _q (CHR⁶¹) _SNR³³R³⁴;

- (CH₂)_q(CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂ ) _q (CHR⁶¹ ) _SNR²⁰CONR³³R⁸ ;

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

-(CH₂)_r(CHR⁶¹)_sPO(OR⁶⁰)₂; -(CH₂)_r(CHR⁶¹)_sS0₂R⁶²; or - (CH₂) _r (CHR⁶¹) _s C₆H₄R⁸;

H; CI; F; CF₃; N0₂; lower alkyl; lower cycloalkyl; lower alkenyl; aryl; lower alkyl-aryl; aryl-lower alkyl; - (CH₂) ₀ (CHR⁶¹) _SR⁷⁷

- (CH₂) o (CHR⁶¹) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵⁶;

- (CH₂)o(CHR⁶¹)NR³³R³⁴ ;

- (CH₂) o (CHR⁶¹) sCOOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _sC0NR⁵⁸R⁵⁹;

- (CH₂) o (CHR⁶¹) _sPO (OR⁶⁰) ₂;

-(CH₂)_o(CHR⁶¹)_sS0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _sC0R⁶⁴;

alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵⁶

-(CH₂)₀(CHR⁶¹)_SNR³³R³⁴;

- (CH₂) o (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) ₅NR²⁰CONR³³R⁸²;

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂;

-(CH₂)₀(CHR⁶¹)_S S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

- (CH₂) _o (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) o (CHR⁶¹) _sCOOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _sC0NR⁵⁸R⁵⁹;

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂;

H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _S0R⁵⁵;

- (CH₂) _m (CHR⁶¹ ) _SNR³³R³⁴;

--((CCHH₂₂))_mm((CCHHRR⁶⁶¹¹))_s _SOOCCOONNRR-³'³³RR^7'5; - (CH₂) _m (CHR⁶¹) _SNR²⁰CONR³³R^;

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

-(CH₂) _o(CHR⁶¹) _sPO (OR⁶⁰) ;

- (CH₂) _o(CHR⁶¹) _sS0₂R⁶²; cor - (CH₂)₀(CHR⁶¹)_S C₆H₄R⁸;

R¹² is H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵;

- (CH₂) _m (CHR⁶¹) _SSR⁵⁶;

- (CH₂) _ra (CHR⁶¹) _SNR³³R³⁴; - (CH₂) _m (CHR⁶¹) _sOCONR³³R⁷⁵;

- (CH₂) _m (CHR⁶¹) _SNR⁰CONR³³R⁸²; - (CH₂) _r (CHR⁶¹) _sCOOR⁵⁷;

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

~ (CH₂) _r (CHR⁶¹) _s S0₂R⁶²; or - (CH₂) _r (CHR⁶¹) _SC₆H₄R⁸;

R¹³ is alkyl; alkenyl; - (CH₂) _q (CHR⁶¹) _S0R⁵⁵; - (CH₂) _q (CHR⁶¹) _SSR⁵

- (CH₂) _q (CHR⁶¹) _SNR³³R³⁴; (CH₂) _q (CHR ) _sOCONR R^,b; - (CH₂) _q (CHR ) _SNR²⁰CONR^' (CH₂ ) _q (CHR⁶¹) ₃COOR⁵⁷ ; - (CH₂) _q (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

(CH₂)_q(CHR⁶¹)_sPO(OR⁶⁰)₂;

-(CH₂)_q(CHR^bl)_s S0₂R"; or - (CH₂) _q (CHR⁶¹) _SC₆H₄R⁸;

R¹⁴ is H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵;

- (CH₂)_ra(CHR⁶¹)_sNR³³R³⁴

(CH₂)_m(CHR^bi) _sOCONR^J¾'^¾; - (CH₂) _m (CHR ) s R^CONR^R¹

(CH₂))q_q ^l(CHR⁶¹)_sCOOR⁵⁷; - (CH₂) _q (CHR ) _sCONR^;

- (CH₂)_q(CHR^bl)_sPO(OR^6U)₂; .

-(CH₂)_q(CHR⁶¹)_sSOR⁶²; or - (CH₂) _q (CHR⁶¹) _s C₆H₄R⁸;

R¹⁵ is alkyl; alkenyl; - (CH₂ ) ₀ (CHR⁶¹ ) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵

- (CH₂) o (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) o ( CHR⁶¹ ) _sOCONR³³R⁷⁵ ; - (CH₂) o (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂) o (CHR⁶¹) sCOOR⁵⁷; - (CH₂ )o(CHR⁶¹)_sCONR⁵⁸R⁵⁹;

- (CH₂) _o(CHR⁶¹)_sPO(OR⁶⁰)₂;

- (CH₂) o(CHR⁶¹)s S0₂R⁶²; or - (CH₂)₀(CHR⁶¹)_SC₆H₄R⁸;

R is alkyl; alkenyl; - (CH₂) ₀ (CHR ) _sOR ; - (CH₂) ₀ (CHR ) _SSR³ ,

- (CH₂) o (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) ₀ (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) _SNR⁰CONR³³R⁸² ; -(CH₂)_o(CHR⁶¹)₃C00R⁵⁷; - (CH₂) ₀ (CHR⁶¹) ₃CONR⁵⁸R⁵⁹;

- (CH₂)_o(CHR⁵¹)_sPO(OR⁶⁰)₂;

-(CH₂)o(CHR⁶¹)_s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R¹⁷ is alkyl; alkenyl; - (CH₂) _q (CHR⁶¹) _sOR⁵⁵; - (CH₂) _q (CHR⁶¹) _SSR⁵⁶;

- (CH₂) _q (CHR⁶¹ ) _SNR³³R³⁴;

-- ((CCHH₂₂)) _qq ((CCHHRR^b6i1)) _ssOOCCOONNRR^J3J3RR^''^b; - (CH₂) _q (CHR⁶¹) _SNR⁰CONR³³R⁸²;

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

- (CH₂) _q (CHR⁶¹ ) _sPO (OR⁶⁰) ;

- (CH₂) _q (CHR⁶¹ )s S0₂R⁶²; or - (CH₂)_q(CHR⁶¹) _SC₆H₄R^S;

R^1B is alkyl; alkenyl; - (CH₂) _p (CHR⁶¹) _sOR⁵⁵; - (CH₂) _p (CHR⁶¹) _SSR⁵⁶;

- (CH₂) _P(CHR⁶¹) _SNR³³R³⁴;

-(CH₂) (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) _p (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

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

- (CH₂) (CHR⁶¹) _sPO (OR⁶⁰) ₂;

- (CH₂) (CHR⁶¹)_s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R¹⁹ is lower alkyl; - (CH₂) _p (CHR⁶¹) _sOR⁵⁵; - (CH₂) _p (CHR⁶¹) _SSR⁵⁶;

- (CH₂) (CHR⁶¹) _SNR³³R³⁴; - (CH₂) p (CHR ) sOCONR R ; - (CH₂) _p (CHR ) _SNR²⁰CONR³³R⁸²;

- (CH₂) _p (CHR⁶¹) sCOOR⁵⁷; - (CH₂) _p (CHR⁶¹) _sCONR ⁸R⁵⁹;

-(CH₂)_P(CHR⁶¹)_SPO(OR⁶⁰)₂;

- (CH₂)_P(CHR⁶¹) S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸; or R¹⁸ and R¹⁹ taken together can form: -(CH₂)₂_₆-;

- (CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-; R²⁰ is H; alkyl; lower cycloalkyl; alkenyl; lower alkyl-aryl or aryl-lower alkyl;

R²¹ is H; alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵;

- (CH₂) > o (CHR⁶¹ )_SSR⁵⁶; -(CH₂)o (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) o(CHR⁶¹ ) _sOCONR³³R⁷⁵; - (CH₂) o (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂) ₀(CHR⁶¹ )_sCOOR⁵⁷; - (CH₂ ) o (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

- (CH₂) o(CHR⁶¹ )_SPO(OR⁶⁰)₂;

- (CH₂) ₀(CHR⁶¹ )s S0₂R⁶²; or - (CH₂) o (CHR⁶¹) _sCgH₄R⁸;

R is H; alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵;

- (CH₂) ₀ (CHR⁶¹) _SSR⁵⁶; - (CH₂) ₀ (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) ₀ (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) _SNR ⁰CONR³³R⁸²;

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂;

- (CH₂)₀(CHR⁶¹) S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R²³ is alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵⁶;

- (CH₂)o(CHR⁶¹)_sNR³³R³⁴;

- (CH₂) ₀ (CHR⁶¹) _sCOOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂;

R²⁴ is alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵⁶;

-(CH₂)₀(CHR⁶¹)_SNR³³R³⁴;

-(CH₂)₀(CHR⁶¹)_SPO(OR⁶⁰)₂;

-(CH₂)o(CHR⁶¹)_s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R²⁵ is H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵;

- (CH₂)_ra(CHR⁶¹)_sSR⁵⁶;

- (CH₂) _m (CHR⁶¹) _SNR³³R³⁴; - (CH₂ ) _m (CHR⁶¹ ) _sOCONR³³R⁷⁵;

- (CH₂)_m(CHR⁶¹) _SNR²⁰CONR³³R⁸²; - (CH₂) ₀ (CHR⁶¹) _sCOOR⁵⁷; - (CH₂) o (CHR ) sCONR R ; - (CH₂) ₀ (CHR ) _sPO (OR ) ₂;

- (CH₂) ₀ (CHR⁶¹) _sS0₂R⁶²; or - (C¾) ₀ (CHR⁶¹) _SC₆H₄R⁸;

is H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵;

- (CH₂) _m (CHR⁶¹) _SSR⁵⁶;

- (CH₂)_ra(CHR⁶¹) _SNR³³R³⁴; - (CH₂) _m (CHR⁶¹) _sOCONR³³R⁷⁵;

- (CH₂) _m (CHR⁶¹) _SNR²⁰CONR³³R⁸²; - (CH₂) ₀ (CHR⁶¹) _sCOOR⁵⁷;

- (CH₂) ₀ (CHR⁶¹) _S S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸; or and R²⁶ taken together can form: - (CH₂) ₂-₆-; - (CH₂) _rO (CH₂) _r

- (CH₂) _rS (CH₂) _r-; or - (CH₂) _rNR⁵⁷ (CH₂) _r- ;

is H; alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵;

- (CH₂) o (CHR⁶¹) _SSR⁵⁶; - (CH₂) ₀ (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) o (CHR⁶¹) _sOCONR³³R⁷⁵;

- (CH₂) o (CHR⁶¹) _SNR²⁰CONR³³R⁸²; - (CH₂) ₀ (CHR⁶¹) _sPO (OR⁶⁰) ₂; - (CH₂) o (CHR⁶¹) _s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

is alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _s-OR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _s S - (CH₂) o (CHR⁶¹) _s NR³³R³⁴;

- (CH₂) o (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) _SNR²⁰CONR³³R⁸² ; - (CH₂) ₀ (CHR⁶¹) _S COOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _s CONR⁵⁸R⁵⁹;

- (CH₂) ₀ (CHR⁶¹) _s PO (OR⁶⁰) ₂;

- (CH₂) o (CHR⁶¹) S0₂R⁶²; or - (CH₂) _Q (CHR⁶¹) _s C₆H₄R⁸;

is alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _S0R⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵' - (CH₂) ₀ (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) o (CHR⁶¹) _s0C0NR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) _SNR ⁰CONR³³R⁸² ;

- (CH₂) ₀ (CHR⁶¹) sCOOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _sC0NR⁵⁸R⁵⁹;

- (CH₂) _o (CHR⁶¹) _sPO (OR⁶⁰) ₂;

- (CH₂) ₀ (CHR⁶¹) _S S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

is H; alkyl, alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵;

- (CH₂)_m(CHR⁶¹) _sNR³⁴R⁶³;

- (CH₂)_m (CHR⁶¹) _sOCONR⁷⁵R⁸²; - (CH₂) _m (CHR⁶¹) _SNR²⁰CONR⁷⁸R⁸²;

- (CH₂) ₀ (CHR⁶¹) sCOR⁶⁴; - (CH₂) ₀ (CHR⁶¹) _s-CONR⁵⁸R⁵⁹,

- (CH₂) ₀ (CHR⁶¹) _SPO (OR⁶⁰) ₂;

is H; lower alkyl; lower cycloalkyl; lower alkyl-aryl; aryl or aryl-lower alkyl; or R³³ and R³⁴ taken together can form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂- ;

-(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-;

R⁵⁰ is H; lower alkyl; lower cycloalkyl; lower alkyl-aryl; or aryl-lower alkyl;

R⁵⁵ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; aryl-lower alkyl;

-(CH₂)_m(CHR⁶¹)_sOR⁵⁷;

- (CH₂) _ra(CHR⁶¹) _SNR³⁴R⁶³; - (CH₂) _m (CHR⁶¹) ₃OCONR⁷⁵R⁸²;

- (CH₂)_m(CHR⁶¹) _SNR²⁰CONR⁷⁸R⁸²; - (CH₂) ₀ (CHR⁶¹) _s-COR⁶⁴;

- (CH₂) _o (CHR⁶¹) COOR⁵⁷; or

- (CH₂) _o (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

R⁵⁶ is H; lower alkyl; lower alkenyl; lower alkyl-aryl;

aryl-lower alkyl;

- (CH₂)_m(CHR⁶¹) _sOR⁵⁷;

- (CH₂) _m (CHR⁶¹) _SNR³⁴R⁶³; - (CH₂) _m (CHR⁶¹) _sOCONR⁷⁵R⁸²;

- (CH₂)_m(CHR⁶¹) _SNR²⁰CONR⁷⁸R⁸²; - (CH₂) ₀ (CHR⁶¹) _s-COR⁶⁴; or

- (CH₂) _o (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

R⁵⁷ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; aryl-lower alkyl;

lower alkyl-heteroaryl; or heteroaryl-lower alkyl;

R⁵⁸ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; aryl-lower alkyl;

lower alkyl-heteroaryl; or heteroaryl-lower alkyl;

R⁵⁹ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; aryl-lower alkyl;

lower alkyl-heteroaryl; or heteroaryl-lower alkyl; or R⁵⁸ and R⁵⁹ taken together can form: -(CH₂)_2-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂)₂S (CH₂)₂- or

-(CH₂)₂NR⁵⁷(CH₂)₂-;

R⁶⁰ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; aryl; or aryl-lower alkyl;

R⁶¹ is alkyl; alkenyl; lower cycloalkyl; lower alkyl-aryl; lower alkyl-heteroaryl; aryl; heteroaryl;

aryl-lower alkyl; heteroaryl-lower alkyl; -(CH₂)_pOR⁵⁵;

- (CH₂) _PNR³³R³⁴; - (CH₂ ) _pOCONR⁷⁵R⁸ ; - (CH₂) _pNR²⁰CONR⁷⁸R⁸² ;

- (CH₂) _oCOOR³⁷; or - (CH₂) _oP0 (OR⁶⁰) ₂; R is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower alkyl-aryl; lower alkyl-heteroaryl; aryl;

heteroaryl; aryl-lower alkyl; or

heteroaryl-lower alkyl;

R⁶³ is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower alkyl-aryl; lower alkyl-heteroaryl; aryl;

heteroaryl; aryl-lower alkyl; or

heteroaryl-lower alkyl;

-COR⁶⁴; -COOR⁵⁷; -CONR⁵⁸R⁵⁹; -S0₂R⁶²; or -PO(OR⁶⁰)₂; or R³⁴ and R⁶³ taken together can form: -(CH₂)₂-6-; - (CH₂) ₂0 (CH₂)

-(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-;

R⁶⁴ is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower alkyl-aryl; lower alkyl-heteroaryl; aryl;

heteroaryl; aryl-lower alkyl; or

heteroaryl-lower alkyl;

- (CH₂)_P(CHR⁶¹) _sOR⁶⁵; - (CH₂) _p (CHR⁶¹) _SSR⁶⁶;

- (CH₂)p(CHR⁶¹) _SNR³⁴R⁶³;

- (CH₂) p (CHR⁶¹) _sOCONR⁷⁵R⁸²; or - (CH₂) _P (CHR⁶¹) _SNR²⁰CONR⁷⁸R⁸²; R⁶⁵ is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower alkyl-aryl; lower alkyl-heteroaryl; aryl;

heteroaryl; aryl-lower alkyl; or

heteroaryl-lower alkyl; -COR⁵⁷;

-COOR⁵⁷; or -CONR⁵⁸R⁵⁹;

R⁶⁶ is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower alkyl-aryl; lower alkyl-heteroaryl; aryl;

heteroaryl; aryl-lower alkyl; or

heteroaryl-lower alkyl; or -CONR⁵⁸R⁵⁹;

R⁶⁷ is H; CI; Br; F; N0₂; -NR³⁴COR⁵⁷; -CF₃; CN; -OCF₃; -OCHF₂;

-OR⁵⁷; -SR⁶²; lower alkyl; or

lower alkenyl;

R⁶⁸ is H; CI; Br; F; N0₂; -NR³⁴COR⁵⁷; -CF₃; CN; -OCF₃; -OCHF₂;

-OR⁵⁷; -SR⁶²; lower alkyl; or

lower alkenyl;

R⁶⁹ is H; CI; Br; F; N0₂; -NR³⁴COR⁵⁷; -CF₃; CN; -OCF₃; -OCHF₂;

-OR⁵⁷; -SR⁶²; lower alkyl; or

lower alkenyl; R'° is H; CI; Br; F; N0₂; -NR³⁴COR⁵⁷; -CF₃; CN; -OCF₃; -OCHF₂;

-OR⁵⁷; -SR⁶²; lower alkyl; or

lower alkenyl;

R⁷¹ is lower alkyl; lower alkenyl; - (CH₂) _p (CHR⁶¹) _sOR⁷⁵;

- (CH₂)p(CHR⁶¹)_sSR⁷⁵;

- (CH₂) p (CHR⁶¹) _SNR³³R³⁴; - (CH₂) _p (CHR⁶¹) _sOCONR³³R⁷⁵;

- (CH₂) p (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂)_o(CHR⁶¹)_sC00R⁷⁵; - (CH₂) _pCONR⁵⁸R⁵⁹; - (CH₂) _pPO (OR⁶²) ₂;

- (CH₂)_pS0₂R⁶²; or

- (CH₂) _o-C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶;

R⁷² is alkyl; alkenyl; lower cycloalkyl; - (CH₂) _p (CHR⁶¹) _sOR⁸⁵; or

-(CH₂)p(CHR⁶¹)_sSR⁸⁵;

R⁷³ is - (CH₂)₀R⁷⁷; - (CH₂) _rO (CH₂) ₀R⁷⁷; - (CH₂) _rS (CH₂) ₀R⁷⁷; or

-(CH₂)_rNR ⁰(CH₂)_oR⁷⁷;

R⁷⁴ is - (CH₂)_PNR⁷⁸R⁷⁹; - (CH₂) _PNR⁷⁷R⁸⁰; - (CH₂) _PC (=NR⁸⁰) NR⁷⁸R⁷⁹;

- (CH₂) _PC (=NOR⁰)NR⁷⁸R⁷⁹;

- (CH₂) _PC (=NNR⁷⁸R⁷⁹) NR⁷⁸R⁷⁹; - (CH₂) _pNR⁸⁰C (=NR⁸⁰) NR⁷⁸R⁷⁹;

- (CH₂) _PN=C (NR⁷⁸R⁸⁰) NR⁷⁹R⁸⁰; - (CH₂) _PC₆H₄NR⁷⁸R⁷⁹;

- (CH₂)_PC₆H₄NR⁷R⁸⁰;

- (CH₂)_PC₆H₄C (=NR⁸⁰)NR⁷⁸R⁷⁹; - (CH₂) _PC₆H₄C (=NOR⁵⁰) NR⁷⁸R⁷⁹;

- (CH₂) _PC₆H₄C (=NNR⁷⁸R⁷⁹) NR⁷⁸R⁷⁹; - (CH₂) _PC₆H₄NR⁸⁰C (=NR⁸⁰) NR⁷⁸R⁷⁹;

- (CH₂) P_PCC₆H₄N=C (NR⁷⁸R⁸⁰)NR'⁹R⁸⁰; - (CH₂) _rO (CH₂) _mNR⁷⁸R⁷⁹;

(CH₂)_rO(CH₂)_mNR⁷⁷R⁸⁰;

(CH₂) _rO (CH₂) _PC (=NR ) NR R⁷⁹; - (CH₂) _rO (CH₂) _PC (=NOR⁵⁰) NR⁷⁸R

(CH₂) _rO (CH₂) _PC (=NNR⁷⁸R⁷⁹) NR⁷⁸R⁷⁹;

(CH₂) _rO (CH₂) _mNR⁸⁰C (=NR⁸⁰) NR⁷⁸R⁷⁹;

(CH₂) _rO (CH₂) _mN=C (NR⁷⁸R⁸⁰) NR⁷⁹R⁸⁰;

(CH₂) _rO (CH₂)pC₆H₄CNR⁷⁸R⁷⁹;

(CH₂) _rO (CH₂) _PC₆H₄C (=NR⁸⁰) NR⁷⁸R⁷⁹;

(CH₂) _rO (CH₂) _PC₆H₄C (=NOR⁵⁰) NR⁷⁸R⁷⁹;

(CH₂) _rO (CH₂) _PC₆H₄C (=NNR⁷⁸R⁷⁹) NR⁷⁸R⁷⁹;

(CHz) rO (CH₂)pC₆H₄NR⁸⁰C (=NR⁸⁰) NR⁷⁸R⁷⁹; - (CH_Z)_ES (CH₂) _mNR⁷⁸R⁷⁹; (CH₂) _rS (CH₂) _mNR⁷⁷R⁸⁰; - (CH₂) _rS (CH₂) _PC (=NR⁸⁰) NR⁷⁸R⁷⁹;

(CH₂ ) _rS (CH₂ ) _PC (=NOR⁵⁰) NR⁷⁸R⁷⁹;

(CH₂) _rS (CH₂) _PC (=NNR⁷⁸R⁷⁹) NR⁷⁸R⁷⁹; - (CH₂) _rS (CH₂) _mNR^auC (=NR ) NR R ;

- (CH₂) _rS (CH₂) _mN=C (NR⁷⁸R⁸⁰) NR⁷⁹R⁸⁰;

- (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) _PNR⁸⁰COR⁶⁴;

- (CH₂) pNR⁸⁰COR⁷⁷;

- (CH₂)pNR⁸⁰CONR⁷⁸R⁷⁹; or - (CH₂) _PC₆H₄NR⁸⁰CONR⁷⁸R⁷⁹;

R is lower alkyl; lower alkenyl; lower cycloalkyl;

lower-alkyl-aryl; or aryl-lower alkyl; or

R³³ and R⁷⁵ taken together can form: -(CH₂)₂_₆-; - (C¾) ₂0 (CH₂) ₂-;

- (CH₂)₂S (CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- ; or

R⁷⁵ and R⁸² taken together can form: -(CH₂ ) ₂- 6- ; - (CH₂) ₂0 (CH₂) ₂-;

-(CH₂)₂S(CH₂)₂-; or

- (CH₂)₂NR⁵⁷(CH₂)₂-;

R⁷⁶ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower-alkyl-aryl; aryl-lower alkyl;

-(CH₂)_o0R⁷²; -(CH₂)₀SR⁷²;

- (CH₂) ₀NR³³R³⁴; - (CH₂) _o0C0NR³³R⁷⁵; - (CH₂) ₀NR²⁰CONR³³R⁸¹;

- (CH₂) _oCOOR⁷⁵; - (CH₂) ₀CONR⁵⁸R⁵⁹; - (CH₂) _oP0 (OR⁶⁰) ₂;

- (CH₂)_pS0₂R⁶²; or

- (CH₂)_oC0R⁶⁴;

R⁷⁷ is -C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶ with the proviso that at least two of R⁶⁷, R⁶⁸, R⁶⁹ and R⁷⁰ are H; or a heteroaryl group of one of the formulae

H6 H7 H8 H9 H10

R is H; lower alkyl; lower cycloalkyl; lower alkyl-aryl; aryl; or aryl-lower alkyl; or

R⁷⁸ and R⁸² taken together can form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

-(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-;

R⁷⁹ is H; lower alkyl; lower alkyl-aryl; aryl; or

aryl-lower alkyl; or

R⁷⁸ and R⁷⁹, taken together, can be -(CH₂)_M-; - (CH₂) ₂0 (CH₂) ₂-; or - (CH₂)₂NR⁵⁷(CH₂)₂-;

R⁸⁰ is H; or lower alkyl;

R⁸¹ is H; lower alkyl; lower cycloalkyl; lower alkyl-aryl; or aryl-lower alkyl; or

R³³ and R⁸¹ taken together can form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂)₂S (CH₂)z-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- ;

R⁸² is H; -CF₃; -OCF₃; -OCHF₂; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl;

R⁸³ is H; lower alkyl; aryl; or -NR⁷⁸R⁷⁹;

R⁸⁴ is - (CH₂) p (CHR⁶¹) _sOH; - (CH₂) _pCOOR⁸⁰; - (CH₂) _p (CHR⁶¹) ₅SH;

- (CH₂) _pCONR⁷⁸R⁷⁹; - (CH₂) _PNR⁸⁰CONR⁷⁸R⁷⁹; - (CH₂) _pC₆H₄CONR⁷⁸R⁷⁹; or - (CH₂) _pC₆H₄NR⁸⁰CONR^7SR⁷⁹;

R⁸⁵ is lower alkyl; or lower alkenyl; R is R'⁴; - (CH₂)₀R⁷⁷; - (CH₂) ₀-CHR³³R⁷⁵; R ;

- [ (CH₂)_U-X' ]_t - (CH₂)_VNR⁷⁸R⁷⁹;

- [ (CH₂) _U-X ' ] _t- (CH₂) _V-C (=NR⁸⁰) NR⁷⁸R⁷⁹;

- [ (CH₂)u-X' ]_t- (CH₂)_vOR⁷⁸; -[ (CH₂) _U-X' ] _t- (CH₂) _v-CONR⁷⁸R⁷⁹; - [ (CH₂)_U-X' ]_t- (CH₂)_V-NR⁸⁰CONR⁷⁸R⁷⁹; - [ (CH₂ ) _U-X ' ] _t- (CH₂ ) _VSR⁷⁸ where X' is -0-, -NR²⁰-, -S-; or -OCOO-, u is 1-3, t is 1-6, and v is 1-3; m is 2-4; o is 0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or 1; the amino acid residue of type C is a residue of formula -NR²⁰CH (R⁷²) CO-;

the amino acid residue of type D is a residue of formula -NR²⁰CH (R⁷³) CO-;

the amino acid residue of type E is a residue of the formula -NR²⁰CH (R⁷⁴) CO-;

the amino acid residue of type F is a residue of the formula -NR²⁰CH (R⁸⁴) CO-; the amino acid residue of type H is a residue of the one of the formulae -NR²⁰-CH (CO-) -alkylene-CH (CO-) -NR²⁰-;

-NR²⁰-CH(CO-) -alkenylene-CH (CO-) -NR²⁰-;

-NR²⁰-CH(CO-) -alkynylene-CH (CO-) -NR²⁰-;

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

-NR ⁰-CH(CO-) - (- (CH₂)_pNR²⁰CO(CH₂)_p-CH(CO-) -NR²⁰-; and

-NR²⁰-CH (CO-) - (- (CH₂) _PNR ⁰CONR²⁰ (CH₂) _p-CH (CO-) -NR²⁰-; non-canonical amino acid residues designate those amino acid residues being neither glycine nor the L- or D-isomers of alanine, arginine, aspartic acid, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,

threonine, tryptophan, tyrosine and valine; and pharmaceutically acceptable salts thereof. In accordance with the present invention these β-hairpin peptidomimetics can be prepared by a process which comprises

(a) coupling an appropriately functionalized solid support with an appropriately N-protected derivative of that amino acid which in the desired end-product corresponds to Xaa", wherein n is 14, 13, 12, 7, 6 or 5, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;

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

(c) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product corresponds to Xaa"^"1, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;

(d) removing the N-protecting group from the product obtained in step (c) ;

(e) effecting steps substantially corresponding to steps (c) and (d) using appropriately N-protected derivatives of amino acids which in the desired end-product are in positions n-2 to 1, any functional group (s) which may be present in said N-protected amino acid derivatives being likewise appropriately protected;

(f) if n is not 14, further effecting steps substantially corresponding to steps (c) and (d) using appropriately N-protected derivatives of amino acids which in the desired end-product are in positions 14 to n + 1, any functional group (s) which may be present in said N-protected amino acid derivatives being likewise appropriately protected;

(g) forming an interstrand linkage between side-chains of appropriate amino acid residues at P2 and Pll; or alternatively, forming the aforesaid linkage subsequent to step (j), as described herein below; (h) detaching the product thus obtained from the solid support ;

(i) cyclizing the product cleaved from the solid support; (j) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group (s) which may in addition be present in the molecule; and

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

Enantiomers of the compounds defined herein before form also part of the present invention. These enantiomers can be prepared by a modification of the above process wherein enantiomers of all chiral starting materials are utilized.

As used in this description, the term "alkyl", taken alone or in combinations, designates saturated, straight-chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms. Similarly, the term "alkenyl", taken alone or in combinations, designates 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 "alkylene" designates a divalent "alkyl", e.g.-CH₂-CH₂-CH₂-CH₂-, having 4 to 24, preferably 4 to 12, carbon atoms. Similarly, the term "alkenylene" designates a divalent "alkenyl", e.g.-CH₂-CH=CH-CH₂-, having 4 to 24, preferably 4 to 12, carbon atoms and containing at least one or, depending on the chain length, up to four olefinic double bonds. Likewise, the term "alkynylene" designates a divalent straight chain or branched hydrocarbon radical, having 4 to 24, preferably 4 to 12, carbon atoms and containing at least one or, depending on the chain length, up to four carbon-carbon triple bonds. The term "lower" designates radicals and compounds having up to 6 carbon atoms. Thus, for example, the term "lower alkyl" designates saturated, straight-chain, or branched hydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. -butyl, isobutyl, tert. -butyl, and the like. Similarly, the term "lower cycloalkyl" designates saturated cyclic hydrocarbon radicals having up to 6 carbon atoms, such as cyclopentyl, cyclohexyl and the like. The term "aryl" designates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be substituted by up to three substituents such as Br, CI, F, CF₃, N0₂, lower alkyl or lower alkenyl. The term "heteroaryl" designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to three heteroatoms selected from the group consisting of O, S and N and said ring(s) being optionally substituted; representative examples of such optionally substituted heteroaryl radicals are indicated hereinabove in connection with the definition of R⁷⁷.

The β-hairpin conformation of Cyclo (-Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵- Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹²-Xaa¹³-Xaa^1'1-) is highly relevant for the anti-infective activity of the β-hairpin peptidomimetics of the present invention and also for the synthesis process defined hereinabove, as incorporation of the residues Xaa⁶, Xaa⁷ and Xaa¹³ near the beginning or near the middle of the linear protected peptide precursors enhances cyclization yields significantly.

Building blocks A1-A69 of the structural element -A-CO- belong to a class of amino acids wherein the N-terminus is a secondary amine forming part of a ring. Among the genetically encoded amino acids only proline falls into this class. The configuration of building block Al through A69 is (D) , and they can be combined with a building block -B-CO- of (L) -configuration . Thus, for example, ^DPro-^LPro constitutes the prototype of such a combination.

It will be appreciated that building blocks -A1-C0- to -A69-CO- in which A has (D) -configuration, are carrying a group R¹ at the β-position to the N-terminus .

The preferred values for R¹ are H and lower alkyl with the most preferred values for R¹ being H and methyl. It will be recognized by those skilled in the art, that A1-A69 are shown in (D) -configuration which, for R¹ being H and methyl, corresponds to the (R) -configuration . Depending on the priority of other values for R¹ according to the Cahn, Ingold and Prelog rules, this configuration may also have to be expressed as (S) .

In addition to R¹ building blocks -A1-C0- to -A69-CO- can carry an additional substituent designated as R² to R¹⁷. This additional substituent can be H, and if it is other than H, it is preferably a small to medium-sized aliphatic or aromatic group. Examples of preferred values for R¹ to R¹⁷ are :

- R¹ is hydrogen or lower alkyl;

- R² is H; lower alkyl; lower alkenyl ;

-(CH₂)_pOR⁵⁵ (where R⁵ : lower alkyl; or lower alkenyl); -(CH₂)_PSR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂) _PNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

-(C¾)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _pOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-6-); - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂)_PNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³: H; lower alkyl; or lower alkenyl; R : H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂-₆-;

- (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) 2-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) ₀N (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) --((CCHH₂₂))₂₂SS((CCHH₂₂))₂₂--; or - (CH₂) ₂NR (CH₂) ₂- (where R^b/: H; or lower alkyl) ;

- ((CCHH₂₂))_ooPP00 (OR^6U) ₂ (where R^bU: H; lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ;

- (CH₂) _qC₆H₄R⁸ (where R⁸ : H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) ; or

- (CH₂) _qCHN₄R⁸.

- R³ is H; lower alkyl; lower alkenyl;

-(CH₂)₀OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); -(CH₂)₀SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mOCONR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

-(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) _raNR⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

- (CH₂) ₀N (R²⁰) COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- ((CCHH₂₂))_ooCC000(R⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl ) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl;

alkenyl; and R⁵⁹: H; or lower alkyl; or

taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- ((CCHH₂₂)) ₂₂SS ((CCHH₂₂)) ₂₂--; or - (CH₂) ₂NR (CH₂) ₂- (where R : H; or lower alkyl) ;

-- ((CCHH₂₂)) _ooPP00 ((OR^bU) ₂ (where R^bu : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

- (CH₂) _qC₆H₄R⁸ (where R⁸ : H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) .

- R⁴ is H; lower alkyl; lower alkenyl;

-(CH₂)_mOR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); -(CH₂)_mSR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂) _mNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) _z- ;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂ ) ₂NR⁵⁷ (CH₂ ) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂)_mOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R^/5: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) _mNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-;

- (CH₂) ₂0(CH₂) 2-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) _raN (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁵⁴ : lower alkyl; or lower alkenyl) ;

- ((CCHH₂₂))₀₀CCOOCOR⁵ (where R : lower alkyl; or lower alkenyl ) ;

- (CH₂) _oC0NR^bBR^bS (where R : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-; -((CCHH₂₂))₂₂SS((CCHH₂₂))₂₂-; or - (CH₂) ₂NR (CH₂) ₂- (where

lower alkyl) ;

-((CCHH₂₂))₀₀PPOO (OR^bu) ₂ (where R^bu : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

- R⁵ is lower alkyl; lower alkenyl;

-(CH₂)_mOR⁵⁵ (where R⁵⁵ : lower alkyl; or lower alkenyl); -(CH₂)_mSR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂) _mNR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂^₆-;

-(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) _mN (R²⁰) COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶ : alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂) ₂-6- - (CH₂) ₂0 (CH₂) ₂-;

-- ((CCHH₂₂)) _ooPPO0 ((OR^bU) ₂ (where R^bU : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R^b : lower alkyl; or lower alkenyl) ; or

- R⁶ is H; lower alkyl; lower alkenyl;

-(CH₂)_o0R⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); -(CH₂)₀SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂) ₀NR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) 2-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (C¾ ) ₂NR⁵⁷ (CH₂ ) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) _oN (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶ : lower alkyl; or lower alkenyl) ;

-((CCHH₂₂))₀₀CCOO(OR (where R^¾/: lower alkyl; or lower alkenyl) ;

- (CH₂) _oCONR^R³⁹ (where R^5S : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-; -- ((CCHH₂₂)) ₂₂SS ((CCHH₂₂)) ₂₂-; or - (CH₂) ₂NR (CH₂) ₂- (where R : H; or lower alkyl) ;

- ((CCHH₂₂)) ooPOO (OR^6U) 2 (where R : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

- (CH₂) _qC₆H₄R⁸ (where R⁸: H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) .

- R⁷ is lower alkyl; lower alkenyl;

-(CH₂)_qOR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); -(CH₂)_qSR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂) _qNR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _qOCONR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _qNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³: H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-;

- (CH₂) ₂0(CH₂) ₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

-(CH₂)_qN(R⁰)COR^M (where R²⁰: H; or lower alkyl; R⁶ : lower alkyl; or lower alkenyl) ;

- ((CCHH₂₂)) _rrCCOOOOR⁵ (where R ' : lower alkyl; or lower alkenyl) ;

- (CH₂) qCONR R (where R^b8 : lower alkyl; or lower alkenyl; and R⁵⁹ : H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: - (CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ; - (CH₂) _rPO (OR^6U) 2 (where R^bu : lower alkyl; or lower alkenyl) ;

- (CH₂) _rS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

H; F; Cl; CF₃; lower alkyl; lower alkenyl;

-(CH₂)_o0R⁵⁵ (where R⁵⁵ : lower alkyl; or lower alkenyl); -(CH₂)₀SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); - (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₀OCONR³³R⁷⁵ (where R³³: H; e¾r lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) 2- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ :

H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R^S1 taken together form: -(CH₂)₂.₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

- (CH₂)_oN(R²⁰)C0R⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

-(CH₂)_oPO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl) ;

- (CH₂)_oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

- (CH₂)_qC₆H₄R⁸ (where R⁸ : H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) .

lower alkyl; lower alkenyl;

-(CH₂)₀OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl);

-(CH₂)₀SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) ₀OCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂)_mNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) ₂- ; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-

(where R⁵⁷: H; or lower alkyl);

-(CH₂)₀N(R²⁰)COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl)

-- ((CCHH₂₂)) _ooCC00(0R ^/ (where R^¾ : lower alkyl; or lower alkenyl) ;

- (CH₂) ₀CONR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

-(CH₂)₀PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl ) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

- (CH₂) _qC₆H₄R⁸ (where R⁸ : H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) . is lower alkyl; lower alkenyl;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂^₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³: H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-;

- (CH₂) ₂0(CH₂) ₂-; -(CH₂)₂S (CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

-(CH₂)₀N(R²⁰)COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oP0 (OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

isH; lower alkyl; lower alkenyl;

-(CH₂)_mOR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); -(CH₂)_mSR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); - (CH₂) _raNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mOCONR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂- ;

- (CH₂) _mNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-;

- (CH₂)₂0(CH₂)₂-; - (CH₂) ₂S (C¾) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) _raN (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)_2-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) >-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂)₀PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

H; lower alkyl; lower alkenyl;

-(CH₂)_mOR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); -(CH₂)_raSR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂)_mNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂.₆-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) 2-; or - (CH₂) ₂NR⁵⁷ (CH₂) 2- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) _mOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) 2-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁷ : H; or lower alkyl) ;

- (CH₂) _mNR²⁰CONR³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: - (CH₂) ₂_₆- ; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

-(CH₂)_mN(R²⁰)COR^M (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

-- ((CCHH₂₂)) _rrCCOOOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _rCONR R (where R : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- ((CCHH₂₂))_rrPPOO(OR^bU)₂ (where R^M : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

lower alkyl; lower alkenyl;

- (CH₂) _qNR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _qOCONR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH - (CH₂) ₂0 (CH₂) ₂ ^~;

- (CH₂) ₂S (CH₂) or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _qNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

-(CH₂)_qN(R²⁰)COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

-(CH₂)_rC00⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _qCONR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹ : H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)_2-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _rP0 (OR⁶⁰) (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂) _rS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

isH; lower alkyl; lower alkenyl;

-(CH₂)_mOR⁵⁵ (where R⁵⁵ : lower alkyl; or lower alkenyl); -(CH „SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂) _raNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂)_mOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂)_mNR²⁰CONR³³R⁸¹ (where R²⁰ : H or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂),S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵ : H; or lower alkyl);

- (CH₂)_mN (R²⁰) COR⁶⁴ (where R²⁰ : H; lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl)

- ((CCHH₂₂))_ooCC00(0R^b' (where R^s : lower alkyl; or lower alkenyl) ;

- ((CCHH₂₂)) ₂₂SS ((CCHH₂₂)) ₂2-; or - (CH₂) ₂NR (CH₂) ₂- (where R^b': H; or lower alkyl) ;

-- ((CCHH₂₂)) _ooPP00 (OR^6U) ₂ (where R^6U : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ;

- R¹⁵ is lower alkyl; lower alkenyl;

-(CH₂)₀OR⁵⁵ (where R^5S: lower alkyl; or lower alkenyl);

-(CH₂)₀SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); - (CH₂) ₀NR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ :

H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R and R taken together form: -(CH₂)₂-₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S (CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

-(CH₂)_oN(R²⁰)COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ; particularly favoured being -NR²⁰CO-lower alkyl (where R²⁰: H; or lower alkyl) ;

- ((CCHH₂₂))_0o(C00R⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl, or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂- ; - ((CCHH₂₂)) ₂₂SS ((CCHH₂₂)) ₂₂-; or - (CH₂) ₂NR (CH₂) ₂- (where R^b': H; or lower alkyl) ;

- ((CCHH₂₂)) _ccPPOO (iOR ) 2 (where R^6U : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

- R¹⁶ is lower alkyl; lower alkenyl;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³: H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

-- (( CCHH₂₂ )) ooCCOOCOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) ₀PO (OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl ) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

- R¹⁷ is lower alkyl; lower alkenyl;

- (CH₂) _qNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _qOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂ ) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) _qNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³: H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R^B1 taken together form: -(CH₂)₂^₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) _qN (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- (CH₂) _rCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _qCONR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _rP0 (OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl ) ;

- (CH₂) _rS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

Among the building blocks Al to A69 the following are preferred: A5 with R² being H, A8, A22, A25, A38 with R² being H, A42, A47, and A50. Also, and particulary, preferred are building blocks of type A8 ' :

wherein R is H or lower alkyl; and R is alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl; especially those wherein R⁶⁴ is n-hexyl (A8'-l); n-heptyl (A8'-2); 4- (phenyl ) benzyl (A8'-3); diphenylmethyl (A8'-4);

3-amino-propyl (A8'-5); 5-amino-pentyl (A8'-6); methyl

(A8'-7); ethyl (A8'-8); isopropyl (A8'-9); isobutyl

(A8'-10); n-propyl (A8'-ll); cyclohexyl (A8'-12); cyclohexylmethyl (A8'-13); n-butyl (A8'-14); phenyl (A8'-15); benzyl (A8'-16); (3-indolyl) methyl (A8'-17); 2- (3-indolyl) ethyl (A8 ' -18 ) ; (4-phenyl) henyl (A8 ' -19 ) ; and n-nonyl (A8 ' -20 ) .

Building block A70 belongs to the class of open-chain -substituted a-amino acids, building blocks A71 and A72 to the corresponding β-amino acid analogues and building blocks A73-A104 to the cyclic analogues of A70 . Such amino acid derivatives have been shown to constrain small peptides in well defined reverse turn or U-shaped conformations (CM. Venkatachalam, Biopolymers 1968 , 6, 1425-1434; W. Kabsch, C. Sander, Biopolymers 1983 , 22, 2577) . Such building blocks are ideally suited for the stabilization of β-hairpin conformations in peptide loops (D. Obrecht, M. Altorfer, J. A. Robinson, "Novel Peptide Mimetic Building Blocks and Straties for Efficient Lead Finding", Adv. Med. Chem. 1999 , Vol.4, 1-68; P. Balaram, "Non-standard amino acids in peptide design and protein engineering", Curr. Opin. Struct. Biol. 1992 , 2, 845-851; M. Crisma, G. Valle, C. Toniolo, S.

Prasad, R.B. Rao, P. Balaram, "β-turn conformations in crystal structures of model peptides containing a. -disubstituted amino acids", Biopolymers 1995 , 35, 1-9; V.J. Hruby, F. Al-Obeidi, W. Kazmierski, Biochem. J. 1990 , 268, 249-262) . It has been shown that both enantiomers of building blocks -A70-CO- to A104-CO- in combination with a building block -B-CO- being an a-amino acid with L-configuration can efficiently stabilize and induce β-hairpin conformations (D. Obrecht, M. Altorfer, J. A. Robinson, "Novel Peptide Mimetic Building Blocks and Strategies for Efficient Lead Finding", Adv. Med. Chem. 1999 , Vol.4, 1-68; D. Obrecht, C. Spiegler, P. Schonholzer, K. Miiller, H. Heimgartner, F. Stierli, Helv. Chim. Acta 1992 , 75, 1666-1696; D. Obrecht, U. Bohdal, J. Daly, C. Lehmann, P. Schonholzer, K. Miiller, Tetrahedron 1995 , 51, 10883-10900; D. Obrecht, C. Lehmann, C. Ruffieux, P. Schonholzer, K. Muller, Helv. Chim. Acta 1995, 78, 1567-1587; D. Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P. Schonholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D. Obrecht, H. Karajiannis, C. Lehmann, P. Schonholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 703-714) .

Preferred values for R²⁰ in A70 to A104 are H or lower alkyl with methyl being most preferred. Preferred values for R¹⁸,

R¹⁹ and R²¹-R²⁹ in building blocks A70 to A104 are the following :

-R¹⁸ is lower alkyl.

-R¹⁹ is lower alkyl; lower alkenyl;

-(CH₂)_pOR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); -(CH₂)_PSR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂)_PNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _pOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _pNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂)_PN(R²⁰)COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl) ;

-- ((CCHH₂₂)) _ppCCOOOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂)_pCONR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹ : H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) 2-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

-(CH₂)_oPO(OR⁶⁰)₂ (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂)_pS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

- (CH₂) oC₆H₄R⁸ (where R⁸: H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) .

H; lower alkyl; lower alkenyl;

- (CH₂) ₀NR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂- ;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl ) ;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³: H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂-₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

-(CH₂)_oN(R²⁰)COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl, or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) 2-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) _oP0 (OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

lower alkyl; lower alkenyl;

- (CH₂) ₂S (CH₂) or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl ) ;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R⁸¹ taken together form: - (CH₂) ₂_₆- ; -(CH₂)₂0(CH₂)₂~; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

- ((CCHH₂₂)) _ooCCO0O(R^ (where R^b/: lower alkyl; or lower alkenyl ) ;

- (CH₂) ₀CONR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl, or lower alkenyl; and R⁵⁹ : H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₀PO (OR⁶⁰) ₂ (where R⁶⁰: lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or - (CH₂) _qC₆H₄R⁸ (where R⁸: H; F; CI; CF; lower alkyl; lower alkenyl; or lower alkoxy) .

H; lower alkyl; lower alkenyl;

- (CH₂) ₀NR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: - (CH₂ ) _2-6- ;

- (CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵ : H; or lower alkyl);

- (CH₂) ₀N (R²⁰) COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ; particularly favoured are NR²⁰CO-lower alkyl (where R²⁰: H; or lower alkyl);

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) ₀CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oP0 (OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂) ₀S0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

- (CH₂) _qC₆H₄R⁸ (where R⁸: H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) . lower alkyl; lower alkenyl;

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

- (CH₂) ₀N (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶ : lower alkyl; or lower alkenyl) ; particularly favoured are NR²⁰CO-lower alkyl (where R²⁰: H; or lower alkyl);

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl, or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-; --((CCHH₂₂))₂₂SS((CCHH₂₂))₂₂'-; or - (CH₂) ₂NR^b (CH₂) ₂- (where R^b/: H; or lower alkyl) ;

--((CCHH₂₂))_ooPP00 (OR ) 2 (where R : lower alkyl; or lower alkenyl);

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

H; lower alkyl; lower alkenyl;

-(CH₂)_mOR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); - (CH₂) _mNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _raOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)_2-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂)_mN (R²⁰) COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- ((CCHH₂₂)) ₂₂SS ((CCHH₂₂)) ₂₂-- ; or - (CH₂) ₂NR (CH₂) ₂- (where R^b/: H; or lower alkyl) ;

- ((CCHH₂₂)) ₀₀PPOO <OR^6U) 2 (where R^bu: lower alkyl; or lower alkenyl) ;

- (CH₂) ₀S0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

- (CH₂) _qC₆H₄R⁸ (where R⁸ : H F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) .

H; lower alkyl; lower alkenyl;

-(CH₂)_mOR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl);

- (CH₂) _mNR³³R³⁴ (where \ : lower alkyl; or lower alkenyl; R³ H; or lower alkyl; or R³³ and R³⁴ taken together form: (CH₂) 2-6" -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or (CH₂) ₂NR (CH₂) ₂- (where R : H; or lower alkyl) ;

- (CH₂) _mOCONR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂-₆- -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

-(CHz lSMR^COR⁶ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl ) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; - ((CCHH₂₂))₂₂SS((CCHH₂₂))₂₂-- ; or - (CH₂) zNR" (CH₂) ₂- (where

lower alkyl) ;

-- ((CCHH₂₂)) _ooPP00 (OR ) 2 (where R : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl ) ; or

- (CH₂) _qC₆H₄R⁸ (where R⁸ : H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy)—; or, alternatively, - R²⁵ and R²⁶ taken together can be

-(CH_z) ₂-6-; -(CH₂)₂0(CH₂)₂-; - (CH₂) ₂S (CH₂) ₂-; or

- (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) .

-R²⁷ is H; lower alkyl; lower alkenyl;

-(CH₂)_o0R⁵⁵ (where R⁵⁵ : lower alkyl; or lower alkenyl); -(CH₂)₀SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂),_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂- ;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S (CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) ₂S (CH₂) _?-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl) ;

- ((CCHH₂₂)) _ooPP00 (OR ) 2 (where R : lower alkyl; or lower alkenyl ) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

lower alkyl; lower alkenyl;

-(CH₂)_o0R⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl);

-(CH₂)₀SR⁵⁶ (where R⁵⁶ : lower alkyl; or lower alkenyl); - (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂ ) ₂N ⁵⁷ (CH₂ ) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; - (CH₂)₂S (CH₂) 2-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oPO (OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

lower alkyl; lower alkenyl;

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ; -(CH₂)₀NR CONR^J¾^ai (where R²⁰ : H; or lower alkyl; R^JJ: H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)2-6-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) ₀N (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶ : lower alkyl; or lower alkenyl) ; particularly favored are NR²⁰CO-lower-alkyl (where R²⁰: H; or lower alkyl);

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

-- ((CCHH₂₂)) ₂₂SS ((CCHH₂₂)) ₂₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- ((CCHH₂₂))_ooPP00 (OR⁶⁰) 2 (where R⁶⁰: lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

Among the building blocks A70 to A104 the following are preferred: A74 with R²² being H, A75 , A76 , A77 with R²² being H, A78 and A79 .

The building block -B-CO- designates an L-amino acid residue. Preferred values for B are: -NR²⁰CH (R⁷¹) -, or -NR²⁰CH (R⁷²) - or, -NR²⁰CH (R⁷³) -, or -NR²⁰CH (R⁷⁴) -, or -NR²⁰CH (R⁸⁴) -, or enantiomers of groups A5 with R² being H, A8 , A22 , A25 , A38 with R² being H, A42 , A47 , and A50. Most preferred building blocks -B-CO- are

Ala L-Alanine

Arg L-Arginine

Asn L-Asparagine

Asp L-Aspartic acid 5ί

Cys L-Cysteine

Gin L-Glutamine

Glu L-Glutamic acid

Gly Glycine

His L-Histidine

He 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-t-Butylalanine

Sar Sarcosine

t-BuG L-tert . -Butylglycine

4AmPhe L-para-Aminophenylalanine

3AmPhe L-meta-Aminophenylalanine

2AmPhe L-ortho-Aminophenylalanine

Phe (mC (NH₂) =NH) L-meta-Amidinophenylalanine Phe (pC (NH₂) =NH) L-para-Amidxnophenylalanine Phe (mNHC (NH₂)=NH) L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)=NH) L-para-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

4C1-Phe L- ^■4-Chlorophenylalanine 3C1-Phe L-3-Chlorophenylalanine

2C1-Phe L-2-Chlorophenylalanine

3, 4C1₂-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- -2-Thienylalanine

Tza L-2-Thiazolylalanine

Mso L-Methionine sulfoxide

AcLys L-N-Acetyl lysine

D r L-2 , 3-Diaminopropionic acid

Dab L-2 , -Diaminobutyric acid

Dbu (2S, 3S) -2 , 3-Diaminobutyric acid

Abu γ-Aminobutyric acid (GABA)

Aha ε-Aminohexanoic acid

Aib -Aminoisobutyric acid

Y (Bzl) L-O-Benzyltyrosine

Bip L-Biphenylalanine

S (Bzl) L-O-Benzylserine

T (Bzl) L-O-Benzylthreonine

hCha L-Homo-cyclohexylalanine

hCys L-Homo-cysteine

hSer L-Homo-serine

hArg L-Homo-arginine

hPhe L-Homo-phenylalanine

Bpa L-4-Benzoylphenylalanine

Pip L-Pipecolic acid

MePhe L-N-Methylphenylalanine

MeNle L-N-Methylnorleucine

MeAla L-N-Methylalanine

Melle L-N-Methylisoleucine

MeVal L-N-Methvaline

MeLeu L-N-Methylieucine 4Hypl (4S) -L-Hydroxyproline

4Hyp2 (4R) -L-Hydroxyproline

4Mpl (4S) -L-Mercaptoproline

4Mp2 (4R) -L-Mercaptoproline

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

A8 ' ' wherein R²⁰ is H or lower alkyl and R⁶⁴ is alkyl; alkenyl;

-[(CH₂) _U-X]_t-CH₃ (where X is -0-; -NR²⁰-, or -S-; u = 1-3, and t = 1-6) , aryl; aryl-lower alkyl; or heteroaryl-lower alkyl; especially those wherein R⁶⁴ is n-hexyl (A8' '-21); n-heptyl (A8''-22); 4- (phenyl) benzyl (A8' '-23); diphenylmethyl (A8' '-24); 3-amino-propyl (A8''-25); 5-amino-pentyl

(A8' '-26); methyl (A8' '-27); ethyl (A8' '-28); isopropyl (A8''-29); isobutyl (A8' '-30); n-propyl (A8''-31); cyclohexyl (A8''-32); cyclohexyl-methyl (A8''-33); n-butyl (A8''-34); phenyl (A8''-35); benzyl (A8' '-36); ( 3-indolyl ) methyl (Α8' '-37) ;2- (3-indolyl) ethyl (A8''-38); (4-phenyl) -phenyl (A8''-39); n-nonyl (A8''-40); CH₃-OCH₂CH₂-OCH₂- (A8' '-41) and

CH₃- (OCH₂CH₂) ₂-OCH₂- (A8 ' ' -42) .

Besides the structural element -B-CO- the β-hairpin peptidomimetics of the present invention can comprise the structural element -A-CO- and amino acid residues belonging to one of the following groups:

- Group C -NR²⁰CH (R⁷²) CO-; "hydrophobic: small to

medium-si zed"

Group D -NR²⁰CH (R⁷³) CO-; "hydrophobic: large aromatic or heteroaromatic" Group -NR CH (R ) CO-; "polar-cationic" and "urea- derived"

Group -NR²⁰CH (R⁸⁴) CO-; "polar-non-charged or

anionic"

Group NR ,20-CH (CO-) -alkylene-CH (CO- -NR

-NR -CH (CO-) -alkenylene-CH (CO-) -NR - -NR²⁰-CH (CO-) -alkynylene-CH (CO-) -NR²⁰- -NR²⁰-CH (CO-) - (CH₂) _pSS (CH₂)_p-CH (CO-) -NR

-NR"^U-CH (CO-) - (CH₂) pNR^UC0 (CH₂)_P-CH (CO-) -NR'^U-

-NR -CH (CO-) - (CH₂) _p R^CONR^zu (CH₂) _P-CH (CO-

NR 'interstrand linkage'

Group C comprises amino acid residues with small to medium-sized hydrophobic side chain groups according to the general definition for substxtuent R^7Z. A hydrophobic residue refers to an amino acid side chain that is uncharged at physiological pH and that is repelled by aqueous solution. Furthermore 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 the corresponding protonated salts thereof, thiols, alcohols, phosphonates , phosphates, ureas or thioureas. However, they may contain hydrogen bond acceptor groups such as ethers, thioethers, esters, tertiary amides, alkyl- or aryl phosphonates and phosphates or tertiary amines. Genetically encoded small-to-medium-sized hydrophobic amino acids include alanine, isoleucine, leucine, methionine and valine . Group D comprises amino acid residues with aromatic and heteroaromatic side chain groups according to the general definition for substxtuent R⁷³. An aromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated π-electron system (aromatic group) . In addition they may contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tetriary amides, alkyl- or aryl phosphonates -and phosphates or tertiary amines . Genetically encoded aromatic amino acids include phenylalanine and tyrosine.

A heteroaromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated π-system incorporating at least one heteroatom such as (but not limited to) 0, S and N according to the general definition for substituent R⁷⁷. In addition such residues may contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tetriary amides, alkyl- or aryl phosphonates -and phosphates or tertiary amines . Genetically encoded heteroaromatic amino acids include tryptophan and histidine.

Group E comprises amino acids containing side chains with polar-cationic, acylamino- and urea-derived residues according to the general definition for substituent R⁷⁴. Polar-cationic refers to a basic side chain which is protonated at physiological pH. Genetically encoded polar-cationic amino acids include arginine, lysine and histidine. Citrulline is an example for an urea derived amino acid residue.

Group F comprises amino acids containing side chains with polar-non-charged or anionic residues according to the general definition for substituent R⁸⁴. A polar-non-charged or anionic residue refers to a hydrophilic side chain that is uncharged and, respectively anionic at physiological pH (carboxylic acids being included) , but that is not repelled by aqueous solutions. Such side chains typically contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, carboxyclic acids and esters, primary and secondary amines, thiols, alcohols, phosphonates, phosphates, ureas or thioureas. These groups can form hydrogen bond networks with water molecules . In addition they may also contain hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tetriary amides, carboxylic acids and carboxylates , alkyl- or aryl phosphonates -and phosphates or tertiary amines. Genetically encoded polar-non-charged amino acids include asparagine, cysteine, glutamine, serine and threonine, but also aspartic acid and glutamic acid.

Group H comprises side chains of preferably (L) -amino acids at opposite positions of the β-strand region that can form an interstrand linkage. Various methods are known to form interstrand linkages including those described by: J. P. Tarn et al., Synthesis 1979 , 955-957; Stewart et al . , Solid Phase Peptide Synthesis, 2d Ed., Pierce Chemical Company, Rockford, III, 1984 ; Ahmed et al . J. Biol. Che . 1975 , 250, 8477-8482; and Pennington et al . , Peptides, pages 164-166, Giralt and Andreu, Eds., ESCOM Leiden, The Netherlands, 1990 ; C.E. Schafmeister et al . , J. Am. Chem. Soc. 2000 , 122, 5891. The most widely known linkage is the disulfide bridge formed by cysteines and homo-cysteines positioned at opposite positions of the β-strand. Preferrably, for the scope of the present invention, disulfide linkages can be prepared using acetamidomethyl (Acm) - or trityl (Trt) - protective groups for cysteine. Another well established interstrand linkage consists in linking ornithines and lysines, respectively, with glutamic and aspartic acid residues located at opposite β-strand positions by means of an amide bond formation. Preferred protective groups for the side chain amino-groups of ornithine and lysine are allyloxycarbonyl (Alloc) and allylesters for aspartic and glutamic acid. Finally, interstrand linkages can also be established by linking the amino groups of lysine and ornithine located at opposite β-strand positions with reagents such as N, N-carbonylimidazole to form cyclic ureas.

As mentioned earlier, Xaa² and Xaa¹¹ of Cyclo (-Xaa¹-Xaa²-Xaa³- Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaaⁿ-Xaa¹²-Xaa¹³-Xaa¹⁴-) are amino acid residues which, taken together, can form an interstrand linkage. Such an interstrand linkage is known to stabilize the β-hairpin conformations and thus constitute an important structural element for the design of β-hairpin mimetics .

Most preferred amino acid residues in Cyclo (-Xaa^x-Xaa²-Xaa³- Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaaⁿ-Xaa¹²-Xaa¹³-Xaa¹⁴-) , are those derived from natural a-amino acids. Hereinafter follows a list of amino acids which, or the residues of which, are suitable for the purposes of the present invention, the abbreviations corresponding to generally adopted usual practice: three letter code one letter code

Ala L-Alanine A

Arg L-Arginine R

^DArg D-Arginine ^DR

Asn L-Asparagine N

Asp L-Aspartic acid D

Cys L-Cysteine C

Glu L-Glutamic acid E

Gin L-Glutamine Q

Gly Glycine G His L-Histidine H

He L-Isoleucine I

Leu L-Leucine L

Lys L-Lysine K

^DLys D-Lysine ^DK

Met L-Methionine M

Phe L-Phenylalanine F

Pro L-Proline P

^DPro D-Proline Dp

Ser L-Serine S

Thr L-Threonine T

Trp L-Tryptophan w

Tyr L-Tyrosine Y

Val L-Valine V

Other a-amino acids which, or the residues of which, are suitable for the purposes of the present invention include:

Cit L- -Citrulline

^DCit D- -Citrulline

Orn L- -Ornithine

^D0rn D- -Ornithine

tBuA L- -t-Butylalanine

Pen L- -Penicillamine

tBuG L- -tert . -Butylglycine

^DtBuG D- -tert . -Butylglycine

4AmPhe L- -para-Aminophenylalanine

^D4AmPhe D- -para-Aminophenylalanine

3AmPhe L- -meta-Aminophenylalanine

^D3AmPhe D- -meta-Aminophenylalanine

2AmPhe L- -ortho-Aminophenylalanine

^D2AmPhe D- -ortho-Aminophenylalanine

Phe (raC (NH₂) = =NH) L- -meta-Amidinophenylalanine

^DPhe (mC (NH₂) =NH) D- -meta-Amidinophenylalanine

Phe (pC (NH₂) = =NH) L- -para-Amidinophenylalanine

^DPhe (pC (NH₂) =NH) D- -para-Amidinophenylalanine Phe (mNHC (NH₂) =NH) L-meta-Guanidinophenylalanine

^DPhe (mNHC (NH₂) =NH) D-raeta-Guanidinophenylalanine

Phe (pNHC (NH₂) =NH) L-para-Guanidinophenylalanine

^DPhe (pNHC (NH₂) =NH) D-para-Guanidinophenylalanine

Agp (2S) -2-Amino-3-guanidino-propionic acid

Agb (2S) -2-Amino-4-guanidino-butanoic acid

2Pal (2S) -2-Amino-3- (pyridine-2' -yl) -propionic acid

4Pal (2S) -2-Amino-3- (pyridine-4 ' -yl) -propionic acid

Phg L-Phenylglycine

C₃al L-3-Cycloproylalanine

C₄al L-3-Cyclobutylalanine

C₅al L-3-Cyclopentylalanine

Cha L-Cyclohexylalanine

C₃g L-Cycloproylglycine

C₄g L-Cyclobutylglycine

C₅g L-Cyclopentylglycine

Nle L-Norleucine

2-Nal L-2-Naphthylalanine

1-Nal L-l-Naphthylalanine

4ClPhe L-4-Chlorophenylalanine

3ClPhe L-3-Chlorophenylalanine

2ClPhe L-2-Chlorophenylalanine

3, 4Cl₂Phe L-3, 4-Dichlorophenylalanine

4FPhe L-4-Fluorophenylalanine

3FPhe L-3-Fluorophenylalanine

2FPhe L-2-Fluorophenylalanine

Thi L-p-2-Thienylalanine

Tza L-2-Thiazolylalanine

Mso L-Methionine sulfoxide

AcLys N-Acetyllysine

^DAcLys N-Acetyl-D-lysine

Dpr 2 , 3-Diaminopropionic acid

^DDpr D-2 , 3-Diaminopropionic acid

Dab 2 , 4-Diaminobutyric acid

DDab (2R) -2, 4-Diaminobutyric acid

Dbu (2S) -2, 3-Diamino-butyric acid ^DDbu (2R) -2, 3-Diamino-butyric acid

Abu γ-Aminobutyric acid ( GABA)

Aha ε-Aminohexanoic acid

Aib a-Aminoisobutyric acid

Cyp 1-Aminocyclopentane carboxylic acid

Y(Bzl) L-O-Benzyltyrosine

H (Bzl) (3S) -2-Amino-3- (1' -benzylimidazole- ' -yl ) - propionic acid

Bip L- (4-phenyl ) henylalanine

S(Bzl) L-O-Benzylserine

T(Bzl) L-O-Benzylthreonine

alloT (2S, 3S) -2-Amino-3-hydroxy-butyric acid

Leu30H (2S, 3R) -2-Amino-3-hydroxy-4-methyl-pentanoic acid

hAla L-Homo-alanine

hArg L-Homo-arginine

^DhArg D-Homo-arginine

hCys L-Homo-cysteine

hGlu L-Homo-glutamic acid

hGln L-Homo-glutamine

hHis L-Homo-histidine

hlle L-Homo-isoleucine

hLeu L-Homo-leucine

hNle L-Homo-norleucine

hLys L-Homo-lysine

^DhLys D-Homo-lysine

hMet L-Homo-methionine

hPhe L-Homo-phenylalanine

hSer L-Homo-serine

hThr L-Homo-threonine

hTrp L-Homo-tryptophan

hTyr L-Homo-tyrosine

hVal L-Homo-valine

hCha L-Homo-cyclohexylalanine

Bpa L-4-Benzoylphenylalanine Tic (3S) -1,2,3, 4 -Tetrahydroisoquinoline-3-carboxylic acid

^DTic (3R) -1,2,3, 4-Tetrahydroisoquinoline-3-carboxylic acid

Tiq (IS) -1, 2, 3, 4-Tetrahydroisoquinoline-l-carboxylic acid

^DTiq (1R) -1,2,3, 4-Tetrahydroisoquinoline-l-carboxylic acid

4AmPyrrl (2S, 4S) -4-Amino-pyrrolidine-2-carboxylic acid ^D4AmPyrrl (2R, 4S) -4-Amino-pyrrolidine-2-carboxylic acid 4AmPyrr2 (2S, 4R) -4-Amino-pyrrolidine-2-carboxylic acid ^D4AmPyrr2 (2R, 4R) -4-Amino-pyrrolidine-2-carboxylic acid 4PhePyrrl (2S, 4R) -4-Phenyl-pyrrolidine-2-carboxylic

acid

D4PhePyrrl (2R, 4R) - -Phenyl-pyrrolidine-2-carboxylic

acid

4PhePyrr2 (2S, 4S ) -4-Phenyl-pyrrolidine-2-carboxylic

acid

^D4PhePyrr2 (2R, 4S ) -4-Phenyl-pyrrolidine-2-carboxylic

acid

5PhePyrrl (2S, 5R) -5-Phenyl-pyrrolidine-2-carboxylic

acid

^D5PhePyrrl (2R, 5R) -5-Phenyl-pyrrolidine-2-carboxylic

acid

5PhePyrr2 (2S, 5S) -5-Phenyl-pyrrolidine-2-carboxylic

acid

^D5PhePyrr2 (2R, 5S ) -5-Phenyl-pyrrolidine-2-carboxylic

acid

4Hypl (4S) -L-Hydroxyproline

D4Hypl (4S) -D-Hydroxyproline

4Hyp2 (4R) -L-Hydroxyproline

^D4Hyp2 (4R) -D-Hydroxyproline

4Mpl (4S) -L-Mercaptoproline

^D4Mpl ( 4S) -D-Mercaptoproline

4Mp2 ( 4R) -L-Mercaptoproline

^D4Mp2 (4R) -D-Mercaptoproline Pip L-Pipecolic acid

^DPip D-Pipecolic acid

NMeAla L-N-Methylalanine

NMeVal L-N-Methylvaline

NMelle L-N-Methylisoleucine

NMeLeu L-N-Methylleucine

NMeNle L-N-Methylnorleucine

NMeMet L-N-Methylmethionine

NMeTyr L-N-Methyltyrosine

NMeHis L-N-Methylhistidine

NMePhe L-N-Methylphenylalanine

NMeTrp L-N-Methyltryptophane

NMeSer L-N-Meth lserine

NMeAsp L-N-Methylaspartic acid

NMeGlu L-N-Methylglutamic acid

NMeLys L-N-Methyllysine

NMe^DLys D-N-Methyllysine

NMeArg L-N-Methylarginine

NMe^DArg D-N-Methylarginine

NMeDab L-N-Methyl-2 , 4-diamino butyric acid

NMe^DDab D-N-Methyl-2 , 4-diamino butyric acid

NMeCys L-N-Methylcysteine

NMeAsn L-N-Methylasparagine

NMeGln L-N-Methylglutamine

NMeThr L-N-Methylthreonine

In a preferred embodiment of the present invention, Xaa¹³ is ^DPro, ^DCha, NMe^DIle, ^DTyr, ^DHis, ^DHis(Bzl), ^D4Pal, NMe^DTyr, NMe^DLys, (ABu)G, ^DIle, NMe^DAla, ^DLys, or ^DDab; Xaa¹⁴ is ^LPro; the aforesaid ^DPro moiety and/or the aforesaid ^LPro moiety being optionally substituted as shown in formulae A8 ' and, respectively, A8 ' ' , as defined above.

Particularly preferred residues for group C are :

Ala L -Alanine

He L -Isoleucine Leu L--Leucine

Met L- -Methionine

Val L- -Valine

tBuA L- -t-Butylalanine

tBuG L- -tert . -Butylglycine

C₃al L- -3-Cycloproylalanine

C₄al L- -3-Cyclobutylalanine

C₅al L- -3-Cyclopentylalanine

Cha L- -Cyclohexylalanine

C₃g L- -Cycloproylglycine

C₄g L- -Cyclobutylglycine

C₅g L- -Cyclopentylglycine

Nle L- -Norleucine

hAla L- -Homo-alanine

hlle L- -Homo-isoleucine

hLeu L- -Homo-leucine

hMet L- -Homo-methionine

hVal L- -Homo-valine

hCha L- -Homo-cyclohexylalanine

NMeAla L- -N-Methy1alanine

NMeVal L- -N-Methylvaline

NMelle L- -N-Methylisoleucine

NMeLeu L- -N-Methy1leucine

NMeNle L- -N-Methylnorleucine

NMeMet L- -N-Methylmethionine

Particularly preferred residues for group D are:

His L-Histidine

Phe L-Phenylalanine

Trp L-Tryptophan

Tyr L-Tyrosine

2Pal (2S) -2-Amino-3- (pyridine-2' -yi) -propionic acid

4Pal (2S) -2-Amino-3- (pyridine-4' -yi) -propionic acid

Phg L-Phenylglycine

2Nal L-2-Naphthylalanine 1-Nal L-l-Naphthylalanine

4ClPhe L-4-Chlorophenylalanine

3ClPhe L-3-Chlorophenylalanine

2ClPhe L-2-Chlorophenylalanine

3,4Cl₂Phe L-3 , 4-Dichlorophenylalanine

4FPhe L-4-Fluorophenylalanine

3FPhe L-3-Fluorophenylalanine

2FPhe L-2-Fluorophenylalanine

Thi L~-2-Thienylalanine

Tza L-2-Thiazolylalanine

Y(Bzl) L-O-Benzyltyrosine

H (Bzl ) (3S) -2-Amino-3- ( 1 ' -benzylimidazole-4 ' -yl ) propionic acid

Bip L- (4-phenyl ) phenylalanine

S(Bzl) L-O-Benzylserine

T(Bzl) L-O-Benzylthreonine

hPhe L-Homo-phenylalanine

hTrp L-Homo-tryptophan

hTyr L-Homo-tyrosine

hHis L-Homo-histidine

Bpa L-4-Benzoylphenylalanine

NMePhe L-N-Methylphenylalanine

NMeTyr L-N-Methyltyrosine

NMeHis L-N-Methylhistidine

NMeTrp L-N-Methyltryptophane

Particularly preferred residues for group E are

Arg L- -Arginine

^DArg D- -Arginine

Lys L- -Lysine

^DLys D- -Lysine

Orn L- -Ornithine

^DOrn D- -Ornithine

Dpr L- -2 , 3-Diaminopropionic acid

^DDpr D- -2 , 3-Diaminopropionic acid

Dab L- -2 , 4-Diaminobutyric acid (2R) -2 , 4-Diaminobutyric acid

Dbu (2S, 3S) -2, 3-Diaminobutyric acid ^DDbu (2R) -2 , 3-Diamino-butyric acid

Cit L-Citrulline

DCit D-Citrulline

4AmPhe L-para-Aminophenylalanine

D4AmPhe D-para-Aminophenylalanine

3AmPhe L-meta-Aminophenylalanine

D3AmPne D-meta-Aminophenylalanine

2AmPhe L-ortho-Aminophenylalanine

D2AmPhe D-ortho-Aminophenylalanine

Phe (mC (NH₂) =NH) L-meta-Amidinophenylalanine

^DPhe (mC (NH₂) =NH) D-meta-Amidinophenylalanine

Phe (pC (NH₂) =NH) L-para-Amidinophenyl lanine ^DPhe (pC (NH₂) =NH) D-para-Amidinophenylalanine

Phe (mNHC (NH₂) =NH) L-meta-Guanidinophenylalanine

^DPhe (mNHC (NH₂) =NH) D-meta-Guanidinophenylalanine

Phe (pNHC (NH₂) =NH) L-para-Guanidinophenylalanine

^DPhe (pNHC (NH₂) =NH) D-para-Guanidinophenylalanine Agp (2S) -2-Amino-3-guanidino-propionic acid

Agb (2S) -2-Amino-4-guanidino-butanoic acid hArg L-Homo-arginine

^DhArg D-Homo-arginine

hLys L-Homo-lysine

DhLys D-Homo-lysine

NMeLys L-N-Methyllysine

NMe^DLys D-N-Methyllysine

N eArg L-N-Methylarginine

NMe^DArg D-N-Methylarginine

NMeDab L-N-Methyl-2, 4-diamino butyric acid

NMe^DDab D-N-Methyl-2 , 4-diamino butyric acid

Particularly preferred residues for group

Asn L-Asparagine

Asp L-Aspartic acid

Cys L-Cysteine Gin L-Glutamine

Glu L-Glutamic acid

Ser L-Serine

Thr L-Threonine

Pen L-Penicillamine

AcLys L-N^' -Acetyllysine

alloT (2S, 3S ) -2-Amino-3-hydroxy-butyric acid

Leu30H (2S, 3R) -2-Amino-3-hydroxy-4-methyl-pentanoic acid

hCys L-Homo-cysteine

hSer L-Homo-serine

hGlu L-Homo-glutaraic acid

hGln L-Homo-glutaraine

hThr L-Homo-threonine

NMeSer L-N-Methylserine

NMeAsp L-N-Methylaspartic acid

NMeGlu L-N-Methylglutamic acid

NMeCys L-N-Methylcysteine

NMeAsn L-N-Methylasparagine

NMeGln L-N-Methylglutamine

NMeThr L-N-Methylthreonine

In a preferred embodiment of the invention the amino acid residues in Cyclo (- -Xaa^Xaa^Xaa^Xaa^Xaa

Xaa⁹-Xaa" -Xaa¹¹- Xaa¹²-Xaa ¹³-Xaa¹⁴-) are:

- Xaa¹: Trp;

- Xaa²: Arg, Dab or Orn;

- Xaa³: lie;

- Xaa⁴: Arg, Dab or Orn;

- Xaa⁵: lie;

- Xaa⁶: °Arg, Dab, ^DDab, Orn;

- Xaa⁷: Asn, Gin, Thr, Leu or Tyr;

- Xaa⁸: Lys, Gin, Trp or His;

- Xaa⁹: Arg or Dab;

- Xaa¹⁰ : Asn, Leu, Cha, Tyr or Trp;

- Xaa¹¹ : Arg or Gin; Xaa¹²: Arg, Dab, Ala or Gin;

Xaa¹³: DPro;

Xaa¹⁴: LPro; Particularly preferred β-peptidomimetics of the invention include those described in Examples 2, 5, 16, and 17.

The process of the invention can advantageously be carried out as parallel array synthesis to yield libraries of β-hairpin peptidomimetics of the invention. Such parallel syntheses allow one to obtain arrays of numerous (normally 12 to 192, typically 96) compounds as described above in moderate to high yields and defined purities, minimizing the formation of dimeric and polymeric by-products. The proper choice of the functionalized solid-support (i.e. solid support plus linker molecule) and site of cyclization play thereby key roles.

The functionalized solid support is conveniently derived from polystyrene crosslinked with, preferably 1-5%, divinylbenzene; polystyrene coated with polyethyleneglycol spacers (Tentagel™) ; and polyacrylamide resins (see also D. Obrecht, J.-M. Villalgordo, "Solid- Supported Combinatorial and Parallel Synthesis of Small-Molecular- Weight Compound Libraries", Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998) .

The solid support is functionalized by means of a linker, i.e. a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures. For the purposes of the present invention two types of linkers are used:

Type 1 linkers are designed to release the amide group under acid conditions (H. Rink, Tetrahedron Lett. 1987, 28, 3783-3790) . Linkers of this kind form amides of the carboxyl group of the amino acids; examples of resins functionalized by such linker structures include 4- [(( (2 , 4-dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetamido) aminomethyl] PS resin, 4- [ ( ( (2 , 4-dimethoxyphenyl ) Fmoc-aminomethyl ) phenoxyacetamido) aminomethyl] -4-methyl-benzydrylamine PS resin (Rink amide MBHA PS Resin), and 4- [ ( ( (2 , -dimethoxy- phenyl) Fmoc-aminomethyl ) phenoxyacetamido) aminomethyl] benzhydrylamine PS-resin (Rink amide BHA PS resin) .

Preferably, the support is derived from polystyrene crosslinked with, most preferably 1-5%, divinylbenzene and functionalized by means of the 4- ( ( (2 , 4-dimethoxy- phenyl ) Fmoc-aminomethyl ) phenoxyacetamido) linker .

Type 2 linkers are designed to eventually release the carboxyl group under acidic conditions. Linkers of this kind form acid-labile esters with the carboxyl group of the amino acids, usually acid-labile benzyl, benzhydryl and trityl esters; examples of such linker structures include 2-methoxy-4-hydroxymethylphenoxy (Sasrin™ linker) , 4- (2 , 4-dimethoxyphenyl-hydroxymethyl) -phenoxy (Rink linker), 4- (4-hydroxymethyl-3-methoxyphenoxy) butyric acid (HMPB linker), trityl and 2-chlorotrityl . Preferably, the support is derived from polystyrene crosslinked with, most preferably 1-5%, divinylbenzene and functionalized by means of the 2-chlorotrityl linker.

When carried out as parallel array synthesis the process of the invention can be advantageously carried out as described herein below but it will be immediately apparent to those skilled in the art how these procedures will have to be modified in case it is desired to synthesize one single compound of the invention.

A number of reaction vessels (normally 12 to 192, typically 96) equal to the total number of compounds to be synthesized by the parallel method are loaded with 25 to 1000 mg, preferably 60 mg, of the appropriate functionalized solid support, preferably 1 to 3% cross-linked polystyrene or Tentagel resin. The solvent to be used must be capable of swelling the resin and includes, but is not limited to, dichloromethane (DCM) , dimethylformamide (DMF) , N-methylpyrrolidone (NMP) , dioxane, toluene, tetrahydrofuran (THF) , ethanol (EtOH) , trifluoroethanol (TFE) , isopropylalcohol and the like. Solvent mixtures containing as at least one component a polar solvent (e. g. 20% TFE/DCM, 35% THF/NMP) are beneficial for ensuring high reactivity and solvation of the resin-bound peptide chains (G.B. Fields, C.G. Fields, J. Am. Chem. Soc. 1991, 113, 4202-4207) .

With the development of various linkers that release the C-terminal carboxylic acid group under mild acidic conditions, not affecting acid-labile groups protecting functional groups in the side chain (s), considerable progresses have been made in the synthesis of protected peptide fragments. The 2-methoxy-4-hydroxybenzylalcohol- derived linker (Sasrin™ linker, Mergler et al . , Tetrahedron Lett. 1988, 29 4005-4008) is cleavable with diluted trifluoroacetic acid (0.5-1% TFA in DCM) and is stable to Fmoc deprotection conditions during the peptide synthesis, Boc/tBu-based additional protecting groups being compatible with this protection scheme. Other linkers which are suitable for the process of the invention include the super acid labile 4- (2 , 4-dimethoxyphenyl-hydroxymethyl) -phenoxy linker (Rink linker, H. Rink, Tetrahedron Lett. 1987, 28, 3787-3790) , where the removal of the peptide requires 10% acetic acid in DCM or 0.2% trifluoroacetic acid in DCM; the 4- (4-hydroxymethyl-3-methoxyphenoxy) butyric acid-derived linker (HMPB-linker, Florsheimer & Riniker, 1991, Peptides 1990: Proceedings of the Twenty-First European Peptide Symposium, 131) which is also cleaved with 1%TFA/DCM in order to yield a peptide fragment containing all acid labile side-chain protective groups; and, in addition, the 2-chlorotritylchloride linker (Barlos et al., Tetrahedron Lett. 1989, 30, 3943-3946), which allows the peptide detachment using a mixture of glacial acetic acid/trifluoroethanol/DCM (1:2:7) for 30 min.

Suitable protecting groups for amino acids and, respectively, for their residues are, for example, for the amino group (as is present e. g. also in the side-chain of lysine)

Cbz benzyloxycarbonyl

Boc tert . -butyloxycarbonyl

Fmoc 9-fluorenylmethoxycarbonyl

Alloc allyloxycarbonyl

Teoc trimethylsilylethoxycarbonyl

Tec trichloroethoxycarbonyl

Nps o-nitrophenylsulfonyl;

Trt triphenymethyl or trityl for the carboxyl group (as is present e. g. also in the side-chain of aspartic and glutamic acid) by conversion into esters with the alcohol components tBu tert. -butyl

Bn benzyl

Me methyl

Ph phenyl

Pac phenacyl

allyl

Tse trimethylsilylet

Tee trichloroethyl; for the guanidino group (as is present e. g. in the side-chain of arginine)

Pmc 2,2,5,7, 8-pentamethylchroman-6-sulfonyl

Ts tosyl (i. e. p-toluenesulfonyl) Cbz benzyloxycarbonyl

Pbf pentamethyldihydrobenzofuran-5-sulfonyl for the hydroxy group (as is present e. g. in the side-chain of threonine and serine) tBu tert. -butyl

Bn benzyl

Trt trityl

Alloc allyloxycarbonyl and for the mercapto group (as is present e. g. in the side-chain of cysteine) Acm acetamidomethyl

tBu tert. -butyl

Bn benzyl

Trt trityl

Mtr 4-methoxytrityl .

The 9-fluorenylmethoxycarbonyl- (Fmoc) -protected amino acid derivatives are preferably used as the building blocks for the construction of the β-hairpin loop mimetics of the invention. For the deprotection, i. e. cleaving off of the Fmoc group, 20% piperidine in DMF or 2% DBU/2% piperidine in DMF can be used.

The quantity of the reactant, i. e. of the amino acid derivative, is usually 1 to 20 equivalents based on the milliequivalents per gram (meq/g) loading of the functionalized solid support (typically 0.1 to 2.85 meq/g for polystyrene resins) originally weighed into the reaction tube. Additional equivalents of reactants can be used, if required, to drive the reaction to completion in a reasonable time. The preferred workstations (without, however, being limited thereto) are Labsource's Combi-chem station, Protein Technologies' Symphony and MultiSyn Tech's-Syro synthesizer, the latter additionally equipped with a transfer unit and a reservoir box during the process of detachment of the fully protected linear peptide from the solid support. All synthesizers are able to provide a controlled environment, for example, reactions can be accomplished at temperatures different from room temperature as well as under inert gas atmosphere, if desired. Amide bond formation requires the activation of the a-carboxyl group for the acylation step. When this activation is being carried out by means of the commonly used carbodiimides such as dicyclohexylcarbodiimide (DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067-1068) or diisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res. Commun. 1976, 73, 336-342), the resulting dicyclohexylurea and, respectively, diisopropylurea is insoluble and, respectively, soluble in the solvents generally used. In a variation of the carbodiimide method 1-hydroxybenzotriazole (HOBt, Konig & Geiger, Chem. Ber . 1970, 103, 788-798) is included as an additive to the coupling mixture. HOBt prevents dehydration, suppresses racemization of the activated amino acids and acts as a catalyst to improve the sluggish coupling reactions. Certain phosphonium reagents have been used as direct coupling reagents, such as benzotriazol-l-yl-oxy-tris- (dimethyl- amino) -phosphonium hexafluorophosphate (BOP, Castro et al . , Tetrahedron Lett. 1975, 14, 1219-1222; Synthesis 1976, 751-752) , or benzotriazol-l-yl-oxy-tris-pyrrolidino- phosphonium hexaflurophoshate (Py-BOP, Coste et al . , Tetrahedron Lett. 1990, 31, 205-208), or 2- (lH-benzotriazol- 1-yl-) 1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TBTU) , or hexafluorophosphate (HBTU, Knorr et al . , Tetrahedron Lett. 1989, 30, 1927-1930); these phosphonium reagents are also suitable for in situ formation of HOBt esters with the protected amino acid derivatives. More recently diphenoxyphosphoryl azide (DPPA) or 0- ( 7-aza-benzotriazol- 1-yl ) -N, N, ' , N' -tetramethyluronium tetrafluoroborate (TATU) or 0- ( 7-aza-benzotriazol-l-yl) -N, N, N' , N ' -tetramethyluronium hexafluorophosphate (HATU) /7-aza-l-hydroxy benzotriazole (HOAt, Carpino et al . , Tetrahedron Lett. 1994, 35, 2279-2281) or - ( 6-Chloro-lH-benzotriazol-l-yl-) -N, N, N' , N' - 1 , 1, 3, 3-tetramethyluronium tetrafluoroborate (TCTU) , or hexafluorophosphate (HCTU, Marder, Shivo and Albericio: HCTU and TCTU: New Coupling Reagents: Development and Industrial Applications, Poster Presentation, Gordon Conference February 2002) have also been used as coupling reagents as well as 1, 1, 3, 3-Bis (tetramethylene) chlorouronxum hexafluoro- phosphate (PyClU) especially for coupling N-methylated amino acids (J. Coste, E. Frerot, P. Jouin, B. Castro, Tetrahedron Lett. 1991, 32, 1967) .

Due to the fact that near-quantitative coupling reactions are essential, it is desirable to have experimental evidence for completion of the reactions. The ninhydrin test (Kaiser et al . , Anal. Biochemistry 1970, 34, 595), where a positive colorimetric response to an aliquot of resin-bound peptide or peptide indicates qualitatively the presence of the primary amine, can easily and quickly be performed after each coupling step. Fmoc chemistry allows the spectrophotometric detection of the Fmoc chromophore when it is released with the base ( eienhofer et al . , Int. J. Peptide Protein Res. 1979, 13, 35-42) .

The resin-bound intermediate within each reaction vessel is washed free of excess of retained reagents, of solvents, and of by-products by repetitive exposure to pure solvent (s) by one of the two following methods :

1) The reaction vessels are filled with solvent (preferably 5 mL) , agitated for 5 to 300 minutes, preferably 15 minutes, and drained to expel the solvent; 2) The reaction vessels are filled with solvent (preferably 5 mL) and drained into a receiving vessel such as a test tube or vial .

Both of the above washing procedures are repeated up to about 50 times (preferably about 10 times) , monitoring the efficiency of reagent, solvent, and by-product removal by methods such as TLC, GC, or inspection of the washings.

The above described procedure of reacting the resin-bound compound with reagents within the reaction tubes followed by removal of excess reagents, by-products, and solvents is repeated with each successive transformation until the final resin-bound fully protected linear peptide has been obtained .

Before this fully protected linear peptide is detached from the solid support, an interstrand linkage between Xaa² and Xaa¹¹ of -Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa¹⁰- Xaa¹¹-Xaa¹²-Xaa¹³-Xaa¹⁴- can be formed.

Interstrand linkages and their formation have been discussed above, in connection with the explanations made regarding groups of the type H which can, for example, be disulfide bridges formed by cysteine and homocysteine residues at opposite positions of the β-strand; or lactam bridges formed by glutamic and aspartic acid residues linking ornithine and, respectively, lysine residues, or by glutamic acid residues linking 2 , 4-diaminobutyric acid residues located at opposite β-strand positions by amide bond formation. The formation of such interstrand linkages can be effected by methods well known in the art.

For the formation of a disulfide bridge preferably a solution of 10 equivalents of iodine solution is applied in DMF or in a mixture of CH₂Cl₂/MeOH for 1.5 h which is repeated for another 3h with a fresh iodine solution after filtering of the iodine solution, or in a mixture of DMSO and acetic acid solution, buffered with 5% NaHC0₃ to pH 5-6 for 4h, or in water after adjusting to pH 8 with ammonium hydroxide solution by stirring for 24h, or in a solution of NMP and tri-n-butylphosphine (preferably 50 eq. ) .

Alternatively, the formation of the disulfide bridge between Xaa² and Xaa¹¹ of -Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa⁹- Xaa¹⁰-Xaaⁿ-Xaa¹²-Xaa¹³-Xaa¹⁴- can be carried out subsequent to the work-up method 2) , as described herein below, by stirring the crude fully deprotected and cyclized peptide for 24h in water containing DMSO up to 15% by volume, buffered with 5% NaHC0₃ to pH 5-6, or buffered with ammonium acetate to pH 7-8, or adjusted with ammonium hydroxide to pH 8. Following evaporation to dryness Cyclo (-Xaa^x-Xaa²-Xaa³- Xaa -Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa^u-Xaa¹²-Xaa¹³-Xaa¹⁴-) , disulfide bond between Cys² and Cys¹¹ is obtained as end-product .

Detachment of the fully protected linear peptide from the solid support is achieved by exposing the loaded resin with a solution of the reagent used for cleavage (preferably 3 to 5 mL) . Temperature control, agitation, and reaction monitoring are implemented as described above. Via a transfer-unit the reaction vessels are connected with a reservoir box containing reservoir tubes to efficiently collect the cleaved product solutions. The resins remaining in the reaction vessels are then washed 2 to 5 times as above with 3 to 5 mL of an appropriate solvent to extract (wash out) as much of the detached products as possible. The product solutions thus obtained are combined, taking care to avoid cross-mixing. The individual solutions/extracts are then manipulated as needed to isolate the final compounds. Typical manipulations include, but are not limited to, evaporation, concentration, liquid/liquid extraction, acidification, basification, neutralization or additional reactions in solution.

The solutions containing fully protected linear peptide derivatives which have been cleaved off from the solid support and neutralized with a base, are evaporated. Cyclization is then effected in solution using solvents such as DCM, DMF, dioxane, THF and the like. Various coupling reagents which were mentioned earlier can be used for the cyclization. The duration of the cyclization is about 6-48 hours, preferably about 16 hours. The progress of the reaction is followed, e. g. by RP-HPLC (Reverse Phase High Performance Liquid Chromatography) . Then the solvent is removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a solvent which is not miscible with water, such as DCM, and the solution is extracted with water or a mixture of water-miscible solvents, in order to remove any excess of the coupling reagent.

Finally, the fully protected peptide derivative is treated with 95% TFA, 2.5% H₂0, 2.5% TIS or another combination of scavengers for effecting the cleavage of protecting groups. The cleavage reaction time is commonly 30 minutes to 12 hours, preferably about 2.5 hours.

Alternatively, the detachment and complete deprotection of the fully protected peptide from the solid support can be achieved manually in glass vessels.

After full deprotection one of the following methods can be used for further work-up:

1) The volatiles are evaporated to dryness and the crude peptide is dissolved in 20% AcOH in water and extracted with isopropyl ether or other solvents which are suitable therefor. The aqueous layer is collected and evaporated to dryness, and the fully deprotected peptide,

Cyclo (-Xaa^Xaa^Xaa^Xaa^Xaa-'-Xaa^Xaa^ aa^Xaa^Xaa^-Xaa¹¹- Xaa¹²-Xaa¹³-Xaa¹⁴-) , is obtained as final product; 2) The deprotection mixture is concentrated under vacuum. Following precipitation of the fully deprotected peptide in diethylether at preferably 0 °C the solid is washed up to about 10 times, preferably 3 times, dried, and the the fully deprotected peptide, Cyclo (-Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷- Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa^u-Xaa¹²-Xaa¹³-Xaa¹⁴-) is obtained as final product, if a disulfide bond between Xaa² and Xaa¹¹ has been formed on solid support as described herein above.

As mentioned earlier, it is thereafter possible, if desired, to convert the fully deprotected product of Cyclo (-Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹- Xaa¹²-Xaa¹³-Xaa¹⁴-) , thus obtained into a pharmaceutically acceptable salt or to convert a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of Cyclo (-Xaa¹-Xaa -Xaa³-Xaa⁴-Xaa⁵-Xaa^B- Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaaⁿ-Xaa¹²-Xaa¹³-Xaa¹⁴-) , or into a different, pharmaceutically acceptable, salt. Any of these operations can be carried out by methods well known in the art .

The β-hairpin peptidomimetics of the invention can be used in a wide range of applications in order to inhibit the growth of or to kill microorganisms. In particular they can be used to selectively inhibit the growth of or to kill microorganisms such as Bacillus subtilis and/or Shigella boydii and/or to inhibit the development of viral pathogens as, for example, human immunodeficiency viruses (HIV) .

They can be used for example as disinfectants or as preservatives for materials such as foodstuffs, cosmetics, medicaments and other nutrient-containing materials. The β-hairpin peptidomimetics of the invention can also be used to treat or prevent diseases related to microbial infection in plants and animals. For use as disinfectants or preservatives the β-hairpin peptidomimetics can be added to the desired material singly, as mixtures of several β-hairpin peptidomimetics or in combination with other anti-infective agents. The β-hairpin peptidomimetics may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well known in the art.

When used to treat or prevent infections or diseases related to such infections, particularly infections related to respiratory diseases such as cystic fibrosis, emphysema, asthma or pneumonia; infections related to skin or soft tissue diseases such as surgical wounds, traumatic wounds, burn wounds or herpes, smallpox, rubella or measles; infections related to gastrointestinal diseases such as epidemic diarrhea, necrotizing enterocolitis, typhlitis or gastroenteritis or pancreatitis; infections related to eye diseases such as keratitis and endophthalmitis; infections related to ear diseases such as otitis; infections related to CNS diseases such as brain abscess and meningitis or encephalitis; infections related to bone diseases such as osteochondritis and osteomyelitis; infections related to cardiovascular diseases such as endocartitis and pericarditis; or infections related to gastrourinal diseases such as epididymitis, prostatitis and urethritis; infections related to liver diseases such as hepatitis; infections related to sexually transmitted diseases such as AIDS; infections related to diseases such as common cold, influenza, parotitis or gingivostomatitis; the β-hairpin peptidomimetics can be administered singly, as mixtures of several β-hairpin peptidomimetics, in combination with other antimicrobial or antibiotic agents, or anti cancer agents, or antiviral (e. g. anti-HIV) agents, or in combination with other pharmaceutically active agents. The β-hairpin peptidomimetics can be administered per se or as pharmaceutical compositions.

The β-hairpin peptidomimetics of the invention can be used in a wide range of applications in order to prevent HIV infections in healthy individuals and slow or halt viral progression in infected patients.

The β-hairpin peptidomimetics of the invention may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well known in the art.

Pharmaceutical compositions comprising β-hairpin peptidomimetics of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxilliaries which facilitate processing of the active β-hairpin peptidomimetics into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.

For topical administration the β-hairpin peptidomimetics of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.

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

For injections, the β-hairpin peptidomimetics of the invention may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hink' s solution, Ringer's solution, or physiological saline buffer. The solutions may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the β-hairpin peptidomimetics of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen-free water, before use .

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation as 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. Such carriers enable the β-hairpin peptidomimetics of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., 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, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP) ; granulating agents; and binding agents. If desired, desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate. If desired, solid dosage forms 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, etc. In addition, flavoring agents, preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets, lozenges, etc. formulated as usual.

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

The compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases such as cocoa butter or other glycerides .

In addition to the formulations described above, the β-hairpin peptidomimetics of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. For the manufacture of such depot preparations the β-hairpin peptidomimetics of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts.

In addition, other pharmaceutical delivery systems may be employed such as liposomes and emulsions well known in the art. Certain organic solvents such as dimethylsulfoxide may also be employed. Additionally, the β-hairpin peptidomimetics of the invention may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent (e.g. for coated stents). Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed.

As the β-hairpin pepdidomimetics of the invention may contain charged residues, they may be included in any of the above-described formulations as such or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than are the corresponding free forms.

The β-hairpin peptidomimetics of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose. It is to be understood that the amount used will depend on a particular application . For example, for use as a desinfectant or preservative, an antimicrobially effective amount of a β-hairpin peptidomimetic of the invention, or a composition thereof, is applied or added to the material to be desinfected or preserved. By antimicrobially effective amount is meant an amount of a β-hairpin peptidomimetic of the invention, or a composition thereof, that inhibits the growth of, or is lethal to, a target microbe population. While the antimicrobially effective amount will depend on a particular application, for use as desinfectants or preservatives the β-hairpin peptidomimetics of the invention, or compositions thereof, are usually added or applied to the material to be desinfected or preserved in relatively low amounts. Typically, the β-hairpin peptidomimetics of the invention comprise less than about 5% by weight of a desinfectant solution or material to be preserved, preferably less than 1% by weight and more preferably less than 0.1% by weight. An ordinary skilled expert will be able to determine antimicrobially effective amounts of particular β-hairpin pepdidomimetics of the invention for particular applications without undue experimentation using, for example, the results of the in vitro assays provided in the examples.

For use to treat or prevent microbial infections or diseases related to such infections, the β-hairpin pepidomimetics of the invention, or compositions thereof, are administered or applied in a therapeutically effective amount. By therapeutically effective amount is meant an amount effective in ameliorating the symptoms of, or in ameliorating, treating or preventing microbial infections or diseases related thereto. Determination of a therapeutically effective amount is well within the capacities of those skilled in the art, especially in view of the detailed disclosure provided herein. As in the case of desinfectants and preservatives, for topical administration to treat or prevent bacterial infections and/or viral infections a therapeutically effective dose can be determined using, for example, the results of the in vitro assays provided in the examples. The treatment may be applied while the infection is visible, or even when it is not visible. An ordinary skilled expert will be able to determine therapeutically effective amounts to treat topical infections without undue experimentation.

For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating β-hairpin peptidomimetic concentration range that includes the IC₅₀ as determined in the cell culture (i.e. the concentration of a test compound that is lethal to 50% of a cell culture) . Such information can be used to more accurately determine useful doses in humans.

Initial dosages can also be determined from in vivo data, e.g. animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data.

Dosage amounts for applications as anti-infective agents may be adjusted individually to provide plasma levels of the β-hairpin peptidomimetics of the invention which are sufficient to maintain the therapeutic effect. Therapeutically effective serum levels may be achieved by administering multiple doses each day.

In cases of local administration or selective uptake, the effective local concentration of the β-hairpin peptidomimetics of the invention may not be related to plasma concentration. One having the ordinary skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

The amount of β-hairpin peptidomimetics administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgement of the prescribing physician . The anti-infective therapy may be repeated intermittently while infections are detectable or even when they are not detectable. The therapy may be provided alone or in combination with other drugs, such as for example other anti-HIV agents or anti-cancer agents, or other antimicrobial agents.

Normally, a therapeutically effective dose of the β-hairpin peptidomimetics described herein will provide therapeutic benefit without causing substantial toxicity.

Toxicity of the β-hairpin peptidomimetics of the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD₅₀ (the dose lethal to 50% of the population) or the LDxoo (the dose lethal to 100% of the population) . The dose ratio between toxic and therapeutic effect is the therapeutic index. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in humans. The dosage of the β-hairpin peptidomimetics of the invention lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within the range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dose can be chosen by the individual physician in view of the patient's condition (see, e.g. Fingl et al. 1975, In: The Pharmacological Basis of Therapeutics, Ch.l, p.l).

The present invention may also include compounds, which are identical to the compounds of the general formula

Cyclo (-Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^-Xaa¹¹- Xaa¹²-Xaa¹³-Xaa¹⁴- ) , except that one or more atoms are

replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. compounds enriched in 2H (D) , 3H, 11C, 14C, 1271 etc. These isotopic analogs and their pharmaceutical salts and formulations are considered useful agents in the therapy and/or diagnostic, for example, but not limited to, where a fine-tuning of in vivo half-life time could lead to an optimized dosage regimen.

The following Examples illustrate the present invention but are not to be construed as limiting its scope in any way.

Examples

1. Peptide Synthesis Coupling of the first protected amino acid residue to the resin

1 g (1.4 mMol) 2-chlorotritylchloride resin (1.4 mMol/g; Barlos et al . Tetrahedron Lett. 1989, 30, 3943-3946) was filled into a dried flask. The resin was suspended in CH₂C1₂ (5 raL) and allowed to swell at room temperature under constant shaking for 30 min . A solution of 0.98 mMol (0.7 eq) of the first suitably protected amino acid residue (see below) in CH₂C1₂ (5 mL) mixed with 960 μΐ (4 eq) of diisopropylethylamine (DIEA) was added. After shaking the reaction mixture for 4 hours at 25 °C, the resin was filtered off and washed successively with CH₂C1₂ (lx) , D F (lx) and CH,C1₂ (lx) . A solution of CH₂Cl₂/MeOH/DIEA (17/2/1, 10 mL) was added to the resin and the suspension was shaken for 30 min. After filtration the resin was washed in the following order with CH₂C1₂ (lx), DMF (lx), CH₂C1₂ (lx), MeOH (lx), CH₂C1₂ (lx), MeOH (lx), CH₂C1₂ (2x) , Et₂0 (2x) and dried under vacuum for 6 hours. Loading was typically 0.6-0.7 mMol/g.

Fmoc-Pro-O-chlorotrityl resin was prepared as a preloaded resin and used in the synthesis. The synthesis was carried out employing a Syro-peptide synthesizer (MultiSynTech) using 24-96 reaction vessels. In each vessel 0.04 mMol of the above resin was placed and the resin was swollen in CH₂C1₂ and DMF for 15 min, respectively. The following reaction cycles were programmed and carried out : Step Reagent Time

1 DMF, wash 2x1 min

2 20% piperidine/DMF 1x5 min, 1x15 min 3 DMF, wash 5x1 min

4a 5 eq Fmoc amino acid/DMF

+5 eq HCTU/DMF, 10 eq DIEA/DMF 1x60 min

5 DMF, wash 3x1 min Step 4a was repeated once.

Unless indicated otherwise, the final coupling of an amino acid was followed by a Fmoc deprotection by applying steps 1-3 of the above described reaction cycle.

Cyclxzation and work up of backbone cyclized peptides

Cleavage of the fully protected peptide fragment

After completion of the synthesis, the resin (0.04 mMol) was suspended in 1 mL (0.13 mMol, 3.4 eq) of 1% TFA in CH₂C1₂ (v/v) for 3 minutes, filtered, and the filtrate was neutralized with 1 mL (0.58 mMol, 14.6 eq) of 10% DIEA in CH₂C1₂ (v/v) . This procedure was repeated three times to ensure completion of the cleavage. The filtrate was evaporated to dryness and a sample of the product was fully deprotected by using a cleavage mixture containing 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% triisopropylsilane (TIS) to be analyzed by reverse phase-HPLC (Ci₈ column) and ESI-MS to monitor the efficiency of the linear peptide synthesis. Cyclization of the linear peptide

The fully protected linear peptide (0.04 mMol) was dissolved in DMF (4 μΜοΙ/mL) . Then 30.4 mg (0.08 mMol, 2 eq) of HATU, 10.9 mg (0.08 mMol, 2 eq) of HOAt and 28 μΐ (0.16 mMol, 4 eq) DIEA were added, and the mixture was vortexed at 25°C for 16 hours and subsequently concentrated under high vacuum. The residue was partitioned between CH₂C1₂ and H₂0/CH₃CN (90/10: v/v) . The CH₂C1₂ phase was evaporated to yield the fully protected cyclic peptide.

Full deprotection of the cyclic peptide

The cyclic peptide obtained was dissolved in 3 mL of the cleavage mixture containing 82.5% trifluoroacetic acid (TFA) , 5% water, 5% thioanisole, 5% phenol and 2.5% ethanedithiole (EDT) . The mixture was allowed to stand at 25 °C for 2.5 hours and thereafter concentrated under vacuum. After precipitation of the cyclic fully deprotected peptide in diethylether (Et₂0) at 0 °C the solid was washed twice with Et₂0 and dried.

Analytical method 1:

Analytical HPLC retention times ( T, in minutes) were determined using a GeminiNX CI 8 3 μπι column with the following solvents A (H₂0 + 0.1% TFA) and B (CH₃CN + 0.09% TFA) and the gradient: 0-0.1 min: 97 % A, 3 % B; 2.7 min: 3 % A, 97 % B; 2.71-3 min: 3 % A, 97 % B; 3.05 min: 97 % A, 3 % B; 3.06-3.3 min: 97 % A, 3 % B.

Analytical method 2 :

Analytical HPLC retention times (RT, in minutes) were determined using a Xbridge C18 2.5 μπι column with the following solvents A (H₂0 + 0.1% TFA) and B (CH₃CN + 0.09% TFA) and the gradient: 0-0.05 min: 97 % A, 3 % B; 3.0 min: 3 % A, 97 % B; 3.01-3.6 min: 3 % A, 97 % B; 3.6 rain: 97 % A, 3 % B; 3.61-4.3 min: 97 % A, 3 % B.

Examples 1-18 as shown in Table 1 were synthesized starting with the amino acid Pro (Xaa¹⁴) , which was grafted to the resin. Starting resin was Fmoc-Pro-O-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to the procedure described above in the following sequence: Resin-Pro¹⁴-Xaa¹³- Xaa¹²-Xaa¹¹-Xaa¹⁰-Xaa⁹-Xaa⁸-Xaa⁷-Xaa⁶-Xaa⁵-Xaa⁴-Xaa³-Xaa²-Xaa¹-.

Following a final Fmoc deprotection as described above, the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated above.

The HPLC-retention times (minutes, see Table 2) for Ex. 1, 2 and 4-16 were determined using the analytical method 1, as described above, whereas the HPLC-retention times (minutes, see Table 2) for Ex. 3, 17 and 18 were determined using the analytical method 2, as described above.

Table 1: Examples (Ex.)

Ex. Seq ID Xaa¹ Xaa² Xaa³ Xaa⁴ Xaa⁵ Xaa⁶ Xaa⁷ Xaa⁸ Xaa⁹ Xaa¹⁰ Xaa¹¹ Xaa Xaa¹³ Xaa

1. Seq ID No 1 Trp Arg He Arg He ^DArg Asn Lys Dab Leu Arg Arg ^DPro Pro

2. Seq ID No 2 Trp Arg He Arg He ^DArg Asn Lys Arg Leu Arg Gin ^DPro Pro

3. Seq ID No 3 Trp Arg He Arg He ^DArg Asn Lys Arg Asn Arg Ala ^DPro Pro

4. Seq ID No 4 Trp Arg He Arg He ^DArg Asn Gin Arg Cha Gin Ala ^DPro Pro

5. Seq ID No 5 Trp Dab He Arg He ^DArg Asn Gin Arg Leu Gin Ala ^DPro Pro

6. Seq ID No 6 Trp Orn He Arg He ^DArg Asn Gin Arg Leu Gin Ala ^DPro Pro

7. Seq ID No 7 Trp Arg He Dab He ^DArg Asn Gin Arg Leu Gin Ala ^DPro Pro

8. Seq ID No 8 Trp Arg He Orn He ^DArg Asn Gin Arg Leu Gin Ala ^DPro Pro

9. Seq ID No 9 Trp Arg He Arg He Orn Asn Gin Arg Leu Gin Ala ^DPro Pro

10. Seq ID No 10 Trp Arg He Arg He Dab Asn Gin Arg Leu Gin Ala ^DPro Pro

11. Seq ID No 11 Trp Arg He Arg He ^DArg Gin Gin Arg Leu Gin Ala ^DPro Pro

12. Seq ID No 12 Trp Arg He Arg He ^DArg Thr Gin Arg Leu Gin Ala ^DPro Pro

13. Seq ID No 13 Trp Arg He Arg He ^DArg Leu Gin Arg Leu Gin Ala ^DPro Pro

14. Seq ID No 14 Trp Arg He Arg He ^DArg Tyr Gin Arg Leu Gin Ala ^DPro Pro

15. Seq ID No 15 Trp Arg He Arg He ^DArg Asn Gin Arg Tyr Gin Ala ^DPro Pro

16. Seq ID No 16 Trp Arg He Arg He ^DArg Asn Gin Arg Trp Gin Ala ^DPro Pro

17. Seq ID No 17 Trp Arg He Arg He ¾ab Asn Trp Dab Asn Arg Dab ^DPro Pro

18. Seq ID No 18 Trp Arg He Arg He ^DArg Asn His Arg Asn Arg Arg ^DPro Pro

Table 2 :

a) %-purity of compounds after prep. HPLC .

2. Biological methods

2.1. Preparation of the peptides Lyophilized peptides were weighed on a Microbalance (Mettler MT5) and dissolved in sterile water to a final concentration of 1 mg/ml . Stock solutions were kept at + 4 °C, light protected.

2.2. Antimicrobial activity of the peptides

The selective antimicrobial activities of the peptides were determined in 96-well plates (Greiner, polypropylene) by the standard NCCLS broth microdilution method (National Committee for Clinical Laboratory Standards 1993. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 3rd ed. Approved standard M7-A6. National Committee for Clinical laboratory standards, Wayne, PA) with slight modifications. Inocula of the microorganisms were diluted into Mueller-Hinton II (MH, cation adjusted) broth + 0.02% BSA and compared with a 0.5 McFarland standard to give appr . 106 colony forming units (CFU)/mL. Aliquots (50 μΐ) of inoculate were added to 50 μΐ of MH broth + 0.02% BSA containing the peptide in serial two-fold dilutions. The following microorganisms were used to determine antibiotic selectivity of the peptides: Bacillus subtilis DSM 10 and Shigella boydii DSM 7532. Antimicrobial activities of the peptides were expressed as the minimal inhibitory concentration (MIC) in μg/mL at which no visible growth was observed after 18-20 hours of incubation at 37 °C. 2.3. Cytotoxicity assay

The cytotoxicity of the peptides to HELA cells (Acc57) and COS-7 cells (CRL-1651) was determined using the MTT reduction assay (T. Mossman, J. Immunol. Meth. 1983, 65, 55-63; M.V. Berridge, A.S. Tan, Arch. Biochem. Biophys . 1993, 303, 474-482) . Briefly, the method was as follows: 4000 HELA cells/well and 3400 COS-7 cells/well were seeded and grown in 96-well microtiter plates for 24 h at 37 °C at 5% C0₂. Thereafter, time zero (Tz) was determined by MTT reduction (see below) . The supernatant of the remaining wells was discarded, and fresh medium and compounds in serial dilutions (12.5, 25 and 50 pg/mL, triplicates) were pipetted into the wells. After incubation of the cells for 48 h at 37 °C at 5% C0₂ the supernatant was discarded again and 100 pL MTT reagent (0.5 mg/mL in RPMI1640 and DMEM, respectively) /well was added. Following incubation at 37 °C for 2-4 h the media were aspirated and the cells were spiked (100 L isopropanol/well) . The absorbance of the solubilized formazan was measured at 595 nm (OD₅₉₅peptide) . For each concentration averages were calculated from triplicates. The percentage of growth was calculated as follows : (ODsgspeptide-ODsgsTz-ODsgsEmpty well) / (OD₅₉₅Tz-OD₅₉₅Empty well) x 100%. The GI₅₀ (Growth Inhibition) concentrations were calculated for each peptide by using a trend line function for the concentrations (50, 25, 12.5 and 0 pg/mL) , the corresponding percentages and the value 50, (=TREND

2.4. Hemolysis

The peptides were tested for their hemolytic activity against human red blood cells (hRBC) . Fresh hRBC were washed three times with phosphate buffered saline (PBS) and centrifuged for 10 min at 2000 x g. Compounds (100 pg/mL) were incubated with 20% hRBC (v/v) for 1 h at 37 °C and shaking at 300 rpm. The final erythrocyte concentration was approximately 0.9 x 10⁹ cells/mL. A value of 0% and 100% cell lyses, respectively, was determined by incubation of hRBC in the presence of PBS containing 0.001% acetic acid and 2.5% Triton X-100 in H₂0, respectively. The samples were centrifuged, the supernatants were 8-fold diluted in PBS buffer and the optical densities (OD) were measured at 540 nm. The 100% lyses value (ΟΟ₅₄₀Η₂Ο) gave an OD₅₄₀ of approximately 0.5-1.0.

Percent hemolysis was calculated as follows : (OD₅₄opeptide/OD₅₄oH₂0) xl00%.

The results of the experiments described in 2.2 - 2.4 are indicated in Table 3 herein below.

Table 3: Minimal inhibitory concentrations (MIC) in

Mueller- Hinton broth, cytotoxicity and hemolysis

Ex. Bactillus Shigella Cytotoxicity Hemolysis subtilis boydii Hela Cells Cos-7

DSM 10 DSM 7532 Cells at

MIC MIC GIso GIso 100 pg/mL

[pg/mL] [pg/mL] [pg/mL] [pg/mL] [%]

1 4 8 > 50 > 50 0.0

2 2 4 > 50 > 50 0.0

3 4 16 > 50 > 50 0.1

4 4 > 16 > 50 > 50 0.8

5 2 16 > 50 > 50 0.0

6 4 > 16 > 50 > 50 0.0

7 4 > 16 > 50 > 50 0.0

8 2 16 > 50 > 50 0.0

9 2 > 16 > 50 > 50 0.0

10 4 > 16 > 50 > 50 0.4

11 4 > 16 > 50 > 50 0.0

12 4 > 16 > 50 > 50 0.7

13 4 16 > 50 > 50 0.0

14 4 16 > 50 > 50 0.0

15 4 16 > 50 > 50 0.0

16 2 16 > 50 > 50 0.5

17 2 4 38 44 0.2

18 16 4 39 > 50 0.3

Claims

1. Compounds of the general formula

Cyclo (-Xaa^Xaa^Xaa^Xaa⁴- Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^-Xaa¹¹- Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are:

Xaa¹: amino acid residue of type C, or of type D,

as described herein below;

- Xaa²: amino acid residue of type E,

as described herein below;

Xaa³: amino acid residue of type C, or of type F,

as described herein below;

Xaa⁴: amino acid residue of type C, or of type E,

as described herein below;

Xaa⁵: amino acid residue of type C,

as described herein below;

Xaa⁷: amino acid residue of type F,

as described herein below, or Gly;

Xaa⁸: amino acid residue of type E,

as described herein below;

- Xaa⁹: amino acid residue of type E,

as described herein below;

Xaa¹⁰: amino acid residue of type C, or of type F,

as described herein below;

Xaa¹¹: amino acid residue of type E, or of type F,

as described herein below;

Xaa¹²: amino acid residue of type C, or of type E,

or of type F, as described herein below;

Xaa¹³: amino acid residue of formula -A-C0-,

as described herein below;

- Xaa¹⁴: amino acid residue of formula -B-CO-,

as described herein below; with the proviso that if

Xaa⁹ is an amino acid residue of type E,

as described herein below,

then Xaa⁹ is Dab; and/or if

Xaa¹² is an amino acid residue of type F, as described herein below,

then Xaa¹² is Gin; and/or

at least two of the amino acid residues of Cyclo (-Xaa¹-Xaa²-Xaa³-Xaa -Xaa⁵-Xaa⁶-Xaa¹-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹- Xaa¹²-Xaa¹³-Xaa¹⁴-) are non-canonical amino acid residues, as described herein below;

compounds of the general formula Cyclo ( -Xaa^x-Xaa²-Xaa³ Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa^B-Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are:

Xaa¹: amino acid residue of type D,

as described herein below;

Xaa²: amino acid residue of type E,

as described herein below;

Xaa³: amino acid residue of type C, or of type F,

as described herein below;

Xaa⁴: amino acid residue of type E,

as described herein below;

Xaa⁵: amino acid residue of type C,

as described herein below;

Xaa⁶: amino acid residue of type E, or the D-isomer of an amino acid residue of type E,

as described herein below;

Xaa⁷: amino acid residue of type C, or of type D,

or of type E, or of type F,

as described herein below, or Gly;

Xaa⁸: amino acid residue of type F,

as described herein below; Xaa⁹: amino acid residue of type E,

as described herein below;

Xaa¹⁰: amino acid residue of type C, or of type D,

or of type F, as described herein below;

Xaa¹¹: amino acid residue of type E, or or type F,

as described herein below;

Xaa¹²: amino acid residue of type C or of type E,

as described herein below;

Xaa¹³: amino acid residue of formula -A-CO-,

as described herein below;

Xaa¹⁴: amino acid residue of formula -B-CO-,

as described herein below;

with the proviso that if

Xaa⁷ is an amino acid residue of type F, as described herein below,

then Xaa is Gin or Thr; and/or if

Xaa¹⁰ is an amino acid residue of type F, as described herein below,

then Xaa¹⁰ is Ser; and/or

at least one of the amino acid residues Cyclo (-Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa Xaa¹²-Xaa¹³-Xaa¹⁴-) is a non-canonical amino acid residue, as described herein below; or compounds of the general formula Cyclo (-Xaa¹-Xaa²-Xaa³- Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are: amino acid residue of type

as described herein below;

amino acid residue of type

as described herein below;

- Xaa³: amino acid residue of type C,

as described herein below; amino acid residue of type E,

as described herein below;

amino acid residue of type C,

as described herein below;

amino acid residue of type E, as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below; amino acid residue of type F,

as described herein below;

amino acid residue of type D,

as described herein below;

amino acid residue of type E,

as described herein below;

amino acid residue of type F,

as described herein below;

amino acid residue of type E,

as described herein below;

amino acid residue of type E,

as described herein below;

amino acid residue of formula -A-C0-, as described herein below;

amino acid residue of formula -B-C0-, as described herein below; or compounds of the general formula Cyclo (-Xaa^L-Xaa²-Xaa³- Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa -Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are:

Xaa¹: amino acid residue of type D,

as described herein below;

Xaa²: amino acid residue of type E,

as described herein below;

- Xaa³: amino acid residue of type E,

as described herein below; Xaa : amino acid residue of type E,

as described herein below;

Xaa⁵: amino acid residue of type C,

as described herein below, or Gly;

- Xaa⁶: amino acid residue of type E, or of type F,

as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below, or -B-CO-, as described herein below or Gly;

- Xaa⁷: amino acid residue of type E, as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below, or Gly; Xaa⁸: amino acid residue of type F,

as described herein below, or Gly;

- Xaa⁹: amino acid residue of type E,

as described herein below;

Xaa¹⁰: amino acid residue of type F,

as described herein below;

Xaa¹¹: amino acid residue of type E,

as described herein below;

Xaa¹²: amino acid residue of type E,

as described herein below;

Xaa¹³: amino acid residue of formula -A-CO-,

as described herein below;

- Xaa¹⁴: amino acid residue of formula -B-CO-,

as described herein below;

with the proviso that at least one of the amino acid residues of Cyclo (-Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa^Xaa⁸- Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹²-Xaa¹³-Xaa¹⁴-) is a non-canonical amino acid residue, as described herein below; or compounds of the general formula Cyclo ( -Xaa¹-Xaa²-Xaa³- Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa^u-Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are: Xaa¹: amino acid residue of type E,

as described herein below;

Xaa²: amino acid residue of type E,

as described herein below;

Xaa³: amino acid residue of type C, or of type F,

as described herein below;

Xaa⁴: amino acid residue of type E,

as described herein below;

- Xaa⁵: amino acid residue of type C, or of type F,

as described herein below;

- Xaa⁷: Gly;

Xaa⁸: amino acid residue of type E, or of type F,

as described herein below;

Xaa⁹: amino acid residue of type E,

as described herein below;

- Xaa¹⁰: amino acid residue of type C, or of type F,

as described herein below;

Xaa¹¹: amino acid residue of type E,

as described herein below;

Xaa¹²: amino acid residue of type E,

as described herein below;

Xaa¹³: amino acid residue of formula -A-CO-,

as described herein below;

Xaa¹⁴: amino acid residue of formula -B-C0-,

as described herein below;

with the proviso that at least two of the amino acid residues of Cyclo (-Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸- Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹²-Xaa¹³-Xaa¹⁴-) are non-canonical amino acid residues; or compounds of the general formula Cyclo (-Xaa¹-Xaa²-Xaa³- Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa^u-Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are: - Xaa¹: amino acid residue of type E,

as described herein below;

Xaa²: amino acid residue of type C, or of type F,

as described herein below;

Xaa³: amino acid residue of type E,

as described herein below;

Xaa⁴: amino acid residue of type E,

as described herein below;

Xaa⁵: amino acid residue of type C,

as described herein below;

- Xaa⁶: amino acid residue of type E,

as described herein below;

Xaa⁷: Gly;

Xaa⁸: amino acid residue of type F,

as described herein below;

- Xaa⁹: amino acid residue of type E,

as described herein below;

Xaa¹⁰: amino acid residue of type E, or of type F,

as described herein below;

Xaa¹¹: amino acid residue of type E, or of type F,

as described herein below;

Xaa¹²: amino acid residue of type E,

as described herein below;

Xaa¹³: amino acid residue of formula -A-CO-,

as described herein below;

- Xaa¹⁴: amino acid residue of formula -B-C0-,

as described herein below;

with the proviso that at least one of the amino acid residues of Cyclo (-Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸- Xaa⁹-Xaa¹⁰-Xaa^ix-Xaa¹²-Xaa¹³-Xaa¹⁴-) are non-canonical amino acid residues ; or compounds of the general formula Cyclo ( -Xaa¹-Xaa²-Xaa³- Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa^u-Xaa¹²-Xaa¹³-Xaa¹⁴-) , wherein the amino acid residues Xaa¹ to Xaa¹⁴ are:

Xaa¹ : amino acid residue of type, E or of type F,

as described herein below;

Xaa²: amino acid residue of type C, or of type D, or of type E, or of type F, as described herein below; Xaa³: amino acid residue of type E, as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below, or Gly; Xaa⁴: amino acid residue of type C, or of type D, or of type E, or of type F, as described herein below; Xaa⁵: amino acid residue of type E,

as described herein below;

Xaa⁶: amino acid residue of type E, or of type F,

as described herein below, or Gly;

Xaa⁸: amino acid residue of type E,

as described herein below;

Xaa⁹: amino acid residue of type D, or of type E,

as described herein below;

as described herein below; Xaa¹⁴: amino acid residue of formula -B-C0-,

as described herein below;

with the proviso that at least two of the amino acid residues of Cyclo ( -Xaa^Xaa^Xaa^Xaa^Xaa^ aa^Xaa^Xaa⁸- Xaa⁹-Xaa¹⁰-Xaa^1I-Xaa¹²-Xaa¹³-Xaa¹⁴-) are non-canonical amino acid residues;

-B-CO- is Gly, NMeGly or the residue of an L-a-amino acid with B being a residue of formula -NR²⁰CH (R⁷¹) -, or NR²⁰CH(R⁷²) -, or -NR²⁰CH (R⁷³) -, or -NR²⁰CH (R⁷ ) - , or -NR²⁰CH (R⁸⁴) - , or the enantiomer of one of the groups Al to A69 as defined hereinafter;

A of -A-CO- is a group of one of the formulae

A1 A2 A3 A4

A10 A11 A12 A13 A14

A72 A74

A81 A82 A83 A84

A86

A91 A92 A93 A94

R is H; lower alkyl; lower cycloalkyl; lower alkyl-aryl or aryl-lower alkyl;

R² is H; alkyl; alkenyl; - (CH₂) _p (CHR⁶¹) _sOR⁵⁵;

- (CH₂)_P (CHR⁶¹) _SSR⁵⁶;

- (CH₂)_p (CHR⁶¹) _SNR³³R³⁴; - (CH₂) _p (CHR⁶¹) _sOCONR³³R⁷⁵;

-(CH₂)_o(CHR⁶¹)_sS0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SR⁷⁷;

- (CH₂) ₀ (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) o (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) o (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂) o (CHR⁶¹) sCOOR⁵⁷; - (CH₂ ) o (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

- (CH₂) ₀ (CHR⁶¹) _SPO (OR⁶⁰) ₂;

- (CH₂) o (CHR⁶¹) _s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R⁴ is H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵; - (CH₂) _ra (CHR⁶¹) _SSR⁵⁶;

- (CH₂) _m(CHR⁶¹) _sNR³³R³⁴;

- (CH₂)_m(CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) _m (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

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

- (CH₂) _P (CHR⁶¹) _SPO (OR⁶⁰) ₂;

- (CH₂)p (CHR⁶¹) _s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R⁵ is H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵;

- (CH₂)_m (CHR⁶¹) _sSR⁵⁶;

- (CH₂) _m(CHR⁶¹) _SNR³³R³⁴; - (CH₂) _m (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂)_m(CHR⁶¹) _SNR²⁰CONR³³R⁸²; - (CH₂) ₀ (CHR⁶¹) _sCOOR⁵⁷

- (CH₂)_o(CHR⁶¹)_sC0NR⁵⁸R⁵⁹ ; - (CH₂) ₀ (CHR⁶¹) _sPO (OR⁶⁰) ₂;

-(CH₂)o(CHR⁶¹)_s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

H; alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵;

- (CH₂) ₀(CHR⁶¹)_SSR⁵⁶; -(CH₂)₀(CHR⁶¹)_SNR³³R³⁴;

-(CH₂ ) o (CHR⁶¹) _sOCONR³³R^'7S; - (CH₂) o (CHR⁶¹) _SNR²⁰CONR^:

- (CH₂ ) o (CHR⁶¹) sCOOR⁵⁷; ^■- (CH₂) o (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

- (CH₂ )o(CHR⁶¹)_SPO(OR⁶⁰);

- (CH₂ )₀(CHR⁶¹)_S S0₂R⁶²; or - (CH₂) o (CHR⁶¹) _SC₆H₄R⁸;

R' is aallkkyyll;; aallkkeennyyll;; -- ((CCHH₂₂) _q (CHR⁶¹) _sOR⁵⁵; - (CH₂) _q (CHR⁶¹) _SNR³³R³

- (CH₂ ) _Q (CHR⁶¹) _SOCONR³³R^" ⁵; - (CH₂) _q (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂; ) _R (CHR⁶¹) sCOOR⁵⁷; - (CH₂) _r (CHR⁶¹) _sCONR^5aR⁵⁹;

- (CH₂)_r(CHR^bl)_sPO(OR^bu)₂;

- (CH₂)_r(CHR⁶¹)₃S0₂R⁶²; or - (CH₂) _r (CHR⁶¹) _s C₆H₄R⁸;

R⁸ is H; CI; F; CF₃; N0₂; lower alkyl; lower cycloalkyl; lower alkenyl; aryl; lower alkyl-aryl; aryl-lower alkyl; - (CH₂) ₀ (CHR⁶¹) _SR⁷⁷

- (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵⁶;

- (CH₂) o (CHR⁶¹) NR³³R³⁴ ;

-(CH₂)_o(CHR⁶¹)_s0C0NR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂)₀ (CHR⁶¹) _sCOOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂;

- (CH₂) o (CHR⁶¹) _sS0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _sCOR⁶⁴;

R⁹ is alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵⁶;

-(CH₂)₀(CHR⁶¹)_SNR³³R³⁴;

- (CH₂) ₀ (CHR⁶¹) ₃OCONR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂) o (CHR⁶¹) _sCOOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _sCONR⁸R⁵⁹;

-(CH₂)₀(CHR⁶¹)_SPO(OR⁶⁰)₂;

R¹⁰ is alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵⁶;

- (CH₂)o(CHR⁶¹)_sNR³³R³⁴;

- (CH₂) ₀ (CHR⁶¹) sCOOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

-(CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂;

- (CH₂)₀(CHR⁶¹)_S S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸; is H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵;

- (CH₂) _m (CHR⁶¹)_sNR³³R³⁴;

- (CH₂) _m (CHR⁶¹) _sOCONR³³R⁷⁵, (CH₂)_m(CHR⁶¹) _sNR^UCONR

- (CH₂) _o(CHR⁶¹) _sCOOR⁵⁷; -( ₂)o(CHR⁶¹)_sCONR⁵⁸R⁵⁹;

- (CH₂) _o(CHR⁶¹) _SPO(OR⁶⁰)₂;

- (CH₂) _o(CHR⁶¹) _sS0₂R⁶²; or

R" is H; alkyl; alkenyl; - (CH₂) _m (CHR ) _sOR

- (CH₂ )_m(CHR⁶¹) sSR⁵⁶;

- (CH₂ )m(CHR⁶¹) _SNR³³R³⁴ ; - ( CH₂ ) _m ( CHR⁶¹ ) _sOCONR³³R⁷⁵ ;

- (CH₂ )_ra(CHR⁶¹) _SNR²⁰CONR³³R⁸²; - (CH₂) _r (CHR⁶¹) _sCOOR⁵⁷;

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

- (CH₂ )_r(CHR⁶¹) s S0₂R⁶²; or - (CH₂) _r (CHR⁶¹) _SC₆H₄R⁸;

R is alkyl; alkenyl; - (CH₂) _q (CHR⁶¹) _sOR⁵⁵; - (CH₂) _q (CHR⁶¹) _SSR⁵

- (CH₂) _q (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) _q (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) _q (CHR⁶¹) _SNR⁰CONR³³R⁸²;

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

- (CH₂) _q (CHR⁶¹) _sPO (OR⁶⁰) ₂;

- (CH₂) _q(CHR⁶¹)_s S0₂R⁶²; or - (CH₂)_q(CHR⁶¹) _SC₆H₄R⁸;

R is H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵;

- (CH₂)_m(CHR⁶¹)_sNR³³R³⁴;

- (CH₂)_m(CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) _m (CHR⁶¹) _SNR²⁰CONR³³R^!

(CH₂) _q (CHR⁶¹) _sCOOR^b/; - (CH I₂) _q (CHR⁶¹) _sCONR^!

-(CH₂)_q(CHR⁶ⁱ)_sPO(OR^6U)₂; .

- (CH₂)_q(CHR⁶¹) _sSOR⁶²; or - (CH₂) _q (CHR⁶¹) _s C₆H₄R⁸;

R¹⁵ is alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵

- (CH₂) o (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) o (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) _SNR²⁰CONR³³R⁸² ;

- (CH₂) o (CHR⁶¹) ₃COOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

- (CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂;

R¹⁶ is alkyl; alkenyl; - (C¾) ₀ (CHR⁶¹) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵

- (CH₂) o (CHR⁶¹) _SNR³³R³⁴;

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

- (CH₂) _o(CHR⁶¹)_sPO(OR⁶⁰)₂;

- (CH₂) o(CHR⁶¹)s S0₂R⁶²; or - (CH₂)₀(CHR⁶¹)_SC₆H₄R⁸; R¹⁷ is alkyl; alkenyl; - (CH₂) _q (CHR⁶¹) _sOR⁵⁵; - (CH₂) _q (CHR⁶¹ ) ₅SR⁵⁶;

- (CH₂) _Q (CHR^G1 ) sNR³³R³⁴;

- (CH₂) _Q (CHR⁶¹ ) _sOCONR³³R⁷⁵; - (CH₂) _Q (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂) _Q (CHR⁶¹ ) sCOOR⁵⁷; - (CH₂) _Q (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

- (CH₂) q (CHR⁶¹ ) _SPO (OR⁶⁰) ₂;

- (CH₂) q (CHR⁶¹ ) s S0₂R⁶²; or - (CH₂) _Q (CHR⁶¹) _SC₆H₄R⁸;

_R18 is alkyl; alkenyl; - (CH₂) _P (CHR⁶¹) _sOR⁵⁵; - (CH₂) _P (CHR⁶¹) _SSR⁵⁶;

- (CH₂) p (CHR⁶¹ ) _SNR³³R³⁴;

- (CH₂) p (CHR⁶¹ ) _sOCONR³³R⁷⁵ ; - ( CH₂ ) _P ( CHR⁶¹) _SNR²⁰CONR³³R⁸² ;

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

- (CH₂) p (CHR⁶¹ ) _sPO (OR⁶⁰) ₂;

- (CH₂) p (CHR⁶¹ ) s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R¹⁹ is lower alkyl; - (CH₂) p (CHR⁶¹) _sOR⁵⁵; - (CH₂) _P (CHR⁶¹) _SSR⁵⁶;

- (CH₂) p (CHR⁶¹ ) _SNR³³R³⁴;

- (CH₂) p (CHR⁶¹; ) _sOCONR³³R⁷⁵ ; - ( CH₂ ) _P ( CHR⁶¹) _SNR²⁰CONR³³R⁸² ;

- (CH₂) p (CHR⁶¹; ) sCOOR⁵⁷; - (CH₂) p (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

- (CH₂) _P (CHR⁶¹: ) _SPO (OR⁶⁰) ₂;

- (CH₂) P(CHR⁶¹: I s S0₂R⁶²; or - (CH₂) o (CHR⁶¹) _SC₆H₄R⁸; or

_R18 and R¹⁹ taken together can form: - (CH₂) ₂~₆ ^_;

- (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-;

R is H; alkyl; lower cycloalkyl; alkenyl; lower alkyl-aryl; or aryl-lower alkyl;

R²¹ is H; alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _SOR⁵⁵;

- (CH₂ ) o (CHR⁶¹) _SSR⁵⁶ ; - (CH₂ ) o (CHR⁶¹) _SNR³³R³⁴;

- (CH₂ ) o (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) o (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂ ) o (CHR⁶¹) _sCOOR⁵⁷; - (CH₂ :) o (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

- (CH₂ ) o (CHR⁶¹) _SPO (OR⁶⁰) ₂;

- (CH₂ ) o (CHR⁶¹) s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R²² H; alkyl; alkenyl; - (CH₂) _C > (CHR⁶¹) _sOR⁵⁵;

- (CH₂ ) o (CHR⁶¹) _SSR⁵⁶; - (CH₂ ) o (CHR⁶¹) _SNR³³R³⁴;

- (CH₂ ) o (CHR⁶¹) sCOOR⁵⁷; - (CH₂ ) o (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

- (CH₂ ) o (CHR⁶¹) _SPO (OR⁶⁰) ₂;

R"^J is alkyl; alkenyl; - (CH₂) ₀ (CHR^bl) _sOR ; - (CH₂) ₀ (CHR⁶¹) _SSR^! - (CH₂) o (CHR⁶¹) _SNR³³R³⁴; - (CH₂) o (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

- (CH₂) _o (CHR⁶¹) _sPO (OR⁶⁰) ₂;

- (CH₂) ₀ (CHR⁶¹) _SNR³³R³⁴;

- (CH₂) _o (CHR⁵¹) _sPO (OR⁶⁰) ₂;

- (CH₂) ₀ (CHR⁶¹) s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R²⁵ is H; alkyl; alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵;

- (CH₂) _m (CHR⁶¹ ) sSR⁵⁶;

- (CH₂) _ra(CHR⁶¹ ) _SNR³³R³⁴; - (< i₂) _M (CHR⁶¹) _SOCONR³³R⁷⁵;

- (CH₂) _m (CHR⁶¹ ) _SNR²⁰CONR³³R^; ; - (CH₂) _O (CHR⁶¹)_sC00R⁵⁷;

-- ((CCHH₂₂)) oo ((CCHHRR^O6I1)) _SsCCOONNRR^S588RR^:5>M9;; - (CH₂) ₀ (CHR⁶¹) _SPO (OR⁶⁰) ₂;

- (CHz) ₀ (CHR⁶¹ )_sS0₂R⁶²; or :H₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R²⁶ is H; alkyl; alkenyl; - (CH₂) _M (CHR⁶¹) _SOR⁵⁵;

- (CH₂) _RA (CHR⁶¹) _SSR⁵⁶;

- (CH₂) ₀ (CHR⁶¹) s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸; or

R²⁵ and R²⁶ taken together can form: - (CH₂) ₂_₆-; - (CH₂) _RO (CH₂

(CH₂) _rS (CH₂) _r-; or - (CH₂) _rNR⁵⁷ (CH₂) r

is alkyl; alkenyl 55.

R" H; ; - (CH₂ ) ₀ (CHR⁶¹) _sOR^'

- (CH₂) ₀ (CHR⁶¹) _SSR⁵⁶; - (CH₂) ₀ (CHR⁶¹ ) _SNR³³R³⁴ ;

- (CH₂) o (CHR⁶¹) _sOCONR³³R⁷⁵;

- (CH₂) ₀ (CHR⁶¹) _SNR²⁰CONR³³R⁸²; - (CH₂) ₀ (CHR⁶¹) _sPO (OR⁶⁰) ₂;

R²⁸ is alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _s-OR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _s SR⁵⁶;

- (CH₂) o (CHR⁶¹) ₃ NR³³R³⁴;

- (CH₂) ₀ (CHR⁶¹) _sOCONR³³R⁷⁵; - (CH₂) ₀ (CHR⁶¹) _SNR²⁰CONR³³R⁸² ;

- (CH₂) o (CHR⁶¹) s COOR⁵⁷; - (CH₂) ₀ (CHR⁶¹) _s CONR⁵⁸R⁵⁹;

- (CH₂) ₀ (CHR⁶¹) _S PO (OR⁶⁰) ₂;

- (CH₂) ₀ (CHR⁶¹) _S S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _s C₆H₄R⁸; R²⁹ is alkyl; alkenyl; - (CH₂) ₀ (CHR⁶¹) _sOR⁵⁵; - (CH₂) ₀ (CHR⁶¹) _SSR⁵⁶;

- (CH₂) o (CHR⁶¹) _SNR³³R³⁴;

- (CH₂)_o(CHR⁶¹)_sPO(OR⁶⁰)₂;

-(CH₂)₀(CHR⁶¹)s S0₂R⁶²; or - (CH₂) ₀ (CHR⁶¹) _SC₆H₄R⁸;

R³³ is H; alkyl, alkenyl; - (CH₂) _m (CHR⁶¹) _sOR⁵⁵;

- (CH₂) _m (CHR⁶¹) _SNR³R⁶³;

- (CH₂) _ra(CHR⁶¹) _sOCONR⁷⁵R⁸²; - (CH₂)_ra(CHR⁶¹) _SNR²⁰CONR⁷⁸R⁸²;

- (CH₂) o(CHR⁶¹)_sCOR⁶⁴; -(CH₂) o (CHR⁶¹) _s-CONR⁵⁸R⁵⁹,

- (CH₂) o (CHR⁶¹) _sPO (OR⁶⁰) 2 ;

- (CH₂) ₀(CHR⁶¹)_S S0₂R⁶²; or - ^■(CH₂)₀(CHR⁶¹)_SC₆H₄R⁸;

R is H; lower alkyl; lower cycloalkyl; lower alkyl-aryl; aryl or aryl-lower alkyl; or

R³³ and R³⁴ taken together can form: -(CH₂)_2-6-; - (CH₂) ₂0 (CH₂)

- (CH₂)₂S (CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-;

R⁵⁰ is H; lower alkyl; lower cycloalkyl; lower alkyl-aryl; aryl-lower alkyl;

R⁵⁵ is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower alkyl-aryl; aryl-lower alkyl;

- (CH₂)_m(CHR⁶¹) _sOR⁵⁷;

- (CH₂)_m(CHR⁶¹) _SNR³⁴R⁶³; - (CH₂) _m (CHR⁶¹) _sOCONR⁷⁵R⁸²;

- (CH₂) o (CHR⁶¹) COOR⁵⁷; or

- (CH₂) o (CHR⁶¹) _sCONR⁸R⁵⁹;

R⁵⁶ is H; lower alkyl; lower alkenyl; lower alkyl-aryl; aryl-lower alkyl;

- (CH₂)_m(CHR⁶¹) _sOR⁵⁷;

- (CH₂) _m (CHR⁶¹) _SNR³R⁶³; - (CH₂) _m (CHR⁶¹) _sOCONR⁷⁵R⁸²;

- (CH₂)_ra(CHR⁶¹) _SNR²⁰CONR⁷⁸R⁸²; - (CH₂) ₀ (CHR⁶¹ ) _s-COR⁶ ; or

- (CH₂) o (CHR⁶¹) _sCONR⁵⁸R⁵⁹;

R⁵⁷ is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower alkyl-aryl; aryl-lower alkyl;

lower alkyl-heteroaryl; or heteroaryl-lower alkyl; R³⁸ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; aryl-lower alkyl;

lower alkyl-heteroaryl; or heteroaryl-lower alkyl; R⁵⁹ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; aryl-lower alkyl;

lower alkyl-heteroaryl; or heteroaryl-lower alkyl; or R⁵⁸ and R⁵⁹ taken together can form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

-(CH₂)₂S(CH₂)₂-; or

- (CH₂)₂NR⁵⁷(CH₂)₂-;

R⁶⁰ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; aryl; or aryl-lower alkyl;

aryl-lower alkyl; heteroaryl-lower alkyl; -(CH₂)_pOR⁵⁵; - (CH₂)_PNR³³R³⁴; - (CH₂) _pOCONR⁷⁵R⁸²; - (CH₂) _PNR²⁰CONR⁷⁸R⁸²;

- (CH₂) _oCOOR³⁷; or - (CH₂) _oP0 (OR⁶⁰) ₂;

R⁶² is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; lower alkyl-heteroaryl; aryl;

heteroaryl; aryl-lower alkyl; or

heteroaryl-lower alkyl;

R⁶³ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; lower alkyl-heteroaryl; aryl;

heteroaryl; aryl-lower alkyl; or

heteroaryl-lower alkyl;

-COR⁶⁴; -COOR⁵⁷; -CONR⁵⁸R⁵⁹; -S0₂R⁶²; or -PO(OR⁶⁰)₂; or

R³⁴ and R⁶³ taken together can form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂- ;

- (CH₂)₂S (CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- ;

R⁶⁴ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; lower alkyl-heteroaryl; aryl;

heteroaryl; aryl-lower alkyl; or

heteroaryl-lower alkyl;

- (CH₂)_P(CHR⁶¹)_S0R⁶⁵; - (CH₂ ) _p (CHR⁶¹ ) _SSR⁶⁶;

- (CH₂)_p(CHR⁶¹) _SNR³⁴R⁶³;

- (CH₂) p (CHR⁶¹) _s0C0NR⁵R⁸²; or - (CH_Z) _P (CHR⁶¹) _SNR²⁰CONR⁷⁸R⁸²; R⁶⁵ is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower alkyl-aryl; lower alkyl-heteroaryl; aryl; heteroaryl; aryl-lower alkyl; or

heteroaryl-lower alkyl; -COR⁵⁷;

-COOR⁵⁷; or -CONR⁵⁸R⁵⁹;

R⁶⁵ is H; lower alkyl; lower alkenyl; lower cycloalkyl; lower alkyl-aryl; lower alkyl-heteroaryl; aryl; heteroaryl; aryl-lower alkyl; or

heteroaryl-lower alkyl; or -CONR⁵⁸R⁵⁹;

R⁶⁷ is H; CI; Br; F; N0₂; -NR³⁴COR⁵⁷; -CF₃; CN; -OCF₃; -OCHF

-OR⁵⁷; -SR⁶²; lower alkyl; or

lower alkenyl;

R⁶⁸ is H; CI; Br; F; N0₂; -NR³⁴COR⁵⁷; -CF₃; CN; -OCF₃; -OCHF -OR⁵⁷; -SR⁶²; lower alkyl; or

lower alkenyl;

R⁶⁹ is H; CI; Br; F; N0₂; -NR³⁴COR⁵⁷; -CF₃; CN; -OCF₃; -OCHF -OR⁵⁷; -SR⁶²; lower alkyl; or

lower alkenyl;

R⁷⁰ is H; CI; Br; F; N0₂; -NR³COR⁵⁷; -CF₃; CN; -OCF₃; -OCHF

-OR⁵⁷; -SR⁶²; lower alkyl; or

lower alkenyl;

R⁷¹ is lower alkyl; lower alkenyl; - (CH₂) _p (CHR⁶¹) _sOR⁷⁵;

-(CH₂)_P(CHR⁶¹)_SSR⁷⁵;

- (CH₂) _p (CHR⁶¹) _SNR²⁰CONR³³R⁸²;

-(CH₂)₀(CHR⁶¹)_SCOOR⁷⁵; - (CH₂) _pCONR⁵⁸R⁵⁹; - (CH₂) _pPO (OR⁶²) ₂,

- (CH₂)_pS0₂R⁶²; or

- (CH₂) _o-C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶;

R⁷² is alkyl; alkenyl; lower cycloalkyl; - (CH₂) _p (CHR⁶¹) _sOR⁸⁵;

-(CH₂)_P(CHR⁶¹)_SSR⁸⁵;

-(CH₂)_rNR²⁰(CH₂)_oR⁷⁷;

R⁷⁴ is - (CH₂)_PNR⁷⁸R⁷⁹; - (CH₂ ) _PNR⁷⁷R⁸⁰; - (CH₂) _PC (=NR⁸⁰) NR⁷⁸R⁷⁹;

- (CH₂) _PC (=NOR⁵⁰) NR⁷⁸R⁷⁹;

- (CH₂)_PC₆H₄NR⁷⁷R⁸⁰;

- (CH₂) _PC₆H₄C (=NR⁸⁰) NR⁷⁸R⁷⁹; - (CH₂) _PC₆H₄C (=NOR⁵⁰) NR⁷⁸R⁷⁹; - (CH₂) _PC₆H₄C (=NNR⁷⁸R⁷⁹) NR⁷⁸R⁷⁹; - (CH₂) _PC₆H₄NR⁸⁰C (=NR⁸⁰) NR⁷⁸R⁷⁹;

- (CH₂) _PC₆H₄N=C (NR⁷⁸R⁸⁰) NR⁷⁹R⁸⁰; - (CH₂) _rO (CH₂) _mNR⁷⁸R⁷⁹;

- (CH₂)_rO(CH₂)_mNR⁷⁷R⁸⁰;

- (CH₂) _rO (CH₂) _PC (=NR⁸⁰) NR⁷⁸R⁷⁹; - (CH₂) _rO (CH₂) _PC (=NOR⁵⁰) NR⁷⁸R⁷⁹,

- (CH₂) _rO (CH₂) _PC (=NNR⁷⁸R⁷⁹) NR⁷⁸R⁷⁹;

- (CH₂) rO (CH₂) _raNR⁸⁰C (=NR⁸⁰) NR⁷⁸R⁷⁹;

- (CH₂) _rO (CH₂) _mN=C (NR⁷⁸R⁸⁰) NR⁷⁹R⁸⁰;

- (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) _mNR⁷⁷R⁸⁰; - (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)_mN=C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;

- (CH₂) _rS (CH₂)_PC₆H₄C (=NOR⁵⁰)NR⁷⁸R⁷⁹;

- (CH₂) _rS (CH₂) _PC₆H₄C (=NNR⁷⁸R⁷⁹) NR⁷⁸R⁷⁹;

- (CH₂) _rS (CH₂)_pC₆H₄NR⁸⁰C (=NR⁸⁰) NR⁷⁸R⁷⁹; - (CH₂) _PNR⁸⁰COR⁶⁴;

- (CH₂) _pNR⁸⁰COR⁷⁷;

- (CH₂) _PNR⁸⁰CONR⁷⁸R⁷⁹; or - (CH₂) _PC₆H₄NR⁸⁰CONR⁷⁸R⁷⁹;

is lower alkyl; lower alkenyl; lower cycloalkyl;

lower-alkyl-aryl; or aryl-lower alkyl; or

and R⁷⁵ taken together can form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂- ;

- (CH₂)₂S (CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-; or

and R⁸² taken together can form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂)₂S (CH₂)₂-; or

- (CH₂)₂NR⁵⁷(CH₂) ₂-;

is H; lower alkyl; lower alkenyl; lower cycloalkyl;

lower-alkyl-aryl; aryl-lower alkyl;

- (CH₂)_o0R⁷²; - (CH₂)₀SR⁷²;

- (CH₂)₀NR³³R³⁴; - (CH₂) _o0C0NR³³R⁷⁵; - (CH₂) _oNR²⁰CONR³³R⁸¹; - (CH₂)_oC00R ; - (CH₂)_oC0NR⁵⁸R⁵⁹; - (CH₂) _oP0 (OR⁶⁰) ₂;

- (CH₂) _pS0₂R⁶²; or

- (CH₂) _oC0R⁶⁴;

H6 H7 H9 H10

H26 H27 H28 H29

H55 R⁷⁸ is H; lower alkyl; lower cycloalkyl; lower alkyl-aryl; aryl; or aryl-lower alkyl; or

R⁷⁸ and R⁸² taken together can form: - (CH₂)₂.₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ,-;

R⁷⁹ is H; lower alkyl; lower alkyl-aryl; aryl; or

aryl-lower alkyl; or

R⁷⁸ and R⁷⁹, taken together, can be - (CH₂) ₂-₇-; - (CH₂) ₂0 (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-;

R⁸⁰ is H; or lower alkyl;

R³³ and R⁸¹ taken together can form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂- ;

- (CH₂) ₂S (CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-;

R⁸² is H; -CF₃; -0CF₃; -OCHF₂; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl;

R⁸³ is H; lower alkyl; aryl; or -NR⁷⁸R⁷⁹;

R⁸⁴ is - (CH₂) _p (CHR⁶¹) _sOH; - (CH₂) _pCOOR⁸⁰; - (CH₂) _p (CHR⁶¹) _SSH;

- (CH₂) _pCONR⁷⁸R⁷⁹; - (CH₂) _PNR⁸⁰CONR⁷⁸R⁷⁹; - (CH₂) _pC₆H₄CONR⁷⁸R⁷⁹; or - (CH₂)_pC₆H₄NR⁸⁰CONR⁷⁸R⁷⁹;

R⁸⁵ is lower alkyl; or lower alkenyl;

R⁸⁶ is R⁷⁴; - (CH₂)₀R⁷⁷; - (CH₂) ₀-CHR³³R⁷⁵; R⁸⁴;

- [ (CH₂)_U-X' ]t - (CH₂) _VNR⁷⁸R⁷⁹;

- [ (CH₂) _U-X ' ] _t- (CH₂) _V-C (=NR⁸⁰) NR⁷⁸R⁷⁹;

- [ (CH₂)_U-X' ]_t- (CH₂)_vOR⁷⁸; -[ (CH₂) _U-X ' ] _t- (CH₂) _v-CONR⁷⁸R⁷⁹; - [ (CH₂)_U-X' ]_t- (CH₂)_V-NR⁸⁰CONR⁷⁸R⁷⁹; -[ (CH₂) _U-X ' ] _t- (CH₂) _VSR⁷⁸ where X' is -0-, -NR²⁰- , -S-; or -0C00-, u is 1-3, t is 1-6, and v is 1-3; m is 2-4; o is 0-4; p is 1-4; q is 0-2; r is 1 or 2; s is or 1; the amino acid residue of type C is a residue of formula -NR²⁰CH (R⁷²) CO-;

the amino acid residue of type D is a residue of formula -NR ⁰CH (R⁷³) CO-;

-NR²⁰-CH (CO-) -alkenylene-CH (CO-) -NR²⁰-;

-NR²⁰-CH (CO-) -alkynylene-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-; non-canonical amino acid residues designate those amino acid residues being neither glycine nor the L- or D-isomers of alanine, arginine, aspartic acid, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,

threonine, tryptophan, tyrosine and valine; and pharmaceutically acceptable salts thereof.

2. Compounds according to claim 1 wherein A is a group of one of the formulae A1-A69;

- R¹ is hydrogen or lower alkyl;

- R² is H; lower alkyl; lower alkenyl;

-(CH₂)_pOR⁵⁵ (where R⁵⁵ : lower alkyl; or lower alkenyl);

-(CH₂)_PSR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl);

- (CH₂) _p0C0NR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-); - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) 2- or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) ₀N (R²⁰) COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶ : lower alkyl; or lower alkenyl)

- ((CCHH₂₂))_ooCC00C0R (where R : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁸R⁹ (where R^b8 : lower alkyl; or lower alkenyl; and R⁵⁹ : H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; -((CCHH₂₂))₂₂SS((CCHH₂₂))₂₂--; or - (CH₂) ₂NR (CH₂) ₂- (where R : H; or lower alkyl) ;

--((CCHH₂₂))_ooPP00 (OR^bu) ₂ (where R^bu : H; lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ;

- R³ is H; lower alkyl; lower alkenyl;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ,NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _mOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) 2- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _mNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂-₆ ^_; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

-((CCHH₂₂))₀₀CCOOCOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) QCONR R (where R^SB : lower alkyl; or lower alkenyl; and R⁵⁹ : H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

-((CCHH₂₂))_ooPP00 (OR^bu) ₂ (where R^bu : lower alkyl; or lower alkenyl) ;

-(CH₂)_oS0₂R (where R^bZ: lower alkyl; or lower alkenyl) ; or

- R⁴ is H; lower alkyl; lower alkenyl;

- (CH₂) _mNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂)₂S (CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _mOCONR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂-₆-;

-(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (C¾) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

- (CH₂) _mN (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R¹ lower alkyl; or lower alkenyl) ;

- ((CCHH₂₂))_ooCC00C0R (where R^b : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCONR^R" (where R^ba : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; - ((CCHH₂₂)) ₂₂SS ((CCHH₂₂)) 2₂-- ; or - (CH₂) ₂NR (CH₂) ₂- (where

lower alkyl) ;

- ((CCHH₂₂)) _ooPP00 (<OR^&°) ₂ (where R : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

- R⁵ is lower alkyl; lower alkenyl;

-(CH₂)_mOR⁵⁵ (where R⁵⁵ : lower alkyl; or lower alkenyl);

-(CH₂)_mSR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); - (CH₂) _mNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mOCONR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH,)₂_₆-; - (CH₂) ₂0 (CH₂) ,-;

- (CH₂) _mNR^Z0CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ :

H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂-₆-; -(CH₂)₂0(CH₂)2-; -(CH₂)2S(CH₂)2-; or ~ (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) _mN (R²⁰) COR⁵⁴ (where R²⁰ : H; or lower alkyl; R⁶ : alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl) ;

-- ((CCHH₂₂)) _ooCCOOOOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl) ;

- (C¾) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

-((CCHH₂₂))_ooPP00i(OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl);

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

- R⁶ is H; lower alkyl; lower alkenyl;

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂)

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-;

-(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

-- ((CCHH₂₂)) _ooCCOOOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ; - (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl)

-- ((CCHH₂₂)) _ooPP00 ((0R^6U) ₂ (where R^b0 : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

- R⁷ is lower alkyl; lower alkenyl;

-(CH₂)_qOR⁵⁵ (where R⁵⁵ : lower alkyl; or lower alkenyl);

-(CH₂)_qSR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); - (CH₂) _qNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _qNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ :

H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) _rCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _qCONR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹ : H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; (CH₂) ₂S (CH₂) 2-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where

lower alkyl) ;

-((CCHH₂₂))_rrPPOO (OR^6U) a (where R^bu : lower alkyl; or lower alkenyl) ;

- (CH₂) _rS0₂R^fa- (where R : lower alkyl; or lower alkenyl) ; or

- R^a is H; F; CI; CF₃; lower alkyl; lower alkenyl;

-(CH₂)_o0R⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl);

-(CH₂)₀SR⁵⁶ (where R^5b: lower alkyl; or lower alkenyl);

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; - ( CH₂ ) ₂S (CH₂ ) ₂- ; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-

(where R⁵⁷ : H; or lower alkyl);

-(CH₂)_oN(R²⁰)COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl)

- ((CCHH₂₂))_ooCC00(0R^b (where R^b/ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCO R^R^ (where R^B : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂.₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) 2-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl ) ;

- (CH₂) _oP0 (OR⁶⁰) 2 (where R⁶⁰: lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

lower alkyl; lower alkenyl;

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³ : H; or lower alkyl; or R³³ and R³⁴ taken together form: - (CH₂) ₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S (CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) ₀N (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) ₀CONR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

-- ((CCHH₂₂))_ooPP00((0R^bU)₂ (where R^6U: lower alkyl; or lower alkenyl) ;

-- ((CCHH₂₂))_ooSS00₂₂IR⁶² (where R⁶ : lower alkyl; or lower alkenyl) ; or - (CH₂) _qC₆H₄R⁸ (where R⁸: H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) .

lower alkyl; lower alkenyl;

- (CH₂) _oNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂) ₂-6-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

-((CCHH₂₂))_ooCC00(0R⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR^bBR⁹ (where R^a : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂^₆-; - (CH₂) ₂0 (CH₂) ₂-;

- ((CCHH₂₂)) ₂₂SS ((CCHH₂₂)) ₂₂--; or - (CH₂) ₂NR^S (CH₂) ₂- (where

lower alkyl) ;

- ((CCHH₂₂))_ooPP00((OR^6U) 2 (where R^bu : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

- (CH₂) _qC₆H₄R⁸ (where R⁸ : H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) . isH; lower alkyl; lower alkenyl;

- (CH₂) _mNR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂) ₂-6- - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mOCONR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂)_raNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂-₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

-(CH₂)_mN(R²⁰)COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oP0 (OR⁶⁰) ₂ (where R⁶⁰: lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

isH; lower alkyl; lower alkenyl;

-(CH₂)_mOR⁵⁵ (where R⁵ : lower alkyl; or lower alkenyl); -(CH₂)_mSR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); - (CH₂) _mNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂- ;

- (CH₂) _mNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³: H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂~₆-; -(CH₂)₂0(CH₂)₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂ ) ₂NR⁵⁷ (CH₂ ) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) _mN (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- ((CCHH₂₂)) _rrCCOOCOR^b/ (where R : lower alkyl; or lower alkenyl) ;

- (CH₂) _rCONR^b8R⁹ (where R⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂^-; - (CH₂) ₂0 (CH₂) ₂-;

- ((CCHH₂₂)) ₂₂SS ((CCHH₂₂)) 2₂-; or - (CH₂) ₂NR^b/ (CH₂) ₂- (where R ^/: H; or lower alkyl) ;

- ((CCHH₂₂)) _rrPPOO (OR^bU) ₂ (where R : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

lower alkyl; lower alkenyl;

- (CH₂) _qNR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)_{2 6}-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _qOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _qNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-;

- (CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

- (CH₂) _qN (R²⁰) COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

-(CH₂)_rC00⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl) ;

- (CH₂) _qCONR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _rPO (OR⁶⁰) a (where R⁶⁰: lower alkyl; or lower alkenyl) ;

- (CH₂) _rS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

isH; lower alkyl; lower alkenyl;

- (CH₂)_mNR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂~;

- (CH₂) _mOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂)_mNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂)_mN (R²⁰) COR⁶⁴ (where R²⁰ : H; lower alkyl; R⁶ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl)

-- ((CCHH₂₂))_ooPP00 (OR^faU) 2 (where R^bJ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R^b2 (where R : lower alkyl; or lower alkenyl) ;

lower alkyl; lower alkenyl;

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂^₆-; - (CH₂) ₂0 (CH₂) ₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) ₀OCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂)_oN(R²⁰)COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶ : lower alkyl; or lower alkenyl) ; particularly favoured being -NR²⁰CO-lower alkyl (where R²⁰: H; or lower alkyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) ₂S (CH₂) 2-; or - (CH₂) ₂NR⁵⁷ (CH₂) 2- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _oP0 (OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂) ₀S0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

lower alkyl; lower alkenyl;

- (CH₂) ₀NR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂^₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ; - (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; - (CH₂)₂0(CH₂) ₂-; - (CH₂)₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

- (CH₂) ₀N (R²⁰) COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl);

- (CH₂) oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- ((CCHH₂₂)) ₂₂SS ((CCHH₂₂)) ,2--; or - (CH₂) ₂NR (CH₂) ₂- (where

lower alkyl) ;

- ((CCHH₂₂)) ₀₀PPOO ((OR ) 2 (where R : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

- R¹⁷ is lower alkyl; lower alkenyl;

- (CH₂) _qNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(C¾)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl ) ;

-(CH₂)₂S(CH₂)₂-; or -(CH₂)₂NR⁵⁷(CH₂)₂- (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) _qNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂-₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵ : H; or lower alkyl);

- (CH₂) _rCOOR⁵¹ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _qCONR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _rPO (OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂) _rS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

- (CH₂) _qC₆H₄R⁸ (where R⁸ : H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) .

3. Compounds according to claim 1 or 2 wherein A is a group of formula

A8" wherein R is H or lower alkyl; and R is alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl; especially those wherein R⁶⁴ is n-hexyl (A8'-l); n-heptyl

(A8'-2); 4- (phenyl) enzyl (A8'-3); diphenylmethyl (A8'-4); 3-amino-propyl (A8'-5); 5-amino-pentyl (A8'-6); methyl

(A8'-7); ethyl (A8'-8); isopropyl (A8'-9); isobutyl (A8'-10); n-propyl (A8'-ll); cyclohexyl (A8'-12); cyclohexylmethyl (A8'-13); n-butyl (A8'-14); phenyl (A8'-15); benzyl (A8'-16); (3-indolyl) methyl (A8'-17); 2- (3-indolyl) ethyl (A8'-18); ( 4-phenyl) henyl (A8'-19); and n-nonyl (A8 ' -20) .

4. Compounds according to claim 1 wherein A is a group of one of the formulae A70 to A104;

-R¹⁸ is lower alkyl.

-R¹⁹ is lower alkyl; lower alkenyl;

- (CH₂) _PNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _pOCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂__S-; - (CH₂) ₂0 (CH₂) ₂- ;

- (CH₂) _PNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³: H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

-(CH₂)_PN(R²⁰)COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl);

- ((CCHH₂₂))_ppCCOOCOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- ( CH₂ ) _pCONR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl; and R⁵⁹ : H ; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: - ( CH₂ ) ₂_₆- ; - ( CH₂ ) ₂0 ( CH₂ ) ₂- ; - ( CH₂ ) ₂S ( CH₂ ) ₂-; or - ( CH₂ ) ₂NR⁵⁷ ( CH₂ ) ₂- (where R⁵⁷ : H ; or lower alkyl) ;

- ( CH₂ ) _oP0 ( OR⁶⁰ ) ₂ (where R⁶⁰ : lower alkyl; or lower alkenyl) ; - (CH₂) _pS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

- (CH₂) ₀C₆H₄ ⁸ (where R⁸: H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) .

H; lower alkyl; lower alkenyl;

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R taken together form: - (CH₂) 2-6~ !

-(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR ' (CH₂) ₂-

(where R : H; or lower alkyl) ;

-(CH₂)_oN(R²⁰)COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- (CH₂) oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl, or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl)

- (CH₂) _oP0 (OR⁶⁰) ₂ (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- ((CCHH₂₂))_ooSS00₂₂R^b2 (where R : lower alkyl; or lower alkenyl) ; or - (CH₂) _qC₆H₄R⁸ (where R⁸ : H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) .

-R²² is lower alkyl; lower alkenyl;

- (CH₂) ₀NR³³R³⁴ (where R³³ : lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) 2~

- (CH₂) ₀OCONR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)_2-6-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)2-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

-- ((CCHH₂₂)) _ooCC0O0OR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl, or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

--((CCHH₂₂))_ooPP00((OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

- (C¾) _qC₆H₄R⁸ (where R⁸ : H; F; CI; CF; lower alkyl; lower alkenyl; or lower alkoxy) . H; lower alkyl; lower alkenyl;

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂.₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(C¾)₂_₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (C¾) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S (CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂)_oN(R²⁰)COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ; particularly favoured are NR²⁰CO-lower alkyl (where R²⁰: H; or lower alkyl);

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl, or lower alkenyl; and R^⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl)

- ((CCHH₂₂))_ooPP00 (OR^bu) ₂ (where R^6lJ : lower alkyl; or lower alkenyl) ;

- (CH₂) ₀S0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

-R²⁴ is lower alkyl; lower alkenyl;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵ : lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂_₆-; - (CH₂) ₂0 (CH₂) Z~ - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _oNR²⁰C0NR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂-

(where R⁵⁷ : H; or lower alkyl);

- (CH₂) ₀ (R²⁰) COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶ : lower alkyl; or lower alkenyl) ; particularly favoured are NR²⁰CO-lower alkyl (where R²⁰: H; or lower alkyl); - (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oP0 (OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

-R²⁵ is H; lower alkyl; lower alkenyl;

-(CH₂)_mOR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); - (CH₂) _mNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂) ₂-6~; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _mNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl);

- (CH₂) _mN (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl);

- (CH₂) oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

-((CCHH₂₂))_ooPP00 (OR^bU) ₂ (where R^6U: lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

-R²⁶ is H; lower alkyl; lower alkenyl;

-(CH₂)_mOR⁵⁵ (where R⁵ : lower alkyl; or lower alkenyl);

- (CH₂) _raNR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) 2- or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) ₂S (CH₂) 2 - or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _mNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³:

H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂-₆-;

- (CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

-(CH₂)_mN(R²⁰)COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

-(CH₂)_oPO(OR⁶⁰)₂ (where R⁶⁰ : lower alkyl; or lower alkenyl);

- (CH₂) _oS0₂R⁶² (where R⁶ : lower alkyl; or lower alkenyl) ; or

- (CH₂) _qC₆H₄R⁸ (where R⁸ : H; F; CI; CF₃; lower alkyl; lower alkenyl; or lower alkoxy)-^-; or, alternatively, - R²⁵ and R²⁶ taken together can be

-(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; - (CH₂) ₂S (CH₂) ₂-; or

- (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷: H; or lower alkyl) .

-R²⁷ is H; lower alkyl; lower alkenyl;

-(CH₂)_o0R⁵⁵ (where R⁵⁵ : lower alkyl; or lower alkenyl); -(CH₂)₀SR⁵⁶ (where R⁵⁶ : lower alkyl; or lower alkenyl);

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵¹ : H; or lower alkyl) ;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³ : H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂^₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂~ (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂-₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) ₀ (R²⁰) COR⁶⁴ (where R²⁰ : H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form

- ((CCHH₂₂)) ₂₂SS ((CCHH₂₂)) ₂₂-; or - (CH₂) ₂NRⁱ" (CH₂) ₂- (where

lower alkyl) ;

-((CCHH₂₂))_ooPP00 (OR^bU) 2 (where R^bU: lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶² : lower alkyl; or lower alkenyl) ; or

lower alkyl; lower alkenyl;

-(CH₂)₀OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl); -(CH₂)₀SR⁵⁶ (where R^5G: lower alkyl; or lower alkenyl);

- (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂~ (where R⁵⁷: H; or lower alkyl) ;

- (CH₂) ₀OCONR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR²⁰CONR^{33 81} (where R²⁰ : H; or lower alkyl; R³³ : H; lower alkyl; or lower alkenyl; R⁸¹ : H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-; -(CH₂)₂0(CH₂)₂-; -(CH₂)₂S(CH₂)₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl);

- (CH₂) ₀N (R²⁰) COR⁶⁴ (where R²⁰: H; or lower alkyl; R⁶⁴ : lower alkyl; or lower alkenyl)

- ((CCHH₂₂))_ooCC00C0R (where R : lower alkyl; or lower alkenyl) ;

- (CH₂) QCONR R (where R^B8 : lower alkyl, or lower alkenyl; and R⁵⁹ : H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂-₆-; - (CH₂) ₂0 (CH₂) 2^"

- (CH₂) _oP0 (OR⁶⁰) ₂ (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂) ₀S0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

-R²⁹ is lower alkyl; lower alkenyl;

-(CH₂)_o0R⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl);

-(CH₂)₀SR⁵⁶ (where R⁵⁶: lower alkyl; or lower alkenyl); - (CH₂) ₀NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl; R³⁴ : H; or lower alkyl; or R³³ and R³⁴ taken together form: -(CH_z) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _o0C0NR³³R⁷⁵ (where R³³: H; lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form: -(CH₂) ₂-6-; - (CH₂) ₂0 (CH₂) ₂-;

- (CH₂) _oNR²⁰CONR³³R⁸¹ (where R²⁰ : H; or lower alkyl; R³³ :

H; lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together form: -(CH₂)₂_₆-;

- (CH₂) ₂0 (CH₂) 2-; - (CH₂) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H or lower alkyl);

- (CH₂)_oN(R²⁰)C0R⁶⁴ (where R²⁰: H; or lower alkyl; R⁶ : lower alkyl; or lower alkenyl) ; particularly favored are NR²⁰CO-lower-alkyl (where R²⁰: H; or lower alkyl);

- (CH₂) _oCOOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oC0NR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl, or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: -(CH₂)₂^₆-; - (CH₂) ₂0 (CH₂) ₂-;

- (C¾) ₂S (CH₂) ₂-; or - (CH₂) ₂NR⁵⁷ (CH₂) ₂- (where R⁵⁷ : H; or lower alkyl) ;

- (CH₂) _oP0 (OR⁶⁰) 2 (where R⁶⁰ : lower alkyl; or lower alkenyl) ;

- (CH₂) _oS0₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl) ; or

5. Compounds according to any one of claims 1 to 4 wherein B is a group of formula -NR²⁰CH (R⁷¹ ) - , or -NR²⁰CH (R⁷² ) - , or -NR²⁰CH (R⁷³) -, or -NR²⁰CH (R⁷⁴ ) - , or -NR²⁰CH (R⁸ ) - , or an enantiomer of one of the groups A5 (with R² being H) ; A8; A22; A25; A38 (with R² being H) ; A42; A47 and A50.

6. Compounds according to claim 5 wherein B-CO is Ala; Arg; Asn; Asp; Cys; Gin; Glu; Gly; His; lie; Leu; Lys; Met; Phe; Pro; Ser; Thr; Trp; Tyr; Val; Cit; Orn; tBuA; Sar; t-BuG; 4AmPhe; 3AmPhe; 2AmPhe; Phe (mC (NH₂) =NH) ; Phe (pC (NH₂ ) =NH) ;

Phe (mNHC (NH₂) =NH) ; Phe (pNHC (NH₂) =NH) ; Phg; Cha; C₄al; C₅al;

Nle; 2-Nal; 1-Nal; 4C1-Phe; 3C1-Phe; 2C1-Phe; 3,4Cl₂Phe;

4F-Phe; 3F-Phe; 2F-Phe; Tic; Thi; Tza; Mso; AcLys; Dpr; A₂Bu;

Dbu; Abu; Aha; Aib; Y(Bzl); Bip; S (Bzl) ; T(Bzl); hCha; hCys; hSer, hArg; hPhe; Bpa; Pip; MePhe; MeNle; MeAla; Melle;

MeVal; MeLeu; 4Hypl; 4Hyp2; 4Mpl; 4Mp2.

7. Compounds according to any one of the claim 1 to 4 wherein B is a group, having (L) -configuration, of formula

A8 ' ' wherein R²⁰ is H or lower alkyl and R⁶⁴ is alkyl; alkenyl; -[ (CH₂) _U-X]_t-CH₃ (where X is -0-; -NR²⁰- , or -S-; u = 1-3, and t = 1-6) , aryl; aryl-lower alkyl; or heteroaryl-lower alkyl; especially those wherein R⁶⁴ is n-hexyl (A8''-21); n-heptyl (A8' '-22); 4- (phenyl) benzyl (A8''-23); diphenylmethyl (A8' '-24); 3-amino-propyl (A8''-25); 5-amino-pentyl

(A8* '-26); methyl (A8''-27); ethyl (A8' '-28); isopropyl (A8''-29); isobutyl (A8''-30); n-propyl (A8''-31); cyclohexyl (A8''-32); cyclohexyl-methyl (A8''-33); n-butyl (A8''-34); phenyl (A8''-35); benzyl (A8' '-36); (3-indolyl) methyl (A8 ' * -37) ; 2- (3-indolyl) ethyl (A8' '-38); (4-phenyl) -phenyl (A8' '-39); n-nonyl (A8''-40); CH₃-OCH₂CH₂-OCH₂- (A8' '-41) and CH₃- (OCH₂CH₂) 2-OCH₂- (A8"-42) .

8. Compounds according to claim 1 wherein Xaa¹³ is ^DPro, ^DCha, NMe^DIle, ^DTyr, ^DHis, ^DHis(Bzl), ^D4Pal, NMe^DTyr, NMe^DLys, (ABu)G, ^DIle, NMe^DAla, ^DLys, or ^DDab; Xaa¹⁴ is ^LPro; the aforesaid ^DPro moiety and/or the aforesaid ^LPro moiety being optionally substituted as shown in formulae A8 ' and, respectively, A8 ' ' , as defined in claim 3 and, respectively, in claim 7.

9. Compounds according to claim 1 wherein the amino acid residues in Cyclo (-Xaa¹-Xaa²-Xaa³-Xaa -Xaa⁵-Xaa⁶-Xaa⁷- Xaa⁸-Xaa⁹-Xaa¹⁰-Xaaⁿ-Xaa¹²-Xaa¹³-Xaa¹⁴-) are : - Xaa¹: Trp;

- Xaa²: Arg, Dab or Orn;

- Xaa³: lie;

- Xaa⁴: Arg, Dab or Orn;

- Xaa⁵: lie;

- Xaa⁶: ^DArg, Dab, ^DDab, Orn;

- Xaa⁷: Asn, Gin, Thr, Leu or

- Xaa⁸: Lys, Gin, Trp or His;

- Xaa⁹: Arg or Dab;

- Xaa¹⁰: Asn, Leu, Cha, Tyr or

- Xaa¹¹: Arg or Gin;

- Xaa¹²: Arg, Dab, Ala or Gin;

- Xaa¹³: DPro;

- Xaa¹⁴: LPro;

10. A compound according to claim 1 wherein the amino acid residues are :

- Xaa¹: Trp;

- Xaa²: Arg;

- Xaa³: lie;

- Xaa⁴: Arg;

- Xaa⁵: lie;

- Xaa⁶: ^DArg;

- Xaa⁷: Asn;

- Xaa⁸: Lys;

- Xaa⁹: Arg;

- Xaa¹⁰: Leu;

- Xaa¹¹: Arg;

- Xaa¹²: Gin;

- Xaa¹³: ^DPro;

- Xaa¹⁴: ^LPro;

or wherein the amin

- Xaa¹: Trp;

- Xaa²: Dab;

- Xaa³: He;

- Xaa⁴ : Arg; - Xaa⁵: He;

- Xaa⁶: ^DArg;

- Xaa⁷: Asn;

- Xaa⁸: Gin;

- Xaa⁹: Arg;

- Xaa¹⁰: Leu;

- Xaa¹¹: Gin;

- Xaa¹²: Ala;

- Xaa¹³: ^DPro;

- Xaa¹⁴: ^LPro;

or wherein the amino acid residues are:

- Xaa¹: Trp;

- Xaa²: Arg;

- Xaa³ : lie;

- Xaa⁴: Arg;

- Xaa⁵: lie;

- Xaa⁶: ^DArg;

- Xaa⁷ : Asn;

- Xaa⁸: Gin;

- Xaa⁹: Arg;

- Xaa¹⁰: Trp;

- Xaa¹¹: Gin;

- Xaa¹²: Ala;

- Xaa¹³: ^DPro;

- Xaa¹⁴: 'Pro;

or wherein the amino acid residues are:

- Xaa¹: Trp;

- Xaa²: Arg;

- Xaa³: lie;

- Xaa⁴: Arg;

- Xaa⁵: He;

- Xaa⁶: ^DDab;

- Xaa⁷: Asn;

- Xaa⁸: Trp;

- Xaa⁹: Dab;

- Xaa¹⁰: Asn;

11. Enantiomers of the compounds as defined in claim 1.

12. Compounds according to any one of claims 1 to 11 for use as therapeutically active substances, particularly as substances having selective anti-infective activity, especially as substances having selective antibacterial activity against Bacillus subtilis and/or Shigella boydii.

13. A pharmaceutical composition containing a compound according to any one of claims 1 to 11 and a pharmaceutically inert carrier, particularly in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, pulmonary or inhalation administration such as tablets, dragees, capsules, solutions, liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions, spray, nebuliser or suppositories.

14. The use of compounds according to any one of claims 1 to 11 for the manufacture of a medicament, particularly intended to be used for preventing or treating infections or diseases related to such infections, particularly infections related to respiratory diseases or skin or soft tissue diseases or gastrointestinal diseases or eye diseases or ear diseases or CNS diseases or bone diseases or cardiovascular diseases or gastrourinal diseases, liver diseases, sexually transmitted diseases or diseases such as common cold, influenza, parotitis or gingivostomatitis, or as a disinfectants or preservatives for foodstuffs, cosmetics, medicaments and other nutrient-containing materials.

A process for the manufacture of compounds according to one of claims 1-10 which process comprises

coupling an appropriately functionalized solid support with an appropriately N-protected derivative of that amino acid which in the desired end-product corresponds to Xaa¹¹, wherein n is 14, 13, 12, 7, 6 or 5, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;

removing the N-protecting group from the product thus obtained;

coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product corresponds to Xaa"^"1, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;

removing the N-protecting group from the product obtained in step (c) ;

effecting steps substantially corresponding to steps (c) and (d) using appropriately N-protected derivatives of amino acids which in the desired end-product are in positions n-2 to 1, any functional group (s) which may be present in said N-protected amino acid derivatives being likewise appropriately protected;

if n is not 14, further effecting steps substantially corresponding to steps (c) and (d) using appropriately N-protected derivatives of amino acids which in the desired end-product are in positions 14 to n + 1, any functional group (s) which may be present in said N-protected amino acid derivatives being likewise appropriately protected;

forming an interstrand linkage between side-chains of appropriate amino acid residues at P2 and Pll; or alternatively, forming the aforesaid linkage subsequent to step (j), as described herein below; detaching the product thus obtained from the solid support ;

cyclizing the product cleaved from the solid support; removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group (s) which may in addition be present in the molecule; and if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound or into a different, pharmaceutically acceptable, salt.

16. A modification of the processes according to claim 15 for the manufacture of compounds according to claim 14 in which enantiomers of all chiral starting materials are used.