WO1993020099A2 - Cck and/or gastrin receptor ligands - Google Patents

Abstract

This invention relates to novel compounds with the general structure A-B-C and their pharmaceutically acceptable salts, to medicinal compositions containing them, and to the use of such medicinal compositions in the treatment of certain disease states. The compounds of the invention are represented schematically as A-B-C wherein S1-S4 are in general lypophilic residues, S5 is a polar or hydrophilic residue, and L1-L5 are optional linking units. The compounds of this invention bind to CCK and/or gastrin receptors with high affinity and are therefore useful in the treatment of diseases which involve the dysfunction of a physiological process regulated by either of these hormones.

Description

CCK AND/OR GASTRIN RECEPTOR LIGANDS

This invention relates to novel compounds that bind to the CCK and/or gastrin receptor with high affinity, to processes for the preparation of these compounds, and to their use in the treatment of certain disease states.

BACKGROUND TO THE INVENTION

Cholecystokinin (CCK) and gastrin are two members of a family of peptide hormones. They were originally discovered and described as agents acting oh organs of the gastrointestinal system. CCK stimulates the contraction of the gall bladder and the release of digestive enzymes from the pancreas. Gastrin stimulates the secretion of gastric acid. More recently CCK has been found in the brain, indicating that it may also act as a neurotransmitter or neuromodulator.

Both CCK and gastrin are biosynthesised as prepro-hormones. The biologically active peptides are then released after a series of post-translational modifications. In the case of CCK a number of active forms are produced which vary in the number of amino acid residues they contain. The smallest is a tetrapeptide (CCK-4) and the largest has 58 residues (CCK-58). A variety of gastrins are also known, of which the 17-residue peptide (G-17) is probably one of the most important. Additionally both CCK and gastrin have a tyrosine residue which is found as both the free phenol and as the O-sulphate. All the biologically active forms of both CCK and gastrin share a common tetrapeptide amide sequence at their C-terminus. The C-terminal sequences of the two peptides are:

. . . -Asp-Tyr*-Met-Gly-T (CCK)

. . . -Glu- Ala-Tyr*-Gly-T (Gastrin)

(Tyr* = tyrosine residue which is optionally O-sulphated; T = Trp-Met-Asp-Phe-NH₂)

Apart from its actions on the gall bladder and pancreas mentioned above CCK also influences secretion, absorption and motility in the stomach and intestines, and causes the secretion of pancreatic hormones such as somatostatin. In the central nervous system CCK appears to be important in anxiogenesis. analgesia and appetite regulation.

Gastrin plays a fundamental part in the control of gastric acid secretion, although the precise mechanism by which this secretion is regulated remains in doubt. Gastrin causes the release of histamine from the ECL-cells in the stomach wall. Histamine then stimulates the parietal cells to secrete acid. It is possible that gastrin can directly stimulate the parietal cells, but this in particular is a point of controversy. Gastrin also increases the blood flow in the stomach wall, but this might also be an indirect effect mediated by histamine, and exerts a trophic effect on the gastric mucosa. (For a more complete review, and leading references, see ref. 1).

CCK and gastrin interact with their target organs through specific receptors located in the cell surface plasma membranes. It is generally agreed that there are two different CCK receptors. The CCK-A (for alimentary) type is found in the peripheral tissue, and is the receptor which mediates the actions of CCK on the pancreas, gall bladder and intestines. It is also found in certain specific brain regions, where it might be involved in the control of appetite. The CCK-B (for brain) receptor type is more widely distributed in the CNS, and is thought to be involved in anxiety and other central actions of CCK. There is only one gastrin receptor type, found particularly in the stomach wall. It appears to show very similar ligand specificity to the CCK-B receptor, and the CCK-B receptor is commonly used as a model for the less readily isolable gastrin receptor.

There is evidence that this simple classification system is incomplete. Some tissues appear to have heterogeneous CCK receptor populations, with both high and low affinity sites, and there is some variation in ligand specificity for CCK-A receptors in tissue preparations from different organs. (For more details see ref. 2).

A number of approaches to the discovery of CCK and gastrin receptor agonists and antagonists have been tried and have led to the development of a wide variety of structural types as pharmacological tools for the elucidation of the function of CCK and gastrin in vivo and as potential drugs (see Figure).

Simple modifications to the natural peptide structures have provided peptides with unusual amino-acids as well as amides, esters and "reduced" and other pseudo-peptides.3 A group from Abbott Laboratories has shown that conformationally restricted amino-acid surrogates can give compounds of high affinity.⁴ Other studies have restricted the peptide conformation by cyclisation between two amino-acid side chains.⁵ Figure: Some Representative CCK/Gastrin Receptor Ligands

Tryptophan derivatives have been widely explored. The earliest compounds studied e.g. benzotript, were not very potent, but more recently disclosed compounds have demonstrated better affinity.⁶ Perhaps the best example of this development is CI-988, a tryptophan "dipeptoid" from Parke-Davis.⁷

A group from Rhone-Poulenc has disclosed a number of compounds which have some analogy with the tryptophan analogues developed by Biomeasure but which lack the indolylmethyl side chain.8

Aspartic and glutamic acids have also provided important compounds. Again the original modest lead, proglumide. has been overtaken by more recent developments.⁹

Microbial metabolites are a traditional source of lead structures, and a number of compounds have been shown to have affinity for the CCK-receptor.10 Probably the most significant of these is asperlicin. It has inspired an enormous effort in the development of benzodiazepine derivatives as CCK ligands. This particular area is probably the most active single area of research into new compounds as CCK and gastrin antagonists. H

A group from Lilly has published its findings on a series of quinazolinones which are also inspired by the structure of asperlicin.¹²

A number of groups have disclosed compounds which can be broadly described as small heterocycles with pendant aromatic substituents.¹³ These compounds may bind in a similar manner to the benzodiazepines.

Cyclic nucleotide derivatives have been known for some time to be CCK antagonists. The best is dibutyryl cyclic GMP, but its affinity for the receptor is only modest compared with other types of compound.¹⁴

Finally, it has been demonstrated that some peptides and their analogues, which are not themselves homologous with CCK/gastrin. have some affinity for the CCK receptor. This has been shown in analogues of substance P, calcitonin-gene-related peptide and somatostatin.15

References.

1. J. Martinez, in "Comprehensive Medicinal Chemistry", volume 3, ed. J.C. Emmett, Pergamon Press, Oxford. 1990. pp. 929-943.

2. L.J. Miller, Receptor Purification, 1, 483-495, 1990. 3. K. Shiosaki et al.. J. Med. Chem., 33. 2950-2952. 1990; R. Gonzalez-Muniz et al.. J. Med. Chem., 33, 3199-3204, 1990: M. Boomgaarden et al., Pharmazie, 45. 377-379, 1990; M.F. Lignon et al., J. Biol. Chem.. 262. 7226-7231. 1987; M. Rodiguez et al., J. Med. Chem.. 30, 1366-1373, 1987; C. Mendre et al.. J. Biol. Chem.. 263, 10641-10645, 1988; M. Rodriguez et al.. J. Med. Chem.. 32. 2331- 2339, 1989.

4. K. Shiosaki et al., in "Peptides: Chemistry, Structure and Biology", Proceedings of the 11^th American Peptide Symposium, ed. J.E. Rivier and G. R. Marshall, ESCOM, Leiden. 1990, pp. 978-980: M.W. Holladay et al., J. Med. Chem., 34, 455-457, 1991.

5. B. Charpentier et al., Proc. Natl. Acad. Sci. USA, 85, 1968-1972, 1988; M.

Rodriguez et al., Int. J. Peptide Protein Res., 35, 441-451, 1990.

6. R.T. Jensen et al., Biochimica Biophysica Acta, 761, 269-277, 1983; J.F. Kerwin jr. et al., J. Med. Chem., 34, 3350-3359, 1991; S.H. Kim (for Biomeasure, Inc.), US Patent 4,902,708, 1990.

7. J. Hughes et al., Proc. Natl. Acad. Sci. USA. 87, 6728-6732, 1990; D.C. Horwell et al., J. Med. Chem., 34, 404-414, 1991.

8. J.D. Bourzat et al. (for Rhone-Poulenc Rorer S.A.), International Patent WO 91/12264, 1991; WO 91/13862, 1991.

9. F. Makovec et al., Eur. J. Med. Chem., 21, 9-20, 1986; R.M. Freidinger et al., J.

Med. Chem., 33, 591-595, 1990; J.F. Kerwin jr. et al., J. Med. Chem., 32, 739- 742, 1989; J.C. Gasc et al., (for Roussel-Uclaf), European Patent Application 0 383 690, 1990; M. Kitazawa et al. (for Kissei Pharmaceutical Co. Ltd.), European Patent Application 0 443 064, 1991; F. Makovec et al., J. Med. Chem., 35, 28-38 , 1992.

10. M.G. Bock et al., J. Med. Chem., 29, 1941-1945, 1986; Y.K.T. Lam et al., J.

Antiobiotics, 44, 613-625, 1991; D.A. Kendrick et al., Bioorganic Medicinal Chem Lett., 2, 9-12, 1992. 11. M.G. Bock et al.. J. Med. Chem., 32. 13-16, 1989; Y. Sato et al. (for Fujisawa Pharmaceutical Co. Ltd.), European Patent Application 0 360 079, 1990; J.C. Gasc and D. Humbert (for Roussel-Uclaf), European Patent Application 0 376 849, 1990; A.P. Calvet et al. (for Jouveinal S.A.), European Patent Application 0 420 716, 1991; M.G. Bock et al. (for Merck & Co. Inc.), European Patent Application 0 434 360, 1991; S. Rault et al. (for Adir & Co.), European Patent Application 0446 133. 1991.

12. M. J. Yu et al.. J. Med. Chem..34. 1505- 1508, 1991.

13. M. Honaga et al., Japan. J. Pharmacol., 46, 319-324, 1988; J.D. Bourzat et al (for Rhone-Poulenc Same), European Patent Application 0 367 678, 1990; J.P. Bras et al. (for Sanofi), European Patent Application 0 432 040, 1991; J.J. Howbert, Presentation at SDR Symposium, "Non-peptide Antagonists for Peptide Receptors", London 1991.

14. J.D. Gardner and R.T. Jensen, Am. J. Physiol., 246, G471-G476, 1984.

15. L. Zhang, et al., Biochimica Biophysica Acta, 972, 37-44, 1988; P.N. Maton et al.. Peptides, 11, 1163-1167, 1990: N. Tahiri-Jouti, Neuropeptides, 19, 65-71, 1991.

DESCRIPTION OF THE INVENTION

The compounds of the present invention are ligands with a high affinity for CCK and/or gastrin receptors. They can be represented by the general formula A-B-C in which A, B and C are subunits as defined below and are linked by covalent bonds. It is presumed that the compounds of this invention achieve their potency by mimicking the C-terminal tetrapeptide which is common to CCK and gastrin, but this is not necessarily always the case. The important features of A, B and C are represented schematically below as general structure a:

in which:

S¹ is an optional substituent group, but when present is a hydrophobic residue

S² is a mandatory substituent, and is always an aromatic (including heteroaromatic) residue

S³ is also mandatory, and is generally a hydrophobic residue (but with the exceptions mentioned below)

S⁴ is mandatory, and is a hydrophobic residue

S⁵ is optional, and is generally a hydrophilic or polar residue

L¹ - L⁵ are linking elements (covalent bonds or chains of atoms) which are optional with the proviso that if S¹ is present then L² must be present, and that at least one of L³ and L⁴ must be present.

Exceptions to the above fall into two categories:

when S⁵ is absent S³ can be a hydrophilic residue, and when B is a group such as a proline residue then L³ can take the place of S³.

It is not the inventors' intention that the above be regarded as a definition of the invention. It is intended to be an aid to understanding the key features of the compounds of the invention, and it will be used below as a guide in explaining the development of the preferred embodiments of the invention. The precise scope of the invention is defined in Claim 1 below. In general, then. A is a unit that can have either one or two hydrophobic residues attatched. When only one is present then it is an aromatic system, and A is a group such as (substituted)phenyl carbamoyl, indoleacetyl or isoquinolinecarbonyl. When both hydrophobic residues are present and the linking unit L¹ is absent then A mimics a blocked aromatic amino-acid such as BOC-tryptophan or benzoyl-phenylglycine. When L¹ is present then A is cyclic. The aromatic residue can either be pendant to this ring or fused to it, giving, for example, a phenylproline and an indoline respectively. In these cases S¹ can be absent or it can be any hydrophobic group, for example a BOC- or a benzoyl group.

For subunit B there are three possibilities. When L³ is present and L⁴ is absent then B is analogous to an amino-acid. or a residue that can mimic an amino-acid, such as, for example O-benzyl-threonine or its "reduced" isostere. When L³ is absent and L⁴ is present then B can be considered to be an N-alkyl amino-acid analogue. When both L³ and L⁴ are present then B is cyclic. The ring can in itself constitute the hydrophobic residue S³, for example when B is a proline residue. Alternatively, the residue can be a pendant group or, if it is cyclic, it can be fused to the ring of B, giving for example a substituted proline or an indoline respectively.

For subunit C, if L⁵ is absent then the subunit is analogous to an N-alkylated amino-acid (as was B with L³ absent and L⁴ present). In this case S³ must be present, and mimics the backbone of the amino-acid. In some of the embodiments of the invention S³ is extended and mimics a dipeptide chain. When L³ is present S⁵ can be absent, or if it is present it performs a function analogous to that just described. With L⁵ present S⁴ can either be pendant to the ring so formed, or it can be fused with it.

We have found that certain combinations of the above options lead to compounds with high affinity for the target receptors, and in some cases with high selectivity between receptor sub-types. The result of our studies is a group of novel compounds with pharmacological properties as good as. and often better than, CCK and gastrin receptor ligands previously described, which makes them useful in the treatment of certain ailments. These compounds are the basis of the present invention.

Conceptually, the compounds of the present invention are derived from the amino-acid sequence of the naturally occuring hormones. The starting point of our investigation was an amide described by Martinez et al. (Int. J. Peptide Protein Res., 28, 529-535, 1986). We found that constraining the conformational freedom of the ester by cyclization gave compounds which retained some affinity for both CCK-A and CCK-B receptors. This key step is represented below.

Comparing the structure of the cyclised compound (b) with the diagramatic representation of the compounds of this invention (a) described above shows the following set of correspondences:

S¹ = BOC

S² = Trp side chain

S³ = Leu side chain

S⁴ = benzyl group

S⁵ = carboxymethyl group

L¹ & L⁴ absent

L², L³ & L⁵ present.

Further investigation demonstrated that potency was improved, particularly with respect to the CCK-A receptor, if the aromatic residue in S⁴ was fused to the C ring (compound c), and that the BOC-amino group could be omitted.

This leads to a first preferred embodiment of the present invention, defined precisely in Claims 19-20, in which:

A is a fused heteroaromatic substituted acyl residue, or an N^α-blocked tryptophan residue; B is a hydrophobic amino-acid residue, or a surrogate of one;

C is a benzo-fused piperidine or pyrrolidine, further substituted with a carboxyl or carboxyalkyl residue, which can be blocked as an ester, or extended, for example, by acylating an amino-acid residue.

In particular, this preferred embodiment of the invention includes;

Ethyl (2R)-1-{tert-butyloxycarbonyl-tryptophanyl-leucyl}-2,3-dihydroindole-2-acetateEthyl (2S)-1-{(2S)-2-(tert-butyloxycarbonyl-tryptophanylamino)-hexanoyl}-2,3-dihydroindole-2-carboxylate

(2R)-1-{Indole-2-carbonyl-phenylalanyl}-2,3-dihydroindole-2-acetic acid

(2R)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetic acid

3-{(2R)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-yl}-propanic acid

(2R)-1-{(2S)-2-(5-Fluoroindole-2-carbonylamino)-4-phenylbutanoyl }-2,3-dihydroindole- 2-acetic acid

(2R)-1-{(2S)-2-(5-Chloroindole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole- 2-acetic acid

(3R)-2-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-1,2,3,4- tetrahydroisoquinoline-3-acetic acid

N-{(2S)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyly-2,3-dihydroindole-2- acetyl}-glycine

3-{(2S)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-carbonylamino}-propanoic acid.

Further investigation revealed that deletion of the S⁵ substituent in the compounds typified by c generally resulted in compounds which were more potent and selective for the CCK-A receptor (e.g. compound d).

This leads to a second preferred embodiment of the present invention, defined precisely in Claims 16-18, in which:

A is a fused heteroaromatic substituted acyl residue, or an N^α-blocked tryptophan residue; B is usually a hydrophobic amino-acid residue, or a similar surrogate, but may also be a hydrophilic amino-acid residue, or a similar surrogate;

C is a benzo-fused piperidine or pyrrolidine.

In particular, this preferred embodiment of the invention includes;

1 -{tert-Butyloxycarbonyl-tryptophanyl-leucyl}-2,3-dihydroindole

1-{(2S)-2-(tert-Butyloxycarbonyl-tryptophanylamino)-hexanoyl}-2,3-dihydroindole 1-{(2S)-2-(3-Indole-3-propanoylamino)-hexanoyl}-2,3-dihydroindole

1-{tert-Butyloxycarbonyl-tryptophanyl-phenylalanyl}-2,3-dihydroindole

1-{(2S)-2-(tert-Butyloxycarbonyl-tryptophanylamino)-4-phenylbutanoyl}-2,3-dihydroindole

1-{tert-Butyloxycarbonyl-tryptophanyl-(β-O-benzyl)-D-aspartyl}-2,3-dihydroindole 1-{tert-Butyloxycarbonyl- tryptophanyl-aspartyl}-2,3-dihydroindole

1-{tert-Butyloxycarbonyl-tryptophanyl-(γ-O-benzyl)-glutamyl}-2,3-dihydroindole

1-{tert-Butyloxycarbonyl-tryptophanyl-glutamyl}-2,3-dihydroindole

2-{tert-Butyloxycarbonyl-tryptophanyl-D-phenylalanyl}-1,2,3,4-tetrahydroisoquinoline 2-{(2R)-2-(tert-Butyloxycarbonyl-tryptophanylamino)-4-phenylbutanoyl}-1,2,3,4-tetrahydroisoquinoline.

Modifications at die A subunit of compounds typified by structure c indicated that smaller groups could be employed without incurring a loss of activity. In particular, the replacement of BOC-Trp with an arylcarbamoyl residue (as in compound e) resulted in compounds which had high affinity for the CCK-A and/or CCK-B/gastrin receptor subtypes.

This leads to a third preferred embodiment of the present invention, defined precisely in Claims 2-7, in which:

A is a substituted or unsubstituted phenylcarbamoyl residue (i.e. L¹, L² and S¹ are absent);

B is a hydrophobic amino-acid, or a similar surrogate;

C is a piperidine or pyrrolidine which may be benzo-fused or may have a pendant hydrophobic substituent, and which is further substituted with a carboxylor carboxyalkyl sidechain or a derivative thereof.

In particular, this embodiment of the invention includes:

(3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-dιreonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Bromophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Methylphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Acetylphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Isopropoxyphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Cyanophenylcarbamoyl)-O-benzyl-threonyl]-1,2.3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-tert-butyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-benzoyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-(4-chlorobenzyl)-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(2S)-2-(3-Trifluoromethylphenylcarbamoylamino)-hexanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid (3R)-2-[(2S)-2-(3-Chlorophenylcarbamoylamino)-hexanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(2S)-2-(N-(3-Chlorophenylcarbamoyl)-methylamino)-hexanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(2S)-2-(3,4-Dichlorophenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(2S)-2-(2-Methylphenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(2S)-2-(4-Methylphenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(2S)-2-(3-Methoxyphenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(2S)-2-(3-Chlorophenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Chlorophenylcarbamoyl)-valyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Bromophenylcarbamoyl)-valyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Methylphenylcarbamoyl)-isoleucyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(2S)-2-(3-Chlorophenylcarbamoylamino)-3,3-dimethylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(S)-α-(3-Chlorophenylcarbamoylamino)-phenylacetyll-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(S)-α-(3-Methylphenylcarbamoylamino)-cyclohexaneacetyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(2S)-3-(2-Adamantyloxycarbonylamino)-2-(phenylcarbamoylamino)-propanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[(2S,3R)-2-(3-Chlorophenylcarbamoylamino)-3-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-[N-(3-Bromophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(2R,4S)-1-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-4-phenylpyrrolidine-2-carboxylic acid

(2R,4R)-1-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-4-phenylpyrrolidine-2-acetic acid (2R,5S)-1-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-5-phenylpyrrolidine-2-carboxylic acid

(3R)-2-[(2S,3R)-3-Benzyloxy-2-(3-chlorophenylcarbamoylamino)-butyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

The modification of the above structural types to give compounds with consistently high affinity and selectivity for CCK-B/gastrin receptors was more involved, but could be achieved in two ways. The first originated in the discovery that by constraining the conformational freedom of the A subunit with the introduction of L¹ the selectivity for CCK-B receptors was improved. This gain could be further improved by the introduction of L⁴ to constrain the B subunit (as in compound f). The affinity and selectivity of these compounds was found to be maintained when L³ was removed (as in compound g).

This leads to a fourth preferred embodiment of the present invention, defined precisely in Claims 12-15, in which:

A is a benzo-fused nitrogen heterocyclic acyl residue in which the nitrogen is substituted with a hydrophobic group (i.e. S¹, S², L¹ and L² all present);

B is a hydrophobic amino-acid residue or a similar surrogate, which preferably incorporates some degree of conformational restriction either through cyclization (as in f or by having a 3-amino-2-naphthoyl residue for B) or through N-substitution (as in g); C is a benzo-fused piperidine or pyrrolidine which may optionally be substituted at up to three positions. If such substituents are present then at least one is hydrophilic (for example a carboxyl or carboxyalkyl).

In particular, this embodiment of the invention includes:

(3R)-2-{N-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-O-benzylthreonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid (3R)-2-{(2S)-2-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)-4-phenylbutanoyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(2R)-1-{(2S)-2-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetic acid

(3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-valyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{((2R)-1-tert-Butylacetyl-2,3-dihydroindole-2-carbonyl)-valyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-valyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-isoleucyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(S)-α-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)-phenylacetyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-D-prolyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-2,3-dihydroindole-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,3S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-3-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,4S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenyldιio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,4S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-benzyloxy-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenoxy-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,4S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R.4S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2.3,4-tetrahydroisoquinoline

Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindoie-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2.3,4-tetrahydroisoquinoline-3-carboxylate

(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindoie-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2.3,4-tetrahydroisoquinoline-3-carboxamide

N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-glycine

(3R)-2-{(2R,5S)-1-((2RH-Neopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-Isopropyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-I,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-(2-Adamantyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrotidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butylcarbamoyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1.2.3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butylacetyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

N-{(3R)-2-{(2R-5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetyl}-proline

N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetyl}-D-proline

(3R)-2-{(2R,5S)-1-((2R)-1-Neopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,5S)-1-((2R)-1-(2-Adamantyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrroIidine-2-carbonyl}-l,2,3.4-tetrahydro-benz[f]isoquinoline-3-carboxylic acid (3R)-2-{(2R,5S)-1-((2R)- 1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-acetic acid (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-(2-naphthyl)-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{N-3-Phenylpropyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{N-Benzyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-3-Phenylpropyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

(3R)-2-{3-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-amino}-propanoyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-Phenethyl-N-((2R)-1-benzyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)(2-{N-Phenethyl-N-((2R)-1-neopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-Phenethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-3-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-(2-Oxo-2-phenylethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-(2-(3-Indolyl)ethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-carboxylic acid (3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-acetic acid

(3R)-2-{N-Pivaloyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-methyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{3-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)-naphdιalene-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{3-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)-naphthalene-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenyl- 2,5-dihydropyrrole-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-methyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2S)-2-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-acetylamino)-4-phenylbutanoyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-proline

N-{(3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-proline

N-{(3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-D-proline

(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-benzyl-pyrrolidine-2-carbonyl}-1,2,3.4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{N-2-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-4-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-2-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-3-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-4-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydro-benz[h]isoquinoline-3-carboxylic acid

(4RS)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-4-acetic acid (4RS)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindoie-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-4-acetic acid

(3R)-2-{(2R,5S)-1-((2R)-1-Cyclobutyloxycarbonyl-2,3-dihydroindoie-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-Cyciopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3.4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,5S)-1-((2R)-1-Cyclopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-(2-exo-Norbornyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-Cyclododecyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{N-Phenethyl-N-((2R)-1-n-propyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

N-{(3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetyl}-proline

(3R)-2-{N-2-(2-Methoxyphenyl)ethyl-N-((2R)-1-(tert-butyloxycarbonyl-2,3-dihydroindole- 2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-(3,3-Dimethylbutyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-Cycloheptyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-((1S)-endo-Bornyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-((1R,2R.3R,5S)-Isopinocampheyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-((lS,2S,3S,5R)-Isopinocampheyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-(3,3-Dimethylbutyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,5S)-1-((2R)-1-(1-Piperidino)carbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3R)-2-{(2R,5S)-1-((2R)-1-(N-Cyclohexyl-N-methylcarbamoyl)-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-(4-tert-Butylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-(2-cis-Methylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-(2-trans-Methylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{N-Phenethyl-N-((2R)-1-(3-cyclohexylpropyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexylmethyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

(3R)-2-{(2R,5S)-1-((2R)-1-(2-Cyclohexylethyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

N-{(3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-proline

N-{(3R)-2-{(2R,5S)-1-((2R)-1-Neopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-proline

(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-propanoic acid

(3R)-2-{N-3-Methylphenethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-(2-(1-Methylpyrrol-2-yl)ethyl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-(2-Thienyl)ethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{N-((2RS)-1,2,3,4-Tetrahydronaphth-2-yl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid

(3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-(4-methoxyphenyl)-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3R)-2-{N-(Indan-2-yl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

The second modification which yields potent and selective CCK-B/gastrin receptor ligands involves the deletion of L⁵ (equivalent to the excision of the cyclic amide bond from b) to give a series of tertiary amides. In this series S¹ is not required and the compounds are structurally less complex (as in h).

This leads to a fifth preferred embodiment of the present invention, defined precisely in Claims 8-11, in which:

A is an acyl residue with an aromatic substituent;

B is a hydrophobic amino-acid or a similar surrogate;

C is an N-substituted amino-acid or similar surrogate, where the N-substituent is an alkyl, cycloalkyl, aralkyl or aryl group, and the carboxy terminus may be the free acid or may be blocked as an ester or amide, or may be extended, for example, by acvlating another amino-acid residue.

In particular, this preferred embodiment of the invention includes:

Methyl N-(2-cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycinate N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycine

1-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-pyrrolidine

Methyl N-{N-(2-cyclphexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D-prolinate

N-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl }-D-proline N-{N-(2-Cyciohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D- pipecolic acid

N-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-glycine 1-{N-(2-Cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-pyrrolidine

1-{N-(2-Cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl }-proline 1-{N-(2-Cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D-proline

1-{N-(Cyclooctylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D-proline

1-{3-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-amino}-propanoyl}-pyrrolidine

N-(3-Cyclohexylpropyl)-N-((2S)-2-(2-indolecarbonylamino)-hexanoyl)-glycine

N-(3-CycIohexylpropyl)-N-(N-(3-indoleacetyl)-phenylalanyl)-glycine

N-(2-Cyclohexylethyl)-N-((2S)-2-(3-isoquinolinecarbonylamino)-4-phenylbutanoyl)-glycine

N-{N-Phenethyl-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D-proline.

1-{N-(2-Cyclohexylethyl)-N-(N-(3-indoleacetyl)-phenylalanyl)-glycyl}-D-proline

1-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-4-phenylbutanoyl)-glycyl}-D-proline

Where the compounds of the present invention are capable of forming salts with inorganic and organic acids and/or bases then those pharmaceutically acceptable salts are included within the scope of the invention. Examples of such salts include sodium, potassium and tetra-alkyl ammonium salts of acidic compounds, and chlorides, sulphates and acetates of basic compounds.

Where the compounds of the present invention contain a carboxylic acid moiety then these may be administered in pro-drug form as simple esters.

SYNTHETIC METHODS GENERAL

The synthesis of the compounds of the present invention can be considered as involving two stages. In Stage 1 the individual components A, B and C in general formula I are prepared from commercially available starting materials if they are not themselves available. During Stage 1 protecting groups may be introduced into A, B and C in order to obviate side reactions in Stage 2. The second phase involves assembling the individual components into the finished compound. During Stage 2, apart from the crucial A-B and B-C bond forming reactions, selective manipulation of the protecting groups may be necessary. At the end of Stage 2 final adjustments can be made to complete the synthesis.

Using general formula I as the target, a typical synthesis might involve the following steps: Stage 1

pre- A⇨ steps⇨ PG¹-A

pre-B⇨ steps⇨ PG²-B

pre-C⇨ steps⇨ C-PG³

where PC¹ - PG³ are protecting groups,

pre- A - pre-C are commercially available precursors.

Stage 2

PG²-B + C-PG³⇨ PG²-B-C-PG³

PG²-B-C-PG³⇨ B-C-PG³

PG¹-A + B-C-PG³⇨ PG¹-A-B-C-PG³

PG¹-A-B-C-PG³⇨ A-B-C

Depending on the precise nature of A, B and C the order in which the components are coupled together may be varied. Thus it might be advantageous to form the A-B fragment first and couple this to C. Another variation is possible when C can be divided into two sub-fragments (e.g. when C is XIX, or XVI with R¹⁴ is XXII). In these cases one of the sub-fragments can be introduced at a late stage. If C is composed of the subfragments C¹-D then Stage 2 of the overall synthesis might be:

PG²-B + C¹-PG³⇨ PG²-B-C¹-PG³

PG²-B-C¹-PG³⇨ B-C¹-PG³

PG¹-A + B-C¹-PG³⇨ PG¹-A-B-C ¹-PG³

PG¹-A-B-C¹-PG³⇨ PG¹-A-B-C¹

PG¹-A-B-C¹ + D⇨ PG¹-A-B-C

PG¹- A-B-C⇨ A-B-C

The chemistry involved in preparing the compounds of the present invention depends on the nature of A, B and C. The specific Examples which follow make use of reactions which are established in the literature for analogous transformations. It is not the inventors' intention to restrict the scope of this patent solely to those reactions described explicitly in the Examples, but to include other methods which a person competent in the art might employ to achieve the same overall transformation. Also included are such variations in the protecting groups and the order of assembly of the fragments as might be used by such a competent person.

The general concepts outlined above (preparation of the fragments, coupling, and protecting group manipulation) will now be illustrated more fully in the following non-limiting Examples.

EXPLANATORY NOTES

In the following Examples: R_f: TLC was performed on commercial silica plates (Merck Art. 5714)

HPLC: Buffer 10.1% TFA/H₂O; Buffer II 0.1% TFA/MeCN

System A: Novapak Cis, 4 μ, 8x100 mm; linear gradient 40% to 90% II into I over 25 min. at 1.5 mL/min.

System B: Spherisorb C₁₈, 5 μ. 4.6x100 mm; linear gradient 40% to 90% II into I over 25 min. at 0.8 mL/min.

AAA: Hydrolysis 6NHCl + phenol at 150°C for 1.5 hr.

¹H ΝMR: Determined at 270 MHz in CDCl₃.

Mass spec: Positive ion FAB.

Reagents were generally used as supplied without purification. Solvents were HPLC grade, except THF which was distilled from Νa/benzophenone. Silica gel for flash chromatography was Merck Kieselgel 60 (230-400 mesh).

1a (3R)-2-tert-Butyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

To a stirred suspension of D-1,2,3.4-tetrahydroisoquinoline-3-carboxylic acid (2.5 g, 14.1 mmol) in dioxan (200 mL) was added di-tert-butyl pyrocarbonate (3.66 g, 16.9 mmol) and a solution of KOH (0.79 g, 14.1 mmol) in H₂O (50 mL). The mixture was stirred at room temperature for 5 hr., and then the solvent was evaporated in vacuo. The residue was taken up in H₂O and the solution was acidified with 10% aq. KHSO₄ to pH=2. The mixture was extracted twice with EtOAc, and the combined extracts were washed with brine, filtered (Whatman^R 1 PS phase separator), and concentrated in vacuo. The residue was triturated with pet. ether (b.p. 60-80°C) to give the title compound as a white solid (3.2 g, 82%).

1b Methyl (3R)-2-tert-Butyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-acetate.

To a stirred solution of la (10.9 g, 39.5 mmol) in EtOAc (120 mL) was added N-methylmorpholine (4.4 mL, 40 mmol). The solution was cooled to -20°C, and isobutyl chloroformate (5.2 mL, 44 mmol) was added dropwise. The mixture was stirred at -15°C for 20 min., men poured into a solution of diazomethane (from Diazald^R, 43 g, 200 mmol) in EtoO. and the resulting solution was stirred at room temperature for 1 hr. Excess diazomethane was destroyed by the addition of glacial AcOH. The solution was washed successively with 1.0M NaHCO₃, H₂O and brine, dried over Na₂SO₄, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:pet ether 25:75 v/v) to give (3R)-2-tert-butyloxycarbonyl-1,2,3,4-tetrahydroisoquinolyl diazomethyl ketone (8.0 g, 26.6 mmol, 67%).

This ketone was dissolved in MeOH (200 mL) and to this solution was added a solution of silver benzoate (2 g, 8 mmol) in Et₃N. The mixture was stirred at room temperature for 40 min., and then the solvent was evaporated in vacuo. The residue was taken up in EtOAc and washed successively with 1.0M NaHCO₃, H₂O, brine, 0.3M KHSO₄, H₂O and brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:pet. ether 18:82 v/v) to give the title ester (6.5 g, 80%). lc Methyl (3R)-1,2,3,4-tetrahydroisoquinoline-3-acetate hydrochloride.

The BOC-protected ester 1b (6.5 g, 21.3 mmol) was taken up in 4N HCl in dioxan (100 mL) and the solution was stirred at room temperature for 90 min. The solvent was removed in vacuo, finally with toluene azeotrope, to give the title compound (5.0 g, 99%).

Id Methyl (3R)-2-[Ν-tert-butyloxycarbonyl-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

To a stirred solution of BOC-(O-benzyl)-threonine (866 mg, 2.8 mmol) and diisopropylethylamine (0.50 mL, 2.88 mmol) in CH₂Cl₂ (20 mL), cooled to -20°C, was added bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl, 733 mg, 2.88 mmol). The mixture was stirred at -20°C for 20 min., men 1c (483 mg, 2 mmol) and diisopropylethylamine (0.35 mL. 2 mmol) were added. The mixture was stirred at room temperature overnight, then poured into EtOAC. The solution was washed successively with 10% KHSO₄, satd. KHCO₃, H₂O and brine, filtered (Whatman^R IPS phase separator), and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:hexane 25:75 v/v) to give the titie compound (678 mg, 68%). le Methyl (3R)-2-[N-(3-chlorophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

A solution of the BOC-protected ester Id (159 mg, 0.32 mmol) in 4N HCl in dioxan (10 mL) was stirred at room temperature for 90 min., then the solvent was removed in vacuo, finally with toluene azeotrope. The residue was taken up in CH₂Cl₂ (10mL) and cooled to 0°C. Diisopropylethylamine (60 μL, 0.32 mmol) was added, then 3-chlorophenylisocyanate (43 μL, 0.35 mmol), and me mixture was stirred at 0°C for 2 hr. The mixture was then diluted with EtOAc and washed successively with 10% KHSO₄, satd. KHCO₃, H₂O and brine, filtered (Whatman^R IPS phase separator) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOActhexane 40:60 v/v) to give the titie compound (152 mg, 86%).

R_f (EtOAc:hexane 50:50 v/v) 0.31

If (3R)-2-[Ν-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

To a stirred solution of the ester le (152 mg, 0.27 mmol) in dioxan (10mL) was added a solution of LiOH ( 13 mg, 0.54 mmol) in H₂O (5mL). The mixture was stirred at room temperature for 1 hr., then the solvent was removed in vacuo. The residue was partitioned between EtOAc and aq. KHSO₄. The organic phase was washed with brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 65:35:1 v/v/v), and the product was taken up in acetonitrile/water and lyophilised to give the title, compound (95 mg, 66%).

R_f (EtOAc:hexane:AcOH 70:30: 1 v/v/v) 0.20

HPLC System A t_R=15.9' >99%

Mass spec (FAB) m/e=536 [M+H]⁺ EXAMPLE 2

2a Methyl (3R)-2-[N-(3-bromophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.32 mmol scale using 1d and 3-bromophenylisocyanate. The product was isolated in 71% yield after flash chromatography on silica gel (eluant EtOAc:hexane 50:50 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.30

2b (3R)-2-[N-(3-Bromophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 2a on a 0.23 mmol scale following the method described for If. The product was isolated in 59% yield (79 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 65:35:1 v/v/v).

R_f (EtOAc:hexane:AcOH 70:30:1 v/v/v) 0.20

HPLC System A t_R-16.1' >98%

Mass spec (FAB) m/e=582 [M+H]⁺

EXAMPLE 3

3a Methyl (3R)-2-[N-(3-methylphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.68 mmol scale using 1d and 3-methylphenylisocyanate. The product was isolated in 67% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

R_f (EtOAc:hexane: AcOH 50:50:1 v/v/v) 0.37

3b (3R)-2-[N-(3-Methylphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 3a on a 0.46 mmol scale following the method described for 1f. The product was isolated in 68% yield (162 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 50:50:1 v/v/v).

R_f (EtOAc:hexane:AcOH 50:50: 1 v/v/v) 0.20

HPLC System A t_R=14.7' >99%

Mass spec (FAB) m/e=516 [M+H]⁺

EXAMPLE 4

4a Methyl (3R)-2-[N-(3-acetylphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1e on a 0.21 mmol scale using 1d and 3-acetylphenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet. ether 45:55 v/v). 4b (3R)-2-[N-(3-Acetylphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 4b on a 0.21 mmol scale following the method described for 1f. The product was isolated in 53% yield (61 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 50:50:2 v/v/v).

HPLC System B t_R=8.8' >95%

Mass spec (FAB) m/e=544 [M+H]⁺

EXAMPLE 5

5a Methyl (3R)-2-[N-(3-isopropoxyphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.31 mmol scale using 1d and 3-isopropoxyphenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet ether 35:65 v/v).

5b (3R)-2-[N-(3-Isopropoxyphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 5a on a 0.31 mmol scale following the method described for 1f. The product was isolated in 40% yield (69 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 45:55:2 v/v/v).

HPLC System B t_R=12.5' >95%

Mass spec (FAB) m/e=560 [M+H]⁺ EXAMPLE 6

6a Methyl (3R)-2-[N-(3-cyanophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.31 mmol scale using 1d and 3-cyanophenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v).

6b (3R)-2-[N-(3-Cyanophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 6a on a 0.31 mmol scale following the method described for 1f. The product was isolated in 34% yield (55 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v).

HPLC System A t_R=13.3' 80%

Mass spec (FAB) m/e=527 [M+H]⁺

EXAMPLE 7

7a Methyl (3R)-2-[N-tert-butyloxycarbonyl-O-tert-butyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1d on a 0.41 mmol scale using N- BOC-O-tert-butyl-threonine instead of N-BOC-O-benzyl-threonine. The product was isolated in 74% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

7b Methyl (3R)-2-[N-(3-chlorophenylcarbamoyl)-O-tert-butyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1e on a 0.30 mmol scale using 7a and 3-chlorophenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v).

7c (3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-tert-butyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 7b on a 0.30 mmol scale following the method described for 1f. The product was isolated in 56% yield (84 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v).

HPLC System A t_R=15.2' >95%

Mass spec (FAB) m/e=502 [M+H]⁺ EXAMPLE 8

8a Methyl (3R)-2-[N-tert-butyloxycarbonyl-O-benzoyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for Id on a 0.50 mmol scale using N- BOC-O-benzoyl-threonine instead of N-BOC-O-benzyl-threonine. The product was isolated in 55% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

8b Methyl (3R)-2-[N-(3-chIorophenylcarbamoyl)-O-benzoyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.27 mmol scale using 8a and 3-chlorophenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

8c (3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-benzoyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 8b on a 0.27 mmol scale following the method described for 1f. The product was isolated in 35% yield (52 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 45:55:2 v/v/v).

HPLC System B t_R=12.2" >95%

Mass spec (FAB) m/e=550 [M+H]⁺ EXAMPLE 9

9a Methyl (3R)-2-[N-tert-butyloxycarbonyl-O-(4-chlorobenzyl)-threonyl]-1,2,3,4- tetrahydroisoquinoIine-3-acetate.

This was prepared following the method described for 1d on a 0.50 mmol scale using N- BOC-O-(4-chlorobenzyl)-threonine instead of N-BOC-O-benzyl-threonine. The product was isolated in 70% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

9b Methyl (3R)-2-[N-(3-chlorophenylcarbamoyl)-O-(4-chlorobenzyl)-threonyl]- 1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1e on a 0.35 mmol scale using 9a and 3-chlorophenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v).

9c (3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-(4-chIorobenzyl)-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 9b on a 0.35 mmol scale following the method described for 1f. The product was isolated in 64% yield (127 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 40:60:2 v/v/v).

HPLC System A t_R=18.0' >99%

Mass spec (FAB) m/e=570 [M+H]⁺ EXAMPLE 10

10a Methyl (3R)-2-[(2S)-2-tert-butyloxycarbonylaminohexanoyl]- 1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1d on a 4.0 mmol scale using N- BOC-(2S)-2-aminohexanoic acid instead of N-BOC-O-benzyl-threonine. The product was isolated in 66% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

10b Methyl (3R)-2-[(2S)-2-(3-trifluoromethylphenylcarbamoylamino)-hexanoyl]- 1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.32 mmol scale using 10a and 3-trifluoromethylphenylisocyanate. The product was isolated in 52% after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 30:70:1 v/v/v).

R_f(EtOAc:pet. ether:AcOH 30:70:1 v/v/v) 0.31

1H NMR δ 0.90 (3H,2t); 1.2-1.8 (m); 3.6 (3H,2s)

10c (3R)-2-[(2S)-2-(3-Trifluoromethylphenylcarbamoylamino)-hexanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 10b on a 0.16 mmol scale following the method described for 1f. The product was isolated in 70% yield (55 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 50:50:2 v/v/v). HPLC System B t_R=12.2" >98%

Mass spec (FAB) m/e=492 [M+H]⁺

EXAMPLE 11

11a Methyl (3R)-2-[(2S)-2-(3-chlorophenylcarbamoylamino)-hexanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.26 mmol scale using 10a and 3-chlorophenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

11b (3R)-2-[(2S)-2-(3-Chlorophenylcarbamoylamino)-hexanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 11a on a 0.26 mmol scale following the method described for

If. The product was isolated in 61% yield (73 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v).

HPLC System A t_R=14.1' >98%

Mass spec (FAB) m/e=458 [M+H]⁺

EXAMPLE 12

12a Methyl (3R)-2-[(2S)-2-(N-tert-butyloxycarbonyl)methylaminohexanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1d on a 0.40 mmol scale using N- BOC-(2S)-2-methylaminohexanoic acid instead of N-BOC-O-benzyl-threonine. The product was isolated in 57% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 20:80 v/v).

12b Methyl (3R)-2-[(2S)-2-(N-(3-chlorophenylcarbamoyl)-methylamino)-hexanoyl]- 1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.23 mmol scale using 12a and 3-chlorophenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

12c (3R)-2-[(2S)-2-(N-(3-Chlorophenylcarbamoyl)-methylamino)-hexanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 12b on a 0.23 mmol scale following the method described for If. The product was isolated in 44% yield (48 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v).

HPLC System A t_R-=14.8' >98%

Mass spec (FAB) m/e=472 [M+H]⁺ EXAMPLE 13

13a Methyl (3R)-2-[(2S)-2-tert-butyloxycarbonylamino-4-phenylbutanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1d on a 1.27 mmol scale using N- BOC-(2S)-2-amino-4-phenylbutanoic acid instead of N-BOC-O-benzyl-threonine. The product was isolated in 71% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 60:40 v/v).

R_f (EtOAc:pet. ether 30:70 v/v) 0.19

13b Methyl (3R)-2-[(2S)-2-(3,4-dichlorophenylcarbamoylamino)-4-phenylbutanoyl]- 1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.30 mmol scale using 13a and 3,4-dichlorophenylisocyanate. The product was isolated in 49% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 30:70:1 v/v/v).

1H NMR δ 3.74,3.64,3.61 (3H,3s)

13c (3R)-2-[(2S)-2-(3,4-Dichlorophenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 13b on a 0.15 mmol scale following the method described for 1f. The product was isolated in 76% yield (62 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 70:30:1 v/v/v). HPLC System B t_R=14.4' 80%

Mass spec (FAB) m/e=540 [M+H] ⁺

EXAMPLE 14

14a Methyl (3R)-2-[(2S)-2-(2-methylphenylcarbamoylaιnino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1e on a 0.33 mmol scale using 13a and 2-methylphenylisocyanate. The product was isolated in 85% yield and used without purification.

14b (3R)-2-[(2S)-2-(2-Methylphenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 14a on a 0.28 mmol scale following the method described for 1f. The product was isolated in 58% yield (78 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 60:40:1 v/v/v).

HPLC System B t_R=10.3' >98%

Mass spec (FAB) m/e=486 [M+H]⁺

EXAMPLE 15

15a Methyl (3R)-2-[(2S)-2-(4-methylphenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.33 mmol scale using 13a and 4-methylphenylisocyanate. The product was isolated in 91% yield and used without purification.

15b (3R)-2-[(2S)-2-(4-Methylphenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 15a on a 0.30 mmol scale following the method described for If. The product was isolated in 69% yield (101 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 60:40:1 v/v/v).

HPLC System B t_R=11.1' >97%

Mass spec (FAB) m/e=486 [M+H]⁺

EXAMPLE 16

16a Methyl (3R)-2-[(2S)-2-(3-methoxyphenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1e on a 0.20 mmol scale using 13a and 3-methoxyphenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet. ether 45:55 v/v).

16b (3R)-2-[(2S)-2-(3-Methoxyphenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 16a on a 0.20 mmol scale following the method described for 1f. The product was isolated in 52% yield (52 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 50:50:2 v/v/v). HPLC System A t_R=12.9' >99%

Mass spec (FAB) m/e=502 [M+H]⁺

EXAMPLE 17

17a Methyl (3R)-2-[(2S)-2-(3-chlorophenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.20 mmol scale using 13a and 3-chlorophenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet ether 45:55 v/v).

17b (3R)-2-[(2S)-2-(3-Chlorophenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 17a on a 0.20 mmol scale following the method described for If. The product was isolated in 74% yield (75 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v).

HPLC System A t_R=15.6' >98%

Mass spec (FAB) m/e=506 [M+H]⁺

EXAMPLE 18

18a Methyl (3R)-2-[N-tert-butyloxycarbonyl-valyl]-1,2,3,4-tetrahydroisoquinoline-3- acetate.

This was prepared following the method described for Id on a 3.0 mmol scale using N- BOC-valine instead of N-BOC-O-benzyl-direonine. The product was isolated in 54% yield after flash chromatography on silica gel (eluant EtOAc:hexane 20:80 v/v).

R_f (EtOAc::hexane 20:80 v/v) 0.27

18b Methyl (3R)-2-[N-(3-chIorophenylcarbamoyl)-valyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.47 mmol scale using 18a and 3-chlorophenylisocyanate. The product was isolated in 61% yield and used without purification.

R_f (EtOAc:hexane 60:40 v/v) 0.33

18c (3R)-2-[N-(3-Chlorophenylcarbamoyl)-valyl]-1,2,3,4-tetrahydroisoquinoline-3- acetic acid.

This was prepared from 18b on a 0.29 mmol scale following the method described for If. The product was isolated in 47% yield (60 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 60:40:2 v/v/v).

R_f (EtOAc:hexane:AcOH 60:40:1 v/v/v) 0.23 HPLC System A t_R=11.9' >90%

Mass spec (FAB) m/e=444 [M+H]⁺

EXAMPLE 19

19a Methyl (3R)-2-[N-(3-bromophenylcarbamoyl)-valyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described fo1 le on a 0.47 mmol scale using 18a and 3-bromophenylisocyanate. The product was isolated in 61% yield and used without purification.

R_f (EtOAc::hexane 60:40 v/v) 0.33

19b (3R)-2-[N-(3-Bromophenylcarbamoyl)-valyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 19a on a 0.29 mmol scale following the method described for If. The product was isolated in 60% yield (85 rag) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 60:40:2 v/v/v).

R_f (EtOAc:hexane:AcOH 60:40:1 v/v/v) 0.24

HPLC System A t_R=12.5' >98%

Mass spec (FAB) m/e=489 [M+H]⁺ EXAMPLE 20

20a Methyl (3R)-2-[N-tert-butyloxycarbonyl-isoleucyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1d on a 0.58 mmol scale using N-BOC-isoleucine instead of N-BOC-O-benzyl-threonine. The product was isolated in 56% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

20b Methyl (3R)-2-[N-(3-methylphenylcarbamoyl)-isoleucyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.16 mmol scale using 20a and 3-metiιylphenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v).

20c (3R)-2-[N-(3-Methylphenylcarbamoyl)-isoleucyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 20b on a 0.16 mmol scale following the method described for If. The product was isolated in 70% yield (49 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v).

HPLC System A t_R=12.4' >98%

Mass spec (FAB) m/e=438 [M+H]⁺ EXAMPLE 21

21a Methyl (3R)-2-[(2S)-2-tert-butyloxycarbonylamino-3,3-dimethylbutanoyl]- 1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1d on a 0.75 mmol scale using N- BOC-(2S)-2-amino-3,3-dimethylbutanoic acid instead of N-BOC-O-benzyl-threonine. The product was isolated in 18% yield after flash chromatography on silica gel (eluant EtOAc::pet. ether 25:75 v/v).

21b Methyl (3R)-2-[(2S)-2-(3-chlorophenylcarbamoylamino)-3,3-dimethylbutanoyl]- 1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1e on a 0.14 mmol scale using 21a and 3-chlorophenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc::pet. ether 35:65 v/v).

21c (3R)-2-[(2S)-2-(3-Chlorophenylcarbamoylamino)-3,3-dimethylbutanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 21b on a 0.14 mmol scale following the method described for 1f. The product was isolated in 73% yield (47 mg) after flash chromatography on silica gel (eluant EtOAc::pet. ether:AcOH 40:60:2 v/v/v).

HPLC System B t_R=10.6' >99%

Mass spec (FAB) m/e=458 [M+H]⁺ EXAMPLE 22

22a Methyl (3R)-2-[(S)-α-tert-butyloxycarbonylamino-phenylacetyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for Id on a 0.50 mmol scale using N- BOC-(S)-α-amino-phenylacetic acid instead of N-BOC-O-benzyl-threonine. The product was isolated in 68% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

22b Methyl (3R)-2-[(S)-α-(3-chlorophenylcarbamoylaιnino)-phenylacetyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1e on a 0.34 mmol scale using 22a and 3-chlorophenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v).

22c (3R)-2-[(S)-α-(3-Chlorophenylcarbamoylaminoι-phenylacetyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 22b on a 0.34 mmol scale following the method described for 1f. The product was isolated in 64% yield (104 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v).

HPLC System A t_R=13.8' >95%

Mass spec (FAB) m/e=478 [M+H]⁺ EXAMPLE 23

23a Methyl (3R)-2-[(S)-α-tert-butyloxycarbonylamino-cyclohexaneacetyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for Id on a 2.0 mmol scale using N- BOC-(S)-α-amino-cyclohexaneacetic acid instead of N-BOC-O-benzyl-threonine. The product was isolated in 58% yield after flash chromatography on silica gel (eluant EtOAc:hexane 25:75 v/v).

R_f (EtOAc:hexane 20:80 v/v) 0.32

23b Methyl (3R)-2-[(S)-α-(3-methylphenylcarbamoylamino)-cyclohexaneacetyl]- 1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1e on a 0.58 mmol scale using 23a and 3-metfιylphenylisocyanate. The product was isolated in 76% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

R_f (EtOAc:hexane: AcOH 50:50:1 v/v/v) 0.43

23c (3R)-2-[(S)-α-(3-Methylphenylcarbamoylamino)-cyclohexaneacetyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 23b on a 0.44 mmol scale following the method described for If. The product was isolated in 57% yield ( 117 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 50:50:2 v/v/v). R_f (EtOAc:hexane: AcOH 50:50:1 v/v/v) 0.21

HPLC System A t_R=!4.3' >99%

Mass spec (FAB) m/e=464 [M+H]⁺

EXAMPLE 24

24a N^α-tert-Butyloxycarbonyl-N^ω-benzyloxycarbonyl-(2S)-2,3-diaminopropanoic acid.

To a stirred ice-cold solution of N^α-BOC-L-diaminopropanoic acid (N. Kuchurczyk et al, Synth. Commun. 19, 1603, 1989: 1.37 g, 6.74 mmol) in H₂O (12 mL) was added a solution of NaOH (0.64 g, 13.5 mmol) in H2O, followed by benzyl chloroformate (1.08 mL. 7.3 mmol). The mixture was stirred and allowed to warm to room temperature over 3 hr.. then the solvent was removed in vacuo. The residue was partitioned between EtOAc and dil KHSO₄, and the organic layer was washed with brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v) to give the title compound

(1.94 g, 85%).

¹H NMR δ 1.15 (9H,s); 3.45 (2H,br); 4.20 ( 1H,br); 5.00 (2H.s); 5.7 (2H.2br); 7.1-7.3

(5H,m)

24b Methyl (3R)-2-[(2S)-3-benzyloxycarbonylamino-2-tert-butyloxycarbonylamino-propanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1d on a 3.3 mmol scale using 24a instead of N-BOC-O-benzyl-threonine. The product was isolated in 76% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 50:50 v/v).

1H NMR δ 1.4 (9H,2s); 3.6 (3H,2s); 7.1-7.4 (9H,m)

24c Methyl (3R)-2-[(2S)-3-(benzyloxycarbonylamino)-2-(phenylcarbamoylaιnino)-propanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1e on a 0.97 mmol scale using 24b and phenylisocyanate. The product was isolated in 98% yield after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 70:30:2 v/v/v).

R_f (EtOAc:pet. ether:AcOH 70:30:2 v/v/v) 0.37

24d Methyl (3R)-2-[(2S)-3-(2-adamantyloxycarbonylamino)-2- (phenylcarbamoylamino)-propanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

To a solution of 24c (380 mg, 0.72 mmol) in MeOH (25 mL) was added 5% Pd-oncarbon (catalytic), and hydrogen was bubbled through the mixture at room temperature/1 atm. for 2 hr. The mixture was filtered through Celite^R and the catalyst was washed with MeOH. The combined filtrates were concentrated in vacuo, finally with toluene azeotrope. The residue was taken up in CH₂CI₂ (10 mL) and 2-adamantyl chloroformate (0.8 mmol) in CH₂CI₂ (5 mL) was added dropwise with stirring, followed by diisopropylethylamine (excess). The mixture was stirred at room temperature for 12 hr. then poured into EtOAc. The solution was washed successively with 10% KHSO₄, satd. KHCO₃, H₂O and brine, filtered (Whatman^R IPS phase separator) and concentrated in vacuo. The residue was used without further purification. 24e (3R)-2-[(2S)-3-(2-Adamantyloxycarbonylamino)-2-(phenylcarbamoylamino)- propanoyl]-1,2-3,4-tetrahydroisoquinoline-3-aceric acid.

This was prepared from 24d on a 0.21 mmol scale following the method described for If. The product was isolated in 52% yield (66 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v).

HPLC System B t_R=12.5' >98%

Mass spec (FAB) m/e=575 [M+H]⁺

EXAMPLE 25

25a Methyl (3R)-2-[(2S,3R)-2-azido-3-phenylbutanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for 1d on a 1.72 mmol scale using (2S,3R)-2-azido-3-phenylbutanoic acid (R. Dharanipragada et al. Tetrahedron Lett.. 30, 6841, 1989) instead of N-BOC-O-benzyl-threonine. The product was isolated in 62% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 20:80 v/v).

25b Methyl (3R)-2-[(2S,3R)-2-(3-chlorophenylcarbamoylamino)-3-phenylbutanoyl]- 1,2,3,4-tetrahydroisoquinoline-3-acetate.

To a degassed solution of 25a (271 mg, 0.69 mmol) in MeOH/CH₂Cl₂ (20 mL + 3 mL) was added NH₄+HCO₂- (174 mg, 0.28 mmol) and 5% Pd-on-carbon (50 mg). The mixture was stirred at room temperature for 5 hr. then filtered though Celite^R. The residue was washed with MeOH and the combined filtrates were concentrated in vacuo. The residue was taken up in CH₂Cl₂, washed successively with 5% KHCO₃ and brine, dried over Na₂SO₄, and the solvent evaporated in vacuo to give methyl (3R)-2-[(2S,3R)-2- amino-3-phenylbutanoyl]- 1,2,3,4-tetrahydroisoquinoline-3-acetate.

One third of the product (ca. 0.23 mmol) was taken up in CH₂Cl₂ and treated with 3- chlorophenylisocyanate as described for 1e. The product was isolated in 15% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

R_f (EtOAc:pet. ether 30:70 v/v) 0.12

1H NMR δ 1.29-1.42 (3H,m); 3.44,3.74 (3H,2s)

25c (3R)-2-[(2S,3R)-2-(3-Chlorophenylcarbamoylamino)-3-phenylbutanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 25b on a 0.035 mmol scale following the method described for 1f. The product was isolated in 88% yield (15 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 60:40:1 v/v/v).

HPLC System B t_R=11.9' >95%

Mass spec (FAB) m/e=506 [M+H]⁺

EXAMPLE 26

26a Methyl (3R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride.

To a stirred suspension of D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (5g, 28 mmol) in MeOH (60 mL) was added acetyl chloride (3.2 mL, 45 mmol), and the mixture was heated at reflux under N₂ for 4 hr. The solvent was removed in vacuo, and the residue was partitioned between EtOAc and aq. KHCO₃. The organic layer was washed with brine, filtered (Whatman^R IPS phase separator), acidified with 4N HCl in dioxan ( 10 mL), and concentrated in vacuo. The residue was washed with pet. ether and dried over KOH to give the title compound as a white powder (3.73 g, 58%).

26b Methyl (3R)-2-[Ν-tert-butyloxycarbonyl-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared following the method described for Id on a 2.4 mmol scale using 26a instead of 1c. The product was isolated in 68% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

26c Methyl (3R)-2-[N-(3-chlorophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared following the method described for 1e on a 0.53 mmol scale using 26b and 3-chlorophenylisocyanate. The product was isolated in 98% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

26d (3R)-2-[N-(3-ChIorophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 26c on a 0.52 mmol scale following the method described for 1f. The product was isolated in 32% yield (84 mg) after repeated flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v and CHCl₃:MeOH:AcOH 100:1:1 v/v/v).

HPLC System A t_R=16.0" >99%

Mass spec (FAB) m/e=522 [M+H]⁺

EXAMPLE 27

27a Methyl (3R)-2-[N-(3-bromophenylcarbamoyl)-O-benzyl-threonyl]-1-2-3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared following the method described for le on a 0.53 mmol scale using 26b and 3-bromophenylisocyanate. The product was isolated in 75% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

27b (3R)-2-[N-(3-Bromophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 27a on a 0.43 mmol scale following the method described for 1f. The product was isolated in 34% yield (82 rag) after repeated flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v and CHCl₃ MeOH:AcOH 100:1:1 v/v/v).

HPLC System A t_R=16.5' >99%

Mass spec (FAB) m/e=566/568 [M+H]⁺

EXAMPLE 28

28a Methyl (2R,4S)-1-[N-tert-butyloxycarbonyl-O-benzyl-threonyl]-4-phenylpyrrolidine-2-carboxylate.

This was prepared following the method described for 1d on a 0.36 mmol scale using methyl (2R,4R)-4-phenylpyrrolidine-2-carboxylate (J. Krapcho et al. J.Med.Chem., 31.1148.1988) instead of 1c. The product was isolated in 82% yield and used without purification.

R_f (EtOAc:pet. ether 40:60 v/v) 0.30

28b Methyl (2R,4S)-1-[N-(3-chlorophenylcarbamoyl)-O-benzyl-threonyl]-4-phenylpyrrolidine-2-carboxylate.

This was prepared following the method described for 1e on a 0.30 mmol scale using 28a and 3-chlorophenylisocyanate. The product was isolated in 77% yield after flash chromatography on silica gel (eluant EtOAc:hexane 30:70 v/v).

R_f (EtOAc:pet. ether 40:60 v/v) 0.20

1H NMR δ 1.29 (3H.d,J=6.2Hz); 3.63 (3H,s)

28c (2R,4S)-1-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-4-phenylpyrrolidine-2-carboxylic acid.

This was prepared from 28b on a 0.23 mmol scale following the method described for If. The product was isolated in 35% yield (40 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 30:70:1 v/v/v).

HPLC System B t_R=18.2' >95%

Mass spec (FAB) m/e=536 [M+H]⁺

EXAMPLE 29

29a Methyl (2R,4R)-1-tert-butyloxycarbonyl-4-phenylpyrrolidine-2-acetate.

This was prepared in a manner analogous to that used to prepare 1b using (2R,4S)-1- tert-butyloxycarbonyl-4-phenylpyrrolidine-2-carboxylic acid (J. Krapcho et al, J.Med.Chem., 31.1148,1988: 400 mg, 1.37 mmol). The product was purified by flash chromatography on silica gel (eluant EtOAc:pet. ether 20:80 v/v) in a yield of 64%.

29b Methyl (2R,4R)-4-phenylpyrrolidine-2-acetate hydrochloride.

This was prepared from 29a (0.4 mmol) using the same procedure as for 1b, assuming a yield of 100%. 29c Methyl (2R,4R)-1-[N-tert-butyloxycarbonyl-O-benzyl-threonyl]-4-phenylpyrrolidine-2-acetate.

This was prepared following the method described for 1d on a 0.38 mmol scale using 29b instead of 1c. The product was isolated in 75% yield and used without purification. R_f (EtOAc:pet. ether 50:50 v/v) 0.40

1H NMR δ 1.44 (9H,s); 3.67 (3H.s)

29d Methyl (2R,4R)-1-[N-(3-chlorophenylcarbamoyl)-O-benzyl-threonyl]-4-phenylpyrrolidine-2-acetate.

This was prepared following the method described for 1e on a 0.28 mmol scale using 29c and 3-chlorophenylisocyanate. The product was isolated in 72% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v).

R_f (EtOAc:pet. ether 40:60 v/v) 0.16

1H NMR δ 1.28 (3H,d,J=5.9Hz); 3.59 (3H.s)

29e (2R,4R)-1-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-4-phenylpyrrolidine-2-acetic acid.

This was prepared from 29d on a 0.20 mmol scale following the method described for 1f. The product was isolated in 69% yield (64 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 60:40:1 v/v/v).

HPLC System B t_R=13.1' >97%

Mass spec (FAB) m/e=550 [M+H]⁺

EXAMPLE 30

30a Ethyl (2R,5S)-5-phenylpyrrolidine-2-carboxylate.

To a solution of ethyl (2R)-3,4-dihydro-5-phenyl-2H-pyrrole-2-carboxylate (J. Ackermann et al, Helv.Chim.Acta, 75. 122. 1990: 1.7 g, 7.8 mmol) and AcOH (5mL) in MeOH (50 mL) was added NaCNBH₃ (1.5 g, 23.5 mmol). The mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was partitioned between EtOAc and satd. KHCO₃, and the organic phase was washed with H₂O and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:pet ether 25:75 then 40:60) to give the title compound (0.90 g, 40%).

30b Ethyl (2R,5S)-1-[N-tert-butyloxycarbonyl-O-benzyl-threonyl]-5-phenylpyrrolidine-2-carboxylate.

This was prepared following the method described for Id on a 0.82 mmol scale using 30a instead of 1c. The product was isolated in 38% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

R_f (EtOAc:hexane 30:70 v/v) 0.17 30c Ethyl (2R,5S)-1-[N-(3-chlorophenylcarbamoyl)-O-benzyl-threonyl]-5-phenylpyrrolidine-2-carboxylate.

This was prepared following the method described for le on a 0.31 mmol scale using 30b and 3-chlorophenylisocyanate. The product was isolated in 80% yield after flash chromatography on silica gel (eluant EtOAc:hexane 30:70 v/v).

R_f (EtOAc:hexane 30:70 v/v) 0.18

30d (2R,5S)-1-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-5-phenylpyrrolidine-2-carboxylic acid.

This was prepared from 30c on a 0.25 mmol scale following the method described for 1f. The product was isolated in 12% yield (16 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 70:30:1 v/v/v).

HPLC System A t_R=18.0" >97%

Mass spec (FAB) m/e=536 [M+H]⁺

EXAMPLE 31

31a Methyl (3R)-2-[(2S,3R)-3-benzyloxy-2-tert-butyloxycarbonylamino-butyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

To a solution of N-BOC-O-benzyl-threonine methyl ester (585 mg, 1.81 mmol) in toluene (10 mL) cooled under N₂ to -78°C was added dropwise DIBAL (3.5 mL. 1.5M in toluene, 5.25 mmol). The mixture was stirred at -78°C for 40 min. then excess DIBAL was quenched by the careful addition of MeOH (1 mL). The mixture was allowed to warm to room temperature and then poured into a vigorously stirred mixture of Et₂O and satd. Rochelle salt. The mixture was stirred for 2 hr., then the phases were separated. The aqueous layer was extracted once with Et₂O, and the combined organic phases were washed with H₂O and brine, dried over Na₂SO₄, and evaporated in vacuo to give N-BOC-O-benzyl-threoninal (509 mg, 96%).

A solution of this aldehyde (435 mg, 1.43 mmol) in MeOH/AcOH (99:1, 10 mL) was added at 0°C to a solution of the free base obtained from lc (268 mg, 1.1 mmol) in MeOH/AcOH (99:1, 10 mL). The mixture was stirred at 0°C for 15 min., then NaCNBH3 (115 mg, 1.9 mmol) was added in portions over 15 min. and the mixture was stirred for a further 30 min. before being allowed to warm to room temperature. The solvent was removed in vacuo. The residue was taken up in EtOAc and washed successively with 10% KHSO₄, satd. KHCO₃, H₂O and brine, filtered (Whatman^R IPS phase separator) and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:pet. ether 20:80) to give the title compound (232 mg, 41%).

31b Methyl (3R)-2-[(2S,3R)-3-benzyloxy-2-(3-chlorophenylcarbamoylamino)-butyl]-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared following the method described for le on a 0.23 mmol scale using 31a and 3-chlorophenylisocyanate. The product was isolated by flash chromatography on silica gel (eluant EtOAc:hexane 25:75 v/v).

31c (3R)-2-[(2S,3R)-3-Benzyloxy-2-(3-chlorophenylcarbamoylamino)-butyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 31b on a 0.23 mmol scale following the method described for If. The product was isolated in 46% yield (55 mg) after flash chromatography on silica gel (eluant CHCl₃:MeOH:AcOH 40:2:1 v/v/v).

HPLC System B t_R=16.4' >98%

Mass spec (FAB) m/e=522 [M+H]⁺ EXAMPLE 32

32a Methyl N-(phenethyl)-glycinate.

To a stirred solution of phenethylamine (2.51 mL, 20 mmol) in MeCN (50 mL) was added diisopropylethylamine (2.59 mL, 20 mmol), K₂CO₃ (1 g, excess), and methyl bromoacetate (1.9 mL, 20 mmol). The mixture was stirred at room temperature for 3 hr. and then concentrated in vacuo. The residue was taken up in EtOAc and the solution was washed successively with 5% KHCO₃, H₂O and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo to give the titie product (3.0 g, 77%) as an oil which was used without further purification.

32b Methyl N-(2-cyclohexylethyl)-glycinate.

To a solution of 32a (55 mmol) in AcOH (100 mL) was added 5% Rh-on-carbon catalyst (0.75 g) and the mixture was shaken under H₂ (40 psi) for 7 days. The catalyst was removed by filtration, toluene was added to the filtrate, and the solvents were evaporated in vacuo. The residue was taken up in 1M HCl and washed with EtOAc. The aqueous phase was saturated with NaHCO₃ and extracted twice with EtOAc. The combined extracts were washed with brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo to give the title product (1.90 g, 61%) as an oil which was used without further purification. 32c Methyl N-(2-cyclohexylethyl)-N-((2S)-2-(tert-butyloxycarbonylamino)-hexanoyl)-glycinate.

To a stirred solution of (2S)-2-tert-butyloxycarbonylaminohexanoic acid (978 mg, 4.2 mmol) in CH₂Cl₂ was added diisopropylethylamine (0.74 mL. 4.2 mmol). The solution was cooled to -20°C and BOP-Cl ( 1.08 g, 4.2 mmol) was added. The solution was stirred at 20°C for 20 min.. then amine 32b (0.60 g, 3.03 mmol) was added and the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 16 hr. then the solvent was evaporated in vacuo. The residue was taken up in EtOAc and the solution was washed with 0.3M KHSO4, satd. KHCO3, H2O and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:hexane 25:75 v/v) to give the title compound (310 mg, 24%).

R_f (EtOAc:hexane 25:75 v/v) 0.16

32d Methyl N-(2-cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycinate.

A solution of the BOC-protected compound 32c (310 mg, 0.75 mmol) in 4N HCl in dioxan (20 mL) was stirred at room temperature for 1 hr then concentrated in vacuo, finally with toluene azeotrope.

Meanwhile, to a stirred solution of 3-indoleacetic acid (184 mg, 1.05 mmol) and pentafluorophenol (202 mg, 1.1 mmol) in CH₂Cl₂ (10 mL), cooled to 0°C, was added water-soluble carbodiimide (WSCD.HCl. Peptide Inst. Inc., 287 mg, 1.5 mmol). The mixture was stirred at 0°C for 1 hr, then the residue from the above HCl deprotection was added, followed by diisopropylethylamine (0.13 mL, 0.75 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was taken up in EtOAc. The solution was washed with 0.3M KHSO₄, satd. KHCO₃, H₂O and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 55:45:1 v/v/v) to give the titie compound (148 mg, 42%). A part of this was taken up in MeCΝ/H₂O and lyophilised.

R_f (EtOAc:hexane: AcOH 50:50:1 v/v/v) 0.17

HPLC System A t_R=18.8' >98%

AAA Peptide content=80%

Mass spec (FAB) m/e=470 [M+H]⁺ EXAMPLE 33

33 N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycine.

This was prepared from 32d on a 0.35 mmol scale following the method described for 1f. The product was isolated in 53% yield (85 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 75:25:2 v/v/v).

HPLC System A t_R=14.6' >99%

AAA Peptide content=76%

Mass spec (FAB) m/e=455 [M+Na]⁺

EXAMPLE 34

34 1-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-pyrrolidine.

To a stirred solution of 33 (86 mg, 0.19 mmol) and hydroxybenzotriazole (33 mg, 0.25 mmol) in CH₂Cl₂ (8 mL), cooled to 0°C, was added WSCD.HCl (73 mg, 0.38 mmol). The mixture was stirred at 0°C for 1 hr.. then pyrrolidine (50 μL, 0.57 mmol) was added. The mixture was stirred at 0°C for a further 2 hrs. then at room temperature overnight. The solvent was removed in vacuo, and the residue was taken up in EtOAc. The solution was washed with 0.3M KHSO₄, satd. KHCO₃, H₂O and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v) and lyophilised from MeCN/H₂O to give the title compound (36 mg, 36%).

HPLC System A t_R=17.8' >98%

AAA Peptide content=80%

Mass spec (FAB) m/e=509 [M+H]⁺ EXAMPLE 35

35 Methyl N-{N-(2-cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D-prolinate.

This was prepared from 33 on a 0.27 mmol scale following the method described for 34 using D-ProOMe instead of pyrrolidine. The product was isolated in 68% yield (105 mg) after flash chromatography on silica gel (eluant EtOAc:hexane 95:5 v/v).

HPLC System A t_R=14.1' >80%

AAA Aha 0.99; Pro 1.01; Peptide content=76%

Mass spec (FAB) m/e=567 [M+H]⁺

EXAMPLE 36

36 N-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D-proline.

This was prepared from 35 on a 0.21 mmol scale following the method described for 1f. The product was isolated in 45% yield (51 mg) after flash chromatography on silica gel (eluant CHCl₃:MeOH: AcOH 40:2:1 v/v/v).

HPLC System A t_R=15.4' >99%

AAA Aha 1.00; Pro 1.00; Peptide content=72%

Mass spec (FAB) m/e=552 [M+K]⁺ EXAMPLE 37

37a Methyl N-{N-(2-cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)- glycyl}-D-pipecolate.

This was prepared from 33 on a 0.27 mmol scale following the method described for 34 using methyl D-pipecolate instead of pyrrolidine. The product was isolated in 85% yield after flash chromatography on silica gel (eluant EtOAc:hexane 85:15 v/v).

R_f (EtOAc:hexane 95:5 v/v) 0.32

37b N-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D- pipecolic acid.

This was prepared from 37a on a 0.17 mmol scale following the method described for 1f. The product was isolated in 10% yield (10 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v).

HPLC System A t_R=17.6' >80%

AAA Peptide content=74%

Mass spec (FAB) m/e=567 [M+H]⁺

EXAMPLE 38

38a N-(2-Cyclohexylethyl)-N-((2S)-2-(tert-butyloxycarbonylamino)-hexanoyl)- glycine.

This was prepared from 32c on a 1.82 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

38b Methyl N-{N-(2-cyclohexylethyl)-N-((2S)-2-(tert-butyloxycarbonylamino)- hexanoyl)-glycyl}-glycinate.

This was prepared from 38a on a 0.91 mmol scale following the method described for 34 using GlyOMe instead of pyrrolidine. The product was used without purification, assuming a yield of 100%.

R_f (EtOAc:pet. ether 75:25 v/v) 0.59

38c Methyl N-{N-(2-cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)- glycyl}-glycinate.

This was prepared from 38b on a 0.91 mmol scale following the method described for 32d using hydroxybenzotriazoie instead of pentafluorophenol. The product was isolated in 44% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 50:50 v/v then neat EtOAc). 38d N-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}- glycine.

This was prepared from 38c on a 0.40 mmol scale following the method described for If. The product was isolated in 49% yield ( 105 mg) after flash chromatography on silica gel (eluant EtOAc:MeOH:AcOH 100:4:4 v/v/v).

HPLC System A t_R=10.0" >98%

AAA Peptide content=79%

Mass spec (FAB) m/e=535 [M+Na]⁺

EXAMPLE 39

39a Methyl N-(cyclohexylmethyl)-glycinate.

This was prepared from cyclohexylmethylamine on a 3.0 mmol scale following the method described for 32a. The product was used without purification, assuming a yield of 100%. 39b Methyl N-(cyclohexylmethyl)-N-((2S)-2-(tert-butyloxycarbonylamino)-hexanoyl)-glycinate.

This was prepared from 39a on a 3.0 mmol scale following the method described for 32c. The product was isolated in 52% yield after flash chromatography on silica gel (eluant EtOAc:hexane 25:75 v/v).

R_f (EtOAc:hexane 25:75 v/v) 0.23

39c Methyl N-(cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycinate.

This was prepared from 39b on a 1.6 mmol scale following the method described for 32d. The product was isolated in 69% yield after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 50:50: 1 v/v/v).

R_f (EtOAc:hexane:AcOH 50:50: 1 v/v/v) 0.20

39d N-(Cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycine.

This was prepared from 39c on a 1.1 mmol scale following the method described for 1f. The product was isolated in 22% yield after flash chromatography on silica gel (eluant EtOAc: AcOH 100:2 v/v).

R_f (EtOAc:AcOH 100:2 v/v) 0.18

39e 1-{N-(2-Cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-pyrrolidine.

This was prepared from 39d on a 0.48 mmol scale following the method described for 34. The product was isolated in 44% yield ( 109 mg) after flash chromatography on silica gel (eluant EtOAc: AcOH 100:2 v/v).

HPLC System A t_R=15.4' >99%

AAA Peptide content=83%

Mass spec (FAB) m/e=495 [M+H]⁺

EXAMPLE 40

40a Methyl 1-{N-(2-cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)- glycyl}-prolinate.

This was prepared from 39d on a 0.23 mmol scale following the method described for 34 using ProOMe instead of pyrrohdme. The product was isolated in 72% yield after flash chromatography on silica gel (eluant EtOAc).

R_f (EtOAc:hexane 90: 10 v/v) 0.14

40b 1-{N-(2-Cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}- proline.

This was prepared from 40a on a 0.16 mmol scale following the method described for If. The product was isolated in 45% yield (38 mg) after flash chromatography on silica gel (eluant EtOAc: AcOH 100:2 v/v).

HPLC System A t_R=l 1.8' >99%

AAA Aha 1.01; Pro 0.99; Peptide content=81%

Mass spec (FAB) m/e=561 [M+Na]⁺

EXAMPLE 41

41a Methyl 1-{N-(2-Cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)- glycyl}-D-prolinate.

This was prepared from 39d on a 0.23 mmol scale following the method described for 34 using D-ProOMe instead of pyrrolidine. The product was isolated in 48% yield after flash chromatography on silica gel (eluant EtOAc).

R_f (EtOAc:hexane 90:10 v/v) 0.14 41b 1-{N-(2-Cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}- D-proline.

This was prepared from 41a on a 0.11 mmol scale following the method described for 1f. The product was isolated in 52% yield (30 mg) after flash chromatography on silica gel (eluant CHCl3:MeOH:AcOH 40:2:1 v/v/v).

HPLC System A t_R=12.1' >99%

AAA Aha 0.98: Pro 1.02; Peptide content=84%

Mass spec (FAB) m/e=561 [M+Na]⁺

EXAMPLE 42

42a Methyl N-(cyclooctylmethyl)-glycinate.

To a stirred solution of cyclooctanecarboxaldehyde (0.70 g, 5 mmol) and GlyOMe.HCl (0.75 g, 6 mmol) in MeOH (50 mL) at room temperature was added AcOH (2 mL), diisopropylethylamine (1.04 mL, 6 mmol) and NaCNBH₃ (0.75 g, 12 mmol). The mixture was stirred at room temperature for 4 hr., then the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and satd. KHCO₃. The organic phase was washed with H₂O and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel

(eluant EtOAc) to give the title compound (500 mg.47%).

R_f (EtOAc) 0.47

¹H NMR δ 2.42 (2H,d,J=6Hz); 3.35 (2H,s); 3.68 (3H.s)

42b Methyl N-(cyclooctylmethyl)-N-((2S)-2-(tert-butyloxycarboιιylamino)-hexanoyl)-glycinate.

This was prepared from 42a on a 2.35 mmol scale following the method described for 32c. The product was isolated in 99% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75).

R_f (EtOAc:pet. ether 25:75 v/v) 0.41

42c Methyl N-(cyclooctylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycinate.

This was prepared from 42b on a 2.35 mmol scale following the method described for 38c. The product was isolated in 79% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 50:50 v/v).

R_f (EtOAc:pet. ether 65:35 v/v) 0.46

HPLC System A t_R=16.3'

1H NMR Major rotamer δ 4.45 (1H,d,J=17Hz); 5.15 (1H,m)

Minor rotamer δ 4.15 (1H,d,J=17Hz); 4.55 (1H,d,J=l7Hz); 4.90 (1H,m)

Mass spec (FAB) m/e=484 [M+H]⁺

42d N-(Cyclooctylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycine.

This was prepared from 42c on a 1.86 mmol scale following the method described for 1f. The product was used without puification, assuming a yield of 100%.

HPLC System A t_R=12.6'

Mass spec (FAB) m/e=470 [M+H]⁺

42e Methyl 1-{N-(cyclooctylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D-prolinate.

This was prepared from 42d on a 1.49 mmol scale following the method described for 33 using D-ProOMe instead of pyrrolidine. The product was isolated in 50% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 80:20 v/v). HPLC System A t_R= 14.8'

Mass spec (FAB) m/e=581 [M+H]⁺

42f 1-{N-(Cyclooctylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D- proline.

This was prepared from 42e on a 0.62 mmol scale following the method described for 1f. The product was isolated in 79% yield (276 mg) without purification.

HPLC System A t_R=12.0' >98%

AAA Aha 1.01; Pro 0.99: Peptide content=84%

Mass spec (FAB) m/e=567 [M+H]⁺

EXAMPLE 43

43a Methyl 3-(phenethylamino)-propanoate.

This was prepared from phenylacetaldehyde and β-AlaOMe on a 5.0 mmol scale following the method described for 42a. The product was isolated in 68% yield and used without further purification. 43b Methyl 3-{N-(phenethyl)-N-((2S)-2-(tert-butyloxycarbonylamino)-hexanoyl)-amino}-propanoate.

This was prepared from 43a on a 3.4 mmol scale following the method described for 32c. The product was isolated in 42% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

43c Methyl 3-{N-(2-cyclohexylethyl)-N-((2S)-2-(tert-butyloxycarbonylamino)-hexanoyl)-amino}-propanoate.

This was prepared from 43b on a 1.43 mmol scale following the method described for 32b. After evaporating the solvent the product was taken up in EtOAc and washed with satd. KHCO₃, H₂O and brine, filtered (Whatman^R IPS phase separator), and the solvent removed in vacuo. The product was used without further purification, assuming a yield of 100%.

43d Methyl 3-{N-(2-cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-amino}-propanoate.

This was prepared from 43c on a 1.43 mmol scale following the method described for 38c. The product was isolated in 64% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 65:35 v/v).

43e 3-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-amino}-propanoic acid.

This was prepared from 43d on a 0.91 mmol scale following the method described for 1f. The product was isolated in 66% yield after flash chromatography (eluant EtOAc:pet.ether:AcOH 80:20:2 v/v/v).

HPLC System A t_R=12.3'

Mass spec (FAB) m/e=470 [M+H]⁺

43f 1-{3-{N-(2-CycIohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-amino}-propanoyl}-pyrrolidine.

This was prepared from 43e on a 0.50 mmol scale following the method described for 33. The product was isolated in 50% yield (95 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v). HPLC System A t_R=14.2' >98%

AAA Peptide content=79%

Mass spec (FAB) m/e=523 [M+H]⁺

EXAMPLE 44

44a Methyl N-(3-phenylpropyl)-glycinate.

This was prepared from 3-phenylpropylamine on a 20 mmol scale following the method described for 32a. The product was used without purification assuming a yield of 100%.

44b Methyl N-(3-cyclohexylpropyl)-glycinate.

This was prepared from 44a on a 20 mmol scale following the method described for 32b. The product was isolated in a yield of 69% and used without further purification. 1H NMR δ 2.50 (2H,t,J=7Hz); 3.34 (2H,s); 3.81 (3H,s) 44c Methyl N-(3-cyclohexylpropyl)-N-((2S)-2-(tert-butyloxycarbonylamino)-hexanoyl)-glycinate.

This was prepared from 44b on a 5.8 mmol scale following the method described for 32c. The product was isolated in 68% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

44d Methyl N-(3-cyclohexylpropyl)-N-((2S)-2-(2-indolecarbonylamino)-hexanoyl)-glycine.

This was prepared from 44c on a 0.59 mmol scale following the method described for 38c. The product was isolated in 90% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

¹H NMR Major rotamer δ 3.64 (1H,d,J=17Hz); 4.21 (1H,d,J=17Hz); 5.05 (1H,m)

Minor rotamer δ 3.85 (1H,d,J=17Hz); 4.21 (1H,d,J=17Hz); 4.80 (1H,m)

44e N-(3-Cyclohexylpropyl)-N-((2S)-2-(2-indolecarbonylamino)-hexanoyl)-glycine.

This was prepared from 44d on a 0.53 mmol scale following the method described for 1f. The product was isolated in 66% yield (120 mg) after flash chromatography (eluant EtOAc:pet.ether:AcOH 60:40:2 v/v/v).

HPLC System A t_R=16.9 >98%

AAA Peptide content=81%

Mass spec (FAB) m/e=456 [M+H]⁺

EXAMPLE 45

45a Methyl N-(3-cyclohexylpropyl)-N-(N-(tert-butyloxycarbonyl)-phenylalanyl)- glycinate.

This was prepared from 44b on a 2.9 mmol scale following the method described for 32c using BOC-Phe instead of BOC-aminohexanoic acid. The product was isolated in 77% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

45b Methyl N-(3-cyclohexylpropyl)-N-(N-(3-indoleacetyl)-phenylalanyl)-glycinate.

This was prepared from 45a on a 2.4 mmol scale following the method described for 38c. The product was isolated in 28% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 70:30 v/v).

45c N-(3-Cyclohexylpropyl)-N-(N-(3-indoleacetyl)-phenylalanyl)-glycine.

This was prepared from 45b on a 0.68 mmol scale following the method described for If. The product was isolated in 46% yield (159 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v).

HPLC System A t_R=14.6' >95%

AAA Peptide content=86%

Mass spec (FAB) m/e=504 [M+H]⁺ EXAMPLE 46

46a Methyl N-(2-cyclohexylethyl)-N-((2S)-2-(tert-butyloxycarbonylamino)-4-phenylbutanoyl)-glycinate.

This was prepared from 32b on a 4.8 mmol scale following the method described for 32c using BOC-amino-4-phenylbutanoic acid instead of BOC-aminohexanoic acid. The product was isolated in 79% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

46b Methyl N-(2-cyclohexylethyl)-N-((2S)-2-(3-isoquinolinecarbonylamino)-4-phenylbutanoyl)-glycinate.

This was prepared from 46a on a 0.75 mmol scale following the method described for 32c using 3-isoquinolinecarboxylic acid instead of 3-indoleacetic acid. The product was isolated in 62% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

46c N-(2-Cyclohexylethyl)-N-((2S)-2-(3-isoquinolinecarbonylamino)-4-phenylbutanoyl)-glycine.

This was prepared from 46b on a 0.47 mmol scale following the method described for If. The product was isolated in 52% yield (121 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v). HPLC System A t_R=17.2' >99%

AAA Peptide content=97%

Mass spec (FAB) m/e=502 [M+H]⁺

EXAMPLE 47

47a Methyl N-phenethyl-N-((2S)-2-(tert-butyloxycarbonylamino)-hexanoyl)- glycinate.

This was prepared from 32a on a 2.6 mmol scale following the method descibed for 32c. The product was isolated in 75% yield after flash chromatography on silica gel (eluant EtOAc:hexane 25:75 v/v).

R_f (EtOAc:hexane 40:60 v/v) 0.35

47b Methyl N-phenethyl-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycinate.

This was prepared from 47a on a 1.2 mmol scale following the method descibed for 32d. The product was isolated in 71% yield after flash chromatography on silica gel (eluant EtOAc:hexane 70:30 v/v).

R_f (EtOAc:hexane 70:30 v/v) 0.16 47c N-Phenethyl-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycine.

This was prepared from 47b on a 0.88 mmol scale following the method descibed for 1f. The product was isolated in 70% yield after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v).

R_f (EtOAc:AcOH 100:2 v/v) 0.21

47d Methyl N-{N-phenethyl-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D-prolinate.

This was prepared from 47c on a 0.22 mmol scale following the method descibed for 34 using D-ProOMe instead of pyrrolidine. The product was isolated in 50% yield after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v).

R_f (EtOAc: AcOH 100:2 v/v) 0.16

47e N-{N-Phenethyl-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D-proline.

This was prepared from 47d on a 0.11 mmol scale following the method descibed for 1f. The product was isolated in 38% yield (23 mg) after flash chromatography on silica gel (eluant CHCl₃:MeOH: AcOH 35:2:1 v/v/v).

HPLC System A t_R=11.2' >98%

AAA Aha 0.99; Pro 1.01: Peptide content=65%

Mass spec (FAB) m/e=569 [M+H]⁺

EXAMPLE 48

48a 1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from (2R)-2,3-dihydroindole-2-carboxylic acid (M. Vincent et al. Tetrahedron Lett., 23, 1677, 1982) on a 65 mmol scale following the method described for 1a. The product was isolated in 98% yield and used without further purification.

48b Methyl (3R)-2-{N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- O-benzyl-threonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1d on a 0.68 mmol scale following the method described for 32d using 48a instead of indole-3-acetic acid. The product was isolated in 82% yield after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 35:65:1 v/v/v). R_f (EtOAc:hexane: AcOH 50:50:1 v/v/v) 0.36

48c (3R)-2-{N-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-O- benzyl-threonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 48b on a 0.56 mmol scale following the method descibed for 1f. The product was isolated in 55% yield (195 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 50:50:1 v/v/v).

HPLC System A t_R=18.0' >98%

Mass spec (FAB) m/e=628 [M+H]⁺

EXAMPLE 49

49a Methyl (3R)-2-{(2S)-2-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonylamino)-4-phenylbutanoyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 13a on a 0.53 mmol scale following the method descibed for 48b. The product was isolated in 80% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 30:70:2 v/v/v). 49b (3R)-2-{(2S)-2-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonylamino)-4-phenylbutanoyl}-1-2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 49a on a 0.21 mmol scale following the method descibed for 1f. The product was isolated in 53% yield (66 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 35:65:2 v/v/v).

HPLC System A t_R=17.2' >98%

AAA Peptide content=85%

Mass spec (FAB) m/e=598 [M+H]⁺

EXAMPLE 50

50a Methyl (2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-acetate.

This was prepared from 48a on a 55 mmol scale following the method descibed for 1b. The intermediate diazoketone was purified by flash chromatography on silica gel (eluant EtOAc:hexane 20:80 v/v), and the product was isolated in 69% yield after flash chromatography on silica gel (eluant EtOAc:hexane 12:88 v/v).

50b Methyl (2R)-2,3-dihydroindole-2-acetate hydrochloride.

This was prepared from 50a on a 3 mmol scale following the method descibed for 1c and was used without purification.

50c Methyl (2R)-1-{(2S)-2-tert-butyloxycarbonylamino-4-phenylbutanoyl}-2,3-dihydroindole-2-acetate.

This was prepared from 50b on a 3 mmol scale following the method descibed for 1d using BOC-homophenylalanine instead of N-BOC-O-benzyl-threonine. The product was isolated in 30% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 16:84 v/v).

50d Methyl (2R)-1-{(2S)-2-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)-4-phenylbutanoyl}-2-3-dihydroindole-2-acetate.

This was prepared from 50c on a 0.88 mmol scale following the method descibed for 48b. The product was isolated in 89% yield after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 30:70:2 v/v/v).

50e (2R)-1-{(2S)-2-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetic acid.

This was prepared from 50d on a 0.16 mmol scale following the method descibed for 1f. The product was isolated in 76% yield (70 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 45:55:2 v/v/v).

HPLC System B t_R=13.5' >95%

AAA Peptide content=92%

Mass spec (FAB) m/e=584 [M+H]⁺ EXAMPLE 51

51a Methyl (3R)-2-{((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- valyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 18a on a 0.41 mmol scale following the method descibed for 48b. The product was isolated in 70% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v then neat EtOAc).

51b (3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-valyl}- 1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 51a on a 0.29 mmol scale following the method descibed for 1f. The product was isolated in 70% yield (108 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 60:40:1 v/v/v).

HPLC System B t_R=10.7' >98%

AAA Peptide content=81%

Mass spec (FAB) m/e=536 [M+H]⁺

EXAMPLE 52

52a Methyl (3R)-2-{((2R)-1-tert-butylacetyl-2,3-dihydroindole-2-carbonyl)-valyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

A solution of 51a (198 mg, 0.36 mmol) in 4N HCl in dioxan (15 mL) was stirred at room temperature for 30 min., then the solvent was evaporated in vacuo, finally with toluene azeotrope. The residue was taken up in CH₂Cl₂ and cooled to -15°C with stirring. Diisopropylethylamine (0.14 mL, 0.80 mmol) and tert-butylacetyl chloride (51 μL, 0.36 mmol) were added and the mixture was stirred at -15°C for 45 min. The solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and 0.3M KHSO₄. The organic phase was washed with satd. KHCO₃, H₂O and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:hexane 55:45 v/v) to give the title compound (100 mg, 50%).

R_f (EtOAc:hexane 60:40 v/v) 0.28

52b (3R)-2-{((2R)-1-tert-Butylacetyl-2,3-dihydroindole-2-carbonyl)-valyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 52a on a 0.18 mmol scale following the method descibed for 1f. The product was isolated in 81% yield (78 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 65:35: 1 v/v/v).

HPLC System A t_R=14.0' >98%

AAA Peptide content=76%

Mass spec (FAB) m/e=534 [M+H]⁺

EXAMPLE 53

53a Methyl (3R)-2-(tert-butyloxycarbonyl-valyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a on a 1.0 mmol scale following the method descibed for 1d using BOC-valine instead of N-BOC-O-benzyl-threonine. The product was isolated in 68% yield after flash chromatography on silica gel (eluant EtOAc:hexane 28:72 v/v). R_f (EtOAc:hexane 25:75 v/v) 0.20

53b Methyl (3R)-2-{((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-valyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 53a on a 0.68 mmol scale following the method descibed for 48b. The product was isolated in 81% yield after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 45:55:1 v/v/v).

R_f (EtOAc:hexancAcOH 50:50:1 v/v/v) 0.30

53c (3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-valyl}- 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 53b on a 0.52 mmol scale following the method descibed for 1f. The product was isolated in 50% yield (150 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 60:40:1 v/v/v). HPLC System A t_R=13.9' >98%

AAA Peptide content=77%

Mass spec (FAB) m/e=522 [M+H]⁺

EXAMPLE 54

54a Methyl (3R)-2-{((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- isoleucyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 20a on a 0.16 mmol scale following the method descibed for 48b. The product was isolated in 94% yield after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 35:65:2 v/v/v).

54b (3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-isoleucyl}- 1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 54a on a 0.15 mmol scale following the method descibed for 1f. The product was isolated in 63% yield (55 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v).

HPLC System A t_R=15.3' >98%

AAA Peptide content=66%

Mass spec (FAB) m/e=550 [M+H]⁺ EXAMPLE 55

55a Methyl (3R)-2-{(S)-α-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonylamino)-phenylacetyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 22a on a 0.23 mmol scale following the method descibed for 48b. The product was isolated in 89% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 35:65:2 v/v/v).

55b (3R)-2-{(S)-α-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonylamino)-phenylacetyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 55a on a 0.21 mmol scale following the method descibed for 1f. The product was isolated in 66% yield (87 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v).

HPLC System A t_R=15.3' >95%

AAA Peptide content=73%

Mass spec (FAB) m/e=570 [M+H]⁺

EXAMPLE 56

56a Methyl (3R)-2-(tert-butyloxycarbonyl-D-prolyl)-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c on a 1.0 mmol scale following the method descibed for 1d using BOC-D-proline instead of N-BOC-O-benzyl-threonine. The product was isolated in 74% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 50:50 v/v).

56b Methyl (3R)-2-{((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-D- prolyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 56a on a 0.37 mmol scale following the method descibed for 48b. The product was isolated in 87% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 70:30:1 v/v/v).

56c (3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-D-prolyl}- 1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 56b on a 0.32 mmol scale following the method descibed for 1f. The product was isolated in 39% yield (67 mg) after flash chromatography on silica gel (eluant CHCl₃:MeOH:AcOH 50:2:1 v/v/v).

HPLC System B t_R=9.5' >98%

AAA Peptide content=73%

Mass spec (FAB) m/e=534 [M+H]⁺ EXAMPLE 57

57a Methyl (3R)-2-{(2R)-1-(tert-butyloxycarbonyl)-2,3-dihydroindole-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c on a 1.13 mmol scale following the method descibed for 1d using 48a instead of N-BOC-O-benzyl-threonine. The product was isolated in 79% yield after flash chromatography on silica gel (eluant EtOAc:hexane 30:70 v/v).

57b Methyl (3R)-2-{(2R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-2,3-dihydroindole-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 57a on a 0.90 mmol scale following the method descibed for 48b. The product was isolated in 64% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (eluant EtOAc:hexane 60:40 v/v) 0.40

57c (3R)-2-{(2R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-2,3-dihydroindole-2-carbonyl}-1,2,3,4-tetrahydroisoquinoIine-3-acetic acid.

This was prepared from 57b on a 0.58 mmol scale following the method descibed for 1f. The product was isolated in 65% yield (219 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 65:35:1 v/v/v).

HPLC System A t_R=17.7' >99%

Mass spec (FAB) m/e=582 [M+H]⁺ EXAMPLE 58

58a Methyl (3R)-2-{(2R,3S)-1-tert-butyloxycarbonyl-3-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c on a 0.17 mmol scale following the method described for 1d using 1-tert-butyloxycarbonyl-3-phenyl-pyrrolidine-2-carboxylic acid (J.Y.L. Chung et al, J.Org.Chem.. 55,270,1990) instead of N-BOC-O-benzyl-threonine. The product was isolated in 75% yield and used without further purification.

R_f (EtOAc:pet. ether 50:50 v/v) 0.18

1H NMR δ 1.28, 1.40, 1.48 (9H,3s); 3.59, 3.66 (3H,2s)

58b Methyl (3R)-2-{(2R,3S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-3-phenyl-pyrroIidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 58a on a 0.098 mmol scale following the method described for 48b. The product was isolated in 78% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 50:50: 1 v/v/v).

R_f (EtOAc:pet. ether:AcOH 60:40: 1 v/v/v) 0.15 58c (3R)-2-{(2R,3S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 3-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 58b on a 0.077 mmol scale following the method described for 1f. The product was isolated in 83% yield (41 mg) without chromatography.

HPLC System B t_R=13.9' >99%

Mass spec (FAB) m/e=610 [M+H]⁺

EXAMPLE 59

59a Methyl (3R)-2-{(2R,4S)-1-tert-butyloxycarbonyl-4-phenylthio-pyrroIidine-2- carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a on a 0.48 mmol scale following the method described for 1d using (2R,4S)-1-tert-butyloxycarbonyl-4-phenylthio-pyrrolidine-2-carboxylic acid (J. Krapcho et al, J.Med.Chem., 31,1148, 1988) instead of N-BOC-O-benzyl-threonine. The product was isolated in 40% yield after flash chromatography on silica gel (eluant EtOAc:hexane 50:50 v/v).

R_f (EtOAc:hexane 60:40 v/v) 0.43 59b Methyl (3R)-2-{(2R,4S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 59a on a 0.20 mmol scale following the method described for 48b. The product was isolated in 61% yield after flash chromatography on silica gel (eluant EtOAc:hexane 50:50 v/v).

R_f (EtOAc:hexane 55:45 v/v) 0.42

59c (3R)-2-{(2R,4S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3.4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 59b on a 0.12 mmol scale following the method described for If. The product was isolated in 43% yield (32 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 85:15:1 v/v).

HPLC System A t_R=20.5' >98%

Mass spec (FAB) m/e=627 [M+H]⁺

EXAMPLE 60

60a Methyl (3R)-2-{(2R,4S)-1-tert-butyloxycarbonyl-4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c on a 0.48 mmol scale following the method described for 1d using (2R,4S)-1-tert-butyloxycarbonyl-4-phenylthio-pyrrolidine-2-carboxylic acid instead of N-BOC-O-benzyl-threonine. The product was isolated in 61% yield after flash chromatography on silica gel (eluant EtOAc:hexane 50:50 v/v).

R_f (EtOAc:hexane 60:40 v/v) 0.39

60b Methyl (3R)-2-{(2R,4S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 60a on a 0.29 mmol scale following the method described for 48b. The product was isolated in 77% yield after flash chromatography on silica gel (eluant EtOAc:hexane 55:45 v/v).

R_f (EtOAc:hexane 60:40 v/v) 0.40

60c (3R)-2-{(2R,4S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 60b on a 0.22 mmol scale following the method described for 1f. The product was isolated in 64% yield (91 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 70:30:1 v/v).

HPLC System A t_R=20.9' >99%

Mass spec (FAB) m/e=642 [M+H]⁺

EXAMPLE 61

61a Methyl (3R)-2-{(2R,4R)-1-tert-butyloxycarbonyl-4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a on a 0.40 mmol scale following the method described for 1d using (2R,4R)-1-tert-butyloxycarbonyl-4-phenylthio-pyrrolidthe-2-carboxylic acid (J. Krapcho et al, J.Med. Chem., 31,1148, 1988) instead of N-BOC-O-benzyl-threonine. The product was isolated in 60% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:2 v/v/v).

61b Methyl (3R)-2-{(2R,4R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 61a on a 0.24 mmol scale following the method described for 48b. The product was isolated in 48% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v). 61c (3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 61b on a 0.12 mmol scale following the method described for 1f. The product was isolated in 69% yield (50 mg) after recrystallization from Et₂O/hexane.

HPLC System B t_R=15.0' >98%

Mass spec (FAB) m/e=628 [M+H]⁺

EXAMPLE 62

62a Methyl (3R)-2-{(2R,4R)-1-tert-butyloxycarbonyl-4-benzyloxy-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a on a 0.68 mmol scale following the method described for 1d using (2R,4R)-1-tert-butyloxycarbonyl-4-benzyloxy-pyrrolidine-2-carboxylic acid (J. Krapcho et al, J.Med.Chem., 31,1148,1988) instead of N-BOC-O-benzyl-threonine. The product was isolated in 43% yield after flash chromatography on silica gel (eluant EtOAc:hexane 50:50 v/v).

R_f (EtOAc:hexane 60:40 v/v) 0.38 62b Methyl (3R)-2-{(2R,4R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-benzyloxy-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 62a on a 0.30 mmol scale following the method described for 48b. The product was isolated in 35% yield after flash chromatography on silica gel (eluant EtOAc:hexane 55:45 v/v).

R_f (EtOAc:hexane 60:40 v/v) 0.36

62c (3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2 ,3-dihydroindole-2-carbonyl)- 4-benzyloxy-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 62b on a 0.11 mmol scale following the method described for 1f. The product was isolated in 29% yield (20 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 90:10:1 v/v).

HPLC System A t_R=8.8' >98%

Mass spec (FAB) m/e=626 [M+H]⁺

EXAMPLE 63

63a Methyl (3R)-2-{(2R,4R)-1-tert-butyloxycarbonyl-4-phenoxy-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a on a 0.59 mmol scale following the method described for 1d using (2R,4R)-1-tert-butyloxycarbonyl-4-phenoxy-pyrroIidine-2-carboxylic acid (J. Krapcho et al. J.Med. Chem.. 31.1148, 1988) instead of N-BOC-O-benzyl-threonine. The product was isolated in 59% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 40:60:2 v/v/v).

63b Methyl (3R)-2-{(2R,4R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenoxy-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 63a on a 0.35 mmol scale following the method described for 48b. The product was isolated in 20% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

63c (3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenoxy-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 63b on a 0.07 mmol scale following the method described for 1f. The product was isolated in 61% yield (26 mg) after recrystallization from MeOH/H₂O.

HPLC System B t_R=13.2' >98%

Mass spec (FAB) m/e=612 [M+H]⁺

EXAMPLE 64

64a Methyl (3R)-2-{(2R,4R)-1-tert-butyloxycarbonyl-4-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c on a 0.24 mmol scale following the method described for 1d using (2R,4S)-1-tert-butyloxycarbonyl-4-phenyl-pyrrolidine-2-carboxylic acid (J. Krapcho et al, J.Med.Chem., 31.1148.1988) instead of N-BOC-O-benzyl-threonine. The product was used without further purification assuming a yield of 100%.

R_f (EtOAc:pet. ether 30:70 v/v) 0.11

64b Methyl (3R)-2-{(2R,4R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 64a on a 0.24 mmol scale following the method described for 48b. The product was isolated in 33% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:1 v/v/v).

R_f (EtOAc:pet. ether:AcOH 40:60: 1 ) 0.09 64c (3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 64b on a 0.08 mmol scale following the method described for 1f. The product was isolated in 100% yield (54 mg) without chromatography.

HPLC System B t_R=15.4' >98%

Mass spec (FAB) m/e=610 [M+H]⁺

EXAMPLE 65

65a Methyl (3R)-2-{(2R,4S)-1-tert-butyloxycarbonyl-4-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c on a 0.24 mmol scale following the method described for 1d using (2R,4R)-1-tert-butyloxycarbonyl-4-phenyl-pyrrolidine-2-carboxylic acid (J. Krapcho et al, J.Med. Chem., 31.1148.1988) instead of N-BOC-O-benzyl-threonine. The product was isolated in 78% yield and used without further purification.

R_f (EtOAc:pet. ether 30:70 v/v) 0.11 65b Methyl (3R)-2-{(2R,4S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-4-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- acetate.

This was prepared from 65a on a 0.31 mmol scale following the method described for 48b. The product was isolated in 74% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 30:70:1 v/v/v).

R_f (EtOAc:pet. ether:AcOH 25:85:1) 0.10

65c (3R)-2-{(2R,4S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 4-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 65b on a 0.30 mmol scale following the method described for 1f. The product was isolated in 79% yield ( 149 mg) without chromatography.

HPLC System B t_R=14.8' >95%

Mass spec (FAB) m/e=610 [M+H]⁺

EXAMPLE 66

66a Methyl (3R)-2-{(2R.4S)-1-tert-butyloxycarbonyl-4-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a on a 0.66 mmol scale following the method described for 1d using (2R,4S)-1-tert-butyloxycarbonyl-4-benzyl-pyrrolidine-2-carboxylic acid (J. Krapcho et al, J.Med.Chem., 31,1148.1988) instead of N-BOC-O-benzyl-threonine. The product was isolated in 55% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 30:70:1 v/v/v).

66b Methyl (3R)-2-{(2R,4S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 66a on a 0.35 mmol scale following the method described for 48b. The product was isolated in 33% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 30:70:1 v/v/v).

66c (3R)-2-{(2R,4S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 66b on a 0.11 mmol scale following the method described for 1f. The product was isolated in 63% yield (43 mg) after recrystallization from MeOH/H₂O.

HPLC System B t_R=14.6' >95%

Mass spec (FAB) m/e=610 [M+H]⁺

EXAMPLE 67

67a Ethyl (2R,5S)-1-tert-butyloxycarbonyl-5-phenyl-pyrrolidine-2-carboxylate.

To a solution of 30a (290 mg, 1.32 mmol) in CH₂Cl₂ (10 mL) was added di-tert-butyl pyrocarbonate (576 mg, 2.64 mmol), and the mixture was stirred at room temperature for 3 hrs. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel (eluant EtOAc:pet. ether 15:85) to give the title compound (400 mg, 95%).

R_f (EtOAc:pet. ether 15:85) 0.35

67b (2R,5S)-1-tert-Butyloxycarbonyl-5-phenyl-pyrrolidine-2-carboxylic acid.

This was prepared from 67a on a 1.25 mmol scale following the method described for If. The product was isolated in 93% yield and used without further purification.

67c 2-{(2R,5S)-1-tert-Butyloxycarbonyl-5-phenyl-pyrroIidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline.

This was prepared from 67b and tetrahydroisoquinoline on a 0.38 mmol scale following the method described for 1d. The product was isolated in 74% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v). 67d 2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline.

This was prepared from 67c on a 0.28 mmol scale following the method described for 48b. The product was isolated in 64% yield (98 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

HPLC System A t_R=25.0' >99%

Mass spec (FAB) m/e=552 [M+H]⁺

EXAMPLE 68

68a Methyl (3R)-2-{(2R,5S)-1-tert-butyloxycarbonyl-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 67b and 26a on a 0.27 mmol scale following the method described for 1d. The product was isolated in 56% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

1H NMR δ 1.13 (9H,s); 3.63 (3H,s); 5.69 (1H,t,J=4Hz)

68b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a on a 1.0 mmol scale following the method described for 48b. The product was isolated in 68% yield (415 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

HPLC System A t_R=24.7' >99%

Mass spec (FAB) m/e=610 [M+H]⁺ EXAMPLE 69

69 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 68b on a 0.13 mmol scale following the method described for 1f. The product was isolated in 50% yield (38 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 60:40:2 v/v/v).

HPLC System A t_R=14.9' >98%

Mass spec (FAB) m/e=618 [M+Na]⁺

EXAMPLE 70

70 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide.

To an ice-cold stirred solution of 69 (107 mg, 0.18 mmol) and pentafluorophenol (37 mg, 0.2 mmol) in CH₂Cl₂ (10 mL) was added WSCD.HCl (478 mg, 0.4 mmol). The mixture was stirred at 0°C for 1 hr., then c. aqueous NH₃ (0.5 mL) was added and vigorous stirring was continued for 3 hr. The mixture was partitioned between EtOAc and H₂O, and the organic phase was washed with 10% KHSO₄, satd. KHCO₃ and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 55:45:2 v/v/v) to give the title compound (87 mg, 81%).

HPLC System A t_R=20.1' >99%

Mass spec (FAB) m/e=595 [M+H]⁺

EXAMPLE 71

71a Methyl N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-glycinate.

This was prepared from 69 on a 0.30 mmol scale following the method described for 38b. The product was isolated in 85% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 65:35 v/v).

71b N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-glycine.

This was prepared from 71a on a 0.26 mmol scale following the method described for 1f. The product was isolated in 71% yield (120 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v).

HPLC System A t_R=18.4' >99%

AAA Peptide content=76%

Mass spec (FAB) m/e=653 [M+H]⁺ EXAMPLE 72

72a (2R)-1-Neopentyloxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

To an ice-cold stirred solution of neopentyl alcohol (88mg, 1 mmol) in CH₂Cl₂ (5 mL) was added triphosgene (110 mg, 0.37 mmol) and pyridine (84 μL, 1.02 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hr. then cooled to 0°C. A solution of methyl (2R)-2,3-dihydroindole-2-carboxylate hydrochloride (107 mg, 0.5 mmol) and diisopropylethylamine (90 μL, 0.45 mmol) in CH₂Cl₂ (2 mL) was added and the mixture was stirred at room temperature for 3 hr. The solvent was removed in vacuo and the residue was taken up in EtOAc. The solution was washed with 1M HCl (×3) and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was taken up in dioxan ( 10 mL) and a solution of LiOH (24 mg, 1 mmol) in H₂O (2 mL) was added. The mixture was stirred at room temperature for 90 min., then the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and 10% aq. KHSO₄. The organic phase was washed with brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo to give the title compound (90 mg, 62%) which was used without further purification. 72b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-neopentyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylate.

This was prepared from 68a and 72a on a 0.29 mmol scale following the method described for 48b. The product was isolated in 50% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v).

72c (3R)-2-{(2R,5S)-1-((2R)-1-Neopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 72b on a 0.14 mmol scale following the method described for 1f. The product was isolated in 81% yield (69 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 60:40:2 v/v/v).

HPLC System A t_R=22.4' >95%

Mass spec (FAB) m/e=610 [M+H]⁺

EXAMPLE 73

73a (2R)-1-Isopropyloxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from isopropanol on a 0.5 mmol scale following the method described for 72a. The product was isolated in 80% yield and used without further purification.

73b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-isopropyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 73a on a 0.33 mmol scale following the method described for 48b. The product was isolated in 59% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 45:55 v/v).

73c (3R)-2-{(2R,5S)-1-((2R)-1-Isopropyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 73b on a 0.19 mmol scale following the method described for 1f. The product was isolated in 63% yield (70 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 60:40:2 v/v/v).

HPLC System A t_R=18.5' >90%

Mass spec (FAB) m/e=582 [M+H]⁺

EXAMPLE 74

74a (2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from cyclohexanol on a 0.5 mmol scale following the method described for 72a. The product was isolated in 72% yield and used without further purification.

74b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylate.

This was prepared from 68a and 74a on a 0.27 mmol scale following the method described for 48b. The product was isolated in 73% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v).

74c (3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

This was prepared from 74b on a 0.20 mmol scale following the method described for 1f. The product was isolated in 84% yield (104 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 55:45:2 v/v/v). HPLC System A t_R=23.0' >95%

Mass spec (FAB) m/e=621 [M+H]⁺

EXAMPLE 75

75a (2R)-1-(2-Adamantyl)oxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from 2-adamantanol on a 0.5 mmol scale following the method described for 72a. The product was isolated in 80% yield and used without further purification.

75b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-(2-adamantyl)oxycarbonyl-2,3-dihydroindole- 2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylate.

This was prepared from 68a and 75a on a 0.33 mmol scale following the method described for 48b. The product was isolated in 29% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v). 75c (3R)-2-{(2R,5S)-1-((2R)-1-(2-Adamantyl)oxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

This was prepared from 75b on a 0.09 mmol scale following the method described for 1f. The product was isolated in 81% yield (49 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 55:45:2 v/v/v).

HPLC System A t_R=27.9' >98%

Mass spec (FAB) m/e=674 [M+H]⁺

EXAMPLE 76

76a (2R)-1-tert-Butylcarbamoyl-2,3-dihydroindole-2-carboxylic acid.

To an ice-cold stirred solution of methyl (2R)-2,3-dihydroindole-2-carboxylate hydrochloride (107 mg, 0.5 mmol) and diisopropylethylamine (110 μL, 0.6 mmol) in CH₂Cl₂ (2 mL) was added tert-butylisocyanate (120 mg, 1.2 mmol). The mixture was allowed to warm to room temperature and stirred for 6 days then the solvent was removed in vacuo and the residue was taken up in EtOAc. The solution was washed with 1M HCl (×3) and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was taken up in dioxan (10 mL), and a solution of LiOH (24 mg, 1 mmol) in H₂O (2 mL) was added. The mixture was stirred at room temperature for 90 min., then the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and 10% aq. KHSO₄. The organic phase was washed with brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo to give the title compound (120 mg, 91%) which was used without further purification.

76b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butylcarbamoyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 76a on a 0.37 mmol scale following the method described for 48b. The product was isolated in 13% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 50:50 v/v).

76c (3R)-2-{(2R,5S)-1-((2R)-1-tert.Butylcarbamoyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 76b on a 0.05 mmol scale following the method described for 1f. The product was isolated in 67% yield (20 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 75:25:2 v/v/v).

HPLC System A t_R=12.2' >98%

Mass spec (FAB) m/e=595 [M+H]⁺

EXAMPLE 77

77a Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butylacetyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68b on a 0.18 mmol scale following the method described for 52a. The product was isolated in 81% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

77b (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butylacetyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 77a on a 0.14 mmol scale following the method described for 1f. The product was isolated in 82% yield (68 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 60:40:2 v/v/v).

HPLC System A t_R=20.0' >99%

Mass spec (FAB) m/e=594 [M+H]⁺

EXAMPLE 78

78a Methyl (3R)-2-{(2R,5S)-1-tert-butyloxycarbonyl-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 67b on a 0.58 mmol scale following the method described for 1d. The product was isolated in 87% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

78b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoqιιinoline-3-acetate.

This was prepared from 78a on a 0.36 mmol scale following the method described for 48b. The product was isolated in 98% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

78c (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 78b on a 0.35 mmol scale following the method described for 1f. The product was isolated in 45% yield (95 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 60:40:3 v/v/v).

HPLC System A t_R=15.7' >99%

Mass spec ( FAB ) m/e=610 [M+H]⁺

EXAMPLE 79

79a Ethyl (2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carboxylate.

This was prepared from 30a on a 1.37 mmol scale following the method described for 48b. The product was isolated in 86% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

R_f (EtOAc:hexane 40:60 v/v) 0.29 79b (2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carboxylic acid.

This was prepared from 79a on a 1.18 mmol scale following the method described for 1f. The product was isolated in 66% yield and used without further purification.

R_f (EtOAc:hexane: AcOH 80:20:2 v/v/v) 0.31

79c Methyl N-{(3R)-2-tert-butyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-acetyl}-prolinate.

This was prepared from 1b on a 1.25 mmol scale in two steps, 1b was hydrolysed following the method described for 1f. and the crude acid was coupled to ProOMe following the method described for 1d. The product was isolated in 86% yield after flash chromatography on silica gel (eluant EtOAc:hexane 60:40 v/v).

R_f (EtOAc:hexane 60:40 v/v) 0.23

79d Methyl N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidlne-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetyl}-prolinate.

This was prepared from 79c on a 0.14 mmol scale in two steps. 79c was deprotected following the method described for 1c, and the crude amine was coupled to 79b following the method described for 1d. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:hexane 80:20 v/v).

R_f (EtOAc:hexane 80:20 v/v) 0.19

79e N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetyl}-proline.

This was prepared from 79d on a 0.14 mmol scale following the method described for 1f. The product was isolated in 45% yield (45 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v).

HPLC System A t_R=18.5' >98%

AAA Peptide content=91%

Mass spec (FAB) m/e=707 [M+H]⁺ EXAMPLE 80

80a Methyl N-{(3R)-2-tert-butyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-acetyl}-D-prolinate.

This was prepared from 1b on a 1.25 mmol scale following the method described for 79c using D-ProOMe. The product was isolated in 43% yield after flash chromatography on silica gel (eluant EtOAc:hexane 70:30 v/v).

R_f (EtOAc:hexane 60:40 v/v) 0.27 80b Methyl N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetyl}-D-prolinate.

This was prepared from 80a on a 0.13 mmol scale following the method described for 79d. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:hexane 80:20 v/v).

R_f (EtOAc:hexane 80:20 v/v) 0.18

80c N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetyl}-D-proline.

This was prepared from 80b on a 0.13 mmol scale following the method described for 1f. The product was isolated in 50% yield (49 mg) after flash chromatography on silica gel (eluant CHCl₃:MeOH: AcOH 50:2:1 v/v/v).

HPLC System A t_R=17.8' >98%

AAA Peptide content=91%

Mass spec (FAB) m/e=707 [M+H]⁺

EXAMPLE 81

81a Methyl (3R)-2-{(2R,5S)-1-((2R)-1-neopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 78b on a 0.27 mmol scale in two steps. 78b was deprotected following the method described for 1c, and the crude amine was reacted with neopentyl chloroformate following the method described for 72a (excluding the final hydrolysis). The product was isolated in 70% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

81b (3R)-2-{(2R,5S)-1-((2R)-1-Neopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 81a on a 0.19 mmol scale following the method described for 1f. The product was isolated in 70% yield (82 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 50:50:2 v/v/v).

HPLC System B t_R=17.5' >95%

Mass spec (FAB) m/e=624 [M+H]⁺

EXAMPLE 82

82a Methyl (3R)-2-{(2R,5S)-1-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 78b on a 0.27 mmol scale following the method described for 81a using cyclohexanol instead of neopentyl alcohol. The product was isolated in 62% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 20:80 v/v).

82b (3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 82a on a 0.17 mmol scale following the method described for 1f. The product was isolated in 82% yield (86 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 50:50:2 v/v/v). HPLC System B t_R=18.1' >98%

Mass spec (FAB) m/e=636 [M+H]⁺

EXAMPLE 83

83a Methyl (3R)-2-{(2R,5S)-1-((2R)-1-(2-adamantyl)oxycarbonyl-2,3-dihydroindole- 2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 78b on a 0.27 mmol scale following the method described for 81a using 2-adamantanol instead of neopentyl alcohol. The product was isolated in 72% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 20:80 v/v).

83b (3R)-2-{(2R,5S)-1-((2R)-1-(2-Adamantyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 83a on a 0.19 mmol scale following the method described for 1f. The product was isolated in 66% yield (88 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 50:50:2 v/v/v).

HPLC System B t_R=2i.4' >99%

Mass spec (FAB) m/e=687 [M]⁺ EXAMPLE 84

84a (3R)-1,2,3,4-Tetrahydro-benz[f]isoquinoline-3-carboxylic acid hydrochloride.

A mixture of D-3-(1-naphthyl)-alanine (5 g, 23.2 mmol), 37% formalin (9 mL) and cone. HCl (40 mL) was heated on a steam bath for 30 min. with occasional swirling. Further formalin (6 mL) and HCl (15 mL) were added and heating was continued for 3 hrs. The mixture was cooled to 4°C and allowed to stand for 2 hrs. The solid product was collected, washed with cold H₂O and acetone, and dried over KOH to give the title compound (3.2 g, 52%).

84b Methyl (3R)-1,2,3,4-tetrahydro-benz[f ]isoquinoline-3-carboxylate hydrochloride.

This was prepared from 84a on a 6.05 mmol scale following the method described for 26a. The product was isolated in 43% yield after flash chromatography of the free amine on silica gel (eluant EtOAc) and stored as the hydrochloride. 84c Methyl (3R)-2-{(2R,5S)-1-tert-butyloxycarbonyl-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-carboxylate.

This was prepared from 67b and 84b on a 0.50 mmol scale following the method described for 1d. The product was isolated in 82% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

84d Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline- 3-carboxylate.

This was prepared from 84c on a 0.41 mmol scale following the method described for 48b. The product was isolated in 81% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

84e (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-carboxylic acid.

This was prepared from 84d on a 0.33 mmol scale following the method described for 1f. The product was isolated in 74% yield (157 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 55:45:2 v/v/v).

HPLC System A t_R=23.0' >98%

Mass spec (FAB) m/e=646 [M+H]⁺

85a (3R)-2-tert-Butyloxycarbonyl-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-carboxylic acid.

This was prepared from 84a on a 6.05 mmol scale following the method described for 1a. The product was isolated in 41% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 35:65:2 v/v/v). 85b Methyl (3R)-2-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-acetate.

This was prepared from 85a on a 2,5 mmol scale following the method described for 1b. The intermediate diazoketone was isolated in 80% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v), and the product was isolated in 75% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 18:82 v/v).

85c Methyl (3R)-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-acetate hydrochloride.

This was prepared from 85a on a 0.49 mmol scale following the method described for 1c. The product was used without purification assuming a yield of 100%.

85d Methyl (3R)-2-{(2R,5S)-1-tert-butyloxycarbonyl-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-acetate.

This was prepared from 67b and 85c on a 0.49 mmol scale following the method described for 1d. The product was isolated in 81% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

85e Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline- 3-acetate.

This was prepared from 85d on a 0.40 mmol scale following the method described for 48b. The product was isolated in 87% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

85f (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-acetic acid.

This was prepared from 85e on a 0.36 mmol scale following the method described for 1f. The product was isolated in 64% yield (151 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 55:45:2 v/v/v).

HPLC System A t_R=24.1' >99%

Mass spec (FAB) m/e=560 [M+H-BOC]⁺ EXAMPLE 86

86a Ethyl (2R)-2-tert-butyloxycarbonylamino-5-oxo-6-phenyl-hexanoate.

To a stirred solution of ethyl N-BOC-D-pyroglutamate (2.06 g, 8 mmol) in THF (10 mL), cooled to -78°C under N2, was added dropwise a solution of benzylmagnesium chloride in THF (5 mL, 2N, 10 mmol). The mixture was allowed to warm to room temperature over 1 hr., and was then poured into 5% aq. KHSO₄. The mixture was extracted with EtOAc, and the organic phase was washed with satd. KHCO₃ and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v) to give the title compound (1.5 g, 54%). ¹H NMR δ 1.28 (3H,t,J=7Hz); 1.47 (9H,s); 3.73 (2H,s); 4.19 (2H,q,J=7Hz)

86b Ethyl (2R,5S)-5-benzyl-pyrrolidine-2-carboxylate.

A solution of 86a (1.5 g, 4.3 mmol) in CH₂Cl₂ (20 mL) and TFA (20 mL) was stirred at 0°C for 1 hr. then concentrated in vacuo. finally with CCl₄ azeotrope. The residue was taken up in EtOH (30 mL). To this solution was added AcOH (3 mL), then diisopropylethylamine (0.87 mL. 5 mmol) and finally NaBH₃CN (0.82 g, 13 mmol) in three portions. The mixture was stirred at room temperature for 3 hr., then the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and satd. KHCO₃, and the organic phase was washed with brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:pet. ether 60:40 v/v) to give the title compound (410 mg, 41%).

1H NMR δ 1.28 (3H,t,J=7Hz); 2.75 (1H,dd,J=14,7Hz); 2.89 (1H,dd,J=14,7Hz); 4.19 (2H,q,J=7Hz)

86c Ethyl (2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-benzyl-pyrrolidine-2-carboxylate.

This was prepared from 86b on a 1.76 mmol scale following the method described for 48b. The product was isolated in 86% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

86d (2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-benzyl-pyrrolidine-2-carboxylic acid.

This was prepared from 86c on a 1.51 mmol scale following the method described for If. The product was used without purification, assuming a yield of 100%.

86e Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 86d on a 0.50 mmol scale following the method described for 1d. The product was isolated in 97% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v). 86f (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 86e on a 0.49 mmol scale following the method described for 1f. The product was isolated in 49% yield (150 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 60:40:2 v/v/v).

HPLC System A t_R=15.2' >99%

Mass spec (FAB) m/e=624 [M+H]⁺

EXAMPLE 87

87a Ethyl (2R)-3,4-dihydro-5-(2-naphthyl)-2H-pyrrole-2-carboxylate.

To a stirred solution of ethyl N-BOC-D-pyroglutamate (2.06 g, 8 mmol) in THF (10 mL), cooled to -78ºC under N₂, was added dropwise a solution of 2-naphthylmagnesium chloride in THF (5 mL, 2N, 10 mmol). The mixture was allowed to warm to room temperature over 1 hr., and was then poured into 5% aq. KHSO₄. The mixture was extracted with EtOAc, and the organic phase was washed with satd. KHCO₃ and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was taken up in CH₂Cl₂ (20 mL) and TFA (20 mL) and stirred at 0°C for 1 hr. then concentrated in vacuo, finally with CCl₄ azeotrope. The residue was taken up in satd. KHCO3 and extracted twice with EtOAc. The combined organic phases were washed with brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:pet. ether 20:80 then 40:60 v/v) to give the title compound (605 mg, 28%).

1H ΝMR δ 1.43 (3H,t,J=7Hz); 4.41 (2H.q,J=7Hz); 5.04 (1H,m)

87b Ethyl (2R,5S)-5-(2-naphthyl)-pyrrolidine-2-carboxylate.

This was prepared from 87a on a 2.27 mmol scale following the method described for 30a. The product was isolated in 56% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

1H ΝMR δ 1.43 (3H,t,J=7Hz): 4.08 ( 1H,m): 4.35 (2H,q,J=7Hz); 4.48 (1H,m)

87c Ethyl (2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-(2-naphthyl)-pyrrolidine-2-carboxylate.

This was prepared from 87b on a 1.26 mmol scale following the method described for 48b. The product was isolated in 99% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

87d (2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-(2-naphthyl)-pyrrolidine-2-carboxylic acid.

This was prepared from 87c on a 1.25 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%. 87e Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-(2-naphthyl)-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a and 86d on a 0.31 mmol scale following the method described for 1d. The product was isolated in 95% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

87f (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-(2-naphthyl)-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 87e on a 0.30 mmol scale following the method described for 1f. The product was isolated in 48% yield (93 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 60:40:2 v/v/v).

HPLC System A t_R=16.5' >98%

Mass spec (FAB) m/e=646 [M+H]⁺

EXAMPLE 88

88a Ethyl (2S,5R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5- phenyl-pyrrolidine-2-carboxylate.

This was prepared from ethyl (2S,5R)-5-phenyl-pyrrolidine-2-carboxylate (the enantiomer of 30a) following the method described for 48b. The product was isolated in 97% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v). R_f (EtOAc:hexane 40:60 v/v) 0.27

88b (2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5- phenyl-pyrrolidine-2-carboxylic acid.

This was prepared from 88a following the method described for 1f. The product was isolated in 69% yield and was used without further purification.

R_f (EtOAc:hexane:AcOH 80:20:2 v/v/v) 0.38 88c Methyl (3R)-2-{(2S,5R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a and 88b on a 0.20 mmol scale following the method described for 1d. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:hexane 50:50 v/v).

R_f (EtOAc:hexane 50:50v/v) 0.24

88d (3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 88c on a 0.20 mmol scale following the method described for 1f. The product was isolated in 55% yield (66 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 55:45:2 v/v/v).

HPLC System A t_R=19.8' >98%

Mass spec (FAB) m/e=595 [M]⁺

EXAMPLE 89

89a Methyl (3R)-2-{(2S,5R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 88b on a 0.20 mmol scale following the method described for 1d. The product was isolated in 87% yield after flash chromatography on silica gel (eluant EtOAc:hexane 50:50 v/v).

R_f (EtOAc:hexane 50:50v/v) 0.26 89b (3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 89a on a 0.17 mmol scale following the method described for 1f. The product was isolated in 53% yield (55 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 55:45:2 v/v/v).

HPLC System A t_R=20.3' >95%

Mass spec (FAB) m/e=610 [M+H]⁺

EXAMPLE 90

90a Methyl N-phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 32a and 48a on a 0.70 mmol scale following the method described for 1d. The product was isolated in 88% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

90b N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 90a on a 0.50 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%. 90c Methyl (3R)-2-{N-phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 90b and 26a on a 0.50 mmol scale following the method described for 1d. The product was isolated in 54% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 35:65:2 v/v/v).

90d (3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 90c on a 0.27 mmol scale following the method described for 1f. The product was isolated in 72% yield (114 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 55:45:2 v/v/v).

HPLC System A t_R=19.9' >99%

Mass spec (FAB) m/e=584 [M+H]⁺

EXAMPLE 91

91a Methyl N-3-phenylpropyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 44a and 48a on a 3.52 mmol scale following the method described for 1d. The product was isolated in 55% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v). R_f (EtOAc:hexane 40:60 v/v) 0.31

91b N-3-Phenylpropyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 91a on a 0.98 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

91c Methyl (3R)-2-{N-3-phenylpropyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a and 91b on a 0.98 mmol scale following the method described for 1d. The product was isolated in 25% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 40:60 v/v) 0.17

91d (3R)-2-{N-3-Phenylpropyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 91c on a 0.25 mmol scale following the method described for 1f. The product was isolated in 43% yield (65 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 70:30: 1 v/v/v).

HPLC System A t_R=20.1' >98%

Mass spec (FAB) m/e=598 [M+H]⁺

92a Methyl N-benzyl-glycinate.

This was prepared from benzylamine on a 4.58 mmol scale following the method described for 32a. The product was isolated in 95% yield and used without further purification.

92b Methyl N-benzyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycinate.

This was prepared from 92a and 48a on a 4.37 mmol scale following the method described for 1d. The product was isolated in 65% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 40:60 v/v) 0.38 92c N-Benzyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 92b on a 1.43 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

92d Methyl (3R)-2-{N-benzyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 92c on a 1.43 mmol scale following the method described for 1d. The product was isolated in 75% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 40:60 v/v) 0.18

92e (3R)-2-{N-Benzyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 92d on a 1.07 mmol scale following the method described for 1f. The product was isolated in 59% yield (374 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 65:35:1 v/v/v).

HPLC System A t_R=19.4' >95%

Mass spec (FAB) m/e=584 [M+H]⁺

EXAMPLE 93

93a Methyl (3R)-2-{N-phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 90b on a 0.41 mmol scale following the method described for 1d. The product was isolated in 83% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v). 93b (3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 93a on a 0.34 mmol scale following the method described for 1f. The product was isolated in 54% yield (110 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 40:60:2 v/v/v).

HPLC System B t_R=15.0' >95%

Mass spec (FAB) m/e=598 [M+H]⁺

EXAMPLE 94

94a Methyl (3R)-2-{N-3-Phenylpropyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 91b on a 0.98 mmol scale following the method described for 1d. The product was isolated in 68% yield after flash chromatography on silica gel (eluant EtOAc:hexane 45:55 v/v).

R_f (EtOAc:hexane 45:55 v/v) 0.15

94b (3R)-2-{N-3-Phenylpropyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 94a on a 0.67 mmol scale following the method described for 1f. The product was isolated in 55% yield (228 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 60:40:1 v/v/v).

HPLC System A t_R=21.0' >98%

Mass spec (FAB) m/e=611 [M]⁺ EXAMPLE 95

95a Methyl 3-phenethylamino-propanoate.

This was prepared from phenylacetaldehyde and β-alanineOMe on a 2.25 mmol scale following the method described for 42a. The product was isolated in 40% yield after flash chromatography on silica gel (eluant CHCl₃:MeOH:AcOH 35:2:1 v/v/v).

95b Methyl 3-{N-phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-amino}-propanoate.

This was prepared from 40a and 95a on a 0.92 mmol scale following the method described for 1d. The product was isolated in 63% yield after flash chromatography on silica gel (eluant EtOAc:hexane 25:75 v/v). 95c 3-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-amino}-propanoic acid.

This was prepared from 95b on a 0.59 mmol scale following the method described for 1f. The product was isolated in 54% yield after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 50:50:1 v/v/v).

HPLC System A t_R=15.9' >98%

Mass spec (FAB) m/e=439 [M+H]⁺

95d Methyl (3R)-2-{3-{N-phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-amino}-propanoyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 26a and 95c on a 0.15 mmol scale following the method described for 1d. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:hexane 60:40 v/v).

R_f (EtOAc:hexane 70:30 v/v) 0.38

95e (3R)-2-{3-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-amino}-propanoyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 95d on a 0.15 mmol scale following the method described for 1f. The product was isolated in 56% yield (50 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v).

HPLC System A t_R=19.3' >95%

Mass spec (FAB) m/e=598 [M+H]⁺

EXAMPLE 96

96a Methyl(3R)-2-{N-phenethyl-N-((2R)-1-benzyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 93a and benzyl chloroformate on a 0.46 mmol scale following the method described for 81a. The product was isolated in 100% yield and used without further purification.

R_f (EtOAc:pet. ether 40:60 v/v) 0.17

96b (3R)-2-{N-Phenethyl-N-((2R)-1-benzyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 96a on a 0.46 mmol scale following the method described for 1f. The product was isolated in 67% yield (194 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 55:45:1 v/v/v).

HPLC System B t_R=14.8' >98%

Mass spec (FAB) m/e=441 [M+H-Cmt]⁺

EXAMPLE 97

97a Methyl (3R)-2-{N-phenethyl-N-((2R)-1-neopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 93a on a 0.46 mmol scale following the method described for 81a. The product was isolated in 100% yield and used without further purification.

R_f (EtOAc:pet. ether 40:60 v/v) 0.21

97b (3R)-2-{N-Phenethyl-N-((2R)-1-neopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 97a on a 0.46 mmol scale following the method described for 1f. The product was isolated in 35% yield ( 101 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 50:50: 1 v/v/v). HPLC System B t_R=16.2' >90%

Mass spec (FAB) m/e=612 [M+H]⁺

EXAMPLE 98

98a Methyl (3R)-2-{N-phenethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 93a on a 0.46 mmol scale following the method described for 82a. The product was isolated in 100% yield and used without further purification.

98b (3R)-2-{N-Phenethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 98a on a 0.46 mmol scale following the method described for 1f. The product was isolated in 25% yield (74 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 50:50:1 v/v/v).

HPLC System B t_R= 17.6' >90%

Mass spec (FAB) m/e=624 [M+H]⁺

EXAMPLE 99

99a 3-Chlorophenylacetaldehyde.

This was prepared from 3-chlorophenethyl alcohol on a 9.58 mmol scale using the standard Swern oxidation conditions (A.J. Mancuso et al, J.Org.Chem., 43, 2480, 1978). The product was used without purification assuming a yield of 100%.

99b Methyl N-3-chlorophenethyl-glycinate.

This was prepared from 99a on a 9.58 mmol scale following the method described for 42a. The product was isolated in 5.5% yield after flash chromatography on silica gel (eluant EtOAc:hexane 80:20 v/v). 99c Methyl N-3-chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 99b and 48a on a 0.50 mmol scale following the method described for 1d. The product was isolated in 47% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

R_f (EtOAc:hexane 40:60 v/v) 0.29

99d N-3-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 99c on a 0.24 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

99e Methyl (3R)-2-{N-3-chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 99d on a 0.12 mmol scale following the method described for 1d. The product was isolated in 23% yield after flash chromatography on silica gel (eluant EtOAc:hexane 45:55 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.25

99f (3R)-2-{N-3-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 99e on a 0.028 mmol scale following the method described for 1f. The product was isolated in 71% yield (12 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 65:35:2 v/v/v).

HPLC System A t_R=22.0' >80%

Mass spec (FAB) m/e=632 [M+H]⁺

EXAMPLE 100

100a Methyl N-(2-oxo-2-phenylethyl)-glycinate.

This was prepared from 2'-aminoacetophenone hydrochloride on a 11.6 mmol scale following the method described for 32a. The product was isolated in 83% yield after flash chromatography on silica gel (eluant EtOAc:pet.ether 90:10).

1H NMR δ 3.56 (2H,s); 3.70 (3H,s); 4.20 (2H,s); 7.4-7.6 (3H,m); 7.9-8.0 (2H,m)

100b Methyl N-(2-oxo-2-phenylethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycinate.

This was prepared from 100a and 48a on a 0.97 mmol scale following the method described for 1d. The product was isolated in 62% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v).

R_f (EtOAc:pet. ether 35:65 v/v) 0.31

1H NMR δ 1.56 (9H,2s); 3.74 (3H,2s) 100c N-(2-Oxo-2-phenylethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 100b on a 0.61 mmol scale following the method described for 1f. The product was isolated in 84% yield and used without further purification.

100d Methyl (3R)-2-{N-(2-oxo-2-phenylethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 100c on a 0.52 mmol scale following the method described for 1d. The product was isolated in 49% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 40:60:1 v/v/v).

1H NMR δ 1.56 (9H,3s); 3.55 (3H,2s)

100e (3R)-2-{N-(2-Oxo-2-phenylethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 100d on a 0.26 mmol scale following the method described for 1f. The product was isolated in 71% yield (113 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 70:30:1 v/v/v).

HPLC System B t_R=13.4' >98%

Mass spec (FAB) m/e=612 [M+H]⁺

101a Methyl N-(2-(3-Indolyl)ethyl)-glycinate.

This was prepared from tryptamine hydrochloride on a 5.0 mmol scale following the method described for 32a. The product was used without purification, assuming a yield of 100%.

101b Methyl N-(2-(3-Indolyl)ethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycinate.

This was prepared from 101a and 48a on a 1.0 mmol scale following the method described for 1d. The product was isolated in 44% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 50:50:2 v/v/v). 101c N-(2-(3-Indolyl)ethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 101b on a 0.44 mmol scale following the method described for 1f. The product was isolated in 40% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether: AcOH 50:50:2 v/v/v).

HPLC System A t_R=10.5' >99%

Mass spec (FAB) m/e=464 [M+H]⁺

101d Methyl (3R)-2-{N-(2-(3-indolyl)ethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 101d on a 0.08 mmol scale following the method described for 1d. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:hexane 55:45 v/v).

R_f (EtOAc:hexane 55:45 v/v) 0.30

101e (3R)-2-{N-(2-(3-Indolyl)ethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 101d on a 0.08 mmol scale following the method described for 1f. The product was isolated in 56% yield (28 mg) after flash chromatography on silica gel (eluant EtOAc:hexancAcOH 70:30:2 v/v/v).

HPLC System A t_R=18.2' >95%

Mass spec (FAB) m/e=659 [M+Na]⁺

EXAMPLE 102

102a Methyl (3R)-2-{N-phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3- carboxylate.

This was prepared from 90b and 84b on a 0.46 mmol scale following the method described for 1d. The product was isolated in 69% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

102b (3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-carboxylic acid.

This was prepared from 102a on a 0.32 mmol scale following the method described for 1f. The product was isolated in 68% yield (138 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 60:40:2 v/v/v).

HPLC System A t_R=22.1' >98%

Mass spec (FAB) m/e=634 [M+H]⁺

EXAMPLE 103

103a Methyl (3R)-2-{N-phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-acetate.

This was prepared from 90b and 85c on a 0.48 mmol scale following the method described for 1d. The product was isolated in 85% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

103b (3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3-acetic acid.

This was prepared from 103a on a 0.41 mmol scale following the method described for 1f. The product was isolated in 74% yield (196 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 55:45:2 v/v/v). HPLC System A t_R=22.4' >98%

Mass spec (FAB) m/e=648 [M+H]⁺

EXAMPLE 104

104a Methyl (2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carboxylate.

To a stirred solution of 48a (1.05 g, 4 mmol) and 4-dimethylaminopyridine (50 mg, 0.4 mmol) in CH₂Cl₂ (20 mL) and MeOH (10 mL) was added WSCD.HCl (1.54 g, 8 mmol). The mixture was stirred at room temperature for 3 hrs. and then concentrated in vacuo. The residue was partitioned between EtOAc and H₂O, and the organic phase was washed with 10% KHSO₄, satd. KHCO₃ and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo to give the title compound (0.89 g, 80%) as an oil which was used without further purification. 104b Methyl N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-methyl)-glycinate.

This was prepared from 104a and GlyOMe on a 3.2 mmol scale following the method described for 31a. The product was isolated in 337c yield after flash chromatography on silica gel (eluant EtOAc:hexane 20:80 then 40:60 v/v).

R_f (EtOAc:hexane 25:75 v/v) 0.08

104c Methyl N-pivaloyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-methyl)-glycinate.

To an ice-cold stirred solution of 104b (70 mg, 0.22 mmol) and diisopropylethylamine (0.15 mL, 0.9 mmol) in CH₂Cl₂ (10 mL) was added pivaloyl chloride (80 mL, 0.66 mmol). The mixture was stirred at 0°C for 2 hrs. and then concentrated in vacuo. The residue was partitioned between EtOAc and H₂O, and the organic phase was washed with 10% KHSO₄, satd. KHCO₃ and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v) to give the title compound (67 mg, 75%).

R_f (EtOAc:hexane 50:50 v/v) 0.34

104d N-Pivaloyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-methyl)-glycine.

This was prepared from 104c on a 0.17 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

104e Methyl (3R)-2-{N-pivaloyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-methyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 104d and 1c on a 0.17 mmol scale following the method described for 1d. The product was isolated in 65% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.25

104f (3R)-2-{N-Pivaloyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-methyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 104e on a 0.11 mmol scale following the method described for 1f. The product was isolated in 50% yield (31 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 60:40:1 v/v/v).

HPLC System A t_R=18.0' >98%

Mass spec (FAB) m/e=564 [M+H]⁺ EXAMPLE 105

105a 3-(Benzyloxycarbonylamino)-naphthalene-2-carboxylic acid.

To a stirred suspension of 3-aminonaphthalene-2-carboxylic acid (4.22 g, 22.5 mmol) in H₂O (37.5 mL) was added 5N NaOH (4.95 mL. 24.8 mmol). The resulting solution was cooled in ice then treated alternately with benzyl chloroformate (4 mL, 28.3 mmol) and 2N ΝaOH (14 mL, 28 mmol) in five equal portions. Acetonitrile (50 mL) was added and the mixture was stirred at room temperature overnight then concentrated in vacuo. The residue was partitioned between EtOAc and 0.3M KHSO₄, and the organic phase was washed with 0.3M KHSO₄, H₂O and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by recrystallisation from acetonitrile to give the title compound (3.09 g, 42%).

105b Methyl (3R)-2-{3-(benzyloxycarbonylamino)-naphthalene-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared from 105a and lc on a 0.78 mmol scale following the method described for 1d. The product was isolated in 76% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v). 105c Methyl (3R)-2-{3-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonylamino)-naphthalene-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 105b and 1c on a 0.59 mmol scale following the method described for 1d. The starting material 105b was deprotected prior to coupling by catalytic hydrogenolysis over 5% Pd-on-C in 1% v/v AcOH/MeOH as solvent for 90 min. The product was isolated in 66% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

105d (3R)-2-{3-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)- naphthalene-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 105c on a 0.39 mmol scale following the method described for 1f. The product was isolated in 52% yield (123 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 50:50:2 v/v/v).

HPLC System B t_R=14.2' >95%

Mass spec (FAB) m/e=606 [M+H]⁺

EXAMPLE 106

106a Methyl (3R)-2-{3-(benzyloxycarbonylamino)-naphthalene-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 105a and 26a on a 1.22 mmol scale following the method described for 1d. The product was isolated in 64% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

106b Methyl (3R)-2-{3-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)-naphthalene-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 106a and 48a on a 0.78 mmol scale following the method described for 105c The product was isolated in 47% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

106c (3R)-2-{3-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)-naphthalene-2-carbonyl}-1,2,3,4-tetrahydioisoquinoline-3-carboxylic acid.

This was prepared from 106b on a 0.38 mmol scale following the method described for 1f. The product was isolated in 70% yield (159 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 70:30:1 v/v/v).

HPLC System B t_R=14.1'>95%

Mass spec (FAB) m/e=592 [M+H]⁺

EXAMPLE 107

107a Methyl (3R)-2-{(2R)-1-benzyloxycarbonyl-4-phenyl-2,5-dihydropyrrole-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c on a 1.3 mmol scale following the method described for 1d using (2R)-1-benzyloxycarbonyl-4-phenyl-2,5-dihydropyrrole-2-carboxylic acid (J. Krapcho et al, J.Med.Chem., 31, 1148, 1988) instead of N-BOC-O-benzyl-threonine. The product was isolated in 48% yield after flash chromatography on silica gel (eluant EtOAc:hexane 55:45 v/v)

107b Methyl (3R)-2-{(2R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4-phenyl-2,5-dihydropyrrole-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-acetate.

This was prepared from 107a and 48a on a 0.63 mmol scale following the method described for 1d. The starting material 107a was deprotected prior to coupling by treatment with 45% HBr in AcOH for 90 min. The product was isolated in 27% yield after flash chromatography on silica gel (eluant EtOAc:hexane 30:70 v/v). 107c (3R)-2-{(2R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-4- phenyl-2-5-dihydropyrrole-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 107b on a 0.17 mmol scale following the method described for 1f. The product was isolated in 40% yield (41 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 40:60:2 v/v/v).

HPLC System B t_R=14.4' >95%

Mass spec (FAB) m/e=508 [M+H]⁺

EXAMPLE 108

108a Methyl (2R,5S)-1-tert-butyloxycarbonyl-5-phenyl-pyrrolidine-2-carboxylate.

This was prepared from 67b on a 1.0 mmol scale following the method described for 104a. The product was used without purification, assuming a yield of 100%.

108b Methyl (3R)-2-{(2R,5S)-1-tert-butyloxycarbonyl-5-phenyl-pyrrolidine-2- methyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 108a and 26a on a 1.0 mmol scale following the method described for 31a. The intermediate aldehyde was isolated in 58% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 20:80 v/v). The product was isolated in 50% yield (based on a 0.58 mmol scale for the second part of the preparation) alter flash chromatography on silica gel (eluant EtOAc:pet. ether 20:80 v/v).

108c Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-methyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 108b and 48a on a 0.29 mmol scale following the method described for 1d. The starting material 107a was deprotected prior to coupling by treatment with 4N HCl in dioxan for 90 min. The product was isolated in 93% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v).

108d (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-methy]}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 108c on a 0.27 mmol scale following the method described for 1f. The product was isolated in 71% yield (111 mg) after flash chromatography on silica gel (eluant CHCl₃:MeOH:AcOH 100:3:2 v/v/v).

HPLC System A t_R=18.2' >99%

Mass spec (FAB) m/e=582 [M+H]⁺

EXAMPLE 109

109a (2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-acetic acid.

This was prepared from 50a on a 0.25 mmol scale following the method described for 1f. The product was used without further purification, assuming a yield of 100%.

109b Methyl (3R)-2-{(2S)-2-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-acetylamino)-4-phenylbutanoyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 13a and 109a on a 0.25 mmol scale following the method described for 32d. The product was isolated in 90% yield after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 25:75:2 v/v/v).

109c (3R)-2-{(2S)-2-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-acetylamino)-4-phenylbutanoyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 109b on a 0.22 mmol scale following the method described for 1f. The product was isolated in 80% yield (109 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 40:60:2 v/v/v).

HPLC System B t_R=15.2' >98%

Mass spec (FAB) m/e=612 [M+H]⁺ EXAMPLE 110

110a 1-{tert-Butyloxycarbonyl-leucyl}-2,3-dihydroindole.

To an ice-cold stirred solution of BOC-Leu (4.62 g, 20 mmol) and pentafluorophenol (4.42 g, 24 mmol) in CH₂Cl₂ (100 mL) was added WSCD.HCl (7.65 g, 40 mmol). The mixture was stirred at 0°C for 1 hr., then indoline (4.0 mL, 36 mmol) and 4-dimethylaminopyridine were added and the mixture was stirred at room temperature for 4 days then concentrated in vacuo. The residue was partitioned between EtOAc and 0.3M KHSO₄, and the organic phase was washed with 0.3M KHSO₄, H₂O and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:pet ether 10:90 v/v) to give the title product (3.41 g, 51%).

110b 1-{tert-Butyloxycarbonyl-tryptophanyl-leucyl}-2,3-dihydroindole.

This was prepared from 110a on a 1.08 mmol scale following the method described for 32d using BOC-Trp instead of indoleacetic acid. The product was isolated in 79% yield (445 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether 30:70 then 50:50 v/v).

HPLC System A t_R=17.5' >95%

AAA Peptide content=99%

Mass spec (FAB) m/e=519 [M+H]⁺ EXAMPLE 111

111a 1-{(2S)-2-(tert-Butyloxycarbonylamino)-hexanoyl}-2,3-dihydroindole.

This was prepared from BOC-aminohexanoic acid on a 8.4 mmol scale following the method described for 110a. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

111b 1-{(2S)-2-(tert-Butyloxycarbonyl-tryptophanylamino)-hexanoyl}-2,3-dihydroindole.

This was prepared from 111a on a 0.88 mmol scale following the method described for 32d using BOC-Trp instead of indoleacetic acid. The product was isolated in 66% yield (300 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 40:60:2 v/v/v).

HPLC System A t_R=14.8' >99%

AAA Peptide content=93%

Mass spec (FAB) m/e=519 [M+H]⁺

EXAMPLE 112

112 1-{(2S)-2-(3-Indole-3-propanoylamino)-hexanoyl}-2,3-dihydroindole.

This was prepared from 111a on a 0.63 mmol scale following the method described for 32d using 3-indole-3-propanoic acid instead of indoleacetic acid. The product was isolated in 96% yield (244 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 30:70:2 then 40:60:2 v/v/v).

HPLC System A t_R=11.6' >95%

AAA Peptide content=88%

Mass spec (FAB) m/e=404 [M+H]⁺

EXAMPLE 113

113a 1-{tert-Butyloxycarbonyl-phenylalanyl}-2,3-dihydroindole.

This was prepared from BOC-Phe on a 0.75 mmol scale following the method described for 110a. The product was isolated in 60% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 20:80 v/v).

113b 1-{tert-Butyloxycarbonyl-tryptophanyl-phenylalanyl}-2,3-dihydroindole.

This was prepared from 113a on a 0.45 mmol scale following the method described for 32d using BOC-Trp instead of indoleacetic acid. The product was isolated in 61% yield ( 152 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether 50:50 v/v). HPLC System A t_R=18.9' >95%

AAA Peptide content=90%

Mass spec ( FAB ) m/e=553 [M+H]⁺

114a 1-{(2S)-2-(tert-Butyloxycarbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole.

This was prepared from BOC-homophenylalanine on a 2.25 mmol scale following the method described for 110a. The product was isolated in 64% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 18:82 v/v).

114b 1-{(2S)-2-(tert-Butyloxycarbonyl-tryptophanylamino)-4-phenylbutanoyl}-2,3- dihydroindole.

This was prepared from 114a on a 0.48 mmol scale following the method described for 32d using BOC-Trp instead of indoleacetic acid. The product was isolated in 73% yield (197 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether 50:50 v/v). HPLC System A t_R=20.2' >98%

AAA Peptide content=100%

Mass spec (FAB) m/e=567 [M+H]⁺

115a 1-{tert-Butyloxycarbonyl-(β-O-benzyl)-D-aspartyl}-2,3-dihydroindole.

This was prepared from BOC-D-Asp(OBzl)OH on a 4.0 mmol scale following the method described for 110a. The product was isolated in 72% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 20:80 v/v).

115b 1-{tert-Butyloxycarbonyl-tryptophanyl-(β-O-benzyl)-D-aspartyl}-2,3-dihydroindole.

This was prepared from 115a on a 1.18 mmol scale following the method described for 32d using BOC-Trp instead of indoleacetic acid. The product was isolated in 45% yield (325 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether 40:60 v/v). HPLC System A t_R=17.2' >99%

AAA Peptide content=91 %

Mass spec (FAB) m/e=611 [M+H]⁺

EXAMPLE 116

116a 1-{tert-Butyloxycarbonyl-(β-O-benzyl)-aspartyl}-2,3-dihydroindole.

This was prepared from BOC-Asp(OBzl)OH on a 4.0 mmol scale following the method described for 110a. The product was isolated in 57% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 20:80 v/v).

116b 1-{tert-Butyloxycarbonyl-tryptophanyl-(β-O-benzyl)-aspartyl}-2,3- dihydroindole.

This was prepared from 116a on a 1.18 mmol scale following the method described for 32d using BOC-Trp instead of indoleacetic acid. The product was isolated in 55% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 40:60 v/v).

116c 1-{tert-Butyloxycarbonyl-tryptophanyl-aspartyl}-2,3-dihydroindole.

This was prepared from 116b on a 0.32 mmol scale following the method described for 1f. The product was isolated in 73% yield (122 mg) without purification.

HPLC System A t_R=8.5' >99%

AAA Peptide content=91%

Mass spec (FAB) m/e=521 [M+H]⁺

EXAMPLE 117

117a 1-{tert-Butyloxycarbonyl-(γ-O-benzyl)-glutamyl}-2,3-dihydroindole.

This was prepared from BOC-Glu(OBzl)OH on a 4.0 mmol scale following the method described for 110a. The product was isolated in 45% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 20:80 v/v). 117b 1-{tert-Butyloxycarbonyl-tryptophanyl-(γ-O-benzyl)-glutamyl}-2,3- dihydroindole.

This was prepared from 117a on a 1.18 mmol scale following the method described for 32d using BOC-Trp instead of indoleacetic acid. The product was isolated in 59% yield (437 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v). HPLC System A t_R=17.9' >99%

AAA Peptide content=94%

Mass spec (FAB) m/e=625 [M+H]⁺

118 1-{tert-Butyloxycarbonyl-tryptophanyl-glutamyl}-2,3-dihydroindole.

This was prepared from 117b on a 0.35 mmol scale following the method described for 1f. The product was isolated in 70% yield (132 mg) after flash chromatography on silica gel (eluant EtOAc then EtOAc:AcOH 100:1 v/v).

HPLC System A t_R=9.1' >98%

AAA Peptide content=87%

Mass spec (FλB) m/e=535 [M+H]⁺ EXAMPLE 119

119a 2-{tert-Butyloxycarbonyl-D-phenylalanyl}-1,2,3,4-tetrahydroisoquinoline.

This was prepared from BOC-D-Phe and tetrahydroisoquinoline on a 0.75 mmol scale following the method described for 110a. The product was isolated in 77% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 25:75 v/v).

119b 2-{tert-Butyloxycarbonyl-tryptophanyl-D-phenylalanyl}-1,2,3,4- tetrahydroisoquinoline.

This was prepared from 119a on a 0.58 mmol scale following the method described for 32d using BOC-Trp instead of indoleacetic acid. The product was isolated in 72% yield (237 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether 50:50 v/v). HPLC System A t_R=18.3' >98%

AAA Peptide content=84%

Mass spec (FAB) m/e=567 [M+H]⁺

120a 2-{(2R)-2-(tert-Butyloxycarbonylamino)-4-phenylbutanoyl}-1,2,3,4- tetrahydroisoquinoline.

This was prepared from BOC-D-homophenylalanine and tetrahydroisoquinoline on a 0.72 mmol scale following the method described for 110a. The product was isolated in 85% yield and used without further purification.

120b 2-{(2R)-2-(tert-Butyloxycarbonyl-tryptophanylamino)-4-phenylbutanoyl}- 1,2,3,4-tetrahydroisoquinoline.

This was prepared from 120a on a 0.67 mmol scale following the method described for 32d using BOC-Trp instead of indoleacetic acid. The product was isolated in 69% yield (270 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 50:50:2 v/v/v).

HPLC System A t_R=16.3' >99%

AAA Peptide content=97%

121a Methyl (2R)-1-{tert-butyloxycarbonyl-leucyl}-2,3-dihydroindole-2-acetate.

This was prepared from BOC-Leu and 50b on a 0.6 mmol scale following the method described for 1d. The product was isolated in 38% yield after flash chromatography on silica gel (eluant EtOAc:hexane 14:86 v/v).

121b Methyl (2R)-1-{tert-butyloxycarbonyl-tryptophanyl-leucyl}-2,3-dihydroindole-2-acetate.

This was prepared from 121a on a 0.67 mmol scale following the method described for 32d using BOC-Trp instead of indoleacetic acid. The product was isolated in 94% yield after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 35:65:2 v/v/v).

121c (2R)-1-{tert-Butyloxycarbonyl-tryptophanyl-leucyl}-2,3-dihydroindole-2-acetic acid.

This was prepared from 121b on a 0.16 mmol scale following the method described for 1f. The product was isolated in 85% yield and used without further purification.

121d Ethyl (2R)-1-{tert-butyloxycarbonyl-tryptophanyl-leucyl}-2,3-dihydroindole-2- acetate.

This was prepared from 121c on a 0.12 mmol scale following the method described for 104a using EtOH instead of MeOH. The product was isolated in 82% yield (60 mg) after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

HPLC System B t_R=17.3' >98%

AAA Peptide content=86%

Mass spec (FAB) m/e=605 [M+H]⁺

EXAMPLE 122

122a Ethyl (2RS)-2,3-dihydroindole-2-carboxylate hydrochloride.

This was prepared from (RS)-indoline-2-carboxylic acid on a 5.0 mmol scale following the method described for 26a using EtOH instead of MeOH. The product was isolated in 96% yield and used without further purification.

122b Ethyl (2RS)-1-{(2S)-2-(tert-butyloxycarbonylamino)-hexanoyl}-2,3-dihydroindole-2-carboxylate.

This was prepared from 122a and BOC-aminohexanoic acid on a 6.0 mmol scale following the method described for 1d. The product was isolated in 62% yield after flash chromatography on silica gel (eluant EtOAc:hexane 25:75 v/v).

122c Ethyl (2S)-1-{(2S)-2-(tert-butyloxycarbonyl-tryptophanylamino)-hexanoyl}-2,3-dihydroindole-2-carboxylate.

This was prepared from 122b on a 1.88 mmol scale following the method described for 32d using BOC-Trp instead of indoleacetic acid. The product was isolated in 20% yield (220 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 28:72:2 v/v/v). The (2R)-indoline epimer was separated at this stage (43% yield). HPLC System B t_R=16.6' >98%

AAA Peptide content=90%

Mass spec (FAB) m/e=591 [M+H]⁺

EXAMPLE 123

123a Methyl (2R)-1-{tert-butyloxycarbonyl-phenylalanyl}-2,3-dihydroindole-2- acetate.

This was prepared from BOC-Phe and 50b on a 0.52 mmol scale following the method described for 1d. The product was isolated in 45% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 15:85 v/v).

123b Methyl (2R)-1-{indole-2-carbonyl-phenylalanyl}-2,3-dihydroindole-2-acetate.

The compound 123a was deprotected on a 0.23 mmol scale following the method described for 1c to give methyl (2R)-1-phenylalanyl-2,3-dihydroindole-2-acetate hydrochloride which was then treated with indole-2-carbonyl chloride in the following manner.

To a stirred suspension of indole-2-carboxylic acid dicyclohexylamine salt (103 mg, 0.30 mmol) in CH₂Cl₂ (15 mL) was added pyridine (32.3 μL, 0.4 mmol) and then SOCl₂ ( 180 μL of 2M solution in CH₂Cl₂, 0.36 mmol). The mixture was stirred at room temperature for 1 min., then the methyl (2R)-1-phenylalanyl-2,3-dihydroindole-2-acetate hydrochloride and 4-dimethylaminopyridine ((25 mg, 0.21 mmol) were added. The mixture was stirred at room temperature for 2 hr. and then concentrated in vacuo. The residue was partitioned between EtOAc and H₂O, and the organic phase was washed with 10% KHSO₄, satd. KHCO₃ and brine, filtered (Whatman^R IPS phase separator), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc:pet ether 20:80 v/v) to give the title compound (32 mg, 28%).

123c (2R)-1-{Indole-2-carbonyl-phenylalanyl}-2,3-dihydroindole-2-acetic acid.

This was prepared from 123b on a 0.066 mmol scale following the method described for 1f. The product was isolated in 90% yield (28 mg) without purification.

HPLC System B t_R=9.9' >90%

Mass spec (FAB) m/e=468 [M+H]⁺

EXAMPLE 124

124a Methyl (2R)-1-{(2S)-2-(tert-butyloxycarbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetate.

This was prepared from BOC-homophenylalanine and racemic 50b on a 5.0 mmol scale following the method described for 1d. The product was isolated in 14% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 18:82 v/v) together with the (2R)-indoline epimer (isolated in 22% yield).

124b Methyl (2R)-1-{(2S)-2-(indole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetate.

This was prepared from 124a on a 0.34 mmol scale following the method described for 123b. The semi-purified product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 35:65:2 v/v/v).

124c (2R)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetic acid.

This was prepared from 124b on a 0.34 mmol scale following the method described for 1f. The product was isolated in 63% yield (196 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 45:55:2 v/v/v).

HPLC System A t_R=14.8' >95%

Mass spec (FAB) m/e=482 [M+H]⁺

EXAMPLE 125

125a (2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-acetic acid.

This was prepared from 50a on a 3.4 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

125b Methyl 3-{(2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-yl}-propanoate.

This was prepared from 125a on a 3.4 mmol scale following the method described for 1b. The product was isolated in 44% yield after flash chromatography on silica gel (eluant EtOAc:hexane 12:88 v/v).

125c Methyl 3-{(2R)-2,3-dihydroindole-2-yl}-propanoate hydrochloride.

This was prepared from 125b on a 1.0 mmol scale following the method described for 1c. The product was used without purification, assuming a yield of 100%. 125d Methyl 3-{(2R)-1-{(2S)-2-(tert-butyloxycarbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-yl}-propanoate.

This was prepared from 125c and BOC-homophenylalanine on a 1.0 mmol scale following the method described for 1d. The product was isolated in 64% yield after flash chromatography on silica gel (eluant EtOAc:hexane 20:80 v/v).

125e Methyl 3-{(2R)-1-{(2S)-2-(indole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-yl}-propanoate.

This was prepared from 125d on a 0.43 mmol scale following the method described for 123b. The product was isolated in 41% yield after flash chromatography on silica gel (eluant EtOAc:hexane 30:70 v/v).

125f 3-{(2R)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-yl}-propanoic acid.

This was prepared from 125e on a 0.18 mmol scale following the method described for 1f. The product was isolated in 56% yield (43 mg) after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 40:60:2 v/v/v).

HPLC System B t_R=11.2' >80%

Mass spec (FAB) m/e=518 [M+H]⁺

EXAMPLE 126

126a Methyl (2R)-1-{(2S)-2-(5-fluoroindole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetate.

This was prepared from 124a and 5-fluoroindole-2-carboxylic acid on a 0.20 mmol scale following the method described for 123b. The product was isolated in 54% yield after flash chromatography oh silica gel (eluant EtOAc:pet ether 35:65 v/v). 126b (2R)-1-{(2S)-2-(5-Fluoroindole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetic acid.

This was prepared from 126a on a 0.11 mmol scale following the method described for 1f. The product was isolated in 73% yield (39 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 45:55:2 v/v/v).

HPLC System A t_R=14.2' >95%

Mass spec (FAB) m/e=500 [M+H]⁺

EXAMPLE 127

127a Methyl (2R)-1-{(2S)-2-(5-chloroindole-2-carbonylamino)-4-phenylbutanoyl}-2-3-dihydroindole-2-acetic acid.

This was prepared from 124a and 5-chloroindole-2-carboxylic acid on a 0.20 mmol scale following the method described for 123b. The product was isolated in 52% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 35:65 v/v).

127b (2R)-1-{(2S)-2-(5-Chloroindole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetic acid.

This was prepared from 127a on a 0.10 mmol scale following the method described for 1f. The product was isolated in 78% yield (42 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether: AcOH 45:55:2 v/v/v).

HPLC System A t_R=16.0' >95%

Mass spec (FAB) m/e=511 [M+H]⁺ EXAMPLE 128

128a Methyl (3R)-2-{(2S)-2-(indole-2-carbonylamino)-4-phenylbutanoyl}-1,2,3,4- tetrahydroisoquinoline-3-acetate.

This was prepared from 13a on a 0.12 mmol scale following the method described for 123b. The product was isolated in 68% yield after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 35:65:2 v/v/v).

128b (3R)-2-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 128a on a 0.09 mmol scale following the method described for 1f. The product was isolated in 66% yield (31 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether: AcOH 40:60:2 v/v/v).

HPLC System A t_R=14.8' >99%

Mass spec (FAB) m/e=496 [M+H]⁺

EXAMPLE 129

129a (2S)-1-{(2S)-2-(tert-Butyloxycarbonylamino)-4-phenvlbutanoyl}-2,3- dihydroindole-2-acetic acid.

This was prepared from the (2S)-indoline epimer of 124a on a 0.68 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%. 129b Benzyl N-{(2S)-1-{(2S)-2-(tert-butyloxycarbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetyl}-glycinate.

This was prepared from 129a and GlyOBzl on a 0.68 mmol scale following the method described for 1d. The product was isolated in 53% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 35:65 v/v).

129c Benzyl N-{(2S)-1-{(2S)-2-(indole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetyl}-glycinate.

This was prepared from 129b and on a 0.36 mmol scale following the method described for 123b. The product was isolated in 45% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 40:60 v/v).

129d N-{(2S)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetyl}-glycine.

This was prepared from 129c on a 0.16 mmol scale following the method described for 1f. The product was isolated in 30% yield (26 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 90:10:2 v/v/v).

HPLC System A t_R=13.6' >95%

Mass spec (FAB) m/e=539 [M+H]⁺

EXAMPLE 130

130a Methyl 3-{(2RS)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino}- propanoate.

This was prepared from racemic 48a and β-alanineOMe on a 1.8 mmol scale following the method described for 1d. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 50:50 v/v). 130b Methyl 3-{(2RS)-2,3-dihydroindole-2-carbonylamino}-propanoic acid hydrochloride.

This was prepared from 130a on a 1.2 mmol scale following the method described for 1c. The product was used without purification, assuming a yield of 100%.

130c Methyl 3-{(2RS)-1-{(2S)-2-(tert-butyloxycarbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-carbonylamino}-propanoic acid.

This was prepared from 130b and BOC-homophenylalanine on a 1.2 mmol scale following the method described for 1d. The product was isolated in 41% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 45:55 v/v).

130d Methyl 3-{(2S)-1-{(2S)-2-(indole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-carbonylamino}-propanoic acid.

This was prepared from 130c on a 0.49 mmol scale following the method described for 123b. The product was isolated in 28% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 55:45 v/v).

130e 3-{(2S)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-carbonylamino}-propanoic acid.

This was prepared from 130d on a 0.09 mmol scale following the method described for 1f. The product was isolated in 97% yield (47 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 70:30:2 v/v/v).

HPLC System A t_R=12.6' >95%

Mass spec (FAB) m/e=539 [M+H]⁺

EXAMPLE 131

131a Methyl N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole- 2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carbonyl}-prolinate.

This was prepared from 69 and ProOMe on a 0.30 mmol scale following the method described for 1d. The product was isolated in 18% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 then 70:30 v/v).

R_f (EtOAc:hexane 70:30 v/v) 0.22

131b N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carbonyl}-proline.

This was prepared from 131a on a 0.06 mmol scale following the method described for 1f. The product was isolated in 49% yield (19 mg) after flash chromatography on silica gel (eluant EtOAc: AcOH 100:2 v/v).

HPLC System A t_R=19.7' >98%

AAA Peptide content=73%

Mass spec (FAB) m/e=693 [M+H]⁺

132a Methyl N-{(3R)-2-tert-butyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-prolinate.

This was prepared from 1a and ProOMe on a 5.4 mmol scale following the method described for 1d. The product was isolated in 68% yield after flash chromatography on silica gel (eluant EtOAc:hexane 70:30 v/v).

132b Methyl N-{(3R)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-prolinate hydrochloride.

This was prepared from 132a on a 0.13 mmol scale following the method described for 1c The product was used without purification assuming a yield of 100%.

132c Methyl N-{(3R)-2-{(2S,5R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole- 2-carbonyl)-5-phenyl-pyrτoiidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-prolinate.

This was prepared from 132b and 88b on a 0.13 mmol scale following the method described for 1d. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:hexane 65:35 v/v).

R_f (EtOAc:hexane 80:20 v/v) 0.38

132d N-{(3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-proline.

This was prepared from 132c on a 0.13 mmol scale following the method described for 1f. The product was isolated in 24% yield (21 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 90: 10:2 v/v/v).

HPLC System A t_R=19.9' >95%

AAA Peptide content=81%

Mass spec (FAB) m/e=693 [M+H]⁺ EXAMPLE 133

133a Methyl N-{(3R)-2-tert-butyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3- carbonyl}-D-prolinate.

This was prepared from 1a and D-ProOMe on a 0.56 mmol scale following the method described for 1d. The product was isolated in 39% yield after flash chromatography on silica gel (eluant EtOAc:hexane 65:35 v/v).

R_f (EtOAc:hexane 70:30 v/v) 0.30

133b Methyl N-{(3R)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-D-prolinate hydrochloride.

This was prepared from 133a on a 0.13 mmol scale following the method described for 1c. The product was used without purification assuming a yield of 100%. 133c Methyl N-{(3R)-2-{(2S,5R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrroIidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-D-prolinate.

This was prepared from 133b and 88b on a 0.13 mmol scale following the method described for 1d. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:hexane 65:35 v/v).

R_f (EtOAc:hexane 80:20 v/v) 0.30

133d N-{(3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-D-proline.

This was prepared from 133c on a 0.13 mmol scale following the method described for 1f. The product was isolated in 57% yield (51 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 95:5:2 v/v/v).

HPLC System A t_R=20.2' >95%

AAA Peptide content=91%

Mass spec (FAB) m/e=693 [M+H]⁺

EXAMPLE 134

134a Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a and 86d on a 0.5 mmol scale following the method described for 1d. The product was isolated in 96% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

134b (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dιhydroindole-2-carbonyl)-5-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 134a on a 0.48 mmol scale following the method described for 1f. The product was isolated in 51% yield (151 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether: AcOH 70:30:2 v/v/v).

HPLC System A t_R=14.4' >99%

Mass spec (FAB) m/e=510 [M+H-BOC]⁺

EXAMPLE 135

135a 2-Chlorophenylacetaldehyde.

This was prepared from 2-chiorophenethyl alcohol on a 9.58 mmol scale following the method described for 99a. The product was used without purification assuming a yield of 100%.

135b Methyl N-2-chlorophenethyl-glycinate.

This was prepared from 135a on a 9.58 mmol scale following the method described for 42a. The product was isolated in 8% yield after flash chromatography on silica gel (eluant EtOAc:hexane 80:20 v/v).

R_f (EtOAc:hexane 80:20 v/v) 0.12

1H NMR δ 2.84-2.88 (4H,m): 3.40 (2H,s); 3.66 (3H,s); 7.06-7.29 (4H,m) 135c Methyl N-2-chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 135b and 48a on a 0.68 mmol scale following the method described for 1d. The product was isolated in 76% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

R_f (EtOAc:hexane 40:60 v/v) 0.26

135d N-2-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 135c on a 0.52 mmol scale following the method described for lf. The product was isolated in 78% yield and used without further purification.

135e Methyl (3R)-2-{N-2-chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 135d and 1c on a 0.20 mmol scale following the method described for 1d. The product was isolated in 58% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.25

135f (3R)-2-{N-2-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 135e on a 0.12 mmol scale following the method described for 1f. The product was isolated in 50% yield (38 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 55:45:2 v/v/v).

HPLC System A t_R=22.3' >90%

Mass spec (FAB) m/e=632 [M+H]⁺

EXAMPLE 136

136a Methyl N-4-chlorophenethyl-glycinate.

This was prepared from 2-chlorophenethylamine on a 6.43 mmol scale following the method described for 32a. The product was isolated in 94% yield and used without purification.

136b Methyl N-4-chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycinate.

This was prepared from 136a and 48a on a 1.7 mmol scale following the method described for 1d. The product was isolated in 84% yield after flash chromatography on stiica gel (eluant EtOAc:hexane 45:55 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.30 136c N-4-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 136b on a 1.48 mmol scale following the method described for 1f. The product was isolated in 75% yield and used without further purification.

136d Methyl (3R)-4-{N-2-chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 136c and 1c on a 0.56 mmol scale following the method described for 1d. The product was isolated in 70% yield after flash chromatography on silica gel (eluant EtOAc:hexane 45:55 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.26

136e (3R)-2-{N-4-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 136d on a 0.39 mmol scale following the method described for 1f. The product was isolated in 60% yield (149 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:hexane:AcOH 65:35:2 v/v/v).

HPLC System A t_R=16.3' >95%

Mass spec (FAB) m/e=628 [M+H]⁺

EXAMPLE 137

137a 2-Methoxyphenylacetaldehyde.

This was prepared from 2-methoxyphenethyl alcohol on a 13.1 mmol scale following the method described for 99a. The product was isolated in 51% yield after flash chromatography on silica gel (eluant EtOAc:hexane 4:96 then 5:95 v/v).

R_f (EtOAc:hexane 5:95 v/v) 0.17

1H NMR 53.57 (2H,d,J=2Hz); 3.75 (3H,s); 6.8-7.3 (4H,m); 9.61 (1H,t,J=2Hz)

137b Methyl N-2-methoxyphenethyl-glycinate.

This was prepared from 137a on a 6.8 mmol scale following the method described for 42a. The product was isolated in 28% yield after flash chromatography on silica gel (eluant EtOAc:hexane 80:20 v/v).

R_f (EtOAc:hexane 80:20 v/v) 0.16 137c Methyl N-2-methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 137b and 48a on a 1.9 mmol scale following the method described for 1d. The product was isolated in 98% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.33

137d N-2-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycine.

This was prepared from 137c on a 1.90 mmol scale following the method described for 1f. The product was isolated in 85% yield and used without further purification.

137e Methyl (3R)-2-{N-2-methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 137d and 1c on a 0.81 mmol scale following the method described for 1d. The product was isolated in 92% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.28

137f (3R)-2-{N-2-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 137e on a 0.75 mmol scale following the method described for 1f. The product was isolated in 52% yield (247 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 55:45:2 v/v).

HPLC System A t_R=21.1' >95%

Mass spec (FAB) m/e=628 [M+H]⁺

EXAMPLE 138

138a 3-Methoxyphenylacetaldehyde.

This was prepared from 3-methoxyphenethyl alcohol on a 13.1 mmol scale following the method described for 99a. The product was isolated in 19% yield after flash chromatography on silica gel (eluant EtOAc:hexane 10:90 v/v).

R_f (EtOAc:hexane 10:90 v/v) 0.20

1H NMR 53.58 (2H,d,J=2.5Hz); 3.73 (3H,s); 6.6-7.2 (4H,m); 9.67 (1H,t,J=2.5Hz)

138b Methyl N-3-methoxyphenethyl-glycinate.

This was prepared from 138a on a 2.6 mmol scale following the method described for 42a. The product was isolated in 42% yield after flash chromatography on silica gel (eluant EtOAc:hexane 90:10 v/v).

R_f (EtOAc:hexane 90:10 v/v) 0.16 138c Methyl N-3-methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 138b and 48a on a 1.1 mmol scale following the method described for 1d. The product was isolated in 86% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 40:60 v/v) 0.30

138d N-3-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 138c on a 0.93 mmol scale following the method described for 1f. The product was used without further purification assuming a 100% yield.

138e Methyl (3R)-2-{N-3-methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 138d and 1c on a 0.47 mmol scale following the method described for 1d. The product was isolated in 91% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.23

138f (3R)-2-{N-3-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 138e on a 0.43 mmol scale following the method described for 1f. The product was isolated in 11% yield (31 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 55:45:2 v/v/v).

HPLC System A t_R=19.6' >80%

Mass spec (FAB) m/e=628 [M+H]⁺ EXAMPLE 139

139a 4-Methoxyphenylacetaldehyde.

This was prepared from 4-methoxyphenethyl alcohol on a 13.1 mmol scale following the method described for 99a. The product was isolated in 17% yield after flash chromatography on silica gel (eluant EtOAc:hexane 10:90 v/v).

R_f (EtOAc:hexane 10:90 v/v) 0.20

1H NMR δ 3.75 (2H,d,J=2.3Hz); 3.75 (3H,s); 7.03 (2H,d,J=9Hz); 7.25 (2H,d,J=9Hz); 9.84 ( 1H,t,J=2.3Hz)

139b Methyl N-4-methoxyphenethyl-glycinate.

This was prepared from 139a on a 2.3 mmol scale following the method described for 42a. The product was isolated in 38% yield after flash chromatography on silica gel (eluant EtOAc:hexane 90:10 v/v).

R_f (EtOAc:hexane 90:10 v/v) 0.17 139c Methyl N-4-methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 139b and 48a on a 0.87 mmol scale following the method described for 1d. The product was isolated in 82% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.30

139d N-4-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 139c on a 0.72 mmol scale following the method described for 1f. The product was isolated in 80% yield and used without further purification.

139e Methyl (3R)-2-{N-4-methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 139d and 1c on a 0.29 mmol scale following the method described for 1d. The product was isolated in 75% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.21

139f (3R)-2-{N-4-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 139e on a 0.22 mmol scale following the method described for 1f. The product was isolated in 47% yield (65 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 55:45:2 v/v/v).

HPLC System A t_R=19.6' >80%

Mass spec (FAB) m/e=628 [M+H]⁺ EXAMPLE 140

140a 1,2,3,4-Tetrahydro-benz[h]isoquinoline-3-carboxylic acid.

This was prepared from β-(2-naphthyl)alanine on a 23 mmol scale following the method described for 84a. The product was isolated in 85% yield as a mixture of benz[g]- and benz[h]-fused isomers which was used without further purification.

140b Methyl 1,2,3,4-tetrahydro-benz[h]isoquinoline-3-carboxylate.

This was prepared from 140a on a 9.9 mmol scale following the method described for 26a. The product was isolated in 2% yield after flash chromatography on silica gel (eluant EtOAc). The benz[g]-fused isomer was also isolated (in 4% yield).

140c Methyl (3R)-2-{N-phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydro-benz[h]isoquinoline-3-carboxylate.

This was prepared from 90b and 140b on a 0.19 mmol scale following the method described for 1d. The product was isolated in 33% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 30:70 v/v).

140d (3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydro-benz[h]isoquinoline-3-carboxylic acid.

This was prepared from 140c on a 0.06 mmol scale following the method described for 1f. The product was isolated in 47% yield (18 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 70:30:2 v/v/v). HPLC System A t_R=21.9' >80%

Mass spec (FAB) m/e=407

EXAMPLE 141

141a (3RS)-4-Amino-3-phenylbutanoic acid.

A suspension of (RS)-4-amino-3-(4-chlorophenyl)butanoic acid in H₂O (100 mL) and MeOH (70 mL) was hydrogenated over 5% Pd-on-carbon at room temperature for 5 hr. The mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the titie compound which was used without further purification assuming a yield of 100%.

141b (4RS)-1,2,3,4-Tetrahydroisoquinoline-4-acetic acid.

This was prepared from 141a on a 4.7 mmol scale following the method described for 84a. The product was used without further purification assuming a yield of 100%. 141c Methyl (4RS)-2-tert-butyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-4-acetate.

This was prepared from 141b on a 4.7 mmol scale in two steps. The acid was esterified following the method described for 26a. The crude product was taken up in CH₂Cl₂ (70 mL) and treated with BOC₂O ( 1.31 g, 6 mmol) and i-Pr₂NEt (excess). The mixture was stirred at room temperature overnight, dilutede with EtOAc, washed with aq. KHSO₄ and brine, filtered (Whatman IPS phase separator), and concentrated in vacuo. The product was isolated in 25% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 20:80 v/v).

141d Methyl (4RS)-2-{N-phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindoie-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoqιunoline-4-acetate.

This was prepared from 90b and 141c on a 0.50 mmol scale following the method described for 79d. The product was isolated in 39% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 40:60 v/v).

141e (4RS)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-4-acetic acid.

This was prepared from 141d on a 0.19 mmol scale following the method described for 1f. The product was isolated in 70% yield (79 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 50:50:2 v/v/v).

HPLC System A t_R=19.0' >90%

Mass spec (FAB) m/e=598 [M+H]⁺

EXAMPLE 142

142a Methyl (4RS)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-4-acetate.

This was prepared from 79b and 141c on a 0.52 mmol scale following the method described for 79d. The product was isolated in 48% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 30:70 v/v).

142b (4RS)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-4-acetic add.

This was prepared from 142a on a 0.16 mmol scale following the method described for 1f. The product was isolated in 71% yield (69 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 50:50:2 v/v/v).

HPLC System A t_R=20.2' >95%

Mass spec (FAB) m/e=610 [M+H]⁺

EXAMPLE 143

143a (2R)-1-Cyclobutyloxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from cyclobutanol on a 2.0 mmol scale following the method described for 72a. The product was isolated in 16% yield after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 35:65:2 v/v/v). 143b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-cyclobutyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 143a on a 0.24 mmol scale following the method described for 79d. The product was isolated in 82% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 35:65 v/v).

143c (3R)-2-{(2R,5S)-1-((2R)-1-Cyclobutyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 143b on a 0.20 mmol scale following the method described for 1f. The product was isolated in 72% yield (85 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 65:35:2 v/v/v).

HPLC System B t_R=14.2' >95%

Mass spec (FAB) m/e=594 [M+H]⁺

EXAMPLE 144

144a (2R)-1-Cyclopentyloxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from cyclopentanol on a 2.0 mmol scale following the method described for 72a. The product was isolated in 75% yield and used without purification. 144b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-cyclopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 78a and 144a on a 0.30 mmol scale following the method described for 79d. The product was isolated in 73% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 35:65 v/v).

144c (3R)-2-{(2R,5S)-1-((2R)-1-Cyclopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 144b on a 0.22 mmol scale following the method described for 1f. The product was isolated in 79% yield (108 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 65:35:2 v/v/v).

HPLC System B t_R=16.3' >98%

Mass spec (FAB) m/e=622 [M+H]⁺

EXAMPLE 145

145a Methyl (3R)-2-{(2R,5S)-1-((2R)-1-cyclopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 144a on a 0.24 mmol scale following the method described for 79d. The product was isolated in 81% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 35:65 v/v). 145b (3R)-2-{(2R,5S)-1-((2R)-1-Cyclopentyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 145a on a 0.19 mmol scale following the method described for 1f. The product was isolated in 69% yield (80 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 65:35:2 v/v/v).

HPLC System B t_R=15.2' >98%

Mass spec (FAB) m/e=608 [M+H]⁺

EXAMPLE 146

146a (2R)-1-(2-exo-Norbornyl)oxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from 2-exo-norbornyl alcohol on a 1.0 mmol scale following the method described for 72a. The product was isolated in 93% yield and used without purification.

146b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-(2-exo-norbornyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 146a on a 0.24 mmol scale following the method described for 79d. The product was isolated in 74% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 35:65 v/v). 146c (3R)-2-{(2R,5S)-1-((2R)-1-(2-exo-Norbornyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 146b on a 0.18 mmol scale following the method described for 1f. The product was isolated in 65% yield (74 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 60:40:2 v/v/v).

HPLC System B t_R=17.2' >98%

Mass spec (FAB) m/e=634 [M+H]⁺

EXAMPLE 147

147a (2R)-1-Cyclododecyloxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from cyclododecanol on a 1.0 mmol scale following the method described for 72a. The product was isolated in 64% yield and used without purification.

147b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-cyclododecyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 147a on a 0.24 mmol scale following the method described for 79d. The product was isolated in 55% yield after flash chromatography on silica gel (eluant EtOAc:pet ether 30:70 v/v). 147c (3R)-2-{(2R,5S)-1-((2R)-1-Cyclododecyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

This was prepared from 147b on a 0.13 mmol scale following the method described for 1f. The product was isolated in 58% yield (53 mg) after flash chromatography on silica gel (eluant EtOAc:pet ether:AcOH 55:45:2 v/v/v).

HPLC System B t_R=25.0' >98%

Mass spec (FAB) m/e=706 [M+H]⁺

EXAMPLE 148

148a Methyl N-phenethyl-N-((2R)-1-n-propyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycinate.

This was prepared from 90a and propyl chloroformate on a 0.48 mmol scale following the method described for 81a. The product was isolated in 88% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 35:65 v/v). 148b N-Phenethyl-N-((2R)-1-n-propyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 148a on a 0.42 mmol scale following the method described for 1f. The product was isolated in 45% yield after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 65:35:2 v/v/v).

148c Methyl (3R)-2-{N-phenethyl-N-((2R)-1-n-propyloxycarbonyl-2-3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 148b on a 0.08 mmol scale following the method described for 1d. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:hexane 55:45 v/v).

R_f (EtOAc:hexane 60:40 v/v) 0.35

148d (3R)-2-{N-Phenethyl-N-((2R)-1-n-propyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 148c on a 0.08 mmol scale following the method described for 1f. The product was isolated in 54% yield (25 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 70:30:2 v/v/v).

HPLC System A t_R=17.9' >98%

Mass spec (FAB) m/e=584 [M+H]⁺

EXAMPLE 149

149a Methyl N-{(3R)-2-{(2S,5R)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetyl}-prolinate.

This was prepared from 79c and 88b on a 0.14 mmol scale following the method described for 79d. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:hexane 80:20 v/v).

R_f (EtOAc:hexane 80:20 v/v) 0.13

149b N-{(3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetyl}-proline.

This was prepared from 149a on a 0.14 mmol scale following the method described for 1f. The product was isolated in 46% yield (46 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v).

HPLC System A t_R=17.6' >95%

AAA Peptide content=91%

Mass spec (FAB) m/e=707 [M+H]⁺

150a (2-Methoxyphenyl)acetaldehyde.

This was prepared from 2-(2-methoxyphenyl)ethanol on a 13.1 mmol scale following the method described for 99ad. The product was isolated in 52% yield after flash chromatography on silica gel (eluant EtOAc:hexane 5:95 v/v).

R_f (EtOAc:hexane 5:95 v/v) 0.17

150b Methyl N-2-(2-methoxyphenyl)ethyl-glycinate.

This was prepared from 150a on a 6.8 mmol scale following the method described for 42a. The product was isolated in 28% yield after flash chromatography on silica gel (eluant EtOAc:hexane 80:20 v/v).

R_f (EtOAc:hexane 80:20 v/v) 0.16 150c Methyl N-2-(2-methoxyphenyl)ethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 48a and 150b on a 1.93 mmol scale following the method described for 1d. The product was isolated in 98% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.33

150d N-2-(2-Methoxyphenyl)ethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 150c on a 1.90 mmol scale following the method described for 1f. The product was isolated in 85% yield and used without purification.

150e Methyl (3R)-2-{N-2-(2-methoxyphenyl)ethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a and 150d on a 0.81 mmol scale following the method described for 1d. The product was isolated in 94% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 40:60 v/v) 0.29

150f (3R)-2-{N-2-(2-Methoxyphenyl)ethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 150e on a 0.76 mmol scale following the method described for 1f. The product was isolated in 57% yield (267 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 55:45:2 v/v/v).

HPLC System A t_R=20.5' >95%

Mass spec (FAB) m/e=614 [M+H]⁺ EXAMPLE 151

151a (2R)-1-(3,3-Dimethylbutyl)oxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from 3,3-dimethylbutanol on a 2.34 mmol scale following the method described for 72a. The product was isolated in 37% yield after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 35:65:2 v/v/v).

151b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-(3,3-dimethylbutyl)oxycarbonyl-2,3- dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 151a on a 0.28 mmol scale following the method described for 79d. The product was isolated in 75% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

R_f (EtOAc:hexane 35:65 v/v) 0.21

151c (3R)-2-{(2R,5S)-1-((2R)-1-(3,3-Dimethylbutyl)oxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrroIidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

This was prepared from 151b on a 0.21 mmol scale following the method described for 1f. The product was isolated in 66% yield (87 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 45:55:2 v/v/v). HPLC System B t_R=17.8' >95%

Mass spec (FAB) m/e=624 [M+H]⁺

152a 1-((2R)-1-Cycloheptyloxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from cycloheptanol on a 2.35 mmol scale following the method described for 72a. The product was isolated in 39% yield after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 35:65:2 v/v/v).

152b Methyl (3R)-2-{(2R-5S)-1-((2R)-1-cycIoheptyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylate.

This was prepared from 68a and 152a on a 0.28 mmol scale following the method described for 79d. The product was isolated in 86% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

R_f (EtOAc:hexane 35:65 v/v) 0.22 152c (3R)-2-{(2R,5S)-1-((2R)-1-Cycloheptyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 152b on a 0.24 mmol scale following the method described for 1f. The product was isolated in 51% yield (78 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 45:55:2 v/v/v).

HPLC System B t_R=18.2' >98%

Mass spec (FAB) m/e=636 [M+H]⁺

153a (2R)-1-((1S)-endo-Bornyl)oxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from ( 1S)-endo-borneol on a 2.34 mmol scale following the method described for 72a. The product was isolated in 59% yield after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 35:65:2 v/v/v).

153b Methyl (3R)-2-{(2R-5S)-1-((2R)-1-((1S)-endo-bornyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 153a on a 0.28 mmol scale following the method described for 79d. The product was isolated in 66% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v). R_f (EtOAc:hexane 35:65 v/v) 0.28

153c (3R)-2-{(2R,5S)-1-((2R)-1-((1S)-endo-Bornyl)oxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

This was prepared from 153b on a 0.19 mmol scale following the method described for 1f. The product was isolated in 47% yield (62 mg) after flash chromatography on silica gel (eluant EtOAc:hexane.ΑcOH 45:55:2 v/v/v).

HPLC System B t_R=20.6' >95%

Mass spec (FAB) m/e=676 [M+H]⁺ EXAMPLE 154

154a (2R)-1-((1R,2R,3R,5S)-Isopinocampheyl)oxycarbonyl-2,3-dihydroindole-2- carboxylic acid.

This was prepared from (1R,2R,3R,5S)-isopinocampheol on a 2.34 mmol scale following the method described for 72a. The product was isolated in 57% yield after flash chromatography on silica gel (eluant EtOAc:hexane.AcOH 35:65:2 v/v/v). 154b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-((1R,2R,3R,5S)- isopinocampheyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2- carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 154a on a 0.28 mmol scale following the method described for 79d. The product was isolated in 70% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

R_f (EtOAc:hexane 35:65 v/v) 0.28

154c (3R)-2-{(2R4S)-1-((2R)-1-((1R,2R,3R,5S)-Isopinocampheyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 154b on a 0.20 mmol scale following the method described for 1f. The product was isolated in 53% yield (73 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 45:55:2 v/v/v).

HPLC System B t_R=21.0' >95%

Mass spec (FAB) m/e=676 [M+H]⁺

EXAMPLE 155

155a (2R)-1-((1S,2S,3S,5R)-Isopinocampheyl)oxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from (1S,2S,3S,5R)-isopinocampheol on a 2.34 mmol scale following the method described for 72a. The product was isolated in 69% yield after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 35:65:2 v/v/v).

155b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-((1S,2S,3S,5R)-isopinocampheyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 155a on a 0.28 mmol scale following the method described for 79d. The product was isolated in 75% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

R_f (EtOAc:hexane 35:65 v/v) 0.27

155c (3R)-2-{(2R,5S)-1-((2R)-1-((1S,2S,3S,5R)-Isopinocampheyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 155b on a 0.21 mmol scale following the method described for 1f. The product was isolated in 39% yield (56 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 45:55:2 v/v/v).

HPLC System B t_R=21.3' >98%

Mass spec (FAB) m/e=676 [M+H]⁺

EXAMPLE 156

156a Methyl (3R)-2-{(2R,5S)-1-((2R)-1-(3,3-dimethylbutyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 78a and 151a on a 0.30 mmol scale following the method described for 79d. The product was isolated in 77% yield after flash chromatography on silica gel (eluant EtOAc:hexane 35:65 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.49

156b (3R)-2-{(2R,5S)-1-((2R)-1-(3,3-Dimethylbutyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 156a on a 0.23 mmol scale following the method described for 1f. The product was isolated in 44% yield (65 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 45:55:2 v/v/v).

HPLC System B t_R=19.0' >98%

Mass spec (FAB) m/e=660 [M+Na]⁺

EXAMPLE 157

157a Methyl (2R)-1-(1-piperidino)carbonyl-2,3-dihydroindole-2-carboxylate.

This was prepared from piperidine on a 1.64 mmol scale following the method described for 72a but without the final hydrolysis. The product was isolated in 44% yield after flash chromatography on silica gel (eluant EtOAc:hexane 30:70 v/v).

R_f (EtOAc:hexane 30:70 v/v) 0.14

157b (2R)-1-(1-Piperidino)carbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from 157a on a 0.71 mmol scale following the method described for 1f. The product was isolated in 72% yield and used without purification.

157c Methyl (3R)-2-{(2R,5S)-1-((2R)-1-(1-piperidino)carbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 157b on a 0.51 mmol scale following the method described for 79d. The product was isolated in 54% yield after flash chromatography on silica gel (eluant EtOAc:hexane 70:30 v/v).

R_f (EtOAc:hexane 70:30 v/v) 0.16

157d (3R)-2-{(2R,5S)-1-((2R)-1-(1-Piperidino)carbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 157c on a 0.28 mmol scale following the method described for 1f. The product was isolated in 18% yield (30 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v).

HPLC System B t_R=14.9' >98%

Mass spec (FAB) m/e=607 [M+H]⁺

158a Methyl (2R)-1-(N-cyclohexyl-N-methylcarbamoyl)-2,3-dihydroindole-2- carboxylate.

This was prepared from N-methyl-cyclohexylamine on a 1.64 mmol scale following the method described for 157a. The product was isolated in 25% yield after flash chromatography on silica gel (eluant EtOAc:hexane 15:85 v/v).

R_f (EtOAc:hexane 30:70 v/v) 0.20

158b (2R)-1-(N-Cyclohexyl-N-methylcarbamoyl)-2,3-dihydroindole-2-carboxylic acid.

This was prepared from 158a on a 0.60 mmol scale following the method described for 1f. The product was isolated in 67% yield and used without purification.

158c Methyl (3R)-2-{(2R,5S)-1-((2R)-1-(N-cyclohexyl-N-methylcarbamoyl)-2,3- dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 158b on a 0.40 mmol scale following the method described for 79d. The product was isolated in 72% yield after flash chromatography on silica gel (eluant EtOAc:hexane 55:45 v/v).

R_f (EtOAc:hexane 70:30 v/v) 0.25 158d (3R)-2-{(2R,5S)-1-((2R)-1-(N-Cyclohexyl-N-methylcarbamoyl)-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 158c on a 0.29 mmol scale following the method described for 1f. The product was isolated in 33% yield (60 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 85:15:2 v/v/v).

HPLC System B t_R=17.6' >99%

Mass spec (FAB) m/e=635 [M+H]⁺

EXAMPLE 159

159a Methyl (2R)-1-(4-tert-butylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carboxylate.

This was prepared from 4-tert-butylcyclohexanol on a 1.64 mmol scale following the method described for 157a. The product was isolated in 50% yield after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 20:80:2 v/v/v). 159b (2R)-1-(4-tert-Butylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from 159a on a 0.82 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

159c Ethyl (2R,5S)-1-((2R)-1-(4-tert-butylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carboxylate.

This was prepared from 30a and 159b on a 0.82 mmol scale following the method described for 1d. The product was isolated in 34% yield after flash chromatography on silica gel (eluant EtOAc:hexane 20:80 v/v).

R_f (EtOAc:hexane 40:60 v/v) 0.46

159d (2R,5S)-1-((2R)-1-(4-tert-Butylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carboxylic acid.

This was prepared from 159c on a 0.28 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

159e Methyl (3R)-2-{(2R,5S)-1-((2R)-1-(4-tert-butylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a and 159d on a 0.28 mmol scale following the method described for 1d. The product was isolated in 93% yield after flash chromatography on silica gel (eluant EtOAc:hexane 30:70 v/v).

159f (3R)-2-{(2R,5S)-1-((2R)-1-(4-tert-Butylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 159e on a 0.26 mmol scale following the method described for 1f. The product was isolated in 35% yield (62 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 65:35:2 v/v/v).

HPLC System B t_R=23.0' >95%

Mass spec (FAB) m/e=678 [M+H]⁺ EXAMPLE 160

160a Methyl (2R)-1-(2-cis-methylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carboxylate.

This was prepared from (±)-2-cis-methylcyclohexanol on a 3.28 mmol scale following the method described for 157a. The product was isolated in 51% yield after flash chromatography on silica gel (eluant EtOAc:hexane 20:80 v/v).

R_f (EtOAc:hexane 30:70 v/v) 0.41

160b (2R)-1-(2-cis-Methylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from 160a on a 1.66 mmol scale following the method described for 1f. The product was isolated in 23% yield and used without purification.

160c Methyl (3R)-2-{(2R,5S)-1-((2R)-1-(2-cis-methylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 160b on a 0.38 mmol scale following the method described for 79d. The product was isolated in 25% yield after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 25:75:1 v/v/v). 160d (3R)-2-{(2R,5S)-1-((2R)-1-(2-cis-Methylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 160c on a 0.09 mmol scale following the method described for 1f. The product was isolated in 48% yield (29 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 70:30:2 v/v/v).

HPLC System A t_R=18.0' >98%

Mass spec (FAB) m/e=636 [M+H]⁺

EXAMPLE 161

161a Methyl (2R)-1-(2-trans-methylcyclohexyl)oxycarbonyl-2,3-dϊhydroindole-2-carboxylate.

This was prepared from ( ±)-2-trans-methylcyclohexanol on a 1.64 mmol scale following the method described for 157a. The product was isolated in 28% yield after flash chromatography on silica gel (eluant EtOAc:hexane 20:80 v/v).

R_f (EtOAc:hexane 30:70 v/v) 0.41 161b (2R)-1-(2-trans-Methylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from 161a on a 0.45 mmol scale following the method described for 1f. The product was isolated in 44% yield and used without purification.

161c Methyl (3R)-2-{(2R,5S)-1-((2R)-1-(2-trans-methylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 68a and 161b on a 0.20 mmol scale following the method described for 79d. The product was isolated in 42% yield after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 25: 75:1 v/v/v).

161d (3R)-2-{(2R,5S)-1-((2R)-1-(2-trans-Methylcyclohexyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 161c on a 0.08 mmol scale following the method described for 1f. The product was isolated in 38% yield (20 mg) after flash chromatography on silica gel (eluant EtOAc:hexancAcOH 65:35:2 v/v/v).

HPLC System B t_R=18.4' >98%

Mass spec (FAB) m/e=636 [M+H]⁺

162a Methyl (2R)-1-(3-cyclohexylpropyl)oxycarbonyl-2,3-dihydroindole-2- carboxylate.

This was prepared from 3-cycIohexylpropanol on a 1.64 mmol scale following the method described for 157a. The product was isolated in 100% yield after flash chromatography on silica gel (eluant EtOAc:hexane 20:80 v/v).

R_f (EtOAc:hexane 30:70 v/v) 0.49

162b (2R)-1-(3-Cyclohexylpropyl)oxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from 162a on a 1.64 mmol scale following the method described for 1f. The product was isolated in 60% yield and used without purification. 162c Methyl N-phenethyl-N-((2R)-1-(3-cyclohexylpropyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 32a and 162b on a 0.99 mmol scale following the method described for 1d. The product was isolated in 82% yield after flash chromatography on silica gel (eluant EtOAc:hexane: AcOH 35:65:1 v/v/v).

162d N-Phenethyl-N-((2R)-1-(3-cyclohexylpropyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 162c on a 0.81 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

162e Methyl (3R)-2-{N-phenethyl-N-((2R)-1-(3-cyclohexylpropyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 162d on a 0.81 mmol scale following the method described for 1d. The product was isolated in 63% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.34

162f (3R)-2-{N-Phenethyl-N-((2R)-1-(3-cyclohexylpropyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 162e on a 0.51 mmol scale following the method described for 1f. The product was isolated in 51% yield (161 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 55:45:2 v/v/v).

HPLC System B t_R=21.5' >98%

Mass spec (FAB) m/e=688 [M+Na]⁺

163a Methyl (2R)-1-cyclohexylmethyloxycarbonyl-2,3-dihydroindole-2-carboxylate.

This was prepared from cyclohexanemethanol on a 1.64 mmol scale following the method described for 157a. The product was isolated in 78% yield after flash chromatography on silica gel (eluant EtOAc:hexane 20:80 v/v).

R_f (EtOAc:hexane 30:70 v/v) 0.49

163b (2R)-1-Cyclohexylmethyloxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from 163a on a 1.27 mmol scale following the method described for 1f. The product was isolated in 55% yield and used without purification. 163c Ethyl (2R,5S)-1-((2R)-1-cyclohexylmethyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carboxylate.

This was prepared from 30a and 163b on a 0.70 mmol scale following the method described for 1d. The product was isolated in 57% yield after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 25:75:1 v/v/v).

163d (2R,5S)-1-((2R)-1-Cyclohexylmethyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carboxylic acid.

This was prepared from 163c on a 0.40 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

163e Methyl (3R)-2-{(2R,5S)-1-((2R)-1-cyclohexylmethyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a and 163d on a 0.40 mmol scale following the method described for 1d. The product was isolated in 64% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.40

163f (3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexylmethyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 163e on a 0.25 mmol scale following the method described for 1f. The product was isolated in 16% yield (24 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 50:50:2 v/v/v).

HPLC System B t_R=18.8' >98%

Mass spec (FAB) m/e=636 [M+H]⁺

164a Methyl (2R)-1-(2-cyclohexylethyl)oxycarbonyl-2,3-dihydroindole-2-caτboxylate.

This was prepared from 2-cyclohexylethanol on a 1.64 mmol scale following the method described for 157a. The product was isolated in 91% yield after flash chromatography on silica gel (eluant EtOAc:hexane 20:80 v/v).

R_f (EtOAc:hexane 30:70 v/v) 0.54

164b (2R)-1-(2-Cyclohexylethyl)oxycarbonyl-2,3-dihydroindole-2-carboxylic acid.

This was prepared from 164a on a 1.50 mmol scale following the method described for 1f. The product was isolated in 55% yield and used without purification. 164c Ethyl (2R,5S)-1-((2R)-1-(2-cyclohexylethyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carboxylate.

This was prepared from 30a and 164b on a 0.82 mmol scale following the method described for 1d. The product was isolated in 56% yield after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 25:75: 1 v/v/v).

164d (2R,5S)-1-((2R)-1-(2-Cyclohexylethyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carboxylic acid.

This was prepared from 164c on a 0.46 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

164e Methyl (3R)-2-{(2R,5S)-1-((2R)-1-(2-cycIohexylethyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a and 164d on a 0.46 mmol scale following the method described for 1d. The product was isolated in 72% yield after flash chromatography on silica gel (eluant EtOAc:hexane 40:60 v/v).

R_f (EtOAc:hexane 50:50 v/v) 0.40

164f (3R)-2-{(2R,5S)-1-((2R)-1-(2-Cyclohexylethyl)oxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 164e on a 0.33 mmol scale following the method described for 1f. The product was isolated in 16% yield (33 mg) after flash chromatography on silica gel (eluant EtOAc:hexane:AcOH 50:50:2 v/v/v).

HPLC System B t_R=21.8' >90%

Mass spec (FAB) m/e=650 [M+H]⁺ EXAMPLE 165

165a Methyl N-{(3R)-2-{(2R,5S)-1-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole- 2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carbonyl}-prolinate.

This was prepared from 74c and ProOMe on a 0.08 mmol scale following the method described for 1d. The product was used without purification, assuming a yield of 100%. R_f (EtOAc:pet. ether 70:30 v/v) 0.22

165b N-{(3R)-2-{(2R,5S)-1-((2R)-1-CycIohexyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrroIidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carbonyl}-proline.

This was prepared from 165a on a 0.08 mmol scale following the method described for 1f. The product was isolated in 57% yield (31 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:1 v/v).

HPLC System A t_R=15.5' >98%

AAA Peptide content=83%

Mass spec (FAB) m/e=604, 272

166a Methyl N-{(3R)-2-{(2R,5S)-1-((2R)-1-neopentyloxycarbonyl-2,3-dihydroindole- 2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carbonyl}-prolinate.

This was prepared from 131a on a 0.30 mmol scale following the method described for 81a. The product was isolated in 32% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 50:50 v/v).

166b N-{(3R)-2-{(2R,5S)-1-((2R)-1-Neopentyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carbonyl}-proline.

This was prepared from 166a on a 0.10 mmol scale following the method described for 1f. The product was isolated in 89% yield (61 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:1 v/v).

HPLC System A t_R=15.1' >98%

AAA Peptide content=76%

Mass spec (FAB) m/e=592, 272

167a Methyl (3R)-2-tert-butyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-propanoate.

This was prepared from 1b on a 3.6 mmol scale. The ester was hydrolysed following the method described for 1f to give the corresponding acid which was then homologated following the method described for 1b. The intermediate diazoketone was purified by flash chromatography on silica ge1 (eluant EtOAc:pet. ether 25:75 v/v) and the title product was isolated in 22% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 20:80 v/v).

R_f (EtOAc:pet. ether 10:90 v/v) 0.12

¹H NMR δ 1.49 (9H,s); 1.6 - 1.9 (2H.m); 2.3 (2H.m); 2.63 (1H,dd,J=16,2 Hz); 3.09 (1H.dd,J=16,6 Hz); 3.64 (3H,s); 4.2 (1H,br); 4.6 (1H,br); 4.9 (1H,br); 7.0 - 7.2 (4H,m)

167b Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-propanoate.

This was prepared from 79b and 167a on a 0.39 mmol scale following the method described for 79d. The product was isolated in 71% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

R_f (EtOAc:pet. ether 30:70 v/v) 0.13

167c (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-propanoic acid.

This was prepared from 167b on a 0.28 mmol scale following the method described for 1f. The product was isolated in 74% yield (130 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 55:45:1 v/v/v).

HPLC System A t_R=15.4' >98%

Mass spec (FAB) m/e=624 [M+H]⁺

168a 3-Methylphenethylamine.

To a stirred solution of 3-methylbenzyl cyanide (1 g, 7.6 mmol) and CoCl₂ (0.49 g, 3.8 mmol) in MeOH (20 mL) was added NaBH₄ (1.2 g, 30.4 mmol) portionwise at room temperature. The mixture was stirred for 30 min then poured onto crushed ice. 10% Aq. KHSO₄ was added until the mixture was strongly acidic (pH 2), and the insoluble material was removed by filtration through Celite. The filtrate was treated with NaOH pellets until basic (pH 10) and extracted once with EtOAc, then twice with CH₂Cl₂. The separate extracts were washed with brine, dried over Na₂SO₄, combined and evaporated to give the title compound (0.60 g, 59%) which was used without purification. 168b Methyl N-3-methylphenethyl-glycinate.

This was prepared from 168a on a 4.45 mmol scale following the method described for 32a. The product was isolated in 6% yield after flash chromatography on silica gel (eluant EtOAc).

168c Methyl N-3-methylphenethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 74a and 168b on a 0.26 mmol scale following the method described for 1d. The product was isolated in 69% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

168d N-3-Methylphenethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 168c on a 0.18 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

168e Methyl (3R)-2-{N-3-methylphenethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 168d on a 0.18 mmol scale following the method described for 1d. The product was isolated in 70% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

168f (3R)-2-{N-3-Methylphenethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 168e on a 0.13 mmol scale following the method described for 1f. The product was isolated in 72% yield (60 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 70:30:1 v/v/v).

HPLC System A t_R=17.1' >98%

Mass spec (FAB) m/e=660 [M+Na]⁺

169a Methyl N-(2-(1-Methylpyrrol-2-yl)ethyl)-glycinate.

This was prepared from 2-(1-methylpyrrol-2-yl)ethylamine on a 8.0 mmol scale following the method described for 32a. The product was isolated in 27% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 70:30 then EtOAc).

169b Methyl N-(2-(1-Methylpyrrol-2-yl)ethyl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycinate.

This was prepared from 74a and 169a on a 2.16 mmol scale following the method described for 1d. The product was isolated in 34% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v). 169c N-(2-(1-Methylpyrrol-2-yl)ethyl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 169b on a 0.73 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

169d Methyl (3R)-2-{N-(2-(1-Methylpyrrol-2-yl)ethyl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 169c on a 0.73 mmol scale following the method described for 1d. The product was isolated in 58% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

169e (3R)-2-{N-(2-(1-Methylpyrrol-2-yl)ethyl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 169d on a 0.42 mmol scale following the method described for 1f. The product was isolated in 75% yield (197 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 80:20:2 v/v/v).

HPLC System A t_R-=15.0^, >98%

Mass spec (FAB) m/e-=627 [M+H]⁺

170a (2-Thienyl)ethylamine.

This was prepared from 2-thienylacetonitriie on an 18.6 mmol scale following the method described for 168a. The product was isolated in 32% yield and used without purification.

170b Methyl N-(2-thienyl)ethyl-glycinate.

This was prepared from 170a on a 5.96 mmol scale following the method described for 32a. The product was isolated in 35% yield after flash chromatography on silica gel (eluant CHCl₃:MeOH:AcOH 30:2:1 v/v/v). 170c Methyl N-(2-thienyl)ethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 74a and 170b on a 1.05 mmol scale following the method described for 1d. The product was isolated in 71% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

170d N-(2-Thienyl)ethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 170c on a 0.75 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

170e Methyl (3R)-2-{N-(2-thienyl)ethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 170d on a 0.75 mmol scale following the method described for 1d. The product was isolated in 59% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

170f (3R)-2-{N-(2-Thienyl)ethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoqιunoline-3-acetic acid.

This was prepared from 170e on a 0.44 mmol scale following the method described for 1f. The product was isolated in 57% yield (157 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 80:20: 1 v/v/v).

HPLC System A t_R=14.8' >98%

Mass spec (FAB) m/e=493 [M+H]⁺

171a (2RS)-2-Benyloxycarbonylamino-1,2,3,4-tetrahydronaphthalene.

To a stirred solution of 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (3 g, 17 mmol) and N-methylmorpholine (2.1 mL, 18.7 mmol) under N₂ was added (PhO)₂P(O)N₃ (4 mL, 18.7 mmol) and the mixture was heated at reflux for 2.5 hr then cooled to room temperature. Benzyl alcohol (3.7 mL, 34 mmol) was added and the solution was heated at reflux overnight, cooled to room temperature, and concentrated in vacuo. The residue was taken up in EtOAc and washed successively with aq. KHSO₄, KHCO₃ (twice), water and brine, filtered (Whatman IPS phase separator) and concentrated. The product was isolated in 57% yield (4.07 g) after flash chromatography on silica gel (eluant EtOAc:pet. ether 10:90 v/v)

171b Methyl N-((2RS)-1,2,3,4-tetrahydronaphth-2-yl)-N-tert-butyloxycarbonylglycinate.

This was prepared from 171a on a 7.1 mmol scale in three steps. The amine was deprotected by catalytic hydrogenolysis over 5% Pd-on-carbon, then alkylated following the method described for 32a and finally reprotected with BOC₂O following the method described for 141c (second part). The product was isolated in 14% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 10:90 v/v).

171c Methyl N-((2RS)-1,2,3,4-tetrahydronaphth-2-yl)-glycinate hydrochloride.

This was prepared from 171b on a 1.0 mmol scale following the method described for 1c The product was used without purification, assuming a yield of 100%.

171d Methyl N-((2RS)-1,2,3,4-tetrahydronaphth-2-yl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 74a and 171c on a 1.0 mmol scale following the method described for 1d. The product was isolated in 48% yield after flash chromatography on sUica gel (eluant EtOAc:pet. ether 30:70 v/v).

171e N-((2RS)-1,2,3,4-Tetrahydronaphth-2-yl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 171d on a 0.48 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

171f Methyl (3R)-2-{N-((2RS)-1,2,3,4-tetrahydronaphth-2-yl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 171e on a 0.48 mmol scale following the method described for 1d. The product was isolated in 52% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v). 171g (3R)-2-{N-((2RS)-1,2,3,4-Tetrahydronaphth-2-yl)-N-((2R)-1- cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

This was prepared from 171f on a 0.25 mmol scale following the method described for 1f. The product was isolated in 60% yield (97 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 45:55: 1 v/v/v).

HPLC System A t_R=16.8' >95%

Mass spec (FAB) m/e=650 [M+H]⁺

EXAMPLE 172

172a Ethyl (2R)-3,4-dihydro-5-(4-methoxyphenyl)-2H-pyrrole-2-carboxylate.

This was prepared from 4-methoxyphenylmagnesium bromide on an 8.0 mmol scale following the method described for 87a. The product was isolated in 82% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 then 40:60 v/v).

172b Ethyl (2R,5S)-5-(4-methoxyphenyl)-pyrrolidine-2-carboxylate.

This was prepared from 172a on a 6.6 mmol scale following the method described for 30a. The product was isolated in 56% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 then 50:50 v/v).

172c Ethyl (2R,5S)-1-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-(4-methoxyphenyl)-pyrrolidine-2-carboxylate.

This was prepared from 74a and 172b on a 0.69 mmol scale following the method described for 1d. The product was isolated in 95% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

172d (2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-(4-methoxyphenyl)-pyrrolidine-2-carboxylic acid.

This was prepared from 172c on a 0.65 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

172e Methyl (3R)-2-{(2R,5S)-1-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-(4-methoxyphenyl)-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate.

This was prepared from 26a and 172d on a 0.32 mmol scale following the method described for 1d. The product was isolated in 69% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

172f (3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5-(4-methoxyphenyl)-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

This was prepared from 172e on a 0.22 mmol scale following the method described for 1f. The product was isolated in 69% yield (95 mg) after flash chromatography on silica gel (eluant EtOAc:AcOH 100:2 v/v).

HPLC System A t_R=15.4' >98%

Mass spec (FAB) m/e=652 [M+H]⁺ EXAMPLE 173

173a Methyl N-(indan-2-yl)-glycinate.

This was prepared from indan-2-amine on an 8.0 mmol scale following the method described for 32a. The product was isolated in 44% yield after flash chromatography on silica gel (eluant EtOAc). 173b Methyl N-(indan-2-yl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycinate.

This was prepared from 74a and 173a on a 0.69 mmol scale following the method described for 1d. The product was isolated in 80% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 30:70 v/v).

173c N-(Indan-2-yl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycine.

This was prepared from 173b on a 0.55 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

173d Methyl (3R)-2-{N-(indan-2-yl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetate.

This was prepared from 1c and 173c on a 0.27 mmol scale following the method described for 1d. The product was isolated in 73% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 40:60 v/v).

173e (3R)-2-{N-(Indan-2-yl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

This was prepared from 173d on a 0.20 mmol scale following the method described for 1f. The product was isolated in ??% yield (75 mg) after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 80:20:2 v/v/v).

HPLC System A t_R=15.8' >98%

Mass spec (FAB) m/e=658 [M+H]⁺

EXAMPLE 174

174a Methyl N-(2-cyclohexylethyl)-N-(N-tert-butyloxycarbonyl-phenylalanyl)- glycinate.

This was prepared from 32b and BOCPheOH on a 2.0 mmol scale following the method described for 1d. The product was isolated in 93% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether 25:75 v/v).

174b Methyl N-(2-cyclohexylethyl)-N-(N-(3-indoleacetyl)-phenylalanyl)-glycinate.

This was prepared from 174a on a 1.86 mmol scale following the method described for 32d. The product was isolated in 52% yield after flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 65:35:1 v/v/v). 174c N-(2-Cyclohexylethyl)- N-(N-(3-indoleacetyl)-phenylalanyl)-glycine.

This was prepared from 174b on a 0.48 mmol scale following the method described for 34. The product was used without purification, assuming a yleid of 100%.

174d Methyl 1-{N-(2-cyclohexylethyl)-N-(N-(3-indoieacetyl)-phenylalanyl)-glycyl}-D- prolinate.

This was prepared from 174c and D-ProOMe on a 0.48 mmol scale following the method described for 34. The product was isolated in 42% yield after flash chromatography on silica gel (eluant EtOAc).

174e 1-{N-(2-Cyclohexylethyl)-N-(N-(3-indoleacetyl)-phenylalanyl)-glycyl}-D-proline.

This was prepared from 174d on a 0.20 mmol scale following the method described for 1f. The product was isolated in 61% yield (72 mg) after flash chromatography on silica gel (eluant CHCl₃:MeOH:AcOH 35:2:1 v/v/v).

HPLC System B t_R=10.4' >95%

AAA Phe 0.98: Pro 1.02: Peptide content=87%

Mass spec (FAB) m/e=587 [M+H]⁺

EXAMPLE 175

175a Methyl N-(2-cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-4-phenylbutanoyl)-glycinate.

This was prepared from 46a on a 1.74 mmol scale following the method described for 32d. The product was isolated in 61% yield alter flash chromatography on silica gel (eluant EtOAc:pet. ether:AcOH 65:35: 1 v/v/v).

175b N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-4-phenylbutanoyl)-glycine.

This was prepared from 175a on a 0.53 mmol scale following the method described for 1f. The product was used without purification, assuming a yield of 100%.

175c Methyl 1-{N-(2-cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-4-phenylbutanoyl)-glycyl}-D-prolinate.

This was prepared from 175b and D-ProOMe on a 0.53 mmol scale following the method described for 34. The product was isolated in 39% yield after flash chromatography on silica gel (eluant EtOAc).

175d 1-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-4-phenylbutanoyl)-glycyl}-D-proline.

This was prepared from 175c on a 0.29 mmol scale following the method described for 1f. The product was isolated in 67% yield ( 116 mg) after flash chromatography on silica gel (eluant CHCl₃:MeOH: AcOH 35:2:1 v/v/v).

HPLC System B t_R=15.8' >98%

AAA Hph 1.04: Pro 0.96; Peptide content=93%

Mass spec (FAB) m/e=623 [M+Na]⁺

BIOLOGICAL TESTING

The compounds of the present invention are potent ligands for the CCK-A and/or CCK-B receptors. Those which are antagonists at the CCK-B receptor also inhibit gastric acid secretion stimulated by pentagastrin. The methods for measuring these activities are described below: Measurement of binding affinity for CCK-A receptors

The pancreas of an SD rat was homogenized in a 20-foid volume of 50 mM Tris-HCl buffer (pH 7.7) by the use of a Polytrone-type homogenizer. the homogenate was twice centrifuged for 10 minutes at 50000 g by the use of an ultra-centrifuge, the precipitate thus obtained was suspended in a 40-fold volume of 50 mM Tris-HCl buffer (containing 0.2% BSA. 5 mM MgCl₂, 0.1 mg/ml bacitracin and 5 mM DTT: pH 7.7), and the suspension was stored at -80°C until the membrane preparations were required.

The membrane preparations were then warmed to room temperature, diluted 1:10 with the buffer and incubated at 37°C for 30 minutes in the presence of [³H]L-364.718 and the test compound then separated by suction filtration. Non-specific binding was determined in the presence of 1 μM L-364.718. The amount of labelled ligand bound to the receptor was measured by the use of a liquid scintillation counter IC₅₀ values were determined, being that concentration of test compound required to inhibit specific binding by 50%.

Measurement of binding affinity for CCK-B receptors

About 100 SD rats were decapitated without anaesthesia, the whole brain was immediately excised from each of the rats and homogenized in 10-fold volume of 0.32 M aqueous solution of sucrose by the use of a Teflon-coated homogenizer, the homogenate thus obtained was centrifuged for 10 minutes at 900 g by the use of a cooled centrifuge, and the supernatant was further centrifuged for 15 minutes at 11500 g. The precipitate thus obtained was dispersed in 50 mM Tris-HCl buffer (pH 7.4) containing 0.08% Triton X-100, this suspension was allowed to stand for 30 minutes and again centrifuged for 15 minutes at 11500 g, the precipitate thus obtained was washed twice with 5 mM Tris-HCl buffer and twice with 50 mM Tris-HCl buffer in that order with centrifugal separation. the washed precipitate was suspended in 50 mM Tris-HCl buffer, and the suspension thus obtained was stored at -80°C until the membrane preparation was required.

The membrane preparations were warmed to room temperature. diluted with 10 mM HEPES buffer (containing 130 mM. NaCl, 5 mM MgCl₂, 1mM EGTA and 0.25 mg/ml bacitracin; pH 6.5) and incubated at 25°C for 120 minutes in the presence of [¹²⁵I]BH-CCK-8 and the test compound. then separated by suction filtration. Non-specific binding was determined in the presence of 1 μM CCK-8. The amount of labelled ligand bound to the receptor was measured by the use of a γ-counter; IC₅₀ values were determined, being that concentration of test compound required to inhibit specific binding by 50%. Table 1 summarises CCK-A and CCK-B binding data for representative examples of the preferred compounds:

Table 1

Example No. Receptor binding affinity IC₅₀ (nM)

CCK-A CCK-B

1 170 20

2 160 10

3 430 43

11 > 10,000 760

16 7,700 480

17 10,000 270

18 6,500 390

19 3,500 290

21 > 10,000 140

24 > 10,000 190

28 4.7 22

30 5,600 100

31 2,700 18

36 > 10,000 2.3

45 > 10,000 30

69 > 10,000 39

74 > 10,000 1.0

75 > 10,000 0.87

85 > 10,000 9.0

89 > 10,000 1.9

97 > 10,000 16

107 > 10,000 56

127 > 10,000 800

131 > 10,000 0.25

136 > 10,000 20

141 > 10,000 4.7

146 > 10,000 9.3

152 > 10,000 2.9

153 > 10,000 1.0 Table 1 (cont.)

Example No. Receptor binding affinity IC₅₀ (nM)

CCK-A CCK-B

160 > 10,000 8.8

165 > 10,000 1.0

171 > 10,000 8.7

174 > 10,000 0.94

Measurement of inhibition of pentagastrin-stimulated gastric acid secretion in rat

A cannula was inserted into the trachea of a rat anaesthetised with urethane (intraperitoneally administered. 1.25 g/Kg), its abdominal wall was incised to expose the gastric and duodenal portions, and a polyethylene cannula was set in the anterior stomach after ligation of the cardia. The duodenum was then subjected to slight section, a polyethylene cannula was inserted from the incised portion toward the stomach, and the pylorus was ligated to fix the cannula.

Physiological saline (with pH adjusted to 7.0) was perfused from the anterior stomach toward the pylorus at a rate of 3 ml/min. and the gastric-acid secretion was measured by continuous titration of the perfusate by the use of a pH-stat (AUT-201; product of Toa Electronics. Ltd.). The continuous titration was carried out by using 25 mM NaOH solution until the pH reached 7.0. and the result was expressed as the amount of gastric acid secreted for every 10 minutes (mE_q/10 min.). Pentagastrin was intravenously administered at a rate of 15 μg/Kg/hr.

The secretion of gastric acid increased upon administration of pentagastrin, reaching the maximum level after 60 minutes and stably maintaining this level after that. A test drug was then intravenously administered, and the secretion of gastric acid was measured: ED₅₀ values were determined, being the amount of the drug required to reduce the amount of secreted gastric acid down to 50% of the maximum level.

Table 2 illustrates representative ED₅₀ values. It can be seen that compounds of the present invention show a substantial advantage over previously reported gastrin antagonists. Table 2

ED₅₀ ( μmol/kg)

Compound of Example 281 of US

Patent No. 4,820,834 (L-365.260) 4.2

Compound of Example 20 of

European Patent No. 0.405,537 Al

(PD- 134308) 2.1

Compound of Example 74 0.74

Compound of Example 153 0.20

The experiments described above demonstrate that the compounds of the present invention are high affinity ligands for the CCK-A and/or the CCK-B receptor, and that those which preferentially bind to the CCK-B receptor can inhibit the stimulation of gastric acid release due to pentagastrin. They are therefore useful in the treatment of disease states in which the CCK-A, CCK-B or gastrin receptor is implicated as a mediating factor.

In the case of the CCK-A receptor such disease states would include pancreatitis, disorders of gastrointestinal motility, irritable bowel syndrome, and CCK-dependent tumours.

In the case of the CCK-B receptor such disease states would include disorders of the central nervous system such as anxiety, psychoses. Parkinson's disease, Tourette's syndrome. Huntingdon's chorea, and neural damage following ischaemia (for example after a stroke).

In the case of the gastrin receptor such disease states would include disorders of the gastro-intestinal system, for example gastric and duodenal ulceration, gastritis, reflux esophagitis, Zollinger-Ellison syndrome, gastrin-sensitive pancreatitis, and gastrinsensitive tumors.

The compounds of the invention can also be used in the control of appetite and pain (including the potentiation of opiate analgesia).

The compounds of this invention and salts thereof can be administered orally (including sublingual administration) or parenterally in the form of tablets, powders, capsules, pilis, liquids, injections, suppositories, ointments and adhesive plasters. The carrier and excipient for pharmaceutical manufacturing can be a solid or liquid, nontoxic medicinal substance, such as lactose. magnesium stearate. starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol and other commonly employed materials.

Examples of formulations using the compounds of this invention are described below.

Preparation of 20 mg-tablets

Compound of Example 4 ( 100 g), lactose (367 g) and corn starch (90g) were homogeneously mixed together by the use of a flow granulating coater (product of Ohgawara Seisakusho), 10% aqueous solution of hydroxypropylcellulose (200 g) was sprayed into the mixture, and granulation was then performed. After drylng, the granules were filtered through a 20-mesh sieve, 20 g of carboxymethylcellulose Ca and 3 g of magnesium stearate were then added, and the mixture was treated in a rotary tablet machine equipped with a pestle of 7 mm × 8.4 R (product of Hata Tekkosho), thus producing tablets each weighing 120 mg.

Preparation of 40 mg-tablets

Compound of Example 4 ( 140 g), lactose (280 g) and corn starch (70g) were homogeneously mixed together by the use of a flow granulating coater (product of Ohgawara Seisakusho). 10% aqueous solution of hydroxypropylcellulose ( 175 g) was sprayed into the mixture, and granulation was then performed. After drylng, the granules were filtered through a 20-mesh sieve. 14.7 g of carboxymethylcellulose Ca and 2.8 g of magnesium stearate were then added, and the mixture was treated in a rotary tablet machine equipped with a pestle of 7.5 mm × 9R (product of Hata Tekkosho), thus producing tablets each weighing 150 mg.

The clinical dosage of the compounds of this invention will be determined by the physician taking into account the precise illness, and the body weight, age, sex, medical history and other factors of the patient to be treated. In general the dosage when administered orally will be between 1 and 1000 mg/day in either a single dose or subdivided into smaller multiple doses.

Claims

1. Compounds of general formula I, or pharmaceutically acceptable salts thereof: A - B - C I

wherein:

A is

or an α-amino acid residue containing an aromatic side-chain (e.g. L-Trp, L-Hph, L-Phe, L-Phg, D-Trp, D-Hph, D-Phe, D-Phg) which is optionally substituted at the N-terminal amino group; the N-terminal substituent is selected from R². B is

C is

D (in the exemplifications of C showing it) is absent, any α-amino or imino acid residue, any N-methylated α-amino acid residue, β-alanine:

R¹ is -H, halo, -OH, -CO₂H, -CF₃, -NO₂, -CN, CH₃, lower alkoxy (C₁ - C₃, linear or branched), lower alkylcarbonyl (C₁ - C₃, linear or branched), phenylcarbonyl;

R² is absent, H, alkyl (C₁ - C₁₀, linear, branched or cyclic), unsubstituted or substituted phenylmethyl (substituents are 1 or 2 of halo, -OH, -CO₂H, -CF₃, -NO₂, -CN, -CH₃, or -OCH₃), -CSR¹⁹, -COR¹⁹, -CO₂R¹⁹, -CONR¹⁹R²⁰, -CH₂CO₂R¹⁹, -CH₂COR¹⁹, -SO₂R¹⁹;

R³ and R⁴ are independently selected from R¹, but when situated on adjacent carbons may form an unsubstituted fused aromatic carbocyclic or heterocyclic ring;

R⁵ is H, -OH, lower alkyl (C₁ - C₆, linear or branched) lower alkoxy (C₁ - C₆, linear or branched), substituted or unsubstituted phenyl or phenylmethyl or phenylmethoxy (substituents are 1 or 2 of halo, -CH₃, -OCH₃, -CO₂H, -NO₂, -CF₃ or -OH), cyclohexyl, cyclohexylmethyl, cyclohexylmethoxy;

R⁶ is H, -(CH₂)_k-X⁴-(CH₂),-R²¹, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphth-1-yl, or 1,2,3,4-tetrahydronaphth-2-yl; R⁷ is H, methyl, or together with R⁸ forms a saturated, unsubstituted, cycloalkyl ring (C₃ - C₆);

R⁸ is H, tert-butyl, cycloalkyl (C₃ - C₈), substituted or unsubstituted phenyl (substituents are 1 or 2 of halo, -CN, -CH₃, -OCH₃, -CO₂H, -NO₂, -CF₃ or -OH), the side chain of a naturally occurring α-amino acid, -CHR²²R²³, or together with R⁷ forms a saturated unsubstituted cycloalkyl ring (C₃ - C₆);

R⁹ and R¹⁰ are independently selected from R⁵, phenylthio, phenoxy, 1-napthyl, 2-napthyl, or when situated on adjacent carbons may together form a fused benzene ring;

R¹¹ and R¹² are independently H, halo, -OH, -NO₂, -CO₂H, -CF₃, -CH₃, -OCH₃, phenyl, or together when on adjacent carbons R¹¹ and R¹² may form a second benzene ring;

R¹³ and R¹⁴ are independently chosen from H, halo, -OH, -NO₂, -CF₃, -CH₃, -OCH₃, -(CH₂)_mCO₂H, -(CH₂)_mCONH₂, -(CH₂)_mCO₂CH₃, -(CH₂)_mSO₃H, or together when situated on adjacent carbons R¹³ and R¹⁴ may form a second fused benzene ring;

R¹⁵ is H, lower alkyl (C₁ - C₆, linear or branched), substituted or unsubstituted phenyl or phenylmethyl (substituents are 1 or 2 of halo, -CH₃, -OCH₃, -CO₂H, -NO₂, -CF₃, -CN or -OH); or

,

where the double bond may be either of cis or trans disposition:

R¹⁶ is defined as R⁵;

R¹⁷ is H, di-lower alkyl (C₁ - C₄) methyl, cycloalkyl (C₃ - C₁₀), -O-cycloalkyl (C₃ -C₁₀), -S-cycloalkyl (C₃ - C₁₀), -SO₂-cycloalkyl (C₃ - C₁₀), -1-adamantyl, -2-adamantyl, unsubstituted or substituted phenyl (substituents are 1 or 2 of halo, -CH₃, -OCH₃, -CO₂H, -NO₂, -CF₃ or -OH); R¹⁸ is -H, -OH, -CO₂H, -CO₂CH₃, alkyl (C₁ - C₆, linear or branched), cycloalkyl (C₃ -C₇), aikoxy (C₁ - C₆, linear or branched), phenylmethyl, phenylmethoxy, NR²⁴R²⁵;

R¹⁹ and R²⁰ are independently selected from H, alkyl ( C₁ - C₁₂, linear or branched), cycloalkyl (C₃ - C₈)-(CH₂)_n- or polycycloalkyl (C₃ - C₁₂)-(CH₂)_n- where said cyclic or said polycyclic group may be further substituted by up to four substituents independently selected from C₁ - C₃ alkyl; substituted or unsubstituted phenyl-(CH₂)_n- (substitutents may be 1 or 2 from halo, -CH₃, -OCH₃, -CO₂H, -NO₂, -CF₃ or -OH), 1-adamantyl, 2-adamantyl, heterocycloalkyl (3-8 membered ring, where heteroatoms are 1 or 2 of -NR²⁶-, -O-, -S-, -SO₂-), or together R¹⁹ and R²⁰ in combination with the N of an NR¹⁹R²⁰ group may form a 3-8 membered heterocyclic ring;

R²¹ is branched alkyl (C₃ - C₈), cycloalkyl (C₃ - C₈), unsubstituted or substituted phenyl (substituents are 1 or 2 of halo, -CF₃, -CO₂H, alkyl (C₁ - C₅, linear or branched), alkoxy (C₁ - C₅, linear or branched), -CN, -NO₂ and -OH), 1- or 2-napthyl, 2- or 3-indolyl; 2-, 3- or 4-pyridyl; 2- or 3-thienyl; 1-, 2- or 3-pyrrolyl; 2- or 3-(l-methyl)pyrrolyl; 2- or 3-fuιyl;

R²² and R²³ are independently H, alkyl (C₁ - C₈, linear or branched),

-(CH₂)_o-X⁵-(CH₂-)_pR²⁷,

-(CH₂)_o-CO₂R²⁷,

-(CH₂)_o-R²⁷,

-(CH₂)_o-CONR²⁸R²⁹,

-OCO(CH₂)_o-R²⁷,

-OCONH(CH₂)_o-R²⁷,

-NHCO₂(CH₂)_o-R²⁷;

R²⁴ and R²⁵ are independently H, alkyl (C₁ - C₆, linear or branched), or together with the N of the NR²⁴R²⁵ group form an unsubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring;

R²⁶ is H, lower alkyl (C₁ - C₄, linear or branched), phenyl or phenylmethyl;

R²⁷ is H, alkyl (C₃ - C₆, linear or branched), cycloalkyl (C₃ - C₈), substituted or unsubstituted phenyl or phenylmethyl (substituents are 1 or 2 of halo, -CH₃, -OCH₃, -CO₂H, -NO₂, -CF₃ or -OH), 1-adamantyl, 2-adamantyl; R²⁸ and R²⁹ are independently R²⁷ or together with the N of the NR²⁸R²⁹ group form an unsubstituted. saturated or unsaturated. 4-7 membered heterocyclic ring, or benzofused 4-7 membered heterocyclic ring; and wherein: a is 0-3

b is 0-2

c is 0 or 1

d is 0-2

e is 0 or 1

f is 0-4

g is 0-3

h is 0-2

i is 0-3

j is 0-2

k is 0-3

l is 0-3

m is 0-3

n is 0 - 4

o is 0-3

p is 0 - 3

q is 0 - 4

X¹ is O, H₂, S

X² is O, H₂,S

X³ is O, H₂,S,F₂

X⁴ is absent, -O-, -CHOH-, -CO-, -SO₂-

X⁵ is absent, -O(CH₂)_q-, -(CH₂)_q-CO-,

-O(CH₂)_q-CO-, -S-(CH₂)_q-, -SO₂(CH₂)_q-,

-SO₂(CH₂)_q-CO-, -SO(CH₂)_q-, -NH(CH₂)_q-,

-NCH₃(CH₂)_q-, -NH(CH₂)_qCO-, NCH₃(CH₂)_qCO-. - - - - - - can be either a single or double bond; when two occur in the same molecule they must be simultaneously double or single.

2. Compounds of Claim 1 or pharmaceutically acceptable salts thereof, wherein:

A is VII

B is X, XIV

C is XV, XVI or XVII

3. Compounds of Claim 2 or pharmaceutically acceptable salts thereof, wherein:

B is X

C is XV

R³ is at the 3- position of the aryl ring

R⁴ is H

R⁶ is H or CH₃

R⁷ is H or CH₃ and wherein: c + d + e= 0 or 1

f is 0 or 1

g is 0, 1 or 2

h is 0 or 1

X¹ is O

X² is O or H₂

4. Compounds of Claim 3 or pharmaceutically acceptable salts thereof, wherein:

R⁶ is H:

R⁷ is H;

R⁸ is tert-butyl, cycloalkyl (C₃ - C₈), substituted or unsubstituted phenyl (substituents are 1 or 2 of halo, alkyl (C₁ - C₃), aikoxy (C₁ - C₃), -CO₂H, -NO₂, -CF₃ or -OH), CHR²²R²³;

R¹³ is H, halo, -CH₃, -OCH₃;

R¹⁴ is H; R¹⁵ is

wherein D is absent, Gly or β-Ala:

R¹⁸ is -OH, lower alkyl (C₁ - C₄, linear or branched), lower alkoxy (C₁ - C₄, linear or branched), NR²⁴R²⁵;

R²² and R²³ are independently H, lower alkyl (C₁ - C₆, linear or branched), lower alkoxy (C₁ - C₄, linear or branched)

-(CH₂)_o-X⁵-(CH₂)_p-R²⁷

-(CH₂)_o-R²⁵

R²⁴ and R²⁵ arc independently H, methyl, ethyl or in combination with the N of the NR²²R²³ group together form an unsubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring; c is 0

d is 0

e is 0 or 1

i is 0 or 1

X³ is O or H₂

5. Compounds of Claim 4 or pharmaceutically acceptable salts thereof, wherein:

R³ is -Cl, -Br, -CH₃ or -OCH₃

R¹³ is H

R¹⁵ is -(CH₂)_i-CO₂H

R²² and R²³ are independently lower alkyl (C₁ - C₆, linear or branched),

-(CH₂)_o-O-(CH₂)_p-Ph, -(CH₂)_o-Ph. e is 0

f is 1

g is 1

h is 0

stereochemistry at R¹⁵ substituent is R.

6. Compounds of Claim 2 or pharmaceutically acceptable salts thereof, wherein:

B is

(X where c = d = e = zero)

C is XVI or XVII R⁶ and R⁷ are independently H or CH₃;

R¹⁵ is

(XXI when D is absent)

R¹⁶ is phenyl, phenylmethyl, phenylmethoxy, cyclohexyl, cyclohexylmethyl, cyclohexylmethoxy;

R¹⁸ is -H, -OH, -NR²⁴R²⁵, lower aikoxy (C₁ - C₃);

R²⁴ and R²⁵ are independently H, lower alkyl (C₁ - C₄, linear or branched), or together with the N of the NR²²R²³ group form an unsubstituted, saturated, 4-7 membered heterocyclic ring; f + g = 1 or 2

i is 0, 1 or 2

X¹ is O

X² and X³ are independently O or H₂.

7. The following particular compounds within claims 2 to 6 or pharmaceutically acceptable salts thereof:

Example No.

1 (3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

2 (3R)-2-[N-(3-Bromophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

3 (3R)-2-[N-(3-Methylphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

4 (3R)-2-[N-(3-Acetylphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

5 (3R)-2-[N-(3-Isopropoxyphenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

6 (3R)-2-[N-(3-Cyanophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

7 (3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-tert-butyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

8 (3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-benzoyl-threonyl]-1,2,3,4- teιrahydroisoquinoline-3-acetic acid.

9 (3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-(4-chlorobenzyl)-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

10 (3R)-2-[(2S)-2-(3-Trifluoromethylphenylcarbamoylamino)-hexanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

11 (3R)-2-[(2S)-2-(3-Chlorophenylcarbamoylamino)-hexanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

12 (3R)-2-[(2S)-2-(N-(3-Chlorophenylcarbamoyl)-methylamino)-hexanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

13 (3R)-2-[(2S)-2-(3,4-Dichlorophenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

14 (3R)-2-[(2S)-2-(2-Methylphenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

15 (3R)-2-[(2S)-2-(4-Methylphenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

16 (3R)-2-[(2S)-2-(3-Methoxyphenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4- tetrahydroisoquinolme-3-acetic acid. Example No.

17 (3R)-2-[(2S)-2-(3-Chlorophenylcarbamoylamino)-4-phenylbutanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

18 (3R)-2-[N-(3-Chlorophenylcarbamoyl)-valyl]-1,2,3,4-tetrahydroisoquinoline-3- acetic acid.

19 (3R)-2-[N-(3-Bromophenylcarbamoyl)-valyl]-1,2,3,4-tetrahydroisoquinoline-3- acetic acid.

20 (3R)-2-[N-(3-Methylphenylcarbamoyl)-isoleucyl]-1,2,3,4-tetrahydroisoquinoline- 3-acetic acid.

21 (3R)-2-[(2S)-2-(3-Chlorophenylcarbamoylamino)-3,3-dimethylbutanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

22 (3R)-2-[(S)-α-(3-Chlorophenylcarbamoylamino)-phenylacetyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

23 (3R)-2-[(S)-α-(3-Methylphenylcarbamoylamino)-cyclohexaneacetyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

24 (3R)-2-[(2S)-3-(2-Adamantyloxycarbonylamino)-2-(phenylcarbamoylamino)- propanoyl]-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

25 (3R)-2-[(2S,3R)-2-(3-Chlorophenylcarbamoylamino)-3-phenylbutanoyl]-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

26 (3R)-2-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid.

27 (3R)-2-[N-(3-Bromophenylcarbamoyl)-O-benzyl-threonyl]-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid.

28 (2R.4S)-l-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-4- phenylpyrrolidine-2-carboxylic acid.

29 (2R,4R)-1-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-4- phenylpyrrolidine-2-acetic acid.

30 (2R,5S)-1-[N-(3-Chlorophenylcarbamoyl)-O-benzyl-threonyl]-5- phenylpyrrolidine-2-carboxylic acid.

31 (3R)-2-[(2S,3R)-3-Benzyloxy-2-(3-chlorophenylcarbamoylamino)-butyl]- 1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

8. Compounds of Claim 1 or pharmaceutically acceptable salts thereof, wherein:

A is II, III, IV, V or VI

B is X

C is XVIII

and wherein:

R¹ is H, -OH, halo, -CH₃, -OCH₃, -CN, -CO₂H or CF₃;

R² is absent. H, alkyl (C₁ - C₆, linear or branched), -CO-alkyl (C₁ - C₆, linear or branched), -CO₂-alkyl (C₁ - C₆, linear or branched);

R⁶ is H, or alkyl (C₁ - C₆, linear or branched);

R⁷ is H;

c is O

X² and X³ are independently H₂ or O.

9. Compounds of Claim 8 or pharmaceutically acceptable salts thereof, wherein:

D (in the exemplifications of C showing it) is absent, Gly, β-Ala, XIX or XX;

and wherein:

R¹ is H;

R² is absent or H;

R⁶ is H

R⁸ is H, the side chain of a naturally occurring α-amino acid, CHR²⁴R²³;

R¹⁸ is -OH, -OCH₃, NR²⁴R²⁵;

R²² and R²³ are independently H, alkyl (C₁ - C₈, linear or branched), -(CH₂)_o-X⁵-(CH₂)_p-R²⁷, -(CH₂)_o-CO₂R²⁷ or (CH₂)_o-R²⁷;

R²⁴ and R²⁵ are independently H or alkyl (C₁ - C₄, linear or branched), or together with the N of the NR²⁴R²⁵ group form an unsubstituted, saturated, 4-7 membered heterocyclic ring; R²⁷ is H, branched alkyl (C₃ - C₆), cycloalkyl (C₃ - C₈), phenyl, 1-adamantyl, 2-adamantyl: a is 0-2

d and e are 0

f is 1-3

i is 1 or 2 - - - - - are all double bonds.

10. Compounds of Claim 9 or pharmaceutically acceptable salts thereof, wherein:

A is

(II where - - - - - is a double bond, R¹ = R² = H, a = 1, X¹ = O)

D is absent,

(XIX where R¹⁶ is H, j = zero)

(XX where R¹⁶ is H, j = zero) and wherein:

R¹⁷ is cycloalkyl (C₅ - C₈);

R²² is H;

R²³ is alkyl (C₁ - C₈, linear or branched), -(CH₂)_o-R²⁷.

11. The following particular compounds within Claims 9 and 10 or pharmaceutically acceptable salts thereof:

Example No.

32 Methyl N-(2-cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)- glycinate.

33 N-(2-CycIohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycine.

34 1-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}- pyrrolidine.

35 Methyl N-{N-(2-cycIohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)- glycyl}-D-prolinate.

36 N-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}- D-proline.

37 N-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}- D-pipecolic acid.

38 N-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}- glycine.

39 1-{N-(2-Cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}- pyrrolidine.

40 1-{N-(2-Cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}- proline.

41 1-{N-(2-Cyclohexylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}- D-proline.

42 1-{N-(Cyclooctylmethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}- D-proline.

43 1-{3-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)- amino}-propanoyl}-pyrrolidine.

44 N-(3-Cyclohexylpropyl)-N-((2S)-2-(2-indolecarbonylamino)-hexanoyl)-glycine.

45 N-(3-Cyclohexylpropyl)-N-(N-(3-indoleacetyl)-phenylalanyl)-glycine.

46 N-(2-Cyclohexylethyl)-N-((2S)-2-(3-isoquinolinecarbonylamino)-4- phenylbutanoyl)-glycine.

47 N-{N-Phenethyl-N-((2S)-2-(3-indoleacetylamino)-hexanoyl)-glycyl}-D-proline. 174 1-{N-(2-Cyclohexylethyl)-N-(N-(3-indoleacetyl)-phenylalanyl)-glycyl}- D-proline.

175 1-{N-(2-Cyclohexylethyl)-N-((2S)-2-(3-indoleacetylamino)-4-phenylbutanoyl)- glycyl}-D-proline.

12. Compounds of Claim 1 or pharmaceutically acceptable salts thereof, wherein:

A is IX,

(II where - - - - - is a single bond)

(IV where - - - - - are single bonds)

(V where - - - - - are single bonds)

B is

(X, where R⁷ is H and c is zero)

XI, XII, XIII and XIV

C is XV

13. Compounds of Claim 12 or pharmaceutically acceptable salts thereof. wherein:

R¹ is H, halo, -CH₃ or -OCH₃.

R⁸ is H or CHR²²R²³ or phenyl.

R¹¹ and R¹² are independently H or phenyl, or together when on adjacent carbons R¹¹ and R¹² may form a second fused aromatic ring, yielding a napthyl moiety.

R¹³ is H,

R¹⁵ is H, or

R¹⁸ is -OH, -OCH₃ or -NH₂;

R²² and R²³ are independentiy H, alkyl (C₁ - C₄, linear or branched), -(CH₂)_o-X⁵-(CH₂)_p-R²⁷, -(CH₂)_o-R²⁷;

R²⁷ is cycloalkyl (C₃ - C₈), phenyl;

and wherein: a is 0 or 1

d is 0 or 1

e is 0

f is 0 - 2

g is 0-2

i is 0 - 2

X¹ is O or H₂

X² is O or H₂

X³ is O or H₂

X⁵ is absent or -O-

14. Compounds of Claim 13 or pharmaceutically acceptable salts thereof, wherein:

A is

(XXVIII with a = zero and X¹ = O);

C is

(XV where f is 1, g is 1, h is 0, R¹³ and R¹⁴ are H, and R¹⁵ is -(CH₂)_iCO₂H),

(XV were f is 1, g is 0, h is 1, R¹³ and R¹⁴ are H, and R¹⁵ is -(CH₂)_iCO₂H);

R² is -CO₂R¹⁹;

R⁹ and R¹⁰ are independently R⁵, phenylthio, phenoxy, 1-napthyl or 2-napthyl; and wherein:

i +j = 0 - 4

X⁴ is absent or -CO-.

15. The following particular compounds covered by Claims 12 to 14, or pharmaceutically acceptable salts thereof:

Example No.

48 (3R)-2-{N-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-O- benzyl-threonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

49 (3R)-2-{(2S)-2-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonylamino)-4-phenylbutanoyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

50 (2R)-1-{(2S)-2-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonylamino)-4-phenylbutanoyl}-2,3-dihydroindole-2-acetic acid.

51 (3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-valyl}- 1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

52 (3R)-2-{((2R)-1-tert-Butylacetyl-2,3-dihydroindole-2-carbonyl)-valyl}- 1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

53 (3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-valyl}- 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

54 (3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- isoleucyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

55 (3R)-2-{(S)-α-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonylamino)-phenylacetyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

56 (3R)-2-{((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- D-prolyl}-1,2,3,4-tetrahydroisoquinoime-3-acetic acid.

57 (3R)-2-{(2R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 2,3-dihydroindole-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

58 (3R)-2-{(2R,3S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 3-phenyl-pyrrohdine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

59 (3R)-2-((2R,4S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

60 (3R)-2-{(2R,4S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-chhydroindole-2-carbonyl)- 4-phenylthio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

61 (3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 4-phenyhhio-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid. E xample No.

62 (3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 4-benzyloxy-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

63 (3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 4-phenoxy-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

64 (3R)-2-{(2R,4R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 4-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

65 (3R)-2-{(2R,4S)-1-((2R)-l-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 4-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

66 (3R)-2-{(2R,4S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 4-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

67 2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-5- phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline.

68 Methyl (3R)-2-{(2R,5S)-1-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylate.

69 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

70 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide.

71 N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3- carbonyl}-glycine.

72 (3R)-2-{(2R,5S)-1-((2R)-1-Neopentyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

73 (3R)-2-{(2R,5S)-1-((2R)-1-Isopropyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

74 (3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid. Example No.

75 (3R)-2-{(2R,5S)-1-((2R)-1-(2-Adamantyl)oxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

76 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butylcarbamoyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

77 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butylacetyl-2,3-dihydroindole-2-carbonyl)-5- phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

78 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

79 N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- acetyl}-proline.

80 N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- acetyl}-D-proline.

81 (3R)-2-{(2R,5S)-1-((2R)-1-Neopentyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-acetic acid.

82 (3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-acetic acid.

83 (3R)-2-{(2R,5S)-1-((2R)-1-(2-Adamantyl)oxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-acetic acid.

84 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3- carboxylic acid.

85 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydro-benz[f]isoquinoline-3- acetic acid.

86 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid. Example No.

87 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-(2-naphthyl)-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

88 (3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

89 (3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

90 (3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

91 (3R)-2-{N-3-Phenylpropyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

92 (3R)-2-{N-Benzyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

93 (3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl)-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

94 (3R)-2-{N-3-Phenylpropyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl)-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

95 (3R)-2-{3-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-amino}-propanoyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

96 (3R)-2-{N-Phenethyl-N-((2R)-1-benzyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

97 (3R)-2-{N-Phenethyl-N-((2R)-1-neopentyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

98 (3R)-2-{N-Phenethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

99 (3R)-2-{N-3-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

100 (3R)-2-{N-(2-Oxo-2-phenylethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3- acetic acid.

101 (3R)-2-{N-(2-(3-Indolyl)ethyl)-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3- acetic acid. Example No.

102 (3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydro-benz[f ]isoquinoline-3-carboxylic acid.

103 (3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetxahydro-benz[f]isoquinoline-3-acetic acid.

104 (3R)-2-{N-Pivaloyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- methyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

105 (3R)-2-{3-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)- naphthalene-2-carbonyl}-1-2,3,4-tetrahydroisoquinoline-3-acetic acid.

106 (3R)-2-{3-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonylamino)- naphthalene-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

107 (3R)-2-{(2R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2-carbonyl)- 4-phenyl-2-5-dihydropyrrole-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- acetic acid.

108 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyιrohdine-2-methyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

109 (3R)-2-{(2S)-2-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydrdindole-2- acetylamino)-4-phenylbutanoyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

131 N-{(3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carbonyl}-proline.

132 N-{(3R)-2-{(2S ,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carbonyl}-proline.

133 N-{(3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-carbonyl}-D-proline.

134 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-benzyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoqumoline- 3-carboxylic acid.

135 (3R)-2-{N-2-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid. Example No.

136 (3R)-2-{N-4-Chlorophenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3- acetic acid.

137 (3R)-2-{N-2-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3- acetic acid.

138 (3R)-2-{N-3-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3- acetic acid.

139 (3R)-2-{N-4-Methoxyphenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3- acetic acid.

140 (3R)-2-{N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole- 2-carbonyl)-glycyl}-1,2,3,4-tetrahydro-benz[h]isoquinoline-3-carboxylic acid.

147 (4RS)-2-(N-Phenethyl-N-((2R)-1-tert-butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-4-acetic acid.

142 (4RS)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 4-acetic acid.

143 (3R)-2-{(2R,5S)-1-((2R)-1-Cyclobutyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid.

144 (3R)-2-{(2R,5S)-1-((2R)-1-Cyclopentyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-acetic acid.

145 (3R)-2-{(2R,5S)-1-((2R)-1-Cyclopentyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid.

146 (3R)-2-{(2R,5S)-1-((2R)-1-(2-exo-Norbornyl)oxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid.

147 (3R)-2-{(2R,5S)-1-((2R)-1-Cyclododecyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid. Example No.

145 (3R)-2-{N-Phenethyl-N-((2R)-1-n-propyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

149 N-{(3R)-2-{(2S,5R)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-acetyl}-proline.

150 (3R)-2-{N-2-(2-Methoxyphenyl)ethyl-N-((2R)-1-(tert-butyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinolme-3-carboxlic acid.

151 (3R)-2-{(2R,5S)-1-((2R)-1-(3,3-Dimethylbutyl)oxycarbonyl-2,3-dihydroindole- 2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid.

152 (3R)-2-{(2R,5S)-1-((2R)-1-Cycloheptyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid.

153 (3R)-2-{(2R,5S)-1-((2R)-1-((1S)-endo-Bornyl)oxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyιrohdine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid.

154 (3R)-2-{(2R,5S)-1-((2R)-1-((1R,2R,3R,5S)-Isopinocampheyl)oxycarbonyl-2,3- dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid.

155 (3R)-2-{(2R,5S)-1-((2R)-1-((1S,2S,3S,5R)-Isopinocampheyl)oxycarbonyl-2,3- dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid.

156 (3R)-2-{(2R,5S)-1-((2R)-1-(3,3-Dimethylbutyl)oxycarbonyl-2,3-dihydroindole- 2-carbonyl)-5-phenyl-pyrrohdine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-acetic acid.

157 (3R)-2-{(2R,5S)-1-((2R)-1-(1-Piperidino)carbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

158 (3R)-2-{(2R,5S)-1-((2R)-1-(N-Cyclohexyl-N-methylcarbamoyl)-2,3- dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid.

159 (3R)-2-{(2R,5S)-1-((2R)-1-(4-tert-Butylcyclohexyl)oxycarbonyl-2.3- dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid. Example No.

160 (3R)-2-{(2R,5S)-1-((2R)-1-(2-cis-Methylcyclohexyl)oxycarbonyl-2,3- dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid.

161 (3R)-2-{(2R,5S)-1-((2R)-1-(2-trans-Methylcyclohexyl)oxycarbonyl-2,3- dihydroindole-2-carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid.

162 (3R)-2-{N-Phenethyl-N-((2R)-1-(3-cyclohexylpropyl)oxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3- acetic acid.

163 (3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexylmethyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid.

164 (3R)-2-{(2R,5S)-1-((2R)-1-(2-Cyclohexylethyl)oxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

165 N-{(3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-carbonyl}-proline.

166 N-{(3R)-2-{(2R,5S)-1-((2R)-1-Neopentyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline- 3-carbonyl}-proline.

167 (3R)-2-{(2R,5S)-1-((2R)-1-tert-Butyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-phenyl-pyrrolidine-2-carbonyl}-1,2,3,4-tetrahydroisoquinoline-3- propanoic acid.

165 (3R)-2-{N-3-Methylphenethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetτahydroisoquinoline-3- acetic acid.

169 (3R)-2-{N-(2-(1-Methylpyrrol-2-yl)ethyl)-N-((2R)-1-cyclohexyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

170 (3R)-2-{N-(2-Thienyl)ethyl-N-((2R)-1-cyclohexyloxycarbonyl-2,3- dihydroindole-2-carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline- 3-acetic acid. Example No.

171 (3R)-2-{N-((2RS)-1,2,3,4-Tetrahydronaphth-2-yl)-N-((2R)-1- cyclohexyloxycarbonyl-2,3-dihydroindole-2-carbonyl)-glycyl}-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

172 (3R)-2-{(2R,5S)-1-((2R)-1-Cyclohexyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-5-(4-methoxyphenyl)-pyrrolidine-2-carbonyl}-1,2,3,4- tetrahydroisoquinoline-3-acetic acid.

173 (3R)-2-{N-(Indan-2-yl)-N-((2R)-1-cycIohexyloxycarbonyl-2,3-dihydroindole-2- carbonyl)-glycyl}-1,2,3,4-tetrahydroisoquinoline-3-acetic acid.

16. Compounds of Claim 1 or pharmaceutically acceptable salts thereof, wherein:

A is

(H where R² is H and - - - - - is a double bond), or an N-terminally blocked α-amino acid residue containing an aromatic side chain; the N-terminal substituent is selected from R²;

B is

C is

and wherein:

R⁶ and R⁷ are independently H or CH₃; R²² and R²³ are independentiy H. alkyl (C₁ - C₈, linear or branched), -(CH₂)_o-R²⁷ or -(CH₂)_o-CO₂R²⁷;

X¹ is H₂ or O

X₂ is H₂, O or S

17. Compounds of Claim 16 or pharmaceutically acceptable salts thereof, wherein:

A is

(XXXV where R¹ is H and X¹ is O) or R²-Trp;

R² is tert-butyloxvcarbonyl, phenylcarbonyl, phenylmethoxycarbonyl;

R⁶ and R⁷ are H.

R¹³ is H.

18. The following particular compounds within Claims 16 and 17 or pharmaceutically acceptable salts thereof:

Example No. 110 1-{tert-Butyloxycarbonyl-tryptophanyl-leucyl)-2,3-dihydroindole.

111 1-{(2S)-2-(tert-Butyloxycarbonyl-tryptophanylamino)-hexanoyl}-2,3- dihydroindole.

112 1 -{(2S)-2-(3-Indoie-3-propanoylamino)-hexanoyl}-2,3-dihydroindole.

113 1-{tert-Butyloxycarbonyl-tryptophanyl-phenylalanyl}-2,3-dihydroindole.

114 1 -{(2S)-2-(tert-Butyloxycarbonyl-tryptophanylamino)-4-phenylbutanoyl}-2,3- dihydroindole.

115 1-{tert-Butyloxycarbonyl-tryptophanyl-(β-O-benzyl)-D-aspartyl}-2,3- dihydroindole.

116 1-{tert-Butyloxycarbonyl-tryptophanyl-aspartyl}-2,3-dihydroindole. Example No.

117 1-{tert-Butyloxycarbonyl-tryptophanyl-(γ-O-benzyl)-glutamyl}-2,3- dihydroindole.

118 1-{tert-Butyloxycarbonyl-tryptophanyl-glutamyl}-2,3-dihydroindole. 119 2-{tert-Butyloxycarbonyl-tryptophanyl-D-phenylalanyl}-1,2,3,4- tetrahydroisoqmnoline.

120 2-{(2R)-2-(tert-Butyloxycarbonyl-tryptophanylamino)-4-phenylbutanoyl}- 1,2,3,4-tetrahydroisoquinoline.

19. Compounds of Claim 1 or pharmaceutically acceptable salts thereof, wherein:

A is

(IV where R²is absent and - - - - - are double bonds)

C

(V where R² is absent and - - - - - are double bonds), or R²-Trp;

B is XXIII;

C is XV;

D is absent, Gly or β-Alanine; and wherein:

R² is tert-butyloxycarbonyl, phenylcarbonyl or phenylmethoxycarbonyl;

R⁶ and R⁷ are independently H or CH₃;

R¹³ and R¹⁴ are H;

R¹⁵ is -(CH₂)_i-CO-D-R¹⁸;

R¹⁸ is -OH, alkoxy (C₁ - C₃, linear or branched), NR²⁴R²⁵;

R²² and R²³ are independently H, alkyl (C₁ - C₈, linear or branched), -(CH₂)_o-CO₂R²⁷, -(CH₂)_o-R²⁷ or -(CH₂)_o-O-(CH₂)_p-R^27: a is 0 or 1

i is 0 - 2

X¹ is O, H₂ or S

X² is O or H₂

20. The following particular compounds within Claim 19 or their pharmaceutically acceptable salts:

Example No.

121 Ethyl (2R)-1-{tert-butyloxycarbonyl-tryptophanyl-leucyl}-2,3- dihydroindole-2-acetate.

122 Ethyl (2S)-1-{(2S)-2-(tert-butyloxycarbonyl-tryptophanylamino)-hexanoyl}- 2,3-dihydroindole-2-carboxylate.

123 (2R)-1-{Indole-2-carbonyl-phenylalanyl}-2,3-dihydroindole-2-acetic acid.

124 (2R)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-2,3- dthydroindole-2-acetic acid.

125 3-{(2R)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-2,3- dihydroindole-2-yl}-propanoic acid.

126 (2R)-1-{(2S)-2-(5-Fluoroindole-2-carbonylamino)-4-phenylbutanoyl}-2,3- dihydroindole-2-acetic acid.

127 (2R)-1-{(2S)-2-(5-Chloroindole-2-carbonylamino)-4-phenylbutanoyl}-2,3- dihydroindole-2-acetic acid.

128 (3R)-2-{(2S)-2-(Indple-2-carbonylamino)-4-phenylbutanoyl}-1,2,3,4- tetrahydroisoquinoline-3-acetic acid. Example No.

129 N-{(2S)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-2,3- dihydroindole-2-acetyl}-glycine.

130 3-{(2S)-1-{(2S)-2-(Indole-2-carbonylamino)-4-phenylbutanoyl}-2,3- dihydroindole-2-carbonylamino}-propanoic acid.

21. A medicinal composition comprising a compound or a salt thereof as defined in any of claims 1 to 20.

22. The medicinal composition of claim 21, which acts as a CCK-A, CCK-B or gastrin receptor antagonist or agonist.

23. The medicinal composition as defined in claim 22, which is a drug for the treatment of diseases or conditions induced by abnormality in a physiological function controlled by gastrin, including gastric and duodenal ulcers, gastritis, reflux esophagitis, gastric, colonic and other gastrin sensitive cancers, and Zollinger-Ellison syndrome.

24. The medicinal composition as defined in claim 22, which is a drug for the treatment of diseases or conditions induced by an abnormality in the physiological function controlled by the central CCK-B receptor, including anxiety, psychoses, Parkinson's disease, Tourette's syndrome, Huntingdon's chorea, disturbed appetite regulation and pain (including the treatment of pain by potentiation of opiate analgesia).

25. The medicinal composition as defined in claim 22, which is a drug for the treatment of diseases or conditions induced by abnormality in a physiological function controlled by the CCK-A receptor including disturbed appetite regulation, pancreatitis, pancreatic cancer, disorders of gastrointestinal motility (including irritable bowel syndrome), and gall bladder dysfunction.

26. A method of making a compound of the structure A-B-C as set out in any preceding claim wherein reactants giving the residues A, B and C are combined sequentially to form the compound.

27. A process for the production of the novel compounds of any of claims 1 to 20 described by the general formula A-B-C (claim 1), which comprises linking the sub-unit A to B-C, via an amide bond, particularly by HOBt/WSCD or bis (2-oxo-3-oxazolidinyl) phosphide chloride mediated couplings.

28. A process for the production of the novel compounds of any of claims 1 to 20 described by the general formula A-B-C (claim 1), which comprises linking the sub-unit A to B-C, via a urea linkage, particularly by reacting the free amino terminus of B-C with the appropriate isocyanate.

29. A process for the production of the novel compounds of any of claims 1 to 20 described by the general formula A-B-C (claim 1), which comprises linking A-B to sub-unit C, via an amide bond, particularly by bis-(2-oxo-3-oxazoiidinyl) phosphinic chloride mediated coupling.

30. A process for the production of novel compounds of any of claims 1 to 20 described by general formula A-B-C (claim 1), which comprises functional group manipulation of compounds A-B-C prepared as described in any of claims 26 to 29, including the hydrolysis of carboxylic esters to carboxylic acids, the removal of amino blocking groups, and the replacement of amino or carboxyl blocking groups with other blocking groups.

31. A method of preparation of a medicament for therapy by CCK-A, CCK-B or gastrin receptor antagonism or agonism, in particular for the diseases or conditions set out in any of claims 23 to 25, wherein a compound as defined in any of claims 1 to 20 is associated with a pharmaceutically acceptable diluent or carrier.

32. A method of therapy by CCK-A, CCK-B or gastrin receptor antagonism or agonism, in particular for the diseases or conditions set out in any of claims 23 to 25, wherein an effective amount of a composition according to any of claims 21 to 25 is administered to a person in need of such therapy.